MXPA97002478A - Inhibition mediated by 5-ht1f of extravasacion meningea neurog - Google Patents

Abstract

The present invention provides a method for the treatment of migraine and associated disorders, which rests on a novel mechanism of action. Treating a person complaining of migraine with compounds or compounds that are selective agonists of 5-HTIF receptors relative to other serotonin receptors that produce undesired effects such as vasoconstriction, inhibits neurogenic meningeal extravasation, which results in pain of the migraine, and the physiological risks of compounds that exhibit vasoconstriction or other side effects are avoided

Description

MEDIATED 5-HT1F INHIBITION OF NEUROGEN MENLOSE EXTRAVASATION DESCRIPTION OF THE INVENTION The diverse physiological activity exhibited by the neurotransmitter serotonin (5-HT) is mediated by at least seven classes of receptors: 5-HT ,, -HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. The most heterogeneous of these classes appears to be 5-HT, subclassified as: 5-HT, 5-HTIB, 5-HTlc, 5-HT, D (Hamon et al., Neuropsychopharmacol., 3 (5/6), 349 -360 (1990)) and 5-HTIE (Leonhardt et al., J. Neurochem., 53 (2), 465-471 (1989)). A human gene expressing an additional class of 5-HT, 5-HTlF, was isolated by Kao et al. (Proc. Nati, Acad. Sci. USA, 9Q, 408-412 (1993)). It has been shown that this 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor already described. Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff (Aren. Neurol.

Psychiatry, 39, 737-763 (1938)). They proposed that the cause of migraine headache is the vasodilatation of the extracranial blood vessels. This point of view is supported by the knowledge that ergot alkaloids and sumatripatan contract cephalic vascular smooth muscle, and are effective in the treatment of migraine. Sumatriptan is a hydrophilic agonist at receptors similar to 5-HT, and does not cross the blood-brain barrier (Humphrey et al., Ann., NY Acad. Sci., 6QQ, 587-600 (1990)). REF: 24405 Recently, several new series of compounds have been described that are said to be useful for the treatment of migraine in WO94 / 03446, WO93 / 11106, WO92 / 13856, EP0438230 and WO91 / 18897. Each of these series of compounds has been developed to optimize the vasoconstrictive activity of sumatriptan mediated by compounds similar to 5-HT. The contraindications of sumatriptan, coronary vasospasm, hypertension and angina, however, are also products of its vasoconstrictive activity (Maclntyre, PD, et al., British Journal of Clinical Pharmacology, 34. 541-546 (1992); Chester, AH, et al., Cardiovascular Research, 24, 932-937 (1990); Conner, JE et al., European Journal of Pharmacology, 161, 91-94 (1990)). While this vascular mechanism for migraine has gained wide acceptance, there is no complete agreement as to its validity. Moskowitz has shown, for example, that the occurrence of migraine headaches is dependent on changes in the diameter of the blood vessels.

(Cephalalgia, 12, 5-7 (1992)). Additionally, Moskowitz has proposed that currently unknown activators stimulate the trigeminal ganglia that innervate the vasculature within the cephalic tissue, giving rise to the release of vasoactive neuropeptides from the aixons that are on the vasculature. These released neuropeptides then initiate a series of events that lead to neurogenic inflammation, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids, in a dose similar to that required to treat acute migraine in humans. While it is believed that this blockade of neurogenic protein extravasation is mediated by 5-HT1D receptors, effective dosages of selective compounds for 5-HT, D do not correlate with in vitro binding at the 5-HT1D binding site. -HT1D The lack of correlation suggests that a receptor subtype different from 5-HT1D can mediate the effects of sumatriptan (Neurology, 43, (suppl 3), S16-S20 (1993)), In addition, it has been reported that receptors a, H3, m-opioid and somatostatin can also be localized on trigeminal vascular fibers, and can block the extravasation of neurogenic plasma. (Matsubara et al., Eur. J. Pharmacol., 224, 145-150 (1992)). Weishank et al. They have reported that sumatriptan and several ergot alkaloids have a high affinity for the 5-HT receptor, F, suggesting a role for the 5-HT1F receptor in migraine (WO93 / 14201). The present invention provides a method for the treatment of migraine and related disorders in mammals, comprising administering an effective amount of a 5-HT1F agonist or a composition exhibiting a 5-HTIF agonist activity, which also exhibits minimal vasoconstrictor effects. . The present invention provides a method for the treatment of migraine and associated disorders, which depends on a novel mechanism of action. Treating a person suffering from migraine with a compound or composition that is a selective agonist at the 5-HT1F receptor relative to other serotonin receptors that produce undesired effects such as vasoconstriction, inhibits the neurogenic meningeal extravasation that results in pain of migraine, and the physiological risks of compounds that exhibit vasoconstriction or other side effects are avoided. This mechanism is operative in mammals, and the preferred mammal is a human. A further embodiment of this invention comprises the administration of a composition exhibiting 5-HT 1 F agonist activity. The composition may be composed of one or more agents which, individually or together, are selective agonists of the 5-HT 1F receptors relative to other serotonin receptors that produce undesired effects such as vasoconstriction. The term "5-HT1F agonist", as used in the description of this invention, is taken to mean a total or partial agonist. A compound that is a partial agonist at the 5-HT1F receptor must exhibit sufficient agonist activity to inhibit naurogenic meningeal extravasation at an acceptable dose. While a partial agonist of any intrinsic activity may be useful for the method of this invention, partial agonists of at least about 50% agomsta effect (E ^) are preferred, and phalonic agonists of at least about 80% agonist effect (E ^,). Most preferred are the total agonists at the 5-HT1F receptor. The inhibition of extravasation of the neuronal protein alone is a necessary but not sufficient condition for the method of this invention. The method of this invention additionally requires that only minimal vasoconstriction occurs at an effective dose for the inhibition of extravasation of the neuronal protein. The ratio of vasoconstriction ECS0 in the rabbit saphenous vein to the inhibition of the extravasation of the neuronal protein ID50 in the guinea pig is defined as the index of Specificity The calculated Specificity Index of these assays identifies compounds or compositions that are capable of distinguishing between these physiological events. The panel of compounds used to test the principle of the invention, and the pharmacological assays required to determine the Specificity index are described below. Compound I Butan-l, 3- [2- (dimethylamino) ethyl] -N-methyl-lH-indol-5-methanesulfonamide (1: 1) 4-dioate (Sumatriptan Succinate) Sumatriptan succinate is commercially available as Imitrex ™, or it may be prepared as described in the U.S. Patent. No. 5,037,845, issued August 6, 1991. Compound II 5-Fluoro-3 < 1- < 2- < 1-methyl-lH-pyrazol-4-yl > ethyl > -4-piperidinyl > -1H- indole Compound II is available by the following procedure. 2- (l-Methyl-3-pyrazolo) -l-ethanol To a mixture of 200 grams (2.85 moles) of 2,3-dihydrofuran and 800 ml (4.81 moles) of triethyl orthoformate was added 0.8 ml (6.5 mmol) of boron trifluoride diethyl ether drop by drop. After an initial exotherm, the reaction mixture was allowed to stir at room temperature for four days. To the reaction mixture were then added 4.0 grams of potassium carbonate, and the reaction mixture was distilled under 8.16 x 10.3 kg / cm2 (6.0 mmHg).

The fractions that distilled between 60 ° C and 130 ° C were collected, to give 261.64 grams (42.1%) of a light yellow oil. MS (m / e): 219 (M +). To a solution of 87.2 grams (0.40 moles) of the yellow oil previously prepared in 787 ml of 1 N HCl was added 21.3 ml (0.40 moles) of methyl hydrazine, and the reaction mixture was stirred at reflux for four hours. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The residual oil was treated with 2N NaOH until it was brought to a basic pH, and the aqueous layer was completely extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and concentrated under reduced pressure to give 32.15 grams (64.5%) of the title compound as a brown oil. MS (m / e): 126 (M +) 'H NMR (DMSO-d6): d 7.45 (s, 1 H); 7.25 (s, 1 H); 4.65 (t, 1 H); 3.75 (s, 3 H); 3.55 (m, 2 H); 2.55 (t, 2 H). l-Methyl-4- (2-methanesulfonyloxyethyl) pyrazole To a solution of 16.0 grams (127 mmol) of 2- (l-Methyl-3-pyrazolo) -1-ethanol and 27 ml (193 mmol) of triethylamine in 550 ml of tetrahydrofuran was added 10.8 ml (140 mmol) of methanesulfonyl chloride with ice bath cooling. Once the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. The volatile compounds were then removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, followed by saturated aqueous sodium chloride, and the remaining organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, to give a crude yield of 28.4 grams of the title compound as a brown oil. The product was used without further purification. 5-Fluoro-3- [1, 215,6-tetrahydro-4-pyridyl] -lH-indole To a solution of 74 grams of potassium hydroxide in 673 ml of methanol were added 10.0 grams (74 mmoles) of 5-fluoroindole. and 23.3 grams (151 mmol) of 4-piperidone.HCl.H2O. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was diluted with 1.3 liters of water, and the resulting precipitate was recovered by filtration and dried under reduced pressure to give 10.75 grams (67.2%) of 5-Fluoro-3- [1, 2.5.6- tetrahydro-4-pyridyl] -lH-indole as a yellow solid. 5-Fluoro-3- (4-piperidinyl) -lH-indole To a solution of 10.75 grams (50 mol) of 5-fluoro-3- [1, 2,5,6-tetrahydro-4-pyridyl] -lH- Indole in 500 ml of ethanol was added 2.0 grams of 5% palladium on carbon, and the reaction mixture was hydrogenated at room temperature for 18 hours, at an initial hydrogen pressure of 4.22 kg / cm2 (60 psi). The reaction mixture was then filtered through a celite bed, and the filtrate was concentrated under reduced pressure, to give an off white solid. The solid was recrystallized from methanol to give 8.31 grams (76.2%) of the title compound as a colorless solid, m.p. = 229-230 ° C. MS (m / e): 218 (M +) Calculated for CI3H15N2F: Theory: C, 71.53; H, 6.93; N, 12.83. Found: C, 71. 81; H, 7.02; N, 12.80. Alkylation To a solution of 2.0 grams (9.2 mmoles) of 5-fluoro-3- (4-piperidinyl) -lH-indole and 2.4 grams (23 mmoles) of sodium carbonate in 50 ml of dimethylformamide were added 1.87 grams (9.2 mmoles). ) of l-methyl-4- (2-methanesulfonyloxyethyl) pyrazole in 5 ml of dimethylformamide. The reaction mixture was stirred at 100 ° C for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water, and the phases were separated. The organic phase was washed thoroughly with water, followed by saturated aqueous sodium chloride. The remaining organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was subjected to chromatography on silica gel, eluting with dichloromethane: methanol 20: 1. The fractions which were found to contain the desired compound were combined and concentrated under reduced pressure to give a yellow oil. The oil was converted to the hydrochloride salt, and crystallized from ethyl acetate / methanol. 1.61 grams (51.1%) of Compound II was recovered as colorless crystals. p.f. = 239 ° C MS (m / e): 326 (M +) Calculated for CI9H23N4F: Theory: C, 62.89; H, 6.67; N, 15.44. Found: C, 62. 80; H, 6.85; N, 15.40. Compound III 5-Hydroxy-3- (4-piperidinyl) -lH-indole oxalate Compound III is available by the following procedure. 5-Benzyloxy-3- [l, 2,5,6-tetrahydro-4-pyridyl] -lH-indole Starting with 5.0 grams (22 mmoles) of 5-benzyloxyindole and 6.88 grams (45 mmoles) of 4-piperidone.HCl H 2 O, 6.53 grams (97.6%) of 5-benzyloxy-3- [1, 2,5,6-tetrahydro-4-pyridyl] -lH-indole was recovered as a pale yellow solid by the procedure described for the synthesis of the 5-fluoro-3- [1, 2,5,6-tetrahydro-4-pyridyl] -lH-indole supra. The material was used in the subsequent step without further purification.

Hydrogenation / Hydrogenolysis To a solution of 1.23 g (4 mmol) of 5-benzyloxy-3- [1, 2,5,6-tetrahydro-4-pyridyl] -lH-indole in 50 ml of tetrahydrofuran: ethanol 1: 1 they added 0.3 grams of 5% palladium on carbon, and the reaction mixture was subjected to hydrogenation at room temperature for 18 hours, with an initial hydrogen pressure of 4.22 kg / cm2 (60 psi). The reaction mixture was then filtered through a celite bed, and the filtrate was concentrated under reduced pressure. The residue was converted to the oxalate salt, and 0.98 grams (80%) of compound III was recovered as a brown foam. p.f. = 67 ° C MS (m / e): 216 (M +) Calculated for C 13 H 16 N 2 O. C 2 H 2 O 4: Theory: C, 58.81; H, 5.92; N, 9.14.

Found: C, 58.70; H, 5.95; N, 9.39. Compound IV 8-chloro-2-diethylamino-l, 2,3,4-tetrahydronaphthalene hydrochloride Compound IV is available by the following procedure. 8-Chloro-2-tetralone A mixture of 30.0 grams (0.176 moles) of o-chlorophenylacetic acid and 40.0 ml of thionyl chloride was stirred at room temperature for 18 hours. The volatiles were then removed in vacuo to give 32.76 grams (99.0%) of o-chlorophenylacetyl chloride as a clear, pale yellow mobile liquid. NMR (CDC13): 7.5-7.1 (m, 4 H), 4.2 (s, 2 H). To a paste of 46.5 g (0.348 mole) of A1C13 in 400 ml of dichloromethane at -78 ° C was added a solution of 32.76 g (0.174 mole) of the o-chlorophenylacetyl chloride previously prepared in 100 ml of dichloromethane dropwise during 1 hour. The dry ice / acetone bath was then replaced with an ice / water bath, and ethylene was bubbled into the reaction mixture, and during this time the temperature rose to 15 ° C. The ethylene addition was discontinued at the end of the reaction. exotherm, and the reaction mixture was stirred at about 5 ° C for 4 hours. Then ice was added to the reaction mixture, to destroy the aluminum complexes. Upon completion of the exotherm, the reaction mixture was diluted with 500 ml of water, and stirred vigorously until all the solid had dissolved. The phases were separated, and the organic phase was washed with 3 x 400 ml of 1 N hydrochloric acid and 2 x 400 ml of saturated aqueous sodium bicarbonate. The remaining organic phase was then dried over sodium sulfate, and concentrated in vacuo to give a pale orange residue. The residue was dissolved in hexane: diethyl ether 1: 1, and poured onto a flash silica column, which was then eluted with hexane: diethyl ether 1: 1 to give a pale yellow residue, which was recrystallized from hexane: diethyl ether 4: 1 to give 10.55 g of the title compound. NMR (CDC13): 7.5-7.2 (m, 3 H); 3.7 (s, 2 H); 3.3-3.0 (t, J = 7 Hz, 2 H); 2.8-2.4 (t J = 7 Hz, 2 H). MS: 180 (60), 165 (9), 138 (100), 117 (52), 115 (50), 103 (48), 89 (20), 76 (25), 74 (18), 63 (30 ), 57 (9), 52 (28), 51 (20), 42 (6), 39 (32). IR (suspension in nujol): 2950 cm'1, 2927 cm 1, 1708 cm'1, 1464 cm 1, 1450 cm 1, 1169 cm ', 1141 cm "1. Reductive Animation To a solution of 0.5 g (2.78 mmoles) of 8-chloro-2-tetralone in 25 ml of cyclohexane were added 1.4 ml (13.9 mmol) of diethylamine, followed by 0.1 g of p-toluenesulfonic acid monohydrate The reaction mixture was then heated to reflux with constant water removal (Dean-Stark trap) for 18 hours The reaction mixture was then cooled to room temperature, and the volatile compounds were removed under reduced pressure. The residue was then dissolved in 15 ml of methanol, to which 1.5 ml of acetic acid were then added, followed by the addition in portions of 0.5 g of sodium borohydride. The reaction mixture was then stirred for 1 hour at room temperature.

The reaction mixture was then diluted with 20 ml of 10% HCl, and stirred for an additional hour. The mixture was then extracted with diethyl ether, and the remaining aqueous phase was poured onto ice, brought to basic pH with ammonium hydroxide, and extracted completely with dichloromethane. These extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was redissolved in dichloromethane, and subjected to chromatography on basic alumina, eluting with dichloromethane. The fractions that were shown to contain the product were combined and concentrated under reduced pressure. The residual oil was dissolved in diethyl ether, and the solution was saturated with hydrogen chloride. The viscous residue was crystallized from acetone / diethyl ether to give 0.20 g (23.2%) of Compound IV as colorless crystals, m.p. = 158-159 ° C MS (m / e): 273 Calculated for C14H21NC1.HC1: Theory: C, 61.32; H, 7.72; N, 5.11. Found: C, 61.62; H, 7.94; N, 5.03. Compound V 6-Hydroxy-3-dimethylamino-l, 2,3,4-tetrahydrocarbazole Compound V is available by the following procedure. Ethylene ketal of 4-dimethylamino-1-cyclohexanone To a solution of 5.0 g (32 mmol) of mono-ethylene ketal of 1,4-cyclohexanedione and 10.80 g (240 mmol) of dimethylamine was added 2.0 ml of acetic acid, and the The mixture was stirred at 0 ° C for 1.5 hours. To this solution were then added 3.62 g (58 mmol) of sodium cyanoborohydride, and the reaction was stirred for an additional hour at room temperature. The pH of the reaction mixture was adjusted to 7 with 16 ml of acetic acid, and the mixture was stirred at room temperature for 18 hours.The volatiles were removed under reduced pressure, and the residue was dissolved in 5% strength tartaric acid solution. The aqueous phase was brought to basic pH with 5 N sodium hydroxide This aqueous phase was completely extracted with dichloromethane.These organic extracts were combined and concentrated under reduced pressure to give 5.04 g (85%) of the title as an oil 4-? metUa ??? ol-cyclohexanone 4.96 g (26.8 mmoles) of ethylene ketal of 4-dimethylamino-1-cyclohexanone were dissolved in 50 ml of formic acid, and the solution was stirred at reflux for 18 hours The reaction mixture was then cooled to room temperature, and the volatiles were removed under reduced pressure, to give 3.78 g (100%) of the title compound. 6-Benzyloxy-3-dimethylamino-l, 2,3,4-tetrahydrocarbazole To a solution of 3.78 g (26.8 mmol) of 4-dimethylamino-1-cyclohexanone and 6.69 g (26.8 mmol) of 4-benzyloxy-phenylhydrazine hydrochloride in 50 g. of ethanol were added 2.17 ml (26.8 mmol) of pyridine. To this solution portions of 5 x 10 ml of water were added, and the reaction mixture was then stored at 0 ° C for 18 hours. The reaction mixture was then diluted with an additional 50 ml of water, and the mixture was completely extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the volatiles were removed under reduced pressure. The residual oil was subjected to flash chromatography on silica gel, eluting with 9: 1 chloroform: methanol. Fractions which showed to contain the desired product were combined and concentrated under reduced pressure, to give 2.14 grams (24.9%) of the title compound . Hydrogenolysis To a solution of 2.14 grams (6.7 mmoles) of 6-benzyloxy-3-dimethylamino-l, 2,3,4-tetrahydrocarbazole in 50 ml of ethanol was added 0.20 grams of 10% palladium on charcoal, and the mixture of The reaction was hydrogenated at room temperature, with an initial hydrogen pressure of 2.8 kg / cm2 (40 psi). After 5 hours, an additional charge of 0.20 grams of 10% palladium on carbon was added, and the reaction mixture was re-pressurized with hydrogen at 2.8 kg / cm2 (40 psi) for 4 hours. The reaction mixture was then filtered through a celite bed, and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on Florisil, eluting with 9: 1 chloroform: methanol. Fractions which were found to contain the desired compound were combined and concentrated under reduced pressure. The residue was again subjected to chromatography on Florisil, eluting with a gradient consisting of chloroform containing 2-10% methanol. The fractions which were shown to contain the product were combined and concentrated under reduced pressure, to give Compound V as a crystalline solid. MS (m / e): 230 (M ") Calculated for C 14 H 18 N 2 O: Theory: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.75; H, 7.83; N, 11.97. To establish that the 5-HT1F receptor subtype is responsible for mediating the neurogenic meningeal extravasation that results in migraine pain, the binding affinity of the panel compounds to the serotonin receptors was first measured, using standard procedures. For example, the ability of a compound to bind to the 5-HT1F receptor subtype was determined essentially as described in N. Adham et al., Proceedings of the National Academy of Sciences (USA), 90, 408-412 (1993 ). For comparison purposes, binding affinities of the compounds to other serotonin receptors were determined, essentially as described below, except that different cloned receptors were used in place of the 5-HT1F receptor clone employed herein.

Membrane Preparation Membranes were prepared from transfected Ltk cells, which were grown at 100% confluence. The cells were washed twice with phosphate-buffered saline, scraped from the culture plates in 5 ml of ice-cold phosphate-buffered saline, and subjected to centrifugation at 200 xg for 5 minutes at 4 ° C. pellet was resuspended in 2.5 ml of ice-cold Tris buffer (20 mM Tris HCl, pH = 7.4 at 23 ° C, 5 mM EDTA), and homogenized with a Wheaton tissue mill. The lysate was subsequently subjected to centrifugation at 200 x g for 5 minutes at 4 ° C, to agglomerate the large fragments, which were discarded. The supernatant was collected and subjected to centrifugation at 400.00 xg for 20 minutes at 4 ° C. The pellet resulting from this centrifugation was washed once in ice-cold Tris wash buffer and resuspended in ice. a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH = 7.4 at 23 ° C. The membrane preparations were kept on ice, and were used within two hours for the radioligand binding assays. Protein concentrations were determined by the Bradford method (Anal. Biochim., 72, 248-254 (1976)). Radioligand binding The binding to [3H 5-HT] was determined using slight modifications of the test conditions for 5-HT1D reported by Herrick-Davis and Titeler (J: Neurochem. , 50, 1624-1631 (1988)), with the omission of masking the ligands. Radioligand binding studies were carried out at 37 ° C, in a total volume of 250 ml of buffer solution (50 mM Tris, 10 M MgCl 2, 0.2 mM EDTA, 10 mM pargyline, 0.1% ascorbate, pH = 7.4 a 37 ° C) in 96-well microtiter plates. Saturation studies were conducted using [3 H] 5-HT in 12 different concentrations, which were in the range from 0.5 nM to 100 nM. The displacement studies were performed using [3H] 5-HT 4.5-5.5 nM. The binding profile of the drugs in competition experiments was determined using 10-12 concentrations of the compound. The incubation times were 30 minutes for both studies, saturation and displacement, based on initial investigations that determined the equilibrium binding conditions. The non-specific binding was defined in the presence of 10 mM 5-HT. The binding was initiated by the addition of 50 ml of membrane homogenates (10-20 mg). The reaction was terminated by rapid filtration through pre-wetted filters (0.5% polyethylene-cinine), using a Brandel 48R Cell Harvester (Gaithersburg, MD). Subsequently, the filters were washed for 5 seconds with ice-cold buffer (50 mM Tris HCl, pH = 7.4 at 4 ° C), dried and placed in flasks containing 2.5 ml of Readi-Safe (Beckman, Fullerton, CA ), and the radioactivity was measured using a Beckman LS 5000TA liquid scintillation counter. The efficiency of the [3H] 5-HT count averaged between 45-50%. Junction data were analyzed by computer-assisted non-linear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). The IC 50 values were converted to K values, using the Cheng-Prusoff equation (Biochem Pharmacol., 22, 3099-3108 (1973)). All the experiments were performed in triplicate. The results of these binding experiments are summarized in Table I. TABLE I SUBTITLES OF RECEIVER (5-HT,) THAT BIND TO SEROTONINE (Ki nm) Compound 5-HT1Da 5-HT1Db 5-HT1E 5-HT1F I 4.8 9.6 2520.0 25.7 II 21.7 53.6 50.3 2.5 III 163.2 196.5 3.9 22.0 IV 13.5 145.3 813.0 129.2 V 791.0 1683.0 73.6 10.3 As reported by RL Weinshank et al., WO93 / 14201, the 5-HTIF receptor is functionally coupled to a G protein, measured by the ability of serotonin and serotonergic drugs to inhibit the production of forskolin-stimulated cAMP in NIH3T3 cells transfected with the 5-HT1F receptor. The activity of adenylate cyclase was determined using standard techniques. A maximum effect is achieved by serotonin. An E ^ is determined by dividing the inhibition of a test compound by the maximum effect, and determining a percent inhibition. (N. Adham et al., Supra; R. L. Weinshank et al. , Proceedings of the National Academy of Sciences (USA), 89, 3630-3634 (1992)), and references cited therein. Measurement of cAMP formation Transfected NIH3T3 cells (estimated Bmax from competition studies of one point = 488 f ol / mg protein) were incubated in DMEM, 5 mM theophylline, 10 mM HEPES (4- [2-hydroxyethyl] - l-piperazinetanesulfonic acid) and 10 mM pargyline for 20 minutes at 37 ° C, and 5% CO2. The drug-effect concentration curves were then conducted, adding 6 different final concentrations of the drug, followed immediately by the addition of forskolin (10 mM). Subsequently, the cells were incubated for an additional 10 minutes at 37 ° C, and 5% CO2. The medium was aspirated, and the reaction stopped by the addition of 100 mM HCl. To demonstrate competitive antagonism, a concentration-response curve for 5-HT was measured in parallel, using a fixed dose of methiothepin (0.32 mM). The plates were stored at 4 ° C for 15 minutes, and then subjected to centrifugation for 5 minutes at 500 xg, to agglomerate the cellular debris, and the supernatant was aliquoted and stored at -20 ° C before determination of the formation of cAMP by radioimmunoassays (kit for radioimmunoassay of cAMP; Advanced Magnetics, Cambridge, MA). Radioactivity was quantified using a Packard COBRA Auto Gamma counter, equipped with programming elements for data reduction.

All tested compounds were found to be antagonists at the 5-HTIF receptor in the cAMP assay. The following test was performed to determine the ability of the panel compounds to inhibit protein extravasation, which is a functional assay for the neuronal mechanism of migraine. The results of this test are summarized in Table II. Protein Extravasation Assay Harian Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) were anesthetized with intraperitoneally sodium pentobarbital (65 mg / kg or 45 mg / kg respectively), and placed in a stereotaxic structure (David Kopf Instruments), with the incisor bar fixed at -3.5 mm for rats, or -4.0 mm for guinea pigs. Following a sagittal incision in the midline of the scalp, two pairs of bilateral holes were drilled through the skull (6 mm posteriorly, 2.0 and 4.0 mm laterally in rats, 4 mm posteriorly and 3.2 and 5.2 mm laterally in the guinea pigs, all coordinates with reference to the bregma). Pairs of stainless steel stimulation electrodes, insulated except at the ends (Rhodes Medical Systems, Inc.), were inserted through the holes in both hemispheres, at a depth of 9 mm (rats) or 10.5 mm (guinea pigs) of the hard. The femoral vein was exposed, and a dose of the test compound (1 ml / kg) was injected intravenously. Approximately 7 minutes later, a dose of 50 mg / kg Evans Blue, a fluorescent dye, was also injected intravenously. Evans Blue was complexed with proteins that were found in the blood, and functioned as a marker for the extravasation of proteins. Exactly 10 minutes post-injection of the test compound, the left trigeminal ganglion was stimulated for 3 minutes, at a current intensity of 1.0 mA (5 Hz, 4 msec) with a potenciostat / galvanostat Model 273 (EG &G Princeton Applied Research ). Fifteen minutes following the stimulation, the animals were sacrificed and exsanguinated with 20 ml of saline. The upper part of the skull was removed to facilitate the collection of the dural membranes. The membrane samples were removed from both hemispheres, rinsed with water, and spread horizontally on microscopic slides. Once dry, the tissues were peeled off with a 70% glycerol / water solution. A fluorescence microscope (Zeiss) was used, equipped with a grid monochromator and a spectrophotometer to quantify the amount of Evans Blue dye in each sample. An excitation wavelength of about 535 nm was used, and the emission intensity at 600 nm was determined. The microscope was equipped with a motorized platform, and it was also interconnected with a personal computer. This facilitated the computer controlled movement of the platform, with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The average and standard derivation of the measurements was determined by the computer. The extravasation induced by electrical stimulation of the trigeminal ganglion was an ipsilateral effect (ie, it occurs only on the side of the dura in which the trigeminal ganglion was stimulated). This allows the other (unstimulated) half of the dura to be used as a control. The ratio of the amount of extravasation in the dura of the stimulated side, compared to the unstimulated side, was calculated. Saline controls provided a ratio of approximately 2.0 in rats, and 1.8 in guinea pigs. In contrast, a compound that effectively prevented extravasation in the dura of the stimulated side would have a ratio of approximately 1.0. A dose-response curve was generated, and the dose that inhibited extravasation by 50% (IDjo) was approximated. TABLE II Inhibition of Protein Extravasation (ID ^ mMol / kg) TDn Compound i.v. (mMol / kg) I 2.6 x 10"8 II 8.0 x 1010 III 8.9 x 10" 9 IV 1.2 x lO'7 V 8.7 x lO'9 To determine if there was a relationship between the affinity of binding to each of the receptors 5-HTIDa, 5-HT1Db 5-HT1E and 5-HT1F and the extravasation of the neuronal protein, the binding affinity for each receptor subtype was plotted against its ID50 in the protein extravasation model. A linear regression analysis was performed on each group of data, and a correlation factor, R2, was then calculated. The results of this analysis are summarized in Table III. TABLE III Correlation Factor (R2) for the Affinity of Union Specific to the Subtype 5-HT? vs Inhibition of Protein Extravasation Subtype 5-HT? Correlation Factor (R2) 5-HT, Dl 0.07 5-HT1Db 0.01 5-HT1E 0.31 5-HT1 F 0.94 An ideally linear relationship would generate a correlation factor of 1.0, indicating a cause and effect relationship between the two variables. The correlation factor determined experimentally between the inhibition of neuronal protein extravasation and the binding affinity of 5-HT1F is 0.94. This almost linear dependence of the IDJ0 on the protein extravasation model on the binding affinity to the 5-HT1F receptor clearly demonstrates that the 5-HT receptor mediates the irihiBlation of neuronal protein extravasation resulting from ganglion stimulation. trigeminal As defined above, the partial agonists of the 5-HT? they may also be useful for the method of this invention. Dihldroergotamine, for example, of the following structure, is a commercially available treatment for migraine: It was shown that dihydroergotamine, when tested in the above assays, binds to the 5-HT? F receptor (Ki = 276 nM), and was still shown in the cAMP assay to be a partial agonist in the receptor of 5-HT1F (Emax = 49.5%). When tested in the neuronal protein extravasation assay, it was shown that dihydroergotamine was a fully effective inhibitor of neuronal protein extravasation (ID50 = 2.43 x 10"8 mMoles / kg), reaching a ratio of 1.0 when compared The sides of the dura It is known that dihydroergotamine is a potent vasoconstrictor (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8ava Edition, 943-947, Pergamon Press, New York, (1990)), and as such would not be a useful compound for the present invention. While a compound must have agonist activity at the 5-HT1F receptor to be useful for the method of this invention, it is imperative that it does not demonstrate appreciable vasoconstrictor effects. Compounds I, U, IV and V of the panel were subsequently tested in the following assay to measure their ability to mediate vasoconstriction in the rabbit saphenous vein. The data of this trial are summarized in Table IV. Contraction of the Rabbit Saphenous Vein New Zealand White male rabbits (1.36-2.72 kg, 3-6 lbs) (Hazleton, Kalamazoo, MI) with a lethal dose of sodium pentobarbital (325 mg) injected into the vein of the artery. Connective tissue-free tissues were dissected, cannulated in situ with polyethylene hose (PE50, outer diameter = 0.97 mm), and placed in petri dishes containing Kreb's bicarbonate buffer (described infra). The tips of two hypodermic needles of 30 gauge stainless steel curved in an L-shape slipped into the polyethylene tube. Blood vessels were gently urged from the cannula to the needles. The needles were then separated, so that the lower needle was attached with thread to a stationary glass rod, and the upper needle was connected with wire to the transducer. Tissues were mounted in organ baths containing 10 ml of modified Krebs solution, of the following composition: NaCl 118.2 mmole, KCI 4.6 mmole, CaCl2.H2O 1.6 mmole, K2HPO4 1.2 mmole, MgSO4 1.2 mmole, dextrose 10.0 mmole and NaHCO3 24.8 mmoles. Tissue bath solutions were maintained at 37 ° C, and air was supplied with 95% O2 and 5% CO2. An optimal optimal latent force of 1 gram was applied to the saphenous vein. Isometric contractions were recorded as changes in grams of force in a Beckman Doppler with Statham UC-3 transducers and junctions for microscale fittings. The tissues were allowed to equilibrate 1 to 2 hours before exposure to drugs. Cumulative agonist-response concentration curves were generated in tissues, and no tissue was used to generate more than two agonist-response concentration curves. All results were expressed as an average EC50, and the maximum response was expressed as a percentage of the response to 67 mM KCI administered initially in each tissue.

Table IV Contraction of the Saphenous Vein of Rabbit Contraction of the Vein Contraction of the Vein Rabbit Saphenous Rabbit Saphenous Compound ECS0 (M) (% Max. KCl) * I 6.6 x 10-7 64.20 II 1.0 x 10- * 13.72 IV 1.0 x 10"6 67.16 V> 1.0 x 10" 12.44 * Any given maximum response, or response to 10"* M, if the maximum contraction is not achieved This vasoconstriction test measures Two important parameters, the saphenous vein contraction (ECJ0) and the maximum contraction as a% of the maximum KCl response, contraction of the saphenous vein (EC »,) is a measure of the dose required to contract the tissue. 50% of the maximum response that the specific compound is capable of mediating.The maximum response that the saphenous vein is capable of exhibiting is measured after the administration of a high concentration (67 mM) of KCl.% Maximum contraction per KCl is the ratio of the maximum response that the specific compound is capable of mediating, divided by the maximum response that the tissue can produce.

The data presented in Tables II and IV clearly show that the panel compounds differ substantially in their ability to inhibit the extravasation of the neuronal protein, and of mediating vasoconstriction. The specificity required for the method of this invention is defined as a separation of the ability to mediate vasoconstriction relative to -HT-mediated inhibition, F of extravasation of the neuronal protein.

One measure of this specificity is the relationship of vasoconstriction to efficacy in the inhibition of the extravasation of the neuronal protein. This relationship, defined as the Specificity index, is presented in table V for the compounds of the panel, where: Specificity index = Vasoconstriction Corrected EC! (M) ID50 Extravasation (mmoles / kg) TABLE V Specificity index Vasoconstriction relative to 5-HT1F-mediated inhibition of extravasation of neuronal protein B A Vasocons- Extravasation triction INDEX OF ID5ß Corrected SPECIFICITY Compound (mMol / kg) (EC50 (M) * B / A RELATIONSHIP) I 2.6 x 10 * 1.03 x 10 * 0.40 II 8.0 x 10 10 7.29 x 10 * 91.12 IV 1.2 x 10"7 1.49 1o9 0.01 V 8.7 x 10-9> 8.03 x 10 '> 923.00 * To correct the values of EC50 for the contraction of the saphenous vein, so that the maximum contraction relative to KCl for each individual compound can be taken into consideration, the vasoconstriction value ID ^ is divided by the% of maximum contraction by KCl to give the "ECJQ ( M) of corrected vasoconstriction. "Compounds II and V exemplify the typical specificity for the compounds useful for the method of this invention, with specificity indices of 91.12 and> 923 respectively.Compounds I and IV, in comparison, while exhibit a significant component of activity on 5-HT1F, do not exhibit any of the desired specificity Sumatriptan (Compound I), a commercial treatment for migraine, barely distinguishes between the two activities, demonstrating greater efficacy by vasoconstriction Ion Compound IV has a much greater capacity to mediate vasoconstriction than to inhibit extravasation of the neuronal protein. The desirability of a compound or composition for use in the method of the present invention, therefore, is determined as follows: 1. Demonstration of affinity for the 5-HT receptor, F, using the method of binding to a radioligand described above; 2. Once the affinity for the 5-HT? F receptor is established, the determination of the agonist, partial agonist or antagonist character is made by the measurement in the cAMP assay previously described; 3. If the compound or composition is shown to be an agonist or partial agonist, with an E ^ of at least about 50%, it is tested to measure the inhibition efficiency of protein extravasation and contraction of the saphenous vein. , using the tests previously described; and 4. Calculate the Specificity index as shown above. While a compound or composition with a Specificity index greater than 1 is useful for the method of this invention, larger values are preferred for the Specificity index. A higher specificity index indicates a greater specificity for the efficacy in the inhibition of extravasation of the neuronal protein on vasoconstriction. The following ranges for the Specificity index are representative of the specificity of the compounds or compositions useful for the invention, and are not intended to limit the invention in any way. A Specificity Index greater than 1. A Specificity Index of a. minus 5. A Specificity Index in the range of 5-10,000. A Specificity Index in the range of 5-1, 000. A Specificity index in the range of 5-100. A Specificity index in the range of 5-10. A Specificity Index of at least 10. A Specificity Index in the range of 10-10, 000 A Specificity index in the range of 10-1, 000. A Specificity index in the range of 10-1,000. A Specificity index in the range of 10-100. A Specificity index of at least 100. A Specificity index in the range of 100-10,000. An Index of Specificity in the range of 100-10,000. An Index of Specificity in the range of 100-1,000. A Specificity Index of a! minus 1,000. A Specificity index in and interval of 1,000-10,000. An Index of Specificity in and interval of 2,000-10,000.

A Specificity Index in the range of 2,000-5,000. A Specificity Index in the range of 4,000-10,000. A Specificity index in the range of 6,000-10,000. A Specificity index in the range of 8,000-10,000. A Specificity Index of at least 10,000. In summary, the utility of a compound or a composition in a method for the treatment of migraine pain and associated disorders without substantial side effects caused by vasoconstriction is determined by its Specificity index. The Specificity index is the ratio of vasoconstriction to efficacy in the inhibition of extravasation of the neuronal protein. The measurement of the ability of a compound or composition to inhibit the extravasation of the neuronal protein is a functional assay for the physiological events that give rise to the pain of migraine. It has been shown that the extravasation of the neuronal protein is inhibited by 5-HT1F receptor antagonists. While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are generally administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes, including oral, buccal, rectal, transdermal. subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art, and comprise at least one active compound. See, for example. REMINGTON'S PHARMACEUTICAL SCIENCES, (lóava edition, 1980). To make the compositions employed in the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or included within such a carrier, which may be in the form of a capsule, sachet, paper or another container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, diamond-shaped tablets, sachets, seals, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments which they contain for example up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, and sterile packaged powders. When preparing a formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by milling it, to provide a substantially uniform distribution in the formulation, for example to about 40 meshes. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agent; emulsifying and dispersing agents; preservatives such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide a rapid, sustained or delayed release of the active ingredient after its administration to the patient., employing procedures known in the art. The compositions are preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compounds are generally effective over a broad dosage range. However, it will be understood that the amount of the compound administered will effectively be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the route of administration selected, the effective compound or compounds administered, the age , weight, and response of the individual patient, and the severity of the patient's symptoms. The following doses are for the purposes of example only, and are not intended to limit the scope of the invention in any way. In some cases, dosage levels below the amount of the example may be more suitable, while in other cases even larger doses may be employed without causing any harmful side effects, provided that such larger doses are divided first. in several smaller doses for administration throughout the day.

Formulation Example 1 Hard gelatine capsules containing the following ingredients are prepared: Quantity Ingredient (mg / capsule) Compound II 30.0 Starch 305.0 Magnesium Stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules, in amounts of 340 mg. Formulation Example 2 A formula for tablets is prepared using the ingredients below: Amount Ingredient (mg / tablet) Compound V 25.0 Cellulose, mirocrystalline 200.0 Colloidal silicon dioxide 5.0 Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Formulation Example 3 A dry powder inhalation formulation is prepared, containing the following components: Ingredient% by Weight Compound II 5 Lactose 95 The active mixture is mixed with the lactose, and the mixture is added to a device for inhalation of dry powder . Formulation Example 4 Tablets are prepared, each containing 30 mg of active ingredient, as follows: Ingredient (mg / tablet) Compound V 30.0 Starch 45.0 Microcrystalline cellulose 35.0 Polyvinylpyrrolidone 4.0 (as a 10% solution in water) Carboxymethyl sodium starch 4.5 Magnesium stearate 0.5 Talcum 1.0 Total 120.0 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. , and they mix thoroughly. The solution of polyvinyl pyrrolidone is mixed with the resulting powders, which are then passed through a sieve or mesh 16 U.S. The granules produced in this manner are dried at 50-60 ° C, and passed through a 16 U.S. mesh screen. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a 30 US mesh screen, are then added to the granules, which, after mixing, are compressed in a tableting machine to provide tablets. , each weighs 120 mg. Formulation Example 5 Capsules are made, each containing 40 mg of medicament, as follows: Amount Ingredient (mg capsule) Compound II 40.0 Starch 109.0 Magnesium stearate 1.0 Total 150.0 The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a No. 20 mesh U.S. sieve, and deposited in hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories are made, each containing 25 mg of active ingredient, corr follows: Ingredient Amount Compound V 25 mg Glycerides of saturated fatty acid at 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. , and is suspended in the previously melted saturated fatty acid glycerides, using the minimum necessary heat. The mixture is then emptied into a suppository mold of nominal 2.0 g capacity, and allowed to cool. Formulation Example 7 Suspensions are made, each containing 50 mg of medication per 5.0 ml dose, as follows: Ingredient Amount Compound II 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and color q. v. Purified water at 5.0 ml The drug, sucrose and xanthan gum are mixed, passed through a No. 10 mesh U.S. , and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color, are diluted with some of the water and added with agitation. Sufficient water is then added to produce the required volume. Formulation Example 8 Capsules are made, each containing 15 mg of medication, as follows: Ingredient (mg / capsule) Compound V 15.0 Starch 407.0 Magnesium stearate 3.0 Total 425.0 The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a No. 20 mesh U.S. sieve, and deposited in hard gelatin capsules in amounts of 425 mg. Formulation Example 9 An intravenous formulation can be prepared as follows: Ingredient AmountCompound II 250.0 mg Isotonic saline 1000 ml Formulation Example 10 A topical formulation can be prepared as follows: Ingredient Amount Compound V 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft white paraffin at 100 g The soft white paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and stirred until they dissolve. The active ingredient is added, and it is stirred until it disperses. The mixture is then cooled until solidified. Formulation Example 11 Sublingual or buccal tablets can be prepared, each containing 10 mg of active ingredient, as follows: Amount Ingredient Per Tablet Compound II 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 mg Total 410.0 mg Glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinyl pyrrolidone are mixed together by continuous stirring, and maintaining the temperature at about 90 ° C. When the polymers have dissolved, the solution cools to about 50-55 ° C, and the medication is slowly mixed. The homogenous mixture is poured into forms made of an inert material, to produce a diffusion matrix containing the drug having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention, in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, the U.S. Patent. No. 5,023,252, filed June 11, 1991, incorporated herein by reference. Such patches can be constructed for continuous, pulsatile summation, or at the request of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the placement of a catheter for the delivery of drugs into the ventrocular system of the host, to bypass the blood-brain barrier. This implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in the U.S. patent. No. 5,011,472, filed April 30, 1991, which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide latency of the drug by the conversion of hydrophilic drugs to lipid-soluble drugs or prodrugs. Latency is usually achieved by blocking the hydroxy, carbonyl, sulfate, and primary amino groups present in the drug, to make the drug more soluble in lipids, and more available for transportation through the blood barrier. -brain. Alternatively, the supply of hydrophilic drugs can be improved by intra-arterial infusion of hypertonic solutions, which can transiently open the blood-brain barrier. The type of formulation used for the administration of the compounds used in the methods of the present invention can be dictated by the particular compounds employed, the type of pharmacokinetic profile desired, the route of administration and the compound (s), and the patient's condition.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (7)

1. CLAIMS 1. The use of a 5-HT1F agonist exhibiting minimal vasoconstrictive properties, the use is characterized because it is for the manufacture of a medically for the prevention or treatment of migraine pain.
2. 2. The use of a 5-HT1F agonist exhibiting minimal vasoconstrictive properties, the use is characterized in that it is for the manufacture of a medically for the inhibition of neurogenic meningeal extravasation.
3. 3. The use of a 5-HT1F agonist according to any of claim 1 or claim 2, the use is characterized in that the 5-HT1F agonist has a Specificity index in the range of 5-10,000.
4. 4. The use of a 5-HT1F agonist according to any of claim 1 or claim 2, the use is characterized in that the 5-HTIF agonist has a specificity index of at least 10.
5. 5. The use of a 5-HT agonist, F according to any of claim 1 or claim 2, the use is characterized in that the 5-HTIF agonist has a specificity index of at least 100.
6. 6. The use of an agonist of 5-HT1F according to any of claim 1 or claim 2, the use is characterized in that the 5-HT1F agonist has a Specificity index of at least 1000.
7. 7. The use of a 5-HT1F agonist according to any of claim 1 or claim 2, the use is characterized in that the 5-HT1F agonist has a Specificity index of at least 10,000.