US5344841A
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Bis-(hydroxylakylamino)-anthraquinone inhibitors of protein kinase C
Assignee: Eli Lilly and Co
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Filing: 1991-10-30
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Granted: 1994-09-06
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Expires: 2011-10-30
Abstract
Abstract PCT No. PCT/US91/08026 Sec. 371 Date Jun. 8, 1992 Sec. 102(e) Date Jun. 8, 1992 PCT Filed Oct. 30, 1991 PCT Pub. No. WO92/07557 PCT Pub. Date May 14, 1992. <IMAGE> ( alpha ) The present invention provides novel substituted anthraquinones having formula ( alpha ), wherein R1 and R2 are independently H, C1-C10 alkyl, aryl, arylalkyl, alkylaryl, or R1 and R2 taken together with the adjacent nitrogen atom N form a substituted or unsubstituted cyclic ring which may contain additional heteroatoms; n and m are independently 1, 2, or 3; A is halogen, OH, alkoxy, OCO(NR3R4), S-C(NH2)=NR5, or when m=1, comprises an oxirane ring with the adjacent oxygen atom; R3, R4, and R5 are independently H, alkyl, or aryl; X is H, OH, NR6R7, Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR8, or CONR9R10; and R6, R7, R8, R9, and R10 are independently H, lower alkyl, or aryl useful for inhibiting protein kinase C and treating conditions related to, or affected by inhibition of protein kinase C, particularly cancer tumors, inflammatory disease, reperfusion injury, and cardiac dysfunctions related to reperfusion injury.
Inventors
- 👤 Jack B. Jiang
- 👤 Mary G. Johnson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 18:00
CPC Classifications
C; C07; C07D; C07D303/00; C07D303/02; C07D303/36; A; A61; A61P; A61P35/00; A61P43/00; C07C; C07C225/00; C07C225/24; C07C225/26; C07C225/32; C07C225/34; C07C225/36; C07C229/00; C07C229/52; C07C229/68; C07C229/72; C07C229/74; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/12; C07C335/00; C07C335/30; C07C335/32; C07C2603/00; C07C2603/02; C07C2603/04; C07C2603/22; C07C2603/24
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
152 words
A method of inhibiting protein kinase C which comprises contacting protein kinase C with an inhibitory amount of a substituted anthraquinone having the formula ##STR4## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl.
Claim 2
Independent Claim
152 words
A method of inhibiting protein kinase C which comprises contacting protein kinase C with an inhibitory amount of a substituted anthraquinone having the formula ##STR4## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl.
Claim 3
Dependent Claim
70 words
The method of claim 1 wherein R 1 and R 2 independently are H or lower alkyl; n and m are independently 1 or 2; A is halogen, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or when m=1 , comprises said oxirane; R 3 , R 4 , and R 5 are independently H or alkyl; and X is H, HO, Cl, Br, I, F, or alkoxy.
Claim 4
Dependent Claim
56 words
The method of claim 2 wherein R 1 and R 2 independently are lower alkyl; m and n are 1; A is Cl, Br, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or comprises said oxirane ring; R 3 , R 4 , and R 5 are H; and X is H or OH.
Claim 5
Independent Claim
157 words
A method of inhibiting an oxidative burst in neutrophils which comprises contacting a neutrophil with a substituted anthraquinone having the formula ##STR5## wherein R 1 and R 2 are independently H, C 1-C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit said oxidative burst.
Claim 6
Independent Claim
157 words
A method of inhibiting an oxidative burst in neutrophils which comprises contacting a neutrophil with a substituted anthraquinone having the formula ##STR5## wherein R 1 and R 2 are independently H, C 1-C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit said oxidative burst.
Claim 7
Dependent Claim
70 words
The method of claim 4 wherein R 1 and R 2 independently are H or lower alkyl; n and m are independently 1 or 2; A is halogen, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or when m=1, comprises said oxirane ring; R 3 , R 4 , and R 5 are independently H or alkyl; and X is H, HO, Cl, Br, I, F, or alkoxy.
Claim 8
Dependent Claim
56 words
The method of claim 5 wherein R 1 and R 2 independently are lower alkyl; m and n are 1; A is Cl, Br, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or comprises said oxirane ring; R 3 , R 4 , and R 5 are H; and X is H or OH.
Claim 9
Dependent Claim
15 words
The method of claim 4 wherein said amount is a protein kinase C inhibitory amount.
Claim 10
Dependent Claim
15 words
The method of claim 5 wherein said amount is a protein kinase C inhibitory amount.
Claim 11
Dependent Claim
15 words
The method of claim 6 wherein said amount is a protein kinase C inhibitory amount.
Claim 12
Independent Claim
153 words
A method for treating inflammation which comprises administering to a mammal suffering from inflammation a substituted anthraquinone having the formula ##STR6## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit inflammation.
Claim 13
Independent Claim
153 words
A method for treating inflammation which comprises administering to a mammal suffering from inflammation a substituted anthraquinone having the formula ##STR6## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, or alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit inflammation.
Claim 14
Dependent Claim
69 words
The method of claim 10 wherein R 1 and R 2 independently are H or lower alkyl; n and m are independently 1 or 2; A is halogen, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or when m=1, comprises said oxirane ring; R.sub. 3, R 4 , and R 5 are independently H or alkyl; and X is H, HO, Cl, Br, I, F, or alkoxy.
Claim 15
Dependent Claim
56 words
The method of claim 11 wherein R 1 and R 2 independently are lower alkyl; m and n are 1; A is Cl, Br, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or comprises said oxirane ring; R 3 , R 4 , and R 5 are H; and X is H or OH.
Claim 16
Dependent Claim
15 words
The method of claim 10 wherein said amount is a protein kinase C inhibitory amount.
Claim 17
Dependent Claim
15 words
The method of claim 11 wherein said amount is a protein kinase C inhibitory amount.
Claim 18
Dependent Claim
15 words
The method of claim 12 wherein said amount is a protein kinase C inhibitory amount.
Claim 19
Independent Claim
153 words
A method of inhibiting keratinocyte proliferation comprising administering to a keratinocyte a compound having the formula ##STR7## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit proliferation of said keratinocyte.
Claim 20
Independent Claim
153 words
A method of inhibiting keratinocyte proliferation comprising administering to a keratinocyte a compound having the formula ##STR7## wherein R 1 and R 2 are independently H, C 1 -C 10 alkyl, aryl, arylalkyl, alkylaryl; n and m are independently 1, 2, or 3; A is Halogen, OH, alkoxy, OCO(NR 3 R 4 ), S--C(NH 2 )═NR 5 , or when m=1, A represents the attachment of the oxygen atom from the adjacent hydroxyl group to form an oxirane ring; R 3 , R 4 , and R 5 are independently H, alkyl, or aryl; X is H, OH, NR 6 R 7 , Cl, Br, I, F, alkyl, aryl, alkoxy, aryloxy, COOR 8 , or CONR 9 R 10 ; and R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, lower alkyl, or aryl in an amount effective to inhibit proliferation of said keratinocyte.
Claim 21
Dependent Claim
70 words
The method of claim 16 wherein R 1 and R 2 independently are H or lower alkyl; n and m are independently 1 or 2; A is halogen, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or when m=1, comprises said oxirane ring; R 3 , R 4 , and R 5 are independently H or alkyl; and X is H, HO, Cl, Br, I, F, or alkoxy.
Claim 22
Dependent Claim
56 words
The method of claim 17 wherein R 1 and R 2 independently are lower alkyl; m and n are 1; A is Cl, Br, OCO(NR 3 R 4 ), SC(NH 2 )═NR 5 , or comprises said oxirane ring; R 3 , R 4 , and R 5 are H; and X is H or OH.
Claim 23
Dependent Claim
15 words
The method of claim 11 wherein said amount is a protein kinase C inhibitory amount.
Claim 24
Dependent Claim
15 words
The method of claim 17 wherein said amount is a protein kinase C inhibitory amount.
Claim 25
Dependent Claim
15 words
The method of claim 18 wherein said amount is a protein kinase C inhibitory amount.
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