Analgesic agents

Details Analgesic agents Analgesic agents

2000-02-07

2001-09-11

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S333000, C546S256000

Reexamination Certificate

active

06288055

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel therapeutic compounds that act as analgesics. These agents exert their beneficial effects by binding to nicotinic acetylcholine receptors (nAChRs) and modulating their activity, thus providing a therapeutic effect. More particularly, the invention relates to novel therapeutic compounds that bind to nAChRs and modulate their activity by acting as multibinding agents. The multibinding agents of the invention comprise from 2-10 ligands covalently connected by a linker or linkers, wherein said ligands in their monovalent (i.e. unlinked) state are capable of binding to nAChRs and modulating their activity. The manner in which the ligands are linked is such that the multibinding agents so constructed demonstrate an increased biological and/or therapeutic effect as compared to the same number of unlinked ligands available for binding to nAChRs.
The compounds of the invention are particularly useful in treating pain in mammals. Accordingly, the invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an effective amount of a compound of the invention, and to methods of using such compounds and pharmaceutical compositions containing them for the treatment of such conditions.
Still further, the invention relates to methods of preparing such compounds.
2. State of the Art
The search for compounds that alleviate pain continues to be a major research effort of the pharmaceutical industry. A variety of commercial and experimental drugs having an analgesic effect are known. For example, the opioid drugs, including opium and opium derivatives, have been in use for many years. These drugs, which act as ligands for opioid receptors, inhibit the transmission of sensory stimuli. Unfortunately, treatment with the opioids may result in undesirable side effects, such as constipation, respiratory depression, addiction, and analgesic tolerance.
Another class of analgesics, known as non-steroidal anti-inflammatory drugs (NSAIDS), are also used to relieve pain. These drugs are effective as analgesics because they inhibit the activity of cyclooxygenases, enzymes that regulate the synthesis of proinflainmatory mediators. The pro-inflammatory mediators, such as prostaglandins and other autocoids, are produced at sites of tissue damage and are a cause of pain. Like the opioid drugs, NSAIDS often cause unpleasant side effects, such as gastrointestinal ulceration and bleeding.
Nicotine and its derivative, epibatidine, produce analgesia. Nicotine, however, is only mildly effective as an analgesic (and is extremely toxic), and treatment with this compound often results in physical dependence. Epibatidine, on the other hand, is a potent analgesic, but also produces serious side effects including hypertension, neuromuscular paralysis, and seizures.
Nicotine and epibatidine exert their biological effects in part by binding to nAChR, a family of receptors widespread in the CNS, PNS, and muscle, and modulating their activity. The nAChR are membrane bound homo- or hetero- pentameric proteins consisting of subunits known as &agr;, &bgr;, &ggr;, &dgr; and &egr;. The subunit composition of the nAChR varies with location. For example, neuronal nAChR, located in the CNS, exists in two forms: 1) homopentameric proteins, consisting of the &agr;
7
subunits; and 2) heteropentameric proteins, consisting of &agr;
4
&bgr;
2
subunits. The nAChRs located at the neuromuscular junction and at the sympathetic ganglia consist of &agr;
1
B
1
&dgr;&ggr;(&egr;) and &agr;
3
, respectively.
Nicotine and epibatidine are ligands that bind nonspecifically to all nAChR. However, the binding of ligands to the neuromuscular type of nAChR does not produce an analgesic effect. In fact this nonspecific binding may result in the detrimental side effects of these drugs. A useful strategy for drug design, therefore, is to synthesize ligands that bind with high specificity to the type of nAChR involved in the perception of pain, such as the neuronal nAChR.
Recently clinically useful variants of epibatidine have been developed (WO 9825920) that result in fewer unpleasant sequela in treated individuals. However, the clinical shortcomings of these drugs and other drugs in current usage are considerable. There continues to exist a need for novel compounds that provide broad spectrum pain relief, including pain due to acute or persistent injury such as that generated from neuropathological processes. Improvements on existing drugs could include greater tissue selectivity, increased efficacy, reduced side effects and a more favorable duration of action.
The multibinding compounds of the present invention fulfill this need.
SUMMARY OF THE INVENTION
This invention relates to novel multibinding compounds that act as analgesics by binding to nicotinic acetylcholine receptors (nAChRs) and modulating their activity.
Accordingly, in one aspect, the present invention relates to novel multibinding agents wherein a multibinding agent comprises 2-10 ligands, which may be the same or different, covalently connected by a linker or linkers, which may be the same or different, each of said ligands comprising a ligand domain capable of binding to an nAChR.
The preferred multibinding agents are represented by Formula I:
(L)
p
(X)
q
  I
in which
L is a ligand that may be the same or different at each occurrence;
X is a linker that may be the same or different at each occurrence;
p is an integer of 2-10; and
q is an integer of 1-20; or
a pharmaceutically acceptable salt or prodrug thereof;
wherein each of said ligands compromising a ligand domain state capable of binding to an nAChR.
Preferably, q is less than p. More preferably, each ligand L is a compound of formula (a):
wherein:
n is an integer of 1-3;
R
2
is hydrogen, alkyl, or a covalent bond connecting the ligand to a linker;
Q is —O—, —NR
5
— (where R
5
is hydrogen, alkyl, a prodrug derivative, or a covalent bond connecting the ligand to a linker), or —S(O)n
1
(where n
1
is 0 to 2);
R
1
is hydrogen, halo, cyano, haloalkyl, alkoxy, alkyl, or a covalent bond connecting the ligand to a linker;
R
3
is hydrogen, halo, or a covalent bond connecting the ligand to a linker; and
R
4
is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, alkoxy, or a covalent bond connecting the ligand to a linker;
or a pharmaceutically acceptable salt thereof;
provided that at least one of R
1
, R
2
, R
3
, and R
4
is a covalent bond connecting the ligand to a linker.
Still more preferably, each linker X in the multibinding compound of Formula I independently has 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—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NR—, —NRC(O)—, C(S), —C(S)O—, —C(S)NR—, —NRC(S)—, or a covalent bond where R is 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, or 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—, —N═C(X
a
)—NR′—, —NR′—C(X
a
)═N—, —P(O)(OR′)—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, heteroaryl and hete

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