Indole derivatives as prodrugs of 5-HT1-like receptor agonists

Details Indole derivatives as prodrugs of 5-HT1-like receptor agonists Indole derivatives as prodrugs of 5-HT1-like receptor agonists

2001-01-12

2002-07-23

Goldberg, Jerome O. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06423731

ABSTRACT:

The present invention is concerned with new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.
Receptors which mediate the actions of 5-hydroxytryptamine (5- have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Humphrey et al., Trends Pharmac Sci., 14, 233-236, 1993), although only the classes nominated 5-HT
1
, 5-HT
2
, 5-HT
3
, and 5-HT
4
have established physiological roles. European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT
1
receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation of the Vth (trigeminal) nerve. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with and/or neurogenically-evoked inflammation dilation of the cranial vasculature. However, it is within the scope of the earlier application that the target tissue may be arty tissue wherein action is mediated by 5-HT
1
receptors of the type referred to above.
EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT
1
receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as “migraine”.
There has now been discovered a class of compounds which, although having relatively little activity themselves at the 5-HT
1
receptor, act as prodrugs releasing active compound after administration. Such compounds thereby provide active compound with improved metabolic stability and bioavailability.
Thus, according to a fist aspect of the present invention there is provided a compound of formula (I):
wherein
A is C
1-6
alkyl, —O—C
1-6
alkyl, or —O-phenyl, or phenyl, optionally substituted by C
1-3
alkyl or halogen;
n is an integer of from 0 to 3;
W is a group of formula (i), (ii) or (iii)
wherein R is hydrogen or C
1-4
alkyl, X is —O—, —S—, —NH—, or —CH
2
—, Y is oxygen or sulphur and the chiral centre * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and
Z is a group of formula (iv), (v) or (vi)
wherein R
1
and R
2
are independently selected from hydrogen and C
1-4
alkyl and R
3
is hydrogen or C
1-4
alkyl;
and salts, solvates and physiologically functional derivatives thereof.
Preferably W is a group of formula (i) and Z is a group of formula (iv)
In another aspect the present invention provides a compound of the formula (Ia)
wherein
A is C
1-6
alkyl, —O—C
1-6
alkyl, —O-phenyl or phenyl, optionally substituted by C
1-3
alkyl or halogen;
n is an integer from 0 to 3;
R is hydrogen or C
1-4
alkyl;
X is —O—, —S—, —NH—or —CH
2
—;
Y is oxygen or sulphur, and
R
1
and R
2
are independently selected from hydrogen and C
1-4
alkyl and salts, solvates and physiologically functional derivatives thereof.
Preferred compounds of formula (Ia) are those wherein n is 1, X is —O— and Y is oxygen. Compounds wherein R
1
and R
2
are independently selected from hydrogen and methyl are preferred, with compounds wherein R
1
and R
2
are both methyl being particularly preferred.
Compounds of formula (I) and (Ia) are capable of existing as optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention.
Examples of preferred compounds of the invention include:
(1) 4-[1-Benzoyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(2) 4-[1-Pivaloyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(3) 4-[1-(2′-toluoyl)-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(4) 4-[1-Benzyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin -2-one;
(5) 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate; and
(6) 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate.
Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, ie basic, compounds. Such salts must clearly have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulphuric, lactic, or tartaric acid The succinate and chloride salts are particularly preferred for medical purposes. Salts having a non-physiologically acceptable anion arc within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
According to a third aspect of the present invention, there is provided a compound of formula (I) or (Ia) or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof for use as a therapeutic agent, specifically as a “5-HT
1
-like” receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine. As indicated, however, target organs for the present compounds other than the carotid vasculature are within the scope of the present invention.
The amount of a compound of formula (I) or (Ia), a salt or solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the specific compound, the use for which it is intended, the means of administration and the recipient. A typical daily dose for the treatment of migraine may be expected to lie in the range 0.01 to 5 mg per kilogram body weight. Unit doses may contain from 1 to 100 mg of a compound of formula (I), for example, ampoules for injection may contain from 1 to 10 mg and orally administrable unit dose formulations such as tablets or capsules may contain from 1 to 100 mg. Such unit doses may be administered one or more times a day separately or in multiples thereof. An intravenous dose may be expected to lie in the range 0.01 to 0.15 mg/kg and would typically be administered as an infusion of from (0.0003 to 0.15 mg per kilogram per minute. Infusion solutions suitable for this purpose may contain from 0.01 to 10 mg/ml.
When the active compound is a salt or solvate of a compound of formula (I) the dose is based on the cation (for salts) or the unsolvated compound.
Hereinafter references to “compound(s) of formula (I) or (Ia)” will be understood to include physiologically acceptable salts and solvates thereof
According to a fourth aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) or (Ia) and/or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a “5-HT
1
-like” receptor agonist is indicated, for example, migraine. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid end is preferably formulated with at least on

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