PRODRUGS OF 4-[3-(TRANS-3-DIMETHYLAMIN0CYCL0BUTYL)-lH-IND0L-5-YL-METHYL]-4( S) 0XAZ0LIDIN-2-0NE, THEIR PREPARATION AND THEIR USE AS "5HT1-LIKE" RECEPTOR AGONISTS
The present invention is concerned with new chemical compounds which act as prodrugs of 4-[3-(traιs-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one, their preparation, pharmaceutical formulations containing Jhem, and their use in medicine, particularly as "5HTι-like" receptor agonists for prophylaxis and treatment of migraine.
Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Hoyer et al., Pharmacol. Rev., 46, 157-203, 1994), although only the classes nominated 5-HT], 5-HT2, 5-HT3, and 5-HT4 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] 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 ofthe Nth (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 excessive dilation of the carotid vasculature and/or neurogenically-evoked inflammation dilation ofthe cranial vasculature. However, it is within the scope of the earlier application that the target tissue may be any tissue wherein action is mediated by 5-HTj receptors of the type referred to above.
EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HTι receptor mentioned above and excellent absoφtion 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".
Published International Application no. WO95/20588 discloses a class of compounds which not only demonstrate improved metabolic stability and the necessary 5HTι receptor agonism, but also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain. The compounds also display partial agonism at the 5HT] receptor and thus may have reduced side effects compared to previously known 5HT] receptor agonists. A particularly preferred
compound described in this International Patent Application is 4-[3-(trans-3- dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-(4S)oxazolidin-2-one.
There has now been discovered a class of compounds which, although having relatively little activity themselves at the 5-HTj receptor, act as prodrugs of 4-[3-(trans-3- dimethylaminocyclobutyl-lH-indol-5-ylmethyl]-4(S)-oxazolid-n-2-one, releasing the aforementioned active compound after administration. Such compounds thereby provide active compound with improved metabolic stability and bioavailability.
Thus, according to a first aspect of the present invention there is provided a compound of formula (I)
wherein A is a C\. alkyl, -O-C]_6 alkyl, -O-phenyl or phenyl group, and may optionally be substituted by one or more substituents selected from Ci .3 alkyl and halogen;
and salts, solvates and physiologically functional derivatives thereof.
A particularly preferred compound of formula (I) is (S)-trans-4-[ 1 -(2-toluoyl)-3-(3- dimethylaminocyclobutyl)-5-indolylmethyl]- 1 ,3-oxazolidin-2-one.
Physiologically acceptable salts are particualriy suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e basic compounds Such salts
must clearly have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of formula (I) include those derived from acetic, hydrochloric hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulphuric, lactic, tartaric or benzoic acid. Benzoates and sulphates are particularly preferred. Salts having a non- physiologically acceptable anion are 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 second aspect of the present invention, there is provided a compound of formula (I) or a physiologically acceptable salt, solvate or physiologically functional derivative thereof for use as a therapeutic agent, specifically as a "5-HT]-like" receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine.
Compounds of formula (I) and physiologically acceptable salts, solvates or physiologically functional derivatives thereof are hereinafter referred to as "compounds ofthe invention".
The amount of a compound of the invention 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 0.0 lμg to 5mg per kilogram body weight, suitably 0.01 μg to lOOμg/ kg and preferably 0.0 lμg to 2μg/kg. Unit doses may contain from lμg to lOOmg ofa compound ofthe invention. Suitably, unit dose formulations contain lμg to Img and preferably lμg to lOOμg of a compound of the invention. For example, ampoules for injection may contain from lμg to lOOμg and orally administrable unit dose formulations such as tablets or capsules may contain from lμg to lOOμg.
Whilst it may be possible for a compound of the invention to be administered as the raw chemical it is preferable to present it as a pharmaceutical formulation. According to a third aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of the invention 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 -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 and is
preferably formulated with at least one compound of the invention as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions ofthe invention.
Possible formulations include those suitable for oral, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration. The most suitable means of administration for a particular patient will depend on the nature and severity ofthe condition being treated and on the nature of the active compound, but, where possible, oral administration is preferred.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non¬ aqueous liquids; or as oil-in-water or water-in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is typically present in such formulations at a concentration of from OJ to 15% w/w.
The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules ofthe active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
Thus, according to a fourth aspect of the present invention, there is provided the use of a compound of the invention in the preparation of a medicament for the prophylaxis or treatment ofa clinical condition for which a "5-HT]-like" receptor agonist is indicated, for example, migraine.
According to a fifth aspect, there is provided a method for the prophylaxis or treatment ofa clinical condition in a mammal, for example, a human, for which a "5-HT -like" receptor agonist is indicated, for example, migraine, which comprises the administration to said mammal ofa therapeutically effective amount ofa compound ofthe invention.
In a further aspect the invention provides a process for the preparation of a compound of the invention which comprises reaction ofthe compound of formula (II)
i.e. the compound 4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one, with a compound of formula (III)
O
(in)
Cl
wherein A is as hereinbefore defined.
The reaction is preferably carried out in the presence of a base such as an organic base, for example triethylamine, pyridine or Hunig's base, or an inorganic base, for example sodium hydride or potassium carbonate. Sodium hydride is preferred. The reaction may be carried out in: polar aprotic solvents such as dimethylformamide or dimethylsulphoxide; aromatic solvents e.g. toluene; ethereal solvents e.g. tetrahydrofuran; or in chlorinated solvents such as dichloromethane. The preferred solvent is dimethylformamide. The reaction may be carried out in the temperature range 0-l00°C with a temperature in the range 0°C to room temperature being preferred.
The compound 4-[3-(trans-3-dimethylaminocyclobutyl)- 1 H-indol-5-ylmethyl]-
4(S)oxazolidin-2-one may be prepared by the methods described in published International Application WO95/20588 incoφorated herein by reference. One particularly suitable method is described in Example 1 hereinafter.
Compounds of formula (III) are commercially available. Alternatively, they can be prepared from known starting materials using standard methods which are well known to those skilled in the art.
Salts, solvates and physiologically functional derivatives of compounds of formula (I) may be prepared from compounds of formula (I) using standard techniques known in the art.
The invention will now be described by way of example only.
Example 1 : 4-f3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]- 4(S)oxazolidin-2-one
(a) Trans-N-(benzyloxycarbonyl)-cyclobutanamine-3-acetaldehyde
Trans-N-(benzyloxycarbonyl)-3-methylenecyclobutanamine (18g, 83 mmol) (prepared as described in EP-A-0366059) and tris(triphenylphosphine)rhodium chloride (400 mg 0.43 mmol) were heated to 70°C in toluene (250ml) under 100 atmospheres of CO:H2 (1 :1 mixture) for 18 hrs. The solvent was evaporated under reduced pressure and the residue chromatographed on silica eluting with 25% ethylacetate in cyclohexane. The first product eluted (r.f. -0.25) was a mixture of cis and trans branched chain aldehydes. The second product eluted (r.f~0J) was a mixture of cis and trans straight chain aldehydes. The trans isomer was crystallised from ether as white needles (mpt = 66-67°C). Microanalysis for C]4H] 7NO3- Calculated C 68.02, H 6.88, N 5.67; Found C 67.92, H 6.90, N 5.63.
(b) 4-[3-(trans-3-aminocvclobutyl)-lH-indol-5-ylmethyl-(4S)-oxazolidin-2-one
The appropriate hydrazine, 4-hydrazinophenyl-(4S)-oxazolidin-2-one (6.3g, 30mmol) and trans-N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (6.3g, 25.5mmol) were heated to 80°C for 7 hours in 1% sulphuric acid (aq) (100ml) and ethanol (150ml). The reaction mixture was evaporated in vacuo and brine added. Extraction with ethyl acetate gave the crude product (10.5g, 83%) MS (FAB) 420 (M+l)+.
The product from the above was refluxed in 10% formic acid-methanol with palladium hydroxide on carbon (lg) for 7 hours. The solvent was removed in vacuo and brine added. The solution was then washed with ethyl acetate and then
made basic (pH 10-12) with dil. ammonium hydroxide solution. Extraction with THF gave the crude product which was purified by flash chromatography (2:14:84 H3, EtOH) (2g, 28%) MS (FAB) 286 (M+l)+.
(c) 4-f3-(trans-3-dimethylaminocyclobutylVlH-indol-5-ylmethyl]-4(S)oxazolidin-2-one
Formaldehyde (0J8 ml, 2.22 mmol) in methanol (5 ml) was added to the product of step (b) (250 mg, 0.88 mmol), acetic acid (0.26ml, 4.55 mmol) and sodium cyanoborohydride (70mg, 1J7 mmol) in methanol (15ml) and stirred at room temperature under a nitrogen atmosphere ovemight.
Water was added and the mixture was washed with ethylacetate. The aqueous phase was then adjusted to pH 10 with potassium carbonate and saturated with sodium chloride. Extraction with ethylacetate gave a sticky gum, which was chromatographed on silica, eluting with 1% 0.88 NH3 solution in methanol (r.f ~0.4) to give an off white powder. Elemental analysis for C\% H23 N3 O2 0.35 CHCI3 Calculated C 62.05, H 6.63, N 11.83 Found C 62.21, H 6.76, N 1 1.55 mpt = Becomes gummy at 77-78°C.
This solvated compound can be dried in vacuo at 80°C to provide an anhydrous compound which has mpt = 159-160°.
Example 2: (S)-trans-4-[ 1 -(2-toluoyl)-3-(3-dimethylaminocyclobutyl)-5-indolylmethylJ- 1 ,3-oxazolidin-2-one
4-[3-(trans-3-dimethylaminocyclobutyl)-lH-indol-5-ylmethyl]-4(S)oxazolidin-2-one (lOOmg, 0.319 mmol) in dry dimethylformamide (0.5ml) was added to sodium hydride (121mg) in dry dimethylformamide (0.5ml) at room temperature. The mixture was stirred at room temperature for 1 hour and 2-toluoyl chloride (33ml, 0.255 mmol) was added over 1 minute. After 4 hours at room temperature, the reaction mixture was treated with saturated aqueous ammonium chloride and dichloromethane (10ml). The mixture was partitioned between water and dichloromethane and the organic phase dried and concentrated. The residue was purified by chromatography (silica-dichloromethane, metanol, ammonia; 94:5:1) to give the title compound. (TLC; Rf : 0.38, silica- dichloromethane, methanol, ammonia) as a gum (4 Img).
IHNMR (360 MHz; d6 DMSO); 2.06 (6H,s); 2J 1, 2.33 (4H, 2m's); 2.25 (3H,S); 2.78 (lH,m); 2.88 (2H,m); 3.52 (lH,m); 4.02,4.07 (2H, 2m's); 4.27 (lH,t); 6.94 (lH,s); 7.21 (lH,d, J=9Hz); 7.38-7.51 (5H, m's); 7.70 (lH,s); 7.92 (!H,dJ=9Hz).
Accurate mass : 431.22089 (C26 H29 N3 O3)