Positive modulators of nicotinic receptor agonists

Details Positive modulators of nicotinic receptor agonists Positive modulators of nicotinic receptor agonists

2002-04-18

2004-06-29

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S451000

Reexamination Certificate

active

06756398

ABSTRACT:

The present invention relates to novel compounds or pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The novel compounds referred to are positive modulators of nicotinic receptor agonists, said positive modulator having the capability to increase the efficacy of the said nicotinic receptor agonists.
BACKGROUND
Cholinergic receptors normally bind the endogenous neurotransmitter acetylcholine (ACh), thereby triggering the opening of ion channels. ACh receptors in the mammalian central nervous system can be divided into muscarinic (mAChR) and nicotinic (nAChR) subtypes based on the agonist activities of muscarine and nicotine, respectively. The nicotinic acetylcholine receptors are ligand-gated ion-channels containing five subunits (for reviews, see Colquhon et al. (1997) Advances in Pharmacology 39, 191-220; Williams et al. (1994) Drug News & Perspectives 7, 205-223; Doherty et al. (1995) Annual reports in Medicinal Chemistry 30, 41-50). Members of the nAChR gene family have been divided into two groups based on their sequences; members of one group are considered &bgr; subunits, while a second group are classified as &agr; subunits (for reviews, see Karlin & Akabas (1995) Neuron 15, 1231-1244; Sargent (1993) Annu. Rev. Neurosci. 16, 403-443). Three of the &agr; subunits, &agr;7, &agr;8 and &agr;9, form functional receptors when expressed alone and thus presumably form homooligorneric receptors.
An allosteric transition state model of the nAChR involves at least a resting state, an activated state and a “desensitized” closed channel state (Williams et al., supra; Karlin & Akabas, supra). Different nAChR ligands can thus differentially stabilize the conformational state to which they preferentially bind. For example, the agonists ACh and (−)-nicotine stabilize the active and desensitized states.
Changes of the activity of nicotinic receptors has been implicated in a number of diseases. Some of these, e.g. myasthenia gravis and ADNFLE (autosomal dominant nocturnal front lobe epilepsy) (Kuryatov et al. (1997) J. Neurosci. 17(23):9035-47), are associated with reductions in the activity of nicotinic transmission either through a decrease in receptor number or increased desensitization, a process by which receptors become insensitive to the agonist. Reductions in nicotinic receptors have also been hypothesized to mediate cognitive deficits seen in diseases such as Alzheimer's disease and schizophrenia (Williams et al., supra). The effects of nicotine from tobacco are also mediated by nicotinic receptors. Increased activity of nicotinic receptors may reduce the desire to smoke.
The use of compounds which bind nicotinic acetylcholine receptors in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, cognitive or attention disorders, attention deficit hyperactivity disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, and Parkinson's disease has been discussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego, Calif.; and in Williams et al., supra.
However, treatment with nicotinic receptor agonists which act at the same site as ACh is problematic because ACh not only activates, but also blocks receptor activity through processes which include desensitization (for a review, see Ochoa et al. (1989) Cellular and Molecular Neurobiology 9, 141-178) and uncompetitive blockade (open-channel block); Forman & Miller (1988) Biophysical Journal 54(1):149-58. Furthermore, prolonged activation appears to induce a long-lasting inactivation. Therefore agonists of ACh can be expected to reduce activity as well as enhance it. At nicotinic receptors in general, and, of particular note, at the &agr;7-nicotinic receptor, desensitization limits the duration of current during agonist application.
Disclosure of the Invention
It has surprisingly been found that certain compounds can enhance the efficacy of agonists at nicotinic receptors. It is believed that compounds having this type of action (hereinafter referred to as “positive modulators”) will be particularly useful for treatment of conditions associated with reductions in nicotinic transmission. In a therapeutic setting such compounds could restore normal interneuronal communication without affecting the temporal profile of activation. In addition, they would not produce long-term inactivation as prolonged application of agonist may.
According to the invention it has been found that compounds of Formula I:
wherein,
R
1a
, R
1b
, R
3a
and R
3b
independently represent hydrogen, or C
1
-C
4
alkyl;
R
2a
and R
2b
independently represents hydrogen, C
1
-C
4
alkyl, or CH
2
CN;
A
1
represents oxygen, sulfur, or NR
4a
;
B
1
represents oxygen, sulfur, or NR
4b
;
R
4a
represents hydrogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl; or together R
3a
and R
4a
form a ring;
R
4b
represents hydrogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl; or together R
3b
and R
4b
form a ring;
A
2
and B
2
independently represent C(O), C(NH), OC(O), NHC(O), NHC(S), SO
2
, or a bond;
Z represents (CH
2
)
n
Y(CH
2
)
m
;
n and m are independently 0-4;
Y represents oxygen, sulfur, NR
5
, CHR
6
, Ar, or Ccy;
Ccy represents a 5-10 membered carbocycle including cyclopentane and adamantane;
Ar represents phenyl, naphthyl; or a 5- or 6-membered heterocyclic ring containing zero to four nitrogens, zero to one sulfurs and zero to one oxygens;
Ar is optionally substituted with one or more substituents selected from: hydrogen, halogen,
C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, CN, NO
2
, CF
3
, CR
7
, NR
8
R
9
, and COOR
10
;
R
7
, R
8
and R
9
are independently hydrogen, C
1
-C
4
alkyl, aryl, heteroaryl, C(O)R
11
, C(O)R
12
,
SO
2
R
13
, or, R
8
and R
9
together may be (CH
2
)
j
Q(CH
2
)
k
, where
Q is oxygen, sulfur, NR
14
, or a bond;
j is 2-4;
k is 0-2;
R
5
, R
6
, R
10
, R
11
, R
12
, R
13
and R
14
are independently hydrogen, C
1
-C
4
alkyl, aryl, or heteroaryl;
or an enantiomer thereof, and pharmaceutically acceptable salts thereof, enhance the efficacy of agonists at nicotinic receptors.
Preferred compounds of the invention include the following:
1,3-Bis(indolyl-5-oxymethyl)benzene;
N,N′-Di(5-indolyl)-1,3-adamantanedicarboxamide;
or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Unless otherwise indicated, the C
1
-C
4
alkyl groups referred to herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, may be straight-chained or branched, and the C
3
-C
4
alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl.
Unless otherwise indicated, the C
2
-C
4
alkenyl groups referred to herein may contain one or two double bonds, e.g., ethenyl, i-propenyl, n-butenyl, i-butenyl, allyl, 1,3-butadienyl. Unless otherwise indicated, the C
2
-C
4
alkynyl groups referred to herein contain one triple bond, e.g., ethynyl, propynyl, 1-or 2-butynyl.
Halogen referred to herein may be fluoride, chloride, bromide, or iodide.
The compounds of the invention have the advantage that they may be less toxic, be more efficaous, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties.
Methods of Preparation
In the reaction schemes and text that follow, R
1a
, R
1b
, R
2a
, R
2b
, R
3a
, R
3b
, A
1
, A
2
, B
1
, B
2
, and Z, unless otherwise indicated, are as defined above for formula I. The compounds of formula I may be prepared according to the methods outlined in Schemes I and II.
Compounds of formula I may be prepared from compounds of formula IIIa or IIIb, wherein R
1a
, R
1b
, R
2a
, R
2b
, R
3a
, R
3b
, A
1
, A
2
, B
1
and B
2
are as defined in formula I, by reaction with an intermediate of formula IIa or IIb, wherein L
a
or

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