Local anesthetic compounds

Details Local anesthetic compounds Local anesthetic compounds

2000-09-28

2002-08-20

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S258100, C540S467000

Reexamination Certificate

active

06436919

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel local anesthetic compounds, pharmaceutical composition containing these compounds, methods of use and methods for preparing these compounds.
2. State of the Art
Local anesthetics are believed to prevent or relieve pain by interrupting nerve conduction. More specifically, such compounds are believed to a specific receptor site within the pore of the sodium channels in the nerves and block ion movement through this pore. Currently, a number of local anesthetics such as benzocaine, bupivacaine, cocaine, lidocaine, mepivacaine are available and are being used as to prevent or relieve pain. However, these drugs have limited utility as they cause adverse side effects such as cardiotoxicity and CNS side effects and/or have short duration of action. Accordingly, there is a need for local anesthetics that have longer duration of action while reducing the undesired side effects.
The compounds of the present invention fulfill this need.
SUMMARY OF THE INVENTION
This invention provides novel compounds that are useful as inhibitors of Na
+
channels and are effective as local anesthetics.
Accordingly, in one aspect, this invention is directed to a compound of Formula (I):
L
1
-X-L
2
  (I)
wherein:
L
1
is represented by:
(i) a group of formula (a):
 where:
E is aryl, heteroaryl, heterocycle, or cycloalkyl;
G is —NR
7
— (where R
7
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle), —O— or —S(O)n— (where n is 0, 1 or 2);
R
1
and R
2
are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, —NR
c
R
d
(where R
c
is hydrogen or alkyl and R
d
is alkyl), carboxy, and carboxyalkyl; or R
1
and R
2
when adjacent to each other together form —OCH
2
O— or —O(CH
2
)
2
O—;
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, —NR
c
R
d
(where R
c
is hydrogen or alkyl and R
d
is alkyl), carboxy, and alkoxycarbonyl; or R
3
and R
4
together with the carbon atom to which they are attached form a carbonyl group;
R
5
and R
6
are independently selected from the group consisting of hydrogen and alkyl; or
(ii) a group of formula (b):
 wherein:
J is —O—, or —S(O)n— (where n is 0, 1, or 2); and
E, G, R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined above;
X is a linker;
L
2
is represented by:
(iii) a group of formula (c):
 wherein:
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl;
W is selected from a covalent bond, —[CR
8
R
9
]
r
—, —[CR
8
R
9
]
r
—C(O)—, —OC(O)—[CR
8
R
9
]
r
—, —C(O)O[CR
8
R
9
]
r
—, —O—[CR
8
R
9
]
r
C(O)—, —C(O)—NH—[CR
8
R
9
]
r
—, or —NH—C(O)[CR
8
R
9
]
r
where r is an integer of 0 to 10, and R
8
and R
9
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and —NR
a
R
b
— where R
a
and R
b
are both alkyl; or
(iv) a group of formula (d):
 where:
U is aryl, heteroaryl, heterocycle, or cycloalkyl;
W
a
is —NR
16
— (where R
16
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle), —O— or —S(O)n— (where n is 0, 1 or 2);
R
10
and R
11
are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, monosubstituted or disubstituted amino, carboxy, and carboxyalkyl; or R
10
and R
11
when adjacent to each other together form —OCH
2
O— or —O(CH
2
)
2
O—;
R
12
and R
13
are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, monosubstituted or disubstituted amino, carboxy, and alkoxycarbonyl; or R
12
and R
13
together with the carbon atom to which they are attached form a carbonyl group;
R
14
and R
15
are independently selected from the group consisting of hydrogen and alkyl; or
(v) a group of formula (e):
 where:
V is —O—, or —S(O)n
1
— (where n
1
is 0, 1, or 2); and
U, W
a
, R
10
, R
11
, R
12
, R
13
, R
14
and R
15
are as defined above; and individual isomers, mixtures of isomers, prodrugs, and pharmaceutical acceptable salts thereof provided that:
when L
1
is a group of formula (a) wherein E is phenyl, R
1
is methyl and is at the 8-position of the quinazolone ring, R
2
, R
5
, R
6
are hydrogen, G is —NR
7
— where R
7
is morpholin-1-ylcarbonylmethyl; X is 1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7,16-diyl; L
2
is Ar—W— where W is methylene, then Ar is not phenyl and is named as 7-[8-methyl-3-(morpholin-4-ylmethyl]-4-(3H)-quinazolinon-2-yl)methyl-16-[(R)-(2-benzyl)]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane; and
when L
1
is a group of formula (a) wherein E is phenyl, R
1
is methyl and is at the 8-position of the quinazolone ring, R
2
, R
5
, R
6
are hydrogen, G is —NR
7
— where R
7
is tetrahydropyran-4-ylaminocarbonylmethyl; X is 1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7,16-diyl; L
2
is Ar—W— where W is —NH—C(O)[CHCH
2
CH
3
]—, then Ar is not 2-methylphenyl and is named as 7-[8-methyl-3-(tetrahydropyran-4-ylaminocarbonylmethyl]-4-(3H)-quinazolinon-2-yl)methyl-16-[(R)-(2-methylphenylaminocarbonyl)prop-1-yl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane.
Preferably, the linker X is a group of the formula:
—X
a
—Z
a
—(Y
a
—Z
a
)
m
—X
a
—
wherein:
m is an integer of from 0 to 20;
X
a
at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —N
+
RR′—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— and a covalent bond where R and R′ as defined below;
Z
a
at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, substituted arylene, substituted heteroarylene, substituted heterocyclene, and a covalent bond;
each Y
a
at each separate occurrence is selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n—, —C(O)NR′—, —NR′ C(O)—, —NR′—C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)
n
CR′R″—, —S(O)
n
—NR′—, —NR′—S(O)
n
—, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that at least one of X
a
, Z
a
, and Y
a
is not a covalent bond.
In a second aspect, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In a third aspect, this invention is directed to a method for producing local anesthesia in a mammal which method comprises administering to a mammal in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In a fourth aspect, this invention is directed to a method for modulating the activity of a Na
+
channel in a mammal, which method comprises administering to said mammal a Na
+
channel modulating amount of a compound of Formula (I) or a

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