Anesthetic Compounds
In one embodiment the invention provides novel compounds of Formula (I) as well as prodrugs, salts, hydrates, solvates and N-oxides thereof. The invention also provides pharmaceutical compositions that include such compounds as well as methods for making and methods for using such compounds in medical therapy.
1 - 2 . (canceled)
3 . A compound of formula IIa or IIb:
or a prodrug, salt, hydrate, solvent or N-oxide thereof,
wherein:
Z is a group of the following formula:
each R 1 is independently hydrogen, —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 or —C(O)NR 6 R 7 ;
p is an integer from 1 to 3;
X is —O— or —S—;
R 2 is the sidechain of an amino acid; or is selected from methyl, 3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl, 2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl, 2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl, 4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl, indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl, 1-methylpropyl, and benzyl; or is (C3-C6) alkyl;
R 4 and R 5 are independently H, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl ring;
R 6 and R 7 are independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; and
R 8 is —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , —C(O)NR 6 R 7 , or aryl which is optionally substituted with one or more —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , or —C(O)NR 6 R 7 ;
wherein the center marked by * in the formula has the absolute configuration shown provided that the compound is not:
4 . (canceled)
5 . The compound of claim 3 wherein Z is:
6 - 7 . (canceled)
8 . The compound of claim 3 wherein Z is:
9 - 13 . (canceled)
14 . The compound of claim 3 wherein R 2 is the sidechain of a natural amino acid.
15 . The compound of claim 3 wherein R 2 is methyl, isopropyl, 2-methylpropyl, 1-methylpropyl, or benzyl.
16 - 17 . (canceled)
18 . The compound of claim 3 wherein R 4 and R 5 are each independently methyl or ethyl.
19 . The compound of claim 3 wherein R 4 and R 5 together with the nitrogen atom to which they are bonded form a piperadino ring.
20 . The compound of claim 3 wherein X is O.
21 . A compound having the structure:
22 . A compound having the structure:
23 - 27 . (canceled)
28 . The compound of claim 3 wherein R 2 is (C3-C6) alkyl.
29 . The compound of claim 3 wherein R 2 is propyl, isopropyl, butyl, isobutyl, secbutyl, pentyl, isopentyl, secpentyl, or hexyl.
30 . A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable vehicle.
31 . (canceled)
32 . A method of inducing or maintaining local anesthesia in a patient comprising administering to the patient a compound of claim 3 .
33 . A method of inducing or maintaining local anesthesia in a patient comprising administering to the patient in need thereof the pharmaceutical composition of claim 30 .
34 . A method of treating or preventing pain in a patient comprising administering to the patient in need thereof a compound of claim 3 .
35 - 37 . (canceled)
38 . The compound of claim 3 , wherein Z is:
wherein R 1 is ethoxy, propoxy or butoxy.
39 . The compound of claim 3 , wherein R 2 is selected from methyl, 3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl, 2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl, 2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl, 4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl, indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl, 1-methylpropyl, and benzyl.
40 . A compound of formula IIa:
or a prodrug, salt, hydrate, solvent or N-oxide thereof,
wherein:
Z is a group of the following formula:
each R 1 is independently hydrogen, —F, —Cl, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 or —C(O)NR 6 R 7 ;
p is an integer from 1 to 3;
X is —O— or —S—;
R 2 is the sidechain of an amino acid; or is selected from methyl, 3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl, 2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl, 2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl, 4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl, indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl, 1-methylpropyl, and benzyl; or is (C3-C6) alkyl;
R 4 and R 5 are independently H, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl ring;
R 6 and R 7 are independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; and
R 8 is —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , —C(O)NR 6 R 7 , or aryl which is optionally substituted with one or more —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , or —C(O)NR 6 R 7 ;
wherein the center marked by * in the formula has the absolute configuration shown.
41 . A compound of formula IIb:
or a prodrug, salt, hydrate, solvent or N-oxide thereof,
wherein:
Z is a group of the following formula:
each R 1 is independently hydrogen, —F, —Cl, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 or —C(O)NR 6 R 7 ;
p is an integer from 1 to 3;
X is —O— or —S—;
R 2 is the sidechain of an amino acid; or is selected from methyl, 3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl, 2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl, 2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl, 4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl, indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl, 1-methylpropyl, and benzyl; or is (C3-C6) alkyl;
R 4 and R 5 are independently H, (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl ring;
R 6 and R 7 are independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; and
R 8 is —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , —C(O)NR 6 R 7 , or aryl which is optionally substituted with one or more —F, —Cl, —Br, —I, —R 6 , —OR 6 , —SR 6 , —NR 6 R 7 , —CF 3 , —CN, —C(O)R 6 , —C(O)OR 6 , —C(O)SR 6 , or —C(O)NR 6 R 7 ;
wherein the center marked by * in the formula has the absolute configuration shown.
42 . A compound of formula IIa:
or a prodrug, salt, hydrate, solvent or N-oxide thereof,
wherein:
Z is a group of the following formula:
R 1 is —OR 6 , wherein R 6 is C1-C6 alkyl;
X is —O—;
R 2 is methyl, isopropyl, 2-methylpropyl, 1-methylpropyl, or benzyl;
R 4 and R 5 are independently H, (C1-C6) alkyl or R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl ring;
wherein the center marked by * in the formula has the absolute configuration shown.