# US 5,332,837 A · CC-1065 analogs

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- Number: US 5,332,837 A
- Document ID: US5332837A
- Status: Granted
- Kind: A
- Application number: 08/010,526
- Filed: 1993-01-22
- Granted: 1994-07-26
- Earliest claimed: 1986-12-19
- Assignees: The Upjohn Company
- Inventors: Robert C. Kelly; David G. Martin; Paul A. Aristoff
- Web page: https://patentgrep.com/patent/US5332837A

## CPC

- C07D 487/04: Ortho-condensed systems
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

This invention concerns 2-acyl-4,5,8,8a-tetrahydro-4-oxycyclopropan[c]pyrrol(3,2-e) indole derivatives of Formula I': ##STR1## the compounds of Formula I' are useful as uv light absorber substances, as chemical intermediates and as prodrugs of known spirocyclopropylpyrroloindole CC-1065 analogs. Representative Formula I' compounds have been shown to possess useful ranges of antitumor activity in standard laboratory animal tests.

## Claims

### Claim 1

A compound of formula ##STR17## where X.sub.8 is --O--, --S-- or --NH--; wherein W is selected from C.sub.1 -C.sub.5 alyl, phenyl or hydrogen;
wherein X is selected from azido, a halogen atom, cyanate, thiocyanate, isocyanate, thioisocyanate, phosphate diester (--PO(OR).sub.2), phosphonyl (--O--PO.sub.2 R), thiophosphonyl (--O--PSOR), sulfinyl (--O--SOR) or sulfonyl (--O--SO.sub.2 R);
wherein Y is selected from --C(O)R, --C(S)R, --C(O)OR.sub.1, --S(O).sub.2 R.sub.1, --C(O)NR.sub.2 R.sub.3, --C(S)NR.sub.2 R.sub.3, or --C(O)NHSO.sub.2 R.sub.4 ;
wherein Z is selected from the group consisting of C.sub.1 -C.sub.5 alkyl, phenyl or hydrogen;
wherein R is selected from the group consisting of C.sub.1 -C.sub.20 alkyl; C.sub.2 -C.sub.6 alkenyl; C.sub.2 -C.sub.6 alkynyl; phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; naphthyl optionally substituted with one or two C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.1 -C.sub.3 alkylthio or nitro;
wherein R.sub.1 is selected from C.sub.1 -C.sub.20 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
wherein R.sub.2 and R.sub.3, being the same or different, are selected from hydrogen, C.sub.1 -C.sub.20 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; with the proviso that both R.sub.2 and R.sub.3 cannot be phenyl or substituted phenyl; and
wherein R.sub.4 is selected from C.sub.1 -C.sub.10 alkyl; phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; naphthyl optionally substituted with one or two C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.1 -C.sub.3 alkylthio or nitro.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein Y is selected from
--COR wherein R is selected from C.sub.1 -C.sub.10 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
--C(O)NHSO.sub.2 R.sub.4 ; or --C(O)NR.sub.2 R.sub.3.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein W is methyl.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein Z is hydrogen.

### Claim 5 (depends on 2)

A compound according to claim 2 where W is methyl and Z is hydrogen.

### Claim 6 (depends on 1)

A compound according to claim 1 where W is methyl, X is chloro and Z is hydrogen.

### Claim 7 (depends on 30)

A compound according to claim 30 where X .sub.8 is --O--.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein Y is selected from --COR wherein R is selected from C.sub.1 -C.sub.10 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
--C(O)NHSO.sub.2 R.sub.4 ; or --C(O)NR.sub.2 R.sub.3.

### Claim 9 (depends on 7)

A compound according to claim 7 where W is methyl.

### Claim 10 (depends on 9)

A compound according to claim 9 where Z is hydrogen.

### Claim 11 (depends on 8)

A compound according to claim 8 where W is methyl and Z is hydrogen.

### Claim 12 (depends on 7)

A compound according to claim 7 where W is methyl, X is chloro and Z is hydrogen.

### Claim 13 (depends on 30)

A compound of claim 30, having the 1(S)-configuration of the stereoisomer of ##STR18## where X .sub.8 is --O--, --S-- or --NH--; wherein W is selected from C.sub.1 -C.sub.5 alkyl, phenyl or hydrogen;
wherein X is selected from azido, a halogen atom, cyanate, thiocyanate, isocyanate, thioisocyanate, phosphate diester (--PO(OR).sub.2), phosphonyl (--O--PO.sub.2 R), thiophosphonyl (--O--PSOR), sulfinyl (--O--SOR) or sulfonyl (--O--SO.sub.2 R);
wherein Y is selected from --C(O)R, --C(S)R, --C(O)OR.sub.1, --S(O).sub.2 R.sub.1, --C(O)NR.sub.2 R.sub.3, --C(S)NR.sub.2 R.sub.3, or --C(O)NHSO.sub.2 R.sub.4 ;
wherein Z is selected from the group consisting of C.sub.1 -C.sub.5 alkyl, phenyl or hydrogen;
wherein R is selected from the group consisting of C.sub.1 -C.sub.20 alkyl; C.sub.2 -C.sub.6 alkenyl; C.sub.2 -C.sub.6 alkynyl; phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; naphthyl optionally substituted with one or two C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.1 -C.sub.3 alkylthio or nitro;
wherein R.sub.1 is selected from C.sub.1 -C.sub.20 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
wherein R.sub.2 and R.sub.3, being the same or different, are selected from hydrogen, C.sub.1 -C.sub.20 alkyl, or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; with the proviso that both R.sub.2 and R.sub.3 cannot be phenyl or substituted phenyl; and
wherein R.sub.4 is selected from C.sub.1 -C.sub.10 alkyl; phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; naphthyl optionally substituted with one or two C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.1 -C.sub.3 alkylthio or nitro.

### Claim 14 (depends on 13)

A compound according to claim 13 wherein Y is selected from
--COR wherein R is selected from C.sub.1 -C.sub.10 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
--C(O)NHSO.sub.2 R.sub.4 ; or --C(O)NR.sub.2 R.sub.3.

### Claim 15 (depends on 13)

A compound according to claim 13 where W is methyl, X is chloro and Z is hydrogen.

### Claim 16 (depends on 15)

A compound according to claim 15 where X.sub.8 is --O--.

### Claim 17 (depends on 16)

A compound according to claim 16 having the formula ##STR19##

### Claim 18 (depends on 17)

A compound according to claim 17 wherein Y is selected from
--COR wherein R is selected from C.sub.1 -C.sub.10 alkyl or phenyl optionally substituted with one, two or three C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro;
--C(O)NHSO.sub.2 R.sub.4 ; or --C(O)NR.sub.2 R.sub.3.

### Claim 19 (depends on 17)

A compound according to claim 17 selected from the group consisting of
(S)-8-(chloromethyl)-6-[[5-[[[6-(diethylamino)-2-benzofuranyl]carbonyl]amin o]-1H-indol-2-yl]carbonyl]-3,6,7,8-tetrahydro-1-methylbenzo[1,2-b4,5-b']dip yrrol-4-yl ester, 2,2-dimethyl-propanoic acid (Cpd #11A); or
(S)-N-[2[[1-(chloromethyl)-1,6-dihydro-8-methyl-5-[[(phenylamino)carbonyl]o xy]benzo[1,2,-b4,3-b']dipyrrol-3-(2H)-yl]carbonyl]-1H-indol-5-yl]-6-(diethy lamino)-2-benzofurancarboxamide (Cpd #11B).

### Claim 20

(S)-N-[2-[[1-(chloromethyl)-1,6-dihydro -8-methyl-5-[[(phenylamino)carbonyl]oxy]benzo[1,2,-b 4,3-b']dipyrrol-3(2H)-yl]carbonyl]-1H-indol-5-yl]-6-(diethylamino)-2-benzo furancarboxamide.