US 6,713,645 B1Granted

Substituted tricyclics

AssigneeEli Lilly and Company

InventorsNicholas James Bach, Susan Elizabeth Draheim, Robert Delane Dillard, Edward David Mihelich, Jason Scott Sawyer, Douglas Wade Beight, Michael LeRoy Phillips, Tulio Suarez, Daniel Jon Sall, Jolie Anne Bastian, Michael Lyle Denney, Gary Alan Hite, Michael Dean Kinnick, Robert Theodore Vasileff, John Michael Morin, Jr., Ho-Shen Lin, Michael Enrico Richett, Richard Waltz Harper, John McNeill McGill, III, Benjamin Alan Anderson, Nancy Kay Harn, Richard James Loncharich, Richard Walter Schevitz

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Abstract

A class of novel tricyclics is disclosed together with the use of such compounds for inhibiting sPLA2 mediated release of fatty acids for treatment of conditions such as septic shock.

Claims2

Dependent claims

A compound of the formula

wherein
PG is an acid protecting group;
R21 is a non-interfering substituent;
R12 is H or CH2R4 where
R4 is H, —(C5-C14)alkyl, —(C3-C14)cycloalkyl;
pyridyl, phenyl or phenyl substituted with from 1-5 substituents selected from the group consisting of —(C1-C6)alkyl, halo, —CF3, —OCF3, —(C1-C4)alkoxy, —CN, —(C1-C4)alkylthio, phenyl (C1-C4)alkyl, —(C1-C4)alkylphenyl, phenyl, phenoxy, —OR9;
where R9 and R10 are independently hydrogen, —CF3, phenyl, —(C1-C4)alkyl, —(C1-C4)alkylphenyl or —phenyl(C1-C4)alkyl;
tetrazole;
tetrazole substituted with —(C1-C4)alkyl or —(C1-C4)alkylphenyl:
or naphthyl;
R3(a) is H, —O(C1-C4)alkyl, halo, —(C1-C6)alkyl, phenyl, —(C1-C4)alkylphenyl;
phenyl substituted with —(C1-C6)alkyl, halo or —CF3;
—CH2OSi(C1-C6)alkyl, furyl, thiophenyl, —(C1-C6)hydroxyalkyl, —(C1-C6)alkoxy(C1-C6)alkyl, —(C1-C6)alkoxy(C1-C6)alkenyl;
or —(CH2)nR8 where R8 is H, —NR9R10, —CN or phenyl where R9 and R10 are independently hydrogen, —CF3, phenyl, —(C1-C4)alkyl, —(C1-C4)alkylphenyl or -phenyl(C1-C4)alkyl and n is 1 to 8:
Z is cyclohexenyl or phenyl;
and
X is halo.

14 more elements

A compound which is selected from the group consisting of:

(3-Carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one;
(3-Carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one;
[(Phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one;
[(3-Fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one;
[(3-Methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one;
(3-Carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl-cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-(4-trifluoromethylphenyl)-9H-carbazol-4(3H)-one;
[(Phenyl)methyl]-5-carbomethoxy-2-(4-trifluoromethylphenyl)-1,2-dihydrocarbozol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-pentylcyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-pentyl-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-pentyl-9-(phenylmethyl)carbazol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-[(1-methyl)ethyl]cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-(1-methylethyl)-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-(1-methylethyl)-9-(phenylmethyl)carbazol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-(hydroxymethyl)cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-(hydroxymethyl)-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-(hydroxymethyl)-9-(phenylmethyl)carbazol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-phenylcyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-phenyl-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-phenyl-9-(phenylmethyl)carbazol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-(4-chlorophenyl)cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-(4-chlorophenyl)-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-(4-chlorophenyl)-9-(phenylmethyl)carbozol-4(3H)-one;
(2-Bromo-3-carbomethoxyanilino)-5-(2-furyl)cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-2-(2-furyl)-9H-carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-2-(2-furyl)-9-(phenylmethyl)carbazol-4(3H)-one;
5-Carbomethoxy-1,2-dihydro-9-(phenylmethyl)-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4(3H)-one;
(3-Carbomethoxy-2-chloroanilino)cyclohex-2-en-1-one;
5-Carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one;
(3-Carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one;
[(Phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Phenoxyphenyl)methyl-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Benzylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(1-Naphthyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3,5-Dimethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-lodophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Chlorophenyl)methyl-5-carbomethoxy-1,2-dihydrocarbozol-4(3H)-one;
[(2,3-Difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2,6-Difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2,6-Dichlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Trifluoromethoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(2-Pyridyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(3-Pyridyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(Cyclohexyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
[(Cyclopentyl)-methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one;
or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof.

54 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/688,106Filed 13 Oct 2000 · division
Priority: 30 Oct 1996
Granted: 30 Mar 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 409/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 209/88
Carbazoles; Hydrogenated carbazoles: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to…
C07F 9/5728
Five-membered rings: condensed with carbocyclic rings or carbocyclic ring systems
C07D
Heterocyclic compounds

Family

Application60/029,849Us provisional application · filed 30 Oct 1996
Application08/959,477Parent of this continuation-in-part · filed 28 Oct 1997
Application09/063,066Parent of this division · filed 21 Apr 1998
US 6,177,440 B1Parent of this division
Application09/063,066Parent of this continuation-in-part
US 6,713,645 B1This patent

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