Method of preparing alkylated salicylamides via a dicarboxylate intermediate
View Patent ↗The present invention relates to a method of preparing an alkylated salicylamide from a protected and activated salicylamide via a dicarboxylated salicylamide intermediate. The present invention also relates to dicarboxylic salicylamide delivery agent compounds for the delivery of active agents. Methods of administration are provided as well.
1. A compound having the formula
wherein
R 1 , R 2 , R 3 , and R 4 are independently hydrogen; halogen; C 1 –C 4 alkoxy, optionally substituted with —OH or F; —OH; C 1 –C 4 alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH 3 ; —SO 3 H; nitrile; or —NR 9 R 10 ;
R 5 a protecting group;
R 6 is an activating group; or
R 5 and R 6 are combined to form a substituted or unsubstituted cyclic group;
R 7 is a linear or branched, C 1 –C 20 alkylene, alkenylene, or alkynylene;
R 7 is optionally substituted with C 1 –C 4 alkyl, C 1 –C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C 1 –C 4 alkoxy, aryl, heteraryl, or vinyl;
R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R 8 and R 11 are independently C 1 –C 4 alkyl or C 1 –C 4 haloalkyl; and
R 9 and R 10 are independently hydrogen, C 1 –C 4 alkyl, or oxygen, and
wherein both carboxylate groups attached to R 7 in the formula above are attached to the end of the alkylene, alkenylene. or alkynylene R 7 chain.
2. A compound selected from
wherein
R 14 and R 15 are independently C 1 –C 4 alkyl; and
R 16 and R 17 are independently hydrogen, C 1 –C 4 alkyl, C 2 –C 4 alkenyl, or C 2 –C 4 alkynyl.
3. The compound of claim 2 , wherein Y is —CH 2 —.
4. The compound of claim 2 , wherein Y is —C(O)—.
5. The compound of claim 2 , wherein R 14 and R 15 are independently methyl or ethyl.
6. A compound having the formula
wherein
R 1 , R 2 , R 3 , and R 4 are independently hydrogen; halogen; C 1 –C 4 alkoxy, optionally substituted with —OH or F; —OH; C 1 –C 4 alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH 3 ; —SO 3 H; nitrile; or —NR 9 R 10 ;
R 7 is a linear or branched, C 1 –C 20 alkylene, alkenylene, or alkynylene;
R 7 is optionally substituted with C 1 –C 4 alkyl, C 1 –C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C 1 –C 4 alkoxy, aryl, heteraryl, or vinyl; and
R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur; and
R 9 and R 10 are independently hydrogen, C 1 –C 4 alkyl, or oxygen,
and wherein both carboxyl groups attached to R 7 in the formula above are attached to the end of the alkylene, alkenylene, or alkynylene R 7 chain,
or a salt thereof.
7. A composition comprising:
(A) an active agent; and
(B) at least one compound of claim 6 .
8. A dosage unit form comprising:
(A) the composition of claim 7 ; and
(B) (i) an excipient,
(ii) a dilutent,
(iii) a disintegrant,
(iv) a lubricant,
(v) a plasticizer,
(vi) a colorant,
(vi) a dosing vehicle, or
(vii) any combination thereof.
9. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering orally to the animal the composition of claim 7 .
10. A method for preparing a composition comprising mixing:
(A) at least one active agent;
(B) the compound of claim 6 ; and
(C) optionally, a dosing vehicle.