US 6,521,658 B1Granted

Cell proliferation inhibitors

AssigneeAbbott Laboratories

InventorsQun Li, Hing Sham, Keith W. Woods, Beth A. Steiner, Stephen L. Gwaltney, II, Kenneth J. Barr, Hovis M. Imade, Saul Rosenberg

Life of this patent

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Abstract

Compounds having formula (I) inhibit cellular proliferation. Processes for the preparation of the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.

Claims11

Dependent claims

A compound having formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein
L1 is shown with its left end attached to R1 and its right end attached to the phenyl ring and is —SO2NR7—, wherein R7 is selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amidinyl,
(d) a nitrogen-protecting group,
(e) alkanoyl,
(f) alkyl,
(g) alkenyl,
(h) alkynyl,
(i) cycloalkyl,
(j) cycloalkylalkyl,
(k) cycloalkenyl,
(l) cycloalkenylalkyl,
(m) aryloyl,
(n) alkoxy,
wherein (e)-(n) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(i) hydroxyl,
(ii) halo,
(iii) cyano,
(iv) azido,
(v) carboxy,
(vi) amidinyl,
(vii) alkyl,
(viii) aryl,
(ix) oxo,
(x) heteroaryl,
(xi) heterocycloalkyl,
(xii) —NRcRd, wherein Rc and Rd are independently selected from the group consisting of
(1′) hydrogen,
(2′) alkyl,
(3′) aryl, and
(4′) alkoxyalkyl, and
(xiii) -(alkylene)—NRcRd,
wherein for (x) and (xi), the heteroaryl and the heterocycloalkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1′) alkyl, and
(2′) a nitrogen protecting group,
(o) heterocycloalkyloyl, wherein the heterocycloalkyloyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl, and
(ii) a nitrogen protecting group, and
(p) —(CH2)xNRARB wherein x is 0-6, and RA and RB are independently selected from the group consisting of
(i) hydrogen,
(ii) alkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) cycloalkenyl, and
(viii) cycloalkenylalkyl;
R1 is indolyl, wherein the indolyl can be optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from the group consisting of
(a) oxo,
(b) azido,
(c) carboxy,
(d) carboxaldehyde,
(e) cyano,
(f) halo,
(g) hydroxy,
(h) nitro,
(i) perfluoroalkyl,
(j) perfluoroalkoxy,
(k) alkyl,
(l) alkenyl,
(m) alkynyl,
(n) alkanoyloxy,
(o) alkoxycarbonyl,
(p) cycloalkyl,
(q) cycloalkylalkyl,
(r) cycloalkenyl,
(s) cycloalkenylalkyl,
(t) alkanoyl,
(u) alkoxy,
(v) cycloalkoxy,
(w) aryloxy,
(x) heteroaryloxy,
(y) thioalkoxy
(z) alkylsulfinyl,
(aa) alkylsulfonyl,
(bb) —NR8R9, wherein R8 and R9 are independently selected from the group consisting of
(i) hydrogen
(ii) alkyl,
(iii) arylalkyl, and
(iv) alkanoyl, wherein the alkanoyl can be optionally substituted with 1 or 2 substituents independently selected from the group consisting of
(1′) halo
(2′) hydroxy, and
(3′) —NR10R11 wherein R10 and R11 are independently hydrogen or alkyl, and
(cc) —SO2NR8R9, wherein R8 and R9 are defined above;
R2 and R6 are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) alkoxy,
(4) thioalkoxy;
and
(5) hydroxy;
and
R3, R4, and R5 are independently selected from the group consisting of
(1) alkyl,
(2) alkoxy,
(3) thioalkoxy, and
(4) hydroxy.

96 more elements

A compound selected from the group consisting of

5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sufonamide,.
N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoic acid,
(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoic acid,
(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoic acid,
(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoic acid,
N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(4-morpholiniylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide, and
N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/579,705Filed 26 May 2000 · continuation in part
Priority: 28 May 1999
Granted: 18 Feb 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07C 323/29
Having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton containing six-membered…
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 235/56
With carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring:…

Family

Application60/136,542Parent of this continuation-in-part · filed 28 May 1999
US 6,521,658 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein
L1 is shown with its left end attached to R1 and its right end attached to the phenyl ring and is —SO2NR7—, wherein R7 is selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amidinyl,
(d) a nitrogen-protecting group,
(e) alkanoyl,
(f) alkyl,
(g) alkenyl,
(h) alkynyl,
(i) cycloalkyl,
(j) cycloalkylalkyl,
(k) cycloalkenyl,
(l) cycloalkenylalkyl,
(m) aryloyl,
(n) alkoxy,
wherein (e)-(n) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(i) hydroxyl,
(ii) halo,
(iii) cyano,
(iv) azido,
(v) carboxy,
(vi) amidinyl,
(vii) alkyl,
(viii) aryl,
(ix) oxo,
(x) heteroaryl,
(xi) heterocycloalkyl,
(xii) —NRcRd, wherein Rc and Rd are independently selected from the group consisting of
(1′) hydrogen,
(2′) alkyl,
(3′) aryl, and
(4′) alkoxyalkyl, and
(xiii) -(alkylene)—NRcRd,
wherein for (x) and (xi), the heteroaryl and the heterocycloalkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1′) alkyl, and
(2′) a nitrogen protecting group,
(o) heterocycloalkyloyl, wherein the heterocycloalkyloyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl, and
(ii) a nitrogen protecting group, and
(p) —(CH2)xNRARB wherein x is 0-6, and RA and RB are independently selected from the group consisting of
(i) hydrogen,
(ii) alkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) cycloalkenyl, and
(viii) cycloalkenylalkyl;
R1 is indolyl, wherein the indolyl can be optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from the group consisting of
(a) oxo,
(b) azido,
(c) carboxy,
(d) carboxaldehyde,
(e) cyano,
(f) halo,
(g) hydroxy,
(h) nitro,
(i) perfluoroalkyl,
(j) perfluoroalkoxy,
(k) alkyl,
(l) alkenyl,
(m) alkynyl,
(n) alkanoyloxy,
(o) alkoxycarbonyl,
(p) cycloalkyl,
(q) cycloalkylalkyl,
(r) cycloalkenyl,
(s) cycloalkenylalkyl,
(t) alkanoyl,
(u) alkoxy,
(v) cycloalkoxy,
(w) aryloxy,
(x) heteroaryloxy,
(y) thioalkoxy
(z) alkylsulfinyl,
(aa) alkylsulfonyl,
(bb) —NR8R9, wherein R8 and R9 are independently selected from the group consisting of
(i) hydrogen
(ii) alkyl,
(iii) arylalkyl, and
(iv) alkanoyl, wherein the alkanoyl can be optionally substituted with 1 or 2 substituents independently selected from the group consisting of
(1′) halo
(2′) hydroxy, and
(3′) —NR10R11 wherein R10 and R11 are independently hydrogen or alkyl, and
(cc) —SO2NR8R9, wherein R8 and R9 are defined above;
R2 and R6 are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) alkoxy,
(4) thioalkoxy;
and
(5) hydroxy;
and
R3, R4, and R5 are independently selected from the group consisting of
(1) alkyl,
(2) alkoxy,
(3) thioalkoxy, and
(4) hydroxy.

96 more elements

Facts

Application

09/579,705Filed 26 May 2000 · continuation in part

Priority

28 May 1999

Granted

18 Feb 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07C 323/29
Having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton containing six-membered…
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 235/56
With carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring:…