US5405598A
Expired / Lapsed
US
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Sensitizing agents for use in boron neutron capture therapy
Assignee: Individual
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Filing: 1992-02-24
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Granted: 1995-04-11
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Expires: 2012-02-24
Abstract
Abstract Compounds of formula I and II <IMAGE> (I) <IMAGE> (II) 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.
Inventors
- 👤 Raymond F. Schinazi
- 👤 Dennis C. Liotta
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 22:14
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/70; A61K31/33; A61K31/395; A61K31/495; A61K31/505; A61K31/519; A61K31/52; A61K41/00; A61K41/0038; A61K41/009; A61K41/0095; C; C07; C07D; C07D411/00; C07D411/02; C07D411/04; C07F; C07F5/00; C07F5/02; C07F5/027; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804; C07F9/00; C07F9/02; C07F9/06; C07F9/08; C07F9/09; C07F9/12; C07F9/547; C07F9/6596
Claims Analysis
Total Claims: 22
Claim 1
Independent Claim
261 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl), R 6 NH-- (wherein R 6 is C 1-4 -alkyl , R 6 R 6 N--, (wherein R 6 is C 1-4 -alkyl), R 6 C (═C) O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 is C 1-4 -alkyl or H; and W is N or CH; or pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
261 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl), R 6 NH-- (wherein R 6 is C 1-4 -alkyl , R 6 R 6 N--, (wherein R 6 is C 1-4 -alkyl), R 6 C (═C) O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 is C 1-4 -alkyl or H; and W is N or CH; or pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
21 words
The compound of claim 1, wherein X is --O--, Y is --S--, and R 1 and R 2 are both --H.
Claim 4
Dependent Claim
29 words
The compound of claim 2, wherein Z is selected from the group consisting of --OH, --OR 5 , and R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl.
Claim 5
Dependent Claim
15 words
The compound of claim 2, wherein A is selected from the group consisting of ##STR17##
Claim 6
Dependent Claim
10 words
The compound of claim 1, which is substantially pure (+)-enantiomer.
Claim 7
Dependent Claim
10 words
The compound of claim 1, which is substantially pure (-)-enantiomer.
Claim 8
Dependent Claim
32 words
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.
Claim 9
Independent Claim
292 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl) , R 6 NH-- (wherein R 6 is C 1-4 -alkyl), R 6 R 6 N-- (wherein R 6 is C 1-4 -alkyl), R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 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.
Claim 10
Independent Claim
292 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl) , R 6 NH-- (wherein R 6 is C 1-4 -alkyl), R 6 R 6 N-- (wherein R 6 is C 1-4 -alkyl), R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 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.
Claim 11
Dependent Claim
21 words
The method of claim 8, wherein X is --O--, Y is --S--, and R 1 and R 2 are both --H.
Claim 12
Dependent Claim
29 words
The method of claim 9, wherein Z is selected from the group consisting of --OH, --OR 5 , and R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl.
Claim 13
Dependent Claim
15 words
The method of claim 9, wherein A is selected from the group consisting of ##STR20##
Claim 14
Dependent Claim
37 words
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.
Claim 15
Dependent Claim
14 words
The method of claim 8, wherein said patient is suffering from a brain glioma.
Claim 16
Dependent Claim
14 words
The method of claim 8, wherein said patient is suffering from a brain melanoma.
Claim 17
Dependent Claim
265 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl) , R 6 NH-- (wherein R 6 is C 1-4 -alkyl), R 6 R 6 N-- (wherein R 6 is C 1-4 -alkyl), R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 is C 1-4 -alkyl or H; and W is N or CH; or acceptable salts thereof; and a pharmaceutically acceptable carrier.
Claim 18
Dependent Claim
265 words
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 , OR 5 (wherein R 5 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) (OR 6 ) 2 (wherein R 6 is C 1-4 -alkyl), --OR 6 (wherein R 6 is C 1-4 -alkyl) , R 6 NH-- (wherein R 6 is C 1-4 -alkyl), R 6 R 6 N-- (wherein R 6 is C 1-4 -alkyl), R 6 C(═O)O-- (wherein R 6 is C 1-4 -alkyl), --SH, or --SR 6 (wherein R 6 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); R 1 and R 2 are each, independently, H, C 1-4 -alkyl, --CF 3 , 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 --B 10 H 10 C 2 R 8 , wherein R 8 is --H, --OH, --CH 2 OH, --CH 2 X (wherein X is F, Cl, Br, I); R 7 is C 1-4 -alkyl or H; and W is N or CH; or acceptable salts thereof; and a pharmaceutically acceptable carrier.
Claim 19
Dependent Claim
16 words
The pharmaceutical composition of claim 15, wherein A is selected from the group consisting of ##STR23##
Claim 20
Dependent Claim
38 words
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.
Claim 21
Dependent Claim
22 words
The pharmaceutical composition of claim 15, wherein X is --O--, Y is --S--, and R 1 and R 2 are both --H.
Claim 22
Dependent Claim
30 words
The pharmaceutical composition of claim 15, wherein Z is selected from the group consisting of --OH, --OR 5 , and R 6 C(═O)O-- (R 6 is C 1-4 -alkyl) .
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1998-04-10 | 1998-10-10 | 1999-04-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2002-04-10 | 2002-10-10 | 2003-04-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2006-04-10 | 2006-10-10 | 2007-04-11 | $7700.00 | Window Closed / Lapsed |