MXPA99011242A - Carboxamides useful as 5-ht1f - Google Patents

Abstract

The present invention provides novel 2-amino-1,2,3, 4-tetrahydro-9H-carbazole-6-carboxamides and 3-amino-10H-cyclohepta[7, 6-b]indole-7-carboxamides of Formula (I), where R1, R2, R3 and n are as described in the specification.

Description

CARBOXAMIDES USEFUL AS 5-HT1P AGONISTS DESCRIPTION OF THE INVENTION Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Olff (Arch. Neurol, Psychiatry, 39, 737-63 (1938)). They have proposed that the cause of the migrainous headache was the vasodilation of the extracranial vessels. This view was supported by the knowledge that alkaloids of rye ergot and sumatriptan, a 5-HT? hydrophilic which does not cross the blood-brain barrier, contract cephalic vascular smooth muscle and are effective in the treatment of migraine (Humphrey, et al., Ann., NY Acad. Sci., 600, 587-600 (1990). Recent work by Moskowitz has shown, however, that the onset of migraine headaches is dependent on changes in vessel diameter (Cephalalgia, 12, 5-7, (1992).) Moskowitz has proposed that triggers currently unknown for pain stimulate the trigeminal ganglia that innervate the vasculature within the cephalic tissue, giving rise to the release of REF: 32073 the vasoactive neuropeptides from the axons on the vasculature.These released neuropeptides then activate a series of events, a As a consequence of this pain, this neurogenic inflammation is blocked by sumatriptan and ergot alkaloids through mechanisms that involve the 5-HT receptors, which and it is thought that they are closely related to the subtype 5-HT1D, located in the trigeminovascular fibers (Neurology, £ 3 (suppl. 3), S16-S20 (1993)). Serotonin (5-HT) shows diverse physiological activities mediated by at least four receptor classes, the most heterogeneous of which appears to be 5-HT ?. A human gene expressing a fifth 5-HT subtype, called 5-HTαF, was isolated by Kao et al. (Proc Nati, Acad Sci USA, 90, 408-412 (1993)). This 5-HT1F receptor shows a pharmacological profile distinct from any serotonergic receptor still described. The high affinity of sumatriptan in this subtype, Ki = 23 nM, suggests a role for the 5-HT? F receptor in migraine. A series of N-aryl-3-amino-1,2,4,4-tetrahydro-9H-carbazole-6-carboxamides have been described by Porter et al. (WO 94/14773, July 7, 1994) as agonists similar to 5-HTx, which showed vasoactive effects. The amides of the present invention are 5-HT? F agonists that inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders without the vasoconstrictive responsibility of the compounds structurally similar. The present invention provides the novel 3-amino-1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamides and the 4-amino-lOH-cyclohepta [7, 6-b] indole-7-carboxamides of the Formula I: wherein: R1 and R1 are independently hydrogen, alkyl of 1 to 4 carbon atoms, or -CH2CH2-aryl wherein aryl is phenyl, phenyl monosubstituted with halo, or 1- (alkyl of 1 to 6 carbon atoms) pyrazole- 4 - i 1 o; R3 is cycloalkyl of 3 to 6 carbon atoms, or a heterocycle; n is 1 or 2; and the pharmaceutically acceptable salts and hydrates thereof. A further embodiment of this invention is a method for increasing the activation of the 5-HT1F receptor by administration of a compound of Formula I. A further embodiment of this invention is a method for increasing the activation of the 5-HT? F receptor to the treatment of a variety of disorders that have been related to decreased neurotransmission of serotonin in mammals. Included in these disorders are depression, migrainous pain, bulimia, premenstrual syndrome or late luteal phase syndrome, dysphoric disorder, alcoholism, tobacco abuse, panic disorder, anxiety, general pain, post-stroke syndrome, traumatic, loss of memory, dementia due to aging, social phobia, attention deficit hyperactivity disorder, destructive behavior disorders, impulse control disorders, borderline personality disorders, obsessive-compulsive disorder, chronic fatigue syndrome, premature ejaculation , erectile difficulty, anorexia nervosa, sleep disorders, autism, mutism, trichotillomania, trigeminal neuralgia, dental pain or pain due to temporomandibular joint dysfunction. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employ a compound of Formula I. In addition, this invention provides pharmaceutical formulations comprising an effective amount for the application of the 5-HT? F receptor of a compound of Formula I, in combination with a carrier, diluent, or pharmaceutically acceptable excipient. The general chemical thermals used in the above formulas have their usual meanings. For example, the term "alkyl" includes groups such as methyl, ethyl, n-propyl-isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like The term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl , and cyclohexyl. The term "alkoxy" includes groups such as methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. The term "halo" includes fluoro, chloro, bromo, and iodo. The term "heterocycle" is taken to mean fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyridin-3-yl, pyridin-4-yl, pyrrole-3. -yl, N-methylpyrrol-3-yl, oxazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, pyrazol-4-yl, pyrimidin-5-yl or pyrazin-4-yl. These heterocycles contain unsubstituted carbon atoms Up to three available carbon atoms within any heterocyclic system may be optionally substituted with substituents independently selected from the group consisting of halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkoxycarbonyl of 1 to 4 carbon atoms The compounds of the present invention possess an asymmetric carbon.This carbon is marked with an asterisk in the following formula: R1 \ N-Rs As such, each of the compounds of the present invention exists not only as a racemate but as the R- and S- enantiomers as well: Enantiomer R Enantiomer S The compounds of the present invention include not only the racemates, but also their respective optically active R- and S-enantiomers and any mixture thereof. While all racemates, mixtures, and individual enantiomers are useful 5-HT1F agonists, it is preferred that the compound exists as a single enantiomer. While all of the compounds of this invention are useful as 5-HT? F agonists, certain classes are preferred. The following paragraphs describe such preferred classes, aa) R1 is hydrogen; ab) R1 is alkyl of 1 to 6 carbon atoms; ac) R1 is ethyl; ad) R1 is methyl; ae) R1 is -CH2CH: -Ar where Ar is 1- (alkyl of 1 to 6 carbon atoms) pyrazol-4-yl; af) R1 is -CH2CH2-Ar where Ar is 1-methylpyrazol-4-yl; ag) R1 is -CH2CH2-Ar where Ar is 1-isopropylpyrazol-4-yl; ah) R2 is hydrogen; ai) R2 is alkyl of 1 to 6 carbon atoms; aj) R2 is ethyl; ak) R2 is methyl; al) R2 is -CH2CH2-Ar where Ar is 1- (C6-C6 alkyl) pyrazol-4-yl; am) R2 is -CH2CH2-Ar where Ar is 1-methylpyrazol-4-yl; an) R2 is -CH2CH2-Ar where Ar is 1-isopropylpyrazol-4-yl; ao) R3 is heterocycle; ap) R 3 is pyridin-3-yl; aq) R3 is pyridin-4-yl; ar) R3 is pyridin-3-yl or pyridin-4-yl monosubstituted with halo; as) R3 is pyridin-3-yl or pyridin-4-yl monosubstituted with chlorine; at) R 3 pyridin-3-yl or pyridin-4-yl monosubstituted with fluoro; au) R3 is fur-2-yl or fur-3-yl; av) R3 is thien-2-yl or thien-3-yl; aw) R3 is pyrrol-3-yl; ax) R3 is oxazol-5-yl; a) R3 is isoxazol-4-yl or isoxazol-5-yl; az) R 3 is pyrazol-4-yl; ba) R3 is pyrimidin-5-yl; bb) R3 is pyrazin-4-yl; be) R3 is fur-2-yl or fur-3-yl optionally substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; bd) R3 is fur-2-yl; be) R3 is fur-3-yl; bf) R3 is thien-2-yl or thien-3-yl optionally substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; bg) R3 is thien-2-yl; bh) R3 is thien-3-yl; bi) R3 is pyridin-3-yl or pyridin-4-yl optionally substituted with halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; bj) R3 is 6-halopyridin-3-yl; bk) R3 is cycloalkyl of 3 to 6 carbon atoms; bl) R3 is cyclopropyl; bm) n is 1; bn) n is 2; bo) The compound is a racemate; bp) The compound is the R-enantiomer; bq) The compound is the S-enantomer; br) The compound is a free base; bs) The compound is a salt; bt) The compound is the hydrochloride salt; bu) The compound is the fumarate salt; bv) The compound is the oxalate salt. It will be understood that the above classes can be combined to form additional preferred classes. The compounds of this invention are useful in a method for increasing the activation of the 5-HT? F receptor for the treatment of a variety of disorders which have been related to decreased neurotransmission of serotonin in mammals. It is preferred that the mammal to be treated by the administration of the compounds of this invention is a human. Since the compounds of this invention are amines, they are basic in nature and consequently react with any of a number of organic and inorganic acids to form pharmaceutically acceptable acid addition salts. Since some of these free amines of the compounds of this invention are typically room temperature oils, it is preferable to convert the free amines to their salts by the addition of pharmaceutically acceptable acids, to facilitate handling and administration, since the latter are routinely solid at room temperature. The acids commonly used to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts in this way are the salts of sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexin-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid, oxalic acid or fumaric acid. The following group is illustrative of the compounds contemplated within the scope of this invention: N- (4-meth ilthien-2-yl) -3- (propyl) amino- 1,2,3,4-tetrahydro-9H- hydrochloride carbazole-6-carboxamide; (+) - N - (thien-3-yl) -3- (dimethyl) amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide sulfate; N- (4-chlorofur-2-yl) -3- (propyl) amino-1, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide; N- (fur-3-yl) -3- (diethyl) amino-1, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide; N- (pyridin-3-yl) -3- (diethyl) amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide phosphate; N- (3-chloropyridin-4-yl) -3- (diethyl) amino- 1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamide; N- (oxazol-5-yl) -3- (propyl) amino- 1, 2, 3, 4-tetrahydro-9H-carbazole-β-carboxamide p-toluenesulfonate; (+) - N- (isoxazol-4-yl) -3- (dimethyl) amino- 1, 2, 3, -tetrahydro-9H-carbazole-6-carboxamide; N- (pyrazol-4-yl) -3- (propyl) amino- 1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamide methanesulfonate; N- (cyclobutyl) -3- (diethyl) amino-, 1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide oxalate; N- (cyclohexyl) -3- (propyl) amino-1,2,3-tetrahydro-9H-carbazole-6-carboxamide; formate of (+) - N - (2-methylpyrimidin-5-yl) -3- (dimethyl) amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide; (-) -N- (thien-2-yl) -4- (methyl) amino-10H-cyclohepta [7, 6-b] indole-7-carboxamide; N- (thien-3-yl) -4- (dimethyl) amino-lOH-cyclohepta [7, 6-b] i do1-7-carboxamide butyn-1,4-dioate; N- (fur-2-yl) -4- (propyl) amino-10H-cyclohepta [7,6-b] indol-7-carboxamide; N- (fur-3-yl) -4- (diethyl) amino-lOH-cyclohepta [7, 6-b] -ido1-7-carboxamide trifluoroacetate; N- (pyridin-3-yl) -4- (diisopropyl) amino-10H-cyclohepta- [7,6-b] indole-7-carboxamide; N- (3-chloropyridin-4-yl) -4- (dibutyl) amino-10H-cyclohepta [7, 6-b] indole-7-carboxamide; (-) - N- (pyrrol-3-yl) -4- (methyl) amino-lOH-cyclohepta [7, 6-b] indo-1-carboxamide tartrate; N- (2-isopropyloxazol-5-yl) -4- (dimethyl) amino-10H-cyclohepta [7,6-b] i dol- 7 -carboxamide; N- (3-bromo-4-methylisoxazol-5-yl) -4- (propyl) amino-lOH-cyclohepta [7, 6-b] indole-7-carboxamide cinnamate; N- (3-ethylpyrazol-4-yl) -4- (diethyl) amino-10H-cyclohepta [7, 6-b] i do1-7-carboxamide; N- (cyclopro-yl) -4- (diisopropyl) amino-lOH-cyclohepta- [7,6-b] indole-7-carboxamide; N- (cyclohexyl) -4- (dibutyl) amino-lOH-cyclohepta- [7,6- b] indo-1-carboxamide mandelate; (-) -N- (2-methoxypyrimidin-5-yl) -4- (methyl) amino-lOH-cyclohepta- [7,6-b] indole-7-carboxamide; N- (2-fluoropyrazin-4-yl) -4- (dimethyl) amino-lOH-cyclohepta- [7,6-b] indole-7-carboxamide; N- (2-cyclobutyl) -4- (propyl) amino-10H-cyclohepta- [7,6- b] indole-7-carboxamide; N- (cyclopentyl) -4- (diethyl) amino-lOH-cyclohepta- [7,6-b] indole-7-carboxamide 4-methoxybenzoate; N- (cyclohexyl) -4- (diisopropyl) amino-lOH-cyclohepta- [7,6-b] indole-7-carboxamide. The compounds of this invention are prepared by methods well known to one of ordinary skill in the art. The compounds of the present invention wherein n is 1 are members of the class commonly known as 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides.

The members of this class are conveniently prepared by the synthesis of Fischer indole, as described in Synthetic Scheme I where R1 'and R2' are independently alkyl of 1 to 6 carbon atoms, or benzyl, together with the nitrogen to which they are united, form a phthalimido group, and R3 is as previously defined.

SYNTHETIC SCHEME I Phenylhydrazine and 4-aminocyclohexanone are condensed together in a suitable solvent, typically a lower alkanol such as ethanol, in the presence of a catalytic amount of acid, such as hydrogen chloride, to give the resulting phenylhydrazone. The reaction is typically carried out from about room temperature to the reflux temperature for about 1 to 24 hours. Once the condensation is complete, the resulting phenylhydrazone can be isolated from the reaction mixture by the addition of water or an aqueous solution of a base such as potassium carbonate, if desired. The product is separated from the mixture as an oil or as a solid. The product can be extracted as a non-miscible solvent in water, typically dichloromethane, or filtered if appropriate. The product can be used in the next step with or without additional purification. The phenylhydrazone undergoes a Fischer indole cyclization in the presence of excess acid. This can be achieved by dissolving the phenylhydrazone in a pure acid, for example, acetic acid. Alternatively, the phenylhydrazone can be dissolved in a lower alkanol which has been treated with an acid, for example, ethanolic hydrogen chloride. If the phenylhydrazone prepared as described above does not require further purification, the original reaction mixture can be conveniently treated with an appropriate acid without isolation of the phenylhydrazone. Many times, the Fischer indole cyclization occurs after the formation of the phenylhydrazone, giving the desired product in a single step. The reaction is carried out from about room temperature to the reflux temperature for about 1 to 24 hours. The reaction product can be recovered by direct filtration, or by extraction after removal of the solvent and neutralization of the acid by the addition of aqueous base. The product can be purified by recrystallization or chromatography as required. While Synthetic Scheme I describes the use of an amidophenylhydrazine, one skilled in the art will appreciate that Fischer indolation can also be performed on the corresponding carboxylic acid or ester. The amide portion can then be introduced later in the synthesis as necessary or desired.

The phenylhydrazines required for the preparation of the compounds of the invention are either commercially available or can be prepared by methods well known to those skilled in the art from 4-nitrobenzoic acid as described in Synthetic Scheme II. R3 is as previously defined.

SCHEME S INTÉ T I CO I I The carboxylic acid can be first converted to the corresponding acid chloride or the bromide under standard conditions such as treatment with chloride or thionyl bromide. The corresponding acid halide, optionally in the presence of an acylation catalyst such as dimethylaminopyridine, is reacted with an appropriate amine in Formula R3-NH2, in the presence of a suitable base. Suitable bases include amines typically used as acid scavengers, such as pyridine or triethylamine, or commercially available polymer-bound bases, such as polyvinylpyridine. Alternatively, the required amine is reacted with an appropriate carboxylic acid in the presence of typical peptide coupling reagents, such as N, N'-carbonyldiimidazole (CDl), N, N '-dicyclohexyl-carbodiimide (DCC) and hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC). A supported form on an EDC polymer has been described (Tetrahedron Letters, 3_4_ (48), 7685 (1993)) and is very useful for the preparation of the compounds of the present invention. The product of these reactions is isolated by standard extractive techniques and purified by standard chromatographic and crystallization techniques as necessary or desired to provide the compounds of the present invention. The isolation of the products from the reactions where a reagent bound to the polymer has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. The product from these reactions can then be purified as described above. The nitrocarboxamides are hydrogenated on a precious metal catalyst, preferably platinum on carbon, at about room temperature with an initial pressure of about 4.2 kg / cm2 (60 psi) for 1 to 24 hours in a suitable solvent, such as an alkanol lower or tetrahydrofuran, to give the corresponding aniline. This aniline is then dissolved in a concentrated acid, such as phosphoric, hydrochloric or hydrobromic acid, and treated with sodium nitrite at a temperature of approximately 0 ° C or lower. After stirring for about one hour, the reaction mixture is added to a solution of tin (II) chloride in concentrated hydrochloric acid, and the mixture is stirred at about 0 ° C for about one hour. The product is isolated by treating the reaction mixture with an aqueous base until it is strongly basic and then extracted with a water-immiscible solvent such as ethyl acetate. The hydrazine product can then be purified by chromatography or crystallization before further reaction if necessary or desired. The person skilled in the art will appreciate that by replacing an appropriate alcohol with the amine in Synthetic Scheme II, the esters useful for the preparation of the compounds of the present invention can be prepared. The 4-substituted cyclohexanones required for the preparation of the compounds of the invention are available by methods well known in the art, as illustrated in Synthetic Scheme III. R1 and R2 are independently hydrogen, alkyl of 1 to 6 carbon atoms or benzyl.

SYNTHETIC SCHEME III The 1,4-cyclohexanedione ono-acetal is reductively aminated with an appropriate amine under standard conditions to give the corresponding 4-aminocyclohexanone ketal. The ketal is then deprotected under aqueous acidic conditions to prepare the corresponding 4-aminocyclohexanone. The compounds of the invention wherein R1 = R ~ = H are prepared from 4- (l-phthalimidyl) cyclohexanone, which is available by methods well known in the art, for example, King et al. (Journal of Medicinal Chemistry, 3_6, 1918 (1993)). Briefly, the 4-aminocyclohexanol is first reacted with the N-carbethoxyphthalimide and the resulting 4- (1-phthalamidyl) cyclohexanol, treated with pyridinium chlorochromate to give the desired ketone. The resulting 4- (1-phthalimidyl) ciciohexanone is then reacted with an appropriate phenylhydrazine followed by the cyclization of Fischer indole to prepare the corresponding 3- (1-phthalimidyl) carbazole. The phthalimide is then removed by reaction with hydrazine at a convenient point after the Fischer indole synthesis to provide the compounds of the invention where R1 = R2 = H. A person skilled in the art will appreciate that the manipulation of the substituent in the position 6 can occur before or after the cyclization described in Synthetic Scheme I. For example, the compounds of the present invention can be prepared from the corresponding carboxylic acids, esters, acid halides, or mixed acid anhydrides as illustrated in Synthetic Scheme IV. R1 'and R2' are independently alkyl of 1 to 6 carbon atoms, benzyl or, together with the nitrogen atom to which they are attached, form a phthalimido group; Z is hydrogen or a suitable nitrogen protecting group; Y is hydroxyl, alkoxy of 1 to 6 carbon atoms, chlorine, bromine, or alkoxycarbonyl of 1 to 6 carbon atoms; and R3 is as previously defined.

SYNTHETIC SCHEME IV The chloride, bromide, or carboxylic acid anhydride, optionally in the presence of an acylation catalyst such as dimethylaminopyridine, is reacted with an appropriate amino of the formula R3-NH2. Alternatively, the required amine is reacted with an appropriate carboxylic acid in the presence of typical peptide coupling reagents. An ester is first hydrolysed to the carboxylic acid and then coupled with an appropriate amine. Each of these techniques are described in Synthetic Scheme II described above. The compounds of the invention where n = 2 are 4-amino-10H-cyclohepta [6,7-b] i dol-7-carboxamides. These compounds are prepared substantially as described for the corresponding 3-amino-1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamides, as illustrated in Synthetic Scheme I, except that a 4-aminocycloheptanone replaces 4-aminocyclohexanone in the synthesis. The 4-aminocycloheptanones required for the synthesis of the compounds of the present invention can be prepared as described in Synthetic Scheme V. R1 'and R2' are independently alkyl of 1 to 6 carbon atoms or benzyl, or together with the atom of nitrogen to which they are attached, they form the phthalimide moiety.

Synthetic Scheme V The appropriate 4-aminocyclohexanone, in an appropriate solvent, for example diethyl ether, is treated with an appropriate Lewis acid such as boron trifluoride for about 20 minutes to about 1 hour at room temperature. To this solution is then added the ethyl diazoacetate, and the resulting mixture is stirred for about 1 hour to about 24 hours at room temperature. The resulting 2-ethoxycarbonyl-5-aminocycloheptanone is isolated by dilution of the reaction mixture with aqueous sodium carbonate and extracted with a water immiscible solvent such as diethyl ether. The reaction product is then dissolved directly in dimethyl sulfoxide which contains sodium chloride and water. The reaction mixture is heated to about 170 ° C for about 1 to about 24 hours, to effect decarboxylation. The desired 4-aminocycloheptanone is recovered by dilution of the reaction mixture with water and extracting with a suitable solvent such as diethyl ether. The reaction product can then be purified by column chromatography, if desired, before further reaction. After reaction with an appropriate phenylhydrazine, the corresponding 4-aminocycloheptanonphenylhydrazone is subjected to the same Fischer indole cyclization conditions as described above. The asymmetry in cycloheptanone, however, leads to the production of the following two isomers: Isomer A Isomer B The isomers A and B can be prepared by crystallization or chromatography at any convenient point in the synthesis of the compounds of the invention. The intermediate carboxylic acid, useful for the preparation of the compounds of the invention, can be either directly synthesized from the 4-carboxyphenylhydrazine by the procedures described in Synthetic Scheme I, or these can be prepared from the bromine derivative correspondent. Prior to handling the bromine substituent, however, the indole nitrogen must first be protected as illustrated in Synthetic Scheme VI. R1"and R2" are alkyl of 1 to 6 carbon atoms or benzyl; LG is chloro, bromo or trifluoromethanesulfonyl; and Ar is phenyl or 2,4,6-triisopropylphenyl.

E S BURNING S INTÉ T I CO VI A solution of the starting material in a suitable solvent, such as tetrahydrofuran or diethyl ether, is added to a suspension of an alkali metal hydride, preferably potassium hydride, in the same solvent. The deprotonation is performed at about -10 ° C to about room temperature for about 1 hour. To this solution is then added an appropriate arylsulfonyl chloride, triisopropylsilyl halide, or triisopropylsilyl triflate and the reaction is allowed to proceed for about 1 to 24 hours. The protected derivative of the indole nitrogen is isolated by treating the reaction mixture with ice to decompose any unreacted hydride, diluting the reaction mixture with water, and then extracting the product with a non-miscible solvent in water such as dichloromethane, ether diethyl or ethyl acetate. The isolated product can be used as it is recovered for the subsequent reactions, or purified by crystallization or chromatography, as desired. The substrate substituted with the thus protected bromo can then be used to provide the required carboxylic intermediate, as described in Synthetic Scheme VII. R1"and R2" are alkyl of 1 to 6 carbon atoms or benzyl; and Z is phenylsulfonyl, 2,4,6-triisopropylphenylsulfonyl, or triisopropylsilyl.

SCHEME S INTÉTICO VII A solution of the brominated compound in a suitable solvent, such as tetrahydrofuran or diethyl ether, is treated with an alkyl lithium, such as n-butyl or t-butyl lithium, at a temperature of about -70 ° C for about one hour to effect a halogen-metal exchange. The resulting anion solution was then treated with carbon dioxide at a temperature of about -70 ° C. The reaction mixture is then allowed to warm gradually to room temperature from about 1 hour to about 24 hours. The resulting product is isolated by dilution of the reaction mixture with aqueous ammonium chloride and extracted with a water-immiscible solvent such as dichloromethane. The product can be further purified by chromatography or recrystallization as necessary.

The final step in the sequence requires the deprotection of the indole nitrogen to give the compounds of the invention as illustrated in Synthetic Scheme VIII. R1", R2" and Z are as previously defined.

Synthetic Scheme VIII When Z is arylsulfonyl, the deprotecting group can be removed by basic hydrolysis in a lower alkanol such as methanol or ethanol. When Z is triisopropylsilyl, the deprotection is conveniently effected by treatment with an anionic fluoride reagent, preferably tetrabutylammonium fluoride, under standard conditions. The compounds of the invention wherein R1 and R2 are independently hydrogen, are available by attaching the corresponding 3-benzylamino compounds to catalytic hydrogenation conditions on a precious metal catalyst, such as palladium or platinum on carbon, or on Raney nickel. These reactions are typically performed in a lower alkanol or in tetrahydrofuran at room temperature at about 60 ° C, for about 1 hour to 24 hours, at a hydrogen pressure of about 4.2 kg / cm 2 (60 p.s.i.). This hydrogenolysis can be carried out before or after the deprotection of the indole nitrogen, as desired. Compounds where one or both of R1 or R2 are hydrogen, can be further functionalized to prepare other compounds of the invention by reductive alkylation. Under these conditions, the primary or secondary amine is reacted with an appropriate aldehyde or ketone to prepare the corresponding imine or enamine. The imine or enamine are then reduced to the desired compound by catalytic hydrogenation or by reduction with an appropriate hydride reducing reagent in the presence of an acid. Preferably, the transformation is carried out by direct alkylation, as illustrated in Synthetic Scheme IX. R1 * is hydrogen or alkyl of 1 to 6 carbon atoms, R2 * is alkyl of 1 to 6 carbon atoms or arylethyl; X * is bromo, -COOH, or R3NHC (0) - and arylethyl is as previously defined.

Synthetic Scheme IX The initial amine and a base are combined in the reaction solvent followed by the addition of the alkylating agent. The reaction solvent can be any non-reactive solvent typically used for alkylations of this type, such as acetonitrile, dimethylformamide or N-methyl-2-pyrrolidinone, limited by the solubility of the substrates. The base must be sufficiently alkaline to neutralize the acid generated during the progress of the reaction, but not so alkaline to deprotonate other sites in the substrate, giving rise to other products. In addition, the base must not compete in any greater degree with the substrate by the alkylating agent. The bases typically used for these reactions are sodium carbonate or potassium carbonate. The reaction mixture is typically stirred at room temperature to 80 ° C, for about 8 hours to 3 days. The alkylated products are isolated by concentration of the reaction mixture under reduced pressure, followed by the division of the resulting residue between water and a suitable organic solvent such as ethyl acetate., diethyl ether, dichloromethane, ethylene chloride, chloroform or carbon tetrachloride. The isolated product can be purified by chromatography, crystallization from a suitable solvent, salt formation or a combination of these techniques. The leaving group (LG) of the alkylating agents can be chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy, 2,2,2-trifluoroethanesulfonyloxy, benzenesulfonyloxy, p-bromobenzenesulfonyloxy, p-nitrobenzenesulphonyloxy or p-toluenesulphonyloxy, all which are useful for the preparation of the compounds of this invention. The specific alkylation agent employed is determined by its commercial availability or a convenient synthesis from commercially available starting materials. Preferred alkylating agents for the synthesis of the compounds of this invention are selected from those where the leaving group is chloro, bromo, iodo or methanesulfonyloxy. The alkylating agents where the leaving group is chloro are prepared from the corresponding alcohol by standard methods, preferably by treatment of the alcohol with pure thionyl chloride at room temperature. The alkylating agents where the leaving group is methanesulfonyloxy are prepared by treating the corresponding alcohol with a methanesulfonyl chloride or methanesulfonic anhydride. The initial alcohols required for the synthesis of the compounds of this invention are either commercially available or can be prepared by using well-established synthetic methodology as described in US Pat. No. 5,521,196, incorporated by reference herein in its entirety. . The compounds of the present invention possess a chiral center, and as such exist as racemic mixtures or individual enantiomers. As stated above, racemates and individual enantiomers are all part of the present invention. The individual enantiomers can be resolved by fractional crystallization of the salts of racemic bases and enantiomerically pure acids, for example, ditolyltartaric acid. Alternatively, the individual enantiomers can be prepared by the use of a chiral auxiliary during the preparation of the compound as described in the following Synthetic Scheme X. X is -Br or -C02H. Synthetic Scheme X The mono- (2,2-dimethylpropan-1, 3-diol) ketal of the 1-cyclohexanedione is reductively aminated under standard conditions with an enantiomer of a-methyl- (4-nitrophenyl) ethylamine (Synthetic Scheme X illustrates the use of the R- (+) - enantiomer The ketal is removed as previously described and the resulting aminocyclohexanone is subjected to the reaction conditions described for Synthetic Scheme I to give a diastereoisomeric mixture.The diastereoisomers are then separated by chromatography or fractional crystallization The amine can then be treated, if desired, with an appropriate alkylating agent, for example, an appropriate alkyl halide, to prepare the corresponding quaternary salt prior to cleavage or cleavage of the a-methyl-4-moiety. -nitrophenyl) ethyl The cleavage of the a-methyl- (4-nitrophenyl) ethyl portion is achieved by reduction of the 4-nitro group, followed by the acid-catalyzed solvolysis of the resulting a-methyl- (-aminophenyl) ethyl ion. The reduction of the nitro group can be achieved by a wide range of reducing agents including, for example, titanium tetrachloride, lithium aluminum hydride, or zinc / acetic acid, or by catalytic hydrogenation. Solvolytic cleavage occurs when the monohydrochloride (or other monobasic salt) of the reaction product is treated with water or an alcohol at room temperature or, in some cases, at elevated temperatures. A particularly convenient condition for removing the a-methyl- (4-nitrophenyl) ethyl portion is the hydrogenation of the amine monohydrochloride in methanol over a sulfided platinum catalyst. The reactions as illustrated in Synthetic Schemes VI-X are for the compounds of the invention which are either carbazoles or 10H-cyclohepta [7, 6-b] Índles. The person skilled in the art, however, will appreciate that the illustrated chemistry is applicable to any kind of compound. The person skilled in the art will also appreciate that the order in which the steps for preparing the compounds of the present invention are carried out, is not important in many cases.

PREPARATION I 6-bromo-3-dimethylamino-9-triisopropylsilyl-l, 2,3,4-tetra idro-9H-carbazole (2, 2-dimethylpropan-l, 3-diol) ketal of 1,4-dimethylamino-cyclohexanone To a solution of 25.0 gm (554.6 mMol) of dimethylamine in 500 mL of methanol was added 50.0 gm (252.2 mol) of the mono-2,2-dimethylpropan-1,3-diolketal of the 1,4-cyclohexanedione and the The reaction mixture was allowed to stir for 2 hours at room temperature. To this solution was then added gradually 31.69 g (504.3 mMol) of sodium cyanoborohydride. Once this addition was complete, acetic acid was added to adjust the mixture to a pH of about 6. The pH was checked periodically and the additions of acetic acid continued to maintain the pH at about 6. When the addition of acetic acid was already did not result in gas evolution, the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 100 mL and then partitioned between 1 N sodium hydroxide and dichloromethane. The remaining aqueous phase was treated with saturated aqueous sodium chloride and again extracted with dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 40.15 gm (70%) of the desired compound as a yellow oil. MS (m / e); 228 (M + l). 4-dimethylaminocyclohexanone A solution of 18.4 gm (81 mMol) of the (2,2-dimethylpropan-1,3-diol) ketal of the 4-dimethylamino-cyclohexanone in 250 mL of 90% formic acid was heated to reflux for 3 hours. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then diluted with 250 mL of water and concentrated to a volume of about 250 mL in a rotary evaporator. The dilution / concentration sequence was then repeated twice more. The residue was then concentrated further to a volume of about 50 mL, made basic with 5 N sodium hydroxide and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 11.8 gm (100%) of the desired compound as a yellow oil. MS (m / e): 141 (M +) NMR (m / e): d 2.50 (m, 2H), 2.28 (, 2H), 2.28 (m, 6H), 2.01 (m, 2H), 1.80 (m, 2H). 4-brornofenilhidrazona of the 4-dimeti laminociciohexanona To a mixture of 6.0 gm (42.0 mMol) of the 4-dimethylamino-cyclohexanone and 9.5 gm (42.0 mMol) of the 4-bromophenyl hydrazine hydrochloride in 100 mL of ethanol was added 3.4 mL (42 mMol) of pyridine. The resulting mixture was then heated to reflux for 2 hours and then stirred at room temperature for 18 hours. The reaction mixture was then treated with aqueous potassium carbonate and extracted perfectly with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was treated with toluene and again concentrated under reduced pressure to give 11.3 gm (87%) of the desired compound. 6-Bromo-3- (dimethyl) amino-1, 2,3,4-tetrahydro-9H-carbazole hydrochloride A solution of 11.3 gm (36.4 mMol) of the 4-bromophenylhydrazone of 4-dimethylamino-cyclohexanone in 250 mL of 4M ethanolic hydrogen chloride was heated to reflux under nitrogen atmosphere for 3 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residual part was dissolved in 200 mL of water and 50 mL of 6 M hydrochloric acid was added to this solution. The mixture was cooled to 0 ° C for 18 hours. The desired product which had crystallized was filtered and dried to give 8.66 gm (72%).

Silylation 8. 66 gm (26.2 mMol) of the 6-bromo-3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole hydrochloride were divided between 1 N sodium hydroxide and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 mL of tetrahydrofuran and the resulting solution was added to a suspension of 8.0 gm (40 mMol) of potassium hydride (20% in mineral oil) in 100 mL of tetrahydrofuran cooled to about 0 ° C. The resulting mixture was stirred for one hour at this temperature and then 8.0 mL (30 mMol) of triisopropylsilyltriol was added thereto and the mixture was allowed to warm gradually to room temperature. After 18 hours, the reaction mixture was treated with ice to decompose the excess potassium hydride. Once all the hydride had been destroyed, the reaction mixture was diluted with 200 mL of water and then extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residual oil was subjected to chromatography on silica gel, eluting sequentially with toluene, toluene: ethyl acetate 9: 1, toluene: ethyl acetate 4: 1, toluene: ethyl acetate 1: 1, and ethyl acetate. The ethyl acetate fractions were combined and concentrated under reduced pressure to give 7.08 gm (60%) of the title compound as a solid, melting point = 92-93 ° C. NMR (CDC13): d 7.52 (d, 1H), 7.39 (dd, 1H), 7.13 (d, 1H), 3.04 (broad dd, 1H), 2.88 (m, 2H), 2.70 (m, 1H), 2.58 (dd, 1H), 2.41 (s, 6H), 2.20 (d, 1H), 1.78 (m, 3H), 1.70 (m, 1H), 1.14 (m, 18H).

PREPARATION II 6-carboxy-3-dimethylamino-9-triisopropylsilyl-l, 2,3,4-tetrahydro-9H-carbazole To a solution of 2.95 gm (6.56 mMol) of 6-bromo-3-dimethylamino-9-triisopropylsilyl-2,3,4-tetrahydro-9H-carbazole in 150 mL of tetrahydrofuran at -78 ° C was added 16.4 mL (26.24 mMol) of t-butyl-lithium (1.6 M in pentane). The dark solution was allowed to stir at this temperature for 1 hour and then carbon dioxide gas was bubbled through the solution until the dark color disappeared to a light yellow color. After allowing the reaction mixture to warm to room temperature it was drained in water, the pH was adjusted to approximately 7, and the mixture was perfectly extracted with dichloromethane. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give 2.31 gm (85%) of the desired compound as a burned-colored foam.

IR: 3022, 2958, 2871, 1465, 1249 cm ": MS (m / e): 414 (M +).

PREPARATION III 4- (1-phthalimidyl) cycloheptanone To a stirred solution of 5.00 gm (20.55 mMol) of 4- (1-phthalimidyl) ciciohexanone in 20 mL of diethyl ester was added 3.79 mL (30.8 mMol) of boron trifluoride ethereate. After stirring for 20 minutes at room temperature, 3.24 mL (30.8 mMol) of ethyl diazoacetate was added dropwise. The resulting solution was stirred for 16 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium carbonate and then extracted with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 15 mL of dimethyl sulfoxide. To this solution were added 1.3 mL of water and 1.5 gm of sodium chloride. The resulting mixture was heated at 170 ° C for 7 hours. The reaction mixture was then cooled, poured into 150 mL of water and extracted with diethyl ether. The combined organic phases were washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel, eluting with hexane: ethyl acetate 6: 4. The fractions that show to contain the product were combined and concentrated under reduced pressure to give 4.17 gm (79%) of the title compound. MS (m / s): 257 (M +).

PREPARATION IV (R) - and (S) -3- (N-a-methyl-4-nitrobenzyl) amino-6-bromo-2-amino-l, 2,3,4-tetrahydro-9H-carbazole Reductive Amination To a solution of 20.0 gm (100.9 mMol) of the mono- (2,2-dimethyl) propane-1,3-diol-monoketal of the 1,4-cyclohexanedione in 250 mL of methanol, 35.0 gm (172.7 mMol) were added. of R- (+) -a-methyl-4-nitrobenzylamine hydrochloride, 25.0 gm (398 mMol) of sodium cyanoborohydride and 10 mL of acetic acid. The reaction mixture was allowed to stir for 18 hours at room temperature. To the reaction mixture was then added an additional charge of 25.0 gm (398 mMol) of sodium cyanoborohydride and the reaction mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was then diluted with dilute aqueous tartaric acid and the solution was exhaustively extracted with dichloromethane. The remaining aqueous phase was made alkaline with aqueous sodium hydroxide and extracted perfectly with dichloromethane. These dichloromethane extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give 33.7 gm (96%) of the 2, 2-dimethylpropan-1,2-diol-ketal of (R) -4- (Na- methyl-4-nitrobenzyl) -aminocyclohexanone as a brown yellow oil. MS (m / e): 348 (M +) Deprotection of the Cetal A solution of 33.42 gm (95.91 mMol) of the 2, 2-dimethyl-propan-1,2-diol-ketal of the (R) -4- (Na-methyl) -4-nitrobenzene) aminocyclohexanone in 250 mL of 98% formic acid, was heated to 40 ° C for 66 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 50 mL and then treated with aqueous potassium carbonate. The basic aqueous mixture was extracted perfectly with dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 22.36 gm (89%) of the (R) -4- (N-a-methyl-4-nitrobenzyl) aminociclohexanone as a brown oil.

Preparation of phenylhydrazone To a solution of 22.3 gm (85.01 mMol) of the (R) -4- (na-methyl-4-nitrobenzyl) aminocyclohexanone in 375 mL of ethanol, 19.0 gm (85.0 mMol) of 4-bromophenylhydrazine hydrochloride and 6.73 were added. gm (85.1 mMol) of pyridine. The reaction mixture was heated at 80 ° C for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic solution was washed sequentially with aqueous potassium carbonate and saturated aqueous sodium chloride. The remaining organic materials were dried over sodium sulfate and concentrated under reduced pressure to give 31.66 gm (86%) of the 4-bromophenyl-hydrazone of the (R) -4- (Na-methyl-4-nitrobenzyl) aminociclohexanone as a solid coffee.

Fischer's Indol Reaction A solution of 31.66 gm (73.4 mMol) of the 4-bromophenyl hydrazone of the (R) -4- (Na-methyl-4-nitrobenzyl) aminocyclohexanone in 500 L of ethanolic hydrogen chloride 3.7 M was stirred under reflux for 18 h. hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between 1 N sodium hydroxide and dichloromethane. The aqueous phase was extracted perfectly with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel, eluting with 5% methanol in dichloromethane, which contained 1% ammonium hydroxide. (3S) - (-) - 3- (N - ((R) -a-methyl-4-nitrobenzyl) amino) -6-bromo-1,2,3,4-tetrahydro-9H-carbazole The diastereomer eluting most rapidly recovered as 9.47 gm (31%) of a reddish-brown oil. MS (m / e): 415 (M +) IR (CHC13): 3471, 2970, 2926, 2845, 1522, 1471, 1348, 857 cm "1. [A] D20 (c = 10, methanol): -122.3 ° Calculated for C20H20N3O2Br: Theory: C, 57.78; H, 4.87; N, 10.14, Found: C, 58.23; H, 5.03; N, 10.12. (3R) - (+) - 3- (N - ((R) -a-methyl-4-nitrobenzyl) amino) -6-bromo-1,2,3,4-tetrahydro-9H-carbazole The diastereomer eluting slower was recovered as 8.13 gm (27%) of pale green crystals. MS (m / e): 415 (M +) IR (CHCl3): 3471, 3012, 2970, 2952, 2846, 1522, 1471, 1348, 857 cm "1. [A] D20 (c = 10, methanol): + 337.9 ° Calculated for C2oH2oN3? 2Br: Theory: C, 57.78; H, 4.87; N, 10.14, Found: C, 58.26; H, 5.03; N, 9.93.

X-ray crystallography determined that the diastereomer eluting slower was the absolute configuration specified.

PREPARATION V Yodhydrate (R) - (+) - 6-bromo-3-dimethylamino-l, 2, 3, 4-tetrahydro-9H-carbazole Quaternization To a solution of 5.00 gm (12.1 mMol) of the (3R) - (+) - 3- (N - ((R) -a-methyl-4-nitrobenzyl) amino) -6-bromo-1, 2, 3 , 4-tetrahydro-9H-carbazole in 150 mL of acetonitrile were added 10.0 mL of iodomethane followed by 5.0 gm of potassium carbonate. The mixture was stirred for 2 days at room temperature and then for 18 hours at reflux. The reaction mixture was then cooled to room temperature and the resulting yellow precipitate was filtered, washed with methanol and dried under reduced pressure to give 3.65 gm (53%) of (R) - (+) - 3-iodide (N, N-dimethyl-N- ((R) - (+) -a-methyl- (4-nitrobenzyl) amino) -6-bromo-1,2,4,4-tetrahydro-9H-carbazole as a solid yellow.

Calculated for C22H25N3? 2BrI: Theory: C, 46.34; H, 4.42; N, 7.37. Found: C, 46.22; H, 4.41; N, 7.30.

Hydrogenolysis A mixture of 0.70 gm (1.23 mMol) of the iodide of (R) - (+) - 3- (N, N-dimethyl-N- ((R) - (+) -a-methyl- (4-nitrobenzyl) amino ) -6-bromo-l, 2, 3, 4-tetrahydro-9H-carbazole and 0.20 gm of sulfur-containing platinum on carbon in 150 mL of methanol were hydrogenated at room temperature for 18 hours at an initial hydrogen pressure of 2.8 kg / cm2 (40 psi) The reaction mixture was then degassed and heated to effect the methanolysis.The reaction mixture was filtered and concentrated under reduced pressure to give 0.471 gm (91%) of the title compound as a light yellow solid, melting point = 252 ° C MS (m / e): 293 (M +) IR (KBr): 3271, 3016, 2924, 2842, 2737, 2709, 1469, 1460, 1435, 1308, 793 cm "1 [a] D20 (c = 10, methanol): + 54.7 ° Calculated for C? 4H18N2BrI: Theory: C, 39.93; H, 4.31; N, 6.65. Found: C, 39.87; H, 4.19; N, 6.38.

PREPARATION VI Resolution of racemic 6-bromo-3-dimethylamino-l, 2, 3, 4- tetrahydro-9H-carbazole To a solution of 5.0 gm (17.06 mMol) of 6-bromo-3-dimethylamino- 1, 2, 3, 4-tetrahydro-9H-carbazole in 200 mL of hot ethyl acetate, a solution of 6.59 gm ( 17.06 mMol) of di-p-toluoyl-D-tartaric acid in 100 mL of ethyl acetate with mixing. After standing for 4 hours, the resulting precipitate was filtered and dried to give 12.0 g of the salt. A suspension of 1.0 gm of this solid was heated to boiling in 10 mL of methanol. This mixture was then cooled to room temperature and allowed to stand for 18 hours. The remaining solid was filtered and dried to give 0.65 gm. This solid was again suspended in 10 mL of boiling methanol and allowed to cool and stand for 18 hours to give 0.52 gm of a solid after filtration and drying under vacuum. This solid was divided between dichloromethane and dilute aqueous sodium hydroxide. The phases were separated and the organic materials were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 7 mL of toluene and allowed to stand at room temperature for 18 hours. The solution was filtered to remove the solid that had formed, and the filtrate was concentrated under reduced pressure to give 0.133 gm of an oil which gradually crystallized, melting point = 131-3 ° C [a] D20 (c = 10, methanol): -83 ° The two methanolic filtrates were combined and concentrated under reduced pressure to give 0.33 gm of a crystal. The crystal was treated as described above to give 0.121 gm of an oil which crystallized gradually, melting point = 131-4 ° C [a] D20 (c = 10, methanol): + 78 ° EXAMPLE 1 N- (pyridin-4-yl) -3-dimethylamino-, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide dihydrochloride A mixture of 0.41 gm (1.0 mMol) of 3-dimethylamino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid, 0.77 gm (4.0 mMol) of 1- (3-hydrochloride -dimethylamino-propyl) -3-ethylcarbodyl ida, 0.54 gm (4.0 mMol) of 1-hydroxybenzotriazole, and 0.38 gm (4.0 mMol) of 4-aminopyridine in 10 mL of dimethylformamide and 50 L of tetrahydrofuran, were stirred together at room temperature for 3 days. The isocyanate resin bonded to the polystyrene was added to the reaction mixture which was stirred at 40 ° C for 6 hours to purify the 4-aminopyridine. The reaction mixture was filtered, concentrated under reduced pressure and the residue subjected to preparative centrifugal thin layer chromatography (PCTLC), eluting with chloroform containing 5% methanol and 0.5% ammonium hydroxide. Fractions containing the desilylated product were combined and concentrated under reduced pressure to provide a yellow oil. This oil was dissolved in dichloromethane and treated with ethanolic hydrogen chloride. The resulting mixture was concentrated under reduced pressure to provide 0.22 gm (54%) of the title compound as a burnt-colored solid. MS (m / e): 293 (M +) Calculated for C2oH22N40-2HCl: Theory: C, 58.97; H, 5.94; N, 13.75. Found: C, 58.77; H, 5.91; N, 13.79.

EXAMPLE 2 S- (-) - N- (pyridin-4-yl) -3- dimethylamino-1, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide dihydrochloride hemihydrate A 0.336 gm (0.81 mMol) mixture of S- (-) - 3-dimethyl-amino-9-trimethylsilyl-2,2,4,4-tetrahydro-9H-carbazole-6-carboxylic acid, 0.171 gm (0.89 g) mMol) of 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride, and 0.084 gm (0.89 mMol) of 4-aminopyridine in 15 L of dimethylformamide was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane and then washed with water. The organic phase was dried with sodium sulfate and then concentrated under reduced pressure. The residue was subjected to chromatography on silica gel as described in Example 1 to give 0.244 gm of the partially desilylated product. The desilylation was completed by mixing with 5 mL of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) in 25 mL of tetrahydrofuran containing 5 mL of boric acid and stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in aqueous tartaric acid and the resulting solution was washed thoroughly with dichloromethane. The remaining aqueous solution was made basic with 5N sodium hydroxide and then perfectly extracted with 10% isopropanol in chloroform. These organic phases were combined, dried over potassium carbonate, and concentrated under reduced pressure. The residue was subjected to PCTLC, eluting with chloroform containing 5% methanol and 0.5% ammonium hydroxide. The fractions containing the product were combined and concentrated under reduced pressure. The residue was dissolved in chloroform containing methanol, and the solution was placed on a VARAN BOND ELUT SCXMR ion exchange column (Varian, Harbor, City, CA, E.U.A.). The column was washed with two volumes of methanol and then the column was eluted with 2 N ammonia in methanol. The fractions containing the product were combined and concentrated under reduced pressure. The residue was dissolved in ethanolic hydrogen chloride and the solution was concentrated under reduced pressure to provide 0.044 gm (18%) of the title compound as a beige solid.

Calculated for C20H22N4O-2HCI-0.5H20: Theory: C, 57.70; H, 6.05; N, 13.46. Found: C, 57.75; H, 5.84; N, 12.83.

General procedure for the coupling of amines with 3-di-methylamino-1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxylic acids To a suspension of 4-5 equivalents of 1-ethy 1-3- (3-dimethylaminopropyl) carbodiimide (Desai et al., Tetrahedron Letters, 34 (48), 7685 (1993)) in chloroform was added one equivalent of 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-3 equivalents of the appropriate amine. The reaction is stirred until the reaction is complete, heat can be applied if necessary. The resin is removed by filtration and the product is isolated by evaporation of the solvent. This procedure is illustrated by Examples 3-7.

EXAMPLE 3 N-cyclopropyl-3- (dimethyl) amino-1, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide Starting with 7.4 mg (0.029 mmol) of 3-dimethylamino-l, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopropylamine, 3.5 mg (41%) of the title compound was recovered. MS (m / e): 298 (M +) EXAMPLE 4 N-cyclopentyl-3-dimethylamino-l, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamide Starting with 7.4 mg (0.029 mmol) of 3-dimethylamino-1,2,4,4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopentylamine, 4.1 mg (41%) of the title compound was recovered. MS (m / e): 342 (M +) EXAMPLE 5 N- (5-methoxycarbonylfur-2-yl) -3-dimethylamino-l, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamide Starting with 7.4 mg (0.029 mmol) of 3-dimethylamino- 1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-amino-5-methoxycarbonylfuran, 1.3 mg (10%) of the composed of the title. MS (m / e): 370 (M +) EXAMPLE 6 N- (2-chloropyridin-3-yl) -3-dimethylamino-1,2,3-tetrahydro-9H-carbazole-6-carboxamide Starting with 7.4 mg (0.029 mmol) of 3-dimethylamino-1,2,3-tetrahydro-9H-carbazole-6-carboxylic acid and 2-chloro-3-aminopyridine, 1.2 mg (9%) of the Title. MS (m / e): 369 (M +) EXAMPLE 7 N- (6-methoxypyridin-3-yl) -3-dimethylamino-1, 2,3,4-tetrahydro-9H-carbazole-6-carboxamide Starting with 7.4 mg (0.029 mmol) of 3-dimethylamino-l, 2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 6-methoxy-3-aminopyridine, 1.8 mg (14%) of the compound was recovered. of the title. MS (m / e): 365 (M +) EXAMPLE 8 N- (pyridin-3-yl) -3- and -4-dimethylamino-l 0H-cyclohepta [7, 6-b] indo-1-7-carboxamides 7-carboxy-3- and 4- (dimethylamino) cyclohepta [7,6-b] indole hydrochloride A suspension of 1.40 mg (7.33 mmol) of 4- (dimethylamino) cycloheptanone and 1115 gm (7.33 mMol) of 4-carboxy-phenylhydrazine in 20.0 mL of 5N hydrochloric acid was heated to reflux for 15 hours. The reaction mixture was then concentrated under reduced pressure to provide the title compound as a black solid. MS (m / e): 272 (M +) To a stirred solution of 0.541 gm (1.75 mMol) of a mixture of 3- and 4-dimethylamino-10H-cyclohepta [7, 6-b] indo1-7 hydrochloride -carboxylic acid in 10 mL of dimethylformamide 0.387 gm (2.38 mMol) of carbonyl-diimidazole was added. The reaction mixture was stirred for 15 minutes at room temperature and then 3.48 mMol of 3-aminopyridine was added. The reaction mixture was stirred at room temperature for 20 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed thoroughly with water, followed by saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel, eluting with chloroform containing 15% methanol and 1% ammonium hydroxide. The fractions containing the isomeric amines were combined and concentrated under reduced pressure to provide the title compounds. The discovery that the 5-HT? F receptor mediates neurogenic meningeal extravasation, thereby causing the pain associated with migraine and associated disorders, is described in US Pat. No. 5,521,196, incorporated by reference herein. In its whole. To demonstrate the use of the compounds of this invention in the treatment of migraine, their ability to bind to the subtype of the -HT? F. The ability of the compounds of this invention to bind to the receptor subtype of -HT? F was measured essentially as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA), 90, 408-412 (1993).

Membranal Preparation: Membranes were prepared from Ltk-transfected cells, which developed up to 100% confluence.

The cells were washed twice with phosphate-buffered saline, scraped from the culture dishes in 5 mL of phosphate-buffered saline and cooled with ice, and centrifuged at room temperature. 200 x g for 5 minutes at 4 ° C. The pellet was resuspended in 2.5 mL of ice-cooled Tris buffer (20 mM Tris-HCl, pH = 7.4 at 23 ° C, 5 M EDTA) and homogenized with Wheaton tissue grinder. The one used was subsequently centrifuged at 200 x g for 5 minutes at 4 ° C to concentrate or convert into pellets or large fragments, which were discarded. The supernatant was collected and centrifuged at 40,000 x g for 20 minutes at 4 ° C. The pellet or button resulting from this centrifugation was washed once in ice-cold Tris wash buffer and resuspended in a final buffer containing 50 mM Tris-HCl and 0.5 M EDTA, pH = 7.4 at 23 ° C. The membrane preparations were kept on ice and used within two hours for the radioligand binding assays. Protein concentrations were determined by the method of Bradford (Anal. Biochem., 72, 248-254 (1976).

Radioligand Link: The (3H-5-HT) linkage was performed using slight modifications of the 5-HT ?D assay conditions reported by Herrick-Davis and Titeler (J. Neurochem, 50, 1624-1631 (1988) with the omission of two masking ligands The radioligand binding studies were carried out at 37 ° C in a total volume of 250 μl of the buffer (50 M Tris, 10 mM magnesium chloride, 0.2 mM EDTA, 10 μm pargyline , 0.1% ascorbate, pH = 7.4 at 37 ° C) in 96-well microtiter plates Saturation studies were conducted using (H) 5-HT at 12 different concentrations in the range of 0.5 nM to 100 nM. The displacement studies were carried out using 4.5-5.5 nM (3H) 5-HT The binding profile of the drugs in the competition experiments was carried out using 6-12 concentrations of the compound. 30 minutes for both displacement and saturation studies based on the initial investigations that determined the conditions of link in the equilibrium. The non-specific binding was defined in the presence of 10 μM 5-HT. The link was initiated by the addition of 50 μL of membrane homogenates (10-20 μg). The reaction was terminated by rapid filtration through pre-hardened filters (0.5% polyethyleneimine) using the Cell Brandel Harvester 48R (Gaithersburg, MD). Subsequently, the filters were washed for 5 seconds with ice-cooled buffer (50 mM Tris-HCl, pH = 7.4 at 40 ° 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%. The link data were analyzed by computer-assisted non-linear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). The IC5c values were converted to Kx values using the Cheng-Prusoff equation (Biochem Pharmacol., 22, 3099-3108 (1973).) All the experiments were performed in triplicate.The representative compounds of this invention were found to have affinity for the 5-HT? F receptor as measured by the procedure described above As reported by RL Weinshank, et al, WO93 / 14201, the 5-HT? F receptor is functionally coupled to a G protein, as measured by the ability of serotonin and serotonergic drugs to inhibit the production of cyclic 7 MP MP (cAMP) stimulated by forskolin in NIH3T3 cells transfected with the 5-HT? F receptor. The activity of adenylate cyclase was determined using standard techniques.A maximum effect is achieved by serotonin.An Emay is determined by dividing the inhibition of a test compound by the maximum effect and determining a percentage inhibition. I. (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 (Bmax estimated from competition studies of a point = 488 fmol / mg protein) were incubated in DMEM, 5 mM theophylline, 10 mM HEPES, (4- [2-hydroxyethyl] -1-piperazinetansulfonic acid and 10 μM pargyline for 20 minutes at 37 ° C, 5% C02. The drug-effect dose curves were then conducted by the addition of 6 different final concentrations of the drug, followed immediately by the addition of forskolin (10 μM). Subsequently, the cells were incubated for an additional 10 minutes at 37 ° C, 5% C02.The medium was aspirated and the reaction stopped by the addition of 100 mM HCl To demonstrate competitive antagonism, a dose of curve-response for 5-HT was measured in parallel, using a fixed dose of methiothepin (0.32 μM) .The plates were stored at 4 ° C for 15 minutes and then centrifuged for 5 minutes at 500 xg to concentrate cellular debris, and the supernatant it was taken in alic uotas and stored at -20 ° C before the evaluation of cAMP formation by radioimmunoassay (radioimmunoassay equipment for cAMP; Advanced Magnetics, Cambridge, MA). The radioactivity will be quantified using a Gamma Packard COBRA Auto counter, equipped with the computer logic of data reduction. Representative compounds of the invention were tested and found to be 5-HT? F receptor agonists in the cAMP assay.

Protein extravasation Rats Would Sprague-Dawley (225-325 g) or guinea pigs from Charles River laboratories (225-325 g) were anesthetized with sodium pentobarbital intraperitoneally (65 mg / kg or 45 mg / kg respectively) and placed in a stereotactic frame (David Kopf Instruments) with the incision bar set to -3.5 mm for the rats or -4.0 mm for the guinea pigs. After an incision in the sagittal scalp of the intermediate line, two pairs of bilateral holes were drilled through the skull (6 mm posteriorly, 2.0 and 4.0 laterally in rats, 4 mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinates are referred to the bregma). Pairs of stainless steel stimulation electrodes (Rhodes Medical Systems, Inc.) are lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 m (guinea pigs) from the dura. The femoral vein was exposed and a dose of the test compound injected intravenously (1 mL / kg). Approximately 7 minutes later, a dose of 50 mg / kg Evans Blue, a fluorescent dye, was also injected intravenously. Evans Blue forms complexes with proteins in the blood and functions as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion is stimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a potenostat / galvanostat Model 273 (EG &G Princeton Applied Research). Fifteen minutes after the stimulation, the animals are sacrificed and bled with 20 mL of saline. The upper part of the skull is removed to facilitate the collection of the dural membranes. The membrane samples are removed from both hemispheres, rinsed with water, and laid flat on microscope slides. Once dry, the tissues are covered with the coverslip, with a 70% glycerol / water solution. A fluorescence microscope (Zeiss) equipped with a grid monochromator and a spectrophotometer was used to quantify the amount of Evans Blue dye in each sample. An excitation wavelength of about 535 nm is used and the emission intensity at 600 nm is determined. The microscope is equipped with a motorized stage and also interconnected with a personal computer. This facilitates the computer controlled movement of the stage with fluorescence measurements at 25 points (500 μm steps) on each dura sample. The mean and standard deviation of the measurements are determined by computer. Extravasation induced by electrical stimulation of the trigeminal ganglia is an ipsilateral effect (for example, occurs only on the side of the dura in which the trigeminal ganglion is stimulated). This allows the other (unstimulated) half of the dura to be used as a control. The proportion of the amount of extravasation in the dura from the stimulated side compared to the dura of the unstimulated side is also calculated. Saline controls produce a ratio of approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a compound that effectively prevents extravasation in the dura of the stimulated side could have a ratio of approximately 1.0. A dose-response curve is generated and the dose that inhibited the extravasation by 50% (ID50) is calculated. Sumatriptan, a commercially available treatment for migraine, shows low bioavailability and relatively short time of action. Its affinity for a number of subtypes of the serotonin receptor, gives rise to undesirable side effects, particularly vasoconstrictional, which severely limits its usefulness in the treatment of migraine. Since the compounds of this invention are potent 5-HT? F receptor agonists, extremely low doses are required to maintain therapeutic levels. In addition, since compounds that are selective for the 5-HT? F receptor in relation to other receptors do not cause vasoconstriction, complications due to vasoconstriction are avoided. The compounds of this invention also inhibit the extravasation of proteins if they are administered before or subsequent to stimulation of the trigeminal ganglia, suggesting that these can be administered before an incipient attack of migraine, to prevent pain, or during a migraine attack. to alleviate the pain. While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually 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, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal routes. Many of the compounds employed in the methods of this invention are effective as 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, (16th ed 1980). In making the compositions employed in the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such carrier, which may be in the form of a capsule, sack, paper or other container . When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a carrier, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, troches, sacks, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing example up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In the preparation of a formulation, it may be necessary to grind the active compound to provide the appropriate particle size prior to combination with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size smaller than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, approximately 40 mesh. 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 methylcellulose. The formulations may also include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxybenzoates; sweetening agents; and agents. flavors. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, by employing procedures known in the art.

The compositions are preferably formulated in a unit dose form, each dose containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dose form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, in association with a pharmaceutically suitable excipient. The active compounds are generally effective over a wide range of doses. For example, the doses per day normally fall in the range of about 0.01 to about 30 mg / kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg / kg / day; in single or divided doses, it is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the effective compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dose ranges, are not intended to limit the invention in any way. In some cases, dose levels below the lower limit of the aforementioned range may be more than adequate, while in other cases, even larger doses must be employed without causing any harmful side effects, with the proviso that such doses more Large ones are first divided into several smaller doses for administration throughout the day.

Formulation Example 1 Hard gelatin capsules are prepared comprising the following ingredients: Ingredient Quantity (mg / capsule) Compound of Example 1 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 tablet formulation is prepared using the following ingredients: Ingredient Quantity (mg / tablet) Compound of Example 2 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Formulation Example 3 A formulation for dry powder inhaler is prepared, which comprises the following components: Ingredient% in Weight Compound of Example 3 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to an accessory for inhalation of dry powder.

Formulation Example 4 Tablets are prepared, each containing 30 mg of the active ingredient, as follows: Ingredient Quantity (mg / tablet) Compound of Example 5 30.0 mg Starches 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as a 10% solution in water) Sodium carboxymethyl 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a non-US mesh screen. 20 and they mix perfectly. The solution of the polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a North American mesh screen 16. The granules thus produced are dried at 50-60 ° C and passed through a wire screen. American mesh no. 16. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh American sieve, are then added to the granules which, after mixing, are compressed in a forming machine. tablets to produce tablets each weighing 120 mg.

Formulation Example 5 Capsules are prepared each containing 40 mg of the drug, as follows: Ingredient Quantity (mg / capsule) Compound of Example 6 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a sieve of North American mesh no. 20, and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories are made, each containing 25 mg of the active ingredient, as follows: Ingredient Amount Compound of Example 7 25 mg Fatty acid glycerides 2,000 mg saturated to The active ingredient is passed through a No. 60 mesh American sieve and suspended in the saturated fatty acid glycerides, previously melted 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 prepared, each containing 5.0 mg of the medication per 5.0 ml dose, as follows: Ingredient Amount Compound of Example 1 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. Taste and color how much is enough Purified water up to 5.0 mi The medicine, sucrose and xanthan gum are mixed, passed through a No. 10 mesh American sieve, and then mixed with a previously made solution of microcrystalline cellulose, and sodium carboxymethylcellulose, in water . Sodium benzoate, flavor and color are diluted with some water and added with agitation. Sufficient water is then added to produce the required volume.

Formulation Example 8 Capsules are prepared each containing 15 mg of medication, as follows: Ingredient Quantity (mg / capsule) Compound of Example 2 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a No. 20 American mesh screen and filled into hard gelatin capsules in amounts of 425 mg.

Formulation Example 9 An intravenous formulation can be prepared, as follows: Ingredient Amount Compound of Example 3 250.0 mg Isotonic saline 1000 ml Formulation Example 10 A topical formulation can be prepared, as follows: Ingredient Amount Compound of Example 4 1-10 g Emulsification wax 30 g Liquid paraffin 20 g Soft white paraffin up to 100 g The white soft paraffin is heated until it melts. The liquid paraffin and the emulsification wax are incorporated and stirred until they dissolve. The active ingredient is added and the agitation is continued until it is dispersed. The mixture is then cooled until it is solid.

Formulation Example 11 Sublingual or buccal tablets, each containing 10 mg of the active ingredient, can be prepared as follows: Ingredient Amount Per Tablet Compound of Example 5 10.0 mg Glycerol 210.5 mg Water 1 3.0 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 polyvinylpyrrolidone are mixed together by continuous stirring and maintained at the temperature of about 90 ° C. When the polymers have dissolved, the solution is cooled to about 50-55 ° C and the drug is mixed slowly. The homogenous mixture is emptied into elaborate forms of an inert material to produce a diffusion matrix containing the drug, which has 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 distribution 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 administration of pharmaceutical agents is well known in the art. See, for example, U.S. Patent No. 5,023,252, issued June 11, 1991, incorporated by reference herein. Such patches can be constructed for continuous, pulsatile, or on demand administration 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 administration of the drug into the host ventricular system to bypass the blood-brain barrier. An implantable delivery system of this type, used for the transport of biological factto specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, issued April 30, 1991, which is incorporated by reference herein. . Indirect techniques, which are generally preferred, usually involve the formulation of the compositions to provide drug latency by the conversion of hydrophilic drugs to drugs or lipid-soluble prodrugs. Latency is generally achieved by blocking the hydroxyl, carbonyl, sulfate, and primary amine groups present on the drug, to render the drug more soluble in lipid and susceptible to transportation through the blood-brain barrier. Alternatively, the administration 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 from the route of administration and the compound (s), and the of the patient.

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.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of the formula I: characterized in that: R1 and R2 are independently hydrogen, alkyl of 1 to 4 carbon atoms, or -CH2CH2-aryl wherein aryl is phenyl, phenyl monosubstituted with halo, or 1- (alkyl of 1 to 6 carbon atoms) pyrazole-4 - i 1 o; R3 is cycloalkyl of 3 to 6 carbon atoms, or a heterocycle; n is 1 or 2; and the pharmaceutically acceptable salts and hydrates thereof.

2. A compound according to claim 1, characterized in that n is 1.

3. A compound according to claim 2, characterized in that R1 and R2 are independently alkyl of 1 to 4 carbon atoms.

4. A pharmaceutical formulation, characterized in that it comprises, in association with a pharmaceutically acceptable carrier, diluent, or excipient, a compound according to any of claims 1 to 3.

5. Use of a compound of formula (I) in accordance with any of claims 1 to 3 for the preparation of a 5-HT receptor activating medicament.

6. Use of a compound of formula (I) according to any of claims 1 to 3 for the preparation of a medicament for the inhibition of extravasation of the peuronal protein.

7. Use of a compound of formula (I) according to any of claims 1 to 3 for the preparation of a medicament for the treatment of migraine.

8. Use of a compound of formula (I) according to any of claims 1 to 3 for the prevention of migraine.

9. The use according to any of claims 5 to 8, characterized in that the mammal is a human. THE SUMMARY OF THE I NVENC ION The present invention provides the novel 2-amino-1, 2, 3, 4-tetrahydro-9H-carbazole-6-carboxamides and the 3-amino-10H-cyclohepta [7, 6-b] indole-7-carboxamides of the Formula (I), wherein R1, R2, R3 and n are as described in the specification.