Sensitizing agents for use in boron neutron capture therapy

• US 5,405,598 A
• Filed: 02/24/1992
• Issued: 04/11/1995
• Est. Priority Date: 02/24/1992
• Status: Expired due to Fees

• Current Assignee: Dennis C. Liotta, Raymond F. Schinazi
• Original Assignee: Dennis C. Liotta, Raymond F. Schinazi
• Inventors: Liotta, Dennis C., Schinazi, Raymond F.
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US07/840,093
• Time in Patent Office: 1,142 Days
• Field of Search: 544/229, 514/64, 424/1.1, 424/9, 424/1.77, 424/1.81
• US Class Current: 424/1.81
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 41/0095 Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 5/027 Organoboranes and organoborohydrides
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 9/12 with hydroxyaryl compounds
• CPC Class Codes: C07F 9/6596 having atoms other than oxygen, sulfur, selenium, tellurium, nitrogen or phosphorus as ring hetero atoms

Abstract

Compounds of formula I and II ##STR1## in which B contains a carboranyl group and one of R₃ and R₄ is a carboranyl group or a boronic acid or ester are useful sensitizing agents for boron neutron capture therapy.

Claims

1. A compound having the formula I:

##STR15## wherein;

Z is OH, --OP(═

O) (OH)₂, --OP(═

O) (OH)OP(═

O) (OH)₂, --OP(═

O) (OH) OP(═

O) (OH) OP(═

O) (OH)₂, OR₅ (wherein R₅ is a hydroxy protecting group selected from the group consisting of tri-C_1-4 -alkylsilyl, di-C_1-4 -alkyl-phenylsilyl, C_1-4 -alkyl-diphenylsilyl, and trityl) , --P (═

O) (OH)₂, --P(═

O) (OR₆)₂ (wherein R₆ is C_1-4 -alkyl), --OR₆ (wherein R₆ is C_1-4 -alkyl), R₆ NH-- (wherein R₆ is C_1-4 -alkyl , R₆ R₆ N--, (wherein R₆ is C_1-4 -alkyl), R₆ C (═

C) O-- (wherein R₆ is C_1-4 -alkyl), --SH, or --SR₆ (wherein R₆ is C_1-4 -alkyl);

X is O, S, NR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

Y is O, S, NR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

R₁ and R₂ are each, independently, H, C_1-4 -alkyl, --CF₃, or --F;

A is a purine or pyrimidine base selected from the group consisting of;

##STR16## wherein D is a carboranyl group having the formula --B₁₀ H₁₀ C₂ R₈, wherein R₈ is --H, --OH, --CH₂ OH, --CH₂ X (wherein X is F, Cl, Br, I);

R₇ is C_1-4 -alkyl or H; and

W is N or CH;

or pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein X is --O--, Y is --S--, and R₁ and R₂ are both --H.

3. The compound of claim 2, wherein Z is selected from the group consisting of --OH, --OR₅, and R₆ C(═

O)O-- (wherein R₆ is C_1-4 -alkyl.

4. The compound of claim 2, wherein A is selected from the group consisting of ##STR17##

5. The compound of claim 1, which is substantially pure (+)-enantiomer.

6. The compound of claim 1, which is substantially pure (-)-enantiomer.

7. The compound of claim 1, which is a salt comprising a counter ion selected from the group consisting of sodium ion, potassium ion, magnesium ion, ammonium ion, and tetra-C_1-4 -alkylammonium ion.

8. A method of boron neutron capture therapy, comprising administering to a patient in need thereof an effective amount of a sensitizing agent which has the formula I:

##STR18## wherein;

Z is OH, --OP(═

O) (OH)₂, --OP(═

O) (OH) OP(═

O) (OH)₂, --OP(═

O) (OH) OP(═

O) (OH) OP(═

O) (OH)₂, OR₅ (wherein R₅ is a hydroxy protecting group selected from the group consisting of tri-C_1-4 -alkylsilyl, di-C_1-4 -alkyl-phenylsilyl, C_1-4 -alkyl-diphenylsilyl, and trityl), --P(═

O) (OH)₂, --P(═

O) (OR₆)₂ (wherein R₆ is C_1-4 -alkyl), --OR₆ (wherein R₆ is C_1-4 -alkyl) , R₆ NH-- (wherein R₆ is C_1-4 -alkyl), R₆ R₆ N-- (wherein R₆ is C_1-4 -alkyl), R₆ C(═

O)O-- (wherein R₆ is C_1-4 -alkyl), --SH, or --SR₆ (wherein R₆ is C_1-4 -alkyl);

X is O, S, NR'"'"' (wherein R'"'"' is H or CC_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

Y is O, S, NR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

R₁ and R₂ are each, independently, H, C_1-4 -alkyl, --CF₃, or --F;

A is a purine or pyrimidine base selected from the group consisting of;

##STR19## wherein D is a carboranyl group having the formula --B₁₀ H₁₀ C₂ R₈, wherein R₈ is --H, --OH, --CH₂ OH, --CH₂ X (wherein X is F, Cl, Br, I);

R₇ is C_1-4 -alkyl or H; and

W is N or CH;

or

pharmaceutically acceptable salts thereof, wherein said patient is suffering from a brain glioma or a brain melanoma.

9. The method of claim 8, wherein X is --O--, Y is --S--, and R₁ and R₂ are both --H.

10. The method of claim 9, wherein Z is selected from the group consisting of --OH, --OR₅, and R₆ C(═

O)O-- (wherein R₆ is C_1-4 -alkyl.

11. The method of claim 9, wherein A is selected from the group consisting of ##STR20##

12. The method of claim 8, wherein said agent of formula I is a salt comprising a counter ion selected from the group consisting of sodium ion, potassium ion, magnesium ion, ammonium ion, and tetra-C_1-4 -alkylammonium ion.

13. The method of claim 8, wherein said patient is suffering from a brain glioma.

14. The method of claim 8, wherein said patient is suffering from a brain melanoma.

15. A pharmaceutical composition, comprising a compound having formula I:

##STR21## wherein;

Z is OH, --OP(═

O) (OH)₂, --OP(═

O) (OH) OP(═

O) (OH)₂, --OP(═

O) (OH) OP(═

O) (OH) OP(═

O) (OH)₂, OR₅ (wherein R₅ is a hydroxy protecting group selected from the group consisting of tri-C_1-4 -alkylsilyl, di-C_1-4 -alkyl-phenylsilyl, C_1-4 -alkyl-diphenylsilyl, and trityl), --P(═

O) (OH)₂, --P(═

O) (OR₆)₂ (wherein R₆ is C_1-4 -alkyl), --OR₆ (wherein R₆ is C_1-4 -alkyl) , R₆ NH-- (wherein R₆ is C_1-4 -alkyl), R₆ R₆ N-- (wherein R₆ is C_1-4 -alkyl), R₆ C(═

O)O-- (wherein R₆ is C_1-4 -alkyl), --SH, or --SR₆ (wherein R₆ is C_1-4 -alkyl);

X is O, S, NR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

Y is O, S, NR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl) or CHR'"'"' (wherein R'"'"' is H or C_1-4 -alkyl);

R₁ and R₂ are each, independently, H, C_1-4 -alkyl, --CF₃, or --F;

A is a purine or pyrimidine base selected from the group consisting of;

##STR22## wherein D is a carboranyl group having the formula --B₁₀ H₁₀ C₂ R₈, wherein R₈ is --H, --OH, --CH₂ OH, --CH₂ X (wherein X is F, Cl, Br, I);

R₇ is C_1-4 -alkyl or H; and

W is N or CH;

or acceptable salts thereof; and

a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein A is selected from the group consisting of ##STR23##

17. The pharmaceutical composition of claim 15, wherein said compound of formula I is a salt comprising a counter ion selected from the group consisting of sodium ion, potassium ion, magnesium ion, ammonium ion, and tetra-C_1-4 -alkylammonium ion.

18. The pharmaceutical composition of claim 15, wherein X is --O--, Y is --S--, and R₁ and R₂ are both --H.

19. The pharmaceutical composition of claim 15, wherein Z is selected from the group consisting of --OH, --OR₅, and R₆ C(═

O)O-- (R₆ is C_1-4 -alkyl) .