IP Library › Granted Patent US 8,410,130

Granted Patent B2

US 8,410,130 · App. 12/267,227 · Granted Apr 2, 2013

Synthesis of 8H-3A-aza-cyclopenta [A ]indenes and 5,10-dihydropyrrolo[1,2-B]isoquinolines derivatives and their use as antitumor therapeutic agents

Inventors: Tsann-Long Su (Xizhi, TW); Ting-Chao Chou (Paramus, NJ)

Assignee: Academia Sinica

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Quick Facts

Patent No.: US 8,410,130
App. No.: 12/267,227
Granted: Apr 2, 2013
Kind: B2

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Abstract

The present disclosure relates to a series of bis(hydroxymethyl) and its bis(carbamate) of 8H-3a-azacyclopenta[a]indene-1-yl and 5,10-dihydropyrrolo-[1,2-b]isoquinolines derivatives (Formula I-Formula IV) as DNA di-alkylating agents. The preliminary antitumor studies indicated that compounds disclosed herein could exhibit potent cytotoxicity in vitro and antitumor therapeutic efficacy in human tumor xenografts and could have little or no cross-resistance to either Taxol or Vinblastine. The results demonstrated that compounds disclosed herein possess potent antitumor therapeutic efficacy and are expected to have potential for clinical applications.

Claims (145)

1. A compound of formula I, II, III, or IV:

and pharmaceutically acceptable salts and mixtures thereof,

wherein:

R 1 is chosen from hydrogen, a C 1 -C 5 linear or branched alkyl group, an aryl, and a benzyl, which may be unsubstituted or substituted;

R 2 , R 3 , R 4 and R 5 are independently chosen from hydrogen, C 1 -C 6 alkyl, OR a , halo, cyano, nitro, NH 2 , NHR b , and N(R b ) 2 , wherein R a is chosen from hydrogen and C 1 -C 10 alkyl, and R b is chosen from hydrogen and C 1 -C 10 alkyl; and

R 6 is chosen from a saturated or unsaturated, linear or branched, C 1 -C 5 alkyl group, an unsubstituted or substituted phenyl group, and an unsubstitued or substituted benzyl group,

and further wherein: when the C 1 -C 5 linear or branched alkyl group is substituted, one or more substituents are independently chosen from halogen, hydroxy, alkoxy, lower alkyl, lower alkenyl, and lower alkynyl; and

when the aryl, the benzyl, or the phenyl group is substituted, one or more substituents are independently chosen from C 1 -C 6 alkyl, OR a , halo, cyano, nitro, NH 2 , wherein R a is as defined above.

2. The compound of formula I according to claim 1 , wherein R 2 ═R 3 ═R 5 ═H.

3. The compound of formula II according to claim 1 , wherein R 2 ═R 3 ═R 5 ═H.

4. The compound of formula III according to claim 1 , wherein R 2 ═R 3 ═R 4 ═R 5 ═H.

5. The compound of formula IV according to claim 1 , wherein R 2 ═R 3 ═R 4 ═R 5 ═H.

6. The compound according to claim 1 , wherein the compound is chosen from:

(2-Hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-Ethyl-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-propyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-isopropyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-butyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-phenyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(2-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(3,4-Dimethoxyphenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(2,6-Dimethoxyphenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(3,4,5-trimethoxyphenyl)-8H-3-aza-cyclopenta[a]inden-1-yl)-methanol;

(2-Hydroxymethyl-3-(4-methylphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(4-nitrophenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(4-Aminophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(4-Flourophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(4-Chlorophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(3,4-Diflourophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-yl)methanol;

(3-(3,4-Dichlorophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-6-methoxy-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol,

(2-Hydroxymethyl-6-nitro-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)-methanol;

(6-Amino-2-hydroxymethyl-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-6-methyl-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)-methanol;

(6-Chloro-2-hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(6-Flouro-2-hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(5,6-dimethoxy-2-hydroxymethyl-3-(2-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-hydroxymethyl-4,5,6-trimethoxy-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(6-dimethylamino-2-hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

Methylcarbamic acid 3-methyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta-[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-ethyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta-[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-propyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-butyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-isopropyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl-methyl ester;

Methylcarbamic acid 2-methylcarbamoyloxymethyl-3-phenyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethylester;

Methylcarbamic acid 3-(4-flourophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-chlorophenyl)-2-methyl-carbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4-difluorophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-methoxyphenyl)-2-methylcarbamoyloxymethyl-8H-3a-azacyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(2-methoxyphenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4-dimethoxyphenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(2,6-dimethoxyphenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4,5-trimethoxyphenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 6-methoxy-3-(4-methoxyphenyl)-2-methylcarbamoyloxy-methyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-methoxyphenyl)-2-methylcarbamoyloxymethyl-6-pyrrolidin-1-yl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-methoxyphenyl)-2-methylcarbamoyloxymethyl-6-piperidin-1-yl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-nitrophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-aminophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 5,6-methylenedioxy-2-methylcarbamoyloxymethyl-3-(2-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 5,6-ethylenedioxy-2-methylcarbamoyloxymethyl-3-(2-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Ethylcarbamic acid 2-ethylcarbamoyloxymethyl-3-(4-methoxy-phenyl)-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester:

Propylcarbamic acid 3-methyl-2-propylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Isopropylcarbamic acid 2-isopropylcarbamoyloxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-2-ylmethyl ester;

Isobutylcarbamic acid 2-isobutylcarbamoyloxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-2-ylmethyl ester;

Phenylcarbamic acid 3-methyl-2-phenylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

(1-Hydroxymethyl-3-methyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)methanol;

(3-Ethyl-1-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)methanol;

(1-Hydroxymethyl-3-phenyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)methanol;

(3-(4-chlorophenyl)-1-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)-methanol;

[3-(4-fluorophenyl)-1-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl]-methanol;

[3-(3,4-difluorophenyl)-1-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl]-methanol;

(1-Hydroxymethyl-3-(2-methoxyphenyl)-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)methanol;

(1-Hydroxymethyl-3-(4-methoxyphenyl)-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl)methanol;

[3-(3,4-dimethoxyphenyl)-1-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-2-yl]methanol;

Methylcarbamic acid 3-methyl-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-ethyl-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 2-methylcarbamoyloxymethyl-3-phenyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Methyl-carbamic acid 3-(4-chlorophenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-(4-fluorophenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4-diflourophenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-(2-methoxyphenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-(4-methoxyphenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4-dimethoxyphenyl)-2-methylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-methyl-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-ethyl-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-phenyl-2-propylcarbamoylmethyl-5,10-dihydropyrrolo-[1,2-b]isoquinolin-1-ylmethyl ester;

Propylethylcarbamic acid 3-(4-chlorophenyl)-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-(4-fluorophenyl)-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-(3,4-diflourophenyl)-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester;

Propylcarbamic acid 3-(4-methoxyphenyl)-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester; and

Propylcarbamic acid 3-(3,4-dimethoxyphenyl)-2-propylcarbamoyloxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-ylmethyl ester.

7. The compound according to claim 1 , wherein the compound is chosen from:

(2-Hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-Ethyl-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-phenyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(2-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(3,4-Dimethoxyphenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(2,6-Dimethoxyphenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-3-(3,4,5-trimethoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)-methanol;

(3-(4-Fluorophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(4-Chlorophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(3-(3,4-Difluorophenyl)-2-hydroxymethyl-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

(2-Hydroxymethyl-6-methoxy-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]inden-1-yl)methanol;

Methylcarbamic acid 3-methyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta-[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-ethyl-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta-[a]inden-1-ylmethyl ester;

Methyl-carbamic acid 2-methylcarbamoyloxymethyl-3-phenyl-8H-3a-aza-cyclo-penta[a]inden-1-ylmethylester;

Methylcarbamic acid 3-(4-fluorophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-chlorophenyl)-2-methyl-carbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(3,4-difluorophenyl)-2-methylcarbamoyloxymethyl-8H-3a-aza-cyclopenta[a]inden-1-ylmethyl ester;

Methylcarbamic acid 3-(4-methoxy-phenyl)-2-methylcarbamoyloxymethyl-8H-3a-azacyclopenta[a]inden-1-ylmethyl ester;