BACKGROUND OF THE INVENTION 
The present invention relates to indole derivatives, to processes and 
intermediates for their preparation, to pharmaceutical compositions 
containing them and to their medicinal use. The active compounds of the 
present invention are useful in treating migraine and other disorders. 
U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent Application 
Publication Number 313397 refer to 5-substituted 3-aminoalkyl indoles. The 
compounds are said to be useful for the treatment of migraine. 
British Patent Application 040279 refers to 3-aminoalkyl-1 
H-indole-5-thioamides and carboxamides. The compounds are said to be 
useful in treating hypertension, Raymond's disease and migraine. 
European Patent Application Publication Number 303506 refers to 
3-poly:hydro-pyridyl-5-substituted-1 H-indoles. The compounds are said to 
have 5-HT.sub.1 receptor agonist and vasoconstrictor activity and to be 
useful in treating migraine. 
European Patent Application Publication Number 354777 refers to 
N-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. The compounds 
are said to have 5-HT.sub.1 receptor agonist and vasoconstrictor activity 
and to be useful in treating cephalic pain. 
European Patent Application Publication Numbers 438230,494774, and 497512 
refers to indole-substituted five-membered heteroaromatic compounds. The 
compounds are said to have 5-HT.sub.1 -like receptor agonist activity and 
to be useful in the treatment of migraine and other disorders for which a 
selective agonist of these receptors is indicated. 
European Patent Application Publication Number 313397 refers to 
5-heterocyclic indole derivatives. The compounds are said to have 
exceptional properties for the treatment and prophylaxis of migraine, 
cluster headache, and headache associated with vascular disorders. These 
compound are also said to have exceptional "5HT.sub.1 -like" receptor 
agonism. 
International Patent Application PCT/GB91/00908 and International Patent 
Application WO 91/18897 refers to 5-heterocyclic indole derivatives. The 
compounds are said to have exceptional properties for the treatment and 
prophylaxis of migraine, cluster headache, and headache associated with 
vascular disorders. These compound are also said to have exceptional 
"5-HT.sub.1 -like" receptor agonism. 
European Patent Application Publication Number 457701 refers to aryloxy 
amine derivatives as having high affinity for 5-HT.sub.1D serotonin 
receptors. These compounds are said to be useful for treating diseases 
related to serotonin receptor dysfunction, for example, migraine. 
European Patent Application Publication Number 497512 A2 refers to a class 
of imidazole, triazole, and tetrazole derivatives which are selective 
agonists for 5-HT.sub.1 -like receptors. These compounds are said to be 
useful for treating migraine and associated disorders. 
International patent application WO 9300086 describes a series of 
tetrahydrocarbazone derivatives as 5-HT.sub.1 receptor agonists useful for 
the treatment of migraine and related conditions. 
Y. Yang, et. al describe the synthesis of 5-arylindoles in Heterocycles, 
Vol. 34, 1395 (1992) via palladium catalyzed cross-coupling reactions. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds of the formula 
##STR2## 
wherein A, B, D, E, and F are each independently nitrogen or carbon; 
R.sub.1 is hydrogen, C.sub.1 to C.sub.6 alkyl, --(CH.sub.2).sub.n R.sub.7, 
or C.sub.1 to C.sub.3 alkyl-aryl; R.sub.2, R.sub.3, R.sub.4, R.sub.5 and 
R.sub.6 are each independently hydrogen, C.sub.1 to C.sub.6 alkyl, aryl, 
C.sub.1 to C.sub.3 alkyl-aryl, halogen (e.g. fluorine, chlorine, bromine 
or iodine), cyano, nitro, --(CH.sub.2).sub.m NR.sub.8 R.sub.9, 
--(CH.sub.2).sub.m OR.sub.9, --SR.sub.9, --SO.sub.2 NR.sub.8 R.sub.9, 
--(CH.sub.2).sub.m NR.sub.8 SO.sub.2 R.sub.9, --(CH.sub.2).sub.m NR.sub.8 
CO.sub.2 R.sub.9, --(CH.sub.2).sub.m NR.sub.8 COR.sub.9, 
--(CH.sub.2).sub.m CONR.sub.7 R.sub.9, or --(CH.sub.2).sub.m CO.sub.2 
R.sub.9 ; R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, 
and R.sub.5 and R.sub.6 may be taken together to form a five- to 
seven-membered alkyl ring, a six-membered aryl ring, a five- to 
seven-membered heteroalkyl ring, having 1 heteroatom of N, O, or S, or a 
five- to six- membered heteroaryl ring having 1 or 2 heteroatoms of N, O, 
or S; R.sub.7 is OR.sub.10, --SR.sub.10, --SO.sub.2 NR.sub.10 R.sub.11, 
--NR.sub.10 SO.sub.2 R.sub.11, --NR.sub.10 CO.sub.2 R.sub.11, --NR.sub.10 
COR.sub.11, --CONR.sub.10 R.sub.11, or --CO.sub.2 R.sub.10 ; R.sub.8, 
R.sub.9, R.sub.10 and R.sub.11 are independently hydrogen, C.sub.1 to 
C.sub.6 alkyl, or C.sub.1 to C.sub.3 alkyl-aryl; m is 0, 1, or 2; n is 2, 
3, or 4; and the above aryl groups and the aryl moieties of the above 
alkyl-aryl groups are each independently phenyl or substituted phenyl, 
wherein said substituted phenyl may be substituted with one to three of 
C.sub.1 to C.sub.4 alkyl, halogen (e.g. fluorine, chlorine bromine or 
iodine), hydroxy, cyano, carboxamido, nitro, or C.sub.1 to C.sub.4 alkoxy, 
and the pharmaceutically acceptable salts thereof. These compounds are 
potent 5-HT.sub.1, agonists with selectivity for the 5-HT.sub.1D receptor 
and are useful in treating migraine and other disorders. 
The compounds of the invention include all optical isomers of formula I 
(e.g. R and S stereogenicity at any chiral site) and their racemic, 
diastereomeric, or epimeric mixtures. 
Unless otherwise indicated, the alkyl and alkenyl groups referred to 
herein, as well as the alkyl moieties of other groups referred to herein 
(e.g. alkoxy), may be linear or branched, and they may also be cyclic 
(e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or 
branched and contain cyclic moieties. 
Preferred compounds of the invention are compounds of the formula I wherein 
B or E is nitrogen; A or F is carbon; R.sub.1 is hydrogen, C.sub.1 to 
C.sub.3 alkyl, or --(CH.sub.2).sub.2 OCH.sub.3. 
The following compounds are particularly preferred: 
3-(N-methylpyrrolidin-3-yl)-5-(pyrimid-5-yl)-1 H-indole; 
5-(pyrimid-5-yl)-3-(pyrrolidin-3-yl)-1 H-indole; 
3-N-(2-methoxyethyl)pyrrolidin-3-yl!-5-(pyrimid-5-yl)-1 H-indole; 
3-(N-ethylpyrrolidin-3-yl)-5-(pyrimid-5-yl)-1 H-indole; 
5(3-cyanopyrid-5-yl)-3-(N-methylpyrrolidin-3-yl)-1 H-indole; 
5(3-cyanopyrid-5-yl)-3-(pyrrolidin-3-yl)-1 H-indole; 
5-(3-cyanopyrid-5-yl)-1-H-3-N-(2methoxyethyl)pyrrolidin-3-yl!-indole; and 
3-(N-methylpyrrolidin-3-yl)-5-(1,2,4-triazin-3-yl)-1 H-indole. 
The present invention also relates to a compound of the formula 
##STR3## 
wherein X is halogen chloride, bromide, iodide! or --OSO.sub.2 CF.sub.3 
and R.sub.12 is hydrogen, methyl, or benzyl. These compounds are useful as 
intermediates in preparing compounds of formula I 
The present invention also relates to a pharmaceutical composition for 
treating a condition selected from hypertension, depression, anxiety, 
eating disorders, obesity, drug abuse, cluster headache, migraine, pain, 
and chronic paroxysmal hemicrania and headache associated with vascular 
disorders comprising an amount of a compound of the formula I or a 
pharmaceutically acceptable salt thereof effective in treating such 
condition and a pharmaceutically acceptable carrier. 
The present invention also relates to a method for treating a condition 
selected from hypertension, depression, anxiety, eating disorders, 
obesity, drug abuse, cluster headache, migraine, pain and chronic 
paroxysmal hemicrania and headache associated with vascular disorders 
comprising administering to a mammal (e.g., a human) requiring such 
treatment an amount of a compound of the formula I or a pharmaceutically 
acceptable salt thereof effective in treating such condition. 
The present invention also relates to a method for treating disorders 
arising from deficient serotonergic neurotransmission (e.g., depression, 
anxiety, eating disorders, obesity, drug abuse, cluster headache, 
migraine, pain and chronic paroxysmal hemicrania and headache associated 
with vascular disorders) comprising administering to a mammal (e.g., a 
human) requiring such treatment an amount of a compound of the formula I 
or a pharmaceutically acceptable salt thereof effective in treating such 
condition. 
The present invention also relates to a method for treating disorders 
arising from deficient serotonergic neurotransmission (e.g., depression, 
anxiety, eating disorders, obesity, drug abuse, cluster headache, 
migraine, pain and chronic paroxysmal hemicrania and headache associated 
with vascular disorders) comprising administering to a mammal (e.g., a 
human) requiring such treatment an amount of a compound of the formula I 
or a pharmaceutically acceptable salt thereof effective in treating such 
condition. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of formula I can be prepared via the following reaction 
scheme: 
##STR4## 
Compounds of formula III wherein X is halogen chloride, bromide, iodide! 
or --OSO.sub.2 CF.sub.3 and R.sub.12 is hydrogen, methyl, or benzyl can be 
prepared from the condensation of a compound of formula IV wherein X is as 
defined above with a compound of formula V wherein R.sub.12 is as defined 
above in an inert solvent. Suitable inert solvents include C.sub.1 to 
C.sub.3 alcohols, acetic acid, formic acid, and N,N-dimethylformamide. The 
preferred solvent is acetic acid. The reaction is usually conducted at a 
temperature of from about 65.degree. C. to about 154.degree. C., 
preferably about 100.degree.C. to about 110.degree.C. 
Compounds of formula 11 wherein X and R.sub.12 are as defined above can be 
prepared via the reduction of a compound of formula III wherein R.sub.12 
is as defined above in an inert solvent. Suitable reducing agents include 
lithium aluminum hydride, lithium borohydride, and diborane. Uthium 
aluminum hydride is the preferred reducing agent. Suitable inert solvents 
include tetrahydrofuran, dioxane, diethyl ether, and other ethers. 
Tetrahydrofuran is the preferred solvent. The reaction is usually 
conducted at a temperature of from about 25.degree. C. to about 
100.degree.C., preferably at about 65.degree. C. 
Compounds of formula VI wherein A, B, D, E, F. R.sub.2, R.sub.3, R.sub.4, 
R.sub.5, and R.sub.6 are as defined above can be prepared from a compound 
of formula VII wherein A, B, D, E, F, R.sub.2, R.sub.3, R.sub.4, R.sub.5, 
and R.sub.6 are as defined above, and Z is halogen chloride, bromide, 
iodide! or --OSO.sub.2 CF.sub.3 via a transition metal catalyzed insertion 
reaction using hexamethyiditin in an inert solvent, usually in the 
presence of a base, lithium chloride, and butylated hydroxytoluene i.e., 
2,6-di-tert-butyl-4 -methylphenol, BHT!. Suitable catalysts are of 
palladium (II) and palladium (0) species, such as palladium (II) acetate, 
palladium (II) chloride, bis(triphenylphosphine)palladium (II) chloride, 
and tetrakis(triphenylphoshine)palladium(0). The preferred catalyst is 
tetrakis(triphenylphoshine)palladium(0). Suitable inert solvents include 
ethers, such as tetrahydrofuran and dioxane, acetonitrile, 
N,N-dimethylformamide, and N- methylpyrrolidin-2-one. Dioxane is the 
preferred inert solvent. Suitable bases include tertiary amines, sodium 
bicarbonate, and sodium carbonate. The preferred base is triethylamine. 
The reaction is usually conducted at a temperature between about 
70.degree. C. and about 210.degree. C., preferably between about 
90.degree. C. and 154.degree. C. 
Compounds of formula Ia wherein A, B, D, E, F, R.sub.2, R.sub.3, R.sub.4, 
R.sub.5, R.sub.6, and R.sub.12 are as defined above can be prepared by the 
transition metal catalyzed aryl cross-coupling reaction between a compound 
of formula 11 wherein X and R.sub.12 are as defined above and a compound 
of formula VI wherein A, B, D, E, F, R.sub.2, R.sub.3, R.sub.4, R.sub.5, 
and R.sub.6 are as defined above in an inert solvent, usually in the 
presence of a base, lithium chloride, and butylated hydroxytoluene i.e., 
2,6di-tert-butyl-4 -methylphenol, BHT!. Suitable catalysts are palladium 
(II) and palladium (0) species, such as palladium (II) acetate, palladium 
(II) chloride, bis(triphenylphosphine)palladium (II) chloride, 
tetrakis(triphenylphoshine)palladium(0). The preferred catalyst is 
bis(triphenylphosphine)palladium (II) chloride. Suitableinertsolvents 
includeacetonitrile, N,N-dimethylformamide, and N-methylpyrrolidin-2-one. 
N,N-dimethylformamide is the preferred inert solvent. Suitable bases 
include tertiary amines, sodium bicarbonate, and sodium carbonate. The 
preferred base is triethylamine. The reaction is usually conducted at a 
temperature between about 70.degree. C. and about 210.degree.C., 
preferably between about 90.degree. C and 154.degree. C. 
Compounds of formula Ib wherein A, B, D, E, F, R.sub.1, R.sub.2, R.sub.3, 
R.sub.4, R.sub.5, and R.sub.6 are as defined above can be prepared from a 
compound of formula Ia wherein R.sub.12 is benzyl, and A, B, D, E, F, 
R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined above via a 
reductive amination using an aldehyde of the formula R.sub.13 CHO, where 
R.sub.13 is C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.8 R.sub.7, or 
C.sub.1 to C.sub.2 alkyl-aryl, s is 1, 2, or 3, and R.sub.7 is as defined 
above, along with a transition metal catalyst, and a hydrogen source in an 
inert solvent. Suitable catalysts include palladium on carbon, Raney 
nickel, platinum oxide, and palladium hydroxide on carbon. The preferred 
catalyst is palladium hydroxide on carbon. Suitable hydrogen sources 
include hydrogen gas, ammonium formate, and formic acid. Hydrogen gas at a 
pressure of from about one to about three atmospheres is the preferred 
hydrogen source. Three atmospheres of hydrogen gas is the preferred 
pressure. Suitable solvents include C.sub.1 to C.sub.4 alcohols, 
acetonitrile, N,N-dimethylformamide, and N-methylpyrrolidine. Ethanol is 
the preferred solvent. The reaction is usually conducted at a temperature 
of from about 25.degree. C. to about 100.degree. C., preferably about 
25.degree. C. to about 50.degree. C. 
Compounds of formula IV, formula V, and formula VII are either commercially 
available or can be prepared using methods known to one skilled in the 
art. Aldehydes of the formula R.sub.13 CHO wherein R.sub.13 is as defined 
above are also either commercially available or can be prepared using 
methods known to one skilled in the art. 
Unless indicated otherwise, the pressure of each of the above reactions is 
not critical. Generally, the reactions will be conducted at a pressure of 
from about one to about three atmospheres, preferably at ambient pressure 
(about one atmosphere). 
The compounds of the formula I which are basic in nature are capable of 
forming a wide variety of different salts with various inorganic and 
organic acids. Although such salts must be pharmaceutically acceptable for 
administration to animals, it is often desirable in practice to initially 
isolate a compound of the formula I from the reaction mixture as a 
pharmaceutically unacceptable salt and then simply convert the latter back 
to the free base compound by treatment with an alkaline reagent, and 
subsequently convert the free base to a pharmaceutically acceptable acid 
addition salt. The acid addition salts of the base compounds of this 
invention are readily prepared by treating the base compound with a 
substantially equivalent amount of the chosen mineral or organic acid in 
an aqueous solvent medium or in a suitable organic solvent such as 
methanol or ethanol. Upon careful evaporation of the solvent, the desired 
solid salt is obtained. 
The acids which are used to prepare the pharmaceutically acceptable acid 
addition salts of the base compounds of this invention are those which 
form non-toxic acid addition salts, i.e., salts containing 
pharmacologically acceptable anions, such as hydrochloride, hydrobromide, 
hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, 
acetate, lactate, citrate or acid citrate, tartrate or bitartrate, 
succinate, maleate, fumarate, gluconate, saccharate, benzoate, 
methanesulfonate and pamoate i.e., 
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)! salts. 
Those compounds of the formula I which are also acidic in nature, e.g., 
where R.sub.2 contains a carboxylate, are capable of forming base salts 
with various pharmacologically acceptable cations. Examples of such salts 
include the alkali metal or alkaline-arth metal salts and particular, the 
sodium and potassium salts. These salts are all prepared by conventional 
techniques. The chemical bases which are used as reagents to prepare the 
pharmaceutically acceptable base salts of this invention are those which 
form non-toxic base salts with the herein described acidic compounds of 
formula I. These non-toxic base salts include those derived from such 
pharmacologically acceptable cations as sodium, potassium calcium and 
magnesium, etc. These salts can easily be prepared by treating the 
corresponding acidic compounds with an aqueous solution containing the 
desired pharmacologically acceptable cations, and then evaporating the 
resulting solution to dryness, preferably under reduced pressure. 
Alternatively, they may also be prepared by mixing lower alkanolic 
solutions of the acidic compounds and the desired alkali metal alkoxide 
together, and then evaporating the resulting solution to dryness in the 
same manner as before. In either case, stoichiometric quantities of 
reagents are preferably employed in order to ensure completeness of 
reaction of maximum product of yields of the desired final product. 
The compounds of the formula I and the pharmaceutically acceptable salts 
thereof (hereinafter, also referred to as the active compounds of the 
invention) are useful psychotherapeutics and are potent serotonin 
(5-HT.sub.1) agonists with selectivity for the 5-HT.sub.1D receptor and 
may be used in the treatment of depression, anxiety, eating disorders, 
obesity, drug abuse, cluster headache, migraine, chronic paroxysmal 
hemicrania and headache associated with vascular disorders, pain, and 
other disorders arising from deficient serotonergic neurotransmission. The 
compounds can also be used as centrally acting antihypertensives and 
vasodilators. The active compounds of the invention can be evaluated as 
anti-migraine agents by testing the extent to which they mimic sumatriptan 
in contracting the dog isolated saphenous vein strip P.P.A. Humphrey et 
al., Br. J. Pharmacol., 94, 1128 (1988)!. This effect can be blocked by 
methiothepin, a known serotonin antagonist. Sumatriptan is known to be 
useful in the treatment of migraine and produces a selective increase in 
carotid vascular resistance in the anesthetized dog. It has been suggested 
W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989)! that this is the 
basis of its efficacy. 
The active compounds of the present invention can also be evaluated via the 
plasma protein extravasation response within the dura mater of guinea pigs 
following unilateral electrical trigeminal ganglion stimulation, as 
described in Markowitz et al., J. Neurosci., 7 (12), 41294136 (1987). The 
extent to which they mimic sumatriptan, in terms of both potency and 
efficacy, is determined in this assay. 
The serotonin 5HT.sub.1 agonist activity is measured in in vitro receptor 
binding assays as described for the 5-HT.sub.1A receptor using rat cortex 
as the receptor source and .sup.3 H!-8-OH-DPAT as the radioligand D. 
Hoyer et al. Eur. J. Pharm., Vol. 118, 13 (1985)! and as described for the 
5-HT.sub.1D receptor using bovine caudate as the receptor source and 
.sup.3 H! serotonin as the radioligand R. E. Heuring and S. J. Peroutka, 
J. Neuroscience, Vol.7, 894 (1987)!. 5-HT agonist activity is defined by 
agents with affinities (IC.sub.50 s) of 250 nM or less at either binding 
assay. 
The compositions of the present invention may be formulated in a 
conventional manner using one or more pharmaceutically acceptable 
carriers. Thus, the active compounds of the invention may be formulated 
for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular 
or subcutaneous) or rectal administration or in a form suitable for 
administration by inhalation or insufflation. 
For oral administration, the pharmaceutical compositions may take the form 
of, for example, tablets or capsules prepared by conventional means with 
pharmaceutically acceptable excipients such as binding agents (e.g. 
pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl 
methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or 
calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); 
disintegrants (e.g. potato starch or sodium starch glycolate); or wetting 
agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods 
well known in the art. Uquid preparations for oral administration may take 
the form of, for example, solutions, syrups or suspensions, or they may be 
presented as a dry product for constitution with water or other suitable 
vehicle before use. Such liquid preparations may be prepared by 
conventional means with pharmaceutically acceptable additives such as 
suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated 
edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous 
vehicles (e.g. almond oil, oily esters or ethyl alcohol); and 
preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). 
For buccal administration the composition may take the form of tablets or 
lozenges formulated in conventional manner. 
The active compounds of the invention may be formulated for parenteral 
administration by injection, including using conventional catheterization 
techniques or infusion. Formulations for injection may be presented in 
unit dosage form e.g. in ampules or in multi-dose containers, with an 
added preservative. The compositions may take such forms as suspensions, 
solutions or emulsions in oily or aqueous vehicles, and may contain 
formulating agents such as suspending, stabilizing and/or dispersing 
agents. Altematively, the active ingredient may be in powder form for 
reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, 
before use. 
The active compounds of the invention may also be formulated in rectal 
compositions such as suppositories or retention enemas, e.g., containing 
conventional suppository bases such as cocoa butter or other glycerides. 
For intranasal administration or administration by inhalation, the active 
compounds of the invention are conveniently delivered in the form of a 
solution or suspension from a pump spray container that is squeezed or 
pumped by the patient or as an aerosol spray presentation from a 
pressurized container or a nebulizer, with the use of a suitable 
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, 
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the 
case of a pressurized aerosol, the dosage unit may be determined by 
providing a valve to deliver a metered amount. The pressurized container 
or nebulizer may contain a solution or suspension of the active compound. 
Capsules and cartridges (made, for example, from gelatin) for use in an 
inhaler or insufflator may be formulated containing a powder mix of a 
compound of the invention and a suitable powder base such as lactose or 
starch. 
A proposed dose of the active compounds of the invention for oral, 
parenteral or buccal administration to the average adult human for the 
treatment of the conditions referred to above (e.g., migraine) is 0.1 to 
200 mg of the active ingredient per unit dose which could be administered, 
for example, 1 to 4 times per day. 
Aerosol formulations for treatment of the conditions referred to above 
(e.g., migraine) in the average adult human are preferably arranged so 
that each metered dose or "puff" of aerosol contains 20 .mu.g to 1000 
.mu.g of the compound of the invention. The overall daily dose with an 
aerosol will be within the range 100 .mu.g to 10 mg. Administration may be 
several times daily, for example 2, 3, 4 or 8 times, giving for example, 
1, 2 or 3 doses each time.