Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed that the cause of migraine headache was vasodilatation of. extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT1 agonist 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 occurrence of migraine headaches is independent of changes in vessel diameter. Cephalalgia. 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT1D subtype, located on the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT1. A human gene which expresses one of these 5-HT1 receptor subtypes, named 5-HT1F, was isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. The high affinity of sumatriptan at this subtype, Ki=23 nM, suggests a role of the 5-HT1F receptor in migraine.
This invention relates to novel 5-HT1F agonists which inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders.
The present invention relates to compounds of formula I: 
or a pharmaceutical acid addition salt thereof, where;
A is hydrogen, halo, xe2x80x94OR4, NH2, or xe2x80x94CF3;
R is hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, or (C1-C6 alkyl)-Ar1;
R1 is xe2x80x94NHxe2x80x94R2xe2x80x94R3, hydroxy, xe2x80x94OSO2Ar2, or NH2;
Ar, Ar1, Ar2, Ar3, and Ar4 are independently an optionally substituted phenyl or optionally substituted heteroaryl;
R2 is xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, or xe2x80x94SO2xe2x80x94;
R3 is hydrogen, optionally substituted C1-C6 alkyl, Ar3, xe2x80x94NR5R6, or OR5; provided R3 is not hydrogen if R2 is either xe2x80x94CSxe2x80x94 or xe2x80x94SO2xe2x80x94;
R4 is hydrogen, optionally substituted C1-C6 alkyl, or Ar; and
R5 and R6 are independently hydrogen, optionally substituted C1-C8 alkyl, or Ar4; or R6 and R5 combine, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring.
This invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier, diluent, or excipient.
In addition, the present invention relates to a method for activating 5-HT1F receptors in mammals comprising administering to a mammal in need of such activation an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
Moreover, the current invention relates to a method for inhibiting neuronal protein extravasation comprising administering to a mammal in need of such inhibition an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
In addition, the present invention relates to a process for preparing the compounds of formula I(a): 
wherein R3 is hydrogen, optionally substituted C1-C6 alkyl, Ar3, xe2x80x94NR5R6, or OR5;
R5 and R6 are independently hydrogen, optionally substituted C1-C8 alkyl, or Ar4; or R6 and R5 combine, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring; and
Ar3 and Ar4 are independently an optionally substituted phenyl or optionally substituted heteroaryl, comprising:
(a) protecting 4-benzoylpiperidine hydrochloride to form an N-protected 4-benzoylpiperidine hydrochloride;
(b) nitrating the N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4-(mononitrobenzoyl)piperidines;
(c) deprotecting the N-protected 4-(mononitrobenzoyl)piperidine mixture to form a mixture of 4-(mononitrobenzoyl)piperidines;
(d) separating the 4-(3-nitrobenzoyl)piperidine from the mixture of 4-(mononitrobenz-oyl)piperidines;
(e) reducing the 4-(3-nitrobenzoyl)piperidine to form 4-(3-aminobenzoyl)piperidine; and
(f) acylating the 4-(3-aminobenzoyl)piperidine.
One embodiment of this invention is a method for increasing activation of the 5-HT1F receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, chronic pain, panic disorder, anxiety, general pain, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism, allergic rhinitis, insect stings, trichotillomania, trigeminal neuralgia, dental pain or temperomandibular joint dysfunction pain. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employ a compound of formula I.
The use of a compound of formula I for the activation of the 5-HT1F receptor, for the inhibition of peptide extravasation in general or due to stimulation of the trigeminal ganglia specifically, and for the treatment of any of the disorders described above, are all embodiments of the present invention.
The general chemical terms used throughout have their usual meanings. For example, the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl. The term xe2x80x9cC1-C8 alkylxe2x80x9d includes those groups listed for C1-C4 alkyl and also refers to saturated, straight, branched, or cyclic hydrocarbon chains of 5 to 8 carbon atoms. Such groups include, but are not limited to, pentyl, pent-2-yl, pent-3-yl, neopentyl, 2,3,4-trimethylpentyl, hexyl, hex-2-yl, hex-3-yl, hex-4-yl, 2,3-dimethylhexyl, 2-ethylhexyl, heptyl, hept-2-yl, hept-3-yl, hept-4-yl, octyl, oct-2-yl, oct-3-yl, oct-4-yl, oct-5-yl, and the like. The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9cC3-C6 alkenylxe2x80x9d refers to mono-unsaturated straight or branched hydrocarbon chains containing from 3 to 6 carbon atoms and, includes, but is not limited to, allyl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like.
The term xe2x80x9cC3-C6 alkynylxe2x80x9d refers to straight or branched hydrocarbon chains containing 1 triple bond and from 3 to 6 carbon atoms and includes, but is not limited to, propynyl, 2-butyn-4-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the like.
The terms xe2x80x9cC1-C6 alkoxyxe2x80x9d and xe2x80x9cC1-C4 alkoxyxe2x80x9d refer respectively to a C1-C6 alkyl and C1-C4 alkyl group bonded through an oxygen atom. The term xe2x80x9cheteroaryloxyxe2x80x9d refers to a heteroaryl or substituted heteroaryl group bonded through an oxygen atom. The term xe2x80x9caryloxyxe2x80x9d refers to a phenyl or substituted phenyl group bonded through an oxygen atom. The term xe2x80x9cC1-C4 acylxe2x80x9d refers to a formyl group or a C1-C3 alkyl group bonded through a carbonyl moiety. The term xe2x80x9cC1-C4 alkoxycarbonylxe2x80x9d refers to a C1-C4 alkoxy group bonded through a carbonyl moiety.
The term xe2x80x9cbenzofused C4-C8 cycloalkylxe2x80x9d is taken to mean a C4-C8 cycloalkyl group fused to a phenyl ring. Examples of these groups include benzocyclobutyl, indanyl, 1,2,3,4-tetrahydronaphthyl, and the like.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
The term xe2x80x9cheterocyclexe2x80x9d is taken to mean stable aromatic and non-aromatic 5- and 6-membered rings containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said rings being optionally benzofused. All of these rings may be substituted with up to three substituents independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyano, nitro, hydroxy, xe2x80x94S(O)mxe2x80x94(C1-C4 alkyl) and xe2x80x94S(O)m-phenyl where m is 0, 1 or 2. Non-aromatic rings include, for example, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl, dioxanyl, pyranyl, and the like. Benzofused non-aromatic rings include indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and the like. Aromatic rings include furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused aromatic rings include isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl, thionaphthyl, indolyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d is taken to mean an aromatic or benzofused aromatic heterocycle as defined in the previous paragraph.
The term xe2x80x9csubstituted C1-C6 alkylxe2x80x9d refers to a C1-C6 alkyl group that is substituted from 1 to 3 times independently with halo, hydroxy, phenyl, 2-phenylethylen-1-yl, diphenylmethyl, naphthyl, substituted phenyl, aryloxy, heterocycle, heteroaryloxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, phenyl(C1-C4 alkyl), substituted phenyl (C1-C4 alkyl), or benzofused C4-C8 cycloalkyl.
The terms xe2x80x9csubstituted phenylxe2x80x9d and xe2x80x9csubstituted phenyl(C1-C4 alkyl)xe2x80x9d are taken to mean that the phenyl moiety in either case is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n where n is 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy.
The term xe2x80x9csubstituted naphthylxe2x80x9d refers to a naphthyl group that may be substituted in the same manner as a substituted phenyl group.
The terms xe2x80x9csubstituted heteroarylxe2x80x9d and xe2x80x9csubstituted heteroaryl(C1-C4 alkyl)xe2x80x9d are taken to mean that the heteroaryl moiety in either case is substituted with up to three substituents independently selected from: halo, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, (C1-C4 alkyl)-S(O)n, and phenyl-S(O)n; where n is 0, 1, or 2.
The term xe2x80x9camino protecting groupxe2x80x9d as used in this specification refers to a substituents commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFMOCxe2x80x9d), and the like; and like amino protecting groups. The species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as xe2x80x9cGreenexe2x80x9d. 
The term xe2x80x9cpharmaceuticalxe2x80x9d when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
By xe2x80x9cpharmaceutical formulationxe2x80x9d it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (a compound of formula I).
Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutical acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
The term xe2x80x9cacid, addition saltxe2x80x9d refers to a salt of a compound of formula I prepared by reaction of a compound of formula I with a mineral or organic acid. For exemplification of pharmaceutical acid addition salts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977.
The pharmaceutical acid addition salts of the invention are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, ethyl acetate and the like. The salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and Acids commonly employed 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 thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex2-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, 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 term xe2x80x9ceffective amountxe2x80x9d means an amount of a compound of formula I which is capable of activating 5-HT1F receptors.
The term xe2x80x9csuitable solventxe2x80x9d refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
All enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. For example, when R1 is NHxe2x80x94R2xe2x80x94R3; R2 is xe2x80x94COxe2x80x94; and R3 is CH(OH)CH3, the CH group of R3 is a chiral center. Such centers are designed xe2x80x9cRxe2x80x9d or xe2x80x9cS.xe2x80x9d For the purposes of the present application, the R and S enantiomers are illustrated below. 
The following group is illustrative of compounds contemplated within the scope of this invention:
4-[3-((3-trifluoromethylphenyl)sulfonyloxy)benzoyl]-piperidine
4-[3-((4-trifluoromethoxyphenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((3-bromophenyl)sulfonyloxy)benzoyl]-1-ethylpiperidine
4-[3-((3-trifluoromethoxyphenyl)sulfonyloxy)benzoyl]-1-propylpiperidine
4-[3-((4-chlorophenyl)sulfonyloxy)benzoyl]-1-butylpiperidine
4-[3-((2-hydroxyphenyl)sulfonyloxy)benzoyl]-1-pentenylpiperidine
4-[3-((4-bromophenyl) sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((3,5-difluorophenyl)sulfonyloxy)benzoyl]-1-propenylpiperidine
4-[3-((3-methylphenyl)sulfonyloxy)benzoyl]-1-butenylpiperidine
4-[3-((pyrid-3-yl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((pyrid-2-yl) sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2,3,4,5,6-pentafluorophenyl)sulfonyloxy)benzoyl]-1-hexenylpiperidine
4-[3-((4-methylphenyl)sulfonyloxy)benzoyl]-1-propynylpiperidine
4-[3-((3,4,5-trifluorophenyl)sulfonyloxy)benzoyl]-1-butynylpiperidine
4-[3-((2,3,4,5-tetrafluorophenyl)sulfonyloxy)benzoyl]-1-pentynylpiperidine
4-[3-((2-trifluoromethylphenyl)sulfonyloxy)benzoyl]-1-hexynylpiperidine
4-[3-((4-fluorophenyl)sulfonyloxy)benzoyl]-1-(phenylmethyl)piperidine
4-[3-((3-chlorophenyl)sulfonyloxy)benzoyl]-1-(phenylethyl)piperidine
4-[3-((4-iodophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((3-fluorophenyl)sulfonyloxy)benzoyl]-1-(2-phenylpropyl)piperidine
4-[3-((4-methoxyphenyl)sulfonyloxy)benzoyl]-1-(pyrrolidin-2-ylmethyl)piperidine
4-[3-((2-methylphenyl)sulfonyloxy)benzoyl]-1-(piperidin-1-ylethyl)piperidine
4-[3-((4-nitrophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2,3-difluorophenyl)sulfonyloxy)benzoyl]-1-(piperazin-2-ylpropyl)piperidine
4-[3-((fur-2-yl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((thiophen-2-yl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2,3,4-trifluorophenyl)sulfonyloxy)benzoyl]-1-(thien-2-ylmethyl)piperidine
4-[3-((pyridin-4-yl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((4-cyanophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((3,4-difluorophenyl)sulfonyloxy)benzoyl]-1-(dioxan-2-ylmethyl)piperidine
4-[3-((2-fluorophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2-trifluoromethoxyphenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((4-fluorophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine hydrochloride
4-[3-(phenylsulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2-bromophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2,3,5-trifluorophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine hydrobromide
4-[3-((2-nitrophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-((2,4,5-trifluorophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine sulfide
4-[3-((2-iodophenyl)sulfonyloxy)benzoyl]-1-methylpiperidine
4-[3-(3-nitrophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-trifluoromethylphenylthioureido)benzoyl]-1-methylpiperidine oxalate
4-[3-(4-trifluoromethoxyphenylthioureido)benzoyl]-1-methylpiperidine methanesulfonate
4-[3-(phenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-bromophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-trifluoromethoxyphenylthioureido)benzoyl]-1-methylpiperidine fumarate
4-[3-(4-chlorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2-hydroxyphenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(4-bromophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3,5-difluorophenylthioureido)benzoyl]-1-methylpiperidine phthalate
4-[3-(3-methylphenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(pyrid-3-ylthioureido)benzoyl]-1-methylpiperidine
4-[3-(pyrid-2-ylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,4,5,6-pentafluorophenylthioureido)benzoyl]-1-methylpiperidine chlorobenzoate
4-[3-(4-methylphenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3,4,5-trifluorophenylthioureido)benzoyl]-1-methylpiperidine citrate
4-[3-(2,3,4,5-tetrafluorophenylthioureido)benzoyl]-1-methylpiperidine tartrate
4-[3-(2-trifluoromethylphenylthioureido)benzoyl]-1-methylpiperidine propanesulfonate
4-[3-(4-fluorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-chlorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(4-iodophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-fluorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(4-methoxyphenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2-methylphenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(4-nitrophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2,3-difluorophenylthioureido)benzoyl]-1-methylpiperidine hydroxybenzoate
4-[3-(fur-2-ylthioureido)benzoyl]-1-methylpiperidine
4-[3-(thiophen-2-ylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,4-trifluorophenylthioureido)benzoyl]-1-methylpiperidine decanoate
4-[3-(pyridin-4-ylthioureido)benzoyl]-1-methylpiperidine
4-[3-(4-cyanophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3,4-difluorophenylthioureido)benzoyl]-1-methylpiperidine monohydrogenphosphate
4-[3-(2-fluorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2-trifluoromethoxyphenylthioureido)benzoyl]-1-1-methylpiperidine sulfite
4-[3-(4-fluorophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2-bromophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,5-trifluorophenylthioureido)benzoyl]-1-methylpiperidine pyrosulfate
4-[3-(2-nitrophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(2,4,5-trifluorophenylthioureido)benzoyl]-1-ethylpiperidine malonate
4-[3-(2-iodophenylthioureido)benzoyl]-1-methylpiperidine
4-[3-(3-nitrophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3-trifluoromethylphenylureido)benzoyl]-1-methylpiperidine xylenesulfonate
4-[3-(4-trifluoromethoxyphenylureido)benzoyl]-1-propylpiperidine glycollate
4-[3-(phenylureido)benzoyl]-1-methylpiperidine
4-[3-((+)-2-hydroxypropylureido)benzoyl]-1-methylpiperidine
4-[3-((xe2x88x92)-3-phenylbutylureido)benzoyl]-1-methylpiperidine
4-[3-(R-2-(diphenylmethyl)propylureido)benzoyl]-1-methylpiperidine
4-[3-(S-2-hydroxypropylureido)benzoyl]-1-methyl-piperidine
4-[3-(3-trifluoromethoxyphenylureido)benzoyl]-1-methylpiperidine lactate
4-[3-(4-chlorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-hydroxyphenylureido)benzoyl]-1-methylpiperidine
4-[3-(4-bromophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3,5-difluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3-methylphenylureido)benzoyl]-1-methylpiperidine
4-[3-(pyrid-3-ylureido)benzoyl]-1-methylpiperidine
4-[3-(pyrid-2-ylureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,4,5,6-pentafluorophenylureido)benzoyl]-1-methylpiperidine mandelate
4-[3-(4-methylphenylureido)benzoyl]-1-methylpiperidine
4-[3-(3,4,5-trifluorophenylureido)benzoyl]-1-methylpiperidine lactate
4-[3-(2,3,4,5-tetrafluorophenylureido)benzoyl]-1-methylpiperidine caprylate
4-[3-(2-trifluoromethylphenylureido)benzoyl]-1-methylpiperidine acrylate
4-[3-(4-fluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3-chlorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(4-iodophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3-fluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(4-methoxyphenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-methylphenylureido)benzoyl]-1-methylpiperidine
4-[3-(4-nitrophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2,3-difluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(fur-2-ylureido)benzoyl]-1-methylpiperidine
4-[3-(thiophen-2-ylureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,4-trifluorophenylureido)benzoyl]-1-methylpiperidine formate
4-[3-(pyridin-4-ylureido)benzoyl]-1-methylpiperidine
4-[3-(4-cyanophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3,4-difluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-fluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-trifluoromethoxyphenylureido)benzoyl]-1-methylpiperidine iodide
4-[3-(4-fluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-bromophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2,3,5-trifluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-nitrophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2,4,5-trifluorophenylureido)benzoyl]-1-methylpiperidine
4-[3-(2-iodophenylureido)benzoyl]-1-methylpiperidine
4-[3-(3-nitrophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-trifluoromethylphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-trifluoromethoxyphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(phenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-bromophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-trifluoromethoxyphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-chlorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-hydroxyphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-bromophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3,5-difluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-methylphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(pyrid-3-ylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(pyrid-2-ylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,3,4,5,6-pentafluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-methylphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3,4,5-trifluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,3,4,5-tetrafluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-trifluoromethylphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-fluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-chlorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-iodophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3-fluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-methoxyphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-methylphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-nitrophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,3-difluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(fur-2-ylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(thiophen-2-ylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,3,4-trifluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(pyridin-4-ylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-cyanophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(3,4-difluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-fluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-trifluoromethoxyphenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(4-fluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-bromophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,3,5-trifluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-nitrophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2,4,5-trifluorophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-(2-iodophenylsulfonamino)benzoyl]-1-methylpiperidine
4-[3-((3-trifluoromethylphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-trifluoromethoxyphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3-bromophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3-trifluoromethoxyphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-chlorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-hydroxyphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-bromophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3,5-difluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3-methylphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((pyrid-3-yl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((pyrid-2-yl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,3,4,5,6-pentafluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-methylphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3,4,5-trifluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,3,4,5-tetrafluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-trifluoromethylphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-fluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3-chlorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-iodophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3-fluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-methoxyphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-methylphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-nitrophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,3-difluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((fur-2-yl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((thiophen-2-yl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,3,4-trifluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((pyridin-4-yl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-cyanophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((3,4-difluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-fluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-trifluoromethoxyphenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((4-fluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-(phenylamidyl)benzoyl]-1-methylpiperidine
4-[3-((2-bromophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,3,5-trifluorophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2-nitrophenyl)amidyl)benzoyl]-1-methylpiperidine
4-[3-((2,4,5-trifluorophenyl)amidyl)benzoyl]-1-methylpiperidine
While all enantiomers, diastereomers, and mixtures thereof, are useful as 5-HT1F agonists, single enantiomers and single diastereomers are preferred. Furthermore, while all of the compounds of this invention are useful as 5-HT1F agonists, certain classes are preferred. The following paragraphs describe such preferred classes.
1) R is hydrogen;
2) R is methyl;
3) R is [1-(isopropyl)pyrazol-4-yl]ethyl;
4) A is hydrogen;
5) A is 2-amino;
6) R1 is xe2x80x94NHxe2x80x94R2xe2x80x94R3;
7) R1 is hydroxy;
8) R1 is xe2x80x94OSO2R3;
9) R1 is NH2;
10) R2 is xe2x80x94COxe2x80x94;
11) R2 is xe2x80x94SO2xe2x80x94;
12) R2 is xe2x80x94CSxe2x80x94;
13) when R2 is xe2x80x94SO2xe2x80x94, R3 is C1-C6 alkyl;
14) when R2 is xe2x80x94SO2xe2x80x94, R3 is selected from the group consisting of methyl, butyl, isopropyl, and cyclohexyl;
15) when R2 is xe2x80x94SO2xe2x80x94, R3 is phenyl;
16) when R2 is xe2x80x94SO2xe2x80x94, R3 is monosubstituted phenyl;
17) when R2 is xe2x80x94SO2xe2x80x94, R3 is selected from the group consisting of 4-iodophenyl, and 4-fluorophenyl;
18) when R2 is xe2x80x94SO2xe2x80x94, R3 is 4-iodophenyl;
19) when R2 is xe2x80x94COxe2x80x94 or xe2x80x94CSxe2x80x94, R3 is xe2x80x94NR5R6;
20) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 and R6 are hydrogen;
21) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is unsubstituted phenylmethyl;
22) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is unsubstituted phenyl;
23) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is 4-fluorophenyl;
24) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is C1-C6 alkyl;
25) when R2 is xe2x80x94COxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is selected from the group consisting of methyl, cyclohexyl, butyl, and isopropyl;
26) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is phenylmethyl;
27) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is, hydrogen and R6 is phenyl;
28) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is halo monosubstituted phenyl;
29) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is 4-fluorophenyl;
30) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is C1-C6 alkyl;
31) when R2 is xe2x80x94CSxe2x80x94 and R3 is NR5R6, R5 is hydrogen and R6 is selected from the group consisting of methyl, butyl, and isopropyl;
32) R2 is xe2x80x94COxe2x80x94 and R3 is phenyl;
33) R2 is xe2x80x94COxe2x80x94 and R3 is phenylmethyl;
34) R2 is xe2x80x94COxe2x80x94 and R3 is C1-C6 alkyl;
35) R2 is xe2x80x94COxe2x80x94 and R3 is selected from the group consisting of methyl, butyl, cyclohexyl, and isopropyl;
36) R2 is xe2x80x94COxe2x80x94 and R3 is monosubstituted phenyl;
37) R2 is xe2x80x94COxe2x80x94 and R3 is selected from the group consisting of 2-nitrophenyl, 3-nitrophenyl, 3-cyanophenyl, 4-nitrophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, and 4-benzylphenyl;
38) 38)R2 is xe2x80x94COxe2x80x94 and R3 is substituted halophenyl;
39) R2 is xe2x80x94COxe2x80x94 and R3 is selected from the group consisting of 3,4,5,6-tetrafluorophenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-bromophenyl, 3-chlorophenyl, 2-iodophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-bromophenyl, 2,3,4,5,6-pentafluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, and 4-hydroxyphenyl;
40) R2 is xe2x80x94COxe2x80x94 and R3 is 4-fluorophenyl;
41) R2 is xe2x80x94COxe2x80x94 and R3 is 4-fluorophenyl additionally monosubstituted;
42) R2 is xe2x80x94COxe2x80x94 and R3 is selected from the group consisting of 2-chloro-4-fluorophenyl, 2-iodo-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-methyl-4-fluorophenyl;
43) R2 is xe2x80x94COxe2x80x94 and R3 is 4-fluorophenyl additionally disubstituted;
44) R2 is xe2x80x94COxe2x80x94 and R3 is selected form the group consisting of 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl;
45) R2 is xe2x80x94COxe2x80x94 and R3 is quinolinyl;
46) R2 is xe2x80x94COxe2x80x94 and R3 is trifluoromethoxy monosubstituted phenyl;
47) R2 is xe2x80x94COxe2x80x94 and R3 is C1-C6 alkoxy monosubstituted phenyl;
48) R2 is xe2x80x94COxe2x80x94 and R3 is hydroxy monosubstituted phenyl;
49) R2 is xe2x80x94COxe2x80x94 and R3 is OR5;
50) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is phenyl;
51) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is phenylmethyl;
52) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is C1-C6 alkyl;
53) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is selected from the group consisting of methyl, butyl, and isopropyl;
54) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is Ar4;
55) when R2 is xe2x80x94COxe2x80x94 and R3 is OR5; R5 is selected from thien-2-yl, pyridin-3-yl, pyridin-2-yl, and fur-2-yl;
56) the compound is an acid addition salt;
57) the compound is the hydrochloride salt;
58) the compound is the oxalate salt; and
59) the compound is the fumarate salt.
It will be understood that the above classes may be combined to form additional preferred classes.
It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
The compounds of formula I wherein R1 is NH2 or NR2R3, and R, R2 and R3 are as defined above, may be prepared from substituted phenyl compounds of formula II and substituted compounds of formula III as illustrated in Scheme 1 below, where X is halide. 
In general, the amide group of formula III may be hydrolyzed to an amine of formula II by well known methodology. See, e.g., Larock, xe2x80x9cComprehensive Organic Transformations,xe2x80x9d pgs. 431-436, VCH Publishers, New York, N.Y., 1989. Additionally, the amine of formula II can then be converted to the amide of formula I(a), the thiourea of formula I(b), the urea of formula I(c), or the sulfonamide of for formula I(d), by well known methodology. See, e.g., Siegal, Tetrahedron Lett., 38:3357-3360, 1997. The acid halides, sulfonylhalides, isocyanates, and thioisocyanates of Scheme I are commercially available or may be prepared by methods known to those skilled in the art.
Additionally, a compound of formula II may be converted to a compound of the formula NHxe2x80x94R2xe2x80x94R3 by peptide coupling procedures, as those taught in the U.S. Pat. No. 5,708,008, herein incorporated by reference.
The compounds of formula III may be prepared from compounds of formula VI and compounds of formula V as illustrated in Scheme 2 below where R is as previously defined. 
The N-methoxy-N-methylamide compounds of formula V are routinely prepared from commercially available N,O-dimethylhydroxylamine hydrochloride and the compound of formula IV or other activated derivative, by methods known to those skilled in the art. In a typical procedure, as outlined by Nahm, et. al., Tetrahedron Lett., 22(39), pp. 3815-3818 (1981), 1 mmol of acid chloride and 1.1 mmol of N,O-dimethylhydroxylamine hydrochloride is dissolved in 10 mL of ethanol-free chloroform at about room temperature. The solution is cooled to about 0xc2x0 C. and 2.2 mmol of pyridine is added. The mixture is partitioned between brine and a 1:1 mixture of ether and methylene chloride. The organic layer is dried with sodium sulfate and concentrated to afford the amide which is purified by silica gel chromatography or by distillation.
The 1-methylisonipecotic acid of formula IV can be prepared by methods well known in the art (J. Med. Chem. 36:457, 1993).
The compounds of formula III can be prepared by methods known to those skilled in the art. In a typical procedure, as outlined by Nahm et al., the compound of formula VI is reacted subsequentially with methyllithium then t-butyllithium, and is then added to a solution 1 mmol of N-methoxy-N-methylamide in 10 mL of dry THF at low temperature. The reaction mixture is stirred at the desired temperature until TLC shows the desired compound. The reaction is poured into 5% HCl in ethanol at about 0xc2x0 C. and the mixture is partitioned between brine and a 1:1 mixture of ether and methylene chloride. The organic extract is dried with Na2SO4 and evaporated in vacuo. The product is then purified by chromatography if necessary or desired.
The compounds of formula I wherein R1 is hydroxy or xe2x80x94OSO2Ar2, and Ar2 is as defined above, may be prepared from substituted compounds of formula VII as illustrated in Scheme 3 below where R is as previously defined. 
A compound of formula VII where R1 is methoxy may be converted to a compound where R1 is hydroxy by cleaving the ether by methods well known to one of ordinary skill in the art, such as that generally described in Bhatt and Kulkarni, Synthesis, 249-282 (1983).
A compound of formula I(e) where R1 is hydroxy may be converted to a compound of the formula xe2x80x94OSO2Ar2 by methods well known to one of ordinary skill in the art, such as that taught by March, Advanced Organic Chemisry, 3rd ed., pg. 44, 1985.
The compounds of formula VII may be prepared from compounds of formula VIII and formula IX as illustrated in Scheme 4 below where R is as previously defined. 
The 4-[3-methoxybenzoyl]-1-(optionally substituted)-pyridine of formula X is routinely prepared from commercially available 3-bromoanisole and ethyl isonicotinate (Journal of Org. Chem. 52:5026, 1987).
A compound of formula X may be converted to a quaternary salt then reduced by methods well known in the art to form a compound of formula XI. The alcohol of formula XI may be converted to the ketone of formula VII by methods well known to the skilled artisan, such as that generally taught by Journal of Org. Chem. 51:5472, 1986.
A preferred process for preparation of the compounds of formula I(a): 
wherein R3 is hydrogen, optionally substituted C1-C6 alkyl, Ar3, xe2x80x94NR5R6, or OR5;
R5 and R6 are independently hydrogen, optionally substituted C1-C8 alkyl, or Ar4; or R6 and R5 combine, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring; and
Ar3 and Ar4 are independently an optionally substituted phenyl or optionally substituted heteroaryl, is illustrated in Scheme 5 below. 
The process of this invention is performed by the following steps:
(a) protecting 4-benzoylpiperidine hydrochloride to form N-protected 4-benzoylpiperidine hydrochloride;
(b) nitrating the N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4-(mononitrobenzoyl)piperidines;
(c) deprotecting the N-protected 4-(mononitrobenzoyl)piperidine mixture to form a mixture of 4-(mononitrobenzoyl)piperidines;
(d) separating 4-(3-nitrobenzoyl)piperidine from the mixture of 4-(mononitrobenzoyl)piperidines;
(e) reducing 4-(3-nitrobenzoyl)piperidine to form 4-(3-aminobenzoyl)piperidine; and
(f) acylating the 4-(3-aminobenzoyl)piperidine.
4-[3-(substituted)benzoyl]piperidine HCl of formula I(a) is prepared in one pot.
Step a) of the process of the invention is performed by combining the 4-benzoylpiperidine hydrochloride with a source useful for applying an amino protecting group in an appropriate medium. Once the reaction is complete, the resulting N-protected 4-benzoylpiperidine can be isolated by standard extractions and filtrations. If desired, the N-protected 4 benzoylpiperidine may be further purified by chromatography or crystallization as appropriate.
The substrate may first be dissolved in an appropriate reaction medium and then added to a mixture of the source of the protecting group. Also, a solution of the substrate in an appropriate reaction medium may be added to a slurry of the source of the protecting group in the same reaction medium. Preferably, the source of the protecting group may act as the reaction media.
Reaction media useful for step a) of the invention must be capable of dissolving a sufficient amount of the 4-benzoylpiperidine and the protecting group for the reaction to proceed. Organic solvents useful as reaction media for the process of this invention include CHCl3, CH2Cl2, hexane, cyclohexane, nitromethane, nitrobenzene, acetonitrile, ether, THF, dioxane, trichloroacetic anhydride, dichloroacetic anhydride, and preferably trifluoroacetic anhydride. The skilled artisan will appreciate that the anhydrides named above will serve to protect the amino group as well as act as reaction solvent.
Source of the protecting group useful for the process of step a) of the invention includes acid halides, sulfenyl halides, sulfonyl halides, chloroformates, acid anhydrides, and preferably trifluoroacetic anhydride, which may also act as the reaction medium.
The process of step a) may be carried out over a large range of concentrations, from about 0.5 molar to about 5 molar of the protecting group. The reaction may also be performed on slurries of the protecting group so long as a sufficient amount of the protecting group is soluble in the reaction medium for the reaction to proceed. Preferably the process is performed in an excess of the source of the protecting group acting as the reaction medium.
Reactions of step a) may be performed between about 5xc2x0 C. and about 40xc2x0 C., preferably between about 10xc2x0 C. and about 25xc2x0 C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
After treatment with the source of the protecting group, the N-protected 4-benzoylpiperidine is treated with the source of nitronium ion to form a mixture of N-protected 4-(mononitrobenzoyl)piperidines. The N-protected 4-benzoylpiperidine may first be dissolved in an appropriate reaction medium and then added to a mixture of the source of the nitronium ion. Also, a solution of the N-protected 4-benzoylpiperidine in an appropriate reaction medium may be added to a slurry of the source of the nitronium ion in the same reaction medium.
Reaction media useful for step b) of the process of the invention must be capable of dissolving a sufficient amount of the 4-benzoylpiperidine, the source of the nitronium ion, and the protecting group for the reaction to proceed. Organic solvents useful as reaction media for the process of this invention include CHCl3, CH2Cl2, hexane, cyclohexane, nitromethane, nitrobenzene, acetonitrile, ether, THF, dioxane, trichloroacetic anhydride, dichloroacetic anhydride, and preferably trifluoroacetic anhydride.
Source of the nitronium ion useful for the process of step b) of the invention include fuming nitric acid and inorganic nitrate salts, preferably ammonium nitrate.
Step b) may be carried out over a large range of concentrations, from about 0.5 molar to about 2 molar of the source of nitronium ion. The reaction may also be performed on slurries of the source of nitronium ion so long as a sufficient amount of the nitronium ion is soluble in the reaction medium for the reaction to proceed. Preferably the process is performed at a concentration from about 1 molar to about 2 molar. A concentration of about 0.9 molar to about 1.4 molar is most preferred.
Reactions of step b) may be performed between about 5xc2x0 C. and about 40xc2x0 C., preferably between about 10xc2x0 C. and about 25xc2x0 C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
Preferably steps a) and b) are combined and the source of the protecting group is acting as reaction medium, in which the source of the nitronium ion may be added directly to the reaction media slurry. All of these methods are useful for the process of the present invention. Step c) of the process of the invention is performed by combining the N-protected 4-(mononitrobenzoyl)-piperidine product of step b) with an appropriate deprotecting agent in a suitable reaction medium. The skilled artisan will appreciate that the nature of the deprotecting agent will depend upon the specific protecting group employed. For example, a strong acid or base will remove a trifluoroacetate protecting group. However, hydrochloric acid is preferred. Once the reaction is complete, as measured by consumption of the substrate, the resulting 4-(mononitrobenzoyl)piperidine products are isolated by standard extractions and filtrations. If desired, the 4-(mononitrobenzoyl)piperidine products may be further purified by chromatography or crystallization as appropriate.
The order and manner of combining the reactants are not important and may be varied as a matter of convenience. The N-protected 4-(mononitrobenzoyl)piperidine products and deprotecting compound may first be combined and then the reaction medium added. Alternatively, the substrate may first be dissolved in an appropriate reaction medium and this solution added to a mixture of the deprotecting compound. Also, a solution of the substrate in an appropriate reaction medium may be added to a slurry of the deprotecting compound in the same reaction medium. Furthermore, a first slurry containing part of the reactants in an appropriate reaction medium may be added to a second slurry of the remaining reactants in an appropriate reaction medium as is desired or convenient. All of these methods are useful for the process of the present invention.
Reaction media useful for step c) of the invention must be capable of dissolving a sufficient amount of the N-protected 4-(mononitrobenzoyl)piperidine products for the reaction to proceed. Organic solvents useful as reaction media for the process of this invention depend upon the choice of deprotecting agent and may include water, DMF, THF, acetone, MeOH, EtOH or isopropyl alcohol.
Depending upon the choice of deprotecting agent, reactions of step c) may be performed between about 40xc2x0 C. and about 100xc2x0 C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
Step c) may be carried out over a large range of id concentrations, from about 0.05 molar to about 1 molar of the N-protected 4-(mononitrobenzoyl)-piperidine products, dependent upon the solubility of the particular product in the chosen reaction medium. Preferably the process is performed at a concentration from about 0.05 molar to about 0.2 molar. A concentration of about 0.08 molar to about 0.1 molar is most preferred.
Step e) of the process of the invention is performed by treating the 4-(mononitrobenzoyl)piperidine product with an appropriate reducing agent in a suitable reaction medium. Once the reaction is complete, as measured by consumption of the substrate, the resulting 4-(monoaminobenzoyl)piperidine products are isolated by standard extractions and filtrations. If desired, the 4-(monoaminobenzoyl)piperidine products may be further purified by chromatography or crystallization as appropriate.
The order and manner of combining the reactants are not important and may be varied as a matter of convenience. The 4-(mononitrobenzoyl)piperidine products and the reducing agent may first be combined and then the reaction medium added. Alternatively, the substrate may first be dissolved in an appropriate reaction medium and this solution added to a mixture of the reducing agent. Also, a solution of the substrate in an appropriate reaction medium may be added to a slurry of the reducing agent in the same reaction medium. Furthermore, a first slurry containing part of the reactants in an appropriate reaction medium may be added to a second slurry of the remaining reactants in an appropriate reaction medium as is desired or convenient. All of these methods are useful for the process of the present invention.
Compounds useful as reducing agents include PtO2 and preferably Pd/C.
Reaction media useful for step e) must be capable of dissolving a sufficient amount of the 4-(mononitrobenzoyl)piperidine products for the reaction to proceed. Organic solvents useful as reaction media for the process of this invention depend upon the choice of reducing agent and may include water, DMF, isopropanol, ethanol or methanol.
The control of temperature is critical during hydrogenation. Depending upon the choice of reducing agent, reactions of step e) may be performed above 20xc2x0 C., preferably above 30xc2x0 C. The skilled artisan will appreciate that contamination of the 4-(monoaminobenzoyl)piperidine HCl compounds with by-products may result at lower temperatures.
Step e) may be carried out over a large range of concentrations, from about 0.05 molar to about 1 molar of the 4-(mononitrobenzoyl)piperidine products, dependent upon the solubility of the particular product in the chosen reaction medium. Preferably the process is performed at a concentration from about 0.1 molar to about 0.5 molar. A concentration of about 0.2 molar to about 0.3 molar is most preferred.
Step f) of the invention is performed by treating the 4-(monoaminobenzoyl)piperidine product of step e) with an appropriate acylating agent in a suitable reaction medium. Once the reaction is complete, as measured by consumption of the substrate, the resulting 4-((substituted)benzoyl)piperidine products are isolated by standard extractions and filtrations. If desired, the 4-((substituted)benzoyl)piperidine products may be further purified by chromatography or crystallization as appropriate.
The order and manner of combining the reactants are not important and may be varied as a matter of convenience. The 4-(monoaminobenzoyl)piperidine products and the acylating agent may first be combined and then the reaction medium added. Alternatively, the substrate may first be dissolved in an appropriate reaction medium and this solution added to a mixture of the acylating agent. Also, a solution of the substrate in an appropriate reaction medium may be added to a slurry of the acylating agent in the same reaction medium. Furthermore, a first slurry containing part of the reactants in an appropriate reaction medium may be added to a second slurry of the remaining reactants in an appropriate reaction medium as is desired or convenient. All of these methods are useful for the process of the present invention.
Compounds useful as acylating agents include acid anhydrides, and preferably acid halides. A more preferred acylating agent is the acid chloride.
The use of propylene oxide as the reaction medium during the acylation of the 4-(monoaminobenzoyl)piperidine HCl is essential.
Depending upon the choice of acylating agent, reactions of step f) may be performed between about 0 and about 40xc2x0 C. The skilled artisan will appreciate that the reaction rates will decrease as temperatures are lowered and increase as temperatures are elevated.
Step f) may be carried out over a large range of concentrations, from about 0.1 molar to about 1 molar of the 4-(monoaminobenzoyl)piperidine products, dependent upon the solubility of the particular product in the chosen reaction medium. Preferably the process is performed at a concentration from about 0.1 molar to about 0.5 molar. A concentration of about 0.1 molar to about 0.2 molar is most preferred.
The skilled artisan will appreciate that the mixture of isomers resulting from the nitration described in step b) of the process of the present invention may be separated at any point convenient or desired. A preferred embodiment of this invention is that the desired 4-(3-nitrobenzoyl)piperidine product is isolated as step d) of the process of the invention. That is, after deprotection, but prior to reduction of the nitro group to provide the corresponding amine. The 4-(3-nitrobenzoyl)piperidine may be isolated from the mixture by standard chromatographic techniques or crystallographic techniques.
The following Preparations and Examples are provided to better elucidate the practice of the present invention and should not be interpreted in any way as to limit the scope of same. Those skilled in the art will recognize that various modifications may be made while not departing from the spirit and scope of the invention.

Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37% formaldehyde (125 ml). 10% Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours.
The catalyst was filtered, washed with water, and the filtrate was concentrated under reduced pressure. The residue was slurried in water and concentrated in vacuo. The residue was slurried in ethanol and concentrated in vacuo to give a white solid. Drying under vacuum at ambient temperature for 18 h gave 42.2 g (76%) of a white solid,
mp 173-5xc2x0 C. MS(m/e): 143 (M+).
Analysis for C7H13NO2:
Calcd: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.24; H, 9.59; N. 9.71.

1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80%) of product as a light yellow liquid.
MS (m/e): 186(M+).
Analysis for C9H18N2O2:

A solution of acetyl chloride (44.0 ml, 0.619 mol) in tetrahydrofuran (20 ml) was added dropwise to a 0xc2x0 C. solution of 3-bromoaniline (101.5 g, 0.590 mol) and triethylamine (87.4 ml, 0.625 mol) in tetrahydrofuran (550 ml). The resulting mixture was stirred 16 h at room temperature. The reaction mixture was quenched with ice/water (500 ml), acidified to pH 1 with 5N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1N hydrochloric acid, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 125.5 g of a red solid. Recrystallization from ethyl acetate/hexanes gave 69.2 g of an off white powder. Filtered a second crop of product to give 26 g of a tan powder. Total yield=75%.
MS(m/e): 214(M+).
Analysis for C8H8BrNO:
Calcd: C, 44.89; H, 3.77; N, 6.54; Found: C, 45.10; H, 3.78; N, 6.57.
To a 0xc2x0 C. mixture of 2-amino-4-fluorobenzoic acid (1.18 g, 7.6 mmol) in 12N hydrochloric acid (2.3 mL) and water (13.7 mL) was added dropwise a solution of sodium nitrite (543 mg, 7.9 mmol) in water (1.2 mL). This resulting diazonium salt solution was stirred 10 min at 0xc2x0 C. A solution of potassium iodide (1.9 g) in sulfuric acid (450 35 xcexcL) and water (3.2 mL) was added dropwise to the 0xc2x0 C. solution. The reaction mixture was heated to 100xc2x0 C. for 2 h then cooled to room temperature. 10% sodium bisulfite solution was added and stirred. The precipitate was filtered, washed with water, air dried and recrystallized from toluene.
mp 144-6xc2x0 C. MS(m/e): 265(Mxe2x88x921).
Analysis for C7H4FIO2:
Calcd: C, 31.61; H, 1.52, N, 0; I, 47.71; Found: C, 31.93; H, 2.14; N, 0.14; I, 42.75.

n-Butyllithium (4.9 ml, 7.9 mmol, 1.6 M in hexanes) was added dropwise to a xe2x88x9273xc2x0 C. solution of 3-bromoanisole (1.48 g, 7.9 mmol) in tetrahydrofuran (30 ml). The reaction mixture was stirred 25 min at xe2x88x9273xc2x0 C. A solution of ethyl isonicotinate (1.3 g, 8.7 mmol) in tetrahydrofuran (20 ml) was added dropwise. The reaction mixture was stirred 1.5 h at xe2x88x9273xc2x0 C. then was allowed to room temperature over 15 min. The reaction mixture was quenched with water/brine and extracted with diethyl ether. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1.8 g of a yellow solid. Purification by radial chromatography (silica gel, 6000 micron rotor, 2% methanol/methylene chloride) then again by radial chromatography (silica gel, 4000 micron rotor, 1% methanol/methylene chloride) gave 1.2 g of a mixture of product and ethyl isonicotinate. This mixture was dissolved ethanol (7 mL) and 5N sodium hydroxide (7 mL) and stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with methylene chloride. The methylene chloride extracts were washed with 1N sodium hydroxide, brine, dried over sodium sulfate and concentrated in vacuo to 860 mg of an orange oil. MS(m/e): 213(M+).
Analysis for C13H11NO2:
Calcd: C, 73.23; H, 5.20; N, 6.59; Found: C, 73.38; H, 5.34; N, 6.47.

A mixture of 4-[3-methoxybenzoyl]pyridine(790 mg, 3.7 mmol) and iodomethane (1.15 ml, 18.5 mmol) in acetone (10 mL) was stirred at room temperature for 48 h. The precipitate was filtered, washed with diethyl ether and dried in vacuo to give 1.2 g (91%) of an orange powder.
Mp 173-174xc2x0 C. MS(m/e): 228 (M+).
Analysis for C14H14INO2:
Calcd: C, 47.34; H, 3.97; N, 3.94; Found: C, 47.91; H, 3.81; N, 3.87.

A mixture of 4-[3-methoxybenzoyl]-1-methylpyridine iodide (730 mg, 2.1 mmol) and platinum oxide (100 mg, 0.44 mmol) in methanol was stirred under a hydrogen atmosphere for 2 h. The catalyst was filtered and washed with methanol then water. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride, washed with 1N sodium hydroxide, dried over sodium sulfate and concentrated in vacuo to give 490 mg of a clear colorless oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 425 mg (87%) of a white solid. Mp 102-104xc2x0 C. MS(m/e): 235(M+).
Analysis for C14H21NO2:
Calcd: C, 71.46; H, 9.00; N, 5.95; Found: C, 71.39; H, 8.94; N, 6.17.

A mixture of [(3-methoxyphenyl)(1-methyl(piperid-4-yl)]methan-1-ol (195 mg, 0.83 mmol) and pyridinium dichromate (468 mg, 1.2 mmol) in methylene chloride was stirred at room temperature for 1 h. The reaction mixture was quenched with isopropanol (5 mL) and stirred for 15 min. This reaction mixture was combined with an identical reaction that used 0.11 mmol of [(3-methoxyphenyl)(1-methyl(piperid-4-yl)]methanol. The mixture was filtered through filter agent, washed with methylene chloride and isopropanol. The filtrate was concentrated under reduced pressure. The product was dissolved then filtered through silica gel using methylene chloride:methanol:ammonium hydroxide (100:10:1) as the solvent. The filtrate was concentrated under reduced pressure to give 200 mg of a brown residue. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:5:0.5) gave 160 mg (83%) of a brown oil. Crystallized as the oxalic acid salt from ethyl acetate/methanol.
Mp 155-6.5xc2x0 C. MS(m/e): 233(M+).
Analysis for C16H21NO6:
Calcd: C, 59.43; H, 6.55; N, 4.33; Found: C, 59.51; H, 6.46; N, 4.30.

A solution of 4-[3-methoxybenzoyl]-1-methylpiperidine (260 mg, 1.1 mmol) in 48% hydrobromic acid (10 mL) was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure to a brown oil. The oil was dissolved in water, basified to pH 9 with ammonium hydroxide, and extracted with methylene chloride. Sodium chloride was added to the aqueous phase and extracted with chloroform/isopropanol (3:1). The organic extracts were combined, dried over sodium sulfate, and concentrated in vacuo to give 240 mg of a tan solid. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 214 mg (88%) of a tan crystalline solid. Mp 161-4xc2x0 C. MS(m/e): 220(M+1).
Analysis for C13H17NO2:
Calcd: C, 71.21; H, 7.81; N, 6.39; Found: C, 70.96; H, 7.51; N, 6.31.

A solution of sodium metaperiodate (2.43 g, 11.3 mmol) in water (20 ml) was added dropwise to a solution of 5-(4-fluorobenzamidyl-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride (2.0 g, 5.2 mmol) in methanol (70 ml) and water (70 ml). Methanol (20 ml) and water (20 ml) were added to aid in stirring. The reaction mixture was stirred at room temperature for 48 hours. The precipitate was filtered and discarded. The filtrate was diluted with 10% aqueous sodium bicarbonate solution (300 ml) and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1.9 g of a dark foam. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:5:0.5 then 100:7.5:0.5) gave 1.0 g (50.5%) of the title compound as a white solid. MS(m/e): 383 (M+).
USPTO Backgrounds
USPTO Backgrounds