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1. (WO1993018765) DERIVES D'INDOLE PRESENTANT UNE ACTION ANTIVIRALE
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS
1. Use of a compound of formula (I)

wherein
the dotted line represents an optional bond;

R1 represents:

-H;

-COR10, -COOR10 where R10 is C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, C1-6alkenyl, or H;

-O R10 wherein R10 is as hereinbefore defined;

-C1-8alkyl, C1-8alkenyl or C3-8cycloalkyl where the alkyl, alkenyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from halogen, cyano, nitro, azido, -OR10, -SR10, -SOR10, -SO2R10, -NR11R12 (where R11 and R12, which may be the same or different, each represent H, -COR10 where R10 is as hereinbefore defined, C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, tetrahydronaphthyl or indanyl or -R11R12 together with the N atom to which they are attached form a 3-, 4-, 5- or 6- membered heterocyclic ring in which from 1 to 3 of the carbon atoms may be replaced by heteroatoms independently selected from O, N and S , which ring being

where possible, partially or completely unsaturated),
(where T Is NH or S, Z is NH, S or O and W is NR11R12 where R11 and R12 are each as defined above), non-aromatic heterocycle,

-NH-non-aromatic-heterocycle and aryl, such heterocycle or aryl groups being optionally substituted by one or more substituents selected from -OR10, -NR13R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6cyaloalkyl hydroxyC1-6alkyl, CONH2, halogen and methylenedioxy, where R10R11 and R12 are each as defined above;

-NR11R12 where R11 and R12 are each as defined above;

-aryl optionally substituted by one or more substituent(s) selected from -OR10, -NR11R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6cycloalkyl, hydroxyC1-6alkyl, CONH2, halogen and methylenedioxy, where R10, R11 and R12 are each a defined above;

- a cyclic group containing from 3 to 6 carbon atoms in which from 1 to 3 of said atoms may be replaced by heteratom(s) independently selected from O, S and N;

-NH-cyclic group containing from 3 to 6 carbon atoms in which from 1 to 3 of said atoms may be replaced by heteratom(s) independently selected from O, S and N.

R2 and R3, which may be the same or different, are each independently selected from:- H ;

-COR10, -COOR10 where R10 is a Chalky!, C3-7cycloalkyl, aryl, arylalkyl, C1-6alkenyl, or H;

-OR10 wherein R10 is as hereinbefore defined;

-C1-8alkyl, C1-8alkenyl or C3-8cycloalkyl where the alkyl, alkenyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from halogen, cyano, nitro, azido, C3-8cycloalkyl -OR10, -CO2R10, -OCOR10, -SR10, -SOR10, SO2R10, -CO2NR11R12, -NR11R12 (where R11 and R12, which may be the same or different, each represent H, -COR10 where R10 is as hereinbefore defined, C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, tetrahydronaphthyl or indanyl or -R11R12 together with the N atom to which they are attached form a 3-, 4-, 5- or 6- membered heterocyclic ring in which from 1 to 3 of the carbon atoms may be replaced by heteroatoms independently selected from O, N and S which ring being

where possible, partially or completely unsaturated);

(where T is NH or S, Z is NH, S or O and W is NR11R12 where R11 and R12 are each as defined above), non-aromatic heterocycle,

-NH-non-aromatic-heterocycle and aryl, such heterocycle or aryl groups being optionally substituted by one or more substituents selected from -OR10, -NR11R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6 cycloalkyl, hydroxylC1-6alkyl, CONH2, halogen and methylene dioxy, where R10R11 and R12 are each as defined above);

-NR 11R12 where R11 and R12 are each as defined above;

-aryl optionalllyy substituted by one or more substituent(s) selected from -OR10, -NR1^12, SR10, -SOR10, -S02R10, C02R10, nitro, cyano, SCN, C1-6alkyl, C3-6cycloalkyl, haloalkyl, hydroxyC alkyl, CONH halogen and methylenedioxy, where. R10, R11 and R12 are each as defined above;

R4 and R5, which may be the same or different, are each independently selected from:

H;

-C1-6alkyl or C3-7cycloalkyl (where the alkyl moiety may be optionally substituted by one or more substituent(s) selected from -OR10 -NR11R12, where R10, R11 or R12 are as defined above, halogen and aryl);

-aryl optionally substituted by one or more substituent(s) selected from OH, -OR10, -NR11R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6alkyl, hydroxyC1-6alkyl, CONH2, halogen and methylenedioxy, where R10R11 and R12 are each as defined above;

R6 and R7, which may be the same or different, each represent one or more ring substituent(s) selected from:

H;

-C1-6alkyl optionally substituted by one or more substituents independently selected from halogen, -NR11R12, cyano, -OR10, azido, -SR10, -SOR10, -SO2R10, wherein R10, R11 and R12 are as hereinbefore defined;

-cyano, nitro, halogen, methylenedioxy, -OR10, -SR10, -SOR10

-NHSO2R10, -SO2R10, -SO2NR1:LR12, -CO2R10, -OCOR10, -CONR13-R12 and -NR11R12 where R10, R11 and R12 are as defined above;

R13 and R14 together form a carbonyl group (>-0) or R13 is X and R14 is Y and X and Y are both H, or one of X and Y is H and the other is -OR or -SR10, wherein R10 is as hereinbefore defined;

or a salt, ester or physiologically functional derivative thereof or a solvate of any thereof, for the manufacture of a medicament for the treatment or prophylaxis of at least one viral infection.

2. Use according to claim 1 wherein the viral infection is selected from herpes virus, retrovirus, hepatatis virus, coxsackie virus and hepatitis C virus infections.

3. Use according to claim 2 wherein the herpes virus infection is selected from HSV1, HSV2 , VZV, CMV, EBV and HHV6.

4. Use according to claim 3 wherein the herpes virus infection is CMV.

5. Use according to any one of claims 1 to 4 wherein the compound of formula (I) is selected from:-

3,4-Bis(7-methyl-1H-indol-3-yl)2,5-dihydro-1H-pyrrolo-2,5-dione;

3,4-Bis(4-fluoro-1H-indol-3-yl)2,5-dihydro-1H-pyrrolo-2,5-dione;

3 ,4-Bis (5-methoxy-1H-indol-3-yl)2,5-dihydro-1-(3-trifluoromethyl phenylmethyl)-1H-pyrrolo-2,5-dione;

3,4-Bis(1H-indol-3-yl)-2,5-dihydro-1-(benzyloxymethyl)-1H- pyrrolo-2,5-dione;

3,4-Bis(6-fluoro-1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo- 2,5-dione;

3,4-Bis(1H-indol-3-yl)-2,5-dihydro-1-(4-dimethylamino phenylmethyl)-1H-pyrrolo-2,5-dione;

3,4-Bis(1H-lndol-3-yl)-2,5-dlhydro-1-(2-pyridylmethyl)-1H-pyrrolo-2,5- dione;

Cis-3,4-Bis(2-methyl-1H-indol-3-yl)-1-(phenylmethyl)-succinimide;

3-(1-Cyclohexylmethyl-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Acetoxypropyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Methoxypropyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Phenoxy phenylmethyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)- 2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

or a salt, ester or a physiologically functional derivative thereof or a solvate of any thereof.

6. A compound of formula (IA)


wherein
the dotted line does not represent a bond R1 represents:

-H;

-COR10, -COOR10 where R10 is C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, C1-6alkenyl, or H;

-OR10 wherein R10 is as hereinbefore defined;

-C1-8alkyl, C1-8alkenyl or C3-8cycloalkyl where the alkyl, alkenyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from halogen, cyano, nitro, azido,

-OR10, -SR10, -SOR10, -SO2R10, -NR11R12 (where R11 and R12, which may be the same or different, each represent H, -COR10 where R10 is as hereinbefore defined, C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, tetrahydronaphthyl or indanyl or -R11R12 together with the N atom to which they are attached form a 3-,4-, 5- or 6-membered heterocyclic ring in which from 1 to 3 of the carbon atoms may be replaced by heteroatoms independently selected from

O, N and S, which ring being where possible, partially or

completely unsaturated),
(where T is NH or S, Z is NH, S or O and W is NR11R12 where R11 and R12 are each as defined above), non-aromatic heterocycle, -NH-non-aromatic-heterocycle and aryl, such heterocycle or aryl groups being optionally substituted by one or more substituents selected from -OR10,

-NR11R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6cycloalkyl, hydroxyC1-6alkyl, CONH2, halogen and methylenedioxy, where R10R11 and R12 are each as defined above;

-NR11R12 where R11 and R12 are each as defined above;

-aryl optionally substituted by one or more substituent(s) selected from -R10, -NN11R12 -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6cycloalkyl, hydroxyC1-6alkyl, CON2, halogen and methylenedioxy, where R10, R11 and R12 are each as defined above;

- a cyclic group containing from 3 to 6 carbon atoms in which from 1 to 3 of said atoms may be replaced by heteratom(s) independently selected from O, S and N:

-NH-cyclic group containing from 3 to 6 carbon atoms In which from 1 to 3 of said atoms may be replaced by heteratom(s) independently selected from O, S and N;

R2 and R3, which may be the same or different, are each

Independently selected from:-

H;

-COR10, -COOR10 where R10 is a C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, C1-6alkenyl, or H;

-OR10 wherein R10 is as hereinbefore defined;

-C1-8alkyl, C1-8alkenyl or C3-8cycloalkyl where the alkyl, alkenyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from halogen, cyano, nitro, azido, C3-8cycloalkyl -OR10, -CO2R10, -OCOR10, -SR10, -SOR10, SOR10, -CO2NR11R12, -NR11R12 (where R11 and R12, which may be the same or different, each represent H, -COR10 where R10 is as hereinbefore defined, C1-6alkyl, C3-7cycloalkyl, aryl, arylalkyl, tetrahydronaphthyl or indanyl or -R11R12 together with the N atom to which they are attached form a 3- , 4- , 5- or 6- membered heterocyclic ring in which from 1 to 3 of the carbon atoms may be replaced by heteroatoms independently selected from O, N and S which ring being

where possible, partially or completely unsaturated);

(where T is NH or S, Z is NH, S or O and W is NR11R12 where R11 and R12 are each as defined above), non-aromatic, heterocycle,

-NH-non-aromatic-heterocycle and aryl, such heterocycle or aryl groups being optionally substituted by one or more substituents selected from -OR10, -NR11R12, -SR10, -SOR10, -SO2R10, -CO2R10, nitro, cyano, SCN, C1-6alkyl (wherein one or more hydrogen atoms are optionally replaced by a halogen atom), C3-6 cycloalkyl, hydroxylC1-6alkyl, CONH2, halogen and methylenedioxy, where R10R11 and R12 are each as defined above);

-NR11R12 where R11 and R12 are each as defined above ;

-aryl optionally substituted by one or more substituent(s) selected from -OR10, -NR11R12, SR10, -SOR10, -SOR10, COR10, nitro, cyano, SCN, C1-6alkyl, C3-6cycloalkyl, haloalkyl, hydroxyC1-6alkyl, CONH2, halogen and methylenedioxy, where R10, R11 and R12 are each as defined above;

R4 and R5, which may be the same or different, are each independently selected from:

H;

-C1-6alkyl or C3-7cycloalkyl (where the alkyl moiety may be optionally substituted by one or more substituent(s) selected from -OR10 -NR13-R12, where R10, R11 or R12 are as defined above, halogen and aryl);

-aryl optionally substituted by one or more substituent(s) selected from OH, -OR -NR11R12 -SR10, -SOR10 -SO2R10

-CO2R10 nitro, cyano SCN, C1-6alkyl wherein one or more hydrogen atoms are optionally replaced by a halogen atom, C3-6alkyl, hydroxyC1-6alkyl, CONH halogen and methylenedioxy, where R10R11 and R12 are each as defined above;

R6 and R7, which may be the same or different, each represent one or more ring substituent(s) selected from:

H;

-C1-6alkyl optionally substituted by one or more substituents

Independently selected from halogen, -NR11R12, cyano, -OR10, azido, -SR10, -SOR10, -SO2R10, wherein R10 , R11 and R12 are as hereinbefore defined.

-cyano, nitro, halogen, methylenedioxy, -OR10, -SR10, -SOR10, -SO2R10, -SO NR11R12, -CO2R10, -OCOR10, -CONR11R12 and -NR11R12 where R10, R11 and R12 are as defined above;

R13 and R14 together form a carbonyl group (>=0) or R13 is X and R14 is Y and X and Y are both H, or one of X and Y is H and the other Is -OR10 or -SR10, wherein R10 is as hereinbefore defined;

or a salt, ester or physiologically functional derivative thereof or a solvate of any thereof; excluding the compounds Cis-3,4-bis-(1H-indo1-3-yl)-2,5-pyrrolidinedione and trans-3,4-bis-(1H-indol-3-yl)-2,5-pyrrolidinedione.

7. A compound of formula (IA) as shown in claim 6 wherein the dotted line represents an optional bond and R13 is X and R14 is Y and one of X and Y is H and the other is -OR10 (excluding OH) or

-SR10 wherein R10.

8. A compound of formula (IA) as shown in claim 6 wherein the dotted line represents a bond, R1 is H or C1-8alkyl optionally substituted by one or more substituents selected from -OR10, -OCOR10, wherein R10 and aryl optional substituted by one or more substituents selected from C1-6alkyl wherein one or more hydrogen atoms are replaced by a halogen atom and -NR11R12 wherein R11 and R12 are as hereinbefore defined; R2 and R3, which may be the same, or different, are each independently selected from H and C1-8alkyl substituted by one or more substituents selected from

-OR wherein R10 is as hereinbefore defined, C3-8cycloalkyl and aryl optionally substituted by one or more substituents selected from C1-6alkyl wherein one or more hydrogen atoms are replaced by a halogen atom and -OR10 wherein R10 is as hereinbefore defined; R4 and R5 which may be the same or different, are each independently selected from H and C1-6alkyl; R6 and R7, which may be the same or different, each represent one or more ring substituent(s) selected from H, C1-6alkyl, -OR10 wherein R10 is as hereinbefore defined and halogen and R13 and R14 together form a carbonyl group; or a salt, ester or physiologically acceptable derivative thereof or a solvate of any thereof; excluding

3,4-bis-1H-indol-3-yl-1-(phenylmethyl)-1H-pyrrole-1,5-dione .

A compound according to claim 8 selected from:-

3,4-Bis(7-methyl-1H-indol-3-yl)2,5-dihydro-1H-pyrrolo-2,5-dione;

3,4-Bis(4-fluoro-1H-indol-3-yl)2,5-dihydro-1H-pyrrolo-2,5-dione;

3,4-Bis(5-methoxy-1H-indol-3-yl)2,5-dihydro-1-(3-trifluoromethyl phenylmethyl)-1H-pyrrolo-2,5-dione;

3,4-Bis(1H-indol-3-yl)-2,5-dihydro-1-(benzyloxymethyl)-1H- pyrrolo-2,5-dione;

3,4-Bis(6-fluoro-1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo- 2,5-dione;

3,4-Bls(1H-indol-3-yl)-2,5-dihydro-1-(4-dimethylamlno phenylmethyl)-1H-pyrrolo-2,5-dIone;

3,4-Bis(1H-indol-3-yl)-2,5-dihydro-1-(2-pyridylmethyl)-1H-pyrrolo-2,5- dione;

Cis-3,4-Bis(2-methyl-1H-indol-3-yl)-1-(phenylmethyl)-succinimlde;

3-(1-Cyclohexylmethyl-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Acetoxypropyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Methoxypropyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-2,5-dihydro-1-methyl-1H-pyrrolo-2,5-dione;

3-(1-(3-Phenoxy phenylmethyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)- 2,5-dlhydro-1-methyl-1H-pyrrolo-2,5-dione;

or a salt, ester or a physiologically functional derivative thereof or a solvate of any thereof.

10. A pharmaceutical formulation comprising a compound according to any one of claims 6 to 9, together with a pharmaceutically acceptable carrier therefore.

11. A formulation according to claim 10 in unit dosage form.

12. A formulation according to claim 11 in the form of a tablet or capsule.

13. A compound according to any one of claims 6 to 9 or a formulation according to any one of claims 10 to 12 for use in therapy.

14. A compound as defined in claim 1 which compound is 3,4-bis(1H- indol-3-yl)-1-(phenylmethyl)-2,5-pyrrolidinedione for use in therapy.

15. A compound as defined in claim 1 which compound is cis-3,4-bis- (1H-indol-3-yl)-2,5-pyrrolidinedione for use in therapy.

16. A method of treatment or prevention of the symptoms or effects of a viral infection in an infected host which comprises administering to said host a therapeutically effective non-toxic amount of a compound of formula (I) as claimed in claim 1.

17. A process for the preparation of a compound of formula (IA) as defined in any one of claims 6 to 9 which comprises:-

(A) for the preparation of a compound wherein the dotted line does not represent a bond and R13 and R14 together form a carbonyl group, by reducing a compound of formula (XVI)



(B) for the preparation of a compound wherein the dotted line does not represent a double bond and R13 and R14 together form a carbonyl group by reacting a compound of formula

(XVII) with a compound of formula (XVIII)



(C) for the preparation of a compound wherein R13 and R14 together form a carbonyl group, by reacting a compound of formula (XI)


with an amine of formula R1NH2 or R1NH3X wherein X1 represents an acid anion.

(D) for the preparation of a compound wherein the dotted line represents a double bond and R13 and R14 together form a carbonyl group, by reacting a compound of formula (XVII) as defined above with a compound of formula (XIX) or (XX)

or



(E) for the preparation of a compound wherein X is H and Y is OH, by reducing a compound of formula (IA) wherein R13 and R14 together form a carbonyl group, optionally converting the compound of formula (IA) so formed to a compound of formula (IA) wherein X and Y are both H;

(F) for the preparation of a compound wherein X is H and Y is

-OR10 or -SR10, by treating a compound of formula (IA) wherein X is H and Y is OH, -OR10' or SR10' with a compound

R10OH or R10SH;

and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions:-

(i) when the compound of formula (IA) is formed, converting it into another compound of formula (IA) having different values of R2, R3, R4, R5, R6 and R7 by treatment with an appropriate reagent and/or under suitable conditions;

(ii) removing any remaining protecting groups;

(iii) when the compound of formula (IA) is formed, converting in into a pharmaceutically acceptable derivative thereof;

(iv) when a pharmaceutically acceptable derivative of a compound of formula (IA) is formed, converting the said derivative into a compound of formula (IA), or a different derivative thereof.