TH

PROCESSES FOR PREPARING NON-PEPTIDYL TACHYKININ RECEPTOR ANTAGONISTS

Priority Claim

This application claims the benefit of United States Provisional Patent Applications 60/009,003, filed December 21, 1995; 60/009,005, filed December 21, 1995; 60/009,004, filed December 21, 1995; 60/009,047, filed December 21, 1995; and 60/010,135, filed January 17, 1996.

Background of the Invention

Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.

Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See. J.E. Maggio, Peptides. 6 (Supplement 3):237-243 (1985) for a review of these discoveries.

Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.

The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.

Substance P is believed inter alia to be involved in the neuro transmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.

Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, gee, e,g„ S.L. Shepheard, et al„ British Journal of Pharmacology. 108:11-20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994).

In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability. Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,491,140, issued February 13, 1996; United States Patent 5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Publication 591,040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993; Canadian Patent Application 2154116, published January 23, 1996; European Patent Publication 693,489, published January 24, 1996; and Canadian Patent Application 2151116, published December 11, 1995.

United States Patent 5,530,009, issued June 25, 1996, describes a 1,2-diacylaminopropane for use in treating conditions associated with an excess of tachykinins. This patent also teaches processes for preparing this compound.

In essence, this invention provides processes for preparing a class of potent non-peptidyl tachykinin receptor antagonists similar to those of United States Patent 5,530,009. By virtue of their non-peptidyl nature, the compounds prepared by the processes of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.

Summary of the Invent on

This invention provides processes for preparing a compound of the formula

which comprises reacting a compound of the formula

with trityl chloride, N-methylmorpholine, and 1,1,1,3,3,3- hexamethyldisilazane, in the presence of acetonitrile.

This invention also provides processes for preparing a compound of the formula

which comprises reacting a compound of the formula

with N-methylmorpholine and 2-chloro-4,6-dimethoxy-l,3,5-triazine, in the presence of acetonitrile, and then adding 2-methoxybenzylamine. In yet another embodiment this invention provides novel processes for preparing a compound of the formula

which comprises reacting a compound of the formula

• 2 HC1

with a compound of the formula

and a haloformate, in the presence of a solvent, and then precipitating by the addition of oxalic acid.

In another embodiment this invention provides processes for preparing a compound of the formula

which comprises reacting a compound of the formula

I I

with water and hydrochloric acid.

Detailed Description and Preferred Embodiments

The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example "°C" refers to degrees Celsius; "N" refers to normal or normality; "mol" refers to mole or moles; "mmol" refers to millimole or millimoles; "g"

refers to gram or grams; "kg" refers to kilogram or kilograms; "L" refers to liter or liters; "ml" means milliliter or milliliters; "M" refers to molar or molarity; "MS" refers to mass spectrometry; and "NMR" refers to nuclear magnetic resonance spectroscopy. As used herein, the term "Ci-Cβ alkyl" refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term "Cj-Cβ alkyl" includes within its definition the term "C ₁ -C ₃ alkyl".

"Halo" represents chloro, fluoro, bromo or iodo.

The term "haloformate" as used herein refers to an ester of a haloformic acid, this compound having the formula

o

II x-c _N 0- R ^d

wherein X is halo, and R ^d is Ci-Cβ alkyl. Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein R ^d is C ₃ -C ₆ alkyl are especially preferred. Most preferred is isobutylchloroformate.

The compounds prepared in the processes of the present invention have an asymmetric center. As a consequence of this chiral center, the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.

The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second

lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.

In addition to the (R)-(S) system, the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.

Patent Cooperation Treaty Publication WO 95/14017, published May 26, 1995, teaches, inter alia, a series of tachykinin receptor antagonists of the formula

wherein: m and n are independently 0-6;

Z is -(CHR ) _p -(CHR ⁶ ) _q -, where,

p is 0 or 1;

q is 0 or 1; and

R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen and C1-C3 alkyl;

Y is

N-R ^a , or CH-NRbRc,

where R ^a , R ^b , and R ^c are independently selected from the group consisting of hydrogen and Ci-Cβ alkyl; and

R ¹ and R ² are independently hydrogen, halo, Ci-Cβ alkoxy, Ci-Cβ alkylthio, nitro, trifluoromethyl, or Ci- C ₆ alkyl;

or a pharmaceutically acceptable salt or solvate thereof. These compounds have been shown to be very active, specific tachykinin receptor antagonists. Particularly preferred compounds are those of Formula I in which m and n are both 1; R ¹ and R ² are independently hydrogen, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, methyl, and ethyl; Z is methylene; and Y, when combined with the heterocyclic group to which it is attached, forms 4-(piperidin-l-yl)piperidin-l-yl, 4- (cyclohexyl)piperazin-l-yl, 4-(phenyl)piperazin-l-yl, or 4- (phenyl )piperidin-l-yl.

Especially preferred is the compound (R)-3-(lH-indol-3-yl)-l- [N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-l-yl) piperidin-l- yl)acetyl)amino]propane and the pharmaceutically acceptable salts and solvates thereof. Most especially preferred is the compound (R)-3-(lH- indol-3-yl)-l-|^-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(p iperidin-l- yl)piperidin-l-yl)acetyl)amino]propane dihydrochloride trihydrate.

The most preferred method of synthesizing this compound is depicted in Scheme I, infra. Many of the steps of this synthesis are described in Patent Cooperation Treaty Publication WO 95/14017, published May 26, 1995, and European Patent Application Publication 693,489, to be published January 24, 1996.

(a)

wherein "Tr" refers to a trityl group, and "NMM" refers to N- methylmorpholine .

Scheme I (continued.

oxalic acid

The present invention describes novel processes for preparing the compounds depicted in Step (g), supra. The advantages of the present process (through an oxalate intermediate, which is then converted to the desired product) over those taught in the art include greater reproducibility, a resulting solid that is easy to handle in subsequent steps, and a greater yield. The prior art process for this acylation reaction directly yielded the dihydrochloride, trihydrate depicted in Step (g). The reproducibility of this reaction is not as great as that of the present invention and, therefore, did not lend itself to a commercial scale.

In the above process, the intermediate amides are reduced to amines using procedures well known in the art. These reductions can be performed using lithium aluminum hydride as well as by use of many other different aluminum-based hydrides. An especially preferred reagent employed in this reduction is RED-AL®, which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. Alternatively, the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usually required for this. Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especially useful in this reduction reaction.

The acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skilled in organic chemistry. One such reaction scheme is a substitution using an anhydride such as acetic anhydride. Another reaction scheme often employed to acylate a secondary amine employs a carboxylic acid preferably with an activating agent. An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine. Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents. One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.

Example 1

Preparation of (R)-3-(lH-indol-3-yl)-2-(N- triphenylmethylamino)propanoic acid, N-methylmorpholine salt (N- trityl-D-tryptophan N-methylmopholine salt).

To a one liter 4 neck flask equipped with mechanical stirrer, condensor, probe, and stopper, were added D-tryptophan (40.0 g, 0.196 mol), acetonitrile (240 ml), and 1,1,1,3,3,3-hexamethyldisilazane (39.5 g, 0.245 mol). The resulting mixture was heated to 50-60°C and stirred until homogeneous. In a separate beaker trityl chloride (60.06 g, 0.215 mol) and acetonitrile (120 ml) were slurried. The slurry was added to the silylated tryptophan mixture and the beaker was rinsed with 40 ml of acetonitrile. To the reaction mixture N-methylmorpholine (23.7 ml, 21.8 g, 0.216 mol) was added and the resulting mixture was stirred for one hour. The progress of the reaction was monitored by chr o mato graphy .

After satisfactory progress, water (240 ml) was added dropwise to the reaction mixture and the resulting mixture was cooled to less than 10°C, stirred for thirty minutes, and filtered. The residue was washed with water, and then dried to obtain 108.15 grams (>99% yield) of the desired title product.

-__ NMR (DMSO-de) δ 2.70 (m, IH), 2.83 (m, 2H), 3.35 (m, IH), 6.92-7.20 (m, 12H), 7.30-7.41 (m, 8H), 10.83 (s, IH), 11.73 (br s, IH). Analysis for C30H26 2O2:

Theory: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.47; H, 5.92; N, 6.10.

Exam le g

Preparation of (R)-3-(lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide.

To a two liter 4 neck flask equipped with mechanical stirrer, condensor, and thermocouple, under a nitrogen atmosphere, were added N-trityl-D-tryptophan N-methylmopholine salt (108.0 g, 0.196 mol), acetonitrile (800 ml), 2-chloro-4,6-dimethoxy-l,3,5-triazine (38.63 g, 0.22 mol), and N-methylmorpholine (29.1 ml). The resulting mixture was stirred at ambient temperature until homogeneous (about ten minutes). After about one hour, 2-methoxybenzylamine (29 ml) was added. The resulting mixture was heated to 35°C and maintained at that temperature overnight. The progress of the reaction was monitored by chromatography. Water (750 ml) was then added dropwise to the reaction mixture and the resulting mixture was cooled to less than 10°C, stirred for thirty minutes, and filtered. The residue was washed with water (about 100 ml), and then dried to obtain the desired title product. (Yield: 87% and 91% in two runs) FDMS 565 (M ⁺ ). *H NMR (CDC1 ₃ ) δ 2.19 (dd, J=6.4 Hz, Δυ=14.4 Hz, IH), 2.64 (d, J=6.5 Hz, IH), 3.19 (dd, J=4.3 Hz, Δυ=14.4 Hz, IH), 3.49 (m, IH), 3.63 (s, 3H), 3.99 (dd, J=5.4 Hz, Δυ=14.2 Hz, IH), 4.25 (dd, J=7.1 Hz, Δυ=14.2 Hz, IH), 6.64 (d, J=2.1 Hz, IH), 6.80 (d, J=8.2 Hz, IH), 6.91 (t, J=7.4 Hz, IH), 7.06-7.38 (m, 21 H), 7.49 (d, J=7.9 Hz, IH), 7.75 (s, IH). Analysis for C38H35N3O2: Theory: C, 80.68; H, 6.24; N, 7.43.

Found: C, 80.65; H, 6.46; N, 7.50.

Preparation C

Reduction of Carbonyl

Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]-2-(N- triphenylmethylamino)propane

RED-A ®. [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.

Pre aration P

Acylation of Secondary Amine

Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)-acetylamino]- 2-(N-triphenylmethylamino)propane

To a stirring solution of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0°C was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(lH-indol-3-yl)- l-[N-(2-methoxybenzyl)acetylamino]-2-(N- triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material. Analysis for C ₄₀ H ₃₉ N ₃ O ₂ :

Theory: C, 80.91; H, 6.62; N, 7.08.

Found: C, 81.00; H, 6.69; N, 6.94.

Preparation E

Deprotecrtion

Preparation of (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane dihydrochloride

A stirring solution of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane in two volumes of methylene chloride was cooled to between -40°C and -50°C. Anhydrous hydrogen chloride gas was added at such a rate that the

temperature of the reaction mixture did not exceed 0°C. The reaction mixture was stirred for 30 minutes to one hour at 0-10°C.

To this reaction mixture was added two volumes of methyl £-butyl ether and the resulting mixture was allowed to stir for 30 minutes to one hour at 0-10°C. The resulting crystalline solid was removed by filtration and then washed with methyl £-butyl ether. The reaction product was dried under vacuum at 50°C. (Yield >98%) Analysis for C ₂ 1H25N ₃ O2 • 2 HC1:

Theory: C, 59.44; H, 6.41; N, 9.90. Found: C, 60.40; H, 6.60; N, 9.99.

Preparation F

Preparation of 2-((4-cyclohexyl)piperazin-l-yl)acetic acid potassium salt hydrate

Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography. The organic fraction was separated and the aqueous phase was back-extracted with methylene chloride. The organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine. The organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yellowish oil.

The title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by

filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C. Analysis for C ₁₂ H2 ₁ KN2O ₂ • 1.5 H ₂ 0: Theory: C, 49.63; H, 7.98; N, 9.65.

Found: C, 49.54; H, 7.72; N, 9.11.

Preparation G

Preparation of (R)-2-[N-(2-((4-cyclohexyl)piperazin-l-yl)acetyl)amino]-3- (lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane

The title compound was prepared by first cooling 2-((4- cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.

To this mixture was then added (R)-2-amino-3-(lH-indol-3- yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride at such a rate that the temperature did not exceed 0°C. Next added to this mixture was N-methyl morpholine at a rate such that the temperature did not exceed 0°C. This mixture was then stirred for about 1 hour at a temperature between -15°C and -8°C.

The reaction was quenched by the addition of 5 volumes of water. The organic layer was washed once with a saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent. To the

filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol. The methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.

The final volume of isopropyl alcohol was then concentrated to three volumes by vacuum. The reaction mixture was cooled to 20°C to 25°C and the product was allowed to crystallize for at least one hour. The desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate. The crystal cake was then dried under vacuum at 50°C. MS 560 (M+l ⁺ ). *H NMR (CDC1 ₃ ) δ 1.09-1.28 (m, 5H), 1.64 (d, J=10 Hz, IH), 1.80-1.89 (m, 4H), 2.10 (s, 3H), 2.24-2.52 (m, 9H), 2.90 (s, 2H), 2.95 (d, J=7 Hz, IH), 3.02 (d, J=7 Hz, IH), 3.12 (dd, J=5, 14 Hz, IH), 3.77 (s, 3H), 4.01 (dd, J=10, 14 Hz, IH), 4.49 (ABq, J=17 Hz, 43 Hz, 2H), 4.56 (m, IH), 6.79-6.87 (m, 3H), 7.05-7.24 (m, 4H), 7.34-7.41 (m, 2H), 7.67 (d, J=8 Hz, IH), 8.22 (s, IH). Analysis for C ₃₃ H ₄ 5N5O ₃ :

Theory: C, 70.81; H, 8.10; N, 12.51.

Found: C, 70.71; H, 8.21; N, 12.42.

Preparation H

Preparation of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt

4-(Piperidin-l-yl)piperidine (1.20 kg, 7.13 mol) was added to methylene chloride (12.0 L) under a nitrogen atmosphere. Tetrabutylammonium bromide (0.150 kg, 0.47 mol) and sodium hydroxide (1.7 L of a 5 N solution, 8.5 mol) were then added. The reaction mixture was cooled to 10-15°C and methyl bromoacetate (1.17 kg, 7.65 mol) was added and the resulting mixture was stirred for a minimum of 16 hours. Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-l-yl)piperidin-l-yl)acetate.

A solution of methyl 2-[4-(piperidin-l-yl)piperidin-l- yl]acetate (2.395 kg, 9.96 mol) in methanol (2.4 L) was added to a solution of potassium hydroxide (0.662 kg, 10.0 mol @ 85% purity) in methanol

(10.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 45-50°C for a minimum of 16 hours.

A solvent exchange from methanol to acetone (15.0 L) was performed on the solution on a rotary evaporator. This solution was slowly cooled to room temperature over 16 hours. The resulting solids

were filtered, rinsed with acetone (5.0 L) and then dried to yield 2.471 kg (93.8%) of 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt. MS 265 (M ⁺¹ )

Preparation I

Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]- 2-[N-(2-(4-(piperidin-l-yl)piperidin-l-yl)acetyl)amino]propa ne dihydrochloride trihydrate

3 H ₂ 0

Under a nitrogen atmosphere 2-(4-(piperidin-l-yl)piperidin- l-yl)acetic acid, potassium salt (0.75 kg, 2.84 mol) was added to methylene chloride (7.5 L). The resulting mixture was cooled to -15 to -8°C and isobutyl chloroformate (0.29 kg, 2.12 mol) was added at such a rate so as to maintain the temperature of the reaction mixture below -8°C. After the addition the resulting reaction mixture was stirred for 90 minutes between -15 and -8°C. The reaction mixture was then cooled to -35°C and solid (R)-

2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]pro pane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C. After the addition, the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C. The reaction was quenched by the addition of deionized water (7.5 L). The reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium

hydroxide. The aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.

The two aqueous fractions were combined, back-extracted with methylene chloride (1.5 L) and then discarded. The organic fractions were combined and washed with deionized water (4 x 3.5 L). These extracts were combined, back-extracted with methylene chloride (1.5 L), and then discarded. The two organic layers were combined and washed with a saturated sodium chloride solution (3.7 L).

The organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator. An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes. Acetone (13.2 L) was then added and the slurry stirred for one hour. The resulting solid was then filtered, washed with acetone (2 x 1.4 L), and dried to yield 633 g (90%) of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-[ N- (2-(4-(piperidin-l-yl)piperidin-l-yl)acetyl)amino]propane dihydrochloride trihydrate.

Ex mple 3

Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]- 2-[N-(2-(4-(piperidin-l-yl)piperidin-l-yl)acetyl)amino]propa ne oxalate

Into a 500 ml jacketed round bottom flask was placed 2-(4- (piperidin-l-yl)piperidin-l-yl)acetic acid, potassium salt (25.0 g, 94.5 mmol) and 375 ml of N,N-dimethylformamide. The resulting slurry was cooled to -19°C and isobutylchloroformate (12.9 g, 94.5 mmol) was added over five minutes. The resulting mixture was stirred for twenty minutes and then (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane dihydrochloride (25.0 g, 58.1 mmol), dissolved in 75 ml of anhydrous N,N-dimethylformamide, was added over ten minutes.

The resulting mixture is then cooled to 0°C, stirred for about ten minutes, and then permitted to warm to room temperature. The progress of the reaction was monitored by chromatography. High performance liquid chromatography showed 99% conversion of the reactants after ninety minutes.

The reaction mixture was partitioned between ethyl acetate (375 ml) and a saturated sodium bicarbonate solution (375 ml). The aqueous layer was back extracted with 375 ml of ethyl acetate. The organic fractions were combined, washed with water (3 x 375 ml), and then dried over magnesium sulfate. Potassium hydroxide is then added to the aqueous fraction from above and this resulting basified solution is extracted with ethyl acetate. This organic fraction is then dried over magnesium sulfate.

The combined dried organic fractions are then treated with a concentrated oxalic acid solution. The resulting solids are filtered and dried at 50°C om a vacuum oven to yield 23.5 grams of the desired intermediate.

As would be appreciated by a skilled practitioner the mixed anhydride process will work in a number of organic solvents, in addition to the anhydrous N,N-dimethylformamide depicted above. Representative examples of solvents which may be employed include acetonitrile, tetrahydrofuran, dichloromethane. The mixed anhydride process can be performed at temperatures below 0°C.

The oxalate can be isolated from ethyl acetate as well as from other solvents, probably including acetone, acetonitrile, and t -butyl methyl ether. The use of oxalic acid is, however, very important for the precipitation as a large number of acids do not give a precipitate. Among those acids attempted, but found not satisfactory for the processes of the present invention, are citric, anhydrous hydrochloric, tartaric, mandelic, trifluoroacetic, p-nitrobenzoic, phenoxyacetic, maleic, fumaric, glutaric, adipic, methanesulfonic, p-toluenesulfonic, pamoic, trans-l,2-cyclohexane dicarboxylic, succinic, phthalic, trans- l,2-diaminocyclohexane-N,N,N',N'-naphthalenedisulfonic, and 5- sulfosalicylic acids. Only oxalic acid and 1,5 -naphthalene disulfonic acid reproducibly produced a solid.

Ex m le 4

Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]- 2-[N-(2-(4-(piperidin-l-yl)piperidin-l-yl)acetyl)amino]propa ne dihydrochloride trihydrate

^• HC1 ^{* 3 H} 2θ

Into a flask were added (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-l-yl)piperi din-l- yl)acetyl)amino]propane oxalate (3.31 g, 4.22 mmol), methylene chloride (30 ml, 39.75 g), and water (30 ml). The resulting mixture was stirred and the pH of the reaction mixture was adjusted to 10-12 using 50% caustic.

The phases were separated and the aqueous phase was extracted with methylene chloride (20 ml) and separated. The combined

organic fractions were back extracted with water (30 ml) and dried over magnesium sulfate. The methylene was removed on an evaporator, leaving a residue. This residue was transferred to a jacketed flask and dissolved into acetone (24 g, 10.25 volumes). Enough water was added to bring the water concentration to eleven percent (by weight) and the resulting mixture was heated to 55°C. Enough concentrated hydrochloric acid was added to lower the pH to 2.0 and the reaction mixture was then permitted to cool to 37°C over 45 minutes. The product solution was seeded and permitted to stir for

10-30 minutes. The product solution was cooled to 19°C over two hours and acetone (11.8 equivalent volumes) was added over three hours, after which time the reaction mixture was stirred for one to three hours, maintaining the temperature at 19°C. The product solution was filtered and the residue was washed with 10.2 equivalents (by volume) of acetone. The residue was then dried in a vacuum oven at 42°C to give the desired title product. Yield 2.407 grams (80.7%).

The compounds prepared by the processes of the present invention are useful as tachykinin receptor-binding compounds. As such, they may be employed as antagonists or agonists of the various tachykinins. These compounds are, therefore, useful in the treatment or prevention of conditions associated with an excess or deficiency of tachykinins. The term "physiological disorder associated with an excess or deficiency of tachykinins" encompasses those disorders associated with an inappropriate stimulation of tachykinin receptors, regardless of the actual amount of tachykinin present in the locale.

These physiological disorders may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post- herpetic and other neuralgias; acute and chronic obstructive airway

diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculo-skeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; atherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine, and Reynaud's disease; emesis; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example the compounds of Formula I may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for

example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.

The results of several experiments demonstrate that many of the compounds of Formula I are selective tachykinin receptor antagonists. These compounds preferentially bind one tachykinin receptor subtype compared to other such receptors. Such compounds are especially preferred.

For example, NK-1 antagonists are most especially preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, sunburn pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.

In addition to pain, NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; atherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.

NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.

In addition to the in vitro binding assays described supra, many of the compounds prepared by the processes of the present invention have also been tested in in vivo model systems for conditions associated with an excess of tachykinins. Of those compounds tested in vivo many have shown efficacy against said conditions.