O.sup.6 -substituted guanine derivatives, a process for their preparation and their use in treating tumor cells

• US 6,043,228 A
• Filed: 12/07/1995
• Issued: 03/28/2000
• Est. Priority Date: 06/08/1993
• Status: Expired due to Fees

• Current Assignee: Cancer Research Campaign Technology Ltd (Cancer Research UK)
• Original Assignee: Cancer Research Campaign Technology Ltd (Cancer Research UK)
• Inventors: Margison, Geoffrey, Willington, Mark Andrew, McMurry, Thomas Brian, Watson, Amanda Jean, Rafferty, Joseph Anthony, Donnelly, Dorothy Josephine, Elder, Rhoderick Hugh, McCormick, Joan Elizabeth, McBlhinney, Robert Stanley, Kelly, Jane
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/568,576
• Time in Patent Office: 1,573 Days
• Field of Search: 514/45, 514/262, 514/276, 514/261, 514/264, 514/277, 536/27.81, 544/264, 544/265, 544/268, 544/269, 544/270
• US Class Current: 514/45
• CPC Class Codes: A01N 43/54 1,3-Diazines; Hydrogenated 1,3-diazines
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07D 473/40 with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Abstract

O⁶ -hetarylalkyl- or naphthylalkylguanine derivatives of the formula ##STR1## wherein Y is H, ribosyl, deoxyribosyl, or R"XCHR'"'"',

wherein X is O or S, R" and R"'"'"' are alkyl, or substituted derivatives thereof,

R'"'"' is H, or alkyl or hydroxyalkyl

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocylic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hereto atom chosen from O, N, or S, or a substituted derivative thereof; or

(ii) naphthyl or a substituted derivative thereof

and pharmaceutically acceptable salts thereof, exhibit the ability to deplete O⁶ -alkylguanine-DNA alkyltransferase (ATase) activity.

A process for preparation of the compounds is described. The compounds have utility in combination with alkylating agents in the chemotherapeutic treatment of tumour cells.

Claims

1. O⁶ -alkylguanine derivatives of formula I:

##STR37## wherein Y is H, ribosyl, deoxyribosyl, or ##STR38## wherein X is O or S, R" and R"'"'"' are alkyl or substituted alkyl, R'"'"' is H, or alkyl or hydroxyalkyl

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring or a substituted 5- or 6-membered heterocyclic ring, optionally with a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic ring fused thereto, the or each heterocyclic or substituted heterocyclic ring having at least one hetero atom chosen from O, N, or S, or

ii) naphthyl or a substituted naphthyl and pharmaceutically acceptable salts thereof, provided that R is not a cyclic group having a heterocyclic ring with more than one S atom in the ring.

2. A compound according to claim 1 wherein R is:

(a) a 5- or 6-membered heterocyclic ring,

(b) a benzo derivative thereof,

(c) a substituted 5- or 6-membered ring, or

(d) a substituted benzo derivative of a 5- or 6-membered heterocyclic ring the O⁶ -alkylguanine moiety being attached to R at either the heterocyclic, the substituted heterocyclic ring, the benzene ring, or the substituted benzene ring.

3. A compound according to claim 1 wherein R is a 5 membered heterocyclic ring, having one S atom therein, or a substituted 5 membered heterocyclic ring, having one S atom therein.

4. A compound according to claim 1 wherein R is a member selected from the group consisting of a thiophene ring, a substituted thiophene ring, a furan ring and a substituted furan ring.

5. A compound according to claim 1 wherein R is a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, wherein the heterocyclic or carbocyclic ring is substituted by halo, haloalkyl, cyano, SO_n R"" where R"" is alkyl and n=0, 1 or 2, or --COOR⁵ wherein R⁵ is alkyl.

6. A compound according to claim 1 wherein R is a member selected from the group consisting of a thiophene ring, a bromo-substituted thiophene ring, a cyano-substituted thiophene ring, a furan ring, a bromo-substituted furan ring, and a cyano-substituted furan ring.

7. A compound according to claim 1 which is O⁶ -thenylguanine.

8. A compound according to claim 1 which is O⁶ -(5-bromothenyl)guanine.

9. A compound according to claim 1 which is a member selected from the group consisting of

O⁶ -(3-thienylmethyl)-guanine,

O⁶ -piperonylguanine,

O⁶ -furfurylguanine,

O⁶ -(3-furylmethyl)-guanine,

O⁶ -(2-benzo[b]thienylmethyl)-guanine,

O⁶ -(2-benzofuranylmethyl)-guanine,

O⁶ -(5-thiazolymethyl)-guanine,

O⁶ -(5-methoxycarbonylfurfuryl)-guanine,

O⁶ -(5-methoxycarbonylfurfuryl)-guanine,

O⁶ -(3-cyanofurfuryl)-guanine,

O⁶ -(2-benzo[b]thienylmethyl)-guanosine,

O⁶ -(4-picolyl)-guanine, and

O⁶ -(2-naphthylmethyl)-guanine.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition according to claim 10 further comprising an alkylating agent.

12. A composition according to claim 11 wherein the alkylating agent is a member selected from the group consisting of 1,3 bis (2-chloroethyl)-1-nitrosourea (BNCU) and temozolomide.

13. A method for depleting O⁶ -alkylguanine-DNA alkyltransferase activity in a host comprising:

administering to the host an effective O⁶ -alkylguanine-DNA alkyltransferase activity depleting amount of a composition according to claim 10.

14. A method according to claim 13 comprising:

administering to the host an effective O⁶ -alkylguanine-DNA alkyltransferase activity depleting amount of a composition comprising O⁶ -thenylguanine and a pharmaceutically acceptable excipient.

15. A method for treating tumour cells in a host comprising:

administering to the host a composition comprising an inactivator compound according to claim 1 in an amount effective to deplete O⁶ -alkylguanine-DNA alkyltransferase activity sufficiently to enhance the effectiveness of a chemotherapeutic alkylating agent; and

administering to the host a composition comprising an alkylating agent in an amount which is effective in combination with the said inactivator compound for treating said tumour cells.

16. A method according to claim 15 wherein the said inactivator compound is O⁶ -thenylguanine.

17. A process for preparing a compound of the formula I ##STR39## wherein Y, R'"'"' and R are as defined in claim 1 which comprises reacting sodium hydride with a solution of RR'"'"'CHOH in an organic solvent, adding 2-amino-N,N,N-trimethyl-1H-purin-6-aminium chloride or 2 amino-6-chloropurine riboside, treatment with weak acid and ether, and extracting the desired product.

18. A compound according to claim 1 wherein R'"'"' is H and R is selected from thiophene and furan rings with a chloro-, bromo- or cyano-substituent in a 1,3- or 1,4-relationship with the methylene group attached to the guanine residue.

20. A compound according to claim 2 which is a member selected from the group consisting of

O⁶ -(5-chlorothenyl)guanine,

O⁶ -(5-cyanothenyl)guanine,

O⁶ -(5-methylsulphinylthenyl)guanine,

O⁶ -(4-chlorothenyl)guanine,

O⁶ -(4-methoxythenyl)guanine,

O⁶ -(5-bromo-3-thienylmethyl)guanine,

O⁶ -(4-cyanothenyl)guanine,

O⁶ -(4,5-dichlorothenyl)guanine,

O⁶ -(2-chloro-4-picolyl)guanine and

O⁶ -(5-bromofurfuryl)guanine.

27. A compound according to claim 1 wherein R'"'"' is H and R is a thiophene ring or a halo-substituted thiophene ring.

28. A compound according to claim 27 wherein R'"'"' is H and R is a bromo-substituted thiophene ring.

29. A method for treating tumour cells in a host comprising:

administering to the host a composition comprising an inactivator compound according to claim 27 in an amount effective to deplete O⁶ -alkylguanine-DNA alkyltransferase activity sufficiently to enhance the effectiveness of a chemotherapeutic alkylating agent; and

administering to the host a composition comprising an alkylating agent in an amount which is effective in combination with the said inactivator compound.

30. A method according to claim 29 wherein R'"'"' is H and R is a bromo-substituted thiophene ring.

31. A compound according to claim 1 wherein R'"'"' is H and R is a thiophene or furan ring with a substituent in a 1, 3 or 1, 4 relationship with the methylene group attached to the guanine residue, the substituent being a member which is selected from the group consisting of halo, cyano, azido, methoxy and SOR"", wherein R"" is alkyl.

19. O⁶ -(4-bromothenyl)guanine.

21. A pharmaceutical composition comprising O⁶ -(4-bromothenyl)guanine and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition according to claim 21 in a form which is suitable for oral administration.

23. A pharmaceutical composition according to claim 21 further comprising an alkylating agent.

24. A pharmaceutical composition according to claim 23 wherein the alkylating agent is a member selected from the group consisting of 1,3 bis (2-chloroethyl)-1-nitrosourea (BNCU) and temozolomide.

25. A method for depleting O⁶ -alkylguanine-DNA alkyltransferase activity in a host comprising:

administering to the host an effective O⁶ -alkylguanine-DNA alkyltransferase activity depleting amount of a composition comprising O⁶ -(4-bromothenyl)guanine and a pharmaceutically acceptable excipient.

26. A method for treating tumour cells in a host comprising:

administering to the host a composition comprising O⁶ -(4bromothenyl)guanine in an amount effective to deplete O⁶ -alkylguanine-DNA alkyltransferase activity sufficiently to enhance the effectiveness of a chemotherapeutic alkylating agent; and

administering to the host a composition comprising an alkylating agent in an amount which is effective in combination with said composition comprising O⁶ -(4bromothenyl)guanine for treating said tumour cells.

32. O⁶ -alkylguanine derivatives of the formula I:

##STR40## wherein Y is H, ribosyl, deoxyribosyl, or ##STR41## wherein X is O or S, R" and R"'"'"' are alkyl or substituted alkyl, R'"'"' is H, or alkyl or hydroxyalkyl;

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring or a substituted 5- or 6-membered heterocyclic ring, optionally with a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic ring fused thereto, the or each heterocyclic or substituted heterocyclic ring having at least one hetero atom chosen from O, N, or S, or

ii) naphthyl or a substituted naphthyl and pharmaceutically acceptable salts thereof, provided that R is not a cyclic group having a heterocyclic ring with more than one S atom in the ring; and

provided that when Y or R is substituted as aforesaid the compound has the ability to deplete O⁶ alkylguanine-DNA alkyltransferase activity.

33. O⁶ -alkylguanine derivatives of the formula I:

##STR42## wherein Y is H, ribosyl, deoxyribosyl, or ##STR43## wherein X is O or S, R" and R"'"'"' are alkyl or suibstituted alkyl, having substitution by one or more of hydroxy, alkoxy, amino, alkylamino, amido or ureido;

R'"'"' is H or alkyl or hydroxyalkyl;

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring or a substituted 5- or 6-membered heterocyclic ring, optionally with a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic ring fused thereto, the or each heterocyclic or substituted heterocyclic ring having at least one hetero atom chosen from O, N, or S, having substitution in the substituted heterocyclic ring(s) or substituted carbocyclic ring(s) by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, azido, methoxy, SO_n R"" where R"" is alkyl and n=0, 1 or 2, or a carboxyl or ester group of the formula --COOR⁵ wherein R⁵ is H or alkyl;

or

(ii) naphthyl or a naphthyl having substitution by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, azido, methoxy, SO_n R"" where R"" is alkyl and n=0, 1 or 2, or a carboxyl or ester group of tho formula --COOR⁵ wherein R⁵ is H or alkyl;

and pharmaceutically acceptable salts thereof,

provided that R is not a cyclic group having a heterocyclic ring with more than one S atom in the ring.

34. A compound according to claim 33 wherein

Y is H, ribosyl, deoxyribosyl, or ##STR44## wherein X is O or S, R" and R"'"'"' are alkyl or substituted alkyl, having substitution by one or more of hydroxy, amino, alkylamino, amido or ureido;

R'"'"' is H or alkyl or hydroxyalkyl;

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring or a substituted 5- or 6-membered heterocyclic ring, optionally with a carbocyclic, substituted carbocyclic heterocyclic or substituted heterocyclic ring fused thereto, the or each heterocyclic or substituted heterocyclic ring having at least one hetero atom chosen from O, N, or S, having substitution in the substituted heterocyclic ring(s) or substituted carbocyclic ring(s) by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, SO_n R"" where R"" is alkyl and n=0, 1 or 2;

or

(ii) naphthyl or a naphthyl having substitution by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, SO_n R"" where R"" is alkyl and n=0, 1 or 2;

and pharmaceutically acceptable salts thereof;

provided that R is not a cyclic group having a heterocyclic ring with more than one S atom in the ring.

35. A compound according to claim 33 wherein Y and R'"'"' are as defined in claim 33 and

R is

(i) a cyclic group having at least one 5- or 6-membered heterocyclic ring or a substituted 5- or 6-membered heterocyclic ring, optionally with a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic ring fused thereto, the or each heterocyclic or substituted heterocyclic ring having at least one hetero atom chosen from O, N, or S, having substitution in the substituted heterocyclic ring(s) or substituted carbocyclic ring(s) by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, SO_n R"" where R"" is alkyl and n=0, 1 or 2, or a carboxyl or ester group of the formula --COOR⁵ wherein R⁵ is H or alkyl;

or

(ii) naphthyl or a naphthyl having substitution by one or more of alkyl, alkenyl, alkynyl, halo, haloalkyl, nitro, cyano, hydroxyalkyl, SO_n R"" where R"" is alkyl and n=0, 1 or 2, or a carboxyl or ester group of the formula --COOR⁵ wherein R⁵ is H or alkyl;

and pharmaceutically acceptable salts thereof;

provided that R is not a cyclic group having a heterocyclic ring with more than one S atom in the ring.