ZA200104281B - 4- and 5-alkynyloxindoles and 4- and 5-alkenyloxindoles. - Google Patents
4- and 5-alkynyloxindoles and 4- and 5-alkenyloxindoles. Download PDFInfo
- Publication number
- ZA200104281B ZA200104281B ZA200104281A ZA200104281A ZA200104281B ZA 200104281 B ZA200104281 B ZA 200104281B ZA 200104281 A ZA200104281 A ZA 200104281A ZA 200104281 A ZA200104281 A ZA 200104281A ZA 200104281 B ZA200104281 B ZA 200104281B
- Authority
- ZA
- South Africa
- Prior art keywords
- dihydro
- lower alkyl
- indol
- pyrrol
- substituted
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 144
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 106
- 125000000623 heterocyclic group Chemical group 0.000 claims description 105
- 150000001875 compounds Chemical class 0.000 claims description 82
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- -1 3- methoxy-1H-pyrrol-2-yl Chemical group 0.000 claims description 47
- 150000002367 halogens Chemical class 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 28
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 22
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000002207 metabolite Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- SXMJIZRSNGTEOK-UHFFFAOYSA-N 5-fluoro-4-iodo-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1I SXMJIZRSNGTEOK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 6
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 6
- 125000005843 halogen group Chemical group 0.000 claims 6
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims 4
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 2
- RSEGQJSFDGPSHB-LGMDPLHJSA-N 2-[4-[1-hydroxy-3-[(3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-2-oxo-1h-indol-4-yl]prop-2-ynyl]-2-methoxyphenoxy]acetic acid Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=C(OC)C(OCC(O)=O)=CC=4)C=CC=C3NC\2=O)=C1OC RSEGQJSFDGPSHB-LGMDPLHJSA-N 0.000 claims 2
- CIBQBCXWQYRSFJ-SDXDJHTJSA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(3-phenoxyprop-1-ynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CCOC=4C=CC=CC=4)C=CC=C3NC\2=O)=C1OC CIBQBCXWQYRSFJ-SDXDJHTJSA-N 0.000 claims 1
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- JIZBUYBBALMSAD-OWBHPGMISA-N (3z)-4-[3-(furan-2-yl)-3-hydroxyprop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4OC=CC=4)C=CC=C3NC\2=O)=C1OC JIZBUYBBALMSAD-OWBHPGMISA-N 0.000 claims 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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Description
4-and S5-Alkynyloxindoles and 4-and 5-Alkenyloxindoles .
The present invention is directed to novel 4- and 5-alkynyloxindoles as well as 4- and 5-alkenyloxindoles which inhibit or modulate protein kinases, in particular JNK protein kinases. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are useful as anti-inflammatory agents, particularly useful in the treatment of rheumatoid arthritis. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or control of inflammation, particularly in the treatment or control of rheumatoid arthritis. This invention is further directed to intermediates useful in the preparation of the foregoing compounds.
Protein kinases are a class of proteins that regulate a variety of cellular functions. This is accomplished by the phosphorylation of specific amino acids on protein substrates resulting in conformational alteration of the substrate protein.
The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. The enzyme activity of the protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. It can . be measured, for example, by determining the amount of a substrate that is converted to a product as a function of time. Phosphorylation of a substrate } occurs at the active-site of a protein kinase.
The JNK (Jun N-terminal kinase) protein kinases (also know as “stress- activated protein kinases” or “SAPK”") are members of the mitogen-activated protein (MAP) kinases. See, e.g., S. Gupta et al., EMBO J., vol. 15 no. 11 (1996) pp. 2760-2770; and Yang et al., Nature, vol. 289 (23 October 1997) pp. 865-870.
Atleast ten JNK isoforms are currently known. See, Gupta, id. As its name indicates, one of the substrates for JNK is c-Jun. JNK phosphorylates the NH, - terminal activation domain of c-Jun on Ser63 and Ser73, causing increased c-Jun transcriptional activity. See Gupta, id. In turn, c-Jun is an AP-1 transcription factor that mediates immediate-early gene expression. See, e.g., A. Minden et al.,
Biochimica et Biophysica Acta 1333 (1997) F85-F104; and P. Agel et. al,,
Biochimica et Biophysica Acta, vol.1072 (1991) pp. 1 29-157.
The JNK protein kinase is markedly activated in response to treatment of cells with pro-inflammatory cytokines or exposure to environmental stress. JNK thus mediates the effect of extracellular stimuli on c-Jun. See Gupta, supra; and
Minden, supra. Accordingly, JNK is a physiological regulator of AP-1 transcriptional activity. Thus, inhibition of JNK activity will inhibit AP-1-dependent transcription of inflammatory and immune mediators which are implicated in pathological proliferative conditions, for example inflammatory diseases and neuro-degenerative diseases, in particular, rheumatoid arthritis. See, eg. Swantek et al., Molecular and Cellular Biology, vol. 17 (1997) pp. 6274-6282; Maroney et al., J. Neuroscience, vol. 18 (1 Jan. 1998) pp. 104-111 ; and Minden, supra, at
Fo2.
The rat homologue of JNK is also called SAPK (stress-activated protein kinase). SAPK isoforms share significant (>90%) sequence identity with the corresponding JNK isoforms [compare Kyriakis et al., Nature, Vol 369 (12 May 1994) pp. 156-160 and Gupta et al., supra). Both JNK and SAPK are capable of phosphorylation of the c-Jun substrate and thus have very similar enzyme activity. }
JNK and SAPK are part of a protein kinase cascade that is activated by various extracellular stimuli. See e.g. Minden supra; and Kyriakis et al., BioEssays Vol 18 (1996) pp. 567-577. JNK and SAPK each can be activated by phosphorylation on specific threonine and tyrosine residues by dual specificity MAP kinase kinases such as MKK4, SEK-1, or MKK7. See Kyriakis et al., supra; and Tournier et al.,
Proceedings of the National Academy of Sciences USA Vol. 94 (July 1997), pp. 7337-7342. The dual specificity MAP kinase kinases can be activated by phosphorylation on serine and/or threonine residues by MAP kinase kinase kinases such as MEKK-1. Thus, measurement of JNK or SAPK enzyme activity may be enhanced by activation by the upstream or preceding kinases. Moreover, measurement of SAPK inhibition is closely correlated with JNK inhibition.
Inhibitors of protein kinase catalytic activity are known in the art. See WO 98/24432 (indoline compounds that inhibit FLK protein kinase); WO 97/45409
“7 wo 0035906 | ; PCT/EP99/09578 (substituted tetralyimethylene-oxindole analogues that inhibit tyrosine kinase). In particular, small molecule inhibitors typically block the binding of substrates by tightly interacting with the protein kinase ATP binding site (or “active site”). See
WO 98/24432. lt is desirable to identify small-molecule compounds that may be s readily synthesized and are effective in inhibiting the catalytic activity of protein kinases, in particular of the JNK protein kinases.
Indolinone (also known as oxindole) compounds asserted to be useful in regulating abnormal cell proliferation through tyrosine kinase inhibition are disclosed for example in WO 96/40116, WO 98/07695, WO 95/01349, WQ 96/32380, WO 96/22976, WO 96/16964 and WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity); Mohammadi et. al, Science,
Vol. 276, 9 May 1997, pp. 955-960. Oxindole derivatives have also been described for various other therapeutic uses: 5,206,261 (improvement of cerebral function);
WO 92/07830 (peptide antagonists); EP 580 502 A1 (antioxidants).
There continues to be a need for easily synthesized, small molecule compounds effective in inhibiting JNK protein kinase and thus useful in the treatment or control of pathological proliferative conditions, for example ‘ 20 inflammatory diseases and neuro-degenerative diseases, in particular, rheumatoid arthritis. It is thus an object of this invention to provide such compounds and compositions containing such compounds.
In one embodiment, the present invention is directed to 4-alkynyloxindoles and 4-alkenyloxindoles of the formula 1 R3 i 2 i 3
R2 / N 0
H and the pharmaceutically acceptable salts thereof, wherein:
R'is lower alkyl that is substituted by aryl, aryloxy, heteroaryl, heteroaryloxy, substituted aryl, substituted aryloxy, substituted heteroaryl, and/or substituted heteroaryloxy, and optionally also may be substituted by R'3, perfiuoroalkyl, cycloalkyl (or cycloalkyl substituted by lower alkyl and/or R'3), or heterocycle (or heterocycle substituted by lower alkyl and/or R'3), and wherein the substitutents on the substituted aryl, substituted aryloxy, substituted heteroaryl, and substituted heteroaryloxy are one or more of
R'™, lower alkyl (optionally substituted by R'), cycloalkyl (optionally substituted by
R'), heterocycle (optionally substituted by R'®); aryl (optionally substituted by R', perfluoroalkyl, lower alkyl, lower alkyl substituted by R'?, cycloalkyl, cycloalkyl substituted by R', heterocycle (optionally substituted by R'®); or heteroaryl (optionally substituted by R*3, perfluoroalkyl, lower alkyl, lower alkyl substituted by
R", cycloalkyl, cycloalkyl substituted by R"™, or heterocycle or heterocycle substituted by R');
RZ is hydrogen, -OR*, -OCOR’, -COR®, -COOR?, -CONR®R’, -NR°R’, halogen, -
NO,, -CN, -SO.R*, -SO:NR®R’, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR® or -NR°R’;
R? is hydrogen, -OR*, -COR®, -COOR*, -CONR°R’, halogen, -CN, -NR°R’, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR® or -NR°R’;
R%is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and for heterocycle), cycloalkyl (optionally substituted by (a), lower alky! and/or heterocycle), heterocycle (optionally substituted by (a), lower alkyl and/or cycloalkyl), aryl (optionally substituted by (a), cycloalkyl, heterocycle and/or halogen), heteroaryl (optionally substituted by (a), cycloalkyl, heterocycle, and/or halogen, where (a) is -OR®, -COOR?, -COR?, -CONR®R®, -NR°R’, -CN, -NO;, -SO:R°, and/or -SO,NR®R®;
R°® is hydrogen, -COR®, -CONR’R® or lower alkyl (optionally substituted by
OR®, -NR°R'°, -N(COR")R'®, -COR?’, -CONR®R™, -SR°® and/or -COOR?;
RS and R’ are each hydrogen, -COR?®, -COOR’, -CONR®RS, -SO:R®
SO,NR®R?, lower alkyl, lower alkyl substituted by (b), cycloalkyl (optionally : substituted by (b), lower alkyl, and/or heterocycle), heterocycle, heterocycle substituted by (b), lower alkyl and/or cycloalkyl), aryl, aryl substituted by (b), lower alkyl, cycloalkyl and/or heterocycle), heteroaryl, heteroary! substituted by (b), lower alkyl, cycloalkyl and/or heterocycle); : or R® and R’ are each cycloalkyl (optionally substituted by (b), lower alkyl and/or heterocycle; heterocycle (optionally substituted by (b), lower alkyl and/or cycloalkyl; aryl (optionally substituted by (b), lower alkyl, cycloalkyl and/or heterocycle; or heteroaryl (optionally substituted by (b), lower alkyl, cycloalkyl and/or heterocycle; where (b) is OR®, -NR®R®, -COOR?, -COR® -CONR®R?®, -CN, -NO, -SO2R®, -
SONR®R’; alternatively, -NR®R’ can form a ring having 3 to 7 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by , 0 one or more of lower alkyl, -OR®, -COR®, -COORS, -CONR®R®, and -NR°R®; - RE is hydrogen, lower alkyl (optionally substituted by cycloalkyl, heterocycle, aryl, heteroaryl, -OR®, -NRR', and/or -N(COR%R'"), aryl (optionally substituted by (c), lower alkyl, cycloalkyl and/or heterocycle), heteroaryl (optionally substituted by (c), lower alkyl, cycloalkyl and/or heterocycle), cycloalkyl (optionally substituted by (c), lower alkyl and/or heterocycle), heterocycle (optionally substituted by (c), lower alkyl and/or cycloalkyl); where (c) is -OR®, -COOR?®, -COR’, -CONR™R?, -NR"R’ -CN, -NO,, -SO:F°, -SO:NR'"R?;
R? and R' are each independently hydrogen or lower alkyl;
R'3is halogen, -OR*, -OCOR*, -COR* -COOR*, -CONR®R’, -NOz, -NR°R’, -CN, -
SO,R*, or -SO.NR°R’;
X is =N- or -CH-; and the dotted bond represented by z is optional .
In another embodiment, the invention is directed to 5-alkynyloxindoles and 5-alkenyloxindoles having the formula: =X
AN 7 N
H i oO
N
H andthe pharmaceutically acceptable salts thereof, wherein:
R'! is hydrogen, -COR®, .COOR®, -CONR®R’, lower alkyl! (optionally substituted by -OR®, -NR®R’, halogen, 15s -NO,, -SO2R"*, -SO:NR°R’, -CN, -COR*, .COOR*, -CONR®R’, cycloalkyl, heterocycle, aryl, and/or heteroaryl), cycloalkyl (optionally substituted by -OR®, -NR°R’, halogen, -NO,, . _SO,R*, -SO:NRR, CN, -COR’,
COOR*, -CONR®R’, lower alkyl, heterocycle, aryl, and/or heteroaryl) heterocycle (optionally substituted by -OR®, -NRPR’, halogen, -NO2, _SO,R*, -SONR®R’, CN, -COR", _COOR?, -CONR®R’, lower alkyl, cycloalkyl, aryl, and/or heteroaryl), aryl (optionally substituted by -OR®, -NR°R’, halogen, -NOz, -SO,R*, -SONR°R’, -CN, -COR*, -COOR?, -CONR®R’, lower alkyl, and/or perfluoroalkyl) or heteroary! (optionally substituted by -ORS, -NR®R’, halogen, -NO, -SO,R?, -SONR°R’, -CN, -COR®, -COOR*, _CONRCR’, lower alkyl, and/or perfluoroalkyl);
R2 is hydrogen, -OR", .OCOR®, -COR®, -COOR?, -CONR°R’, - NRCR’, halogen, -NO,, -CN, -SOzR*, -SO,NR®R7, perfluoroalkyl, lower alky! (optionally substituted by OR* .-NR°®R’, cycloalkyl, heterocycle, -COR’, -COOR*, -CONRPR’, -CN, -NO, -S0,R*, -SO.NRCR’ and/or halogen), ! cycloalkyl (optionally substituted by -OR*, -NR°R’, lower alkyl, heterocycle, -COR?, _COOR"*, -CONR®R’, CN, -NO2, -SO2R*, -SO.NR®R’ and/or halogen), or heterocycle (optionally substituted by -OR*, -NR®R’, lower alkyl, cycloalkyl, COR‘, _COOR*, -CONRPR’, -CN, -NO, -SO.R*, -SO,NR®R’ and/or halogen), and
R® through R’, X and z are as defined for formula | above.
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more of the above- described compounds and a pharmaceutically acceptable carrier or excipient. . The present invention is also directed to the use of a compound of claim 1 or 13 or prodrugs and pharmaceutically active metabolites of such compound in
B the preparation of a medicament for the treatment or control of inflammatory diseases, particularly rheumatoid arthritis.
The present invention is also directed to intermediates useful in the preparation of the above-described 4- and 5-alkynyloxindoles and 4- and 5- alkenyloxindoles.
As used herein, the following terms shall have the following definitions. “Aryl" means an aromatic group having 5 to 10 atoms and consisting of 1 or 2 rings. “Aryloxy” means an aryl radical that includes at least one oxygen and which is attached to rest of molecule via the oxygen atom.
“Cycloalkyl” means a non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms.
Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
“Effective Amount” means an amount of at least one compound of formula and/or Ii, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, that inhibits the development or proliferation of (1) an inflammatory disease or response and/or (2) a neuro-degenerative disease or response, such as for example, and not as a limitation, rheumatoid arthritis. “Halogen” means fluorine, chlorine, bromine or iodine. “Heteroaryl’ groups are aromatic groups having 5 to 10 atoms, one or 2 rings, and containing one or more hetero atoms.
Examples of heteroaryl groups are 2-, 3- or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl and quinolyl. “Heteroaryloxy” means a heteroaryl radical that includes at least one oxygen and which is attached to rest of molecule via the oxygen atom.
“Hetero atom” means an atom selected from N, O and S. “Heterocycle” means a 3- to 10-membered non-aromatic, partially or completely saturated hydrocarbon group, such as tetrahydroquinolyl, which contains one or two rings and at least one hetero atom. “ICs” refers to the concentration of a particular 4- or 5-alkynyloxindole or 4- or 5-alkenyloxindole required to inhibit 50% of cJun phosphorylation, which is a measure of inhibition of SAPK activity. 1Cso can be measured, inter alia, using the assay described herein in Example 102. “ower Alkyl” denotes a straight-chain or branched saturated aliphatic hydrocarbon having 1 t0 6, preferably 1 to 4, carbon atoms.
Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like. “y “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts which retain the biological effectiveness and properties of the compounds of formula | or I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
Sample base-addition salts include those derived from sodium, potassium, ammonium, and quaternary ammonium hydroxide, such as for example tetramethylammonium hydroxide.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
“Pharmaceutically active metabolite” means a metabolic product ofa . compound of formula | or |i which is pharmaceutically acceptable and effective. “Prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to any of the compounds of formula lor lt or to a pharmaceutically acceptable salt of a compound of formula | or II.
A prodrug may be inactive when administered to a subject but is converted in vivo to an active
~ compound of formula | or Hl.
“Substituted,” as in substituted alkyl means that the substitution can occur at one or more positions, that one or more substituents may be selected, and, unless otherwise indicated, that the substituents are independently selected from the specified options.
PCT/EP99/09578
L 10
In one embodiment, the invention is concemed with compounds of formulae | and Il, wherein Ris hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and /or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and/or heterocycle), or heterocycle (optionally substituted by (a), lower alkyl 5s andlor cycloalkyl), where (a) is -OR®, -COOR?, -COR?®, -CONR®R’, -NR®R’, -CN, -
NO», -SO,R?, and/or ~SO2NR°R?; and R® is hydrogen, -COR®, -CONR®R® or lower alky} (optionally substituted by -OR®, -NR°R'®, -N(COR%)R', -COR?, -
CONRR'® and/or -COOR?: and R' through R'’, X and z are as above.
In a preferred embodiment, the invention is directed to compounds of the formula | wherein R' is : lower alkyl that is substituted by aryl or substituted aryl, and optionally also substituted by halogen, -OR*, -COR?*, -COOR?®, "CONR®R , cycloalkyl, heterocycle, -COOR* CONRER’, cycloalkyl which is substituted by OR* -NR®R’, COOR®, 1s CONRPR’, and/or heterocycle which is substituted by OR* and -NR°R’, COOR®, ' CONRPR’: and wherein the substituents on the substituted aryl are selected from halogen, -OR?, -COR", -COOR®, -CONR®R’, -NO, NR®R’, -SO2R", -
SO,NRPR’, -CN, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR*and ~~ -NR®R’, COOR*, CONR°R’, cycloalkyl which is substituted by OR*and -NR®R’, COOR*, CONRPR’, or heterocycle which is substituted by OR* and -NR®R’, COOR*, CONR°R’; lower alkyl that is substituted by heteroaryl or substituted heteroaryl, and optionally also substituted by halogen, -OR?, -COR?, -COOR*, -CONRPR’, cycloalkyl, heterocycle, cycloalkyl which is substituted by OR®, COOR*, CONR°R’, and/or -
NR®R”. and/or heterocycle which is substituted by -OR*, COOR®*, CONR®R’, and/or -NR®R’: and wherein thé substituents on the substituted heteroaryl are selected from halogen, -OR®, COR‘, -COOR*, NR°R, -SOR*, -SONR°R’, -NO;, -CN, -CONRCR’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR* -NRER7, COOR*, CONR®R’, cycloalkyl which is substituted by -OR*,
NRER’, COOR*, CONRPR’, and/or heterocycle which is substituted by -OR?, -
NRER’, COOR* and/or CONR®R’), } : AMENDED SHEET
PCT/EP99/09578 ® ary! (optionally substituted by halogen, -OR*, -COR®, -COOR*, -CONR®R’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR* , -NR°R’,
COOR*, CONRPR’, cycloalkyl which is substituted by -OR*, COOR*, CONRER’, and/or -NR®R’, and heterocycle which is substituted by -OR*, COOR?, CONR°R, and/or -NR®R), or heteroaryl (optionally substituted by halogen, -OR*, -COR?, -COOR?, -CONRER’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR?%,
COOR®, CONRPR’, and/or -NR®R’, cycloalkyl which is substituted by -OR®,
COOR* CONRPR’, and/or -NRPR’, and/or heterocycle which is substituted by -
OR*, COOR*, CONR®R’, and/or -NR®R’).
In another preferred embodiment, the invention is concerned with compounds of formulae | and Il, wherein ‘
Xis CH and R®is lower alkoxy; further, wherein
R'is lower alkyl substituted by phenyl which is substituted by one to three ’ substituents from the group hydroxy, lower alkoxy, di-(lower alkyl)-amino, di-(lower alkyl)amino-lower alkoxy, morpholino-lower alkyl, carboxy-lower alkoxy and lower ~ alkanoylamino; or R'is lower alkyl substituted as before and additionally by hydroxy; or wherein :
R'is lower alkyl substituted by pyridyl, pyrrolyl, N-lower alkyl-pyyrolyl, thienyi, lower-alkoxy substitituted thienyl, furyl, 1,3-benzodioxolyl, or lower-alkoxy substituted 1,3-benzodioxolyl; or wherein : R'is lower alkyl substituted as before and additionally by hydroxy; or wherein R' is pyridyl.
Also preferred are compounds of formula | wherein the optional bond z is present. BE
Preferred compounds of formula Il are those R® is hydrogen, -OR*, -NR®R’, and/or lower alkyl (optionally substituted by -OR® and/or -NRR7);
R* is hydrogen, lower alkyl (optionally substituted by one or more
AMENDED SHEET
-OR®, -COORS, -COR2, -CONR®R?), cycloalkyl (optionally substituted by one or more -OR5, -COOR?, -COR®and -CONR®R?®), or heterocycle (optionally substituted by one or more -OR?®, -COORS®, -COR® and -CONR®R®);
RSis hydrogen, -COR8, -CONR®R?, or lower alkyl;
R® and R’ are each independently hydrogen, -COR®, -COOR®, -CONR®R?, or lower alkyl (optionally substituted by one or more of -OR® , -NR®R®, COOR?, and
CONR®R?), or alternatively, -NR®R’ optionally form a ring having 3 to 7 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by one or more of lower alkyl, -OR®, -COR®, -COORS, -CONR®R®, and -NR°R?;
R®is hydrogen or lower alkyl (optionally substituted by one or more of aryl, heteroaryl, -OR®, COOR®, CONR°R', and —NR°R%);
R'is aryl (optionally substituted by -OR® and/or -NR®R’);
R'is hydrogen, -COR*, -COOR*, -CONR°R’, lower alkyl (optionally substituted by one or more of -OR* -NR®R’, cycloalkyl, heterocycle, -COR?*, -COOR?*, -CONR®R’, -CN, -NO, -SO,R*, -SO,
NR®R’ and halogen), cycloalkyl (optionally substituted by one or more of -OR®, -NR°R’, lower alkyl, heterocycle, -COR®, -COOR?*, -CONR®R’, -CN, -NO,, -SO,R*, -S0,
NRPR’ and halogen), or heterocycle (optionally substituted by one or more of -OR®, -NR®R’, lower alkyl, cycloalkyl, -COR?, -COOR?*, -CONR®R’, -CN, -NO,, -SO2R*, -S0,
NRCR’ and halogen); and the optional bond z is present.
The invention further relates to novel intermediates useful in the preparation of compounds of formula I:
) ° WO 00/35906 i” PCT/EP99/09578 1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one, (2)-1,3-Dihydro-3-{(1 H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H- indol-2-one, (Z)-5-Bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol- 2-one, (Z)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5- (trimethylsilyl)ethynyl-2H-indol-2-one, (Z2)-5-Bromo-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene}-2H- indol-2-one, (2)-1,3-Dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5- (trimethylsilyl)ethynyl-2H-indol-2-one.
The compounds disclosed herein and covered by the above formulae may exhibit tautomerism or structural isomerism. It is intended that the "15 invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or : structural isomeric form utilized within the formulae drawn above.
General Synthesis Schemes : 20 The compounds of formulas | and Il may be prepared by processes known v in the art. Suitable processes for synthesizing these compounds are provided in the examples. Generally, these compounds may be prepared according to the following synthesis schemes.
Compounds of Formula |: Scheme
General Step 1
R3
A R3
X
R2 | 3 1% Piperidine A / P) + i =
N o tH N in 2-propanol » RZ / N 1H O 2 No where A=Brorl,X=NorC H 3
General Step 2a
R3 R! R3
X
R! A 4 j) Catalyst, Cul / A + oo fn” EtsN. DMF 3
Il R H Heat R2 / N o ————> 0 4 N N 3 H , H where A=Brorl, X=NorC
General Step 2b
R? R3 R3
X X
I 7 § 1) AgNO, EOH, H,0 | 7
R2 f~ NT 2)KCN,EOH, H,0 po ON oF —_———— o
N where R' = Trimethylsilyl N : pH H
General Step 2C
R3 Ar R3 / 3 Catalyst, Cul / 3
ATL, IN EtsN, DMF » NY
A R H Heat R HN 6 0 — > 0)
N N
5 H H where A = Br or |, Ar = aryl or heteroaryl, X=N or C 7
Compounds 1 and 2 are either available from commercial sources or are 5 synthesized by methods known in the at. Compounds 1 and 2 are reacted in piperidine to yield compound 3. When R’ of the compound to be synthesized is other than Ar, compound 3 is then reacted with compound 4, which is also either available from commercial sources or is synthesized by methods known in the art, to yield compound |. See, General Step 2a. When R? of the product to be synthesized is Ar, then compound | wherein R' is trimethylsilyl is further reacted with AgNOs and KCN in accordance with General Step 2b to yield compound 5. In accordance with General Step 2c, compound 5 is then reacted with compound 6, which is either available from commercial sources or is synthesized by methods known in the art, to yield compound 7.
Compounds of Formula II: Scheme |i 3
R'2 R3 x y S 1% Piperidine R'2 / ) o+ N in 2-Propanol / N
H ———————
N 0 Y= Brorl ©
N
H
8 9 10 3 3 . X X / Riz S$! Catalyst, Cul RM Riz / Pp) - Et;N, DMF Nu
Tov / H Heat NN / N o EE — 0]
N Y= Brorl N
H H
11 10 i
Compounds of formula 8 and 9 are available from commercial sources.
These compounds are reacted in piperidine in an appropriate solvent to yield a compound of formula 10. Compounds of formula 10 are then reacted with a compound of formula 11, which is also commercially available, to yield a compound of formula Il.
In an alternative embodiment, the present invention is directed to pharmaceutical compositions comprising at least one compound of formula | or li or a prodrug thereof, or a pharmaceutically acceptable salt of a compound of formula | or Il or a prodrug of such compound.
These pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.
The pharmaceutical compositions of the present invention comprising compounds of formula | or ll, prodrugs of such compounds, or the salts thereof, may be manufactured in a manner that is know in the art, e.g. by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, dragee-making, or lyophilizing processes. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, maize starch or derivatives thereof, talc, steric acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are vegetable oils, waxes, . fats, semi-solid or liquid poll. Depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerin, vegetable oils, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols.
The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances, including additional active ingredients other than those of formula 1 or II.
‘ + WO 00/35906 ’ . PCT/EP99/09578
As mentioned above, the compounds of formula | or ll, prodrugs thereof, and their salts, and compositions containing these compounds are useful in the treatment or control of inflammatory diseases and neuro-degenerative diseases, in : particular, in the treatment or control of rheumatoid arthritis.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound of formula or [I can vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg. preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion. : The compounds of the present invention may be synthesized according to known techniques, such as for example General Scheme | provided above. The following examples illustrate preferred methods for synthesizing the compounds and formulations of the present invention.
Example 1: General Synthesis Methods and Starting Materials
Method A: Preparation of 1-alkyl or 1-aryl-2-propyn-1-ols via Grignard addition to aldehydes oH
R—CHO + =MgC! _THF _ =<
R
A solution of the appropriate aldehyde (4.0 mmol) in 30 mL dry tetrahydrofuran, under argon, was cooled to 0 °C with an ice bath. Ethynylmagnesium chloride (5 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at
0 °C or room temperature for 1 to 3 h. The reaction was quenched by the addition of a saturated ammonium chloride solution in water (15 mL), and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3x30 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield the desired propargy alcohol which was used in the coupling reaction without further purification.
Method B: Preparation of 1-alkyl or 1-aryl-2-propyn-1-ols via Grignard addition to aldehydes
R-CHO + ==—MgCl __ THF _ ="
R
A solution of the appropriate aldehyde (4.0 mmol) in 30 mL dry tetrahydrofuran, : under argon, was cooled to 0 °C with an ice bath. Ethynylmagnesium chloride (10 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at 0 °C or room temperature for 1 to 3 h. The reaction was quenched by the addition of a saturated ammonium chloride solution in water (15 mL), and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3x30 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield the desired propargyi alcohol which was used in the coupling reaction without further purification.
Method C: Preparation of 4-alkynyloxindoles via Palladium(0)-mediated coupling ’
R H
OH X Catalyst, Cul = ( + oa Et;N, DMF
R 0 Heat
N [ &
N
A solution of the appropriate 4-iodooxindole (4 mmol), and the appropriate alkyne (4.4 mmol) in 3 mL dimethylformamide and 3 mL triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (I) iodide (16 mg, 0.1 mmol) and palladium (0) catalyst (see Examples) (0.04 mmol) were added, and the reaction was heated, under argon, at a temperature between 60 to 90 °C, for 6 to 96 hours. After cooling, water (20 mL) was added and the precipitate was filtered off and dried. The product was purified via either flash column chromatography (SiO2, 230-400 mesh with ethyl acetate/hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent).
Method D: Preparation of 4-alkynyloxindoles via Palladium(0)-mediated coupling rR. OH
OH X Catalyst, Cul = + or Et:N, DMF
R 0) Heat
N [ o k
A solution of the appropriate 4-bromooxindole (4 mmol), and the appropriate alkyne (4.4 mmol) in 3 mL dimethylformamide and 3 mL triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (1) iodide (16 mg, 0.1 mmol) and catalyst (0.04 mmol) were added, and the reaction was heated, under argon, at between 60 to 90 °C for 6 to 96 hours. After : cooling, water (20 mL) was added and the precipitate was filtered off and dried.
The product was purified via either flash column chromatography (SiO2, 230-400 : mesh with ethyl acetate/hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent).
Method E: Preparation of methyl esters from carboxylic acids
R—CO,H + CHyN; Ether R—CO,CH,
To a solution of the appropriate carboxylic acid (15.3 mmol) in diethyl ether (30 mL) was added a solution of diazomethane (20 mmol, 0.47 M in ether). The reaction was stirred at room temperature for 1 hour at which time a few drops of acetic acid was added. The solution was washed with saturated sodium bicarbonate (3x25 mL) and the solvent was evaporated to yield the desired methy) ester which was used without further purification.
Method F: Preparation of carboxylic acids from the methyl esters 1) THF, HO
R—CO,CH; + LiOH 2) Acid R—CO,H
The appropriate methyl ester (0.14 mmol) was dissolved in a mixture of 2 mL tetrahydrofuran and 2 mL water. Lithium hydroxide (2.8 mmol, 20 equiv.) was : added, and the reaction was stirred at room temperature from 1 to 96 hours. The tetrahydrofuran was then evaporated and 10 mL water was added. The aqueous layer was then extracted with ethyl acetate (2x10 mL) and the aqueous layer was then acidified to pH = 2 with 1 N hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (4x20 mL), and the combined organic extracts were washed with a saturated solution of sodium chloride and were then dried over magnesium sulfate. The ethyl acetate was then evaporated and the product was recrystallized from ethanol.
Method H: Mitsunobu Coupling of N-(2-hydroxyethyl)morpholine to phenols log . eS dead ORE “N is Z © TT » RF (Lo
To a solution of the appropriate phenol (3.3 mmol), N-(2-hydroxyethyl)morpholine (4.9 mmol), and triphenylphosphine (5.0 mmol) in tetrahydrofuran (30 mL), under argon, was added via an addition funnel a solution of diethyl azodicarboxylate (5.0 mmol, 0.863 g) in 15 mL tetrahydrofuran. The reaction was stirred at room : temperature for 14 hours at which time water (15 mL) was added and the tetrahydrofuran was evaporated. The aqueous layer was extracted with ethyl acetate (4x30 mL), and the combined organic extracts were washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent evaporated. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane.
Method J: Preparation of 4-alkynyloxindoles via Palladium(0)-mediated coupling
Ar
Ar Catalyst, Cul
X + Et;N, DMF 0) Heat
X=Br, | N —_—> 0
H N
H
A solution of the appropriate 4-ethynyl-oxindole (4 mmol), and the appropriate aryl halide (4.4 mmol) in 3 mL dimethylformamide and 3 mL triethyl amine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (I) iodide (16 mg, 0.1 mmol) and palladium (0) catalyst (0.04 mmol) were added, and the reaction was heated, under argon, at between 60 to 90 °C for 12 to 96 hours. After cooling, water (20 mL) was added and the precipitate was filtered off and dried. The product was purified via either flash column chromatography . (SiO2, 230-400 mesh with ethyl acetate/hexane as solvent) or with reverse phase
HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent).
Method K: Hydrolysis of trimethylsilyl alkyne to alkyne
Po ade —_— ! y Flo = } R—=———SChs 2) KCN, H,0 R——==CH
CHs ————
To a solution of the appropriate trimethylsilyl alkyne (4 mmol) in EtOH (80 mL), with addition of THF until complete dissolution if necessary, was added dropwise a solution of AgNO3 (1.46 g, 8.59 mmol) in EtOH (5 mL) and water (15 mL). The mixture was stirred at room temperature for 1 h, then treated with a solution of
KCN (2.71 g 41.6 mmol) in water (10 mL). After stirring for an additional 20 min, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3X 100 mL). Combined EtOAc layers was dried (MgSO4) and concentrated to dryness under reduced pressure to yield the above-identified product.
Method L: o Zn, NH,CI
AN CH 30H, HO R—NH,
To a solution of nitro compound in 10% water in methanol was added Zn dust and
NH4Cl. The mixture was heated at reflux for 6 h then filtered through Celite® (Fisher Scientific). Filtrate was concentrated in vacuo. The product was purified via either flash column chromatography (SiOz, 230-400 mesh with ethyi acetate/hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent).
Method M: nd + RTNH; Hao, THE Al "
C) I lo) 10. To a mixture of amino compound in THF and saturated aqueous NaHCO3 was added a THF solution of the acid chloride dropwise. The mixture was stirred for 3 h to 10 days at room temperature then diluted with ethyl acetate. The phases were separated and the organic solution was washed with water then dried (MgS04). The product was purified via either flash column chromatography (SiO2, 230-400 mesh with ethyl acetate/hexane as solvent) or with reverse phase
HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent).
Method N: Preparation of 3-aryimethylene-substituted oxindoles via coupling with aldehyde Ar (DR Ho. Ar 1% Piperidine rd _ + hig in 2-propanol 'e)
N © > So
H
A solution or suspension of the appropriate oxindole (1 mmol), and excess aldehyde (1 to 2 mmol) in 2 mL of 1% piperidine in 2-propanol was heated at between 60 to 90 °C for 1 to 48 hours. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol, and dried.
Starting Material 1: (Z)-4-Bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2- yl)methylene]-2H-indol-2-one
FHs
Br / \ / N
H
0)
N .
H
A mixture of 4-bromo-1,3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess 3-methoxy-2-pyrrolecarboxyaldehyde (70.8 mg, 0.57 mmol) (prepared according to F. Bellamy, J. Chem. Research (S) (1979) 18-19; J. Chem.
Research (M) (1979) 0106-0116) in 1% piperidine in 2-propanol (1 mL) was heated at 85 °C for 2 h. Hot water (1 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%).
Starting Material 2: (Z)-1,3-Dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2- yl)methylene]-2H-indol-2-one
EH, / \ / °N - H 0
N
H
A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (prepared according to T.
Fukuyama et al., J. A. Chem. Soc. 118:7426-7427 (1996)) (0.51 g, 1.97 mmol), and excess 3-methoxy-2-pyrrolecarboxyaldehyde (0.30 g, 2.36 mmol) (see
Bellamy, supra) in 1% piperidine in 2-propanol (10 mL) was heated at 85 °C for 4 h. Hot water (10 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.46 g, 64%).
Starting Material 3: (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2- yl)methylene]-5-nitro-2H-indol-2-one
SH
? r / \ / N o% H 0]
N
H
A mixture of 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one (from Example 4 infra) (0.113 g, 0.44 mmol), and excess 3-methoxy-2-pyrrolecarboxyaldehyde (66.3 mg, 0.53 mmol) (see Bellamy, supra) in 1% piperidine in 2-propanol (2 mL) was heated at 85 °C for 3 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.136 g, 85%).
Starting Material 4: (Z)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]- 4-(2-trimethylsilyl-ethynyl)-2H-indol-2-one
H
HO] CH, £ Hs
Q
J f °N
H . 0]
N
H
Trimethylsilyl acetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z)- 4-bromo-1,3-dihydro-3-{(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.05 g, 6.42 mmol) (Starting Material 1) using (Ph3P)2PdCli2 (0.23 g) (Aldrich) and Cul (61 mg) (Aldrich) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 80 °C for 2 days in accordance with method D above. (Yield 1.3 g, 60%).
Starting Material 5: (Z)-1,3-Dihydro-4-ethynyi-3-[(3-methoxy-1H-pyrrol-2- yl)methylene}-2H-indoi-2-one
CH, / lo}
It J / H 0
H
A solution of (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(2- 5 trimethylsilyl-ethynyl)-2H-indol-2-one (1.3 g, 3.86 mmol) (Starting Material 4) in
EtOH (80 mL) was treated with AGNO3 (1.46 g, 8.59 mmol) in ethanol (5 mL) and water (15 mL) at room temperature for 1 h followed by KCN (2.71 g, 41.6 mmol) in water (10 mL) according to method K above. (Yield 1.02 g, 100%).
Starting Material 6: 5-Bromo-1,3-dihydro-2H-indol-2-one
Br =
N
H
1,3-Dihydro-2H-indol-2-one (5.25 g, 39.43 mmol) (Aldrich) was treated with a 1:1 solution of glacial acetic acid and distilled water (246 mL). The resulting reaction mixture was cooled to 0 °C and then slowly treated with N- bromosuccinimide (14.03 g, 78.85 mmol) (J.T. Baker). After the complete addition of N-bromosuccinimide, the cooling bath was removed, and the reaction mixture was stirred at 23 °C for 1 h. Upon stirring at 23 °C, the reaction mixture became viscous and a white solid precipitated. The reaction mixture was poured into 500 mL distilled water and filtered to provide a crude white solid. Recrystallization from methanol provided pure 5-bromo-1,3-dihydro-2H-indol-2-one as a light pink solid. (Yield 5.28 g, 63%; mp 219 - 220 °C).
Starting Material 7: (Z)-5-Bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene}- 2H-indol-2-one 7 \ 8 / 0]
N
H
A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (Starting Material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich)
in 2-propanol (73 mL) was treated with 10-12 drops of piperidne. The reaction mixture was heated at reflux for 20 h and then allowed to cool to 23 °C, at which time, the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to provide pure (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid which was used without further purification. (Yield 4.01 9, 95%; mp 267 - 268 °C).
Starting Material 8: (Z)-1,3-Dihydro-5-iodo-3-[(1 H-pyrrol-2-yl)methylene)-2H- indol-2-one / \ 0
N
To a solution of [[1-[[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2- yllmethyljtriphenyiphosphonium iodide (2.3 g, 4.0 mmol) (prepared according to the procedure of: V. H. Rawal et. al., J. Org. Chem. 1987, 52(1), 19-28) in 36 mL
DMF at 0 °C under argon, was added slowly NaH (0.13 g, 5.4 mmol). The mixture was stirred at 0 °C for 45 min. The solution was then allowed to warm to room temperature and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The solution was heated at reflux for 15 h, at which time acetone (1 mL) was added and the solvent mixture was evaporated. The residue was then purified via flash column chromatography (25% EtOAc/hex) to yield (Z)-1,3-dihydro-5-iodo-3-[(1H-pyrrol-2- yl)methylene]-2H-indol-2-one. (Yield 1.05 g, 83%).
Starting Material 9: (Z)-4-Bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]- 2H-indol-2-one : 73
Sey 0]
N
A mixture of 4-bromo-1,3-dihydro-2H-indol-2-one (0.2 g, 0.94 mmol) (see T.
Kosuge et. al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess pyrrole- 2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 °C for 2 h. Hot water (2 mL) was added. On cooling, the
Claims (24)
1. A compound having the formula R' R? bz X l= I 2 N ] : R / 0
N . H 5s and the pharmaceutically acceptable salts thereof, Co wherein: - R'is lower alkyl that is substituted by aryl, aryloxy, heteroaryl, heteroaryloxy, substituted aryl, substituted aryloxy, substituted heteroaryl, and/or substituted heteroaryloxy, and optionally also may be substituted by R', perfluoroalkyl, cycloalkyl (or cycloalkyl substituted by lower alkyl and/or R'3), or heterocycle (or a heterocycle substituted by lower alkyl and/or R'3), : and wherein the substititents on the substituted aryl, substituted aryloxy, substituted heteroaryl, and substituted heteroaryloxy are one or more of a R™, lower alkyl (optionally substituted by R'), cycloalkyl (optionally substituted by R'), heterocycle (optionally substituted by R'3); aryl (optionally substituted by R', : perfluoroalkyl, lower alkyl, lower alkyl substituted by R', cycloalkyl, cycloalkyl substituted by R'®, heterocycle (optionally substituted by R'®); or heteroaryl ~ (optionally substituted by R'®, perflucroalkyl, lower alkyl, lower alkyl substituted by © R™, cycloalkyl, cycloalkyl substituted by R'?, or heterocycle or heterocycle substituted by R™); or SE - aryl (optionally substituted by halogen, -OR?*, -COR?*, -COOR*, -CONR®R’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR*, -NR°R’, : COOR?*, CONRER’, cycloalkyl which is substituted by -OR*, COOR*, CONR®R’, oo and/or -NRPR’, and heterocycle which is substituted by -OR*, COOR*, CONR®R’, oo and/or -NRPR’), or AMENDED SHEET oe
PCT/EP99/09578 : PY 89a heteroaryl (optionally substituted by halogen, -OR?, -COR?, -COOR®, -CONRCR?, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR*, COOR*, CONRPR’, and/or -NR°R’, cycloalkyl which is substituted by -OR?, COOR*, CONRPR’, and/or -NR°R’, and/or heterocycle which is substituted by : -OR* COOR*, CONR®R’, and/or -NR®R). : R? is hydrogen, -OR?*, -OCOR?*, -COR?, -COOR®*, -CONR°R’, -NR®R’, halogen, : -NO,, -CN, -SO,R*, -SO.NRPR’, perflucroalkyl, lower alkyl or lower alkyl substituted by -OR® or -NR°R’; AMENDED SHEET
R? is hydrogen, -OR*, COR, -COOR®, -CONR®R’, halogen, -CN, -NR°R’, perflucroalkyl, lower alkyl or lower alkyl substituted by -OR® or -NR°R”: R* is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and /or 5 heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and/or heterocycle), heterocycle (optionally substituted by (a), lower alkyl and/or cycloalkyl), aryl (optionally substituted by (a), cycloalkyl, heterocycle and/or halogen), heteroaryl (optionally substituted by (a), cycloalkyl, heterocycle, and/or halogen, where (a) is -OR®, -COOR?, -COR?, -CONR®R®, -NR®R’ , -CN, -NO¢, -SO,R®, and/or -SO.NR°R%; R® is hydrogen, -COR?®, -CONR®R® or lower alkyl (optionally substituted by -OR’, -NR°R'®, -N(COR®)R'®, -COR®, -CONR°R", -SR? and/or -COOR?; ° R® and R’ are each hydrogen, -COR®, -COOR?®, -CONR®R?®, -SO,R®
-SO.NR®R?, lower alkyl, lower alkyl substituted by (b), cycloalkyl (optionally substituted by (b), lower alkyl, and/or heterocycle), heterocycle, heterocycle substituted by (b), lower alkyl and/or cycloalkyl), aryl, aryl substituted by (b), lower alkyl, cycloalkyl and/or heterocycle), heteroaryl, heteroaryl substituted by (b), lower alkyl, cycloalkyl and/or heterocycle); or R® and R’ are each cycloalkyl (optionally substituted by (b), lower alkyl and/or heterocycle; heterocycle (optionally substituted by (b), lower alkyl and/or cycloalkyl; aryl (optionally substituted by (b), lower alkyl, cycloalkyl and/or heterocycle; or heteroaryl (optionally substituted by (b), lower alkyl, cycloalkyl and/or heterocycle; where (b) is OR®, -NR®R®, -COOR?, -COR®, -CONR®R®, -CN, -NO, -SO,R®,
-SO.NR®R®; alternatively, -NR°R’ can form a ring having 3 to 7 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by one or more of lower alkyl, -OR?®, -COR®, -COOR®, -CONR®R?®, and -NR°R?;
y PCT/EP99/09578 N C § R® is hydrogen, lower alkyl (optionally substituted by cycloalkyl, heterocycle, aryl, heteroaryl, -OR?, -NR°R', and/or -N(COR%)R'), aryl (optionally substituted by (c), lower alkyl, cycloalkyl and/or heterocycle), heteroaryl (optionally substituted by (c), lower alkyl, cycloalkyl and/or heterocycle), cycloalkyl (optionally substituted by (c), lower alkyl and/or heterocycle), heterocycle (optionally substituted by (c), lower alkyl and/or cycloalkyl); where (c) is -OR’, -COOR®, -COR?, -CONR'®R®, -NR'°R® -CN, -NO2, -SO,R?, -SO,NR"R?; R®and R' are each independently hydrogen or lower alkyl; R'is halogen, -OR’, -OCOR®, -COR* -COOR, -CONR®R’, -NO,, -NR®R?, -CN, -SOR", or -SONRR'; Xis =N- or -CH-; and the dotted bond represented by z is optional .
2. A compound of claim 1, wherein Ris lower alkyl that is substituted by aryl or substituted aryl, and optionally also substituted by halogen, -OR?, -COR?, -COOR?, -CONR®R’, cycloalkyl, heterocycle, -COOR?*, CONR®R’, cycloalkyl which is substituted by OR? -NR®R’, COOR?, CONRPR’, and/or heterocycle which is substituted by OR* and -NR®R’, COOR?, CONR®R’; and wherein the substituents on the substituted aryl are selected from halogen, -OR*, -COR*, -COOR?*, -CONR®R’, -NO,, NR°R?, -SO,R*, -SO,NR®R?, CN, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR*and ~~ -NR®R’, COOR*, CONR®R’, cycloalkyl which : is substituted by OR*and -NR®R’, COOR*, CONR®R’, or heterocycle which is substituted by OR* and -NR®R’, COOR*, CONR®R; lower alkyl that is substituted by heteroaryl or substituted heteroaryl, and optionally also substituted by halogen, -OR*, -COR*, -COOR®, -CONR®R’, cycloalkyl, heterocycle, cycloalkyl which is substituted by OR*, COOR*, CONR®R’, and/or -NRPR’, and/or heterocycle which is substituted by -OR*, COOR*, CONR®R’, AMENDED SHEET :
and/or -NR®R’; and wherein the substituents on the substituted heteroaryl are selected from halogen, -OR?, -COR?, -COOR*, NR®R’, -SO,R*, -SO.NR®R’, -NO,, -CN, -CONR®R’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR® -NR°R’, COOR*, CONR®R’, cycloalkyl which is substituted 's by-OR®, -NR°R’, COOR’, CONR®R’, and/or heterocycle which is substituted by -OR® -NR®°R’, COOR* and/or CONR®R’), aryl (optionally substituted by halogen, -OR*, -COR*, -COOR*, -CONR®R’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR® , -NR°R’, COOR*, CONR®R’, cycloalkyl which is substituted by -OR®, COOR*, CONRER’, and/or -NR°R’, and heterocycle which is substituted by -OR®, COOR*, CONR®R’, and/or -NR®R’), or heteroaryl (optionally substituted by halogen, -OR?, -COR?, -COOR*, -CONR®R’, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -ORS, COOR*, CONR®R’, and/or -NR°R’, cycloalkyl which is substituted by -OR?, COOR*, CONR®R’, and/or -NR®R’, and/or heterocycle which is substituted by -OR®, COOR*, CONR®R’, and/or -NR°R’).
3. A compound of any one of claims 1 or 2, wherein X is CH and R® is lower alkoxy.
4, A compound of any one of claims 1-3 wherein R' is lower alkyl substituted by phenyl which is substituted by one to three substituents from the group hydroxy, lower alkoxy, di-(lower alkyl)-amino, di-(lower alkyl)amino-lower alkoxy, morpholino-lower alkyl, carboxy-lower alkoxy and lower alkanoylamino; or R'is lower alkyl substituted as before and additionally by hydroxy.
5. A compound of any of claims 1-4, wherein R' is lower alkyl substituted by pyridyl, pyrrolyl, N-lower alkyl-pyyrolyl, thienyl, lower-alkoxy substitituted thienyl, furyl, 1,3-benzodioxolyl, or lower-alkoxy substituted 1,3- benzodioxolyl; or R'is lower alkyl substituted as before and additionally by hydroxy.
. © WO 00/35906 o3 PCT/EP99/09578
6. A compound of any one of claims 1-3 wherein Ris pyridyl.
7. A compound of claim 1 or 2 wherein the optional bond z is present.
}
8. A compound of claim 4 which is rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(4-methoxyphenyl)- 1-propynyi}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (H), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-hydroxyphenyl)-1-propynyi]-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (1), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-methoxyphenyl)-1-propynyl}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (J), rac-(Z)-4-{3-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo- 1H-indol-4-yl]-1-hydroxy-2-propynyl]benzoic acid methyl ester (K), rac-(Z)-4-[3-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yi)methylene]-2-oxo- 1H-indol-4-yl]-1-hydroxy-2-propynyljbenzoic acid (L), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(2-methoxyphenyl)-1-propynyl]-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (M), rac-(Z)-4-[3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (N), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-1- propynyl}-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0), ) rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(4-hydroxyphenyl)-1-propynyl}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Q), rac-(Z)-1,3-Dihydro-4-[3-(4-dimethylaminophenyl)-3-hydroxy-1-propynyl]-3- [(3-methoxy-1H-pyrrol-2-y)methylene]-2H-indol-2-one (R), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(4-phenoxyphenyl)-1-propynyl}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]}-2H-indol-2-one (S), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-phenyl-1-butynyl]-3-[(3-methoxy-1H- pyrrol-2-yl)ymethylene)-2H-indol-2-one (T), rac-(Z)-1,3-Dihydro-4-[3-[4-(3-dimethylaminopropoxy)-phenyl}-3-hydroxy-1- propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (V), rac-(Z)-1,3-Dihydro-4-[3-(2,3-dimethoxyphenyl)-3-hydroxy-1-propynyl}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (EE),
rac-(Z)-1,3-Dihydro-4-[3-(3,4-dimethoxyphenyl)-3-hydroxy- 1-propynyl]-3-[(3- methoxy-1 H-pyrrol-2-yl)methylene]-2H-indol-2-one (FF), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1- propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (HH), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-[3-methoxy-4-{2-(4-morpholinyl)-ethoxy]- phenyl}-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (MM), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-[3-methoxy-4-[2-(4-morpholinyl)-ethoxy]- phenyl}-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]}-2H-indol-2-one hydrochloride salt (NN), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(2,4,5-trimethoxyphenyl)-1-propynyl]-3- [(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (PP), rac-(Z)-[4-[3-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo- 1H-indol-4-yl}-1-hydroxy-2-propynyl]-2-methoxyphenoxylacetic acid methyl ester (QQ), rac-(Z)-{4-[3-[2,3-Dihydro-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene}-2-oxo- 1H-indol-4-yl]-1-hydroxy-2-propynyl}-2-methoxyphenoxy]acetic acid (RR), rac-(Z)-4-[3-hydroxy-3-(4-methoxy-1,3-benzodioxol-6-yl)-1-propynyl}-1,3- dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (SS), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-[4-[2-(4-morpholinyl)-ethoxy]-phenyl]-1- propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (TT), rac-(Z)-4-[3-(4-Chloro-2-methyisulfanyimethoxy-phenyl)-3-hydroxy-1- propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (uu), rac-(2)-4-[3-(3-Chlorophenyl)-3-hydroxy-1-propynyi}-1,3-dihydro-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (WW), rac-(2)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo- 1H-indol-4-yl}-1-hydroxy-2-propynyljphenoxylacstic acid 1,1-dimethylethyl ester (XX), rac-(Z)-[4-[3-[2,3-dihydro-3-{(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo- 1H-indol-4-yl}-1-hydroxy-2-propynyllphenoxylacetic acid(YY), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-nitrophenyl)-1-propynyi]-3-[(3- methoxy-1H-pyrrol-2-yl)methylene}-2H-indol-2-one (ZZ), rac-(Z)-4-[3-(3-Aminophenyl)-3-hydroxy-1-propynyl}-1,3-dihydro-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (AAA),
rac-(Z)-4-{3-(4-Acetamidophenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3- methoxy-1 H-pyrrol-2-yl)methylene]-2H-indol-2-one (BBB), or rac-(Z)-1,3-Dihydro-4-(3-hydroxy-3-phenyl-1-propynyl)-3-[(3-methoxy-1H- pyrrol-2-yl)methylene]-2H-indol-2-one (FFF).
9. A compound of claim 5 which is rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-pyridinyl)- 1-propynyl}-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene]-2H-indol-2-one (X), Synthesis of rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1- propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (AA), rac-(2)-1 ,3-Dihydro-4-[3-hydroxy-3-(thiophen-3-yl)- 1-propynyl]-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (BB), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(1H-pyrrol-2-yl)-1-propynyi]-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (DD), rac-(Z)-1,3-Dihydro-4-[3- hydroxy-3-(2-pyridinyl)-1 -propynyl]-3-{(3-methoxy-1 H-pyrrol-2-ylymethylene}-2H- indol-2-one (JJ), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(2-thiophenyl)-1-propynyi}-3-[(3- methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (KK), rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propynyl]-3- } 20 [(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (OO), or rac-(Z)-1,3-Dihydro-4-[3-(2-furanyl)-3-hydroxy-1-propynyl]-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene]-2H-indol-2-one (VV).
10. A compound of claim 6 which is (Z)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-((3- pyridinyl)ethynyi]-2H-indol-2-one (CCC), (Z2)-1,3-Dihydro-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene]-4-[(2- pyridinyl)ethynyl}-2H-indol-2-one (DDD), (Z2)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene}-4-[(4- pyridinyl)ethynyl]-2H-indol-2-one (EEE), (2)-1,3-Dihydro-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene}-5-nitro-4-[(3- pyridinyl)ethynyl]-2H-indol-2-one (GGG), (Z2)-5-Amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene}-4-[(3- pyridinyl)ethynyl]-2H-indol-2-one (HHH), or
(2)-N-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-4-[(3- pyridinyl)ethynyl]-1 H-indol-5-yl}-2-thiopheneacetamide UDX
11. A compound of claim 1 which is 4-[(E)-2-(2-Chlorophenyl)-ethenyl]-1,3-dihydro-(Z)-3-[(1H-pyrrol-2- yl)methylene}-2H-indol-2-one (KKK), 1,3-Dihydro-(Z)-3-[(1H-pyrrol-2yl)methylene]-[(E)-2-phenylethenyl])-2H-indol- 2-one (LLL), 1,3-Dihydro-(Z)-3-[(3-methoxy-1H-pyrrol-2yl)methylene]-[(E)-2- phenylethenyl}-2H-indol-2-one (MMM), 1,3-Dihydro-4-[(E)-2-(4-methoxyphenyl)-ethenyl]-(Z)-3-[(1H-pyrrol-2- yl)methlene]-2H-indol-2-one (NNN), 1,3-Dihydro-(Z)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(E)-2-(4- methoxy-phenyl)-ethenyl}-2H-indol-2-one (O00), 4-[(E)-2-[2,3-Dihydro-(Z)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo- 1H-indol-4-yl]ethenyl]benzoic acid methyl ester (PPP), or 1,3-Dihydro-4-[(E)-2-(3,4-dimethoxyphenyl)-ethenyl]-(Z)-3-[(3-methoxy-1H- pyrrol-2-yl)methylene]-2H-indol-2-one (QQQ).
12. Acompound of claim 1, which is ] (Z2)-1,3-Dihydro-4-(phenylethynyl)-3-[(3-methoxy- 1H-pyrrol-2-yl)methylene]- 2H-indol-2-one (D), (Z)-1,3-Dihydro-4-[(4-methoxyphenyl)ethynyl}-3-[(3-methoxy- 1H-pyrrol-2- ylymethylene]-2H-indol-2-one (G) or (Z)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(3-phenoxy-1- propynyl)-2H-indol-2-one (Y).
13. A compound having the formula:
. © WO 00/35906 or PCT/EP99/09578 RS XX 78 H i 0 N and the pharmaceutically acceptable salts thereof, wherein: R'is hydrogen, -COR*, -COOR*, -CONRR’, lower alky! (optionally substituted by -OR®, -NR®R’, halogen, -NO,, -SOzR*, -SO.NR°R’, -CN, -COR?*, -COOR?*, -CONR°R’, cycloalkyl, heterocycle, aryl, and/or heteroaryl), cycloalkyl (optionally substituted by -OR?, -NR®R’, halogen, -NO,, -SO,R*, -SO,NR°R’, -CN, -COR®, -COOR?*, -CONR®R’, lower alkyl, heterocycle, aryl, and/or heteroaryl) heterocycle (optionally substituted by -OR®, -NR®R’, halogen, -NO,, -SO;R*, -SO.NR°R’, -CN, -COR*, -COOR?*, -CONR°®R’, lower alkyl, cycloalkyl, aryl, and/or heteroaryl), aryl (optionally substituted by the group consisting of 1s -OR®, -NR®R’, halogen, -NO,, -SO.R*, -SO,NR®R’, -CN, -COR?, -COOR", -CONRP®R’, lower alkyl, and/or perfluoroalkyl) or heteroaryl (optionally substituted by -OR®, -NR®R’, halogen, -NO,,
-SO.R*, -SO.NR°R’, -CN, -COR*, -COOR*, -CONR®R’, lower alkyl, and/or perfluoroalkyl); R'? is hydrogen, -OR*, -OCOR*, -COR*, -COOR*, -CONR®R’, - NR°R’, halogen, -NO,, -CN, -SO,R*, -S0,NRPR7, perfluoroalkyl, lower alkyl (optionally substituted by OR* ,-NR®R’, cycloalkyl, heterocycle, -COR?, -COOR®*, -CONR®R’, -CN, -NO,, -SO,R*, -SO,NR°R’ and/or halogen), cycloalkyl (optionally substituted by -OR*, -NR®R’, lower alkyl, heterocycle, -COR?*, -COOR®, -CONR®R’, -CN, -NO,, -SO.R*, -SO,NR®R’ and/or halogen), or : :
heterocycle (optionally substituted by -OR*, -NR®R’, lower alkyl, cycloalkyl, -COR?, -COOR’, -CONR?R’, -CN, -NO,, -SO,R*, -SO.NR°R’ and/or halogen), and 5s R3through R’, X and z are as defined for formula | in claim 1.
14. A compound of claim 1 or 13, wherein R* is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and /or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and/or heterocycle), or heterocycle (optionally substituted by (a), lower alkyl and/or cycloalkyl), where (a) is -OR®, -COOR?®, -COR®, -CONR®R®, -NR®R’, -CN, -NO, -SO;R®, and/or —-SO-NR®R®; and RS is hydrogen, -COR®, -CONR®R® or lower alkyl (optionally substituted by -OR®, -NR°R'®, -N(COR®)R'®, -COR®, -CONR°R'® and/or -COOR?); and R', R2, R®, R®, R®, R'°, X and z are as in claim 1.
15. A compound of claim 13 wherein R? is hydrogen, -OR*, -NR®R’, and/or lower alkyl (optionally substituted by -OR® and/or -NR®RY); R* is hydrogen, lower alkyl (optionally substituted by one or more -ORS, -COORS®, -COR®, -CONR®R®), cycloalkyl (optionally substituted by one or more -OR®, -COOR®, -COR® and -CONR®R®), or heterocycle (optionally substituted by one or more -OR?®, -COOR®, -COR® and -CONR®R?); R® is hydrogen, -COR®, -CONR®R?®, or lower alkyl; R® and R’ are each independently hydrogen, -COR®, -COOR®, -CONR®R®, or lower alkyl (optionally substituted by one or more of -OR? , -NR®R®, COOR?, and CONR®R®), or alternatively, -NR®R’ optionally form a ring having 3 to 7 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by one or more of lower alkyl, -OR®, -COR®, -COOR?®, -CONR®R®, and -NR°R®;
R® is hydrogen or lower alkyl (optionally substituted by one or more of aryl, heteroaryl, -OR®, COOR?’, CONR’R'’, and -NR°R'%); s R'is aryl (optionally substituted by -OR® and/or -NR®R?); R'? is hydrogen, -COR*, -COOR*, -CONR®R’, lower alkyl (optionally substituted by one or more of -OR* -NR®R’, cycloalkyl, heterocycle, -COR®, -COOR*, -CONR®R’, -CN, -NO,, -SO,R*, -SO, NR®R and halogen), cycloalkyl (optionally substituted by one or more of -OR?*, -NR°R’, lower alkyl, heterocycle, -COR?, -COOR*, -CONRER’, -CN, -NO,, -SO,R*, -SO, NR®R’ and halogen), or heterocycle (optionally substituted by one or more of -OR?, -NR®R’, lower alkyl, cycloalkyl, -COR*, -COOR*, -CONR®R’, -CN, -NO,, -SO.R*, -SO, NR®R” and halogen); and the optional bond z is present.
16. A compound of claim 13 which is (Z2)-1,3-Dihydro-5-ethynyl-3-[(1H-pyrrol-2-yi)methylene]-2H-indo!-2-one (8SS), (Z2)-1,3-Dihydro-5-(4-hydroxyphenyl)ethynyl-3-[( 1H-pyrrol-2-yl)methylene]- 2H-indol-2-one (TTT), (Z)-1,3-Dihydro-5-(3-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methyiene]-2H- indol-2-one (UUU), (2)-1,3-Dihydro-5-phenylethynyl-3-[(1H-pyrrol-2-yl)methylene)-2H-indol-2- one (VVV), (2)-1,3-Dihydro-5-(3-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]- 2H-indol-2-one (WWW), (Z)-1,3-Dihydro-5-(2-nitrophenyl)ethynyl-3-{(1H-pyrrol-2-yl)methylene]-2H- indol-2-one (XXX), (Z)-1,3-Dihydro-5-(4-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H- indol-2-one (ZZ2),
(Z)-5-(4-Aminophenyl)ethynyl-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H- indol-2-one (AAAA), (Z)-1,3-Dihydro-5-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H- indol-2-one (DDDD), (Z)-1,3-Dihydro-5-(3-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene}-2H- indol-2-one (EEEE), (2)-1,3-Dihydro-5-(2-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H- indol-2-one (FFFF), (Z2)-1,3-Dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)- methylenel-2H-indol-2-one (GGGG), (2)-1,3-Dihydro-5-(4-methoxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)-methylene]- 2H-indol-2-one (HHHH), (2)-1,3-Dihydro-3-[(1H-pyrrol-2-yl)-methylene]-5-(2-thiophenyl)ethynyi-2H- indol-2-one (lll), or (Z)-1,3-Dihydro-5-ethynyl-3-[(4-methyl-1H-imidazol-5-yl)methylene)-2H-indol-2- one, trifluoroacetate salt (LLLL).
17. The compounds 1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one, (2)-1,3-Dihydro-3-{(1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H- indol-2-one, (2)-5-Bromo-1 3-dihydro-3-{(3-methoxy-1 H-pyrrol-2-yl)methylene}-2H-indol- 2-one, (2)-1,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)-5- (trimethylsilyl)ethynyl-2H-indol-2-one, (2)-5-Bromo-1,3-dihydro-3-[(4-methyi-1H-imidazol-5-yl)methylene}-2H- indol-2-one, (2)-1,3-Dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5- (trimethyisilyl)ethynyl-2H-indol-2-one.
18. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 or 13 and a pharmaceutically acceptable carrier or excipient.
19. The compounds of claim 1 and 13 for use as medicaments.
] 101 PCT/EP99/09578
20. The use of a compound of claim 1 or 13 or prodrugs and pharmaceutically active metabolites of such compound in the preparation of a medicament for the treatment or control of inflammatory diseases, particularly rheumatoid arthritis.
21. A substance or composition for use in a method for the treatment or control of inflammatory diseases, particularly rheumatoid arthritis, said substance or compasition comprising a compound as claimed in claim 1 or 13, or prodrugs or pharmaceutically active metabolites of such a compound, and said method comprising administering said substance or composition.
22. The novel compounds, compositions and use as described hereinbefore, especially with reference to the Examples.
23. A substance or composition for use in a method of treatment according to claim 21, substantially as herein described and illustrated.
24. A new compound; a new composition; a new use of a compound as claimed in claim 1 or claim 3, or a prodrug or pharmaceutically active metabolite of such a compound; or a substance or composition for a new use in a method of treatment; substantially as herein described. AMENDED SHEET
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ZA200104281A ZA200104281B (en) | 1998-12-17 | 2001-05-24 | 4- and 5-alkynyloxindoles and 4- and 5-alkenyloxindoles. |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR035156A1 (en) |
CO (1) | CO5261520A1 (en) |
PE (1) | PE20001354A1 (en) |
UY (1) | UY25856A1 (en) |
ZA (1) | ZA200104281B (en) |
-
1999
- 1999-12-14 PE PE1999001247A patent/PE20001354A1/en not_active Application Discontinuation
- 1999-12-14 CO CO99078061A patent/CO5261520A1/en not_active Application Discontinuation
- 1999-12-15 AR ARP990106418 patent/AR035156A1/en unknown
- 1999-12-16 UY UY25856A patent/UY25856A1/en not_active Application Discontinuation
-
2001
- 2001-05-24 ZA ZA200104281A patent/ZA200104281B/en unknown
Also Published As
Publication number | Publication date |
---|---|
PE20001354A1 (en) | 2000-11-29 |
AR035156A1 (en) | 2004-05-05 |
CO5261520A1 (en) | 2003-03-31 |
UY25856A1 (en) | 2001-07-31 |
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