Preparation and use of alkylating agents

• US 20050123475A1
• Filed: 07/26/2004
• Published: 06/09/2005
• Est. Priority Date: 07/24/2003
• Status: Active Grant

• Current Assignee: Queen's Medical Center
• Original Assignee: Queen's Medical Center
• Inventors: Lim, John L.
• Granted Patent: US 7,776,309 B2
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 213/08 by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 215/40 with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 227/16 by reactions not involving the amino or carboxyl groups
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 269/06 by reactions not involving the formation of carbamate groups
• CPC Class Codes: C07C 271/34 with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 319/14 of sulfides
• CPC Class Codes: C07C 323/03 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 323/58 with amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 67/10 by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond preparation from carboxylic acid halides C07C67/14
• CPC Class Codes: C07C 69/68 Lactic acid esters
• CPC Class Codes: C07C 69/78 Benzoic acid esters
• CPC Class Codes: C07D 213/20 Quaternary compounds thereof
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

The present disclosure provides methods of synthesizing alkylating agents and methods of use.

Claims

1. A method of alkylating a target compound comprising:

a) synthesizing an alkylating agent having the formula;

X—

(CR¹R²)_aCR³R⁴-LG

wherein,

a is 0, 1, 2 or 3,

R¹, R², R³ and R⁴ are independently H, X or alkyl,

X is a halogen or a label, with the proviso that at least one X is a halogen,

LG is a leaving group; and

b) directly reacting said alkylating agent with a target compound comprising an alkylation reactive group under conditions suitable for the alkylation of said target compound.

2. The method according to claim 1, wherein said alkylating agent has the formula

X—

CH₂CH₂-LG

wherein,

X is [¹⁸F]; and

LG is a sulfonate ester.

3. The method according to claim 1, wherein said alkylating agent has the formula

X—

CH₂-LG,

wherein,

X is [¹⁸F]; and

LG is a sulfonate ester.

4. The method according to claim 1, wherein said alkylating agent has the formula

CH₃—

CH₂(X)—

CH₂-LG,

wherein,

X is [¹⁸F]; and

LG is a sulfonate ester.

5. The method according to claim 1, wherein said alkylating agent has the formula

X—

CH₂—

CH₂—

CH₂-LG,

wherein,

X is [¹⁸F]; and

LG is a sulfonate ester.

6. The method according to claim 1, wherein the precursor of said alkylating agent has the formula LG-(CR¹R²)_aCR³R⁴-LG.

7. The method according to claim 1, wherein said precursor has the formula LG-(CH₂)₂-LG.

8. The method according to claim 1, wherein, a is 0 and R³ and R⁴ are alkyl.

9. The method according to claim 2, 3, 4, 5, 6, 7 or 8, wherein LG is selected from the group consisting of tosylate, mesylate or triflate ester.

10. The method according to claim 1, wherein said alkylation reactive group comprises an alkyl, substituted alkyl, alcohol, carboxyl acid, saturated cycloalkyl, unsaturated cycloalkyl, aryl, substituted aryl, saturated heterocycle, unsaturated heterocycle, sulfhydryl, amine, N, O, S or C.

11. The method according to claim 1, wherein said target compound is selected from the group consisting of morphine, heroin, pethine, tamoxifen, codeine, nicotine, thioproperazine, diazepam, caffeine, flunitrazepam, hexamethonium, methiodide, quinuclidinyl benzilatem MQNB, neostigmine, MPP, NMS, tyrosine, spiperone, and spiroperidol.

12. The method according to claim 11, wherein said alkylated target compound is [¹⁸F]fluoromethyl-MQNB, [¹⁸F]N-fluoromethyl-MPP, [¹⁸F]FNMS, [¹⁸F]fluoroethylspiperone, [¹⁸F]fluoromethyl-neostigmine, [¹⁸F]fluoromethyl-tyrosine.

13. The method according to claim 1, wherein said target compound is selected from the group consisting of glucose, lactic acid, hexobarbital, thymidine, iodoantipyrine, antipyrine and coenzyme Q.

14. The method according to claim 1, wherein said target compound is dimethylethanolamine.

15. The method according to claim 14, wherein the alkylated target compound is [¹⁸F]N,N-methyl-N-fluoromethylethanolamine.

16. The method according to claim 14, wherein the alkylated target compound is [¹⁸F]N,N-methyl-N-fluoroethylethanolamine.

34. An ¹⁸F-labeled target compound made according to the method of claim 1 or 17.

17. A method of synthesizing an ¹⁸F-labeled target compound comprising, contacting an alkylating reagent having the formula

a) synthesizing an alkylating agent having the formula:

X—

(CR¹R²)_aCR³R⁴-LG

wherein,

a is 0, 1, 2 or 3,

R¹, R², R³ and R⁴ are independently H, X or alkyl,

X is a halogen or a label, with the proviso that at least one X is a halogen,

LG is a leaving group; and

with a target compound comprising an alkylation reactive group under conditions suitable for the alkylation of said target compound, wherein the alkylated target compound is other than [¹⁸F]FCH, [¹⁸F]FECh or [¹⁸F]fluorodeoxyglucose.

18. The method according to claim of claim 17, wherein LG is a sulfonate ester.

19. The method according to claim 18, wherein said sulfonate ester is selected from the group consisting of tosylate, mesylate and triflate ester.

20. The method according to claim 17, wherein said target compound is selected from the group consisting of morphine, heroin, pethine, tamoxifen, codeine, nicotine, thioproperazine, diazepam, caffeine, flunitrazepam, hexamethonium, methiodide, quinuclidinyl benzilatem MQNB, neostigmine, MPP, NMS, tyrosine, spiperone, and spiroperidol.

21. The method according to claim 20, wherein said alkylated target compound is [¹⁸F]fluoromethyl-MQNB, [¹⁸F]N-fluoromethyl-MPP, [¹⁸F]FNMS, [¹⁸F]fluoroethylspiperone, [¹⁸F]fluoromethyl-neostigmine, [¹⁸F]fluoromethyl-tyrosine.

22. The method according to claim 17, wherein said target compound is selected from the group consisting of glucose, lactic acid, hexobarbital, thymidine, iodoantipyrine, antipyrine and coenzyme Q.

23. A method of alkylating dimethylethanolamine comprising:

a) synthesizing an alkylating agent having the formula;

¹⁸F—

(CH₂)_a-LG

wherein,

a is 1 or 2,

LG is a leaving group; and

b) directly reacting said alkylating agent with a dimethylethanolamine under conditions suitable for the alkylation of said dimethylethanolamine.

24. The method according to claim 23, wherein said alkylating agent has the formula

¹⁸F—

CH₂CH₂-LG

wherein,

LG is a sulfonate ester.

25. The method according to claim 23, wherein said alkylating agent has the formula

¹⁸F—

CH₂-LG,

wherein,

LG is a sulfonate ester.

26. The method according to claim 23, wherein the precursor of said alkylating agent has the formula LG-(CH2)_a-LG.

27. The method according to claim 23, 24, 25 or 26, wherein LG is selected from the group consisting of tosylate, mesylate or triflate ester.

28. The method according to claim 23, wherein said fluoroalkylated choline is [¹⁸F]N,N-dimethyl-N-fluoromethylethanolamine.

29. The method according to claim 23, wherein said fluoroalkylated choline is [¹⁸F]N,N-dimethyl-N-fluoroethylethanolamine.

30. A computer readable memory to direct a computer to function in a specified manner, comprising:

a) executable instructions to direct a computer that controls a synthesis module to synthesize in a reaction vessel an alkylating agent having the formula;

X-(CR¹R²)_aCR³R⁴-LG

wherein,

a is an integer from 0 to 2,

R¹, R², R³ and R⁴ are independently H or X,

X is a halogen or a label, with the proviso that at least one X is a halogen,

LG is a leaving group,

using a halide ion and a catalyst; and

b) executable instructions directing said computer that controls said synthesis module to directly react in said reaction vessel said alkylating agent with a target compound comprising an alkylation reactive group under conditions suitable to alkylate said target compound.

31. The computer readable memory according to claim 30, further comprising:

c) executable instructions directing said computer that controls said synthesis module to bind the alkylated target compound to a first solid support, wherein said reaction vessel and said first solid support are in fluidic communication.

32. The computer readable memory according to claim 31, further comprising:

d) executable instructions directing said computer that controls said synthesis module to elute said alkylated target compound from said first solid support.

33. The computer readable memory according to claim 32, further comprising:

e) executable instructions directing said computer that controls said synthesis module to bind the eluted alkylated target compound to a second solid support, wherein said first and second solid supports are in fluidic communication, and to elute said alkylated target compound from said second solid support.

35. A composition comprising a compound selected from the group consisting of [¹⁸F]alkylmorphine, [¹⁸F]alkylheroin, [¹⁸F]alkylpethine, [¹⁸F]alkyltamoxifen, [¹⁸F]alkylcodeine, [¹⁸F]alkylnicotine, [¹⁸F]alkylthioproperazine, [¹⁸F]alkyldiazepam, [¹⁸F]alkylcaffeine, [¹⁸F] alkylflunitrazepam, [¹⁸F]alkylhexamethonium, [¹⁸F]alkylmethiodide, [¹⁸F]alkylquinuclidinyl benzilatem, [¹⁸F]alkyl-MQNB, [¹⁸F]alkylneostigmine, [¹⁸F]alkyl-MPP, [¹⁸F]alkyl-NMS, [¹⁸F]alkyltyrosine, [¹⁸F]alkylspiperone, and [¹⁸F]alkylspiroperidol.