IP Library › Granted Patent US 6,887,869

Granted Patent B2

US 6,887,869 · App. 10/250,383 · Granted May 3, 2005

Mikanolide derivatives, their preparation and therapeutic uses

Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S.)

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Quick Facts

Patent No.: US 6,887,869
App. No.: 10/250,383
Granted: May 3, 2005
Kind: B2

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Abstract

The invention concerns novel mikanolide derivatives, their preparation method and their therapeutic uses, in particular as anti-cancer and anti-viral agents. The compounds correspond to general formula (1) corresponding to general sub-formulae (I) 1 and (I) 2 , wherein: R 1 represents H, SR 4 or NR 4 R 5 ; R 2 represents SR 6 or NR 6 R 7 ; R 3 represents OH, O(CO)R 14 , OSiR 15 R 16 R 17 , O(CO)OR 18 or O(CO)NHR 18 , each of the radicals R 4 , R 6 , R 15 , R 16 and R 17 representing independently (in particular) an alkyl radical, the radicals R 5 and R 7 representing (in particular) radicals selected independently among a hydrogen atom and an alkyl radical, and each of the radicals R 14 and R 18 representing independently (in particular) an alkyl or cycloalkyl radical, or one among aryl, heteroaryl, aralkyl or heteroalkyl radicals optionally substituted; provided that when the compounds correspond to the general sub-formula (I) 2 , then R 1 does not represent a hydrogen atom

Claims (123)

1. A compound of the formula:

corresponding to sub-formulae:

wherein

R 1 is selected from the group consisting of hydrogen, —SR 4 and —NR 4 R 5 ;

R 2 is —SR 6 or —NR 6 R 7 ;

R 3 is selected from the group consisting of OH, —O(CO)R 14 , —OSiR 15 R 16 R 17 , —O(CO)OR 18 and —O(CO)NHR 18 ;

R 4 and R 6 are individually selected from the group consisting of, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl and aralkyl optionally substituted on the aryl by at least one member of the group consisting of alkyl, hydroxy and alkoxy,

R 5 and R 7 are individually selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl and aralkyl optionally substituted on the aryl by at least one member of the group consisting of alkyl, hydroxy and alkoxy or R 4 and R 5 form together with the nitrogen atom which carries them a heterocycle with 5 to 7 ring members the additional member being selected from the group consisting of —CR 8 R 9 —, —NR 10 —, —O— and —S—, it being understood that there can only be one member chosen from —O— or —S— in said heterocycle,

or R 6 and R 7 form together with the nitrogen atom which carries them a heterocycle with 5 to 7 ring members, the additional member being selected from the group consisting of —CR 11 R 12 —, —NR 13 —, —O— and —S— it being understood however that there can only be one member chosen from —O— or —S— in said heterocycle,

R 8 , R 10 , R 11 and R 13 are individually hydrogen, alkyl, alkoxycarbonyl and aralkyl,

R 9 and R 12 are individually hydrogen or alkyl or each of R 9 and R 12 being able to form respectively together with R 8 and R 11 —O—(CH 2 ) 2 —O— attached on either side to the carbon atom which carries it, such a radical only being present once at most per NR 4 R 5 or NR 6 R 7

R 14 is selected from the group consisting of alkyl, cycloalkyl, adamantyl, aryl, heteroaryl, aralkyl and heteroaralkyl optionally substituted on the aryl or heteroaryl by at least one member of the group consisting of halogen, alkyl, haloalkyl, nitro, hydroxy, alkoxy, alkylthio and phenyl;

or R 14 is such that R 14 —COOH is a natural amino acid or the optical enantiomer of such an amino acid;

R 15 , R 16 and R 17 are individually alkyl, or phenyl;

R 18 is selected from the group consisting of alkyl, cycloalkyl, adamantyl, aryl, heteroaryl, aralkyl and heteroaralkyl optionally substituted on the aryl or heteroaryl by at least one member of the group consisting of halogen, alkyl, haloalkyl, nitro, hydroxy, alkoxy, alkylthio and phenyl;

it being understood however that when the compounds correspond to sub-formula (I) 2 , then R 1 is not hydrogen;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein it has sub-formula (I) 1 or is a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 , wherein:

R 1 is hydrogen or —NR 4 R 5 ;

R 2 is —NR 6 R 7 ;

R 3 is selected from the group consisting of —OH, —O(CO)R 14 , —OSiR 15 R 16 R 17 and —O(CO)NHR 18 .

4. A compound of claim 1 , wherein it has sub-formula (I) 2 .

5. A compound of claim 1 , selected from the group consisting of:

12-diisopropylaminomethyl-7-methyl-3,6,10,15-tetraoxapentacyclo [12.2.1.0 2,4 .0 5,7 .0 9,13 ]heptadec-1(17)-ene-11,16-dione;

12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

ethyl 1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-12-yl]-4-piperidinecarboxylate;

12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl acetate;

3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene;

ethyl 3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl carbonate;

11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-ene-4,14-dione;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-yl benzoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-yl acetate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl cyclohexanecarboxylate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 4-fluorobenzoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl heptanoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 4-(trifluoromethyl)benzoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 2-thiophenecarboxylate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 3,3-dimethylbutanoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 1-benzothiophene-2-carboxylate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 2-furoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0 2,6 .0 8,10 ]hexadec-13(16)-en-11-yl 5-nitro-2-furoate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.0 8.10 ]hexadec-13(16)-en-11-yl 2-thienylacetate;

12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-yl phenoxyacetate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 4-tert-butylphenylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl thien-2-ylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 2-methoxyphenylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl 2(methylthio)phenylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 2-ethoxyphenylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl thien-3-ylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 1-benzothien-3-ylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl N-(ter-butoxycarbonyl)glycinate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl thien-3-ylacetate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 1-benzothien-3-ylacetate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl thiophene-3-carboxylate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 5-phenylthien-2-ylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 1-adamantylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl 2-naphthylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl 2-tert-butyl-6-methylphenylcarbamate;

8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl 2,5-dimethoxyphenylcarbamate;

and a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A composition of claim 6 , wherein the compound is selected from the group consisting of: