HK1078561B - Novel compounds, their use and preparation - Google Patents

Description

Novel compounds, their use and process for their preparation

The application is a divisional application of Chinese patent application No.98803764.5, with the application date being 26/3/1998 and the priority date being 27/3/1997.

Technical Field

The present invention relates to novel therapeutically active compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the preparation of medicaments.

Background

WO 89/06644 and WO94/11337 disclose tertiary 3, 3-diphenylpropylamines having anticholinergic activity, in particular for the treatment of urinary incontinence. SE-A-215499 discloses secondary 3, 3-diphenylpropylamines having a promoting effect on the heart and blood circulation. U.S. Pat. No. 3,446,901, GB-A-1,169,944 and GB-A-1,169,945 disclose 3, 3-diphenylpropylamines having antidepressant activity. DE-B1-1216318 discloses the preparation of diphenylalkylamines having an effect on the heart and blood circulation.

Summary of The Invention

According to the present invention, novel therapeutically active diarylpropylamines have been found which, like the 3, 3-diphenylpropylamines disclosed in the above-mentioned WO 89/06644 and WO94/11337, have good anticholinergic activity and are therefore also useful for controlling acetylcholine-mediated physiological activities, such as urination.

In one aspect, the present invention provides novel compounds of formula I, and salts thereof with physiologically acceptable acids, and where optical isomers of such compounds may exist, racemic mixtures and individual enantiomers thereof:

wherein:

R¹is hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, amino, alkylcarbonylamino, alkylcarbonyloxy or halogen;

R²and R³Independently hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, halogen, alkoxycarbonylalkyl, carbamoyl or aminosulfonyl;

R⁴is ω -hydroxyalkoxy, ω -aminoalkoxy, ω -aminoalkylamino, alkoxyalkyl, hydroxyalkoxyalkylaminoalkyl, dihydroxyalkyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, carbamoylalkyl, carboxamidoalkyl, carboxy, amino, nitro, cyano, nitrilo, cyanoalkyl, azido, alkyl of at least 2 carbon atoms, alkoxy of at least 2 carbon atoms or hydroxyalkyl of at least 2 carbon atoms;

R⁵is hydrogen, halogen or alkyl;

ar is aryl or heteroaryl which may be substituted once or independently twice with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, hydroxyalkyl, halogen, alkoxycarbonylalkyl, carbamoyl and sulfamoyl; and

R⁶and R⁷Are identical or different hydrocarbon radicals which together contain at least 3 carbon atoms and bear one or more hydroxyl groups, where the carbon atoms may be linked to one another by oxygen atoms, and where R⁶And R⁷May form a ring together with the nitrogen atom on the amine;

with the following conditions: (a)

(i) when R is²、R³And R⁵When at least 2 of them are not hydrogen atoms, or

(ii) When R is¹Not hydroxy or methoxy and Ar is not phenyl which is ortho-substituted by hydroxy or methoxy, or

(iii) When Ar is heteroaryl, or

(iv) When R is⁶And R⁷When at least one is an aromatic or cycloalkyl group, then R⁴Or hydrogen atom, methyl, methoxy, hydroxy, hydroxymethyl, halogen, carbamoyl or aminosulfonyl;

and (b) when Ar is unsubstituted phenyl, then R¹、R²、R³、R⁴And R⁵Not all hydrogen atoms.

In another aspect of the invention there is provided a compound having the general formula I above for use in the treatment, in particular in the treatment of urinary incontinence related disorders.

In a further aspect of the invention, there is provided a pharmaceutical composition comprising one or more compounds of formula I as described above as active ingredients, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmaceutically active agents.

In a further aspect of the invention there is provided a method of treating a patient (animal, including human) suffering from a condition associated with urinary incontinence, which method comprises administering to the patient an effective amount of a compound of formula I as described above.

In a further aspect the present invention provides compounds of formula I for use as pharmaceutically active substances, in particular as anticholinergic agents.

In another aspect, the present invention provides the use of a compound of formula I as described above for the manufacture of a medicament for the treatment of a disorder associated with urinary incontinence.

In a further aspect of the invention there is provided a process for the preparation of a compound of formula I as hereinbefore described.

Detailed Description

The present invention includes novel 3, 3-diarylalanines and pharmaceutically acceptable salts thereof that are characterized by formula I above and that are useful as anticholinergic agents. The compounds are particularly useful for treating urinary incontinence.

A subset of the compounds of formula I are defined as follows: substituent R⁴Is ω -hydroxyalkoxy, ω -aminoalkoxy, ω -aminoalkylamino, alkoxyalkyl, hydroxyalkoxyalkylaminoalkyl, dihydroxyalkyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, carbamoylalkyl, carboxamidoalkyl, carboxy, amino, nitro, cyano, nitrilo, cyanoalkyl or azido.

This subclass has a class of compounds, wherein R¹Is hydrogen or methyl, R²、R³And R⁵Or both are hydrogen, or R²、R³And R⁵One of which is methyl, methoxy, hydroxy, carbamoyl, aminosulfonyl or halogen and the others are hydrogen, Ar is phenyl or phenyl mono-or independently di-substituted with the following substituents methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen.

Another subclass of compounds of formula I is defined as where Ar is heteroaryl.

This subclass has a class of compounds, wherein R¹Is hydrogen or methyl, R²、R³、R⁴And R⁵Or both are hydrogen, or R²、R³、R⁴And R⁵One of which is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen and the remainder are hydrogen.

Yet another subclass of compounds of formula I is defined below: r¹Is hydrogen, alkyl, hydroxyalkyl, trifluoromethyl, amino, alkylcarbonylamino, alkylcarbonyloxy or halogen. Preferably, Ar is not phenyl substituted ortho-position with hydroxy or alkoxy.

Within this subclass is a group of compounds wherein R¹Is hydrogen or methyl, R²、R³、R⁴Or both are hydrogen, or R²、R³、R⁴And R⁵One of which is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen and the remainder is hydrogen, Ar is phenyl or phenyl which is substituted once or, independently, twice by methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen.

Another subclass of compounds of formula I is defined below: r⁶And R⁷At least one of which is an aromatic hydrocarbon group, a cycloalkyl group or a hydrocarbon chain in which carbon atoms are connected to each other at one or more positions by oxygen atoms.

Within this subclass is a group of compounds wherein R¹Is hydrogen or methyl, R²、R³、R⁴And R⁵Or both are hydrogen, or R²、R³、R⁴And R⁵One of which is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen and the remainder is hydrogen and Ar is phenyl or phenyl substituted once or independently twice by methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen.

In the compounds of the formula I, the "alkyl" used alone or in combination is preferably C_1-8Alkyl, i.e. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof, more preferably C_1-6Alkyl, especially C_1-4An alkyl group.

Similarly, "alkoxy" used alone or in combination is preferably C_1-8Alkoxy, i.e. methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof, more preferably C_1-6Alkoxy, especially C_1-4An alkoxy group.

"aryl" means phenyl or naphthyl. "heteroaryl" means a 5-or 6-membered heteroaromatic ring having 1 to 3 heteroatoms, which ring may be fused to an aromatic carbocyclic ring, such as a benzene ring. Examples of heteroaryl groups are morpholinyl, thienyl, furyl, piperazinyl, piperidinyl, imidazolinyl, pyrazolinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

"halogen" includes fluorine, chlorine, bromine and iodine.

When the aryl group is mono-substituted, it is preferably substituted in the 2-position. When the aryl group is disubstituted, it is preferably substituted in the 2 and 4 positions. Preferred substituents are methyl, methoxy, hydroxy, hydroxymethyl, halogen, alkoxycarbonylalkyl, carbamoyl and sulfamoyl, especially methyl, hydroxymethyl and halogen. Aryl is preferably phenyl.

Preferred heteroaryl groups are thienyl, pyrrolyl, thiazolyl, oxazolyl, methylthiazolyl and methylpyrrolyl.

R¹Preferably hydroxy, halogen, trifluoromethyl, amino, methoxy or hydroxymethyl,

R²And R³Preferably selected from hydrogen, hydroxy and methoxy.

R⁴Preference is given to hydrogen, formyl, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl, carboxamidoalkyl, carbamoylalkyl, aminoalkyl, amino, azido, cyanoalkyl, carboxyl or carboxyalkyl. R⁴More preferred is hydrogen, formyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ethoxymethyl, methoxycarbonyl, amino, aminopropyl, acetyl, 1, 2-hydroxyethyl, ethylaminomethyl or hydroxyethoxyethylaminoethyl.

R⁵Hydrogen is preferred.

R⁶And R⁷Independently of one another, are preferably saturated hydrocarbon radicals, in particular saturated aliphatic hydrocarbon radicals, e.g. C_1-8Alkyl, especially C_1-6Alkyl or adamantyl, R⁶And R⁷Together containing at least 3, preferably at least 4 carbon atoms. R⁶And R⁷May carry 1 or more hydroxyl groups, and R⁶And R⁷May form a ring together with the nitrogen atom. Preferably R⁶And R⁷At least one of which comprises a branched carbon chain.

NR⁶R⁷Examples of radicals are diethylamino, diisopropylamino, methyl-tert-butylamino, methyl-tert-pentylamino, piperidino, 2, 6, 6-tetramethylpiperidino, methylcyclobutylamino, methylcyclopentylamino, methylcyclohexylamino, methylcycloheptylamino, pyrrolidin-1-yl, 2, 5, 5-tetramethylpyrrolidin-1-yl, N-methyl-N-adamantylamino, especially diisopropylamino.

Representative compounds of formula I are:

n, N-diisopropyl-3- (2-fluorophenyl) -3-phenylpropylamine hydrochloride,

n, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- (2-hydroxy-5-methoxycarbonylphenyl) -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- (5-acetyl-2-hydroxyphenyl) -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropanamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (1-hydroxyethyl) phenyl ] -3-phenylpropanamine, and its 3(R) -isomer,

n, N-diisopropyl-3 (R) - [ 5- (1 (R) ]^*) 2-dihydroxyethyl) -2-hydroxyphenyl ] -3-phenylpropylamine and 1 (S) thereof^*) -an isomer of (I) or (II),

n, N-diisopropyl-3- [ 2-hydroxy-5- (6-hydroxyhexyl) phenyl ] -3-phenylpropanamine, and its (R) -isomer,

n, N-diisopropyl-3- [ 5-ethoxymethyl-2-hydroxyphenyl ] -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 5- (3-aminopropyl) -2-hydroxyphenyl ] -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 5- (3-acetamidopropyl) -2-hydroxyphenyl ] -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 5- (2-cyanoethyl) -2-hydroxyphenyl ] -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- (5-amino-2-hydroxyphenyl) -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- (5-azido-2-hydroxyphenyl) -3-phenylpropylamine, and the (R) -isomers thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (3-hydroxypropyl) phenyl ] -3-phenylpropylamine, and the (R) -isomers thereof,

N-cyclobutyl-N-methyl-3- (2-hydroxyphenyl) -3-phenylpropylamine

N, N-diisopropyl-3- (2-hydroxyphenyl) -3- (2-thienyl) propylamine,

n, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3- (2-thienyl) propanamine, and the (R) -isomers thereof.

According to the invention, the compounds of the formula I can be prepared by known methods, in particular

a) Reacting a compound of formula II

Wherein R is¹To R⁵And Ar is as defined above for compounds of formula I, Y is a leaving group, with an amine HNR⁶R⁷Reaction of wherein R⁶And R⁷As defined above; or

b) Reduction of a compound of formula III

Wherein R is¹To R⁷And Ar is as defined for compounds of formula I and any of the hydroxy groups may be protected; or

c) N-alkylation of secondary amines of the formula IV

Wherein R is¹To R⁵And Ar is as defined for compounds of formula I; and any hydroxyl group may be protected, wherein Z is as defined for R⁶And R⁷The same; or

d) Reduction of compounds of formula Va or Vb

Wherein R is¹To R⁷And Ar is as defined for compounds of formula I and any of the hydroxy groups may be protected, W represents hydroxy or halogen; or

e) R in the compound of formula VI¹a is converted into a hydroxyl group, and the hydroxyl group,

wherein R is²To R⁷And Ar is as defined for the compound of formula I, and R¹a is carboxy or alkoxy; or

f) Reducing the alkenyl group in the compound of formula VII to an alkyl, hydroxyalkyl or dihydroxyalkyl group,

wherein R is¹、R⁶、R⁷And Ar is as defined for the compound of formula I, and R²b to R⁵One of b is alkenyl and the remainder is as defined above for R²To R⁵The definition of (1); or

g) The compound of the formula I is shown in the specification, wherein R is¹To R⁵To R, into one or more substituents of¹To R⁵The other substituents in (1); or

h) Reacting a compound of formula VIII

Wherein R is¹To R⁷As defined for compounds of formula I and X is oxygen or sulfur, with compounds of formula IX

CH₃N≡C： IX

To form a compound of formula Ia

Wherein R is¹To R⁷And X is as defined above; or

i) Reacting a compound of formula VIII as described above, wherein X is oxygen, with a compound of formula X

To form a compound of formula Ib

Wherein R is¹To R⁷As defined for compounds of formula I; or

j) Reacting a compound of formula XI

Wherein R is¹To R⁷As defined for compounds of formula I, to compounds of formula XII

Wherein R is¹To R⁷As defined for compounds of formula I; or

k) Reacting a compound of formula XIII

Wherein R is¹To R⁷As defined for compounds of formula I and X is oxygen or sulfur, into compounds of formula XIV

Wherein R is¹To R⁷And X is as defined for the compounds of formula I, and R⁸And R⁹Each is hydrogen or alkyl; and is

i) If necessary, removing the hydroxyl protecting group from the resulting compound;

ii) if desired, converting the base of the formula I prepared into its salts, and vice versa, using a physiologically acceptable acid; and/or

iii) if desired, separating the resulting mixture of optical isomers into the individual enantiomers.

Suitable reaction conditions for the above reaction can be readily selected by those skilled in the art by referring to similar known methods and suitable conditions of the following specific examples. The necessary starting materials are known or prepared by reference to known methods of preparation of compounds.

The separation of the mixture of optical isomers into the individual enantiomers in accordance with ii) above can be carried out, for example, by fractional crystallization of a salt thereof with a chiral acid or by chromatography on a chiral column.

Depending on the pharmaceutical method used, the compounds of the formula I according to the invention, in free base form or in salt form with physiologically acceptable acids, can be formulated into suitable pharmaceutical forms, for example compositions for oral, parenteral or nasal spray. Such pharmaceutical compositions of the invention comprise an effective amount of a compound of formula I, together with a compatible and pharmaceutically acceptable carrier or diluent. The carrier may be any inert organic or inorganic substance suitable for enteral, transdermal or parenteral administration, for example, water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmaceutically active substances, and customary additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, and the like.

For example, the compositions of the present invention may be formulated in solid or liquid forms for oral administration, such as tablets, capsules, powders, syrups, elixirs and the like, and for parenteral administration, such as sterile solutions, suspensions, emulsions and the like.

The compounds and compositions described above may be used for the same therapeutic indications as the compounds of WO 89/06644 or WO94/11337 described above, i.e. for the treatment of acetylcholine-mediated diseases, such as urinary incontinence, in particular urinary incontinence. The dosage of a particular compound will vary with its strength, the mode of administration, the age and weight of the patient, and the severity of the condition being treated. For example, the daily dose may be from about 0.01mg to about 4mg per kg body weight, in a single administration or in multiple administrations of about 0.05mg to about 200mg per kg body weight.

The invention is further illustrated by the following non-limiting examples and pharmacological tests.

General theory

NMR data were obtained from a Joel JNM-EX 270 or Varian Unity 500 spectrometer. Spectra were recorded at 30 ℃ with Tetramethylsilane (TMS) as an internal standard. The infrared spectra were recorded using a Perkin-Elmer model 841 spectrophotometer. Uncorrected melting points were determined using a Koeffler apparatus. Gas chromatography was performed using HP5940 equipped with a 10m HP-1 column and the furnace temperature was heated in a linear temperature gradient mode. Quenching the lithium aluminum hydride reduction reaction was carried out by the V.Micovic and M.Mihailvic methods (J. org. chem.)18，1190(1953))。

Example 1

N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine hydrochloride

A solution of N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine (2.75g, 7mmol) in THF (40ml) was added to lithium aluminum hydride (LAH, 0.50g, 13mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction was quenched and the solvent was evaporated. The residue is chromatographed on silica gel (toluene: triethylamine 19: 1). The title compound was crystallized by dissolving the free amine in diethyl ether and adding a solution of hydrogen chloride in diethyl ether. Yield 0.75g (27%); melting point is 70-75 ℃;

¹HNMR(DMSO-d6)δ 1.17(q，3H)，1.23(t，3H)，2.18(d，3H)，2.47(m，2H)，2.84-3.07(m，2H)，3.15(m，1H)，3.37(m，1H)，3.42(d，2H)，3.46(s，2H)，3.67(m，1H)，3.74(m，2H)，4.30(m, 1H), 4.76(br, 1H), 6.71(d, 1H), 6.80(d, 1H), 7.06(d, 1H), 7.1.6(t, 1H), 7.27(t, 2H), 7.33(d, 2H), 9.29(d, 1H) and 10.07(br, 1H) · (C, 1H)₂₃H₃₃NO₃·HCl)C，H，N·

The starting compound N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamide was prepared as follows:

1.1 trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylic acid

A solution of triethyl phosphonoacetate (22.4g, 0.10mol) in THF (150ml) was added to sodium hydride (80%, 2.7g, 0.09mol) over 15 minutes under a nitrogen atmosphere. The resulting mixture was refluxed for 15 minutes, then 2-benzyloxy-5-methyl-benzophenone (15.1g, 0.25mol) in THF (50mL) was added and most of the THF was distilled off. Ethanol was added until the solution became clear and refluxing continued for several minutes. Water was added to make the total volume 1 liter, and the mixture was washed with diethyl ether. Hydrochloric acid was added to the aqueous phase to obtain crystals. The pure trans isomer was prepared from ethanol by crystallization. Yield 10.4g (60%).

¹H NMR (DMSO-d6) Δ 2.24(s, 3H), 4.92(s, 2H), 6.41(s, 1H), 6.87(d, 1H), 6.98(d, 1H), 7.03(m, 2H)7.12(m, 1H), 7.22(m, 3H), 7.29(m, 1H), 7, 30(m, 1H) and 7.33-7.39(m, 3H).

1.2 Trans-N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide

DCC (5.2g, 17mmol) in THF (20mL) was added to a solution of trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylic acid (6.9g, 20mmol), 2- (2-isopropylaminoethoxy) -ethanol, triethylamine (2.5g, 25mmol) and hydroxysuccinimide (2.8g, 24mmol) in THF (50 mL). The reaction mixture was stirred for 20 hours. The solvent was evaporated and the residue was chromatographed on silica gel (using a gradient from toluene to ethyl acetate). Yield 5.9g (62%).

1.3 Trans-N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamide

A solution of trans-N- (5-hydroxy-3-oxopentyl) -N-isopropyl-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide (5.9g, 12mmol) in acetic acid (50mL) was hydrogenated over 16h with Pd/C (10%, 0.5g), filtered, and the solvent evaporated, leaving a residue which was chromatographed on silica gel (ethyl acetate) yield 2.83 (61%).

Example 2

N-cycloheptyl-N-methyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine hydrochloride

A solution of N-cycloheptyl-N-methyl-3- (2-hydroxy-5-methylphenyl) -3-hydrocinnamamide (0.93g, 2.5mmol) in THF (20mL) was added to LAH (0.22g, 5.6mmol) and the mixture was stirred at reflux temperature for 30 min. The reaction was quenched and the solvent was evaporated. The residue was chromatographed over silica gel (chloroform: methanol, 9: 1). Dissolving the free amine in ether, and adding ether containing hydrogen chloride to obtain amine salt. Yield 0.45g (46%); the melting point is 230 ℃ and 232 ℃.¹H NMR (DMSO-d6) delta 1.27-1.70(m, 10H), 1.88(br, 1H), 2.05(d, 1H), 2.17(s, 3H), 2.42(br, 1H), 2.60(s, 3H), 2.85(br, 2H), 3.34(m, 1H), 4.30(t, 1H), 6.72(d, 1H), 6.80(dd, 1H), 7.05(br, 1H), 7.15(t, 1H), 7.27(t, 2H), 7.31(d, 2H), 9.31(s, 1H) and 10.53(br, 1H) (C, 1H)₂₄H₃₃NO·HCl)C，H，N.

The starting compound N-cycloheptyl-N-methyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamide is prepared as follows:

2.1N-cycloheptyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylpropionamide

DCC (5.2g, 25mmol) in THF (50mL) was added to a solution of trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylic acid (example 1.1, 6.9g, 20mmol), cycloheptylamine (2.6g, 23mmol), triethylamine (2.0g, 20mmol) and hydroxysuccinimide (2.4g, 21mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 1 hour. Another portion of cycloheptylamine (1.3g) was added and the reaction mixture was stirred for an additional 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ether and washed sequentially with hydrochloric acid (1M), water and brine. After evaporation of the solvent, the residue was crystallized from toluene-hexane to give 7.3g (83%) of the product.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.25-1.74(m, 10H), 2.30(s, 3H), 3.83(m, 1H), 4.95(s, 2H), 5.50(d, 1H), 6.49(s, 1H), 6.90-7.08(m, 4H), and 7.12-7.44(m, 9H).

2.2N-cycloheptyl-N-methyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide

A solution of N-cycloheptyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide (4.4g, 10mmol) and methyl iodide (4g, 30mmol) in DMF (10mL) was added to sodium hydride (80%, 1.2g, 40mmol) at room temperature, and the mixture was stirred for 60 minutes. Methanol was added to destroy excess sodium hydride and the mixture was then partitioned between toluene and water. The organic layer was dried (MgSO₄) And the solvent was evaporated. The residue was crystallized from toluene-hexane to give 4.4g (97%).¹H NMR(CDCl₃) (almost 1: 1 mixture of geometric isomers)

δ 1.20-1.80(m, 12H), 2.30(m, 3H)2.61(s, 1.5H), 2.71(s, 1.5H), 3.93(m, 0.5H), 4.46(m, 0.5H), 4.81(m, 1H), 6.43(m, 1H), 6.81(m, 2H) and 7.08-7.35 (m, 10H).

2.3N-cycloheptyl-N-methyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropionamide

A solution of N-cycloheptyl-N-methyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylpropionamide (3.15g, 7mmol) in acetic acid (40mL) was hydrogenated over Pd/C (10%, 0.2g) for 72 h. The reaction mixture was filtered and the solvent was evaporated. The residue was chromatographed on silica gel (toluene: ethyl acetate, 9: 1). Yield 0.95g (37%).

¹H NMR(CDCl₃)δ 1.26-1.98(m，12H) 2.02(s, 3H), 2.12(s, 3H), 2.28(m, 1H), 2.52(m, 1H), 2.71(m, 1H), 4.36(dd, 1H), 6.39(s, 1H), 6.76(s, 2H), 7.15(m, 2H) and 7.25(m, 5H).

Example 3

N-cyclohexyl-N-methyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine hydrochloride

A solution of N-cyclohexyl-N-methyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide (4.0g, 9mmol) in THF (90mL) was added to LAH (0.50g, 13mmol) in THF (5mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction was quenched and the solvent was evaporated. The resulting oil was hydrogenated in acetic acid (70mL) over Pd/C (10%, 1g) for 20 h. After filtration and evaporation of the solvent, the residue was chromatographed on silica gel (chloroform: methanol, 99: 1). The free amine was dissolved in diethyl ether and hydrogen chloride in diethyl ether was added. Yield 1.2g (36%); melting point 179-.

¹H NMR (DMSO-d6) delta 1.05(m, 1H), 1.21-1.38(m, 4H), 1.51(d, 1H), 1.74(br, 2H), 1.86(br, 1H), 2.00(d, 1H), 2.17 and 2.19(s, 3H), 2.39-2.56(m, 2H), 2.63(m, 3H), 2.82(m, 1H), 2.93(m, 1H), 3.17(m, 1H), 4.32(q, 1H), 6.73 and 6.75(d, 1H), 6.79 and 6.81(t, 1H), 7.02 and 7.10(d, 1H), 7.14-7.18(m, 1H), 7.25-7.29(m, 2H), 7.33(t, 2H), 9.34(br, 1H), and 10.78 (c.78)₂₃H₃₁NO·HCl)C，H，N.

The starting compound N-cyclohexyl-N-methyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide was prepared as follows:

3.1N-cyclohexyl-N-methyl-trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylamide

DCC (5.2g, 25mmol) in THF (50mL) was added to a solution of trans-3- (2-benzyloxy-5-methylphenyl) -3-phenylacrylic acid (example 1.1, 6.9g, 20mmol), N-methyl-cyclohexylamine (2.6g, 23mmol), triethylamine (2.0g, 20mmol) and hydroxysuccinimide (2.4g, 21mmol) in THF (50 mL). Stirring the mixtureThe mixture should be allowed to stand for 2 hours. A second portion of DCC (2.5g, 13mmol) and N-methyl-cyclohexylamine (1.5g, 13mmol) was added and the reaction mixture was allowed to stir for 16 hours. Diethyl ether and hydrochloric acid (1M) were added and the organic phase was washed with brine. The organic layer was evaporated and the residue was chromatographed on silica gel (toluene: ethyl acetate 9: 1). Yield 5.5g (63%).¹H NMR(DMSO-d₆) (approximately 1: 1 mixture of geometric isomers)

δ 0.88-1.06(m, 2H), 1.16-1.39(m, 5H), 1.55(t, 2H), 1.67(br, 1H), 2.21(s, 1.5H), 2.23(s, 1.5H), 2.56(s, 1.5H), 2.67(s, 1.5H), 3.67(m, 0.5H), 4.05(m, 0.5H), 4.82(s, 1H), 4.85(s, 1H), 6.57(s, 0.5H), 6.59(s, 0.5H), 6.84(dd, 1H), 6.87(d, 0.5H), 6.89(t, 1H), 6.95(dd, 1H), 6.98(d, 0.5H), 7.12(dd, 1H), 7.17(m, 3H), 7.27(m, 27H), and 2.32 (m, 3H).

Example 4

N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylpropylamine hydrochloride

borane-SMe in THF (7mL, 14mmol)₂The composite was gently refluxed for 30 minutes under a weak stream of nitrogen. N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylpropionamide (1.55g, 4.2mmol) was added to the refluxed solution, and the reflux was continued for 1 hour. The reaction mixture was partitioned between ether and sodium hydroxide (1M). The solvent of the organic layer was evaporated. The residue was chromatographed on silica gel (toluene: triethylamine 9: 1) to give the free amine. The free amine was dissolved in ether and a solution of hydrogen chloride in ether was added to give the hydrochloride salt, and the resulting oil was stirred in ether several times to give crystals. Yield 0.39g (23%); melting point 143-.

¹H NMR (DMSO-d6) delta 1.19(q, 6H), 1.25(dd, 6H), 2.53(m, 1H), 2.70(m, 1H), 2.87(m, 2H), 3.59(m, 2H), 4.38(t, 1H), 7.24(t, 1H), 7.35(t, 2H), 7.39(d, 2H), 7, 45(t, 1H), 7.68(t, 1H), 7.74(t, 2H) and 10.25(br, 1H) analysis₂₂H₂₈NF₃·HCl)C，H，N·

The starting compound N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylpropanamide is prepared as follows:

4.1N, N-diisopropylacetamide phosphoric acid diethyl ester

A mixture of triethyl phosphite (23g, 0.14mol) and N, N-diisopropyl-2-bromoacetamide (29g, 0.13mol) was heated to 110 deg.C and reacted for 3 hours to yield 35g (97%) of product. The product was used without purification.

4.2N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylacrylamide

A solution of diethyl N, N-diisopropylacetamide phosphate (8.4g, 30mmol) in THF (20mL) was added dropwise to sodium hydride (80%, 0.85g, 29mmol) over 30 minutes, maintaining the temperature below 30 ℃. A solution of 2-trifluoromethyl-benzophenone (5.0g, 20mmol) in THF (20mL) was added and the reaction mixture was heated to 50 deg.C and maintained at this temperature for 16 h. The second phosphorus ylide (15mmol) prepared above was added. After 24 hours of reaction at 50 ℃, the mixture was partitioned between ether and water. The ether layer was evaporated and the residue was chromatographed on silica gel (toluene: ethyl acetate 9: 1) to give 3.0g (41%) of a mixture of E-and Z-isomers. The symbols a and b represent different isomers.¹H NMR(CDCl₃-d) δ 0.80(d, 6Ha), 1.08(d, 3Hb), 1.24(t, 6Hb), 1.31(d, 3Hb), 1.44(d, 6Ha), 3.32(m, 1Ha), 3.34(m, 1Hb), 4.19(m, 1Hb), 4.32(m, 1Ha), 6.04(s, 1Ha), 6.65(s, 1Hb), and 7.18-7.75(m, 9Ha, 9Hb).

4.3N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylpropanamide

A solution of N, N-diisopropyl-3- (2-trifluoromethylphenyl) -3-phenylacrylamide (2.95g, 8.1mmol) in ethanol (50mL) was hydrogenated with Pd/C (10%, 300mg) at normal pressure for 24 hours. The catalyst is filtered off, part of the solvent is evaporated and the product is recovered after crystallization. Yield 1.78g (60%).

¹H NMR(CDCl₃D) δ 1.16(m, 6H), 1.30(m, 6H), 2.86(dd, 1H), 3.11(dd, 1H), 3.41(m, 1H), 4.03(m, 1H), 5.12(m, 1H) and 7.10-7.78(m, 9H).

Example 5

N, N-diisopropyl-3- (2-hydroxyphenyl) -3- (3-pyridyl) -propylamine dihydrochloride

A solution of N, N-diisopropyl-3- (2-methoxyphenyl) -3- (3-pyridyl) -propionamide (2.8g, 8mmol) in THF (25mL) was added to LAH (1.3g, 32 mmol). The reaction mixture was refluxed for 4 hours, then quenched and the solvent evaporated. The residue was subjected to silica gel chromatography (toluene: triethylamine 99: 1) to obtain 2.2 g. The product (1.3g, 4mmol) was dissolved in dichloromethane (20mL), the resulting solution was cooled to-78 ℃ and boron tribromide (1g, 8mmol) was added dropwise, and the reaction mixture was allowed to reach room temperature over 1 hour. The reaction mixture was washed with sodium hydroxide (1M) and brine, and the organic phase was dried (MgSO₄) And the solvent was evaporated. The residue was subjected to silica gel chromatography (toluene: triethylamine, 9: 1) to obtain 0.35 g. The free amine was dissolved in ether and hydrogen chloride-containing ether was added to give the dihydrochloride salt, which was crystalline and rapidly rearranged to a hard glass.

¹H NMR (DMSO-d6) Δ 1.22(dd, 6H), 1.28(dd, 6H), 2.60(m, 1H), 2.70(m, 1H), 2.93(m, 2H), 3.60 (m', 2H), 4.60(t, 1H), 6.85(t, 1H), 6.89(d, 1), 7.11(t, 1H), 7.38(d, 1H), 7.96(dd, 1H), 8.46(d, 1H), 8.75(d, 1H), 8.85(s, 1H), 9.90(br, 1H) and 10.14(s, 1H).

The starting compound N, N-diisopropyl-3- (2-methoxyphenyl) -3- (3-pyridyl) -propionamide was prepared as follows:

5.12-methoxyphenyl-3-pyridinyl-methanones

A solution of 2-bromoanisole (21g, 0.11mol) in diethyl ether (100mL) was added to the magnesium turnings over 45 minutes while heating. After the addition was complete, reflux was continued for 15 minutes. The Grignard reagent obtained is cooled to 0 ℃ and 3-A solution of cyanopyridine (10g, 0.10mol) in diethyl ether (100 mL). The mixture was refluxed for several minutes. Hydrochloric acid (20mL, 0.24mol) and 2-propanol (20mL) were added and reflux continued for 30 min. Adding water and ether, and separating. The aqueous phase was basified (2M NaOH) and extracted with ether. The combined organic phases were dried (MgSO)₄) After evaporation, 17g of product were obtained. The crude product was chromatographed on silica gel (toluene: ethyl acetate 19: 1) to give 3.75g (19%) of product.

¹H NMR(CDCl₃D) δ 3.76(s, 3H), 7.01(d, 1H), 7.10(t, 1H), 7.41(dd, 1H), 7.46(dd, 1H), 4.53(m, 1H), 8.12(d, 1H), 8.75(s, 1H) and 8.94(s),

2N, N-diisopropyl-3- (2-methoxyphenyl) -3- (3-pyridyl) -propionamide

A solution of diethyl N, N-diisopropylacetamide phosphate (diethyl N, N-diisopropyl acetamide phosphate) (example 4.1, 9.3g, 33mmol) in THF (40mL) was added dropwise over 15 minutes to sodium hydride (80%, 1.0g, 33 mol). The mixture was heated to 40 ℃ for 15 minutes, then cooled to 5 ℃ and a solution of 2-methoxyphenyl-3-pyridinyl-one (4.5g, 21mmol) in THF (10mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ether and water and the organic phase was dried (MgSO₄) After that, evaporation was carried out to obtain 7.1g of a solid substance. This product was hydrogenated over Pd/C (10%, 0.2g) in acetic acid (50mL) for 48 h. The reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ether and hydrochloric acid (1M) and the different phases were separated. The aqueous phase was basified (2M sodium hydroxide) and extracted with ether. The combined organic phases were dried (MgSO)₄) And then filtered. At the onset of crystallization, the mixture was diluted with hexane. Filtration gave 2.9g (40%) of product.

¹H NMR(CDCl₃D) δ 1.14(dd, 6H), 1.28(d, 6H), 3.04(dd, 2H), 3.38(m, 1H), 3.74(s, 3H), 4.05(m, 1H), 5.00(t, 1H), 6.84(d, 1H), 6.92(t, 1H), 7.19(m, 3H), 7.57(d, 1H), 8.39(m, 1H) and 8.55(d, 1H).

Example 6

N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylpropylamine hydrochloride

A solution of N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylpropionamide (3.1g, 9.4mmol) in THF (20mL) was added to LAH (1.0g, 25mmol) and the reaction mixture was stirred at reflux temperature for 2 h. Additional LAH (0.5g) was added and refluxed for an additional 2 hours. The reaction was quenched and the solvent was evaporated. The residue was chromatographed on silica gel (toluene: ethyl acetate, 3: 1) to give 0.4g of the free amine as a slurry. The amine was dissolved in isopropanol/diethyl ether and the amine salt was prepared by adding diethyl ether containing hydrogen chloride. Yield 0.32g (10%); melting point 152-.¹H NMR (DMSO-d6) Δ 1.19(dd, 6H), 1.26(dd, 6H), 2.57(m, 2H), 2.86(m, 1H), 2.97(m, 1H), 3.58(m, 2H), 4.36(t, 1H), 6.69(dd, 1H), 7.14(m, 1H), 7.22(m, 2H), 7.29(m, 1H), 7.32(d, 2H), 7.33(s, 2H), 7.54(m, 1H) and 10.24(br, 1H). Innalyzing (C.C.C.₂₁H₂₈NF & HCl) H, N; c: calculated, 72.1; found 72.6.

Analysis (C)₂₁H₂₈NF & HCl) H, N; c: calculated, 72.1; found 72.6.

The starting compound N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylpropanamide is prepared as follows:

6.1 Trans-N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylacrylamide

A solution of diethyl N, N-diisopropylacetamide phosphate (example 4.1, 8.4g, 30mmol) in THF (20mL) was added dropwise over 30 minutes to sodium hydride (80%, 0.85g, 25mmol) and the temperature was kept below 40 ℃. A solution of 2-trifluoromethyl-benzophenone (4.0g, 20mmol) in THF (10mL) was added and the reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between ether and brine. The organic layer was dried (MgSO₄) And then evaporated to give a crystal. Recrystallization from hexane gave 3.9g (60%) of the product.

¹H NMR(CDCl₃-d) δ 0.85(d, 6H), 1.39(d, 6H), 3.29(m, 1H), 4.27(m, 1H), 6.29(s, 1H), 7.10(m, 3H) and 7.30(m, 6H).

6.2N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylpropanamide

A solution of trans-N, N-diisopropyl-3- (2-fluorophenyl) -3-phenylacrylamide (3.25g, 10mmol) was hydrogenated with Pd/C (10%, 300mg) in acetic acid (30mL) for 24 hours. The catalyst was filtered off and the solvent was evaporated to yield 3.1g (96%) of product.

¹H NMR(CDCl₃D) δ 1.12(q, 6H), 1.28(q, 6H), 3.05(d, 2H), 3 · 38(m, 1H), 4.03(m, 1H), 4.93(t, 1H) and 6.94-7.32(m, 9H).

Example 7

(R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

Hydrogen chloride in diethyl ether was added to a solution of (R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine (0.81g, 2.4mmol) in diethyl ether and 2-propanol. The crystals were filtered to give 0.4g (45%) of the product; melting point 178-. [ alpha ]_Hg-40 ° (c1.1 in methanol).¹H

NMR (DMSO-d6) delta 1.16(d, 3H), 1.20(d, 3H), 1.24(d, 3H), 1.27(d, 3H), 2.54(m, 2H), 2.84(m, 1H), 2.97(m, 1H), 3.58(br, 2H), 4.38(t, 1H), 7.08(d, 1H), 7.22(t, 1H), 7.32(m, 4H), 7.65(dd, 1H), 7.83(d, 1H), 9.80(s, 1H), 9.86(br, 1H)10.99(s, 1H). analysis (C)₂₂H₂₉NO₂HCl) H, N; c: calculated, 70.3; found 70.8.

Analysis (C)₂₂H₂₉NO₂HCl) H, N; c: calculated, 70.3; found 70.8.

The starting compound (R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine was prepared as follows:

1 (R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine DDQ (1.1 eq.) was added to a solution of the following composition: (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropylamine mandelate (prepared as described in WO94/11337, see example 1) (2.46g, 5mmol), dichloromethane (20mL) and phosphate buffer (pH7, 0.1 mL). Sodium hydroxide solution (20mL, 1M) and ether were then added and the phases separated. The aqueous phase was extracted twice with dichloromethane-diethyl ether (2: 1). The organic phase was dried (MgSO)₄) And then evaporated. The residue was crystallized from ethyl acetate-hexane to give 1.35g (80%) of the product.

Example 8

(R) -N, N-diisopropyl-3- [ 5- (7-hydroxy-2-aza-5-oxaheptyl) -2-hydroxyphenyl ] -3-phenylpropanamine di- (S) mandelate salt

Sodium cyanoborohydride (0.25g, 3.9mmol) was added to a solution of (R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl) -3-phenylpropylamine (example 7.1, 1.25g, 3.7mmol) and 2-ethoxy- (2-amino) -ethanol (19.5g, 18mmol) in methanol (10 mL). Hydrochloric acid (concentrated) was added to adjust the pH to about 3. After 3 hours, the pH was adjusted to about 1 and the solvent was evaporated. The residue was partitioned between ether and water, the solvent was evaporated and the residue was chromatographed on silica gel (chloroform: triethylamine: methanol, 88: 10: 2). The purified amine and (S) -mandelic acid (2 eq) were dissolved in 2-propanol-diethyl ether and the desired product crystallized (unstable and immediately oily). Yield 0.2g (7%); melting point (decomposition).

¹H NMR (free amine) (CDCl)₃-d) δ 1.05(d, 6H), 1.09(d, 6H), 2.10(m, 1H), 2.35(m, 2H), 2.67(m, 3H), 3.19(m, 2H), 3.47(m, 2H), 3.49(t, 2H), 3.56(d, 2H), 3.63(t, 2H), 4.45(dd, 1H), 6.75(d, 1H), 6.79(d, 1H), 6.95(dd, 1H), 7.18(m, 1H), and 7.26-7.33(m, 4H).

Example 9

(R) -N, N-diisopropyl-3- (2-hydroxy-5-methoxycarbonyl-phenyl) -3-phenylpropylamine hydrochloride

(R) -N, N-diisopropyl-3- (2-benzyloxy-5-methoxycarbonyl-phenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1) (0.92g, 2mmol) was hydrogenated over Pd/C (10%, 50mg) at room temperature for 2 h. The catalyst was filtered off and the solution was treated with hydrogen chloride to give the amine salt. Yield 0.66g (81%); melting point 177-178 ℃; [ α ] D-23 ° (c1.0, methanol).¹H NMR(DMSO-d6)δ 1.19(dd，6H)，

1.25(dd, 6H), 2.48(m, 2H), 2.85(m, 1H), 2.95(m, 1H), 3.58(m, 2H), 3.78(s, 3H), 4.38(t, 1H), 6.98(d, 1H), 7.20(m, 1H), 7.31(d, 2H), 7, 32(s, 2H), 7.69(dd, 1H), 7.81(d, 1H), 9.85(br, 1H), 10.74(s, 1H).

(C₂₃H₃₁NO₃·HCl)H，N，C.

Example 10

N, N-diisopropyl-3- (2-hydroxymethyl) phenyl-3-phenylpropylamine hydrochloride

A solution of N, N-diisopropyl-3- (2-carboxyphenyl) -3-phenylpropylamine hydrochloride (1.88g, 5mmol) in THF (30mL) was added to LAH (1.5g, 38mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched and the solvent was evaporated. The residue was dissolved in hot ether-2-propanol (100mL, 1: 4) and additional ether containing HCl was added. After cooling, the product was filtered and dried at 60 ℃ (vacuum). Yield 1.2g (68%); melting point 223-.¹H NMR (DMSO-d6) delta 1.18(t, 6H), 1.25(q, 6H), 2.91(m, 2H), 3.26 (2H overlapping solvent peak), 3.57(m, 2H), 4.38(t, 1H), 4.43(d, 1H), 4.74(d, 1H), 5.22(s, 1H), 7.20(q, 2H), 7.25-7.35(m, 5H), 7.40(dd, 2H), 9.95(s, 1H)₂₂H₃₁NO·HCl)H，N，C.

Example 11

(S) -N, N-diisopropyl-3- [ 2-hydroxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropylamine hydrochloride

(S) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropylamine (0.67g, 1.5mmol) was hydrogenated over Pd/C (10%, 67mg) at normal pressure in ethanol (20mL) overnight. The catalyst was filtered off and the solvent was evaporated. The residue was partitioned between ether and sodium hydroxide (1M). The aqueous layer was extracted with ether. The combined organic layers were washed with water and dried (MgSO)₄) The solvent is evaporated. The amine obtained is dissolved in diethyl ether-isopropanol and reacted with hydrogen chloride in diethyl ether to give the amine salt. Yield 0.37 g; melting point 219-; [ alpha ]_D-11.4 ° (c ═ 1.0, methanol);

¹HNMR(CD₃OD) δ 1.30(d, 12H), 2.36-2.60(m, 2H), 2.68(t, 2H), 3.05(t, 2H), 3.60-3.72(m, 4H), 4.40(t, 1H), 6.73(d, 1H), 6.90(dd, 1H), 7.0(s, 1H), 7.17-7.38(m, 5H)₂₃H₃₃NO₂·HCl·0·2H₂O)C，H，N.

The starting compound (S) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-hydroxy) ethylphenyl ] -3-phenylpropanamine was prepared as follows:

11.1 (S) -N, N-diisopropyl-3- (2-benzyloxy-5-vinylphenyl) -3-phenylpropylamine

Under nitrogen, (S) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1) (8g, 12.7mmol), Pd (OAc)₂A mixture of (28mg, 0.12mmol), tri-o-tolyl-phosphine (74mg, 0.14mmol) and tributylamine (5.9mL, 24.5mmol) in dimethylacetamide (50mL) was heated to 60 ℃. Ethylene gas was passed to a pressure of 8 bar. After stirring overnight, the reaction mixture was cooled to room temperature. Nitrogen was passed through the reaction flask and toluene and water were added. The aqueous phase was extracted with toluene and the combined organic layers were dried (MgSO₄) And then concentrated. The residue was treated with sodium hydroxide (1M) and extracted with ether and toluene. The organic layer was dried (MgSO₄) And then concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate-methanol 90: 10 to 0.06% NH)₃A 90: 10 gradient of ethyl acetate-methanol). Yield 1g (18%);

¹H NMR(CDCl₃)δ 0.94(d，12H)，2.20(br，2H)，2.37(br，2H)，3.0(br，2H)，4.38(t，1H)，5.0(s，2H)，5.11(d，1H)，5.61(d，1H)，6.60-6.70(m，1H)，6.80(d，1H)，7.12-7.19(m，12H).

11.2 (S) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-hydroxyethyl) -phenyl ] -3-phenylpropanamine

A solution of (S) -N, N-diisopropyl-3- (2-benzyloxy-5-vinylphenyl) -3-phenylpropylamine (1g, 2.34mmol) in THF (25mL) was added to 9-BBN (THF solution, 0.5M, 11.7mL, 5.85mmol) at 0 deg.C under nitrogen. After stirring for 3 hours, additional 9-BBN (2.3mL, 1.2mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 0.5 hour. Further cooled to 0 ℃ and 1M sodium hydroxide (10mL) and H were added sequentially₂O₂(30% aqueous solution, 10 mL). After stirring for 1 hour, water was added and the mixture was extracted with ether. The organic layer was washed with water and brine, dried (MgSO)₄) And then concentrated. The residue was chromatographed on silica gel (diethyl ether to 1% NH)₃A gradient of ether of (a). Yield 0.67g (64%).¹H

NMR(CDCl₃)δ 0.90(d，12H)，2.10-2.18(m，2H)，2.30-2.37(m，2H)，2.80(t，2H)，2.90-3.0(m，2H)，3.80(br，2H)，4.40(t，1H)，5.0(s，2H)，6.80(d，1H)，7.0(m，1H)，7.10-7.38(m，11H).

Example 12

(R) -N, N-diisopropyl-3- [ 2-hydroxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropylamine hydrochloride

The title compound and starting compound were prepared by an analogous method to that described in example 11, except that (S) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine was changed to (R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1).

Yield 0.35g (33%);melting point 209-215 ℃; [ alpha ]_D+9.8 ° (c ═ 1.0, methanol);

¹H NMR(CD₃OD) δ 1.29(d, 12H), 2.40-2.60(m, 2H), 2.67(t, 2H), 3.04(t, 2H), 3.61-3.72(m, 4H), 4.40(t, 1H), 6.70(d, 1H), 6.90(dd, 1H), 7.0(s, 1H), 7.18-7.40(m, 5H)₂₃H₃₃NO₂·HCl·0·2H₂O) C, H, n. preparation of starting compound:

12.1 (R) -N, N-diisopropyl-3- (2-benzyloxy-5-vinylphenyl) -3-phenylpropylamine yield 5.5g (53%);¹H NMR(CDCl₃)δ 0.94(d，12H)，2.20(br，2H)，2.37(br，2H)，3.0(br，2H)，4.38(t，1H)，5.0(s，2H)，5.11(d，1H)，5.61(d，1H)，6.60-6.70(m，1H)，6.80(d，1H)，7.12-7.19(m，12H).

12.2 (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-hydroxyethyl) -phenyl ] -3-phenylpropanamine

Yield 1.2g (75%);¹H NMR(CDCl₃)δ 0.89(d，12H)，2.15(m，2H)，2.32(m，2H)，2.80(t，2H)，2.95(m，2H)，3.80(br，2H)，4.40(t，1H)，4.98(s，2H)，6.80(d，1H)，6.96(m，1H)，7.10-7.35(m，11H).

example 13

(R) -N, N-diisopropyl-3- (5-acetyl-2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

(R) -N, N-diisopropyl-3- (5-acetyl-2-benzyloxyphenyl) -3-phenylpropylamine (1g, 2.25mmol) was treated as described in example 11. Yield 0.6g (68%); melting point 105-; [ alpha ]_D32.6 ° (c1.02, methanol);

¹H NMR(DMSO-d₆)d1.18-1.28(m，12H)，2.5(m，3H)，2.50-2.62(m，2H)，2.86(m，1H)，2.97(m，1H)，3.58(m，2H)，4.38(t，1H)，6.99(d，1H)，7.2(m，1H)，7.29-7.35(m，4H)，7.73(dd，1H)，7.85(d，1H)，9.90(br，1H)，10.70(s，1H).Anal.(C₂₃H₃₁NO₂·HCl·0.4H₂O)C，H，N.

the starting compound (R) -N, N-diisopropyl-3- (5-acetyl-2-benzyloxyphenyl) -3-phenylpropylamine was prepared as follows:

13.1 (R) -N, N-diisopropyl-3- (5-acetyl-2-benzyloxyphenyl) -3-phenylpropylamine

To a solution of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (example 12) (10.2g, 21.23mmol) in DMF (100mL) under nitrogen at room temperature was added triethylamine (2.58g, 25.47mmol), TlOAc (6.15g, 23.35mmol), isobutyl vinyl ether (14mL, 106.14mmol), DPPP (0.87g, 2.12mmol) and Pd (OAc)₂(0.24g, 1.06 mmol). The reaction temperature was raised to 100 ℃ and stirred for 3 hours, cooled to room temperature, filtered and treated with HCl (5%, 250mL) and stirred for an additional 2 hours. The reaction mixture was extracted repeatedly with dichloromethane and the combined organic layers were dried (MgSO₄) Filtered and the solvent evaporated. Under reduced pressure, triethylamine and DMF were distilled off to give 9g (98%) of the product;

¹H NMR(CDCl₃) δ 1.22(m, 12H), 2.52-2.70(m, 7H), 3.40(br, 2H), 4.34(t, 1H), 5.10(s, 1H), 6.90(d, 1H), 7.17-7.40(m, 10H), 7.82(m, 1H) and 7.92(s, 1H).

Example 14

N, N-diisopropyl-3 (R) - [ 2-hydroxy-5- (1-hydroxyethyl) phenyl ] -3-phenylpropylamine fumarate

N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1-hydroxyethyl) -phenyl ] -3-phenylpropylamine (2.7g, 6.05mmol) was hydrogenated with Pd/C (0.27g, 10%) for 2h at normal pressure in ethanol. The catalyst was filtered off and the solvent was evaporated. The oil obtained is chromatographed on silica gel (toluene: triethylamine, 90: 10). Fumaric acid (0.13g, 1.13mmol) dissolved in hot ethanol was added to a solution of the free base in ether to give the fumarate salt of the amine as white crystals (0.44g, 83%); melting point 240-℃；〔α〕_D+9.8 ° (c1.02, methanol);

¹H NMR(DMSO-d₆) δ 1.05(d, 6H), 1.26(dd, 3H), 2.20-2.30(m, 2H), 2.55-2.67(m, 2H), 3.30(m, 2H), 4.32(t, 1H), 4.59(q, 1H), 6.53(s, 2H), 6.72(dd, 1H), 6.93(dd, 0.5H), 7.12-7.17(m, 1H), 7.21-7.31(m, 5H). assay (C.₂₃H₃₃NO₂·C₄H₄O₄·0.3H₂O)C，H，N.

The starting compound N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1-hydroxyethyl) phenyl ] -3-phenylpropylamine was prepared as follows:

14.1N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1-hydroxyethyl) -phenyl ] -3-phenylpropanamine

N, N-diisopropyl-3 (R) - (5-acetyl-2-benzyloxyphenyl) -3-phenylpropylamine (prepared as described in example 13.1) dissolved in anhydrous THF (3.5g, 7.90mmol) was added to LiAlH₄(0.2g, 5.41 mmol). After stirring for 2 hours, additional LiAlH was added₄(50mg, 1.32mmol) and the reaction mixture was stirred for 1.5 h. The reaction was quenched and the solvent was evaporated. The residue was chromatographed on silica gel (toluene: E)₃N90: 10) to give 2.74g (78%) of an oil which slowly crystallizes when stored at room temperature.

Example 15

(+) -N, N-diisopropyl-3 (R) - [ 5- (1- (R) ]^*) 2-dihydroxyethyl) -2-hydroxyphenyl ] -3-phenylpropylamine fumarate.

N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1 (R) - [ 2 ] -benzyloxy-5 is treated in analogy to the procedure described in example 14^*) 2-Dihydroxyethyl) phenyl ] -3-phenylpropylamine (0.55g, 1.2mmol) gave white crystals, 0.32g (55%); melting point 196-200 ℃; [ alpha ] D +13.5 ° (c1.0, methanol);¹H NMR

(CD₃OD)δ 1.28(m，12H)，2.40-2.48(m，1H)，2.52-2.60(m，1H)，3.03-(t，2H) 3.55(d, 2H), 3.66(m, 2H), 4.42(t, 1H), 4.57(t, 1H), 6.7(s, 2H), 6.79(d, 1H), 7.05(dd, 1H), 7.16-7.21(m, 2H), 7.28(m, 2H), 7.36(m, 2H). assay (C)₂₃H₃₃NO₃·C₄H₄O₄)C，H，N.

The starting compound N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1 (R)^*) The preparation of 2-dihydroxyethyl) phenyl ] -3-phenylpropylamine is as follows:

15.1N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1 (R)^*) 2-dihydroxyethyl) phenyl ] -3-phenylpropylamine

To an ice-cold solution of AD-mix-. alpha.5.7 g in water (20mL) and tert-butanol (10mL) was added a solution of N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5-vinylphenyl ] -3-phenylpropylamine (example 12.1) (1.74g, 4.1mmol) dissolved in tert-butanol (10 mL). After stirring for 1 hour, the ice bath was removed and the reaction mixture was stirred for an additional 21 hours. Adding Na₂SO₃(6g) After stirring for 1 hour, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were dried (MgSO₄) The solvent is evaporated. The residue was subjected to silica gel chromatography (ethyl acetate: triethylamine 90: 10) to obtain 0.55g of a product.

¹H NMR(CDCl₃)δ 0.9(s，6H)，0.95(s，6H)，2.15-2.20(m，2H)，2.30-2.38(m，2H)，2.96(m，2H)，3.60-3.70(m，2H)，4.41(t，1H)，4.75(m，1H)，5.0(s，2H)，6.85(d，1H)，7.10-7.35(m，12H).

Example 16

(-) -N, N-diisopropyl-3 (R) - [ 5- (1 (S)^*) 2-dihydroxyethyl) -2-hydroxyphenyl ] -3-phenylpropylamine fumarate

N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1 (S)) is treated in analogy to the procedure described in example 11^*) 2-Dihydroxyethyl) phenyl ] -3-phenylpropylamine (1.1g, 2.4mmol) gave white crystals, 0.25g (21%); melting point 208-;〔α〕_D-8 ° (c1.02, methanol);₁H NMR(CD₃OD)

δ 1.28(m, 12H), 2.39-2.47(m, 1H), 2.51-2.59(m, 1H), 3.03(t, 2H), 3.51-3.53(m, 2H), 3.67(m, 2H), 4.42(t, 1H), 4.54(dd, 1H), 6.68(s, 2H), 6.78(d, 1H), 7.06(dd, 1H), 7.16-7.20(m, 2H), 7.26(m, 2H), 7.34-7.36(m, 2H) analysis₂₃H₃₃NO₃·C₄H₄O₄)C，H，N.

The starting compound N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (1 (S)^*) 2-dihydroxyethyl) phenyl ] -3-phenylpropylamine was prepared as described in example 15.1 for N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5-vinylphenyl ] -3-phenylpropylamine (prepared in example 12.1), but using AD-mix-. beta.instead of AD-mix-. alpha.was used. Yield 1.2g (44%).

Example 17

(R) - [ N, N-diisopropyl-3- [ 2-hydroxy-5- [ 6-hydroxyhexyl ] -phenyl ] -3-phenylpropylamine hydrochloride

N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (6-hydroxyhex-1-enyl) phenyl ] -3-phenylpropylamine (0.35g, 0.72mmol) was treated as described in example 14. Yield 0.10g (31%); melting point 147-; [ alpha ]_D+8.2 ° (c1.01, methanol);

¹H NMR(CD₃OD) δ 1.25-1.32(m, 16H), 1.45-1.54(m, 4H), 2.40-2.48(m, 3H), 2.51-2.59(m, 1H), 3.0-3.10(m, 2H), 3.51(t, 2H), 3.68(m, 2H), 4.40(t, 1H), 6.72(d, 1H), 6.86(dd, 1H), 6.91(d, 1H), 7.19(m, 1H), 7.30(t, 2H), 7.34-7.36(m, 2H).

(C₂₇H₄₁NO₂·HCl·2H₂O) C, N, H: calculated value, 9.6; found, 8.3.

The starting compound (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (6-hydroxyhex-1-enyl) phenyl ] -3-phenylpropanamine is prepared as follows:

17.1 (R) -N, N-diisopropyl-3- (2-benzyloxy-5-formylphenyl) -3-phenylpropylamine

Under a nitrogen atmosphere, N-butyllithium (2.5M in hexane, 19mL, 47.5mmol) was added to a solution of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1) (8.9g, 18.52mmol) in dry ether (100mL) maintained at-40 ℃. After stirring for 1.5h, additional n-butyllithium (10mL, 25mmol) was added, and over a further 2h, additional n-butyllithium (5mL, 12.5mmol) was added. The reaction was stirred for 15 min, DMF (6mL, 77.8mmol) was added, and after stirring for an additional 20 min, DMF (5mL, 64.8mmol) was added. The reaction temperature was raised to room temperature, and after stirring for 35 minutes, NH was added in sequence₄Cl (saturated), water and diethyl ether. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried (MgSO)₄) The solvent is evaporated. The residue was chromatographed on silica gel (toluene: triethylamine 90: 10) to give 8g (100%) of a yellow oil;¹H NMR(CDCl₃)δ 0·90(m，12H)，2.12-2.40(m，4H)，2.95(m，2H)，4.44(t，1H)，5.10(s，2H)，6.95(d，1H)，7.15-7.36(m，10H)，7.70(dd，1H)，7.91(s，1H)，9.88(s，1H).

17.2 (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (5-carboxypent-1-enyl) phenyl ] -3-phenylpropanamine

Potassium tert-butoxide (2.1g, 18.62mmol) was added to a mixture of 4-carboxybutyl-triphenylphosphonium bromide (4.1g, 9.31mmol) in THF (25mL) under a nitrogen atmosphere at-10 ℃. The mixture turned orange, and after stirring for 10 min, a solution of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-formylphenyl) -3-phenylpropylamine (2g, 4.65mmol) in THF (10mL) was added. After stirring for 4 hours, hydrochloric acid (1M) and ether were added and the different layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO)₄) The solvent is evaporated. The residue was chromatographed on silica gel (ethyl acetate: triethylamine 90: 10) followed by methanol to give 3g of product containing traces of triphenylphosphine. The product does not need to beFurther purification was carried out and used in the next step.

17.3(R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (6-hydroxyhex-1-enyl) phenyl ] -3-phenylpropanamine

(R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (5-carboxypent-1-enyl) phenyl ] -3-phenylpropanamine was reduced as described in example 10. Yield 0.35g (15%).

Example 18

(R) -N, N-diisopropyl-3- [ 5- (2-diisopropylaminoethyl) -2-hydroxyphenyl ] -3-phenylpropylamine hydrochloride

(R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-diisopropylaminoethyl) phenyl ] -3-phenylpropylamine (0.6g, 1.13mmol) was refluxed with concentrated HCl (25mL) overnight. The reaction mixture was basified with 10M sodium hydroxide and extracted with diethyl ether. The organic layer was dried (MgSO₄) After concentration in vacuo, 0.5g of oil was obtained and the oil was purified on a reverse phase PEP-RPC HR30/26 preparative column eluted with a gradient of acetonitrile (containing 0.1% TFA) and milliQ-water (containing 0.1% TFA). The pure fractions were combined and extracted with diethyl ether and 10M sodium hydroxide. The resulting ether solution was treated with ether containing hydrogen chloride. Yield 50mg (9%); [ alpha ]_D+1.4 ° (c 0.94, methanol);

¹H NMR(CD₃OD) δ 1.27-1.34(m, 12H), 1.36-1.42(m, 12H), 2.50-2.58(m, 1H), 2.60-2.67(m, 1H), 2.95(t, 2H), 3.05(m, 2H), 3.15-3.27(m, 2H), 3.70(m, 2H), 3.75(m, 2H), 4.40(t, 1H), 6.80(d, 1H), 7.02(dd, 1H), 7.13(d, 1H), 7.20(m, 1H), 7.31(m, 1H), 7.39-7.41(m, 1H). analysis. (C)₂₉H₄₆N₂O·2HCl·0·4H₂O)C，H，N·

The starting compound N, N-diisopropyl-3 (R) - [ 2-benzyloxy-5- (2-diisopropylaminoethyl) phenyl ] -3-phenylpropylamine was prepared as follows:

18.1N, N-diisopropyl-3 (R) - (5-formylmethyl-2-benzyloxy-phenyl) -3-phenylpropylamine

DMSO (1.1mL, 15.5mmol) in dichloromethane was added dropwise to oxalyl chloride (0.64mL, 7.74mmol) under nitrogen at-78 ℃. After stirring for 10 min, a solution of (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropylamine (example 12.2) (2.3g, 5.16mmol) in dichloromethane was added and the reaction mixture was stirred for 1 h. Triethylamine (5.4mL, 38.7mmol) was added and the temperature was raised to room temperature. The reaction mixture was dissolved in water and dichloromethane. The organic layer was dried (MgSO₄) Concentrated in vacuo and the product was used in the next step without further purification.

18.2 (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-diisopropylaminoethyl) phenyl ] -3-phenylpropanamine

Diisopropylamine (4.2mL, 30mmol) was dissolved in methanol (12 mL). 5M HCl in methanol (2mL), N-diisopropyl-3 (R) - (5-formylmethyl-2-benzyloxyphenyl) -3-phenylpropylamine (5mmol) in methanol (10mL), and sodium cyanoborohydride (0.22g, 3.5mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight, methanol was evaporated and ether and water were added. The organic layer was dried (MgSO₄) Concentration in vacuo afforded 3g of crude product which was chromatographed on silica gel (toluene: triethylamine 95: 5). Yield 0.65g (25%);

¹HNMR(CDCl₃)δ 0.88-0.91(m，18H)，1.20(d，9H)，2.10-2.20(m，2H)，2.30-2.38(m，2H)，2.87-3.10(m，4H)，4.34(m，1H)，4.98(d，2H)，6.75-6.97(m，2H)，7.10-7.30(m，11H).

example 19

(R) -N, N-diisopropyl-3- (5-ethoxymethyl-2-hydroxyphenyl) -3-phenylpropylamine

(R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethyl-phenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1) (3.9g, 11.5mmol) and Al₂O₃(115g, 1.13mol) was taken up in ethyl acetate (0.5L)The flow was for 60 hours. Filtering out Al₂O₃The ethyl acetate was evaporated. The residue is chromatographed on silica gel (toluene: triethylamine 90: 10) to give 2.5g (59%) of product. Fumaric acid (0.17g, 1.48mmol) dissolved in warm ethanol was added to a solution of the free base in ether (0.55g, 1.48mmol) to give the fumarate salt; melting point 174-177 ℃; [ alpha ]_D+5.5 ° (c1.02, methanol);

¹H NMR(CD₃OD) δ 1.15(t, 3H), 1.27-1.30(m, 12H), 2.41-2.49(m, 1H), 2.52-2.60(m, 1H), 3.04(dd, 2H), 3.49(q, 2H), 3.67(m, 2H), 4.35(s, 2H), 4.43(t, 1H), 6.69(s, 2H), 6.80(d, 1H), 7.04(dd, 1H), 7.12(d, 1H), 7.18-7.37(m, 4H) analysis (C₂₄H₃₅NO₂·C₄H₄O₄)C，H，N.

Example 20

N-isopropyl-3- (5-carboxy-2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

N-benzyl-N-isopropyl-3- (2-benzyloxy-5-carboxyphenyl) -3-phenylpropylamine (1.3g, 2.6mmol) was dissolved in HOAc. Palladium on charcoal (10%, 0.13g) was added and the mixture was hydrogenated at room temperature for 48 hours. The catalyst was filtered off and the solvent was evaporated. The resulting oil was purified on a reverse phase PEP-RPC HR30/26 preparative column eluted with a gradient solvent consisting of acetonitrile (containing 0.1% TFA) and milliQ water (containing 0.1% TFA). Purification was done in 16 batches of approximately 100mg of material each time. The pure fractions were combined and lyophilized to give 0.57g of the trifluoroacetate salt. This crystal was dissolved in 1M HCl and lyophilized to give 0.4g (43%) of the hydrochloride salt as white crystals; melting point 155-160 ℃;¹H NMR

(DMSO-d₆) δ 1.17(d, 3H), 1.19(d, 3H), 2.30-2.38(m, 1H), 2.38-2.46(m, 1H), 2.72(br, 1H), 2.80(br, 1H), 3.25(m, 1H), 4.40(t, 1H), 6.94(d, 1H), 7.18-7.22(m, 1H), 7.29-7.33(m, 4H), 7.66(dd, 1H), 7.76(d, 1H); and (6) analyzing.

(C₁₉H₂₃NO₃·HCl·0.5H₂O)C，H，N.

The starting compound, N-benzyl-N-isopropyl-3- (2-benzyloxy-5-carboxyphenyl) -3-phenylpropylamine, was prepared as follows:

20.13- (2-benzyloxy-5-bromophenyl) -3-phenylpropionaldehyde

3- (2-phenoxy-5-bromophenyl) -3-phenylpropanol (16.5g, 41.5mmol), the preparation of which is described in WO94/11337, see example 1C, was reacted as described in example 18.1. The combined organic layers were washed with 2M HCl, 10% NaHCO₃Washed with water and brine, dried (MgSO)₄) Evaporation gave 16g (98%) of a yellow crystalline product which was used in the next step without further purification; the melting point is 99-100 ℃;

¹H NMR(CDCl₃)δ 3.10(dd，2H)，5.0(s，2H)，4.98-5.10(m，1H)，6.76(d，1H)，7.16-7.38(m，12H)，9.65(s，1H).

20.2N-benzyl-N-isopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine

To a solution of N-benzylisopropylamine (34mL, 0.20mol) in methanol (80mL) was added a solution of 5M HCl in methanol (16.2mL, 80.9mmol), followed by a solution of 3- (2-benzyloxy-5-bromophenyl) -3-phenylpropanal (16.0g, 40.5mmol) in methanol (20mL) and sodium cyanoborohydride (1.78g, 28.3 mmol). The resulting solution was stirred for 17 hours. The solvent was evaporated and diethyl ether was added to the resulting slurry. The solution was washed 3 times with water and MgSO₄Drying and evaporating. The residue was subjected to silica gel chromatography (hexane: ethyl acetate 75: 25) to obtain 15.9g of a slurry. The product was dissolved in diethyl ether and HCl in diethyl ether was added to afford the hydrochloride salt of the title compound. The resulting oil was washed with diethyl ether, dissolved in 10M sodium hydroxide and extracted 3 times with diethyl ether. Purification by silica gel chromatography (gradient from dichloromethane to dichloromethane with 1% triethylamine) gave 7g (33%) of the product as a colourless oil.¹H NMR(CDCl₃)δ 0.84(d，3H)，0.90(d，3H)，2.02-2.12(m，2H)，2.38(t，2H)，2.90(m，1H)，3.50(d，2H)，4.50(t，1H)，4.95(s，2H)，6.70(s，1H)，7.10-7.35(m，17H).

20.3N-benzyl-N-isopropyl-3- (2-benzyloxy-5-carboxyphenyl) -3-phenylpropylamine

A mixture of magnesium turnings (1.18g, 48.6mmol) and iodine (one small crystal) was gently heated. A mixture of N-benzyl-N-isopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (6.0g, 11mmol) and 1, 2-dibromoethane (0.2mL, 2.3mmol) in anhydrous THF (25mL) was added dropwise to the refluxing mixture under a nitrogen atmosphere. After refluxing for 2 hours, 1, 2-dibromoethane (0.59mL, 6.8mmol) was added. The mixture was left under nitrogen overnight. This mixture was added with 1, 2-dibromoethane (0.93mL, 10.8mmol) to the warmed magnesium turnings (1.18g, 48.6mmol) and iodine (a small crystal). After 30 minutes of reflux, the mixture was cooled to room temperature and CO was bubbled through₂A gas. After 3 hours, ammonium chloride (aq, 15%, 50mL) was added followed by diethyl ether (100 mL). The different layers were separated and the organic layer was dried (MgSO₄) And concentrated to give 5.8g of oil. The crude product was chromatographed on silica gel (eluting with a gradient of acetone to 5% ethanol in acetone) to give the pure product (1.3g, 23%) as an oil. N-benzyl-N-isopropyl-3- (2-benzyloxyphenyl) -3-phenylpropylamine (3.1g) was prepared as a by-product of this reaction.

¹H NMR(CDCl₃)δ 0.98(d，3H)，1.10(d，3H)，2.30-2.40(m，2H)，2.46-2.65(m，2H)，3.40(br，1H)，3.85(br，2H)，4.30(br，1H)，4.98(br，2H)，6.80(d，1H)，7.10-7.40(m，15H)，7.95(d，1H)，7.95(d，1H)，8.20(s，1H).

Example 21

N-benzyl-N-isopropyl-3- (2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

N-benzyl-N-isopropyl-3- (2-benzyloxy-5-carboxyphenyl) -3-phenylpropylamine (3.1g, 6.90mmol) was prepared as in example 20.3 and refluxed in concentrated HCl (30mL) for 20 h. The reaction mixture was cooled to room temperature and the liquid was decanted. The remaining oil was washed with water and diethyl ether and then dissolved in 2-propanol. The solution was evaporated and treated with 10M sodium hydroxide to give the free base. Silica gel chromatography (hexane: ethyl acetate 75: 25) afforded 0.5g of the compound, which was purified on a reverse phase PEP-RPC HR30/26 preparative column eluted with a gradient of acetonitrile (containing 0.1% TFA) and milliQ water (containing 0.1% TFA). The pure fractions were combined and extracted with diethyl ether and 10M sodium hydroxide. To the resulting ether solution, saturated ether-HCl (gas) was added dropwise. Filtering and recovering the generated hydrochloride crystals; melting point 115 and 122 DEG C

¹H NMR(DMSO-d₆) δ 1.28(m, 6H), 2.27-2.38(m, 1H), 2.48-2.55(m, 1H), 2.72-2.97(m, 2H), 3.55(m, 1H), 4.23(m, 2H), 4.35(m, 1H), 6.68-6.74(m, 1H), 6.82(dt, 1H), 6.96-7.24(m, 7H), 7.38-7.42(m, 3H), 7.64-7.68(m, 2H), 9.55(d, 1H), 10.62(br, 1H)₂₅H₂₉NO·HCl)C，H，N.

Example 22

(R) -N, N-diisopropyl-3- [ 5- (3-aminopropyl) -2-hydroxyphenyl ] -3-phenylpropylamine dihydrochloride

(R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-cyanovinyl) phenyl ] -3-phenylpropylamine (3.20g, 7.07mmol) was dissolved in 100% acetic acid and 10% Pd/C (0.52g) was added. The mixture was hydrogenated at room temperature overnight (60 psi). The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in water, basified with sodium hydroxide (11M), extracted with ethyl acetate and the organic phase dried (MgSO)₄) And then evaporated. The residue is chromatographed on silica gel (toluene: ethyl acetate: triethylamine: methanol, 20: 5: 1.5: 1). The resulting amine was again dissolved in ether and a solution of ether saturated with HCl was carefully added. The precipitate was filtered off to give 0.30g (10%) of product;

¹H NMR(CD₃OD)δ 1.29(m，12H)，1.88(m，2H)，2.51(m，2H)，2.59(t，2H)，2.88(t，2H)，3.04(t，2H)，3.68(m，2H)，4.40(t，1H)，4.55(bs，1H)，6.76(d，1H)，6.93(d，1H)，7.03(s，1H)，7.19(t，1H)，7.30(t，2H)，7.37(d，2H)；mp.226-228℃；[α]_D+11.5 ° (C ═ 1.0, methanol)₂₄H₃₆N₂O＊2HCl)C，H，N.

The starting compound (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-cyanovinyl) phenyl ] -3-phenylpropanamine was prepared as follows:

22.1 (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-cyanovinyl) phenyl ] -3-phenylpropanamine

To a solution of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (13.87g, 28.87mmol), prepared as described in WO94/11337, see example 1, in DMF (140mL), was added triethylamine (5.00mL, 36.10mmol), Pd (OAc)₂(0.32g, 1.44mmol), tris (o-tolyl) phosphine (1.76g, 5.77mmol) and acrylonitrile (2.39mL, 36.10 mmol). The reaction mixture was stirred overnight at 115 ℃ in a sealed flask equipped with a reflux condenser under nitrogen. The resulting mixture was concentrated, and the residue was dissolved in diethyl ether and washed with 2M aqueous sodium hydroxide and water. The organic phase was dried (MgSO)₄) Petroleum ether was then added to the organic phase to form a precipitate. Recrystallization from ethanol gave 5.50g (42%) of product.

¹H NMR(CDCl₃)δ 0.90(s，6H)，0.95(s，6H)，2.15(q，2H)，2.35(q，2H)，2.95(m，2H)，4.40(t，1H)，5.05(s，2H)，5.70(d，1H)，6.85(d，1H)，7.10-7.50(m，13H).

Example 23

(R) -N, N-diisopropyl-3- [ 5-3- (acetylaminopropyl) -2-hydroxy-phenyl ] -3-phenylpropylamine hydrochloride

To a solution of (R) -N, N-diisopropyl-3- [ 5- (3-aminopropyl) -2-hydroxyphenyl ] -3-phenylpropylamine (example 22) (0.45g, 1.23mmol) in methanol (45mL) was added acetic anhydride (0.23mL, 2.47 mmol). The mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was dissolved in water, basified with 11M aqueous sodium hydroxide solution and extracted with toluene. With MgSO₄Will be organicThe phases were dried, filtered and evaporated. The resulting amine was dissolved in ether and a solution of ether saturated with HCl was carefully added. The precipitate formed is filtered off to give 0.55g (100%) of product.

¹H NMR(CD₃OD)δ 1.27(m，12H)，1.75(m，2H)，2.08(s，3H)，2.52(m，4H)，3.04(t，2H)，3.20(t，2H)，3.68(m，2H)，4.40(t，2H)，6.72(d，1H)，6.90(d，1H)，6.99(s，1H)，7.19(t，1H)，7.30(m，4H)；

Melting point 171-175 ℃; [ alpha ]_D+3.6 ° (c ═ 0.5, methanol). (C)₂₆H₃₈N₂O₂*HCl)C，H，N。

Example 24

(R) -N, N-diisopropyl-3- [ 5- (2-cyanoethyl-2-hydroxyphenyl ] -3-phenylpropylamine hydrochloride

(R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-cyanovinyl) phenyl ] -3-phenylpropylamine (example 22.1), (4.00g, 8.84mmol) was treated as described in example 22, but the hydrogenation was carried out at normal pressure. Yield 1.35g (38%).

¹H NMR(CD₃OD)δ 1.14(s，6H)，1.16(s，6H)，2.50(m，2H)，2.79(t，2H)，3.05(t，2H)，3.68(m，2H)，4.39(t，2H)，6，75(d，1H)，6.98(d，1H)，7.09(s，1H)，7.19(t，1H)，

7.32(m, 4H); melting point 156-; [ alpha ]_D+4.0 ° (c ═ 0.5, methanol); analysis (C)₂₄H₃₂H₂O*1.0HCl*0.25H₂O) C, H; n: calculated value, 6.9; found 6.4.

Example 25

(R) -N, N-diisopropyl-3- [ 5- (2-carbamoylethyl) -2-hydroxy-phenyl ] -3-phenylpropanamine hydrochloride

(R) -N, N-diisopropyl-3- [ 5- (2-cyanoethyl) -2-hydroxyphenyl ] -3-phenylpropylamine (example 24) was stirred at 50 deg.C) (2.00g, 5.48mmol) in concentrated hydrochloric acid for 2 hours and then evaporated. The residue was dissolved in water, basified with 11M aqueous sodium hydroxide solution and extracted with toluene. The organic layer was dried (MgSO₄) Filtered and evaporated. The residue was chromatographed using toluene, ethyl acetate, triethylamine, methanol (7: 2: 1). The product is obtained by using ether-hydrogen chloride.

Yield 0.9g (39%);¹H NMR(CD₃OD)δ 1.31(m，12H)，2.44(t，2H)，2.53(m，2H)，2.78(t，2H)，3.04(t，2H)，3.67(m，2H)，4.39(t，1H)，6.72(d，1H)，6.82(d，1H)，7.02(s，1H)，7.18(t，1H)，7.32(m，4H)；

melting point 200-; [ alpha ]_D+7.6 ° (c ═ 0.5, methanol).

Analysis (C)₂₄H₃₄N₂O₂*1.0HCl*0.5H₂O)C，H，N。

Example 26

(R) -N, N-diisopropyl-3- [ 5- (2-carboxyethyl) -2-hydroxyphenyl ] -3-phenylpropylamine hydrochloride

KOH (3.75g, 66.8mmol) was added to a solution of (R) -N, N-diisopropyl-3- [ 5- (2-carbamoylethyl) -2-hydroxyphenyl ] -3-phenylpropanamine (from example 25, 0.50g, 1.31mmol) in ethanol (15mL) and water (10 mL). The resulting mixture was stirred at 100 ℃ overnight. The solvent was evaporated and the residue was redissolved in water and washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitate was recovered by filtration and washed with 2M HCl. The product was purified on a reverse phase PEP RPC HP 30/26 preparative column (Pharmacia Biotech AB, Sweden) using 20-60% acetonitrile with 0.1% TFA as gradient eluent. The fractions were combined, hydrochloric acid (2mL, concentrated) was added and the solvent was evaporated. The residue was crystallized from methanol-ether to give 0.37g (0.96mmol, 74%) of product;¹HNMR(CD₃OD)δ 1.28(m，12H)，2.48(m，4H)，2.76(t，2H)，3.04(t，2H)，3.67(m，2H)，4.39(t，1H)，6.72(d，1H)，6.92(d，1H)，7.00(s，1H)，7.19(t，1H)，7.32(m，4H)；

melting point 205-; [ alpha ]_D+3.7 ° (c ═ 1.0, methanol). Analysis (C)₂₄H₃₃NO₃*1.0HCl)C，H，N。

Example 27

(R) -N, N-diisopropyl-3- (5-amino-2-hydroxyphenyl ] -3-phenylpropylamine dihydrochloride

(R) -N, N-diisopropyl-3- (5-azido-2-benzyloxyphenyl) -3-phenylpropylamine (0.90g, 2.03mmol) was dissolved in acetic acid and 10% Pd/C (210mg, catalyst) was added. The mixture was stirred, contacted with hydrogen (1 atm) and reacted at room temperature overnight. The Pd/C catalyst was filtered off and dried (MgSO)₄) Filtered and evaporated. The crude product was chromatographed on silica gel (n-hexane: ethanol: triethylamine, 7: 3: 1). The hydrochloride was prepared with diethyl ether/hydrogen chloride. The resulting oil was freeze dried to remove water. Yield 0.30g (37%);

¹H NMR(DMSO)δ 1.13-1.33(m，12H)，2.47(m，2H)，2.82(br，1H)，2.98(br，1H)，3.57(br，2H)，4.38(t，1H)，6.96(d，1H)，7.08(d，1H)，7.19(s，1H)，7.22(m，1H)，7.32(m，4H)，10.05(br，2H)，10.13(s，1H)；

melting point 180-; [ alpha ]_D+21.0 ° (c ═ 0.1, methanol).

Analysis (C)₂₁H₃₀N₂O*2.0HCl*0.5H₂O)C，H，N。

The starting compound (R) -N, N-diisopropyl-3- (5-azido-2-benzyloxyphenyl) -3-phenylpropylamine was prepared as follows:

27.1 (R) -N, N-diisopropyl-3- (5-azido-2-benzyloxyphenyl) -3-phenylpropylamine

To a mixture of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (10.00g, 20.81mmol), prepared as described in WO94/11337, see example 1, and magnesium (1.57g, 64.52mmol) in THF (50mL) was added 1, 2-dibromoethane (3.59mL, 41.63mmol) and the mixture was allowed to dryThe solution was self-refluxed in one array. After refluxing the mixture for 1 hour, the solution was cooled, and a solution of tosylazide (4.10g, 20.81mmol) in ether (100mL) was added, stirring was continued while maintaining the temperature at 0 deg.C, then the temperature was raised to room temperature, and the reaction was carried out for 4 hours. A solution of tetrasodium pyrophosphate decahydrate (4.46g, 10.00mmol) in 50mL of water was added. The precipitate was filtered off and the filtrate was evaporated. The residue was extracted with diethyl ether and the organic phase was dried (MgSO)₄) And then evaporating. The residue was chromatographed over silica gel (n-hexane: ethanol, 8: 2). The product was crystallized from ethanol to yield 1.15g (13%) of product; IR (KBr)2116 (N)₃)cm^-1；¹HNMR(CDCl₃)δ 0.92(d，12H)，2.10(m，2H)，2.33(m，2H)，2.95(m，2H)，4.40(t，1H)，5.00(s，2H)，6.81(d，2H)，6.97(s，1H)，7.10-7.40(m，10H).

Example 28

(R) -N, N-diisopropyl-3- (5-azido-2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

To a solution of (R) -N, N-diisopropyl-3- (5-amino-2-hydroxyphenyl) -3-phenylpropylamine (0.25g, 0.76mmol) in 0.78M HCl (5.35mL, 4.20mmol) at-10 deg.C was added NaNO dissolved in water (0.4mL)₂(0.05g, 0.76mmol) and the mixture was stirred for 20 minutes. NaN dissolved in 0.4mL of water₃(57mg, 0.88mmol) was added to the mixture and the mixture was stirred at-10 ℃ for 30 minutes. The mixture was basified with 11M aqueous sodium hydroxide (pH7-8) and extracted with ether. Dry the ether layer (MgSO)₄) Evaporation gave an oil which was chromatographed over silica gel (toluene: ethyl acetate: triethylamine, 7: 2: 1). The product was dissolved in ether and a solution of hydrogen chloride in ether was added. The precipitate was filtered off to give light brown crystals (0.07g, 0.18mmol, 24%). IR (KBr)2111 (N)₃)Cm^-1；¹H NMR(CD₃OD)δ 1.29(m，12H)，2.50(m，2H)，3.04(m，2H)，3.68(m，2H)，4.40(t，1H)，6.68(s，1H)，6.81(m，2H)，7.23(m，1H)，7.35(m，4H)；mp.131-134℃；[α]_D-5.0 ° (c ═ 0.1, methanol).

The starting compound (R) -N, N-diisopropyl-3- (5-amino-2-hydroxyphenyl) -3-phenylpropylamine was prepared as follows:

28.1 (R) -N, N-diisopropyl-3- (2-hydroxyphenyl) -3-phenylpropylamine

(R) -N, N-diisopropyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (prepared as described in WO94/11337, see example 1) was treated as described in example 1.3 (7.30g, 15..2 mmol). Yield 4.47g (94%).

28.2 (R) -N, N-diisopropyl-3- [ 2-hydroxy-5- (4-methylphenylazo) phenyl) -3-phenylpropanamine

Adding NaNO₂(0.27g, 4.30mmol) was added to a mixture of hydrochloric acid (0.64mL, 7.70mmol, conc.) and p-methylaniline (0.41g, 3.80mmol) in ice water (20 mL). The mixture was stirred at 0 ℃ for 10 minutes, and a solution of (R) -N, N-diisopropyl-3- (2-hydroxyphenyl) -3-phenylpropylamine (1.00g, 3.21mmol) in THF (3mL) and an ice-cold solution of water (12mL) and sodium hydroxide (0.69g, 17.32mmol) was added. After stirring the mixture for 20 minutes, it was extracted with toluene and dried (MgSO₄) Evaporation gave an oil which was chromatographed (toluene: ethyl acetate: triethylamine, 8: 1) to give 0.83g, 1.93mmol (60%) of the title compound.

¹H NMR(CDCl₃)δ 1.12(d，6H)，1.19(d，6H)，2.22(m，1H)，2.43(m，5H)，2.79(m，1H)，3.32(m，2H)，4.57(d，1H)，6.98(d，1H)，7.24(m，3H)，7.36(m，4H)，7.66(m，4H).

28.3 (R) -N, N-diisopropyl-3- (5-amino-2-hydroxyphenyl) -3-phenylpropylamine

Adding Na at 75 deg.C₂S₂O₄A solution of (1.23g, 12.8mmol) in water (10mL) was added over 15 minutes to a solution of (R) -N, N-diisopropyl-3- [ 2-hydroxy-5- (4-tolylazo) phenyl ] -3-phenylpropylamine (0.55g, 1.28mmol) in ethanol (50 mL). Adding additional anhydrous Na in 10 portions₂S₂O₄(1.23g, 12.8 mmol). Water was added to the solution, which was then extracted with diethyl ether. Is dried withOrganic layer (MgSO)₄) Evaporating to obtain an oily substance, and performing silica gel chromatography (n-hexane, ethanol, triethylamine, 7: 3: 1) to obtain an oily substance. This product was dissolved in ethanol and a solution of hydrogen chloride in ether was added. The solvent was evaporated, redissolved in water and dried under vacuum to yield 0.25g (60%) of product.

Example 29

(R) -N, N-diisopropyl-3- [ 2-hydroxy-5- (3-hydroxypropyl) -phenyl) -3-phenylpropylamine hydrochloride

A solution of (R) -N, N-diisopropyl-3- [ 5- (2-ethoxycarbonylethyl) -2-hydroxyphenyl ] -3-phenylpropylamine (2.0g, 4.86mmol) in THF (50mL) was added dropwise to LAH (0.28g, 7.29 mmol). After stirring for 2 hours, the reaction was quenched and the solvent was evaporated. The residue was recrystallized from ethanol-water. The product was dissolved in ethanol and diethyl ether containing hydrogen chloride was added. The white crystals were filtered off to give 0.82g (46%) of product; melting point 204-; [ alpha ]_D+12.8 ° (c ═ 1.0, methanol);¹NMR (DMSO). delta.1.18 (t, 6H), 1.24(t, 6H), 1.63(m, 2H), 2.47(m, 4H), 2.87(br, 2H), 3.38(q, 2H), 3.57(br, 2H), 4.32(t, 1H), 4.42(t, 1H), 6.74(d, 1H), 6.83(d, 1H), 7.03(s, 1H), 7.17(t, 1H), 7.30(m, 4H) analysis.

(C₂₄H₃₅NO₂＊1.0HCl)C，H，N.

The starting compound (R) -N, N-diisopropyl-3- [ 5- (2-ethoxycarbonylethyl) -2-hydroxyphenyl ] -3-phenylpropylamine was prepared as follows:

29.1 (R) -N, N-diisopropyl-3- [ 2-benzyloxy-5- (2-ethoxycarbonylethyl) phenyl ] -3-phenylpropylamine

A solution of triethyl phosphonoacetate (6.93mL, 34.92mmol) in THF (50mL) was added dropwise to NaH (0.84g, 29.10mmol, 80%). The resulting mixture was cooled to 0 ℃ and a solution of (R) -N, N-diisopropyl-3- (2-benzyloxy-5-formylphenyl) -3-phenylpropylamine (prepared as described in example 17.1) (5.00g, 11.64mmol) in THF (50mL) was added dropwise. The mixture was stirred at 0 ℃ for 3 hours. Evaporation ofThe residue was redissolved in toluene and washed twice with water. The organic layer was dried (MgSO₄) The solvent was evaporated to give 5.0g (86%) of product.

29.2 (R) -N, N-diisopropyl-3- [ 5- (2-ethoxycarbonylethyl) -2-hydroxyphenyl) -3-phenylpropylamine

(R) -N, N-diisopropyl-3- [ 2-benzyloxy) -5- (2-ethoxycarbonylethyl) phenyl ] -3-phenylpropylamine (3.0g, 5.98mmol) was treated as described in example 1.3. Yield 2.0g (81%);¹H NMR(CDCl₃)δ 1.08(d，6H)，1.12(d，6H)，1.18(t，3H)，2.05(m，2H)，2.37(m，4H)，2.72(t，2H)，3.22(m，2H)，4.03(q，2H)，4.48(m，1H)，6.55(s，1H)，6.86(m，2H)，7.28(m，5H).

example 30

N, N-diisopropyl-3- (5-ethylaminomethyl-2-hydroxyphenyl) -3-phenylpropylamine

(R) -N, N-diisopropyl-3- (5-formyl-2-hydroxyphenyl-3-phenylpropylamine (prepared in example 7.1) (1.23g, 3.62mmol) was dissolved in methanol (20mL), ethylamine [ 3.62mL, 21.7mmol (6M in methanol hydrochloride) ] and sodium cyanoborohydride (0.14g, 2.17mmol) were added, the mixture was stirred at room temperature overnight, the solvent was evaporated, the residue was chromatographed over silica gel (toluene: ethyl acetate: triethylamine, 7: 3: 1), the product was dissolved in diethyl ether, diethyl ether containing hydrogen chloride was added, the resulting oil was stirred in diethyl ether overnight to give a crystal, yield 0.70g (44%), (m.p. 140-_D-5.0 ° (c ═ 0.5, methanol);

¹H NMR(CD₃OD) δ 1.30(m, 15H), 2.59(m, 2H), 3.05(m, 4H), 3.70(m, 2H), 4.07(s, 2H), 4.42(t, 1H), 6.85(d, 1H), 7.20(m, 2H), 7.30(t, 2H), 7.41(d, 2H), 7.50(s, 1H) assay (C)₂₄H₃₆N₂O＊2.0HCl＊0·5H₂O)C，H，N.

Example 31

N-cyclobutyl-N-methyl-3- (2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

A solution of N-cyclobutyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (1.60g, 3.44mmol) in acetic acid was hydrogenated with Pd/C (160mg, 10%) overnight at room temperature. The solution was basified with sodium hydroxide (11M) and the mixture was filtered. The filtrate was extracted with ethyl acetate and dried (MgSO)₄) The solvent is evaporated. The residue was chromatographed on silica gel (toluene: triethylamine, 9: 1). The free amine was dissolved in ether and ethereal hydrogen chloride was added to give an oil. This oil was crystallized from 2-propanol to give 0.90g (79%) of product; melting point 153-155 ℃;¹H NMR(CD₃OD) δ 1.78(m, 2H), 2.22(m, 4H), 2.48(m, 2H), 2.72(s, 3H), 2.95(br, 2H), 3.68(m, 1H), 4.44(t, 1H), 6.78(t, 1H), 6.79(d, 1H), 7.03(t, 1H), 7.12(d, 1H), 7.18(t, 1H), 7.28(t, 2H), 7.34(d, 2H); analysis (C)₂₀H₂₅NO 1.0HCl 0.32-propanol) C, H, N.

The starting compound, N-cyclobutyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine, was prepared as follows:

31.1N-cyclobutyl-3- (2-benzyloxy-5 \ bromophenyl) -3-phenylpropylamine

5M HC 1-methanol (3.50mL, 17.\1mmol) was added to a solution of cyclobutylamine (4.50mL, 53.15mmol) in methanol (14 mL). This mixture was added to 3- (2-benzyloxy-5-bromophenyl) -3-phenylpropionaldehyde (example 20.1) (3.50g, 8.86mmol) and sodium cyanoborohydride (0.389g, 6.20mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel (toluene: ethyl acetate: triethylamine, 92: 4). Yield 2.61g (65%);¹H NMR(CDCl₃)δ 1.57(m，5H)，2.14(m，4H)，2.47(t，2H)，3.16(m，1H)，4.45(t，1H)，5.00(s，2H)，6.75(d，1H)，7.10-7.47(m，12H).

31.2N-cyclobutyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine

5M HCl-methanol (0.46mL, 2.32mmol), formaldehyde (0.870g, 28.97mmol) and sodium cyanoborohydride (0.255g, 4.056mmol) were added to a solution of N-cyclobutyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (2.61g, 5.79mmol) in methanol (8 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel (hexane: triethylamine, 9: 1). Yield 1.59g (59%);¹H NMR(CDCl₃)δ1.59(m，2H)，1.73(m，2H)，1.91(m，2H)，2.06(s，3H)，2.16(m，4H)，2.68(m，1H)，4.38(t，1H)，5.00(s，2H)，6.72(d，1H)，7.12-7.58(m，12H).

example 32

N-cyclopentyl-N-methyl-3- (2-hydroxyphenyl) -3-phenylpropylamine hydrochloride

N-cyclopentyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (2.46g, 5.14mmol) was treated as described in example 31. The crude product was crystallized without chromatography from ethanol/water. Yield 1.24g (70%),

¹H NMR(DMSO)δ 1.48(br，1H)，1.66(br，2H)，1.85(br，1H)，2.46(br，2H)，2.68(s，3H)，2.87(br，2H)，3.53(m，1H)，4.35(t，1H)，6.77(t，1H)，6.83(d，1H)，7.01(t，1H)，7.16(t，1H)，7.27(t，3H)，7.33(d，2H)，9.57(br，1H)，10.85(br，1H)；

melting point 169-172 ℃; analysis (C)₂₁H₂₇NO*HCl)C，H，N。

The starting compound, N-cyclopentyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine, was prepared as follows:

3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (prepared as described in example 20.1) (7.00g, 17.71mmol) was reacted with cyclopentylamine as described in example 31.1. Yield 4.9g (59%);¹H NMR(CDCl₃)δ 1.20(m，2H)，1.40-1.80(m，6H)，2.18(m，2H)，2.55(t，2H)，2.98(m，1H)，4.45(t，1H)，5.00(s，2H)，6.75(d，1H)，7.10-7.45(m，12H).

32.2N-cyclopentyl-N-methyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine

A solution of N-cyclopentyl-3- (2-benzyloxy-5-bromophenyl) -3-phenylpropylamine (3.50g, 7.53mmol) was treated as described in example 31.2. Yield 2.46g (68%);

¹H NMR(CDCl₃)δ 1.10-1.80(m，8H)，2.19(m，5H)，2.36(m，2H)，2.58(m，1H)，4.37(t，1H)，4.98(s，2H)，6.72(d，1H)，7.10-7.50(m，12H).

example 33

N, N-diisopropyl-3- (2-aminophenyl) -3-phenylpropylamine hydrochloride

LAH (0.94g, 24.8mmol) was added to a solution of N, N-diisopropyl-3- (2-aminophenyl) -3-phenylpropylamine (1.6g, 4.98mmol) in THF (90 mL). The mixture was allowed to stir at room temperature for 72 hours. The reaction was quenched and the solvent was evaporated. The crude residue was purified on a reverse phase PEP RPC HR30/26 preparative column (Pharmacia Biotech AB, Sweden) eluting with 20% acetonitrile containing i% TFA. Hydrochloric acid was added to the pure distillate and the solvent was evaporated. The residue was redissolved in water and lyophilized to give 88mg (5%) of product; melting point: 138 ℃ and 142 ℃;

¹H NMR(DMSO)δ 1.25(m，12H)，2.47(m，1H)，2.65(m，1H)，2.87(m，1H)，3.13，(m，1H)，3.59(br，2H)，4.58(t，1H)，7.20-7.37(m，5H)，7.42(m，2H)，7.54(d，2H)，9.94(br，2H).

analysis C₂₁H₃₀N₂·HCl·H₂O) C, H, H: calculated values: 8.5; measured value: 7.9.

the starting compound, N-diisopropyl-3- (2-aminophenyl) -3-phenylpropylamine, was prepared as follows:

33.12- (3, 5-dimethyl-4-hydroxyphenylazobenzophenone)

Ice (500mL), hydrochloric acid (16.8mL, 202mmol, conc.), 2-aminobenzophenone (20.00g, 101mmol) and NaNO were stirred together₂(9.0g，131mmol) was added to a solution of 2, 6-dimethylphenol (18.40g, 151mmol) and sodium hydroxide (16.20g, 404mmol) in ice water (100 mL). After 20 minutes, the mixture was extracted with diethyl ether. With hydrochloric acid (6M), NaHCO₃The organic phase was washed (aqueous solution) and dried (MgSO)₄) The solvent was then evaporated. The crude residue was chromatographed on silica gel (toluene), the pure eluates combined and evaporated to a red oil. This oil was crystallized from hexane/toluene to yield 7.73g (23%) of product.

33.22- (3, 5-dimethyl-4-toluenesulfonyloxyphenylazo) benzophenone A mixture of 2- (3, 5-dimethyl-4-hydroxyphenylazo) benzophenone (7.73g, 23.41mmo1) and tosyl chloride (9.4g, 49mmol) in pyridine (20mL) was stirred at 90 ℃ for 9 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with sodium hydroxide (2M) and hydrochloric acid (2M) and dried (MgSO)₄) The solvent is evaporated. The product was crystallized from ethanol to yield 7.6g (67%) of product.¹H NMR(CDCl₃)δ 2.08(s，6H)，2.49(s，3H)，7.05(s，2H)，7.37(m，4H)，7.48(m，1H)，7.62(m，3H)，7.82(m，5H).

33.3N, N-diisopropyl-3- [ 2- (3, 5-dimethyl-4-toluenesulfonyloxyphenyl-azo) phenyl ] -3-phenylacrylamide

2- (3, 5-dimethyl-4-toluenesulfonyloxyphenylazo) benzophenone (7.22g, 14.9mmol) was treated as described in example 4.2 but reacted with 3 equivalents of diethyl N, N-diisopropylacetamidophosphonate and sodium hydride. Yield 4.5g (50%).¹H NMR(CDCl₃)δ0.72(d，3H)，0.82(br，3H)，1.28(d，3H)，1.42(d，3H)，2.10(s，3H)，2.14(s，3H)，2.45(s，3H)，3.25(m，1H)，4.28(m，1H)，6.05and6.63(s，1H)，7.00-7.90(m，15H).

33.4N, N-diisopropyl-3- [ 2- (3, 5-dimethyl-4-hydroxyphenyl-azo) phenyl ] -3-phenylacrylamide

Potassium hydroxide (10.3mL, 6M) and N, N-diisopropyl-3- [ 2- (3, 5-dimethyl-4-toluenesulfonyloxyphenyl-azo-group)) A solution of phenyl ] -3-phenylacrylamide (3.5g, 5.74mmol) in ethanol (110mL) was refluxed for 1 hour. The mixture was acidified with hydrochloric acid (concentrated) and the solvent was evaporated. The residue was partitioned between toluene and water. The organic layer was dried (MgSO₄) The solvent is evaporated. The crude residue was chromatographed on silica gel (toluene: ethyl acetate, 9: 2). Yield 1.3g (50%).¹H NMR(CDCl₃)δ 0.71(d，3H)，0.80(br，3H)，1.27(d，3H)，1.40(d，3H)，2.20(s，3H)，2.23(s，3H)，3.25(m，1H)，4.35(m，1H)，5.52(brd，1H)，6.05 and 6.60(s，1H)，7.00-7.80(m，11H).

3.5N, N-diisopropyl-3- (2-aminophenyl) -3-phenylacrylamide

N, N-diisopropyl-3- [ 2- (3, 5-dimethyl-4-hydroxyphenyl-azo) phenyl ] -3-phenylacrylamide (2.58g, 5.68mmol) was treated as described in example 28.3. The crude residue was crystallized from aqueous ethanol. Yield 1.23g (67%).

Example 34

N, N-diisopropyl-3- (benzoxazol-2-yl) -3-phenylpropylamine hydrochloride

A mixture of N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropylamine (2.51g, 8.6mmol), 75% aqueous ethanol (15mL), and 2M NaOH (8.5mL, 17mmol) was refluxed overnight. After evaporation of the solvent, the residue was acidified with 2M HCl and the solvent was evaporated. The remaining semi-crystalline oily mixture was heated at 200 ℃ for 2 hours under nitrogen with ortho-aminophenol (1.8g, 16.5mmol) and polyphosphoric acid (12 g). The slightly cooled hard solid was dissolved in water and washed once with ether. The aqueous phase was basified (11M NaOH) and extracted twice with ether. The combined organic phases were dried (Na)₂SO₄) The solvent is evaporated. The crude product is chromatographed on silica gel (petroleum ether/triethylamine, 97: 3). Pure amine hydrochloride precipitated from ether as white crystals, 1.27g (39%); melting point 197-198 deg.C;

¹H NMR(CDCl₃)δ

1.49(m，12H)，2.80-3.20(m，4H)，3.48(br，2H)，4.45(t，1H)，7.25-7.48(m，8H)，7.70(m，1H)，11.48(br，1H).

the starting compound N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropylamine was prepared as follows: 34.1N, N-diisopropyl-3-cyano-3-phenylpropylamine

An 80% dispersion of sodium hydride (2.82g, 94mmol) in mineral oil was washed with petroleum ether and dried under a stream of nitrogen. Anhydrous DMF (100mL) was added. Benzyl cyanide (12.1g, 103mmol) was added to the stirred suspension over 20 min. The temperature was increased to about 45 ℃. The mixture was stirred for a further 15 minutes. 2-chloroethyl-diisopropylamine (15.4g, 94mmol) was added. This amine was completely consumed in 30 minutes. Under reduced pressure, most of the DMF was evaporated and the residue was dissolved in water/diethyl ether. The aqueous phase was extracted once with ether and the combined organic phases were evaporated twice with 2M HCl. The combined aqueous phases were basified (11M NaOH) and extracted twice with ether. The combined organic phases were then dried (Na)₂SO₄) The solvent is evaporated. The crude product was subjected to silica gel chromatography (petroleum ether: triethylamine, 40: 1) to give the title compound, 16.8g (67%) as a colorless liquid.¹H NMR(CDCl₃)δ 1.01(m，12H)，1.97(m，2H)，2.62(m，2H)，3.00(m，2H)，4.02(dd，1H)，7.17-7.40(m，5H).

4.2N, N-diisopropyl-3-carbamoyl-3-phenylpropylamine

N, N-diisopropyl-3-cyano-3-phenylpropylamine (11.6g, 47.5mmol) was reacted with H₂SO₄(90%, 100mL) and the mixture was stirred at 100 ℃ for 30 minutes. The reaction mixture was poured into ice, basified (11M NaOH), and extracted twice with ether. The combined organic phases were dried (Na)₂SO₄) After which the solvent was evaporated to give the title compound as a colourless oil, 12.4g (100%);¹H NMR(CDCl₃)δ 1.26(m，12H)，2.14(m，1H)，2.60(m，1H)，2.73(t，2H)，3.31(m，2H)，3.86(t，1H)，6.06(br，2H)，7.51-7.61(m，5H).

34.3N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropylamine

N, N-diisopropyl-3-carbamoyl-3-phenylpropylamine (26.5g, 0.100mol) was added to a solution containing concentrated HNO₃(13.3g, 0.21mol) in an aqueous ethanol solution (90%, 300mL) was refluxed for five days. Most of the solvent was evaporated under reduced pressure and the residue was mixed with water/diethyl ether. The organic phase was washed once with water. The combined aqueous phases were basified (11M NaOH) and extracted twice with ether. The organic phase is then dried (Na)₂SO₄) The solvent is evaporated. The crude product was subjected to silica gel chromatography (petroleum ether: triethylamine, 97: 3) to give the title compound as a colorless liquid, 20.1g (68.7%);

¹H NMR(CDCl₃)δ 0.96(m，12H)，1.21(t，3H)，1.81(m，1H)，2.22(m，1H)，2.40(t，2H)，3.66(dd，1H)，4.12(m，2H)，7.20-7.32(m，5H).

example 35

N, N-diisopropyl-3- (oxazol-5-yl) -3-phenylpropylamine hydrochloride

The freshly distilled methyl isocyanide (1.66g, 40.4mmol) was dissolved in anhydrous THF (75mL) under nitrogen and the mixture was cooled to-78 ℃. 1.4M N-butyllithium (29mL, 40.5mmol) was slowly added to the solution, followed by a solution of N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropylamine (4.71g, 16.2mmol) in THF (10 mL). The reaction temperature was raised to-20 ℃ and quenched with HOAc (10mL) at this temperature. The solvent was evaporated and the residue was mixed with ether/water. The organic phase was washed once with water, the combined aqueous phases were basified with 11M NaOH and extracted twice with ether. The organic phases are combined and dried (Na)₂SO₄) The solvent is evaporated. The crude product was chromatographed on silica gel (chloroform: methanol: concentrated ammonia, 490: 10: 1). Precipitation of pure amine with HCl saturated ether afforded the title compound as a glassy oil, 1.4g (48%).¹H NMR(CD₃OD)δ 1.21-1.40(m，12H)，2.57(m，1H)，2.68(m，1H)，2.91(m，1H)，3.23(m，1H)，3.72(m，2H)，4.41(dd，1H)，7.39(m，5H)，7.52(s，1H)，9.13(s，1H).

Example 36

N, N-diisopropyl-3- (imidazol-4 (5) -yl) -3-phenylpropylamine dihydrochloride

N, N-diisopropyl-3-oxazol-5-yl-3-phenylpropionamide (0.76g, 2.6mmol) was mixed with formamide (5 mL). The mixture was heated to 175 ℃ and reacted for 6 hours. The solvent was evaporated in vacuo (1mmHg) and the residue partitioned between 1M HCl and ether. The aqueous phase was basified (11M NaOH) and extracted twice with ether. The combined organic phases were dried (Na)₂SO₄) The solvent is evaporated. The light brown oil was dissolved in diethyl ether and added to a suspension of Lithium Aluminium Hydride (LAH) (0.70g, 5.4mmol) in diethyl ether. The reaction mixture was stirred at room temperature overnight. The reaction was quenched and the solvent was evaporated. The crude amine was dissolved in ethyl acetate and the hydrochloride salt precipitated from HCl saturated diethyl ether to afford the title compound as hygroscopic crystals, 0.32g (35%);¹HNMR(CDCl₃)δ 1.38(m，12H)，2.80(m，2H)，3.00(m，1H)，3.16(m，1H)，3.64(br，2H)，4.41(m，1H)，6.89(s，1H)，7.27-7.41(m，5H)，8.78(s，1H)，10.32(br，2H).

the starting compound N, N-diisopropyl-3-oxazol-5-yl-3-phenylpropionamide (0.76g, 2.6mmol) was prepared as follows:

36.13-cyano-3-phenylpropionic acid

Ethyl cinnamate (85.3g, 0.484mol), potassium cyanide (64.2g, 0.986mol) and ammonium chloride (38.9g, 0.726mol) were mixed with DMF aqueous solution (90%, 360 mL). The mixture was stirred at 105 ℃ for 7 hours. The slightly cooled mixture was filtered and most of the DMF was evaporated. The residue was dissolved in diethyl ether and 1M HCl. The aqueous phase was extracted twice with diethyl ether. The combined ether phases were evaporated, the black oil was suspended in ethanol (200mL) and 2M NaOH (250mL) and stirred at room temperature for 2 h. The mixture was diluted with brine (200mL) and water (400mL) and washed twice with diethyl ether. After acidification (2M HCl), the aqueous phase was extracted three times with ether. The organic phase was dried (MgSO)₄) The solvent was evaporated to give the title compound as a black oil, 74g (87%);

¹H NMR(CDCl₃)δ 1.05(d，3H)，1.17(d，3H)，1.22(d，6H)，2.68(dd，1H)，3.16(dd，1H)，3.4(br，1H)，3.76(m，1H)4.19(dd，1H)，7.31(m，5H)，8.9(br，1H).

36.2N, N-diisopropyl-3-cyano-3-phenylpropionamide

3-cyano-3-phenylpropionic acid (67.7g, 0.389mol) was dissolved in 2-PrOH. KOH (18.4g, 0.33mol) dissolved in 2-PrOH (200mL) was carefully added to the filtered acid solution, diethyl ether (100mL) was added and the precipitate was filtered off. The dried acid salt (51.9g, 0.24mol) was suspended in benzene (400mL) and oxalyl chloride was carefully added. The reaction mixture was stirred at 80 ℃ for 2 hours. The solvent was evaporated and the residue was co-evaporated twice with benzene. The brown oil was dissolved in benzene (200mL) and cooled in an ice bath. A solution of diisopropylamine (82g, 0.81mol) in benzene (200mL) was added to the reaction mixture over 45 minutes with stirring. The mixture was allowed to warm slowly to room temperature and reacted overnight. The solvent was evaporated and the residue was dissolved in ether and 1M HCl. The organic phase was washed successively with water, 1M NaOH, water and then dried (Na)₂SO₄) The solvent was evaporated to give the title compound as a dark brown oil, 41.7g (41%);

¹H NMR(CDCl₃)δ 1.07(d，3H)，1.17(d，3H)，1.36(m，6H)，2.77(m，1H)，2.97(m，1H)，3，51(br，1H)，3.81(m，1H)，4.50(dd，1H)，7.39(m，5H).

36.3N, N-diisopropyl-3-carbamoyl-3-phenylpropanamide

N, N-diisopropyl-3-cyano-3-phenylpropionamide (21.1g, 82mmol) was dissolved in ethanol (130mL) and 2M NaOH (100 mL). Hydrogen peroxide (30%, 20.2mL, 200mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered, washed with water and dried to give the title compound as white crystals, 15.6g (69%):

¹H NMR(CDCl₃)δ 1.09(d，3H)，1.19(d，3H)，1.31(m，6H)，2.51(dd，1H)，3.30(dd，1H)，3.41(m，1H)，4.02(m，1H)，4.18(dd，1H)，5.7(br，1H)，6.4(br，1H)，7.21-7.42(m，5H).

36.4N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropionamide

Treatment of N, N-diisopropyl-3-carbamoyl-3-phenylpropanamide (refluxed for two days without chromatography) as described in example 34.3 gave the title compound as a colorless semi-crystalline oil, 15.9g (93%);¹H NMR(CDCl₃)δ 1.19(m，9H)，1.36(m，6H)，2.53(dd，1H)，3.18(dd，1H)，3.4(br，1H)，3.98(m，1H)，4.15(m，3H)，7.31(m，5H).

36.5N, N-diisopropyl-3-oxazol-5-yl-3-phenylpropionamide

The procedure described above for example 35 was followed, starting from N, N-diisopropyl-3-ethoxycarbonyl-3-phenylpropionamide. Chromatography of the crude product on silica gel (petroleum ether: ethyl acetate, 3: 2) gave the title compound as a pale yellow oil, 0.77g (46%);

¹H NMR(CDCl₃)δ 1.00(d，3H)，1.14(d，3H)，1.29(m，6H)，2.98(m，2H)，3.4(br，1H)，3，93(m，1H)，4.79(t，1H)，6.82(s，1H)，7.28(m，5H)，7.76(s，1H).

example 37

N, N-diisopropyl-3- (oxazol-2-yl) -3-phenylpropylamine hydrochloride

A mixture of N, N-diisopropyl-3-carbamoyl-3-phenylpropylamine prepared in example 34.2 (4.05g, 15.4mmol), 1, 2-dichloroethyl: ethyl ether (2.32g, 16.2mmol), water (0.300g, 16.6mmol) and formic acid (50mL) was stirred at 75 ℃ for 3 h. The formic acid was evaporated off and the residue was dissolved in water/diethyl ether. The aqueous phase was basified (11M NaOH) and extracted twice with ether. The organic phase was dried (Na)₂SO₄) The solvent is evaporated. The crude product is chromatographed on silica gel (petroleum ether: triethylamine, 97: 3). The pure amine was precipitated with ether saturated with HCl to give the hydrochloride salt,the title compound was obtained as white crystals, 0.61g (12%): melting point 157-;

¹H NMR(DMSO(d₆))δ 1.11(m,12H),2.35(m,1H),2.63(m,1H),3.03(m,2H),3.56(m,2H),4.451H),7.21-7.40(m,6H)8.06(d,1H),10.20(br,1H)

example 38

N, N-diisopropyl-3-phenyl-3- (thiazol-2-yl) propylamine hydrochloride

The title compound was prepared in a similar manner as described for example 37. From N, N-diisopropyl-3-phenyl-3-thiocarbamoylpropylamine (1.11g, 4.0mmol) the title compound was obtained as white crystals, 1.12g (82%): melting point 155-;

preparation of the starting Compound N, N-diisopropyl-3-phenyl-3-thiocarbamoylpropylamine 38.1N, N-diisopropyl-3-phenyl-3-thiocarbamoylpropylamine

To a solution of N, N-diisopropyl-3-cyano-3-phenylpropylamine prepared in example 34.1 (3.45g, 14.3mmol) and triethylamine (2.0g, 20mmol) in anhydrous pyridine (10mL) was added H₂S gas until saturated. Is characterized in that H₂Stirring for 5 days at 65 ℃ under an atmosphere of S. Pyridine was evaporated and the crude product was chromatographed on silica gel (chloroform: methanol: concentrated aqueous ammonia, 380: 20: 1) to give the title compound as a colorless glassy oil, 3.1g (78%):

¹H NMR(CDCl₃)δ0.99

(m，12H)，2.07(m，1H)，2.40(m，3H)，3.05(m，2H)，4.10(t，1H)，7.20-7.45(m5H)，7.7-8.1(b，1H)，8.0-8.5(br，1H.

example 39

N, N-diisopropyl-3- (4-methylthiazol-2-yl) -3-phenylpropylamine hydrochloride

The title compound was prepared in a similar manner as described for example 37. N, N-diisopropyl prepared from example 38.1-3-phenyl-3-thiocarbamoylpropylamine (1.5g, 5.4mmol) with 2-chloropropanone (0.75g, 8.1mmol) gives the title compound as a white amorphous mass, 1.1g (56%): melting point 178-;¹H NMR(CDC1₃)δ 1.44(m，12H)，2.50(s，3H)，2.98(m，3H)，3.18(m，1H)，3.60(m，2H)，6.94(d，1H)，7.30-7.47(m，5H)，11.15(br，1H).

example 40

N, N-diisopropyl-3- (thiazol-5-yl) -3-phenylpropylamine hydrochloride

The title compound was prepared in a similar manner as described for example 35. Reaction with N, N-diisopropylamino-3-ethoxythiocarbonyl-3-phenylpropylamine (1.14g, 3.7mmol) gave a crude product which was chromatographed on silica gel (petroleum ether: triethylamine, 97: 3) to give the title compound as white crystals, 0.19g (30%); melting point 193-;

¹H NMR(CDCl₃)δ 1.1.34(m，12H)，2.85(m，4H)，5.56(m，2H)，4.29(t，1H)，7.26-7.39(m，5H)，7.73(s，1H)，8.71(s，1H)11.61(br，1H)..

the starting compound N, N-diisopropylamino-3-ethoxythiocarbonyl-3-phenylpropylamine was prepared as follows:

40.1N, N-diisopropyl-3-ethoxythiocarbonyl-3-phenylpropylamine

To N, N-diisopropyl-3-cyano-3-phenylpropylamine prepared in example 34.1 (2.9g, 12mmol) in absolute ethanol (50mL, molecular sieves)) Into the ice-cooled solution, HCl gas was introduced until saturation. The reaction was stirred under HCl atmosphere at room temperature overnight. The solvent was carefully evaporated and the residual oil was dissolved in anhydrous pyridine (100 mL). To this solution triethylamine (5.7g, 56mmol) was added and the resulting dark suspension was purged with H₂S gas until saturated. Reaction mixture with dark olive green color in H₂S atmosphere and standing overnight at 65 ℃. Evaporation of the solvent, residueThe material was partitioned between 1M HCl and ether, the aqueous phase was basified (11M NaOH), and extracted twice with ether. The organic phase was dried (Na)₂SO₄) The solvent is evaporated. Chromatography of the crude product on silica gel (chloroform: methanol: concentrated aqueous ammonia, 198: 1) gives the title compound as a pale yellow liquid, 1.24g (33%):¹H NMR(CDCl₃)δ 0.95(m，12H)，1.34(t，2H)，1.97(m，1H)，2.37(m，3H)，2.98(m，2H)，4.10(t，1H)4.46(m，2H)，7.13-7.39(m，5H).

EXAMPLE 41

N, N-diisopropyl-3- (2-hydroxyphenyl) -3- (2-thienyl) -propylamine fumarate

To a suspension of Lithium Aluminum Hydride (LAH) (0.51g, 13.3mmol) in THF (30mL) was added N, N-diisopropyl-3- (2-hydroxyphenyl) -3- (2-thienyl) propionamide (2.0g, 5.33mmol), and the mixture was heated to 50 ℃ overnight. The reaction mixture was quenched and the solvent was evaporated. The residue was dissolved in ether, extracted twice with 2M HCl and the combined aqueous phases washed twice with ether. Basified aqueous phase (11M NaOH), extracted three times with ether, washed the combined organic phases once with brine, dried (MgSO)₄) The solvent is evaporated. Crystallisation of its fumarate salt from methanol gives the title compound as white crystals, 1.52g (58%): melting point 203-;

¹H NMR(DMSO)δ 1.00(d，12H)，2.02(q，2H)，2.33(m，2H)，3.18(m2H)，4，62(t，1H)，6.50(s，1H)，6.68-7.18(m，6H)，7.28(t，1H).

the starting compound N, N-diisopropyl-3- (2-hydroxyphenyl-3- (2-thienyl) propanamide was prepared as follows:

41.1N, N-diisopropyl-3- (2-thienyl) acrylamide

Under nitrogen, 2-bromothiophene (2.28g, 14.0mmol), N-diisopropylacrylamide (1.55g, 10.0mmol), palladium (II) acetate (34mg, 0.15mmol), tri-o-tolylphosphine (183mg, 0.6mmol), tri-N-butylamine (2.04g, 11.0mmol) and anhydrous D were combinedMF (5 mL). The mixture was heated to 130 ℃ and reacted for 9 hours. Diethyl ether and water were added to the slightly cooled mixture. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed twice with 2M HCl, once with water, once with brine and dried (MgSO)₄) The solvent is evaporated. Chromatography of the crude product on silica gel (petroleum ether: ethyl acetate, 4: 1) gave a yellow oil, 1.58g (66%):¹H NMR(CDCl₃)δ1.35(br，12H)，3.9(br，1H)，4.1(br1H)，6.65(d，1H)，7.00-7.30(m，3H)，7.72(d，1H).

41.22-Methoxyphenyllithium

2-Methoxybromobenzene (8.44g, 45.1mmol) was dissolved in anhydrous ether (15 mL). The mixture was cooled to-78 ℃. N-butyllithium (17.8mL, 45.0mmol) was added, and the mixture was stirred at-78 ℃ for one hour and then at-10 ℃ for 20 minutes. The aryl lithium solution is used immediately.

41.3N, N-diisopropyl-3- (2-methoxyphenyl) -3- (2-thienyl) propanamine

Copper (I) bromide-dimethyl sulfide complex (4.63g, 22.5mmol) was dissolved in dimethyl sulfide (18mL) and diethyl ether (15 mL). The solution was cooled to 0 ℃ and 2-methoxyphenyllithium (example 41.2) (45mmol) was added. After 10 minutes, the temperature was reduced to-78 ℃. Trimethylsilyl chloride (4.89g, 45.0mmol) was added, followed by a solution of N, N-diisopropyl-3- (2-thienyl) acrylamide (example 41.1) (3.56g, 15mmol) in diethyl ether (20 mL). The temperature was slowly raised to room temperature overnight. With saturated NH₄The reaction was quenched with concentrated aqueous ammonia (10 mL). Ether (80mL) was added and the mixture was filtered through celite. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed once with brine and dried (MgSO)₄). The solvent was evaporated and the crude product was chromatographed on silica gel (petroleum ether: ethyl acetate, 3: 1) to give a yellow oil, 3.75g (73%):

¹H NMR(CDCl₃)d 1.12(t，6H)，1.29(t，6H)，3.02(m，2H)，3.4(br，1H)，3.80(s，3H)，4.03(m，1H)，5.26(t，1H)，6.8-7.3(m，7H).

41.4N, N-diisopropyl-3- (2-hydroxyphenyl) -3- (2-thienyl) propanamide

A solution of N, N-diisopropyl-3- (2-methoxyphenyl) -3- (2-thienyl) propanamide (2.37g, 6.9mmol) in dichloromethane (35mL) was cooled to-78 deg.C and boron tribromide (5.9g, 23.57mmol) was added. The reaction mixture was slowly warmed to room temperature. The reaction was quenched by the slow addition of water (20 mL). With NaHCO₃(solid) pH adjusted to about 6 with CH₂Cl₂The mixture was extracted three times. The combined organic phases were washed once with brine and dried (MgSO)₄) The solvent was then evaporated. This crude product (2.46g, 107%) was used directly without further purification.

¹H NMR(CDCl₃)δ 1.05(d，3H)，1.20(m，6H)，1.35(d，3H)，3.16(m，2H)，3.4(br，1H)，4.0(m，1H)，5.24(dd.1H)，6.7-7.2(m，7H).

Examples 42-54 and 57 and 58 were prepared as described in example 41 starting from the appropriate acrylamide and aryl bromide.

Example 42

N, N-diisopropyl-3- (2, 4-dihydroxyphenyl) -3- (2-thienyl) propanamine

The crude product was crystallized from petroleum ether/ethyl acetate to give the title compound, 0.41g, as pale pink crystals: melting point 102-,¹H NMR(CDCl₃)δ 1.11(m，12H)，2.01(m，1H)，2.41(m，2H)，2.72(m，1H)，3.26(m，2H)，4.66(dd，1H)，6.30(dd，1H)，6.45(d，1H)，6.73(d，1H)，6.91-7.00(m，2H)，7.17(dd，1H).

example 43

N, N-diisopropylamino-3- (2-methoxyphenyl) -3- (2-thienyl) propanamine fumarate

White crystals, 0.95 g: melting point 153-155 ℃;¹H NMR(CD₃OD)δ1.28(m，12H)，2.48(m，2H)，3.05(m，2H)，3.68(m，2H)，3.85(s，3H)，4.71(t，1H)，6.68(s，2H)，6.89-7.03(m，4H)，7.20-7.30(m，3H).

example 44

N, N-diisopropyl-3- (2, 4-dimethoxyphenyl) -3- (2-thienyl) propylamine fumarate

White crystals, 1.52 g: melting point 103-;¹H NMR(CD₃OD)δ1.28(m，12H)，2.46(m，2H)，3.04(m，2H)，3.66(m，2H)，3.77(s，3H)，3.82(s，3H)，4.60(t，1H)，6.46-6.58(m，2H)，6.68(s，2H)，6.91-6.97(m，2H)，7.09-7.26(m，2H).

example 45

N, N-diisopropyl-3- (3-methoxyphenyl) -3- (2-thienyl) propanamine hydrochloride

White crystals, 1.16 g; the melting point is 95-97 ℃;¹H NMR(CD₃OD)δ1.28(d，12H)，2.49(m，2H)，2.96(m，1H)，3.13(m，1H)，3.68(m，2H)，3.77(s，3H)，4.31(t，1H)，6.83(m，1H)，6.68-7.02(m，4H)，7.27(m，2H).

example 46

N, N-diisopropyl-3- (4-methoxyphenyl) -3- (2-thienyl) -propylamine hydrochloride as a white amorphous substance, 0.50 g; melting point 157-160 ℃;¹HNMR(CD₃OD)δ 1.31(m，12H)，2.47(m，2H)，2.94(m，1H)，3.12(m，1H)；3.68(br，2H)，3.77(s，3H)，4.28(t，1H)，6.87-7.00(m，4H)，7.23-7.32(m，3H).

example 47

N-isopropyl-N-methyl-3- (2-methoxyphenyl) -3- (2-thienyl) propanamine fumarate

White crystals, 1.32 g; melting point 141-;¹H NMR(CD₃OD) δ1.24(m，6H)，2.50(m，2H)，2.73(s，3H)，3.04(m，2H)，3.58(m，1H)，3.84(s，3H)，4.73(t，1H)，6.68(s，2H)，6.96(m，4H)，7.24(m，3H).

example 48

N, N-diisopropyl-3-phenyl-3- (2-thienyl) propanamine hydrochloride

White crystals, 0.74 g; melting point 165-166 ℃;¹H NMR(CD₃OD)1.28(d，12H)，2.52(m，2H)，2.96(m，1H)，3.13(m，1H)，3.70(br，2H)，4.34(t，2H)，6.92-7.04(m，2H)，7.20-7.42(m，6H).

example 49

N-cyclohexyl-N-methyl-3-phenyl-3- (2-thienyl) propanamine hydrochloride

White crystals, 1.1 g; melting point 197-;¹H NMR(CD₃OD)δ1.15-1.52(br，5H)，1.68(br，1H)，1.90(br，4H)，2.51(br，2H)，2.78(s，3H)，2.91-3.40(m，3H)，4.31(t，1H)，6.92-7.04(m，2H)，7.20-7.40(m，6H).

example 50

N, N-diethyl-3-phenyl-3- (2-thienyl) propanamine fumarate

White crystals, 1.7g (total yield 49%); melting point 135-;¹HNMR(CD₃OD)δ 1.22(t，3H)，2.50(m，2H)，2.90-3.26(m，6H)，4.30(t，1H)，6.68(s，2H)，6.92-7.03(m，2H)，7.20-7.40(m，6H).

example 51

N-isopropyl-N-methyl-3-phenyl-3- (2-thienyl) propanamine hydrochloride

White crystals, 1.6 g; melting point 139-144 ℃;¹H NMR(CD₃OD)δ1.24(m，6H)，2.52(m，2H)，2.75(s，3H)，3.03(m，2H)，3.59(m，1H)，4.32(t，1H)，6.92-7.04(m，2H)，7.20-7.40(m，6H).

example 52

N- [ 3-phenyl-3- (2-thienyl) propyl ] pyrrolidine fumarate

Crystallization from 2-propanol, 1.1 g; melting point 144-145 ℃;

¹H NMR(CD₃OD)δ 2.02(m，4H)2.31(m，2H)，2.97-3.42(m，6H)，4.29(t，1H)，6.69(s，2H)，6.91-7.01(m，2H)，7.18-7.38(m，6H).

example 53

N- [ 3-phenyl-3- (2-thienyl) propyl ] piperidine hydrochloride

The hydrochloride was crystallized from ethyl methyl ketone, 0.84 g; melting point 193-;

¹H NMR(CD₃OD)δ1.40-2.00(b，6H)，2.54(m，2H)，2.82-3.80(m，6H)，4.29(t，1H)，6.91-7.03(m，2H)，7.20-7.42(m，6H).

example 54

N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3- (2-thienyl) propylamine hydrochloride

White crystals, 2.1 g; melting point 205-;¹H NMR(CDCl₃)δ1.36(m，12H)，2.18(s，3H)，2.63(m，2H)，2.95(m，2H)，3.54(m，4H)，4.61(t，1H)，6.76-7.01(m，5H)，7.16(d，1H).

example 55

(R^*) N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3- (2-thienyl) propanamine

To a solution of the racemic free base of N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -2-thienylpropylamine (20g, 0.06mol, prepared in example 54) in anhydrous ethanol (50g) was added a solution of L- (+) -tartaric acid (9.5g, 0.063mol) in ethanol (60 g). The salt formed was filtered off, crystallized twice from ethanol/methanol (10/1) using 10ml per gram of crystals to give the title compound as white crystals (6.8g, 14.1 mmol): melting point 214-215 ℃; [ alpha ]_Hg+17.3 ° (c-3.82, methanol).

Example 56

(S^*) N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3- (2-thienyl) propanamine

The free base was recovered from the mother liquor obtained from the first crystallization to obtain (R) of example 55^*) N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3- (2-thienyl) propanamine. As described above, this amine was treated with an excess of 5% ethanol solution of D- (-) -tartaric acid to give the title compound as white crystals, 6.1g (12.7 mmol); melting point 214 ℃; [ alpha ]_Hg-17.5 ° (c-3.85, methanol).

Example 57

N, N-diisopropyl-3-phenyl-3- (3-thienyl) propanamine hydrochloride

White crystals, 0.94 g; melting point 141-;¹H NMR(CDCl₃)δ1.42(m，12H)，2.87(m，4H)，3.56(br，2H)，3.98(t，1H)，6.94(dd，1H)，7.27(m，7H)，11.4(br，1H).

the starting compounds were prepared as follows:

57.1N, N-diisopropyl-3- (3-thienyl) acrylamide

A60% dispersion of sodium hydride in mineral oil (3.9g, 98mmol) was washed several times with petroleum ether and dried under a stream of nitrogen. Sodium treated anhydrous THF was added followed by diethyl N, N-diisopropylacetamide phosphonate (27.4g, 98 mmol). When the evolution of gas had ceased, a solution of thiophene-3-carbaldehyde (10.0g, 89.2mmol) in THF (50mL) was added at a rate such that the temperature did not exceed 45 ℃. After stirring at room temperature for 1 hour, the reaction was quenched with 4mL of water and stirred for another 1 hour. The solvent was evaporated and the residue was dissolved in ether/2M NaOH. The organic phase was washed once with water and once with brine, dried (Na)₂SO₄) And then evaporated. Chromatography of the crude product on silica gel (petroleum ether: ethyl acetate, 4: 1) gave the title compound as a light brown oil, 14.8g (70%):¹H NMR(CDCl₃)δ 1.37(b，12H)，3.86(br，1H)，4.10(br，¹H)，6.68(d，1H)，7.27-7.41(m，3H)，7.59(d，1H).

example 58

N, N-diisopropyl-3- (2-furyl) -3-phenylpropylamine hydrochloride

White crystals, 60 mg; melting point 139-141 ℃;¹H NMR(CDCl₃)δ1.41(br，12H)，2.64(m，1H)，2.85(m，3H)，3.55(m，2H)，3.98(t，1H)，6.16(d，1H)，6.31(dd，1H)，7.30(m，6H)，11.4(br，1H).

the starting compounds were prepared as follows:

58.1N, N-diisopropyl-3- (2-furyl) acrylamide

The title compound was prepared as a colorless oil from furfural as described in example 57.1, 11.2g (75%);

¹HNMR(CDCl₃)δ 1.32(d，12H)，4.0(br，2H)，6.41(m，2H)，6.76(d，1H)，7.38(m，2H).

example 59

N, N-diisopropyl-3- (N-methylpyrrol-2-yl) -3-phenyl-propylamine fumarate

A solution of N, N-diisopropyl-3- (N-methyl-pyridin-2-yl) -3-phenyl-propionamide (4.92g, 15.7mmol) in THF (75mL) was added dropwise to a stirred mixture of LAH (2.38g, 62.8 mmol). Stirring was continued overnight at 50 ℃. A yellow oil was obtained by standard purification procedures and was isolated as fumarate salt, 2.74g (42%): the melting point is 134-6 ℃;¹H NMR(CD₃OD) δ 1.27(d, 6H), 1.29(d, 6H), 2.24(m, 1H), 2.48(m, 1H), 2.97(dt, 1H), 3.26(dt, 1H), 3, 32(s, 3H), 3.69 (heptad, 2H), 4.08(t, 1H), 6.05(t, 1H), 6.16(m, 1H), 6.57(dd, 1H), 6.71(s, 2H) and7.19-7.34(m, 5H).

The starting compounds were prepared as follows:

59.1N, N-diisopropyl-3- (N-methylpyrrol-2-yl) -acrylamide

Referring to example 4.2, prepared from N-methyl-2-pyrrolidinecarboxaldehyde and N, N-diisopropyl-dimethylphosphonoacetamide (N, N-diisopropy1-dimethyl phosphonamide) is the title compound prepared as 7.61g (92%):

¹H NMR(CDCl₃) δ 1.32(d, 6H), 1.35(d, 6H), 3.68(s, 3H), 4 · 00(m, 2H), 6.13(t, 1H), 6.55-6.66(3H) and7, 57(d, 1H).

59.2N, N-diisopropyl-3- (N-methylpyrrol-2-yl) -3-phenyl-propionamide

The title compound was prepared in analogy to the procedure described for example 41.3 from N, N-diisopropyl-3- (N-methylpyrrolidin-2-yl) -acrylamide to yield 4.92g (78%) of product:¹HNMR(CDCl₃) δ 0.85-1.32(4d rotamer, 12H), 2.91(d, 2H), 3.31(s, 3H)3.45(m, 1H), 3.88(m, 1H), 4.65(t, 1H), 6.07(2H), 6.50(dd, 1H) and 7.15-7.22(5H).

Example 60

3- (N-Methylpyrrol-2-yl) -3-phenyl-1-pyrrolidinopropane fumarate

Referring to example 59, the title compound was prepared using N, N-tetramethylene-dimethylphosphonoacetamide to yield 950mg (36%, total yield) of the product: the melting point is 194-5 ℃;

¹HNMR(CD₃OD) δ1.27(d，12H)，2.2-2.6(m，2H)3.05(m，2H)，3.66(sept.，2H)，4.03(t，1H)，6.02(_{two double peaks}2H), 6.64(t, 1H), 6.69(s, 2H) and 7.28(m, 5H).

Biological evaluation

The compounds prepared in the examples were tested for pharmaceutical activity in an in vitro method.

Study of in vitro function

Killing in a manner of hitting neckMale guinea pigs weighing about 300g were sacrificed and bled. The smooth muscle bundles of the bladder are dissociated in Krebs-Henseleit solution (pH 7.4). The fascicle samples were placed longitudinally on 2 hooks in a thermostatically (37 ℃) controlled organ bath (5 ml). One of the hooks is adjustable and connected to a load cell (FT03, Grass Instruments). Continuously introducing carbogold (93.5% O) into Krebs-Henseleit solution₂/6.5％CO₂) To maintain the pH at 7.4. Isometric tension (isometrisation) was recorded using Grass Polygraph (model 79D). The resting tension initially applied to each fascicle was about 5mN and the sample was allowed to stabilize for at least 45 minutes. The resting tension was repeatedly corrected and the samples were washed several times during the stabilization.

Carbachol (carbachol chloride) was used as a standard muscarinic receptor agonist. Each experiment was carried out by adding two consecutive times of carbachol (3X 10) in high concentration^-6M), the samples were first tested for viability and reproducibility of their contractile response. The concentration-response curve for kappa-buckles was obtained by cumulative addition of carbachol to the organ bath (i.e. stepwise increase of agonist concentration until maximal contractile response), followed by washing, with a rest period of at least 15 minutes before addition of a fixed concentration of test compound (antagonist) to the organ bath. After 60 minutes incubation with the antagonist, a second cumulative carbachol concentration-response plot was obtained. The response is expressed as a percentage of the maximal response relative to carbachol. The Ec50 values for carbachol were derived graphically and the dose ratio (r) was calculated without antagonist (control) and with antagonist. Calculating dissociation constant K of antagonist by equation (1)_B(Schild, H.I., Br.J.Pharmacol.Chemother, 1949, 4, 277-280), wherein [ A ] is the concentration of the test compound:

K_B＝〔A〕/r-1 (1)

obtained K_BThe values are shown in Table 1 below.

TABLE 1

Example numbering	KValue nM	Example numbering	KValue nM	Example numbering	KValue nM
						13456789101112131415161718192022	4992361323361013263.81714311.18154.515323.51722.933152.8	2324272829303132333435363738394041424344	1.051.917.18.551.5139143656803177326405202072358147.6286292285	45464748495051525355565960	5128691315901541183501542360690707

Claims (12)

1. A compound of formula (I)

Wherein:

R¹is hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy (C)_1-6Alkyl), trifluoromethyl, amino, (C)_1-6Alkyl) carbonylamino group, (C)_1-6Alkyl) carbonyloxy or halogen,

R²and R³Independently hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy (C)_1-6Alkyl), halogen, (C)_1-6Alkoxy) carbonyl (C)_1-6Alkyl), carbamoyl or aminosulfonyl,

R⁴is formyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, ethoxymethyl, methoxycarbonyl, amino, aminopropyl, acetyl, 1, 2-dihydroxyethyl, ethylaminomethyl or hydroxyethoxyethylaminoethyl,

R⁵is a hydrogen atom, and is,

ar is an aryl or heteroaryl group which may be mono-or independently di-substituted with a substituent which is C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy (C)_1-6Alkyl), halogen, (C)_1-6Alkoxy) carbonyl (C)_1-6Alkyl), carbamoyl or aminosulfonyl; and

R⁶and R⁷Are identical or different aliphatic C_1-6Alkyl, both together containing at least 4 carbon atoms, wherein R⁶And R⁷At least one carbon chain comprising a branch;

the precondition is that:

(i) when R is²And R³When not a hydrogen atom, or

(ii) When R is¹Not hydroxy or methoxy and Ar is not phenyl which is ortho-substituted by hydroxy or methoxy, or

(iii) When Ar is a heteroaryl group, the compound is,

then R is⁴Optionally hydroxymethyl;

salts of the compounds with physiologically acceptable acids, or when the compounds may exist in the form of optical isomers, racemic mixtures or individual enantiomers of the compounds.

2. The compound according to claim 1, wherein Ar is heteroaryl.

3. A compound according to claim 2, wherein R¹Is hydrogen orMethyl, and R²And R³Or both are hydrogen, or R²And R³One is methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen and the other is hydrogen.

4. A compound according to claim 1, wherein R¹Is hydrogen, C_1-6Alkyl, hydroxy (C)_1-6Alkyl), trifluoromethyl, amino, (C)_1-6Alkyl) carbonylamino group, (C)_1-6Alkyl) carbonyloxy or halogen, and Ar is not ortho-substituted by hydroxy or C_1-6Alkoxy-substituted phenyl.

5. A compound according to claim 4, wherein R¹Is hydrogen or methyl, R²And R³Or both are hydrogen, or R²And R³One is methyl, methoxy, hydroxy, carbamoyl, aminosulfonyl or halogen and the other is hydrogen and Ar is phenyl or phenyl mono-or independently di-substituted with methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, aminosulfonyl or halogen.

6. A compound according to any one of claims 1-2, wherein R¹Is hydroxy, halogen, trifluoromethyl, amino, methoxy or hydroxymethyl.

7. A compound according to any one of claims 1-2, wherein R²And R³Independently hydrogen, hydroxy or hydroxymethyl.

8. A compound according to any one of claims 1-2, wherein Ar is thienyl, pyrrolyl, thiazolyl, oxazolyl, methylthiazolyl or methylpyrrolyl.

9. A compound according to claim 1, which is:

n, N-diisopropyl-3- (5-formyl-2-hydroxy-phenyl) -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- (2-hydroxy-5-methoxycarbonylphenyl) -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- (5-acetyl-2-hydroxyphenyl) -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (2-hydroxyethyl) phenyl ] -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (1-hydroxyethyl) phenyl ] -3-phenylpropylamine, or the 3(R) -isomer thereof,

n, N-diisopropyl-3 (R) - [ 5- (1 (R) ]^*) 2-dihydroxyethyl) -2-hydroxyphenyl ] -3-phenylpropylamine or 1 (S) thereof^*) -an isomer of (I) or (II),

n, N-diisopropyl-3- (5-ethoxymethyl-2-hydroxyphenyl) -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- [ 5- (3-aminopropyl) -2-hydroxyphenyl ] -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- (5-amino-2-hydroxyphenyl) -3-phenylpropylamine, or the (R) -isomer thereof,

n, N-diisopropyl-3- [ 2-hydroxy-5- (3-hydroxypropyl) -phenyl ] -3-phenylpropylamine, or the (R) -isomer thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 9 for the preparation of an anticholinergic agent.

12. Use according to claim 11, wherein the anticholinergic is for the treatment of urinary incontinence-related disorders.