MXPA01008077A - 5-ht1 - Google Patents

Abstract

The present invention relates to a compound of formula (I) and a process for making;or a pharmaceutical acid addition salt thereof;which are useful for activating 5-HT1F receptors and inhibiting neuronal protein extravasation in a mammal.

Description

-HT1F AGONISTS Description of the invention Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychia try, 39: 737-63, 1938. They proposed that the cause of migraine headache was vasodilation of the extracaneal vessels. This view was supported by the knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HTJ agonist which does not cross the brain-blood barrier, contract vascular cephalic smooth muscles and are effective in the Migraine treatment. Humphrey, and collaborators, Ann. NY Acad. Sci. , 600: 587-600, 1990. The recent work of Moskowitz has shown, however, that the presentation of migraine headaches depends on the changes in the diameter of the vessels. Cephalalgia, 12: 5-7, 1992. Moskowitz has proposed that the initiating agents usually unknown for pain stimulate the trigeminal ganglia which innervate the vasculature within the cephalic tissue, causing the release of the vasoactive neuropeptides of the axons on the vasculature. REF: 131853 These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumitriptan and ergot alkaloids by the mechanisms that involve the 5-HTJ receptors that are thought to be closely related to the 5-HT? D subtype, located on the trigeminovascular fibers. . Neurology, 43 (supp. 3): S16-S20 1993. Serotonin (5-HT) exhibits diverse physiological activities mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT? . A human gene which expresses one of these subtypes of the 5-HT? Receptor, named 5-HT? F, was isolated by Kao et al. Proc. Na ti. Acad. Sci. USA, 90: 408-412, 1993. This 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor already described. The high affinity of sumatriptan in this subtype, Ki = 23 nM, suggests a role of the 5-HTF receptor in migraine. This invention relates to new 5-HT? F agonists which inhibit the extravasation of the peptide due to the stimulation of the trigeminal ganglia, and therefore are useful for the treatment of migraine and associated disorders. The present invention relates to the compounds of the formula I: or a pharmaceutical acid addition salt thereof, wherein; A is hydrogen, halo, -OR4, NH2, or -CF3; R is hydrogen, alkyl with C? -C, alkenyl with C3-Cß, alkynyl with C3-C6, or (alkyl with Ci-C? J-Ar1; R1 is -NH-R2-R3, hydroxy, -OS02Ar2, or NH2; Ar, Ar1, Ar2, Ar3, and Ar4 are independently optionally substituted phenyl or optionally substituted heteroaryl, R2 is -CO-, -CS-, or -S02-, R3 is hydrogen, alkyl optionally substituted Ci-Cβ, Ar3, -NR5R6, or OR5, provided that R3 is not hydrogen if R2 is either -CS- or -S02-, R4 is hydrogen, alkyl with optionally substituted C? -Cß, or Ar, and R5 and R6 are independently hydrogen, alkyl with C? -C8 optionally substituted, or Ar4; or R6 and R5 are combined, 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-HT? F 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. In addition, the present invention relates to a method for inhibiting the extravasation of neuronal protein, which comprises administering to a mammal in need of such inhibition, an effective amount of a compound of formula I, or an acid addition salt. pharmaceutical company. In addition, the present invention relates to a process for preparing the compounds of the formula I (a): wherein R 3 is hydrogen, optionally substituted C 1 -C 6 alkyl, Ar 3, -NR 5 R 6, or OR 5; R5 and R6 are independently hydrogen, alkyl with optionally substituted Cj-Cs, or Ar4; or R6 and R5 are combined, 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 and optionally substituted phenyl or optionally substituted heteroaryl, which comprises: (a) protecting the 4-benzoylpiperidine hydrochloride to form an N-protected 4-benzoylpiperidine hydrochloride; (b) nitrate N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4- (mono-nitrobenzoyl) piperidines; (c) deprotecting the mixture of 4- (mononitrobenzoyl) -N-protected piperidines 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 4- (3-aminobenzoyl) piperidine.

One embodiment of this invention is a method of increasing activation of the 5-HT? F receptor to treat a variety of disorders which are linked to reduced neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal syndrome, alcoholism, tobacco abuse, chronic pain, panic disorder, anxiety, general pain, post-traumatic syndrome, memory loss, dementia of aging, social phobia, hyperactivity disorder due to lack of attention, disruptive behavior disorders, impulse control disorders, personality disorder uncertain or doubtful, the syndrome of chronic fatigue, premature ejaculation, erectile difficulty, anorexia nervosa, sleep disorders, autism, mutism, allergic rhinitis, insect bites, trichotillomania, trigeminal neuralgia, dental pain or pain of temperomandibular joint dysfunction. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employs a compound of the formula I. The use of a compound of the formula I for the activation of the 5-HT? F receptor, for the inhibition of the extravasation of the peptide in general or due to the 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 the text have their usual meanings. For example, the term "C 1 -C 4 alkyl" refers to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl. The term "C 1 -C 8 alkyl" includes those groups listed for C 1 -C 4 alkyl and also refers to straight, branched, or cyclic, saturated 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 "cycloalkyl with C3-Ca" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C3-C6 alkenyl" refers to straight or branched monounsaturated hydrocarbon chains containing from 3 to 6 carbon atoms and includes, but is not limited to, allyl, l-buten-4-yl, 2-buten -4-yl, l-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, l-hexen-6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl 'and the like. The term "C3-C6 alkynyl" refers to straight or branched hydrocarbon chains containing 1 triple bond and 3 to 6 carbon atoms and includes, but is not limited to, propynyl, 2-butyl-4-yl, l-butin-4-yl, l-pentyl-5-yl, 2-pentin-5-yl and the like. The terms "C6-C6 alkoxy" and "C4-C4 alkoxy" refer respectively to an alkyl group with Ci-Ce and C?-C4 alkyl, linked through an oxygen atom. The term "heteroaryloxy" refers to heteroaryl or a group of substituted heteroaryl attached through an oxygen atom. The term "aryloxy" refers to a phenyl or substituted phenyl group linked through an oxygen atom. The term "acyl with C" -C "refers to a formyl group or an alkyl group with C1-C3 attached through a carbonyl moiety. The term "alkoxycarbonyl with C" -C "refers to a group of C 1 -C 4 alkoxy linked through a carbonyl moiety. The term "cycloalkyl with benzofused C 4 -Cß" is taken to mean a cycloalkyl group with C 4 -C β fused to a phenyl ring. Examples of these groups include benzocyclobutyl, indanyl, 1,2,3,4-tetrahydronaphthyl, and the like.

The term "halo" includes fluoro, chloro, bromo and iodo. The term "heterocycle" is taken to mean rings of 5 and 6 aromatic and non-aromatic, stable elements, containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the rings are optionally benzofused. All of these rings can be substituted with up to three substituents independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyano, nitro, hydroxy, -S (0) m- (alkyl) with C? -C4) and -S (0) m-phenyl where m is 0, 1 or 2. The non-aromatic rings include, for example, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl, dioxanyl, pyranyl, and the like . Non-aromatic benzofused 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. The benzofused aromatic rings include isoquinolinyl, benzoxazolyl, benzothiazolyl, quinolinyl, benzofuranyl, thionaphthyl, indolyl and the like.

The term "heteroaryl" is taken to mean a benzofused aromatic or aromatic heterocycle as defined in the previous paragraph. The term "alkyl with substituted Ci-C6" refers to an alkyl group with Ci-Ce which is substituted 1 to 3 times independently with halo, hydroxy, phenyl, 2-phenylethylene-1-yl, diphenylmethyl, naphthyl, phenyl substituted, aryloxy, heterocycle, heteroaryloxy, alkenyl with C2-C6, alkynyl with C2-C6, cycloalkyl with C3-C8, alkoxy with C? -4, alkoxycarbonyl with C? -C4, phenyl (alkyl with Ci-C), phenyl (alkyl with C? -C4), or cycloalkyl with benzofused C-C8. The terms "substituted phenyl" and "substituted phenyl (C 1 -C 4 alkyl)", are taken to mean that the phenyl portion in any case is substituted with a substituent selected from the group consisting of halo, nitro, cyano, amino , trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, alkyl with Ci-Cß, alkoxy with Ci-Cß, (alkyl with C? -C4) S (0) n where n is 0, 1, or 2, (alkyl with C? ~ C) 2 amino, acyl with Ci-C, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, alkyl with C? ~ C, or alkoxy with C? _C4.

The term "substituted naphthyl" refers to a group of naphthyl which may be substituted in the same manner as a substituted naphthyl group. The terms "substituted heteroaryl" and "substituted heteroaryl (C 1 -C 4 alkyl)" are taken to mean that the heteroaryl portion is in any case substituted with up to three substituents independently selected from: halo, cyano, nitro, hydroxy, alkoxy with C? -C4, alkyl with C? ~ C, (alkyl with Ci-C) -S (0) n, and phenyl-S (0) n; wherein n is 0, 1, or 2. The term "amino protecting group" as used in this specification refers to 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 triflyl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane type blocking groups such as benzyloxycarbonyl, -fluorenylmethoxycarbonyl ("FMOC"), and the like, and similar amino protecting groups. The amino protecting group species employed are not critical since the derived 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 breaking or altering the rest of the molecule. Additional examples of the groups referred to by the above terms are described by T. Greene, "Protective Groups in Organic Synthesis", John Wiley and sons, New York, N.Y., 1991, Chapter 7 hereinafter referred to as "Greene". The term "pharmaceutical" when used herein as an adjective means substantially non-toxic and substantially non-detrimental to the recipient. By "pharmaceutical formulation" it is further understood 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 the amines, they are of basic nature and consequently react with any of a number of organic and inorganic acids to form the 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 "acid addition salt" refers to a salt of a compound of formula I prepared by the reaction of a compound of the formula I with a mineral or organic acid. pharmaceutical acid addition salts see, for example, 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 the formula I with an equimolar or excess amount of the acid. The reagents are generally combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, ethyl acetate and the like. The salts usually precipitate out of the solution within about one hour to about ten days and can be isolated by filtration or other conventional methods. The acids commonly used to form the acid addition salts are the inorganic acids such as hydrochloric acid, hydrobromic acid, iohydric acid, sulfuric acid, phosphoric acid, and the like, and the acids commonly employed to form such salts are the inorganic acids such such as hydrochloric acid, hydrobromic acid, iodhydric 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 are thus 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, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylenebenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with the hydrochloric acid, oxalic acid or fumaric acid. The term "effective amount". means an amount of a compound of the formula I which is capable of activating the 5-HT1F receptors. The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to the previous reaction that sufficiently solubilizes the reactants to produce a medium within which the desired reaction is carried out.

All enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. For example, when R1 is NH-R2-R3; R2 is -C0-; and R3 is CH (0H) CH3, the CH group of R3 is a chiral center. Such centers are designated "R" or "S". For the purposes of the present application, the R and S enantiomers are illustrated below.

Isomer S Isomer R The following groups are illustrative of the compounds contemplated within the scope of this invention: 4- [3- ((3-trifluoromethylphenyl) sulfonyloxy) benzoyl] -piperidine 4- [3- ((4-trifluoromethylphenyl) sulfonyloxy) enzoyl] -1 -piperidine 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-difluoromethylphenyl) sulfonyloxy) benzoyl] -1-propenylpiperidine 4- [3- ((3-methylphenyl) sulfonyloxy) enzoyl] -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-hexinylpiperidine 4- [3- ((4-fluorophenyl) sulfonyloxy) enzoyl] -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-rethoxyphenyl) sulfonyloxy) benzoyl] -1- (pyrrolidin-2-ylmethyl) piperidine 4- [3- ((2-methylphenyl) sulfonyloxy) enzoyl] -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] -l- (dioxan-2-ylmethyl) piperidine 4- [3- ((2-fluorophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 4- [3- ((2-trifluoromethoxyphenyl) sulfonyloxy) benzoyl] -1-methylpiperidine hydrochloride 4- [3- ((4-fluorophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 4- [3- (phenylsulfonyloxy) benzoyl] -1-methylpiperidine 4- [3- ((2- bromophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine hydrobromide of 4- [3- ((2,3,5-trifluorophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 4- [3- ((2-nitrophenyl) sulfonyloxy) benzoyl ] -1-m Ethylpiperidine 4- [3- ((2,4-, 5-trifluorophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 4- [3- ((2-iodophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 4- [3 (4- (Nitrophenylthioureido) benzoyl] -1-methylpiperidine oxalate oxalate of 4- [3- (3-trifluoromethylphenylthioureido) benzoyl] -1-methylpiperidine methanesulfonate of 4- [3- (4-trifluoromethoxyphenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (phenylthioureido) benzoyl] -1-methylpiperidine 4- [3- ((3-bromophenylthioureido) benzoyl] -1-methylpiperidine fumarate of 4- [3- (3-trifluoromethoxy-phenylthioureido) benzoyl] -1-methylpiperidine 4- [ 3- (4-chlorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (2-hydroxyphenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (4-bromophenylthioureido) benzoyl] -1-methylpiperidine phthalate 4- [ 3- (3,5-difluorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (3-methylphenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (pyrid-3-ylthioureido) benzoyl] -1-methylpiperidine 4 - [3- (pyrid-2-ylthioureido) benzoyl] -1-meti lpiperidine chlorobenzoate of 4- [3- (2, 3,4, 5, 6-pentafluorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (4-methylphenylthioureido) benzoyl] -1-methylpiperidine citrate of 4- [3- (3,4,5-trifluorophenylthioureido) enzoil ] -1-methylpiperidine 4- [3- (2, 3, 4, 5-tetrafluorophenylthioureido) benzoyl] -1-methylpiperidine propansulfonate tartrate 4- [3- (2-trifluoromethylphenylthioureido) enzoyl] -1-methylpiperidine 4- [4-methylpiperidine] tartrate 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 hydroxybenzoate of 4- [3- (2,3-difluorophenylthioureido) enzoyl] -1-methylpiperidine 4- [3- (fur-2-ylthioureido) benzoyl] -1-methylpiperidine 4- [ 3- (thiophen-2-ylthioureido) benzoyl] -1-methylpiperidine decanoate of 4 - [3- (2, 3, 4-trifluorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (pyridin-4-ylthioureido) enzoyl] -1-methylpiperidine 4- [3- (4-cyanophenylthioureido) enzoyl] - 1-methylpiperidine phosphate mono-acid 4- [3- (3,4-difluorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (4-fluorophenylthioureido) benzoyl] -1-methylpiperidine sulfite from 4- [3- (2- trifluoromethoxyphenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (4-fluorophenylthioureido) enzoyl] -1-methylpiperidine 4- [3- (2-bromophenylthioureido) benzoyl] -1-methylpiperidine pyrosulfate 4- [3- (2, 3, 5-trifluorophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (2-nitrophenylthioureido) benzoyl] -1-methylpiperidine malonate of 4- [3- (2,4,5,5-trifluorophenylthioureido) benzoyl] -1-ethylpiperidine 4- [3- (2-iodophenylthioureido) benzoyl] -1-methylpiperidine 4- [3- (3-nitrophenylureido) benzoyl] -1-methylpiperidine xylene sulfonate 4- [3- (3-trifluoromethylphenylureido) benzoyl] -1-methylpiperidine 4- [3- (4-trifluoromethoxyphenylureid) glycolate o) benzoyl] -1-propylpiperidine 4- [3- (phenylureido) benzoyl] -1-methylpiperidine 4- [3- ((+) -2-hydroxypropylureido) benzoyl] -1-methylpiperidine 4- [3- ((- ) -3-phenylbutylureido) benzoyl] -1-methylpiperidine 4- [3- (R-2- (diphenylmethyl) propylureido) benzoyl] -1-methylpiperidine 4- [3- (S-2-hydroxypropylureido) benzoyl] -1- 4- [3- (3-trifluoromethoxy-phenyl-ureido) enzoyl] -1-methylpiperidine-4- (3- (4-chlorophenyl) -ido) -benzoyl] -1-methylpiperidine-4- [3- (2-hydroxyphenyl-ureido) enzoyl] -methyl-piperidine lactate 1-Methylpiperidine 4- [3- (4-bromophenyl) -ido-benzoyl] -1-methylpiperidine 4- [3- (3, 5-difluorophenyl-ureido) -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 mandelate 4- [3- (2, 3, 4, 5, 6-pentafluorophenylureido) enzoyl] -1-methylpiperidine 4- [3-. { 4-methylphenylureido) benzoyl] -1-methylpiperidine lactate of 4- [3- (3, 4, 5-trifluorophenylureido) benzoyl] -1-methylpiperidine 4- [3- (2, 3, 4, 5-tetrafluorophenylureido) caprylate benzoyl] -1-methylpiperidine 4- [3- (2-trifluoromethylphenylureido) benzoyl] -1-methylpiperidine 4- [3- (4-fluorophenyl-ureido) benzoyl] -1-methylpiperidine 4- [3- (3-chlorophenyl) acid) acrylate benzoyl] -1-rnethylpiperidine 4- [3- (4-iodophenylureido) benzoyl] -1-methylpiperidine 4- [3- (3-fluorophenyl-ureido) enzoyl] -1-methylpiperidine 4- [3- (4-methoxyphenyl-ureido) -benzoyl] -1-methylpiperidine 4- [3- (2-methylphenylureido) benzoyl] -1-methylpiperidine 4- [3- (4-nitrophenylureido) benzoyl] -1-methylpiperidine 4- [3- (2,3-difluorophenyl) -ido) benzoyl] -1-methylpiperidine 4- [3- (fur-2-ylureido) benzoyl] -1-methylpiperidine 4- [3- (thiophen-2-ylureido) benzoyl] -1-methylpiperidine formate 4- [3- (2, 3, 4-trifluorophenyl-ureido) enzoyl] -1-methylpiperidine 4- [3- (pyridin-4-ylureido) benzoyl] -1-methylpiperidine 4- [3- (4-cyanophene nilureido) enzoyl] -1-methylpiperidine 4- [3- (3,4-difluorophenyl) -ido) enzoyl] -1-methylpiperidine 4- [3- (2-fluorophenyl) -l-benzoyl] -1-methylpiperidine 4- [3- (2-trifluoromethoxyphenylureido) benzoyl] -1-methylpiperidine 4- [3- (4-fluorophenyl-ureido) benzoyl] -1-methylpiperidine iodide 4- [3- (2-bromophenyl) -lido] benzoyl] -1-methylpiperidine 4- [3- (2,3-, 5-trifluoromethylphenylureido) benzoyl] -1-methylpiperidine 4- [3- (2-nitrophenylureido) benzoyl] -1 -methylpiperidine 4- [3- (2,4,5-trifluoromethylphenylureido) benzoyl] -1-methylpiperidine 4- [3- (2-iodophenylureido) benzoyl] -1-methylpiperidine 4- [3- (3-nitrophenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (3-trifluoromethylphenylsulfonamino) benzoyl] -l-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) enzoyl] -1-methylpiperidine 4- [3- ( 2-hydroxyphenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (4-bromophenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (3, 5-difluorophenylsulfonamino) enzoyl] -1-methylpiperidine 4- [3- ( 3-methylphenylsulfonamino) enzoyl] -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) enzoyl] -1-methylpiperidine 4- [3- (3-chlorophenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (4-iodophenylsulfonamino) enzoyl] -1-methylpiperidine 4- [3- (3-fluorophenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (4-methoxyphenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (2-methylphenylsulfonamino) enzoyl] -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) enzoyl] -1-methylpiperidine 4- [3- (pyridin-4-ylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (4-cyanophenylsulfonamino) benzoyl] -l-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) enzoyl] -1-methylpip eridin 4- [3- (2-nitrophenylsulfonamino) benzoyl] -1-methylpiperidine 4- [3- (2,4- trifluorophenylsulfonamino) enzoyl] -1-methylpiperidine 4- [3- (2-iodophenylsulfonamino) benzoyl] - 1-methylpiperidine 4- [3- ((3-trifluoromethylphenyl) amidyl) benzoyl] -1-methylpiperidine 4- [3-. { (4-trifluoromethylphenyl) amidyl) benzoyl] -1-methylpiperidine 4- [3- ((3-bromophenyl) amidyl) benzoyl] -1-methylpiperidine 4- [3- ((3-trifluoromethoxyphenyl) amidyl) benzoyl] -l- methylpiperidine 4- [3- ((4-chlorophenyl) amidyl) benzoyl] -1-methylpiperidine 4- [3- ((2-hydroxyphenyl) amidyl) enzoyl] -1-methylpiperidine 4- [3- ((4-bromophenyl)) amidyl) enzoyl] -1-methylpiperidine 4- [3- ((3,5-difluorophenyl) amidyl) enzoyl] -1-methylpiperidine 4- [3- ((3-methylphenyl) amidyl) enzoyl] -1-methylpiperidine 4- [3- (pyrid-3-yl) amidyl) enzoyl] -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] -l-methylpiperidine 4- [3- (2-trifluoromethylphenyl) amidyl) enzoyl] -1-methypiperidine 4- [3- (4-fluorophenyl) amidyl) enzoyl] -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) enzoyl] -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) enzoyl] -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 Although all enantiomers, diastereomers, and mixtures thereof, are useful as 5-HT? F agonists, simple enantiomers and simple diastereomers are preferred. In addition, although all of the compounds of this invention are useful as 5-HTiF 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 -NH-R2-R3; 7) R1 is hydroxy; 8) R1 is -OS02R3; 9) R1 is NH2; 10) R2 is -CO-; 11) R2 is -S02-; 12) R2 is -CS-; 13) when R2 is -S02-, R3 is alkyl with C? -C6; 14) when R2 is -S02-, R3 is selected from the group consisting of methyl, butyl, isopropyl, and cyclohexyl; 15) when R2 is -S02-, R3 is phenyl; 16) when R2 is -S02-, R3 is monosubstituted phenyl; 17) when R2 is -S02-, R3 is selected from the group consisting of 4-iodophenyl, and 4-fluorophenyl; 18) when R2 is -S02-, R3 is 4-iodophenyl; 19) when R2 is -CO- or -CS-, R3 is -NR5R6; 20) when R2 is -CO- and R3 is NR5R6, R5 and R6 are hydrogen; 21) when R2 is -CO- and R3 is NR5R6, R5 is hydrogen and R6 is unsubstituted phenylmethyl; 22) when R2 is -CO- and R3 is NR5R6, R5 is hydrogen and R6 is unsubstituted phenyl; 23) when R2 is -CO- and R3 is NR5R6, R5 is hydrogen and R6 is 4-fluorophenyl; 24) when R2 is -CO- and R3 is NR5R6, R5 is hydrogen and R6 is alkyl with C? -C6; ) when R2 is -CO- 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 -CS- and R3 is NR5R6, R5 is hydrogen and R6 is phenylmethyl; 27) when R2 is -CS- and R3 is NR5R6, R5 is hydrogen and R6 is phenyl; 28) when R2 is -CS- and R3 is NR5R6, R5 is hydrogen and R6 is phenyl monosubstituted with halo; 29) when R2 is -CS- and R3 is NR5R6, R5 is hydrogen and R6 is 4-fluorophenyl; 30) when R2 is -CS- and R3 is NR5R6, R5 is hydrogen and R6 is alkyl with Ci-Cβ; 31) when R2 is -CS- and R3 is NR5R6, R5 is hydrogen and R6 is selected from the group consisting of methyl, butyl, and isopropyl; 32) R2 is -CO- and R3 is phenyl; 33) R2 is -CO- and R3 is phenylmethyl; 34) R2 is -CO- and R3 is alkyl with C? -C6; 35) R2 is -CO- and R3 is selected from the group consisting of methyl, butyl, cyclohexyl, and isopropyl; 36) R2 is -CO- and R3 is monosubstituted phenyl; 37) R2 is -CO- 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) R2 is -CO- and R3 is substituted halophenyl; 39) R2 is -CO- 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 -CO- and R3 is 4-fluorophenyl; 41) R2 is -CO- and R3 is 4-fluorophenyl monosubstituted further; 42) R2 is -CO- 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 -CO- and R3 is 4-fluorophenyl further disubstituted; 44) R2 is -CO- and R3 is selected from the group consisting of 2,4,6-trifluoromethyl, 3,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl; 45) R2 is -CO- and R3 is quinolinyl; 46) R2 is -CO- and R3 is phenyl monosubstituted with trifluoromethoxy; 47) R2 is -CO- and R3 is phenyl monosubstituted with alkoxy with C? -C6; 48) R2 is -CO- and R3 is phenyl monosubstituted with hydroxy; 49) R2 is -CO- and R3 is OR5; 50) when R2 is -CO- and R3 is OR5; R5 is phenyl; 51) when R2 is -CO- and R3 is OR5; R5 is phenylmethyl; 52) when R2 is -CO- and R3 is OR5; R5 is alkyl with C? -C6; 53) when R2 is -CO- and R3 is OR5; R5 is selected from the group consisting of methyl, butyl, and isopropyl; 54) when R2 is -CO- and R3 is OR5; R5 is Ar4; 55) when R2 is -CO- 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 can be combined to form additional preferred classes. It is preferred that the mammal to be treated by the administration of the compounds of this invention is the human. The compounds of the formula I wherein R 1 is NH 2 or NR2R3, and R, R2 and R3 are as defined above, can be prepared from the substituted phenyl compounds of the formula II and the substituted compounds of the formula III as illustrated in Scheme 1 below, wherein X is halide Scheme 1 In general, the amide group of the formula III can be hydrolyzed to an amine of the formula II by the well-known methodology. See, for example, Larock, "Comprehensive Organic Transformations," pages 431-436, VCH Publishers, New York, NY, 1989. Additionally, the amine of formula II can then be converted to the amide of formula I (a) , the thiourea of the formula I (b), the urea of the formula I (c), or the sulfonamide for the formula I (d), by the well-known methodology. See, for example, Siegal, Tetrahedron Lett. , 38: 3357-3360, 1997. The acid halides, sulfonylhalides, isocyanates, and thioisocyanates of Scheme I are commercially available or can be prepared by methods known to those skilled in the art. Additionally, a compound of formula II can be converted to a compound of formula NH-R2-R3 by peptide-binding methods, such as those taught in U.S. Pat. No. 5,708,008, incorporated herein for reference. The compounds of the formula III can be prepared from the compounds of the formula VI and the compounds of the formula V as illustrated in Scheme 2 below where R is as previously defined.

Scheme 2 The N-methoxy-N-methylamide compounds of the formula V are prepared routinely from the commercially available N, 0-dimethylhydroxylamine hydrochloride and the compound of the formula IV or other activated derivative, by methods known to those skilled in the art. art. In a typical procedure, as described by Nahm, et al., Tetrahedron Lett. , 22 (39), pp. 3815-3818 (1981), 1 mmol of the acid chloride and 1.1 mmol of the N, 0-dimethylhydroxylamine hydrochloride are dissolved in 10 ml of ethanol-free chloroform at about room temperature. The solution is cooled to approximately 0 ° C and 2.2 mmoles of the pyridine are 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 give 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 described by Nahm et al., the compound of the formula VI is subsequently reacted with methyl lithium then with t-butyl lithium, and then 1 mmol of the N-methoxy-N-methylamide is added to a solution. my dry THF at low temperature. The reaction mixture is stirred at the desired temperature until the CCD shows the desired compound. The reaction is poured into 5% HCl in ethanol at about 0 ° C and the mixture is partitioned between brine and a 1: 1 mixture of ether and methylene chloride. The organic extract is dried with Na 2 SO 4 and evaporated in vacuo. The product is then purified by chromatography if necessary or desired. The compounds of the formula I wherein R 1 is hydroxy or -OS02Ar 2, and Ar 2 is as defined above, can be prepared from the substituted compounds of the formula VII as illustrated in Scheme 3 below where R is as previously defined Scheme 3 A compound of formula VII wherein R 1 is methoxy can be converted to a compound wherein R 1 is hydroxy by cleaving the ether by methods well known to one of ordinary skill in the art, such as those generally described in Bhatt and Kulkarni, Synthesis, 249-282 (1983).

A compound of the formula I (e) wherein R1 is hydroxy can be converted to a compound of the formula -0S02Ar2 by methods well known to one of ordinary skill in the art, such as those taught by March, Advanced Organic Chemistry , 3 / a. ed., page 44, 1985. The compounds of formula VII can be prepared from the compounds of formula VIII and formula IX as illustrated in Scheme 4 below where R is as previously defined.

Scheme 4 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 can 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 can be converted to the ketone of formula VII by methods well known to the person skilled in the art, such as those taught generally by Journal of Org. Chem. 51: 5472, 1986. A preferred process for the preparation of the compounds of the formula I (a): wherein R3 is hydrogen, alkyl with optionally substituted Ci-Ce, Ar3, -NR5R6, or OR5; R5 and R6 are independently hydrogen, alkyl with optionally substituted C? -C8, or Ar4; or R6 and R5 are combined, 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 and optionally substituted phenyl or optionally substituted heteroaryl, and are illustrated in Scheme 5 given below.

Scheme 5 Protective group (XXV) (XX) (xxi / xxp / xxpi) (XXVI) Raso e R-C. (the) The process of this invention is carried out by the following steps: (a) protecting the 4-benzoylpiperidine hydrochloride to form the N-protected 4-benzoylpiperidine hydrochloride; (b) nitrate N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4- (mononitrobenzoyl) piperidines; (c) deprotecting the mixture of 4- (mononitrobenzoyl) -N-protected piperidines 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 4- (3-aminobenzoyl) piperidine.

The 4- [3-benzoyl (substituted)] pyridine HCl of the formula I (a) is prepared in a vessel. Step a) of the process of the invention is carried out by combining the hydrochloride of 4-benzoylpiperidine with a source useful for applying an amino protecting group in an appropriate medium. Once the reaction complements, the resulting N-protected 4-benzoylpiperidine can be isolated by standard extractions and filtrations. If desired, the N-protected 4-benzoylpiperidine can be further purified by chromatography or crystallization as appropriate. The substrate was first dissolved in an appropriate reaction medium and then added to the source of the protecting group. Also, a solution of the substrate in an appropriate reaction medium can be added to a suspension of the source of the protecting group in the same reaction medium. Preferably, the source of the protecting group can act as the reaction medium. The means of the reaction useful for step a) of the invention may be capable of dissolving a sufficient amount of the 4-benzoylpiperidine and the protecting group for the reaction to proceed. Organic solvents useful as the reaction medium for the process of this invention include CHC13, CH2C12, 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 to act as the solvent of the reaction. The source of the protecting group useful for the process of step a) of the invention include the acid halides, the sulfenyl halides, the sulfonyl halides, the chloroformates, the acid anhydrides, and preferably the trifluoroacetic anhydride, which may also act as the means of reaction. The process of step a) can be carried out over a wide range of concentrations, from about 0.5 molar to about 5 molar of the protecting group. The reaction can also be carried out on the suspensions of the protecting group since a sufficient amount of the protective group is soluble in the reaction medium for the reaction to proceed. Preferably, the process is carried out in an excess of the source of the protecting group which acts as the reaction medium. The reactions of step a) can be carried out between about 5 ° C and about 40 ° C, preferably between about 10 ° C and about 25 ° C. The skilled artisan will appreciate that the reaction rates will be reduced when temperatures are reduced and will increase when temperatures are high. After treatment with the source of the protecting group, the N-protected 4-benzoylpiperidine is treated with the nitronium ion source to form a mixture of N-protected 4- (mononitrobenzoyl) piperidines. The N-protected 4-benzoylpiperidine can first be dissolved in an appropriate reaction medium and then added to the source mixture of the nitronium ion. Also, a solution of the N-protected 4-benzoylpiperidine in an appropriate reaction medium can be added to a suspension of the nitronium ion source in the same reaction medium. The means of the reaction 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 the reaction medium for the process of this invention include CHC13, CH2C12, hexane, cyclohexane, nitromethane, nitrobenzene, acetonitrile, ether, THF, dioxane, trichloroacetic anhydride, dichloroacetic anhydride, and preferably trifluoroacetic anhydride. The source of the nitronium ion useful for the process of step b) of the invention includes the fuming nitric acid and the inorganic nitrate salts, preferably the ammonium nitrate. Step b) can be carried out over a wide range of concentrations, from about 0.5 molar to about 2 molar of the nitronium ion source. The reaction can also be carried out on the suspensions of the nitronium ion source since a sufficient amount of the nitronium ion is soluble in the reaction medium for the reaction to proceed. Preferably the process is carried out at a concentration of about 1 molar to about 2 molar. A concentration of about 0.9 molar to about 1.4 molar is more preferred. The reactions of step b) can be carried out between about 5 ° C and about 40 ° C, preferably between about 10 ° C and about 25 ° C. The skilled artisan will appreciate that the reaction rates will be reduced when the temperatures are reduced and will increase when the temperatures are high. Preferably steps a) and b) are combined and the source of the protecting group is acting as the reaction medium, in which the source of the nitronium ion can be added directly to the suspension of the reaction medium. All of these methods are useful for the process of the present invention. Step c) of the process of the invention is effected by combining the product of the N-protected 4- (mononitrobenzoyl) -piperidine from step b) with an appropriate deprotection agent in a suitable reaction medium. The skilled artisan will appreciate that the nature of the deprotection agent will depend on the specific protecting group employed. For example, a strong acid or base will remove a protection group of trifluoroacetate. However, hydrochloric acid is preferred. Once the reaction complements, as measured by substrate consumption, the resulting 4- (mononitrobenzoyl) piperidine products are isolated by standard extractions and filtrations. If desired, the 4- (mononitrobenzoyl) piperidine products can be further purified by chromatography or crystallization where appropriate. The order and manner of combining of combining the reagents are not important and can be varied as a matter of convenience. The N-protected 4- (mononitrobenzoyl) -piperidine products and the deprotection compound can be combined first and then the reaction medium is added. Alternatively, the substrate can be first dissolved in an appropriate reaction medium and this solution added to a mixture of the deprotection compound. Also, a solution of the substrate in an appropriate reaction medium can be added to a suspension of the deprotection compound in the same reaction medium. In addition, a first suspension containing part of the reagents in an appropriate reaction medium can be added to a second suspension of the remaining reagents in an appropriate reaction medium when desired or convenient. All of these methods are useful for the process of the present invention.

The means of the reaction useful for step c) of the invention should be capable of dissolving a sufficient amount of the N-protected 4- (mononitrobenzoyl) piperidine products for the reaction to proceed. The organic solvents useful as the reaction medium for the process of this invention depend on the choice of the deprotection agent and may include water, DMF, THF, acetone, MeOH or isopropyl alcohol. Depending on the choice of the deprotection agent, the reactions of step c) can be carried out at about 40 ° C to about 100 ° C. The skilled artisan will appreciate that the reaction rates will be reduced when the temperatures are reduced and will increase as the temperatures rise. Step c) can be carried out over a wide range of concentrations, from about 0.05 molar to about 1 molar of the products of the 4- (mononitrobenzoyl) -piperidine N-protected, depending on the solubility of the particular product in the medium of the chosen reaction. Preferably, the process is carried out 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 more preferred.

Step e) of the process of the invention is effected by treating the product of 4- (mononitrobenzoyl) piperidine with an appropriate reducing agent in a suitable reaction medium. Once the reaction is complete, as measured by substrate consumption, the resulting 4- (monoaminobenzoyl) piperidine products are isolated by standard extractions and filtrations. If desired, the 4- (monoaminobenzyl) piperidine products can be further purified by chromatography or crystallization when appropriate. The order and manner of combining the reagents are not important and can be varied as a matter of convenience. The products of 4- (mononitrobenzyl) piperidine and the resulting agent can be combined first and then added to the reaction medium. Alternatively, the substrate can be first 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 can be added to a suspension of the reducing agent in the same reaction medium. In addition, a first part containing the suspension of the reagents in an appropriate reaction medium can be added to a second suspension of the remaining reagents in an appropriate reaction medium when desired or convenient. All of these methods are useful for the process of the present invention. Compounds useful as reducing agents include Pt02 and preferably Pd / C. The means of the reaction useful for step e) must be capable of dissolving a sufficient amount of the 4- (mononitrobenzoyl) piperidine products for the reaction to proceed. The organic solvents useful as the reaction medium for the processes of this invention depend on the choice of the reducing agent and can include water, DMF, isopropanol, ethanol or methanol. The control of the temperature is critical during the hydrogenation. Depending on the choice of reducing agent, the reactions of step e) can be carried out above 20 ° C, preferably above 30 ° C. The skilled artisan will appreciate that contamination of 4- (monoamino-benzoyl) piperidine HCl compounds with by-products may result at lower temperatures. Step e) can be carried out over a wide range of concentrations, from about 0.05 molar to about 1 molar of the products of 4- (mononitrobenzyl) piperidine, depending on the solubility of the particular product in the chosen reaction medium . Preferably, the process is carried out at a concentration of about 0.1 molar to about 0.5 molar. A concentration of about 0.2 molar to about 0.3 molar is more preferred. Step f) of the invention is effected by treating the product of the 4- (monoaminobenzoyl) piperidine from step e) on an appropriate acylating agent in a suitable reaction medium. Once the reaction complements, as measured by substrate consumption, 4- (benzoyl (substituted)) piperidine products are isolated by standard extractions and filtrations. If desired, the 4- (benzoyl (substituted)) piperidine products can be further purified by chromatography or crystallization when appropriate.The order and manner of combining the reagents are not important and can be varied as a matter of The products of 4- (monoaminobenzoyl) piperidine and the acylating agent can be combined first and then added to the reaction medium.Alternatively, the substrate can be dissolved first in an appropriate reaction medium and this solution added Also, a solution of the substrate in an appropriate reaction medium can be added to a suspension of the acylating agent in the same reaction medium. Reagents in an appropriate reaction medium can be added to a second suspension of the remaining reagents in an appropriate reaction medium. When desired or convenient. All of these methods are useful for the process of the present invention. The compounds useful as the acylating agents include the acid anhydrides, and preferably the acid halides. A preferred acylating agent is the acid chloride. The use of propylene oxide as the reaction medium during the acylation of 4- (monoaminobenzoyl) piperidine HCl is essential. Depending on the choice of the acylating agent, the reactions of step f) may be carried out between about 0 and about 40 ° C. The skilled artisan will appreciate that the reaction rates will be reduced when the temperatures are reduced and will increase when the temperatures are high. Step f) can be carried out over a wide range of concentrations, from about 0.1 molar to about 1 molar of the 4- (monoaminobenzoyl) piperidine products, depending on the solubility of the particular product in the chosen reaction medium. Preferably, the process is carried out at a concentration of about 0.1 molar to about 0.5 molar. A concentration of about 0.1 molar to about 0.2 molar is more preferred. The skilled artisan will appreciate that the mixture of the isomers resulting from the nitration described in step b) of the process of the present invention can be separated at any convenient or desired point. 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, ie, after deprotection, but prior to the reduction of the nitro group to provide the corresponding amine. The 4- (3-nitrobenzoyl) piperidine can be isolated from the mixture by chromatographic techniques or standard crystallographic techniques. The following Preparations and Examples are provided to better understand the practice of the present invention and should not be construed in any way as limiting the scope thereof. Those skilled in the art will recognize that various modifications can be made as long as they do not depart from the spirit and scope of the invention.

Preparations Preparation 1 1-methylisonipecotic acid COOH N CH, Isonipecotic acid (50 g, 0.387 mol) is dissolved in water (500 ml) and 37% formaldehyde (125 ml). 10% palladium on charcoal (50 g) is added and the mixture is stirred under a hydrogen atmosphere at 4.22 kg / cm2 (60 psi) at room temperature for 18 hours. The catalyst was filtered, washed with water, and the filtrate is concentrated under reduced pressure. The residue is converted to a suspension in water and concentrated in vacuo. The residue is converted to a suspension in ethanol and concentrated in vacuo to give a white solid. Drying under vacuum at room temperature for 18 h gave 42.2 g (76%) of a white solid, m.p. 173-5 ° C. MS (m / e): 143 (M +). Analysis for CH13N02: Cale: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.24; H, 9.59; N, 9.71.

Preparation 2 N-methoxy-N-methyl (1-methylisonipecotamide) The 1-methylisonipecotic acid (5.5 g, 38.4 mmol) is dissolved in dimethylformamide (100 mL) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N, 0-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) are added and the reaction mixture is stirred for 5 minutes. Add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) and the resulting homogeneous solution is stirred for 63 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution made basic to pH 9 with a 5N sodium hydroxide solution. This aqueous solution is extracted with methylene chloride, then saturated with sodium chloride and extracted with chloroform / isopropanol (3/1). The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene methanol chloride: ammonium hydroxide, 100: 10: 1) gave 5.7 g (80%) of the product as a faint yellow liquid. MS (m / e): 186 (M +). Analysis for CgHi8N202: Preparation 3 3-Bromoacet anilide A solution of acetyl chloride (44.0 ml, 0.619 moles) in tetrahydrofuran (20 ml) is added dropwise to a solution at 0 ° C of 3-bromoaniline (101.5 g, 0.590 moles) and triethylamine (87.4 ml, 0.625 moles). in tetrahydrofuran (550 ml). The resulting mixture is stirred 16 h at room temperature. The reaction mixture is cooled with ice / water (500 ml), acidified to pH 1 with 5N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts are washed with IN hydrochloric acid, water, brine, then dried over sodium sulfate. The solvent is removed under reduced pressure to give 125.5 g of a red solid. Recrystallization from ethyl acetate / hexanes gave 69.2 g of a colorless white powder. A second crop of the product is filtered to give 26 g of a tan powder. Total yield = 75%. MS (m / e): 214 (M +). Analysis for C8H8BrNO: Cale: C, 44.89; H, 3.77; N, 6.54; Found: C, 45.10; H, 3.78; N, 6.57.

Preparation 4 4-Fluoro-2-iodobenzoic acid To a mixture at 0 ° C of 2-amino-4-fluorobenzoic acid (1.18 g, 7.6 mmol) in 12N hydrochloric acid (2.3 ml) and water (13.7 ml) is added dropwise a solution of sodium nitrite (543 mg , 7.9 mmole) in water (1.2 ml). This solution of the resulting diazonium salt is stirred 10 minutes at 0 ° C. A solution of potassium iodide (1.9 g) in sulfuric acid (450 35 μl) and water (3.2 ml) is added dropwise to the solution at 0 ° C. The reaction mixture is heated at 100 ° C for 2 h then cooled to room temperature. The 10% sodium bisulfite solution is added and stirred. The precipitate is filtered, washed with water, dried with air and recrystallized from toluene, m.p. 144-6 ° C. MS (m / e): 265 (M-1) Analysis for C7H4FI02: Cale: C, 31.61; H, 1.52; N, 0; I, 47.71; Found: C, 31.93; H, 2.14; N, 0.14; I, 42.75.

Preparation 5 4- [3-methoxybenzoyl] piperidine N-butyllithium (4.9 ml, 7.9 mmol, 1.6 M in hexanes) is added dropwise to a solution at -73 ° C of 3-bromoanisole (1.48 g, 7.9 mmol) in tetrahydrofuran (30 ml). The reaction mixture is stirred 25 minutes at -73 ° C. A solution of the ethyl isonicotinate (1.3 g, 8.7 mmol) in tetrahydrofuran (20 ml) was added dropwise. The reaction mixture is stirred 1.5 h at -73 ° C then left at room temperature for 15 minutes. The reaction mixture is 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 the product and ethyl isonicotinate. This mixture is dissolved in ethanol (7 ml) and 5N sodium hydroxide (7 ml) and stirred at room temperature for 16 h. The solvent is removed under reduced pressure. The residue is diluted with water and extracted with methylene chloride. The methylene chloride extracts are washed with IN 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 C? 3H N02: Cale: C, 73.23; H, 5.20; N, 6.59; Found: C, 73.38; H, 5.34; N, 6.47.

Preparation 6 4- [3-methoxybenzoyl] -1-methylpyridinium iodide A mixture of 4- [3-methoxybenzoyl] pyridine (790 mg, 3.7 mmol) of iodomethane (1.15 ml, 18.5 mmol) in acetone (10 ml) is stirred at room temperature for 48 hours. The precipitate is filtered, washed with diethyl ether and dried in vacuo to give 1.2 g (91%) of an orange powder. P.f. 173-174 ° C. MS (m / e): 228 (M +) • Analysis for C? H? 4IN02: Cale: C, 47.34; H, 3.97; N, 3.94; Found: C, 47.91; H, 3.81; N, 3.87.

Preparation 7 [(3-methoxyphenyl) (1-methyl (piperid-4-yl)] methanol A mixture of 4- [3-methoxybenzoyl] -1-methylpyridine iodide (730 g, 2.1 mmol) and platinum iodide (100 mg, 0.44 mmol) in methanol is stirred under a hydrogen atmosphere for 2 h. The catalyst is filtered and washed with methanol then with water. The filtrate is concentrated under reduced pressure. The resulting residue is dissolved in methylene chloride, washed with IN 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. P.f. 102-104 ° C. MS (m / e): 235 (M +). Analysis for C? H2] N02: Cale: C, 71.46; H, 9.00; N, 5.95; Found: C, 71.39; H, 8.94; N, 6.17.

Preparation 8 4- [3-methoxybenzoyl] -1-methylpiperidine oxalate 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 is stirred at room temperature for 1 hour. The reaction mixture is quenched with isopropanol (5 ml) and stirred for 15 minutes. The reaction mixture is combined with an identical reaction using 0.11 mmoles of [(3-methoxyphenyl) (1-methyl (piperid-4-yl)] methanol.The mixture is filtered through a filter agent, washed with Methylene chloride and isopropanol The filtrate is concentrated under reduced pressure The product is dissolved and then filtered through silica gel using methylene chloride: methanol: ammonium hydroxide (100: 10: 1) as the solvent. Concentrate 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: 2.0: 5) gave 160 mg (83 %) of a brown oil, crystallized as the oxalic acid salt from ethyl acetate / methanol, MP 155-6.5 ° C. MS (m / e): 233 (M +). Analysis for C? 6H2? N06 : Cale: C, 54.93; H, 6.55; N, 4.33; Encont .: C, 59.51; H, 6.46; N, 4.30.

Preparation 9 4- [3-hydroxybenzoyl] -1-methylpiperidine A solution of 4- [3-methoxybenzoyl] -1-methylpiperidine (260 mg, 1.1 mmol) in 48% hydrobromic acid (10 mL) is refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure to a brown oil. The oil is dissolved in water, basified to pH 9 with ammonium hydroxide, and extracted with methylene chloride. Sodium chloride is 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. P.f. 161-4 ° C. MS (m / e): 220 (M + 1). Analysis for C? 3 H17N02: Cale: C, 71. twenty-one; H, 7 81; N, 6. 39; Encont. : C, 70. 96; H, 7 51; N, 6. 31.

Preparation 10 4- [2- (formamidyl) -5- (4-fluorobenzamidyl) benzoyl] -1- methylpiperidine A solution of the sodium metaperiodate (2.43 g, 11.3 mmol) in water (20 ml) is added dropwise to a solution of 5- (4-fluorobenzamidyl-3- (1-methylpiperidin-4-yl) -lH- hydrochloride. indole (2.0 g, 5.2 moles) in methanol (70 ml) and water (70 ml), methanol (20 ml) and water (20 ml) were added to aid stirring, the reaction mixture was stirred at room temperature for 48 hours The precipitate is filtered and discarded The filtrate is diluted with 10% aqueous sodium bicarbonate solution (300 ml) and extracted with ethyl acetate.The organic extracts are washed with water and brine, dried on 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 +).

Examples Example 1 4- [3- (Methylamino) benzoyl] -1-methylpiperidine The methyl lithium (1.4 M in diethyl ether, 37.4 mL, 52.3 mmol) is added to a solution at -78 ° C. 3-bromoacetanilide (11.5 g, 53.7 mmol) in tetrahydrofuran (250 mi) The reaction is stirred 15 minutes at -78 ° C. The tert-butyllithium (1.7 M in pentane, 62.4 ml, 106 mmol) is added over 30 minutes to the reaction mixture at -78 ° C. The reaction is stirred 10 minutes at -78 ° C. N-methoxy-N-methyl (1-methyl (4-piperidyl)) formamide (5.0 g, 26.8 mmol) in tetrahydrofuran (20 mL) is added dropwise to a homogeneous yellow solution. The reaction mixture was stirred and allowed to warm to room temperature for 21 hours. The reaction mixture is cooled to 10 ° C, quenched with ice, extracted with a solution of IN hydrochloric acid. The aqueous extracts are washed with diethyl ether, basified to pH 12 with the 5N sodium hydroxide solution and extracted with diethyl ether. The diethyl ether extracts are dried over sodium sulfate and the solvent is removed under reduced pressure to give 6.1 g of a yellow oil. The basic aqueous solution was extracted again with chloroform / isopropanol (3: 1). These extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 3.4 g of a yellow oil. Both oils were combined and purified by flash chromatography (silica gel, methylene chloride: methanol: ammonium hydroxide, 100: 7.5: 0.75) to give 5.7 g (81%) of the product as a yellow oil. MS (m / e): 261 (M + 1), 259 (M-1).

Example 2 4- [3- (Methylamidyl) enzoyl] -1-methylpiperidine oxalate 4- [3- (Methylamidyl) benzoyl] -1-methylpiperidine (283 mg, 1.1 mmol) in ethyl acetate was added to oxalic acid (99 mg, 1.1 mmol) in ethyl acetate. The resulting precipitate was filtered, washed with ethyl acetate, and dried under vacuum to give 270 mg (71%) of the tan powder. p.f. 153-4 ° C. MS (m / e): 261 (M + 1), 259 (M-1). Analysis for C? 7H22N206: Cale: C, 58.28; H, 6.33; N, 8.00; Found: C, 58.03; H, 6.56; N, 7.74.

Example 3 4- [3-aminobenzoyl] -1-methylpiperidine A solution of 4- [3- (methylamidyl) benzoyl] -1-methylpiperidine (5.68 g, 21.8 mmol) in hydrochloric acid (140 mL) is heated to reflux for 1.75 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (25 ml) and basified with concentrated ammonium hydroxide. The precipitate and the resulting solution were cooled for 1 hour, filtered, and dried under vacuum at room temperature for 16 h to give 3.6 g of a tan powder (76%). MS (m / e): 219 (M + l) Analysis for C? 3H? 8N20: Cale: C, 71.53; H, 8.31; N, 12.83; Found: C, 71.52; H, 8.20; N, 12.90, Example 4 4- [3- (4-fluorobenzamidyl) enzoyl] -1-methylpiperidine The 4-fluorobenzoyl chloride (0.98 ml, 8.3 mmol) is added dropwise to a solution at 0 ° C of 4- [3-aminobenzoyl] -1-methylpiperidine (1.64 g, 7.5 moles) and triethylamine (1.3 ml, 9.0 g). immoral) in tetrahydrofuran (20 ml). The reaction mixture is stirred 2 h at room temperature, diluted with ethyl acetate and a solution of IN sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 2.5 g (98%) of a foam. MS (m / e): 341 (M + 1), 339 (M-1).

Example 5 4 - [[3- (4-Fluorobenzamidyl) benzoyl] -1-methylpiperidine oxalate hemihydrate A solution of 4- [3- (4-fluorobenzamidyl) benzoyl] -1-methylpiperidine (200 mg, 0.59 mmol) in ethyl acetate is added to a solution of oxalic acid (53 mg, 0.59 mmol) in ethyl acetate . The resulting precipitate is filtered, washed with ethyl acetate, and dried at room temperature under vacuum. 250 mg (99%) of the oxalate salt was obtained as a tan powder. p.f. - foam at 95 ° C MS (m / e): 341 (M + l) Analysis for C22H23FN2O6-0.5H2O: Cale: C, 60.13; H, 5.50; N, 6.37; Found: C, 59.94; H, 5.44; N, 6.48.

Example 6 4- [[3- (fur-2-ylamidyl) benzoyl] -1-methylpiperidine hydrochloride 2-furoyl chloride (0.15 ml, 1.5 mmol) is added to a solution of 4- [3-aminobenzoyl] -1-methylpiperidine (257 mg, 1.2 mmol) and triethylamine (0.2 ml, 1.4 mmol) in tetrahydrofuran (10 ml). my). The reaction mixture is stirred 2 h at room temperature. The reaction mixture is diluted with ethyl acetate and 1N sodium hydroxide is then extracted with ethyl acetate. The ethyl acetate extracts were washed with IN sodium hydroxide, water, brine, then dried over sodium sulfate. The solvent is removed under reduced pressure to give 440 mg. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol: ammonium hydroxide, 100: 5: 0.5) gave 350 mg (95%) of a foam. Crystallization as the hydrochloric acid salt from ethyl acetate / ethanol gave 320 mg of a yellow powder with m.p. > 200 ° C, MS (m / e): 313 (M + 1), 311 (M-1). Analysis for C? 8H2? ClN203: Cale: C, 61.98; H, 6.07; N, 8.03; Found: C, 61.86; H, 5.78; N, 8.02.

Example 7 4- [3- (benzamidyl) benzoyl] -l-methylpiperidine oxalate Benzoyl chloride (0.12 mL, 1.0 mmol) is added to a solution of 4- [3-aminobenzoyl] -1-methylpiperidine (200 mg, 0.92 mmol) and triethylamine (0.15 mL, 1.1 mmol) in tetrahydrofuran (10 mL). ). The reaction mixture is stirred 64 h at room temperature. The reaction mixture is diluted with ethyl acetate and a solution of sodium hydroxide IN then extracted with ethyl acetate. The ethyl acetate extracts were washed with a solution of IN sodium hydroxide, water, brine, then dried over sodium sulfate. The solvent is removed under reduced pressure to give 324 mg of a yellow oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol: ammonium hydroxide, 100: 5: 0.5) gave 287 mg (97%) of a yellow oil. Crystallization as the oxalic acid salt from ethyl acetate gave 240 mg of yellow crystals. MS (m / e): 323 (M + 1), 321 (M-1). Analysis for C22H24N2? 6: Cale: C, 64.07; H, 5.86; N, 6.79; Found: C, 63.89; H, 5.94; N, 7.07.

Example 8 4- [3- (Methylsulfonylamino) benzoyl] -1-methylpiperidine Methanesulfonyl chloride (0.2 ml, 2.6 mmol) is added to a mixture of 4- [[3-aminobenzoyl] -1-methylpiperidine hydrochloride (526 mg, 1.8 mmol) and triethylamine (0.8 ml, 5.8 mmol) in DMF ( 17 mi). The reaction mixture is stirred 16 h at room temperature then concentrated in vacuo. Purification by flash chromatography. { silica gel, methylene chloride: methanol: ammonium hydroxide, 100: 10: 1) then radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol, 97.5: 2.5 then methylene chloride: metal: ammonium hydroxide, 100: 5: 1) gave 57 mg (11%) of the product. MS (m / e): 296 (M +). Analysis for C? 4H20N2O3S: Cale: C, 56.74; H, 6.80; N, 9.45; Found: C, 56.94; H, 6.68; N, 9.22.

Example 9 4- [3- ((pyrid-4-yl) amidyl) benzoyl] -l-methylpiperidine hydrochloride 4- [3-aminobenzoyl] -1-methylpiperidine is added (200 mg, 0.92 mmol) and dimethylformamide (5 ml) in one portion to a solution of isonicotinic acid (124 mg, 1.0 mmol), 1-hydroxybenzotriazole (136 mg, 1.0 mmol), 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide (193 mg, 1.0 mmol) in dimethylformamide (5 mL). The reaction mixture is stirred 24 h at room temperature. The reaction mixture is diluted with ethyl acetate and a 10% potassium carbonate solution then extracted with ethyl acetate. The ethyl acetate extracts are washed with water, brine, then dried over sodium sulfate. The solvent is removed under reduced pressure to give 460 mg. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol: ammonium hydroxide 100: 5: 0.5) then again methylene chloride: methanol: ammonium hydroxide, 100: 2.5: 0.25) gave 235 mg (79%) of a clear, colorless oil. Crystallization as the dichlorhydric acid salt from ethyl acetate / ethanol gave 235 mg of a white powder with m.p. > 200 ° C. MS (m / e): 324 (M + 1). Analysis for d9H23Cl2N302: Cale: C, 57.48; H, 5.85; N, 10.60; Found: C, 57.45; H, 5.85; N, 10.52.

Example 10 4- [3- (2,4-difluorobenzamidyl) benzoyl-1-methylpiperidine hydrochloride] 2,4-difluorobenzoyl chloride (100 μl, 0.82 mmol) is added to a mixture of 4- [3-aminobenzoyl] -1-methylpiperidine dihydrochloride (200 mg, 0.69 mmol), tetrahydrofuran (5 ml) and a hydroxide solution. of sodium IN (2.4 ml). The reaction mixture is stirred 24 h at room temperature. The reaction mixture is diluted with ethyl acetate and the IN sodium hydroxide solution is then extracted with ethyl acetate. The ethyl acetate extracts are washed with brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 220 mg. This mixture contained the product and 4- [3-aminobenzoyl] -l-methylpiperidine which did not react. This mixture is dissolved in tetrahydrofuran and triethylamine (144 μl, 1.03 mmol) is added to the solution followed by 2,4-difluorobenzoyl chloride (100 μl, 0.82 mmol). The resulting mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with ethyl acetate and then a solution of sodium hydroxide is added with ethyl acetate. The ethyl acetate extracts were washed with a 1N sodium hydroxide solution, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil is dissolved in methylene chloride: methanol: ammonium hydroxide (100: 5: 0.5) and the resulting precipitate is filtered and discarded. Purification by radial chromatography (silica gel, 1000 micron rotor, methylene chloride: methanol: ammonium hydroxide, 100: 5: 0.5) gave 200 mg (81%) of a clear colorless oil. Crystallization as the hydrochloric acid salt from ethyl acetate / ethanol gave 185 mg of a white powder. P.f. 181-3 ° C. MS (m / e): 359 (M + 1). Analysis for C20H2? ClF2N2O2: Cale: C, 60.84; H, 5.36; N, 7.09; Found: C, 61.01; H, 5.28; N, 7.31.

Example 11 4- [3- (4-hydroxybenzamidyl) benzoyl] -1-methylpiperidine hydrochloride 4-Acetoxybenzoyl chloride (200 mg, 0.92 mmol) in tetrahydrofuran (10 mL) is added to 4- [3-aminobenzoyl] -1-methylpiperidine (200 mg, 0.92 mmol) and triethylamine (0.5 mL, 3.6 mmol) in tetrahydrofuran (10 ml). The reaction mixture is stirred 64 h at room temperature. The reaction mixture is diluted with ethyl acetate and water and then extracted with ethyl acetate. The ethyl acetate extracts are washed with water, brine, then dried over sodium sulfate. The solvent is removed under reduced pressure to give 493 mg of the product. This product is dissolved in methanol (5 ml) and a 5N sodium hydroxide solution (5 ml) and stirred until the hydrolysis of the acetate is complete. The solvent is removed under reduced pressure. The residue is dissolved in water and the pH of the solution is adjusted to 8-9 with the hydrochloric acid solution IN. This solution is extracted with chloroform / isopropanol (3: 1) and dried over sodium sulfate. The solvent was removed under reduced pressure to give 270 mg of a foam. Purification by flash chromatography (silica gel, 5% 2M ammonia in methanol / methylene chloride then 10% ammonia in methanol / methylene chloride) gave 240 mg (77%). Crystallization as the hydrochloric acid salt from ethyl acetate / ethanol gave 220 mg of a colorless white powder. P.f. > 200 ° C. MS (m / e): 339 (M + 1), 337 (M-1). Analysis for C20H23ClN2O3: Cale: C, 64.08; H, 6.18; N, 7.47; Found: C, 64.27; H, 6.40; N, 7.45.

Example 12 4- [3- (2-iodo-4-fluorobenzamidyl) benzoyl] -1-methylpiperidine hydrochloride A mixture of 2-iodo-4-fluorobenzoic acid (194 mg, 0.73 mmol) and phosphorous pentachloride (152 mg, 0.73 mmol) in diethyl ether (5 mL) is stirred at room temperature for 2 h. The solvent is removed under reduced pressure to give the 2-iodo-4-fluorobenzoyl chloride. A solution of 2-iodo-4-fluorobenzoyl chloride in tetrahydrofuran (5 mL) is added to a solution of 4- [3-aminobenzoyl] -1-methylpiperidine ketone (145 mg, 0.66 mmol) and triethylamine (0.5 mL, 3.6 mmol) in tetrahydrofuran (5 ml). The reaction mixture is stirred 16 h at room temperature. The reaction mixture is diluted with ethyl acetate and water and then extracted with ethyl acetate. The ethyl acetate extracts were washed with a 0.2 N sodium hydroxide solution, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure. Prepurification by elution through a small amount of silica gel (5% 2M ammonia in methanol / methylene chloride) then purification by radial chromatography (silica gel, 2000 micron rotor, 2.5% 2M ammonia in methanol / methylene chloride) gave 266 mg of a white foam. It was recrystallized as the hydrochloric acid salt from ethyl acetate / ethanol then recrystallized from ethyl acetate / methanol to provide 120 mg (48%) of a colorless white powder. P.f. > 250 ° C. MS (m / e): 467 (M + 1), 465 (M-1).

Analysis for C20H2? ClFIN2O2: Cale: C, 47.78; H, 4.21; N, 5.57; Found: C, 47.71; H, 4.14; N, 5.44 Example 13 4- [3- (4-fluorophenylsulfonyl) oxybenzoyl] -1-methylpiperidine A solution of 4-fluorobenzenesulfonyl chloride (109 mg, 0.56 mmol) in THF (2.0 mL) is added to 4- [3-hydroxybenzoyl] -1-methylpiperidine (102 mg, 0.46 mmol) in 0.2 N sodium hydroxide (2.6 mL, 0.51 mmol) and THF (2.6 mi). The solution is stirred at room temperature for 2.5 hours. The solution is diluted with ethyl acetate, washed with 0.2 N sodium hydroxide, water, brine, dried over sodium sulfate, and concentrated in vacuo to give 170 mg (97%). The hydrochloric acid salt was formed in ethyl acetate and concentrated in vacuo. The residue is dissolved in acetone and concentrated in vacuo to give a white foam. EM (m / e) 378 (M + l). Analysis for C? 9H2? ClFN04S: Cale: C, 55.15; H, 5.11; N, 3.38; Found: C, 55.36; H, 5.67; N, 3.19.

Example 14 4- [3- (4-Fluorobenzamidyl) benzoyl] -1-methylpiperidine hydrochloride Chloroformate 1-chloroethyl (435 μl, 4.0 mmol) was added dropwise to a 0 ° C solution of 4- [3- (4-fluoro-benzamidyl] enzoyl] -1-methylpiperidine (686 mg, 2.0 mmol ) in 1,2-dichloroethane (15 ml.) The reaction mixture is warmed to room temperature then heated to reflux for 1.5 hrs. An additional amount of 1-chloroethyl chloroformate (400 μl, 3.7 mmol) is added and the reaction mixture is refluxed for 50 minutes.

The reaction mixture is concentrated in vacuo. The residue is dissolved in methanol (15 ml) and heated to reflux for 2 h. The solvent is removed under vacuum to give 780 mg of a brown oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol: ammonium hydroxide 95: 5: 0.5 then methylene chloride: methanol: ammonium hydroxide, 92.5: 7.5: 0.75) gave 220 mg (33%) of a white foam. Crystallization as the hydrochloride salt from ethyl acetate / ethanol gave a white solid. P.f. > 225 ° C. MS (m / e): 327 (M + 1). Analysis for C? 9H20ClFN2O2: Cale: C, 62.90; H, 5.56; N, 7.72; Found: C, 62.71; H, 5.39; N, 7.62.

Example 15 4- [3- (4-Fluorobenzamidyl) benzoyl] -1- [(1- isopropylpyraz-4-yl) ethyl] piperidine oxalate A mixture of 4- [3- (4-fluorobenzamidyl) benzoyl] -1-methylpiperidine (397 mg, 1.2 mmol), lH-pyrazole-4-ethanol, 1- (1-methylethyl) -, methanesulfonate (396 mg, 1.7 mmol), and potassium carbonate (336 mg, 2.4 mmol) in dimethylformamide (20 mL) is heated at 80 ° C for 21 hours. The reaction mixture is cooled to room temperature and diluted with water and ice. This mixture is extracted with ethyl acetate / diethyl ether and the organic extracts are washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 600 mg of a yellow oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride: methanol: 97.5: 2.5: 0.25 ammonium hydroxide) gave 120 mg (21%) of a yellow oil. Crystallization as the oxalic acid salt from ethyl acetate gave 135 mg of a dim yellow powder. MS (m / e): 463 (M + 1), 461 (M-1). Analysis for C29H33FN406: Cale: C, 63.03; H, 6.02; N, 10.14; Found: C, 62.89; H, 6.29; N, 9.94.

Example 16 4- [3- (benzamidyl) benzoyl] -1-methylpiperidine A mixture of 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and benzoyl chloride (39 μl, 0.336 mmol) in methylene chloride (1 ml) is mixed for 18 h at room temperature. The solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column (Siegel, MG; Hahn, PJ; Dressman, BA; Fritz, JE; Grunwell, JR; Kaldor, SW Tetrahedron Lett., 1997, 38, 3357-3360). The column is rinsed thoroughly with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 37.6 mg (> 100%) of the title compound. MS (m / e): 332 (M + 1), 321 (M-1).

The compounds of Examples 17 to 21 were prepared by the procedure described in detail in Example 16.

Example 17 4- [3-N '- (N-phenylmethylureido) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and benzyl isocyanate (85 μl, 0.688 mmol), 79.1 mg (98%) of the title compound were recovered. MS (m / e): 352 (M + 1), 350 (M-1).

Example 18 4- [3-N '- (N- (4-fluorophenyl) thioureido) benzoyl] -1- methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-fluorophenyl isothiocyanate (105 mg, 0.685 mmol), 87.5 mg (> 100%) of the title compound was recovered. MS (m / e): 372 (M + 1), 370 (M-1).

Example 19 4- [3- (2-methoxybenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- (3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-methoxybenzoyl chloride (102 μL, 0.685 mmol), 62.6 mg (78%) of the title compound were recovered. m / e): 353 (M + l), 351 (Ml).

Example 20 4- [3- (4-fluorophenylsulfonylamino) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-fluorobenzenesulfonyl chloride (133 mg, 0.683 mmol), 80.4 mg (93%) of the title compound was recovered. MS (m / e): 377 (M + 1), 375 (M-1).

Example 21 4- [3- (phenylmethoxyamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and benzyl chloroformate (98 μl, 0.686 mmol), 77.3 mg (96%) of the title compound were recovered. MS (m / e): 353 (M + 1), 351 (M-1).

Example 22 4- [3- (2-bromobenzamidyl) benzoyl] -1-methylpiperidine A mixture of 4- [3-aminobenzoyl] -l-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl) -polystyrene (100 mg, 0.260 mmol) in methylene chloride (1 mL) is allowed to sit for 5 minutes . To this mixture is added 2-bromobenzoyl chloride (151 mg, 0.687 mmol). The reaction mixture is combined for 2 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. The filtrate solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column (Siegel, MG; Hahn, PJ; Dressman, BA; Fritz, JE; Grunwell, JR; Kaldor, SW Tetrahedron Lett., 1997, 38, 3357-3360). The column is rinsed with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 45.6 mg (50%) of the title compound. MS (m / e): 401, 403 (M + 1), 399, 401 (M-1).

The compounds of Examples 23 to 40 were prepared by the procedure described in detail in Example 22.

Example 23 4- [3- (2-fluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-fluorobenzoyl chloride (82 μl, 0.687 mmol), 76.8 mg (99%) of the title compound were recovered. MS (m / e): 341 (M + 1), 339 (M-1).

Example 24 4- [3- (2-Chlorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-chlorobenzoyl chloride (87 μl, 0.687 mmol), 79.9 mg (98%) of the title compound were recovered. MS (m / e): 357 (M + 1), 355 (M-1).

Example 25 4- [3- (2- (trifluoromethyl) benzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2- (trifluoromethyl) benzoyl chloride (101 μl, 0.687 mmol), 81.9 mg (92%) of the title compound were recovered. . MS (m / e): 391 (M + 1), 389 (M-1).

Example 26 4- [3- (2-methylbenzamidyl) enzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-methylbenzoyl chloride (90 μL, 0.687 mmol), 73.1 mg (95%) of the title compound were recovered. MS (m / e): 337 (M + 1), 335 (M-1).

Example 27 4- [3- (3-bromobenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -l-methylpiperidine (50 mg, 0.229 mmol) and 3-bromobenzoyl chloride (91 μl, 0.687 mmol), 29.3 mg (32%) of the title compound were recovered. MS (m / e): 401, 403 (M + 1), 399, 401 (M-1).

Example 28 4- [3- (3-chlorobenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 3-chlorobenzoyl chloride (120 mg, 0.687 mmol), 67.6 mg (83%) of the title compound were recovered. MS (m / e): 357 (M + 1), 355 (M-1).

Example 29 4- [3- (3-methoxybenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 g, 0.229 mmol) and 3-methoxybenzoyl chloride (97 μl, 0.687 mmol), 78.6 mg (97%) of the title compound were recovered. MS (m / e): 353 (M + 1), 351 (M-1). ? s Example 30 4- [3- (3- (trifluoromethyl) benzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 3- (trifluoromethyl) benzoyl chloride (104 μl, 0.687 mmol), 88.6 mg (99%) of the title compound were recovered. MS (m / e): 391 (M + 1), 389 (M-1). 0 Example 31 4- [3- (3-methylbenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 3-ethylbenzoyl chloride (91 μL, 0.687 mmol), 74.0 mg (96%) of the title compound were recovered. MS (m / e): 337 (M + 1), 335 (M-1). is Example 32 4- [3- (4-fluorobenzamidyl) benzoyl] -1-methyl? Iperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-fluorobenzoyl chloride (81 μl, 0.687 mmol), 61.1 mg (78%) of the title compound were recovered. MS (m / e): 341 (M + 1), 339 (M-1). s Example 33 4- [3- (4-methoxybenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-methoxybenzoyl chloride (117 mg, 0.687 mmol), 81.5 mg (> 100%) of the title compound were recovered. MS (m / e): 353 (M + 1), 351 (M-1).

Example 34 4- [3- (4-phenylbenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-biphenylcarbonyl chloride (150 mg, 0.687 mmol), 30.8 mg (34%) of the title compound were recovered. MS (m / e): 399 (M + 1), 397 (M-1).

Example 35 4- [3- (4-trifluoromethylbenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4- (trifluoromethyl) benzoyl chloride (102 μL, 0.687 mmol), 88.0 mg (98%) of the title compound were recovered. . MS (m / e): 391 (M + 1), 389 (M-1).

Example 36 4- [3- (4-methylbenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 4-methylbenzoyl chloride (91 μL, 0.687 mmol), 74.0 mg (96%) of the title compound were recovered. MS (m / e): 337 (M + 1), 335 (M-1).

Example 37 4- [3- (2-iodobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-iodobenzoyl chloride (183 mg, 0.687 mmol), 16.0 mg (16%) of the title compound were recovered. MS (m / e): 449 (M + 1), 447 (M-1).

Example 38 4- [3- (2-nitrobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 2-nitrobenzoyl chloride (91 μl, 0.687 mmol) but the reaction mixture was mixed for 24 h at room temperature, 82.5 mg (98%) of the title compound were recovered. MS (m / e): 368 (M + 1), 366 (M-1).

Example 39 4- [3- (3-nitrobenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 3-nitrobenzoyl chloride (128 mg, 0.687 mmol), 17.4 mg (21%) of the title compound were recovered. MS (m / e): 368 (M + 1), 366 (M-1).

Example 40 4- [3- (3-Cyanobenzamidyl) benzoyl] -l-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and 3-cyanobenzoyl chloride (114 mg, 0.687 mmol), 21.2 mg (27%) of the title compound were recovered. MS (m / e): 348 (M + 1), 346 (M-1).

Example 41 4- [3- (4-nitrobenzamidyl) benzoyl] -1-methylpiperidine To a mixture of 4- [3-aminobenzoyl] -1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl) -polystyrene (176 mg, 0.458 mmol) in tetrahydrofuran (1 mL) is added 4-nitrobenzoyl chloride (85 mg). mg, 0.458 mmol) in tetrahydrofuran (1 mL). The reaction mixture is mixed for 18 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. The filtered solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 93 mg (> 100%) of the title compound. MS (m / e): 368 (M + 1), 366 (M-1). Analysis for C20H2? N304: Cale: C, 65.38; H, 5.76; N, 11.44; Found: C, 65.47; H, 5.88; N, 11.40.

Example 42 4- [3- (3-fluorobenzamidyl) benzoyl] -1-methylpiperidine A mixture of 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl) -polystyrene (50 mg, 0.130 mmol) in tetrahydrofuran (1 mL) is allowed to stand for 5 minutes. 3-Fluorobenzoyl chloride (28 μL, 0.229 mmol) and tetrahydrofuran (1 mL) are added to the reaction mixture. The reaction mixture is mixed for 18 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and left to stand for 5 minutes. This mixture is poured over a strong cation exchange column Varian Mega Bond Elut ™. The column was rinsed with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 43 mg (> 100%) of the title compound. MS (m / e): 341 (M + 1), 339 (M-1).

The compounds of Examples 43 to 46 were prepared by the procedures described in detail in Example 42.

Example 43 4- [3- (4-bromobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 4-bromobenzoyl chloride (50 mg, 0.229 mmol), 57.1 mg (> 100%) of the title compound were recovered. MS (m / e): 401, 403 (M + 1), 399, 401 (M-1).

Example 44 4- [3- (4-chlorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 4-chlorobenzoyl chloride (29 μl, 0.229 mmol), 44.8 mg (> 100%) of the title compound were recovered. MS (m / e): 357 (M + 1), 355 (M-1).

Example 45 4- [3- (4-iodobenzamidyl) enzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 4-iodobe zoilo chloride (61 mg, 0.229 mmol), 60.1 mg (> 100%) of the title compound were recovered. . MS (m / e): 449 (M + 1), 399, 447 (M-1).

Example 46 4- [3- (4-Cyanobenzamidyl) benzoyl] -1-methylpiperidine Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 4-cyanobenzoyl chloride (38 mg, 0.229 mmol), 48.4 mg (> 100%) of the title compound were recovered. MS (m / e): 348 (M + 1), 346 (M-1).

Example 47 4- [3- (2, 3, 4, 5, 6-pentaflurobenzamidyl) benzoyl] -1- ethylpiperidine A mixture of 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and piperidinomethyl-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) is allowed to stand for 10 minutes. Pentafluorobenzoyl chloride (33 μL, 0.229 mmol) is added to the reaction mixture. The reaction mixture is mixed for 2 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 51 mg (> 100%) of the title compound.

MS (m / e): 413 (M + 1), 411 (M-1).

The compounds of Examples 48 to 66 were prepared by the procedure described in detail in Example 47.

Example 48 4- [3- (2,6-difluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2,6-difluorobenzoyl chloride (29 μl, 0.229 mmol) and mixing for 24 h, 46.6 mg (> 100%) of the title compound were recovered. MS (m / e): 359 (M + 1), 357 (M-1).

Example 49 4- [3-. { isopropylamidyl) enzoyl] -1-methylpiperidine-methyl (4-piperidyl)) carbonyl] phenyl} propanamide Beginning with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and isobutyryl chloride (24 μl, 0.229 mmol), 36.7 mg (> 100%) of the title compound were recovered. MS (m / e): 289 (M + 1), 287 (M-1).

Example 50 4- [3- (phenylmethylmethyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and phenylacetyl chloride (30 μl, 0.229 mmol), 43.8 mg (> 100%) of the title compound were recovered. MS (m / e): 337 (M + 1), 335 (M-1).

Example 51 4- [3- (Butylamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and valeryl chloride (27 μl, 0.229 mmol), 38.8 mg (> 100%) of the title compound were recovered. MS (m / e): 303 (M + 1), 301 (M-1).

Example 52 4- [3- (cyclohexylamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and cyclohexanecarbonyl chloride (31 μL, 0.229 mmol), 41.1 mg (> 100%) of the title compound were recovered. MS (m / e): 329 (M + 1), 327 (M-1).

Example 53 4- [3- (1-naphthylamidyl) enzoyl] -1-methylpiperidine The 1-naphthoyl chloride is mixed for 24 h (44 mg, 0.229 mmol) in tetrahydrofuran (1 mL) and 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 45.6 mg (> 100%) of the title compound are recovered. MS (m / e): 373 (M + 1), 371 (M-1).

Example 54 4- [3- (2-naphthylamidyl) benzoyl] -1-methylpiperidine The 1-naphthoyl chloride (44 mg, 0.229 mmol) in tetrahydrofuran (1 mL) and 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) are mixed for 24 h and 45.6 mg are recovered (>100%) of the title compound. MS (m / e): 373 (M + 1), 371 (M-1).

Example 55 4- [3- (2, 5-difluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2,5-difluorobenzoyl chloride (28 μl, 0.229 mmol), 44.7 mg (> 100%) of the title compound were recovered. MS (m / e): 359 (M + 1), 357 (M-1).

Example 56 4- [3- (3, 4-difluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 3,4-difluorobenzoyl chloride (29 μl, 0.229 mmol) and mixing for 24 h, 45.6 mg (> 100%) of the title compound were recovered. MS (m / e): 359 (M + 1), 357 (M-i).

Example 57 4- [3- (3, 5-difluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 3,5-difluorobenzoyl chloride (29 μl, 0.229 mmol) and mixing for 24 h, 46.1 mg (> 100%) of the title compound were recovered. MS (m / e): 359 (M + 1), 357 (M-1).

Example 58 4- [3- (2, 3-difluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2,3-difluorobenzoyl chloride (28 μl, 0.229 mmol) and mixing for 24 h, 43.5 mg (> 100%) of the title compound were recovered. MS (m / e): 359 (M + 1), 357 (M-1).

Example 59 4- [3- (4-trifluoromethoxybenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 4- (trifluoromethoxy) benzoyl chloride (36 μl, 0.229 mmol) and mixing for 24 h, 50.1 mg (> 100% ) of the title compound were recovered. MS (m / e): 407 (M + 1), 405 (M-1).

Example 60 4- [3- (2-trifluoromethoxybenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2- (trifluoromethoxy) enzoyl chloride (37 μl, 0.229 mmol) and mixing for 24 h, 49.8 mg (> 100% ) of the title compound were recovered. MS (m / e): 407 (M + 1), 405 (M-1).

Example 61 4- [3- (2, 3, 6-trifluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 2,3,6-trifluorobenzoyl chloride (30 μl, 0.229 mmol) and mixing during 24 h, 47.7 mg (> 100%) of the title compound were recovered. MS (m / e): 377 (M + 1), 375 (M-1).

Example 62 4- [3- (2, 4, 5-trifluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2,4,5-trifluorobenzoyl chloride (29 μl, 0.229 mmol) and mixing for 24 h, 46.2 mg (> 100 %) of the title compound were recovered. MS (m / e): 377 (M + 1), 375 (M-1).

Example 63 4- [3- (3-trifluoromethoxybenzamidyl) enzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and 3- (trifluoromethoxy) benzoyl chloride (37 μl, 0.229 mmol) and mixing for 24 h, 50.4 mg (> 100% ) of the title compound were recovered. MS (m / e): 407 (M + 1), 405 (M-1).

Example 64 4- [3- (2, 4,6-trifluorobenzamidyl) enzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine- (25 mg, 0.115 mmol) and 2,4,6-trifluorobenzoyl chloride (30 μl, 0.229 mmol) and mixing for 24 h, 45.1 mg (> 100%) of the title compound were recovered. MS (m / e): 377 (M + 1), 375 (M-1).

Example 65 4- [3- (2, 3, 4-trifluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2,3,6-trifluorobenzoyl chloride (29 μl, 0.229 mmol) and mixing during 24 h, 46.4 mg (> 100%) of the title compound were recovered. MS (m / e): 377 (M + 1), 375 (M-1).

Example 66 4- [3- (2-Chloro-4-fluorobenzamidyl) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and 2-chloro-4-fluorobenzoyl chloride (32 μl, 0.229 mmol) and mixing for 24 h, 44.9 mg (> 100 %) of the title compound were recovered. MS (m / e): 375 (M + 1), 373 (M-1).

Example 67 4- [3- (2,3,4,5-tetrafluorobenzamidyl) benzoyl] -1- methylpiperidine A mixture of 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl) -polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) is allowed to sit for 10 minutes. 2,3,4,5-Tetrafluorobenzoyl chloride (31 μL, 0.229 mmol) is added to the reaction mixture. The reaction mixture is mixed for 24 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with 7M ammonia in methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. This purification was not successful. The solvent is concentrated in vacuo. The residue is dissolved in water, basified with ammonium hydroxide, and extracted with methylene chloride. The organic extracts were washed with brine, glacial acetic acid (0.5 ml) was added to the organic extracts and the solution mixed for 5 minutes. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed with methanol to remove the impurities, then treated with 7M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 43.7 mg (97%) of the title compound. MS (m / e): 395 (M + 1), 393 (M-1).

Example 68 4- [3- (3,4,5-trifluorobenzamidyl) benzoyl] -1-methylpiperidine Following the previous example and starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25.0 mg, 0.115 mmol) and 3, 4, 5, -trifluorobenzoyl chloride (30 μl, 0.229 mmol), 42.5 mg are recovered (99%) of the title compound. MS (m / e): 377 (M + 1), 375 (M-1). ? 5 Example 69 4- [3- (aminoamidyl) enzoyl] -1-methylpiperidine A mixture of 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl) -polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) is allowed to stand for 10 minutes. 4-Fluorophenyl chloroformate (30 μL, 0.229 mmol) is added to the reaction mixture. The reaction mixture is mixed for 24 hours at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtrate solution and the solution is mixed. This mixture is poured onto a strong cation exchange column Varian Mega Bond Elut "" *. The column is rinsed with methanol to remove the impurities, then csp 7M ammonia in ethoxy is treated to elute the product from the column. The solvent is removed under vacuum and the residue is purified by chromatography with silica gel (methylene chloride: methanol: ammonium hydroxide, 100: 5: 0.5). The solvent is evaporated to give the title compound. MS (m / e): 262 (M + 1), 260 (M-1).

Example 70 4- [3- (phenylureido) enzoyl] -1-methylpiperidine 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0. 115 mmole) and phenyl isocyanate (37 μl, 0.344 mmole) in methylene chloride (2 ml) are mixed for 72 h at room temperature. The solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is thoroughly rinsed with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was stirred with a 5N sodium hydroxide solution (1 ml). The solvent is removed under vacuum and the residue is purified by chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 97.5: 2.5: 0.25 then 95: 5: 0.5). The solvent is evaporated to give 28.5 (74%) of the title compound. MS (m / e): 338 (M + 1), 336 (M-1).

Example 71 4- [3- (4-fluorophenyl) -ido) benzoyl] -1-methylpiperidine 4- [3-aminobenzoyl] -l-methylpiperidine is mixed (25 mg, 0.115 mmol) and 4-fluorophenyl isocyanate (39 μl, 0.344 mmol) in methylene chloride (2 ml) for 72 hrs at room temperature. The solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is thoroughly rinsed with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was stirred with a 5N sodium hydroxide solution (1 ml). The solvent is removed under vacuum and the residue is purified by chromatography with silica gel (methylene chloride: methanol: ammonium hydroxide, 97.5: 2.5: 0.25 then 95: 5: 0.5). The solvent is evaporated to give 27.4 mg (67%) of the title compound. MS (m / e): 356 (M + 1), 354 (M-1).

Example 72 4- [3- (cyclohexylilureido) benzoyl] -1-methylpiperidine 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0. 115 mmole) and cyclohexyl isocyanate (44 μl, 0.344 mmole) in methylene chloride (2 ml) are mixed for 72 h at room temperature. The solution is diluted with 10% acetic acid in methanol and poured onto a strong Cationic Variety Mega Bond Elut ™ column. The column is rinsed thoroughly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated and the residue is dissolved in tetrahydrofuran (2 ml). Cyclohexyl isocyanate (44 μl, 0.344 mmol) and poly (4-dimethylaminopyridine) (82 mg, 0.115 mmol) are added and the reaction mixture is mixed for 5 days. The reaction mixture is filtered and the filter cake is washed with methanol. The solution is diluted with 10% acetic acid in methanol and poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is thoroughly rinsed with methanol to remove the impurities, then treated with 2M ammonia to elute the product from the column. The solvent is evaporated to give 36.4 mg (93%) of the title compound. MS (m / e): 344 (M + 1), 342 (M-1).

The compounds of Examples 73 to 74 were prepared by the procedure described in detail in Example 72.

Example 73 4- [3- (phenylthioureido) enzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and phenyl isothiocyanate (82 μl, 0.688 mmol), 40.5 mg (100%) of the title compound were recovered. MS (m / e): 35 (M + 1), 352 (M-1).

Example 74 4- [3- (benzylthioureido) benzoyl] -1-methylpiperidine Starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and benzyl isothiocyanate (92 μl, 0.688 mmol), 37.6 mg (89%) of the title compound were recovered. MS (m / e): 368 (M + 1), 366 (M-1).

Example 75 4- [3- (phenoxyamidyl) enzoyl] -1-methylpiperidine HCl salt Allow 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg) to stand, 0.115 mmol) and poly (4-vinyl pyridine) (50 mg, 0.400 mmol, cross-linked at 2%) in tetrahydrofuran (2 mL) for 10 minutes. Phenyl chloroformate (43 μl, 0.344 mmol) is added and the reaction mixture is mixed for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is thoroughly rinsed with methanol to remove the impurities, then treated with 2 M hydrochloric acid in methanol to elute the product from the column. The solvent is evaporated to give 38.9 mg (91%) of the title compound. MS (m / e): 339 (M + 1), 337 (M-1).

Example 76 4- [3- (butoxamidyl) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 mL) are allowed to stand during 10 minutes. Butyl chloroformate (44 μl, 0.344 mmol) is added and the reaction mixture is mixed for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 36.6 mg (100%) of the title compound. MS (m / e): 319 (M + 1), 317 (M-1).

Example 77 4- [3- (isopropylureido) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine (50 mg, 0.400 mmol, cross-linked at 2%) in tetrahydrofuran (2 ml) for 10 hours are allowed to stand. minutes Isopropyl isocyanate (34 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature The reaction mixture is filtered and the filter cake is rinsed with methanol Acetic acid is added glacial (0.5 ml) to the filtered solution and the solution is mixed in. This mixture is poured over a strong Varian Mega Bond Elut ™ cation exchange column.The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia. in methanol to elute the product from the column.The solvent is evaporated and the residue is purified by chromatography with silica gel (gradient of 1-3%, 2M ammonia in methanol: methylene chloride) .The solvent evaporates to give 21.8 mg (63%) of the title compound MS (m / e): 30 4 (M + 1), 302 (M-1).

Example 78 4- [3- (methylureido) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Methyl isocyanate (20 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated and the residue is purified by chromatography with silica gel (2% 2M ammonia in methanol: methylene chloride). The solvent is evaporated to give 28.1 mg (89%) of the title compound. MS (m / e): 276 (M + 1), 274 (M-1).

Example 79 4- [3- (methoxyamidyl) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Methyl chloroformate (27 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated and the residue is purified by chromatography on silica gel (gradient 1-3%, 2M ammonia in methanol: methylene chloride). The solvent is removed under vacuum. The residue is dissolved in methylene chloride (2 ml), polystyrene methylisocyanate is added (130 mg, 0.130 mmol, 1% crosslinked polystyrene-co-divinylbenzene), and the reaction mixture is mixed at room temperature 96. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed in. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column.The column is rinsed abundantly with methanol to remove the impurities, then Treat with 2M ammonia in methanol to elute the product from the column.The solvent is evaporated to give 22.3 mg (70%) of the title compound MS (m / e): 277 (M + 1), 275 (Ml).

Example 80 4- [3- (isopropoxyamidyl) enzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Isopropyl chloroformate (344 μl, 0.344 mmol, IM in toluene) is added and the reaction mixture is combined for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent evaporates. The residue is dissolved in methylene chloride (2 mL), polystyrene methylisocyanate (130 mg, 0.130 mmol, poly (styrene-co-divinylbenzene crosslinked at 1%) is added, and the reaction mixture is combined at 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol, glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed in. This mixture is poured onto a strong Varian Mega cation exchange column. Bond Elut ™ The column is rinsed abundantly with methanol to remove impurities, then treated with 2M ammonia in methanol to elute the product from the column.The solvent is evaporated to give 28.9 mg (83%) of the title compound. (m / e): 305 (M + l), 303 (Ml).

Example 81 4- [3- (Butylsulfonylamino) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Butanesulfonyl chloride (45 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured over a strong cation exchange column Varian Mega Bond Elut ™. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated and the residue is purified by chromatography with silica gel (1-3% gradient, 2M ammonia in methanol: methylene chloride). The solvent is removed under vacuum. The residue is dissolved in methylene chloride (2 ml), polystyrene methylisocyanate (130 mg, 0.130 mmol, poly (styrene-co-divinylbenzene 1% crosslinked) is added, and the reaction mixture is combined 96 at room temperature An additional amount of polystyrene methylisocyanate (230 mg, 0.230 mol) is added to the reaction mixture and mixing is continued for another 7 days.The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed in. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column.The column is rinsed abundantly with methanol to remove the impurities, then treat with 2M ammonia in methanol to elute the product from the column.The solvent is evaporated and the residue is purified by radial chromatography (silica gel, 1000 micron rotor, methylene chloride: 2M ammonia in methanol, 100: 2 then 100: 4). The solvent is concentrated in vacuo to give 14.6 mg (38%) of the title compound. MS (m / e): 339 (M + 1), 337 (M-1).

Example 82 4- [3- (butyl thioureido) enzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Butyl isothiocyanate (41 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature.

An additional amount of butyl isothiocyanate is added (100 μl, 0.829 mol) to the reaction mixture and mixing is continued for another 6 days. Polystyrene methylisocyanate (230 mg, 0.230 mmol, 1% crosslinked polystyrene-co-divinylbenzene) is added and the reaction mixture is combined for 7 days at room temperature, the reaction mixture is filtered and the cake of the reaction mixture is filtered. The filter is rinsed with methanol, glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed in. The mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. Remove impurities, then treat with 2M ammonia in methanol to elute the product from the column.The solvent is evaporated and the residue is purified by radial chromatography (silica gel, 1000 micron rotor, methylene chloride: 2M ammonia in methanol , 100: 2 then 100: 4) The solvent is concentrated in vacuo to give 20.3 (53%) of the title compound MS (m / e): 334 (M + 1), 332 (Ml).

Example 83 4- [3- (isopropylthioureido) benzoyl] -1-methylpiperidine Following the previous example and starting with 4- [3-aminobenzoyl] -l-methylpiperidine (25 mg, 0.115 mmol) and isopropyl isothiocyanate (133 μl, 1,401 mmol), 15.6 mg (43%) of the title compound are recovered. .

MS (m / e): 320 (M + 1), 318 (M-l) Example 84 4- [3- (butylureido) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and the poly (4-vinyl pyridine) (50 mg, 0.400 mmol, crosslinked at 2%) in tetrahydrofuran (2 ml) are allowed to stand during 10 minutes. Butyl isocyanate (39 μl, 0.344 mmol) is added and the reaction mixture is combined for 96 h at room temperature. An additional amount of butyl isocyanate (100 μl, 0.888 mmol) is added to the reaction mixture and mixing is continued for another 6 days. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed abundantly with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 44.4 mg (> 100%) of the title compound. MS (m / e): 318 (M + 1), 316 (M-1).

Example 85 4- [3- (methylthioureido) benzoyl] -1-methylpiperidine Following the previous example and starting with 4- [3-aminobenzoyl] -1-methylpiperidine (25 mg, 0.115 mmol) and methyl isothiocyanate (124 μl, 1813 mmol), 22.0 mg (66%) of the title compound were recovered . MS (m / e): 292 (M + 1), 290 (M-1).

Example 86 4- [3- (thien-2-ylamidyl) benzoyl] -1-methylpiperidine Allow 4- [3-aminobenzoyl] -1-methylpiperidine (30 mg, 0.137 mmol) and (piperidinomethyl) -polystyrene (106 mg, 0.276 mmol) in tetrahydrofuran (2 mL) to stand for 5 minutes. 2-thiophenecarbonyl chloride is added (29 μl, 0.275 mmol) to the reaction mixture. The reaction mixture is combined for 18 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with methanol. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is evaporated to give 44.9 mg (> 100%) of the title compound. MS (m / e): 329 (M + 1), 327 (M-1).

Example 87 4- [3- (pyrid-3-ylamidyl) benzoyl] -1-methylpiperidine The 4- [3-aminobenzoyl] -1-methylpiperidine (30 mg, 0.137 mmol) and (piperidinomethyl) -polystyrene (250 mg, 0.650 mmol) in dimethylformamide (2 mL) are allowed to stand for 5 minutes. Nicotinyl chloride hydrochloride (49.0 mg, 0.275 mmol) in dimethylformamide (1 ml) is added to the reaction mixture. The reaction mixture is combined for 18 h at room temperature. The reaction mixture is filtered and the filter cake is rinsed with tetrahydrofuran. Glacial acetic acid (0.5 ml) is added to the filtered solution and the solution is mixed. This mixture is poured onto a strong Varian Mega Bond Elut ™ cation exchange column. The column is rinsed with methanol to remove the impurities, then treated with 2M ammonia in methanol to elute the product from the column. The solvent is concentrated in vacuo and the residue is purified by radial chromatography (silica gel, 1000 micron rotor, 1-3% gradient, 2M ammonia in methanol: methylene chloride). The solvent is concentrated in vacuo to give 32.5 mg (88%) of the title compound. MS (m / e): 324 (M + 1), 322 (M-1).

Example 88 4- [3- (pyrid-2-ylamidyl) benzoyl] -1-methylpiperidine Following the previous example and starting with 4- [3-aminobenzoyl] -1-methylpiperidine (30 mg, 0.137 mmol) and picolinoyl chloride hydrochloride (49.0 mg, 0.275 mmol), 39.3 mg (> 100%) of the compound of the title were recovered. MS (m / e): 324 (M + 1), 322 (M-1).

Example 89 2-amino-5- (4-fluorobenzamidyl) benzoyl) -1-methylpiperidine To a solution of 2-formamidyl-5- (4-fluorobenzamidyl) -benzoyl) -1-methylpiperidine (500 mg, 1.3 mmol) in methanol (20 mL) is added 5N sodium hydroxide. (2.6 ml, 13.0 mmol). The resulting reaction mixture is stirred at room temperature for 3 hours and 40 minutes then an additional amount of 5N aqueous sodium hydroxide (2.6 ml, 13.0 mmol) is added. The reaction mixture is stirred at room temperature for 1.5 hours, 5N aqueous sodium hydroxide (5.0 ml, 25.0 mmol) is added, and the mixture is heated at 45 ° C for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 480 mg of a yellow oil. Purification by flash chromatography (silica gel, methylene chloride: methanol: ammonium hydroxide, 100: 5: 0.5) gave 460 mg (50.5%) of the title compound as a yellow foam. MS (m / e): 355 (M + 1). Analysis for C22H23C1F2N2: Cale: C, 67.95; H, 6.24; N, 11.82; Found: C, 67.33; H, 6.09; N, 11.58.

Experiment 90 4- (o / p / m-nitrobenzoyl) -l-trifluoromethylcarbonylpiperidines The suspension of the commercially available 4-benzoylpiperidine hydrochloride (2.257 g, 0.01 mole) in trifluoroacetic anhydride (15 ml) is refluxed for 5 hours. The reaction is checked by CCD [silica gel / ethyl acetate-hexane (2: 3)]. The turbid solution is allowed to stir for 16 hours at room temperature. The reaction mixture is cooled to 5-6 ° C (ice bath) and NH4N03 (1.68 g, 0.021 mol) is added in portions over 45 minutes. The addition is complemented, the suspension is subsequently stirred for 1 hour at 6-10 ° C and then allowed to reach RT (room temperature). The reaction is checked by CCD [silica gel / ethyl acetate-hexane (2: 3)]. The solution is concentrated under vacuum to give a yellowish liquid residue. The residue is dissolved in CH2C12 (60 mL) and the resulting organic solution is washed with demineralized H20 (2x25 mL). The organic layer is dried over MgSO4 (4. g), filtered and evaporated by centrifugation to dryness. The yellowish oil is received in pure ethanol (2x15 ml), concentrated under reduced pressure and dried under vacuum to obtain a yellow solid (3.12 g, 94%) of a mixture of 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine. , 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, 4- (4-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (62/33/5), as determined by NMR.

Experiment 91 4- (o / p / m-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidines The hydrochloride of 4-benzoylpiperidine (2257 g, 0.01 mol) is refluxed for 7 h in trifluoroacetic anhydride (15 mL, 22.3 g, 0.106 mol). Then, the resulting solution is allowed to stir for 20 h at room temperature. To the cold reaction mixture (5 ° C) is added dripping (20 minutes) HN03 fuming (1.32 g, 0.87 ml, 0.021 moles) keeping the T of the mass at 6-7 ° C. The addition is supplemented, the suspension is subsequently stirred for 1 h at 6-10 ° C (reaction verified by CCD [silica gel / ethyl acetate-hexane (2: 3)]). The suspension is heated to RT for 20 h and the resulting solution is evaporated by centrifugation under reduced pressure. The reddish residue is dissolved in CH2C12 (60 mL) which is washed with demineralized H20 (2x25 mL). The organic layer is dried over MgSO4 (5 g), filtered and concentrated to dryness. The yellow oil is received in pure ethanol (2x30 ml), concentrated under reduced pressure and dried under vacuum at 50 ° C to give a yellow solid (3.2 g, 97%) of a mixture of 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, and 4- (4-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (64/32/4), as determined by NMR.

Example 92 4- (o / m-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidines A mixture of 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, 4- (2-nitrobenzoyl) -l-trifluoromethylcarbonylpiperidine, and 4- (4-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (64/32/4) (56.7 g , 0.172 moles) is heated in isopropanol (280 ml) at 70 ° C until the solution complements. Then, the reddish solution is cooled to room temperature. The precipitation at T of the mass = 46-47 ° C is observed. Then the yellow suspension is subsequently treated for 3 h at room temperature before filtration. The filtered yellow solid is washed with isopropanol (2x30 ml) and n-pentane (50 ml). Drying at 50 ° C under vacuum produced 46 g (85%) of a mixture of 4- (3-nitrobenzoyl) -l-trifluoromethylcarbonylpiperidine, and 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine [67 (m) : 33 (o)].

Example 93 4- (3-nitrobenzoyl) piperidine HCl The mixture of 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine and 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine [67 (m): 33 (o)] (40.36 g, 0.122 mol) is heated with reflux in isopropanol (1.39 1) containing 37% HCl (209 ml) for 18 hours. The reaction is checked by CCD [silica gel / ethyl acetate-hexane (2: 3)]. The resulting solution is allowed to cool to room temperature and crystallization occurred at the mass T = 35 ° C. Then the suspension was subsequently stirred for 3 hours at room temperature. The precipitate is collected by filtration, washed with ethanol (100 ml) and ethyl ether (100 ml) and dried under vacuum at 50 ° C to give 4- (3-nitrobenzoyl) piperidine HCl as a pale yellow solid. (17.81 g, 54%). p.f. = 267.6 ° C The mother liquors were concentrated to dryness and the residue was dried under vacuum at 50 ° C to give 15.23 g of the composition of 4- (2-nitrobenzoyl) piperidine and 4- (3-nitrobenzoyl) piperidine (80 / 20) solid white colorless. Analysis for C? 2H? 4N203 HCl: Cale: C, 53.24; H, 5.58; N, 10.35; Found: C, 53.16; H, 5.69; N, 10.66.

Example 94 4- (3-nitrobenzoyl) piperidine HCl To a suspension of 2.8 g (8.48 mmoles) of the mixture of 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, and 4- (4-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (62: 33: 5) in isopropanol (60 mL) is added 37% HCl (10 mL). The reaction mixture is refluxed for 8 h and a complete solution is rapidly observed. Then, the solution is allowed to cool to room temperature and is subsequently stirred for 4 hours. The precipitate is filtered, rinsed with isopropanol (2 × 5 ml) and ethyl ether (5 ml). Drying under vacuum at 50 ° C yielded pure 4- (3-nitrobenzoyl) piperidine HCl (956 mg, 42%).

Example 95 4- (3-Nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, and 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine 4- (3-Nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (4.9 g (0.148 mol)) and 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine (67:33) were added to isopropanol (100 ml) and 37% HCl (15 mi) The suspension is refluxed for 10 h until the hydrolysis is complete. The reaction is checked by CCD [silica gel / ethyl acetate-hexane (2: 3)]. The resulting yellow solution is allowed to cool to room temperature and the resulting suspension was subsequently stirred for 10 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dried under vacuum for 16 h at 50 ° C. 4 g (100%) of the mixture of 4- (3-nitrobenzoyl) piperidine HCl and 4- (2-nitrobenzoyl) piperidine were isolated as a faint colored solid.

Example 96 Purification of 4- (3-nitrobenzoyl) piperidine HCl The suspension of the mixture of 4- (3-nitrobenzoyl) piperidine HCl and 4- (2-nitrobenzoyl) piperidine HCl (67 (m) / 33 (o)) (720 mg, 2.66 mmol) in pure ethanol (42 ml) ) is refluxed for 1 hour. Then, the reaction mixture is allowed to cool to room temperature and is subsequently stirred for 3 h before filtration. The solid is filtered, washed with ethanol (5 ml) and ethyl ether (5 ml) and dried under vacuum at 50 ° C for 16 h to give 417 mg (58%) of 4- (3-nitrobenzoyl) piperidine. Pure HCl.

Example 97 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine 1. 25 g (0.046 mole) of the 4 - (- nitrobenzoyl) piperidine HCl is refluxed for 4.5 h in trifluoroacetic anhydride (7.5 ml). The reaction is verified by CCD [silica gel / AcOEt-hexane (40/60)]. The solution is allowed to cool to room temperature and the solution is concentrated under reduced pressure. The residue is taken up in isopropanol (2x5 mL) and concentrated to dryness to give 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine as a faint colored solid. The 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine was recrystallized from isopropanol (10 mL). The suspension is refluxed until complete dissolution and the solid was filtered to RT after the subsequent stirring for 18 hours. The precipitate was washed successively with isopropanol (2 ml) and n-pentane (5 ml). Drying under reduced pressure at 50 ° C gave 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine as a white solid (1.43 g, 94%). p.f. = 110.0 ° C AE for C? 4H? 3F3N204: Cale: C, 50.92; H, 3.97; N, 8.48; Found: C, 50.80; H, 3.80; N, 8.54.

Example 98 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine The mixture of 4- (2-nitrobenzoyl) piperidine HCl and 4- (3-nitrobenzoyl) piperidine HCl (80:20) (9.7 g, 0.0358 mol) is refluxed for 6 h in trifluoroacetic anhydride (55 ml) . The reaction is verified by CCD [silica gel / ethyl ether-hexane (96/4)]. The solution is allowed to stir overnight at room temperature. Then, the solution is concentrated under reduced pressure. The residue is taken up in isopropanol (2x50 ml), concentrated and dried under vacuum to give about 11.3 g (96%) of the mixture of 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, and 4- (3-nitrobenzoyl) ) -1-trifluoromethylcarbonylpiperidine. The 80/20 mixture of 4- (2-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine, and 4- (3-nitrobenzoyl) -1-trifluoromethylcarbonylpiperidine was recrystallized from isopropanol (1 g in 60 ml) to give 74% yield of the ortho derivative of 4- (2-nitrobenzoyl) -l-trifluoromethylcarbonylpiperidine after drying under vacuum at 50 ° C for 16 h. p.f. = 125.9 ° C EA for C12H? 4N203 HC1 »H20: Cale: C, 50.92; H, 3.97; N, 8.48; Found: C, 50.45; H, 3.81; N, 8.51.

Example 99 4- (2-n? Trobenzo? L) piperidma HCl The 4- (2-n-trobenzoyl) -1-t-fluoro-methylcarbonylpiperidine (5 g (0.0151 mol)) is refluxed for 13 h in isopropanol (100 ml) containing 37% HCl (25 ml). The reaction is verified by CCD [silica gel / ethyl ether]. The resulting solution is allowed to cool to room temperature where precipitation was observed. Then, the suspension is stirred for an additional 2 hours and filtered. The solid is washed with isopropanol (10 ml) and n-pentane (15 ml). 3.46 g (84 L) of 4 - [[(2-nitrobenzoyl) piperidma HCl are isolated after drying ba or vacuum at 50 ° C for 16 hours. P.f. = 239.1 ° C EA for C? H ^ C1N20"HC1" H20: Cale: C, 49.92; H, 5.93; N, 9.70; Found: C, 49.94; H, 5.67; N, 9.75.

Example 100 4- (3-aminobenzoyl) piperidine HCl A Parr bottle of 220 ml at a thermostat temperature of 28-29 ° C is charged with a suspension of 10% Pd / C (18.2 mg) in methanol (20 ml) followed by 4- (3-nitrobenzoyl). piperidine HCl (1 g, 3.69 mmol). The reactor is placed under a hydrogen atmosphere (2.81 kg / cm2 (40 psi)). The hydrogenation is supplemented within 1 hour. The catalyst is removed by filtration and rinsed with methanol (2x5 ml). The filtrate is evaporated by centrifugation and the solid dried under vacuum at 50 ° C for 8 hours to give 890 mg (100%) of the crude 4- (3-aminobenzoyl) piperidine HCl. The 4- (3-aminobenzoyl) piperidine HCl (11.51 g (47.8 mmol)) is then suspended in ethanol (147 ml) and refluxed for 1 hour. The mixture is allowed to stir at RT for 2 h. Then, the precipitate is filtered and successively rinsed with ethanol (2X15 ml) and ethyl ether (30 ml). The solid is dried under vacuum at 50 ° C for 16 h giving 11.05 g (45.9 mmol) of the 4- (3-aminobenzoyl) piperidine HCl purified in 96% yield. P.f. = 208-210 ° C EA for Ci2H16N20: Cale: C, 59.87; H, 7.12; N, 11.64; Found: C, 59.66; H, 7.13; N, 11.94.

Example 102 4- [3- (4-fluorobenzamidyl) benzoyl] piperidine HCl The 4- (3-aminobenzoyl) piperidine HCl (10.87 g (45.15 mmoles)) is converted to a suspension in pure ethanol (220 ml) in the presence of propylene oxide (3.185 g, 3.84 ml, 54.84 mmol) at room temperature during 15 minutes. The p-fluorobenzoyl chloride (8.93 g, 6.65 ml, 56.44 mmol) is then added dropwise. During the addition, a partial dissolution was observed before the formation of a thick precipitate. The temperature rose from 22 ° C to 33 ° C during acylation. The suspension was subsequently stirred at room temperature for 4 h. Then, the precipitate was filtered, washed with ethanol (22 ml) and diethyl ether (40 ml). 15.38 g (94%) of 4- [3- (4-fluorobenzamidyl) benzoyl] piperidine HCl were obtained after drying at 50 ° C under vacuum for 12 hours. The compounds of this invention are useful for increasing the activation of the 5-HT? F receptor. An increase in the activation of 5-HT? F is useful to treat a variety of disorders which have been related to reduced neurotransmission of serotonin in mammals, for example, migraine headaches. For further instruction on the links between the activation of 5-HT1F and migraine, see the previously incorporated reference of U.S. Pat. No. 5,708,008. To demonstrate the use of the compounds of this invention in the treatment of migraine, their ability to bind to the 5-HTiF receptor subtype was determined. The ability of the compounds of this invention to bind to the 5-HTiF receptor subtype was measured essentially as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA), 90: 408-412, 1993. Membrane preparation: Membranes were prepared from transfected Ltk cells (transfected with the human 5-HT? Receptor sequence) which were grown to 100% confluency. The cells were washed twice with the salted solution buffered with phosphate, scraped from the culture plates in 5 ml of the phosphate-buffered saline solution, cooled with ice, and centrifuged at 200 x gravity for 5 minutes at 4 °. C. The microspheres were resuspended in 2.5 ml of the ice-cold Tris buffer (20 mM Tris HCl, pH = 7.4 at 23 ° C, 5 mM EDTA) and homogenized with a Wheaton tissue grinder. The lysate was subsequently centrifuged at 200 x gravity for 5 minutes at 4 ° C to convert the large fragments into microspheres which were discarded. The supernatant is collected and centrifuged at 40,000 x gravity for 20 minutes at 4 ° C. The microspheres resulting from this centrifugation were washed once in the ice-buffered Tris wash buffer and resuspended in a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH = 7.4 at 23 ° C. The membrane preparations were maintained on ice and used within 2 hours for the radioligand binding assays. The protein concentrations were determined by the Bradford method. Anal Bi ochem. , 72: 248-254, 1976. Radioligand binding: [3H-5-HT] binding was effected using slight modifications of the 5-HTiF assay conditions reported by Herrick-David and Titeler [J. Neurochem. , 50: 1624-1631, 1988) with the omission of the masking ligands. Ligand binding studies were achieved at 37 ° C in a total volume of 250 μl of the buffer solution (50 mM Tris, 10 mM MgCl 2, 0.2 mM EDTA, 10 μM pargyline, 0.1% ascorbate, pH = 7.4 at 37 ° C) in 96-well microtiter plates. Saturation studies were carried out using [3H] 5-HT in 12 different concentrations ranging from 0.5 nM to 100 nM. The displacement studies were performed using 4.5-5.5 nM [3H] -HT. The binding profile of the drugs in the competition experiments was carried out using 6-12 concentrations of the compound. Incubation times were 30 minutes for both saturation and displacement studies based on the initial investigations which determined equilibrium binding conditions. The non-specific binding was defined in the presence of 10 μM 5-HT. Binding was initiated by the addition of 50 μl membrane homogenates (10-20 μg). The reaction was terminated by rapid filtration through pre-rinsed filters (0.5% polyethylenimine) using the 48R Cell Brandel Harvester device (Gaithersburg, MD). Subsequently, the filters were washed for 5 seconds with the ice-cold buffer (50 mM Tris HCl, pH = 7.4 at 4 ° C), dried and placed in ampoules containing 2.5 ml Readi-Safe (Beckman, Fullerton, CA) and the radioactivity was measured using a scintillation counter in the Beckman LS 5000TA liquid. The efficiency of the count of [3H] 5-HT averaged between 45-50%. The binding data were analyzed by computer-aided non-linear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). The IC 50 values were converted to the K values using the Cheng-Prussoff equation. Biochem.

Pharmacol. , 22: 3099-3108, 1973. All experiments were carried out in triplicate. Representative compounds of this invention were found to have affinity to the 5-HT? F receptor as measured by the procedure described above. As reported by R.L. Weinshank, et al, WO93 / 14201, the 5-HT? F receptor is functionally linked to a G protein as measured by the ability of serotonin and serotonergic drugs to inhibit the production of forskolin-stimulated cAMP in NIH3T3 cells transfected with the 5-HT1F receptor. The activity of adenylate cyclase was determined using standard techniques. A maximum effect is achieved by serotonin. An Emax is determined by dividing the inhibition of a test compound by the maximum effect and determining a percent inhibition. N. Adham, et al., Supra; R. L. Weinshank, et al., Proceedings of the National Academy of Sciences (USA), 89: 3630-3634, 1994; and the references cited there. Measurement of cAMP formation: cells NIH3T3 transfected from the human 5-HT1F receptor (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 effect curves of the drug dose were then obtained by adding 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 response curve 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 x gravity to convert the cellular debris into microspheres, and aliquots were taken from the supernatant and stored at -20 ° C before the formation evaluation. of cAMP by radioimmunoassay (set or set of radioimmunoassay of cAMP; Advanced Magnetics, Cambridge, MA). The radioactivity was quantified using a Packard COBRA Auto Gamma counter, equipped with data reduction programs. Representative compounds of the invention that showed affinity to the 5-HT1F receptor were tested and found to be agonists at the 5-HT? F receptor in the cAMP assay. 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 the desired pharmacokinetic profile from the route of administration and the compound (s) , and the patient's condition. Formulations capable of oral or injectable administration 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 general, a formulation of the present invention includes an active ingredient (a compound of formula I) and is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier such that it may be in the form of a capsule, sachet, 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 vehicle, carrier or medium for the active ingredient. Accordingly, the formulations can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for 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 other ingredients. If the active compound is substantially insoluble, it is commonly ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, of approximately 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, cellulose microcrystalline, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally 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 flavoring agents. The compounds of the invention can be formulated to provide a sustained or delayed, rapid release of the active ingredient after administration to the patient employing procedures well known in the art.

The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. The term "active ingredient" refers to a compound of formula I.

Formulation Example 1 Hard Gelatin Capsules Quantity Ingredient (mg / capsule) 4- [3- ((3-bromophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 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 Tablet Quantity Ingredient (mg / tablet) 4- [3- ((4-iodophenyl) sulfonyloxy) benzoyl] -1-methylpiperidine 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 Dry Powder Inhaler Ingredient Weight% 4- [3- (3-nitrophenylthioureido) benzoyl] -1-methylpiperidine 5 Lactose 95 The active ingredient is mixed with the lactose and the mixture is added to an inhalation device for the dry powder.

Formulation Example 4 Tablet Amount Ingredient (mg / tablet) 4- [3- (fur-2-ylthioureido) benzoyl] -1-methylpiperidine 30.0 Starch 45.0 Microcrystalline cellulose 35.0 Polyvinylpyrrolidone (as a 10% solution in water) 4.0 Carboxymethyl and sodium 4,5 Stearate magnesium 0.5 Talcum 1.0 Total 120.0 mg The active ingredient, starch and cellulose are passed through a U.S. sieve. No. 20 mesh and mix thoroughly. The solution of the polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. of mesh 16. The granules thus produced are dried at 50 ° C-60 ° C and passed through a U.S. mesh 16. Carboxymethyl sodium starch, magnesium stearate, and talc, previously passed through a U.S. sieve. No. 30 mesh, are then added to the granules which, after mixing, are compressed on a tabletting machine to give tablets each weighing 120 mg.

Formulation Example 5 Capsules Quantity Ingredient (mg / capsule) 4- [3- (pyridin-4-ylthioureido) benzoyl] -1-methylpiperidine 40.0 Starch 109.0 Magnesium stearate 1.0 Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are combined, passed through a U.S. sieve. No. 20 mesh, and filled in hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories Ingredient Quantity 4- [3- (3-nitrophenylsulfonylamino) benzoyl] -1-methylpiperidine 25 mg Saturated fatty acid glycerides up to 2,000 mg The active ingredient is passed through a U.S. sieve. No. 60 and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of a nominal capacity of 2.0 g and allowed to cool.

Formulation Example 7 Suspensions Ingredient Quantity 4- [3- (pyrid-3-ylureido) benzoyl] -1-methylpiperidine 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg flavor and color qv Purified water up to 5.0 mi The active ingredient, sucrose and xanthan gum are mixed, passed through a U.S. sieve. No. 10 mesh, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavor, and color are diluted with some of the water and added with agitation. Then enough water is added to produce the required volume.

Formulation example 8 Capsules Quantity Ingredient (mg / capsule) 4- [3- (2-hydroxyphenylsulfonylamino) benzoyl] -1-methylpiperidine 15.0 Fécula 407.0 Magnesium stearate 3.0 Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are combined, passed through a U.S. sieve. No. 20 mesh, and filled into hard gelatin capsules in amounts of 425 mg.

Formulation Example 9 Intravenous Formulation Ingredient Quantity 4- [3- (4-fluorophenylsulfonylamino) benzoyl] -1-methylpiperidine 250.0 mg Isotonic saline solution 1000 ml Formulation Example 10 Topical Formulation Ingredient Quantity 4- [3- ((2-Bromophenyl) amidul) benzoyl] -1-methylpiperidine 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin up to 100 g The white soft paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and agitated until they dissolve. The active ingredient is added and stirring is continued until it is dispersed. The mixture is then cooled until it becomes solid.

Formulation Example 11 Oral or Sublingual Tablets Quantity Ingredient (mg / tablet) 4- [3- (thiophen-2-ylsulfonylamino) benzoyl] -1-methylpiperidine 10. .0 Glycerol 210. .5 Water 143, .0 Sodium citrate 4., 5 Polyvinyl alcohol 26. , 5 Polyvinylpyrrolidone 15., 5 Total 410., 0 mg Glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are mixed together by continuous stirring and maintaining the temperature at about 90 ° C. When the polymers are already in solution, the solution is cooled to about 50-55 ° C and the active ingredient is slowly mixed. The homogenous mixture is poured into the shapes made of an inert material to produce a diffusion matrix containing the drug having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Although 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 formulations can be administered by a variety of routes including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. For transdermal administration, a transdermal delivery device ("patch") is necessary. Such transdermal patches can be used to provide a continuous or discontinuous infusion of a compound of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Pat. No. 5,023,252, incorporated herein by reference. Such patches can be constructed for a continuous, pulsating, or on-demand supply of pharmaceutical agents.

Frequently, it would be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the placement of a catheter for the delivery of the drug into the host ventricular system to bypass or avoid the blood-brain barrier. One such implant delivery system, used for the transport of biological factors for specific anatomical regions of the body, is described in U.S. Pat. No. 5,011,472, which is incorporated herein for reference. The supply of hydroflucos drugs can be improved by the intra-arterial infusion of hypertonic solutions which can temporarily open the blood-brain barrier. A compound of the formula I is preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, in association with an appropriate pharmaceutical excipient as it was previously written. The active compounds are generally effective over a broad dosage range. For example, dosages per day normally fall within the range of about 0.0001 to about 30 mg / kg of body weight. In the treatment of adult humans, the range of from about 0.1 to about 15 mg / kg / day, in a single or divided dose, is especially preferred. However, it will be understood that the amount of the compound administered will actually be determined by the physician, taking into account the relevant circumstances, including the condition to be treated, the route of administration chosen, the compound or the actual compounds administered, the age , the weight, and the response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not proposed to limit the scope of the invention in any way. In some cases the dosage levels below the lower limit of the aforementioned range may be more appropriate, although in other cases even larger doses may be employed without causing any deleterious side effects, provided that such larger doses are first divided into several doses smaller for administration all day.

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 (18)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula I: or a pharmaceutical acid addition salt thereof, characterized in that; A is hydrogen, halo, -OR4, NH2, or -CF3; R is hydrogen, alkyl with C? -C4, alkenyl with C3-C?, Alkynyl with C? -s, or (alkyl with C? -C6) -ArA * R1 is -NH-R2-R3, hydroxy, -OS02Ar2, or NH2; Ar, Ar1, Ar2, Ar3, and Ar4 are optionally substituted phenyl or optionally substituted heteroaryl; R2 is -CO-, -CS-, or -S02-; R3 is hydrogen, alkyl with Ci-Ce optionally substituted with Ar3, -NR5R6, or OR5; provided that R3 is not hydrogen if R2 is either -CS- or -S02-; R 4 is hydrogen, optionally substituted C 1 -C 6 alkyl, or Ar; and R 5 and R 6 are independently hydrogen, optionally substituted C 1 -C 8 alkyl, or Ar 4; or R6 and R5 are combined, together with the nitrogen atom to which they are attached, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring; wherein the substituted phenyl is mono-substituted phenyl with a substituent selected from halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, alkyl with Ci-Cß, alkoxy with Ci-Ce, (alkyl with C1-C4) S (0) n, (C 1 -C 4) alkyl 2 amino, acyl with C 1 -C 4, or two or three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, alkyl with C 1 -C 4, and alkoxy with C? ~ C4; n is 0, 1, or 2; heteroaryl is a benzofused or aromatic aromatic or aromatic 5 or 6 membered ring containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; substituted heteroaryl is heteroaryl substituted with up to three substituents selected from the group consisting of halo, cyano, nitro, hydroxy, alkoxy with C? -C4, alkyl with C? -C4, (alkyl with Cx-C4) -S (0) n - and phenyl-S (0) n-; substituted alkyl is alkyl substituted from 1 to 3 times independently with a substituent selected from the group consisting of halo, hydroxy, phenyl, 2-phenylethylene-1-yl, diphenylmethyl, naphthyl, substituted phenyl, aryloxy, heterocycle, heteroaryloxy, alkenyl with C2 -C6, alkynyl with C2-C6, cycloalkyl with C3-C8, alkoxy with C? -C4, alkoxycarbonyl with C? ~ C4, phenyl (alkyl with C? ~ C4), phenyl (alkyl with C? -C4) substituted, and cycloalkyl with benzofused C4-C8; and heterocycle is a 5 or 6 membered aromatic or non-aromatic ring containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the ring is optionally benzofused and the ring or benzofused ring is optionally substituted with up to three substituents selected from the groups consisting of halo, alkoxy with C? ~ C, alkyl with Cj.-C, cyano, nitro, hydroxy, (alkyl with Ci-C4) -S (0) n-, and phenyl- S (0) n-.
2. 2. The compound according to claim 1, characterized in that A is hydrogen.
3. 3. The compound according to any of claims 1 or 2, characterized in that R is methyl.
4. 4. The compound according to any of claims 1-3, characterized in that Ri is -NH-R2-R3.
5. 5. The compound according to any of Claims 1-4, characterized in that R2 is C = 0.
6. 6. The compound according to any of Claims 1-5, characterized in that R3 is Ar3.
7. 7. The compound according to any of Claims 1-6, characterized in that Ar3 is 4-fluorophenyl.
8. 8. The compound according to any of Claims 1-6, characterized in that Ar3 is 4-fluorophenyl mono or disubstituted additionally.
9. 9. The compound according to any of Claims 1-6, characterized in that Ar3 is selected from the group consisting of 2-iodo-4-fluorophenyl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, 2 , 4-difluorophenyl, and 2-methyl-4-fluorophenyl.
10. 10. A pharmaceutical formulation, characterized in that it comprises a compound of formula 1 of claim 1, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier, diluent, or excipient.
11. 11. A process for the manufacture of the compounds of formula I (a): Ka) characterized in that R3 is hydrogen, alkyl with A-C, optionally substituted, Ar3, -NRÍJR6, or OR5; R and R are independently hydrogen, optionally substituted C 1 -C 8 alkyl, or Ar 4; or R6 and R5 combine, together with the nitrogen atom to which they are fixed, to form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thio orpholine ring. Ar3 and Ar4 are independently an optionally substituted phenyl or an optionally substituted heteroaryl; wherein the substituted phenyl is mono-substituted phenyl with a substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C? -C6 alkyl, Ci-C? alkoxy, (alkyl dC) S (0) n, amino (C 1 -C 4 alkyl) 2, c: L ± 0 of C 1 -C 4 or two or three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, Ci-C 4 alkyl and alkoxy from A - C4. n is 0.1 or 2; heteroaryl is a 5- or 6-membered aromatic or benzofused aromatic ring of 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; "substituted heteroaryl" is a heteroaryl substituted with more than three substituents independently selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, (d-C4 alkyl) -S (0) n -, and phenyl-S (0) n-; alkyl substituted is alkyl substituted from one to three times independently with a substituent selected from the group consisting of halo, hydroxy, phenyl, 2-phenylethylene-1-yl, diphenylmethyl, naphthyl, substituted phenyl, aryloxy, heterocycle, heteroaryloxy, C2-alkenyl C6, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, phenyl (C1-C4 alkyl), and benzofused C4-C8 cycloalkyl; heterocycle is a 5- or 6-membered aromatic or non-aromatic ring containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, such ring is optionally benzofused and such ring or benzofused ring is substituted with more than three substituents independently selected from the groups consisting of halo, C1-C4 alkoxy, Ci-C4 alkyl, cyano, nitro, hydroxy, (C1-C4 alkyl) -S (0) n-, and phenyl-S (0) n -; characterized in that it comprises: (a) protecting the 4-benzoylpiperidine hydrochloride to form an N-protected 4-benzoylpiperidine hydrochloride; (b) nitrate N-protected 4-benzoylpiperidine hydrochloride to form a mixture of N-protected 4- (mononitrobenzoyl) piperidines; (c) deprotecting the mixture of N-protected 4- (mononitrobenzoyl) -piperidines to form a mixture of 4- (mononitrobenzoyl) iperidines; (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 4- (3-aminobenzoyl) piperidine.
12. 12. The process according to claim 11, characterized in that steps a) and b) are combined.
13. 13. The process according to any of claims 11-12, characterized in that the source of the protecting group of step a) is trifluoroacetic anhydride.
14. 14. The process according to any of claims 11-13, characterized in that the nitronium ion is ammonium nitrate.
15. 15. The use of a compound of Formula I according to claim 1 for the manufacture of a medicament for activating 5-HT1F receptors in a mammal.
16. 16. The use of a compound of Formula I according to claim 1 in the manufacture of a medicament for inhibiting neuronal protein in a mammal.
17. 17. The use of a compound of Formula I according to claim 1 for the manufacture of a medicament for treating migraine.
18. 18. The use according to any of claims 15-17 wherein the mammal is human.