The present invention relates to therapeutically active piperidine compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in the treatment of anoxia, traumatic injury, ischemia, migraine and epilepsy.

It is well known that accumulation of calcium in the brain cells (calcium overload) is seen after periods of uncon¬ trolled hyperactivity in the brain, such as after convul¬ sions, migraine, anoxia and ischemia. As the concentration of calcium in the cells is of vital importance for the re¬ gulation of cell function, an uncontrolled high concentra- tion of the cell calcium will lead to, or indirectly cause the symptoms and possibly also the degenerative changes combined with the above diseases.

Therefore, calcium overload blockers selective for brain cells will be useful in the treatment of anoxia, traumatic injury, ischemia, migraine and epilepsy.

Well known calcium antagonists such as nifedipine, verapa- mil and diltiazem have activity against peripheral calci- urn uptake, e.g. in blood vessels and the heart, however, they have shown only very low activity against calcium overload in brain cells.

Accordingly it is an object of the invention to provide novel compounds having activity against calcium overload in brain cells.

The novel compounds of the invention are piperidine com¬ pounds having the general formula I

wherein

3 R is 3,4-methylenedxoxypheny , phenyl, naphthyl, or a 5 or 6 membered heterocyclic group containing one or two N, 0 or S - atoms being saturated, partly saturated or aroma¬ tic which are optionally substituted with one or more halo¬ gen, amino, C- _g -alkyl mono- or disubstituted amino, C, _fi - alkoxy, cyano, mono- or poly halogenated C._,-alkyl, C _? _ _fi - alkenyl, C- _fi -alkyl, C,, j.-alkylene, trifluoromethoxy, hy¬ droxy, hydroxy C.._.-alkyl, or trifluoromethyl;

n is 0 to 4;

R is hydrogen, straight or branched C, _R -alkyl, C. _p -al- koxy-C ₁ _ _n -alkyl, C ₃ _ ₈ -cycloalkyl, C ₂ _ _β -alkenyl, C. _R - cycloalkylalkyl, acetyl or C ₂ _ ₆ -alkynyl;

X is one or more amino, NC , C._,--alkyl mono- or disub¬ stituted amino, C, „-alkanoylamino, carboxy, C.._ ₆ -alkyl mono- or disubstituted ureido, C., ,-alkyl substituted with amino which are optionally mono- or disubstituted with C. ,-alkyl, unsubstituted carbamoyl or C. _fi -alkyl optionally substituted with phenyl and/or hydroxy N-mono or disubstituted carbamoyl, unsubstituted sulfamoyl, Cl,-o,- alkyl N-substituted sulfamoyl, C-_,-alkyl S-substituted sulfamoyl, C, _fi -alkyl N- and S-substituted sulfamoyl, or

a 5 or 6 membered heterocyclic group containing one or two N, 0 or S - atoms being saturated, partly saturated or aromatic, the heterocyclic group can be fused to the ring and, when Y is NR and/or n is 1 to 4 X is halogen, C ₁ _ ₆ -alkyl, C ₂ _g-alkenyl, C ₃ _ _g -cycloalkyl, C. _g -cycloal- kylalkyl, C, _g -alkoxy, cyano, mono- or poly halogenated C, _β -alkyl, hydroxy or hydrogen;

Y is 0, S or NR wherein R is hydrogen or C, ₅ ~alkyl, or a salt thereof with a pharmaceutically-acceptable acid.

Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sul¬ phate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically- acceptable inorganic or organic acid addition salts.

The invention also relates to a method of preparing the above mentioned compounds. These methods comprise

a) reacting a compound having the formula II

3 wherein X, Y, n and R have the meanings defined above, with a compound having the general formula R -Z, wherein

Z is a leaving group such as e.g. halogen or sulfonates and R has the meaning defined above; or

b) .reacting a compound having the formula III

wherein X and R have the meanings defined above, and Z is a leaving group such as e.g. halogen or sulfonates,

3 with a compound hav Λing the general formula R (CH__ )_1YH, wherein n, Y and R have the meanings defined above; or

c) reacting a compound having the formula IV

wherein Y is 0 or NR; X, R and R have the meanings defin- ed above, with an activated aromatic fluorine compound by means of NaH or alkoxide in dimethylformamide or dimethyl- acetamide.

The preparation of compounds of formula IV proceeds by pro- cedures described in European patent appl. nos. EP-A-374674 and EP-A-374675 and in US patent Nos. 4,861,893 and 4,902,801 with proper modification of the substitution pattern. Com¬ pounds III are prepared from IV by known chemical pro¬ cedures.

The pharmacological properties of the compounds of the in¬ vention can be illustrated by determining their capability

SUBSTITUTESHEET

to inhibit calcium uptake into brain synaptosomes.

PRINCIPLE

Depolarization of neuronal membranes leads to an opening of socalled "voltage operated calcium channels" (VOC) in the membranes which allows a massive influx of calcium from the extracellular space. A crude synaptosomal prepara¬ tion (socalled P ₂ fraction) contains small vesicles surroun- ded by neuronal membrane and it is possible in such a preparation to study a depolariza ion-induced opening of VOC. In the present model 45Ca influx is induced in the synaptosomes by depolarization with elevated potassium concentrations, and the effect of test substances on this stimulated uptake is studied (Nachshen, D.A. and Blaustein,

M.P., Mol. Pharmcol., 16, 579 (1979)).

ASSAY

A male Wistar rat is decapitated and the cerebral cortex removed and homogenized in 10 ml. of ice-cold 0.32 M sucrose using a glass homogenizer with a teflon pestle. All subsequent steps for isolation of synaptosomes are done at 0-4 ^C C. The homogenate is centrifuged at 1000 x g for 10 min and the resulting supernatant is re-centrifuged at 18000 x g for 20 min. This pellet (P ₂ ) is resuspended in 0.32 M sucrose (5 ml per g of original tissue) with a teflon pestle.

Aliquots (0.050 ml) of this crude synaptosomal suspension are added to glass tubes containing 0.625 ml of NaCl buffer (136 mM NaCl, 4 mM KC1, 0.35 m CaCl ₂ , 1.2 mM gCl ₂ , 20 mM Tris HC1, 12 mM glucose, pH 7.4) and 0.025 ml of various drug solutions in 48% Ethanol. The tubes are pre-incubated for 30 min on ice and then for 6 min at 37 ^C C in a water bath.

SUBSTITUTESHEET

The uptake is immediately initiated by adding 0.4 ml of d .

CaCl ₂ (specific activity = 29-39 Ci/g; 0.5 μCi/assay), in 145 mM NaCl for non-depolarized samples and in 145 mM

KC1 for depolarized samples. The incubation is continued for 15 s.

The uptake is terminated by rapid filtration through GF-C glass fiber filters which are washed three times with 5 ml of a cold solution containing 145 mM KC1, 7 mM EGTA and 20 mM Tris HC1, pH 7.4. The amount of radioactivity on the filter disc is determined by liquid scintillation spectrometry.

TEST PROCEDURE

Test substances are dissolved in 10 ml of 48% ethanol at a concentration of 0.44 mg/ml. Dilution are made in 48% ethanol to give final concentrations of 0.1, 0.3, 1, 3 and 10 μg/ml. Experiments are performed in triplicate. Controls for depolarized and nondepolarized samples are included in the assay and test substances are only tested in depolarized samples. 25-75% inhibition of stimulated uptake must be obtained before calculating the IC-- ₀ value.

RESULTS

The test value will be given as IC,- ₀ (the concentration (μg/ml) of test substance which inhibit 50% of stimulated uptake of 45Ca (uptake in depolarized samples corrected for basal uptake in nondepolarized samples ) ). The IC,-,, ou value is estimated from dose response curves.

Test results obtained by testing some compounds of the present invention will appear from the following table 1

SUBSTITUTESHEET

Nifedipine 26 Verapamil 16 Diltiazem > 90 Flunarizine 20

well known calcium antagonists.

The compounds of the invention, together with a conventio¬ nal adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled cap¬ sules, or liquids, such as solutions, suspensions, emul¬ sions, elixirs, or capsules filled with the same, all for

oral use, in the form of suppositories for rectal admini¬ stration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective calcium overload block¬ ing amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets con¬ taining ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharma¬ cy.

Conventional excipients are such pharmaceutically accept¬ able organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleterious- ly react with the active compounds.

Examples of such carriers are water, salt solutions, alco¬ hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mix¬ ed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are in- jectable solutions or suspensions, preferably aqueous so¬ lutions with the active compound dissolved in polyhydroxy- lated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or a carbo¬ hydrate carrier or binder or the like, the carrier prefer- ably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir of the like can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when admini¬ stered to patients, e.g. humans, as a drug.

A typical tablet which may be prepared by conventional tabletting techniques contains:

Magnesii stearas 0.25 mg Ph.Eur.

Due to te high calcium overload blocking activity, the com¬ pounds of the invention are extremely useful in the treat¬ ment symptoms related to an accumulation of calcium in brain cells of mammals, when administered in an amount effective for blocking activity of compounds of the inven¬ tion includes both activity against anoxia, traumatics

01672 PCT/DK91/00206

10

injury, ischemia, migraine and epilepsy. The compounds of the invention may accordingly be administered to a subject e.g., a living animal body, including a human, in need of a calcium overload blocker, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simul- tanously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutanous) route, in an effective calcium overload blocking amount, and in any event an amount which is effective for the treatment of anoxia, traumatic injury, ischemia, migraine, epilepsy, or neurodegenerative diseases due to their calcium over¬ load blocking activity. Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physi- cian or veterinarian in charge.

The invention will now be described in further detail with reference to the following examples.

EXAMPLE 1

(+)trans-1-methyl-3-(3,4-methylenedioxyphenoxymethyl)-4- (4-nitrophenyl)piperidine, hydrochloride (1)

(-)cis-3-hydroxymethyl-l-methyl-4-(4-nitrophenyl)piperidi ne

(2) (30 g) was dissolved in dry toluene (400 ml). Triethyl- amine (24.3 g) and subsequently benzenesulphonyl chloride (25.5 g) were added under stirring. The mixture was stirred at room temperature for 17 h, filtered and washed with 4N NaOH (2 x 400 ml). The toluene phase was separated, dried with MgSO. and evaporated to dryness. The resulting mixture was crystallized from methanol. M.p. 122.2-122.8°C, identi¬ fied by H NMR as 3-benzenesulphonyloxymethyl-l-methyl-4- (4-nltrophenyl)piperidine (3).

Compound (3) (7.9 g) dissolved in MIBC (200 ml) was added to a solution of sesamol (3.06 g) and NaOH (0.88 g) in MIBC (200 ml). The mixture was stirred 2 h at 130°C fil¬ tered and evaporated to dryness. The residue was evaporat- ed with 3 x 200 ml toluene to remove residual MIBC.

The residue was extracted several times with ether and the combined ether phase was washed with NaOH (4N) and dried. Subsequent evaporation followed by purification on a sili¬ ca gel column using CH ₂ C1 ₂ /CH ₃ 0H 9/1 as eluent gave compound (1) (3.5 g) precipitated as the hydrochloride. M.p. 190-195°C, identified by ¹ H NMR and MS.

(-)trans-l-methyl-3-(3,4-methylenedioxyphenoxymethyl)-4- (4-nitrophenyl)piperidine, hydrochloride (4)

Was prepared as desribed for compound (1) using (+)cis- 3-hydroxymethyl-l-methyl-4-(4-nitrophenyl)piperidine as starting material. M.p. 203-208°C.

(+)trans-l-methyl-4-(4-nitrophenyl)-3-(4-trifluorome- thylphenoxymethyl)piperidine, oxalate (5)

(-)cis-3-hydroxymethyl-l-methyl-4-(4-nitrophenyl) piperi¬ dine (5 g) was dissolved in DMF (50 ml) and added dropwise to a mixture, of NaH (1.06 g) and DMF (50 ml) held at 70°C.

After stirring for 30 min at 70°C 4-fluorobenzotrifluoride (3.57 g) was added and the reaction mixture warmed for 2.5 h at 90°C. After cooling to RT overnight, H ₂ 0 (100 ml) and toluene (200 ml) was added, and the toluene phase was separated, dried (MgSO.) and evaporated to dryness. The crude product was purified on a silica gel column using CH ₂ C1 ₂ /CH ₃ 0H 9/1 as eluent. Compound (5) was precipitated as the oxalate by means of anhydrous oxalic acid in acetone

Identified by ¹ H NMR and MS.

(+)trans-3-(3,4-methylenedioxyphenoxymethyl)-4-(4-nitro¬ phenyl)piperidine, hydrochloride (6)

Was prepared from compound (1) (2.4 g) by treatment with

1-chloroethyl chloroformate (1.02 g) in 1,2-dichloroethane (100 ml) as described by Olofson et. al (J. Org. Chem. !9 (1984) 2081). Rinse up on a silica gel column gave 1.5 g of compound (6). M.p. 95-100°C.

(+)trans-3-(3,4-methylenedioxyphenoxymethyl)-4-(4-nitro¬ phenyl)-1-pentylpiperidine, hydrochloride (7)

Compound (6) (1 g) was dissolved in abs. ethanol (50 ml). K-CO (0.7 g) and 1-bromopentane (0.63 ml) were added. Reflux for 6 h, filtering and evaporation to dryness gave a crystalline mass which was extracted with NaOH(4N)- ether. The etheral layer was dried, evaporated and puri- fied on a silica gel column using CH ₂ C1 ₂ /CH ₃ 0H 9/1 as eluent. Precipitated as the hydrochloride from acetone/- ether. Yield 0.5 g. M.p. 57°C.

(-)trans-1-methyl-4-(4-nitrophenyl)-3-(3-trifluoromethyl- phenoxymethyl)piperidine, hydrochloride (8)

Compound (8) was prepared from (+)cis-3-hydroxymethyl-l- methyl-4-(4-nitrophenylJpiperidine as described for com¬ pound (1) using 3-trifluoromethylphenol instead of sesamol. The crude product was purified on a silica gel column using CH ₂ Cl ₂ /O_ ₃ 0H 9/1 as eluent. Identified by ¹ H NMR. M.p. 271-272°C.

(-)trans-4-(4-nitrophenyl)-3-(3-trifluoromethylphenoxy- methyl)piperidine, hydrochloride (9)

Compound (9) was prepared from compound (8) (3.4 g) as described under the preparation of compound (6). Yield 2.8 g of a hard glass identified as compound (9) by ^■ " ^" H NMR.

EXAMPLE 2

(+)trans-4-(4-aminophenyl)-3-(3,4-methylenedioxyphenoxy- methyl)-1-pentylpiperidine, hydrochloride (10)

Compound (7) (0.39 g) in abs. ethanol (50 ml) was hydro- genated at atm. pressure using 5% PdC (50 mg) as catalyst. The reaction mixture was filtered, evaporated to dryness. Extraction with NaOH(4N)-ether, separation of the etheral layer, drying (MgSO.), followed by evaporation to dryness gave an yellow oil which was purified on a silica gel column and precipitated as a very hygroscopic hydrochloride from acetone-ether. Identified by H NMR.

EXAMPLE 3

(+-)trans-1-butyl-4-(4-dimethylaminophenyl)-3-(4-trifluor o- methylphenoxymethyl)piperidine, hydrochloride (11)

l-Butyl-3-hydroxymethyl-4-(4-dimethylaminophenyl)piperidi ne (12) (8.5 g) (prepared from 4-dimethylaminobenzaldehyde and ethyl N-butylamidomalonate analogous to the procedure described in US patent 4,902,801) was treated with NaH

(1.4 g) and 4-fluorobenzotrifluoride (9.6 g) in DMF (150 ml) using the procedure described for the preparation of compound (5). The crude product was purified on a silica gel column giving 11.7 g crystals after precipitation as the hydrochloride. M.p. 223.4-223.7°C.

(+-)trans-4-(4-dimethylaminophenyl)-1-(2-methylbutyl)-3- (4-trifluoromethylphenoxymethyl)piperidine, hydrochloride (13)

Was prepared as described for compound (11) from the 1- (2-methylbutyl) analogue of compound (12) (2 g), NaH (0.32 g) and 4-fluorobenzotrifluoride (2.16 g) in DMF (100 ml). 3 g crude product was purified on a silica gel column identified as compound (13) by MS and H NMR. M.p. 237.2-237.6°C.

(+-)trans-l-butyl-4-(4-dimethylaminophenyl)-3-(2-trifluor o- methylphenoxymethyl)piperidine, hydrochloride (14)

Preparation as described for compound (11) using 1 g of compound (12), 2-fluorobenzotrifluoride (1.2 g) and NaH (0.174 g) in DMF (100 ml). The crude product was precipi¬ tated as the hydrochloride from acetone-ether giving 0.4 g of crystals. M.p. 213.9-214.9°C.

SUBSTITUTESHEET

(+-)trans-l-butyl-4-(4-dimethylaminophenyl)-3-(3,4-methylene - dioxyphenoxymethyl)piperidine, hydrochloride (15)

3-benzenesulphonyloxymethyl-l-butyl-4-(4-dimethyl-amino- phenyl)piperidine (16) (2 g) (prepared from compound (12), benzenesulphonyl chloride and triethylamine by known procedures) was treated with sesamol (0.73 g) and NaOH (0.21 g) in MIBC as described for the preparation of compound (1). Reflux for 2 h. The crude product was puri¬ fied several times on a silica gel column using CH ₂ C1 ₂ / CH^OH 9/1 as eluent. Yield 0.05 g of colourless crystals after precipitation as the hydrochloride. M.p. 211.5-214°C.

(+-)trans-1-butyl-4-(4-dimethylaminophenyl)-3-(3-trifluor o- methylphenoxymethyl)piperidine, hydrochloride (17)

0.4 g of l-butyl-3-chloromethyl-4-(4-dimethylaminophenyl) piperidine (18) in DMF (25 ml) (prepared from compound

(12) by known procedures) was added to a 70 C hot mixture of 3-trifluoromethylphenol (0.28 g) and NaH (0.09 g) in DMF (25 ml). Reaction time 2 h at 100°C. Evaporation with 3 x 100 ml toluene. The residue was extracted with NaOH (4N)-ether, the etheral layer separated and dried (MgSO.), purified on a silica gel column and precipitated with concentrated HC1 from acetone. Yield 0.22 g of colourless crystals. M.p. 221-223°C.

(+-)trans-4-(4-dimethylaminophenyl)-3-(3,4-methylenedioxy - phenoxymethyl)-1-(2-methylbutyl)piperidine, hydrochloride (19)

Was prepared from the crude l-(2-methylbutyl)-analogue of (18) (3.8 g), NaH (0.81 g) and sesamol (2.13 g) in DMF (50 ml) as described for compound (17). The crude product

SUBSTITUTESHEET

was purified several times on a silica gel column using ethylacetate and heptane/ether 4/1 as eluents. Compound (19) was identified by ^H NMR and MS. M.p. 238.5-239.5°C.

EXAMPLE 4

l-butyl-3-(4-methoxybenzylaminomethyl)-4-phenylpiperidi- ne, HCl (20)

2.5 g (0.6 mmol) 3-(benzensulfonyloxymethyl)-l-butyl-4- phenyl-piperidine (21) was mixed with 825 mg (6 mmol) 4-methoxybenzylamine and heated for 4 h at 90°C. The re¬ sulting crystals were washed with CH ₂ C1 ₂ . The precipitate was stirred in 4N NaOH and extracted with ether. Dried with MgSO., evaporated in vacuo. The hydrochloride was precipitated from an acetone/ether solution. Yield: 2.3 g-

¹ H-NMR: 0.8-1.3 (m, 3H); 1.3-2.5 (m, 14H); 2.6-3.3 (m, 2H), 3.4 (s, 2H); 3.7 (s, 3H); 6.6-7.2 (m, 9H).

l-butyl-3-(4-trifluoromethylphenylaminomethyl)-4-phenyl- piperidine, HCl (22)

2.5 g (0.6 mmol) (21) was added to 965 mg (6 mmol) 4-tri- fluoromethylaniline. The reaction mixture was heated for 3 h at 90°C. The resulting oil was dissolved in CH ₂ C1 ₂ and washed with 4N NaOH. Then the oil was washed with IN HCl and extracted with ether to get rid of some impurity. The water phase was added NaOH. Then extracted with ether. Dried with MgSO., evaporated in vacuo. The remaining oil was acidified with cone. HCl. Yield: 1.0 g crystals. M.p. 131- 135°C.

l-butyl-3-(4-methoxyphenylaminomethyl)-4-phenyl-piperi¬ dine, HCl (23)

2.5 g (6 mmol) of (21) was added to 725 mg (6 mmol) p-ani- sidine and 5 ml pyridine. The reaction mixture was heated at 100°C for 3-4 h. The reaction mixture was washed with 4N NaOH and extracted with ether. The ether phase was evaporated stirred in IN HCl washed with CH ₂ C1 ₂ . The water phase was added solid NaOH, extracted with ether and dried, evaporated in vacuo giving 400 mg oil which was acidified with cone. HCl, giving 600 mg crystals with m.p. 192-204°C. GC-MS showed that it was a mixture of two isomers 34:64%.

M.p. 192- 204 ^U C.

EXAMPLE 5

3-(4-methoxybenzylaminomethyl)-1-methyl-4-phenyl-piperi¬ dine, HCl (24)

3.4 g (10 mmol) (21) was mixed with 1.37 g p-methoxyben- zylamine. The reaction mixture was refluxed for 2 h, wash¬ ed with 4N NaOH and extracted with ether. The ether phase was dried with MgSO. and evaporated in vacuo. The remain¬ ing oil (2.1 g) was precipitated with oxalic acid. Yield 2.2 g crystals. M.p. 192-200°C.

3-(3-fluorobenzylaminomethyl)-l-methyl-4-(4-methoxyphe- nyl)-piperidine, HCl (25)

1.0 g (4.3 mmol) 3-aminomethyl-4-(4-methoxyphenyl)-l-me- thyl-piperidine (26) was dissolved in 30 ml EtOH, 2 g ^K 2 ^C0 3 ^{and 613 m} & ( ⁴ « ³ mmol) 3-fluorobenzylchloride added. The reaction mixture was refluxed for 6 h, filter¬ ed and evaporated in vacuo. Addition of ether to the oil

18

precipitated the base. The crude base was chromatographed on a silica gel column with CH ₂ C1 ₂ : MeOH:DEA as eluent. The oil was acidified with cone. HCl. Yield: 72 mg hard glass. M.p. 240°C.

3-(4-fluorobenzylaminomethyl)-l-methyl-4-(4-methoxyphe- nyl)-piperidine, HCl (27)

1.5 g (6.4 mmol) (26) was dissolved in 50 ml EtOH. 2 g

^K 2 ^C0 ₃ ^{was a<} ^ed together with 925 mg (6.5 mmol) 4-fluoro- benzyl chloride. The reaction mixture was refluxed for 6 h. Subsequently the reaction mixture was filtered and eva¬ porated in vacuo. Addition of ether precipitated the base. The crude base was chromatographed on silica gel with

CH ₂ C1 ₂ , MeOH, DEA as eluent. The product was precipitated from an acidified ether, acetone solution yielding 260 mg. M.p. 265-266°C.

3-(2-fluorobenzylaminomethyl)-l-methyl-4-(4-methoxyphe- nyl)piperidine, HCl (28)

1.0 g (4.3 mmol) (26) was dissolved in 30 ml EtOH. 2 g ^K 2 ^C0 ₃ ^an( ^13 mg (4.3 mmol) 2-fluorobenzylchloride were added. The reaction mixture was refluxed for 6 h. Then the reaction mixture was filtered and evaporated in va¬ cuo. Some crystalline compound was obtained by adding ether. The ether phase was washed with acid and subse- quently with base, evaporated to dryness, dissolved in acetone then acidified with cone. HCl. The HCl-salt was chromatographed on silica gel with CH ₂ C1 ₂ :MeOH:DEA as eluent. Yield: 110 mg of the HCl-salt. M.p. 251°C.

(+-) 3-(4-methoxyphenylaminomethyl)-l-methyl-4-phenylpipe- ridine, HCl (29)

5 g (14.5 mmol) 3-(benzenesulfonyloxymethyl)-l-methyl-4- phenyl-piperidine (30) was dissolved in 50 ml pyridine and 1.8 g (15 mmol) p-anisidine was added. The reaction mixture was refluxed for 8 h. The pyridine was removed in vacuo. The remaining oil was washed with 4N NaOH and ex¬ tracted with ether. Dried with MgSO. and evaporated to dryness giving 1.7 g oil. The oil was chromatographed on a silica gel column with CH ₂ Cl ₂ :Me0H 9:1 as eluent. The compound was crystallized as the HCl-salt. Yield: 190 mg

^■ 'Ή-NMR: 1.6-2.2 (m, 6H); 2.4 (s, 3H); 2.6-3.2 (m, 4H); 3.7 (s, 3H); 6.2-6.6 (q, 4H); 7.2 (s, 5H).

(+-) trans-l-pentyl-4-phenyl-3-(1,2,3,4-tetrahydro-5-naph- thylaminomethyl)-piperidine, HCl (31)

4.3 g (10.7 mmol)3-(benzenesulfonyloxymethyl)-4-phenyl-l- pentyl-piperidine (32) was dissolved in 80 ml toluene-MBC 1:1 0.86 ml pyridine was added. The reaction mixture was heated for 72 h at 80 C. The reaction mixture was evapo- rated in vacuo. The oil was dissolved in ether and washed with 4N NaOH. The water phase was extracted with ether, dried with MgSO. and evaporated giving 5 g black oil which was chromatographed on silica gel with CH ₂ Cl ₂ :MeOH 19:1 as eluent. The HCl-salt precipitated from an acidified acetone ether solution. Yield: 34 mg. M.p. 214-216°C.

(-) trans-3-(benzylaminomethy1)-l-butyl-4-phenylpiperi- dine, HCl (33)

1.5 g (3.9 mmol ) ( - ) trans-3-(benzenesulfonyloxymethyl )- l-butyl-4-phenyl-piperidine (34 ) was mixed with benzyl -

SUBSTITUTE SHEET

amine (20 ml) and heated for 24 h at 85°C. The reaction mixture was washed with 4N NaOH and extracted with ether. The ether phase was dried with MgSO. and evaporated in vacuo. The remaining yellow oil (1.3 g) was chromatograph- ed on silica gel with CH ₂ Cl ₂ /MeOH 9:1 as eluent. The di- HCl-salt was recrystallized twice from MeOH/acetone. M.p. > 280°C.

EXAMPLE 6 (-) trans l-butyl-3-(2-phenylethylaminomethyl)-4-phenyl- piperidine, HCl (35)

1 g (2.6 mmol) (34) was mixed with 15 ml 2-phenylethyl- amine and heated for 25h at 85°C. The ether phase was dried with MgSO. and evaporated in vacuo. 3 g yellow oil was obtained. The oil was purified by chromatography on silica gel with CH ₂ C1 ₂ MeOH 9:1 as eluent. 1.1 g oil was acidified with cone. HCl and the di-HCl-salt precipitated from acetone/ether. Yield 0.95 g white crystals. M.p. 220- 220.8°C.

EXAMPLE 7 (-) trans-4-(4-fluorophenyl)-l-pentyl-3-(4-trifluoromethyl- benzyloxymethyl)-piperidine, HCl (36)

(+) cis 3-benzenesulfonyloxymethyl-4-(4-fluorophenyl)-l- pentyl piperidine (37) was dissolved in 4-trifluoromethyl- benzylalkohol (5 g) and 5 ml toluene. 0.2 g NaH (50%) was added under N~. The reaction mixture was heated for 18h at 65°C. Then it was washed with 4 N NaOH and extracted with ether. The organic phase was dried with MgSO. and evaporated in vacuo. 1 g yellow oil was chromatographed on a silica gel column with CH ₂ Cl ₂ :MeOH 9:1 as eluent.

Subsequently it was chromatographed with ethyl acetate as eluent. 0.47- g oil was acidified with cone. HCl, 0.5 g

SUBSTITUTESHEET

white crystals precipitated. M.p. 134.6°C.

(+-) trans-3-(2-(4-methoxyphenoxy)ethoxymethyl)-1-methyl- 4-phenylpiperidine, oxalate (38)

8.5 g (2.45 mmol) (30) was dissolved in dry toluene, 4.9 g (2.9 mmol) 2-(4-methoxyphenoxy)ethanol and 1 g NaH was added. The reaction mixture was refluxed under N ₂ for 34 h. The toluene phase was washed with 4 N NaOH and extract¬ ed with ether. The organic phase was dried with MgSO. and evaporated in vacuo. 8.1 g yellow oil was chromatographed on silica gel column with CH ₂ Cl ₂ :MeOH 9:1 as eluent.

The oxalate was a hard glass. M.p. 35-57 C.

(+-) trans-3-(2-(4-methoxyphenoxy)ethoxymethyl)-4-phenyl- piperidine, oxalate (39)

3.7 g (1.04 mmol) (38) as the free base was dissolved in dry toluene under N ₂ . 2.23 g (1.56 mmol) 1-chloroethyl chloroformate was dropped slowly to the ice-cooled reac¬ tion mixture. Then the reaction mixture was refluxed for 5h. 20 ml MeOH was added and refluxed further for lh. Eva¬ poration in vacuo gave a brown oil which was washed with 4N NaOH and extracted with CH ₂ C1 ₂ . Dried with MgSO. and evaporation gave 3.6 g oil, which was chromatographed on a silica gel column with CH ₂ Cl ₂ /MeOH 9:1 as eluent. The oxalate precipitated from acetone/ether. Yield 3.1 g. M.p. 138.8-140.8°C.

(+-) trans-3-(2-(4-methoxyphenoxy)ethoxymethyl)-1-pentyl- 4-phenyl-piperidine, oxalate (40)

2.15 (5 mmol) (39) was dissolved in 50 ml EtOH. 4 g K ₂ C0 ₃

was added together with excess pentyl bromide. The reac¬ tion mixture was heated for 18 h at 60°C. Filtration and evaporation in vacuo. The oil was washed with 4 N NaOH and extracted with ether. The ether phase was treated with charcoal and dried with MgSO.. The residue after evapor¬ ation was chromatographed on a silica gel column with CH ₂ C1 ₂ MeOH (9:1) as eluent. 1.15 g oil was treated with oxalic acid. Yield 1.2 g. M.p. 123-125°C.

EXAMPLE 8

(+-) trans 4-(4-dimethylaminophenyl)-3-(4-trifluoromethyl- phenoxymethyl) piperidine, hydrochloride (41)

Was prepared from compound (13) (3 g) and 1-chloroethyl chloroformate (1 g) in dry 1,2-dichloroethane (50 ml) as described for compound (6). Yield 62%. M.p. 195.5-199.6°C (d).

(+-) trans 4-(4-dimethylaminophenyl)-l-ethyl-3-(4-trifluoro- methylphenoxymethyl) piperidine, hydrochloride (42)

Was prepared from (41) (0.35 g) and ethyl iodide (0.4 g) in abs. ethanol (30 ml), heating to 60°C for 8 h, and subsequently at room temperature for 48 h in the presence of I _j CO (0.4 g). Purification as described for compound (7) gave a yield of 38% of (42). M.p. 225.8-228.1°C.

(+-) trans 4-(4-dimethylaminophenyl)-l-propyl-3-(4-tri- fluoromethylphenoxymethyl) piperidine, hydrochloride (43)

Preparation from (41) (0.35 g) and 1-iodopropane (0.2 ml) by heating in ethanol of 70°C for 8 h, as described for compound (42). Yield 37%, m.p. 224.2-225.2°C.

SUBSTITUTESHEET

EXAMPLE 9

(+-) trans 4-(4-diethylaminophenyl)-l-(2-methyl-butyl)-3- (4-trifluoromethylphenoxymethyl) piperidine hydrochloride (44)

Was prepared from 4-(4-diethylaminophenyl)-3-hydroxymethyl- l-(2-methylbutyl) piperidine (45) and 4-fluorobenzotri- fluoride as described for compound (11). Compound (45) was prepared from ethyl N-(2-methylbutylJamidomalonate and 4-diethylaminobenzaldehyde as described above. Yield of (46) 50%. M.p. 250.7-250.9°C.

(+-) trans 4-(4-diethylaminophenyl)-3-(4-trifluoromethyl phenoxymethyl) piperidine, hydrochloride (46)

Preparation by dealkylation of (44) as decribed for compound (41). Yield 23%. M.p. 220.5 - 227.6°C.

EXAMPLE 10

3-benzenesulfonyloxymethyl-1-butyl-4-dimethylaminophenyl piperidine (47)

Was prepared from (12) and benzenesulphonyl chloride as described under the preparation of compound (1). The crude product, identified by H NMR and shown by HPLC to be more than 80% pure, was used for the preparation of the following compounds by adding a solution of (47) in DMF to a mixture of the appropriate phenol and NaH in

DMF. Stirring at RT or under heating until complete con¬ sumption of (47) could be proved by HPLC. Subsequently

the mixture was evaporated to dryness and the product was isolated using the purification procedure described for the preparation of compound (1).

(+-) trans l-butyl-4-(4-dimethylaminophenyl)-3-(5,6,7,8- tetrahydro-2-naphthoxymethyl) piperidine, hydrochloride (48)

From (47) (1 g) and 5,6,7,8-tetrahydro-2-naphthol (0.45 g) by heating for 2 h. Yield 18%. M.p. 216.7 - 2176.6°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl) 3-(3-methylphenoxymethyl) piperidine, hydrochloride (49)

From (47) (1 g) and 3-methylphenol (0.33 g) by heating for 2.5 h. Yield 21%, m.p. 230.2 - 230.9°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl)3-(4-fluoro- phenoxymethyl) piperidine, hydrochloride (50)

From (47) (1 g) and 4-fluorophenol (0.34 g) by heating for 2 h. Yield 35%, m.p. 225.5°C (d).

(+-) trans 1-butyl-3-(4-chlorophenoxymethyl)-4-

(4-dimethylaminophenyl) piperidine, hydrochloride (51)

From (47) (1 g) and 4-chlorophenol (0.39 g) by standing aatt nroom temperature overnight. Yield 34%, m.p. 211.1°C

(d).

(+-) trans l-butyl-3-(3,4-dichlorophenoxymethyl) 4-(4-dimethylaminophenyl) piperidine, HCl (52)

From (1 g) (47) and 3,4-dichlorophenol (0.5 g) by standing at room temperature overnight. Yield 15%, m.p. 234.2-234.6°C.

(+-) trans l-butyl-3-(2-cyanophenoxymethyl)-4-(4-dimethyl- aminophenyl) piperidine, HCl (53)

From (47) (1 g) and 2-cyanophenol (0.36 g) by standing overnight at room temperature. Yield 8%. M.p. 200-201°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl) 3-(3-nitrophenoxymethyl) piperidine, HCl (54)

From (47) (1 g) and 3-nitrophenol (0.48 g) by standing at room temperature overnight. Yield 3%. M.p. 236-237°C.

(+-) trans l-butyl-3-(3-cyanophenoxymethyl) 4-(4-dimethylaminophenyl) piperidine, HCl (55)

From (47) (1 g) and 3-cyanophenol (0.36 g) by standing at room temperature for 24 h. Yield 12%. M.p. 237.2-238.8°C.

(+-) trans l-butyl-4-(4-cyanophenoxymethyl)-4-(4-dimethyl- aminophenyl) piperidine, HCl (56)

From (47) (1 g) and 4-cyanophenol (0.36 g) by standing at room temperature for 48 h. Yield 21%, m.p. 179-181°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl)-3-(4-nitro- phenoxymethyl) piperidine, HCl (57)

From (47) (1 g) and 4-nitrophenol (0.48 g) by standing overnight at room temperature. Yield 3%, m.p. 215.5 C. The compound was somewhat contaminated with l-butyl-3-chloromethyl-4-(4-dimethylaminophenyl) piperidine, HCl.

EXAMPLE 11

(-)trans-3-(benzyloxymethyl)-4-(4-fluorophenyl)-l-pentyl- piperidine, HCl (58)

1 g (0.0024 mol) (+) cis-3(benzenesulfonyloxymethyl)-4- (4-fluorophenyl)-l-pentyl-piperidine (59) was stirred in benzyl alcohol (10 ml) 0.2 g (0.004 mol) NaH was added under N ₂ . The reaction mixture was heated for 16 h at 65°C.

The remaining benzyl alcohol was removed in vacuo. The oil was chromatographed on a silica gel column with CH ₂ Cl ₂ /MeOH (9:1) as eluent. 0.65 yellow oil was acidified by cone. HCl. The HCl salt was recrystallized from ethyl acetate. M.p. 138-139°C.

(-)trans-4-(4-fluorophenyl)-l-pentyl-3-(3-trifluoromethyl - benzyloxymethyl)-piperidine, HCl (60)

The compound was prepared in the same manner as described for (58). Yield 230 mg oxalate. M.p. 80-80.2°C.

(-)trans-4-(4-fluorophenyl)-l-pentyl-3-(2-trifluoromethyl- benzyloxymethyl)-piperidine, HCl (61)

The compound was prepared in the same manner as described for (58). Yield 200 mg HCl-salt. M.p. 56.7-57°C.

EXAMPLE 12

(+)-trans-l-butyl-4-(4-dimethylaminophenyl)-3-(4-trifluor o- methylphenoxymethyl)piperidine (-)-di-p-toluoyltartrate (62)

(HH)-trans-l-butyl-3-hydroxymethyl-4-(4-diraethylaminophe nyl)■ piperidine (50 g) was dissolved in dry dimethyl foππamide (200 ml). Potassium tert-butoxide (23.3 g) was added to the solution and the mixture was stirred at room temperature for 15 min. 4-Fluorobenzotrifluoride (26.4 ml) was added and the mixture was stirred for 1 h. Water (300 ml) was added and the mixture extracted three times with toluene (600 ml). The toluene extract was extracted with water (200 ml), dried over potassium carbonate and evaporated under reduced pressure giving a yellow oil (75.8 g). The oil was dissolved in acetone (400 ml) at

50°C and (-)-p-ditoluoyltartaric acid (70.6 g) was added. The solution was stirred for 1 h cooled in an ice bath and the precipitate filtered off. Washed with acetone and dried. Yield 68.2 g. M.p. 118-120°C.

(-)-trans-l-butyl-4-(4-dimethylarainophenyl)-3-(4-trifluo ro- methylphenoxymethyl)piperidine (+)-di-p-toluoyltartrate (63)

The filtrate from the preparation of (62) was evaporated, redissolved in dichloromethane (450 ml), extracted with

SUBSTITUTESHEET

excess saturated sodium carbonate solution. The dichloro- methane phase was extracted with water (300 ml), dried over magnesium sulfate and evaporated under reduced pres¬ sure. Yield 44.2 g. The residue was dissolved in acetone (350 ml) at 50°C. (+)-p-ditoluoyltartaric acid (39.3 g) was added. The mixture was stirred overnight, cooled in ice-water, the precipitate filtered off, washed with acetone and dried. Yield 61.4 g, m.p. 118-140°C.

(+)-trans-l-butyl-4- (4-dimethylaminophenyl)-3-(4-triflu- oromethylphenoxymethyl)piperidine dihydrochloride (11)

The piperidine base was prepared as described above from (+_)-trans-l-butyl-3-hydroxymethyl-4-(4-dimethylaminophenyl) ■ piperidine and 4-fluorobenzotrifluoride in dimethyl form- amide with potassium tert-butoxide. The dihydrochloride was precipitated from an acetone solution by addition of 2.2 equivalents of cone, hydrochloric acid. The filtrate was evaporated at reduced pressure and the residue redis- pensed in acetone giving in all about 90% of the dihydro¬ chloride. M.p. 211-215°C.

(+)-trans-l-butyl-4-(4-dimethylaminophenyl)-3-(4-trifluor o- methylphenoxymethyl)piperidine dihydrochloride (64)

The piperidine base was liberated from the (-)-p-ditoluoyl- tartrate salt (62) (68 g) by extraction of a dichlorome- thane suspension (500 ml) with saturated sodium carbonate. Sodium carbonate was added until pH was 9.45. The dichlo- romethane phase was separated, washed with water (200 ml), dried over magnesium sulphate and evaporated under reduc¬ ed pressure. The dihydrochloride was precipitated from an acetone solution (400 ml) by addition of cone, hydrochlo¬ ric acid (14.2 ml). Yield 34.9 g . The product was recrys- tallized from 140 ml acetone and 40 ml methanol. Yield

SUBSTITUTE SHEET

21.3 g, m.p. 215-216°C, [ ] ²⁰ = + 68.62°C.

(-)-trans-l-butyl-4-(4-dimethylaminophenyl)-3-(4-trifluor o- methylphenoxymethyl)piperidine dihydrochloride (65)

The piperidine base was liberated from the (+)-p-ditoluoyl salt (63) (61.4 g) as described above for the (+)-isomer and isolated as the dihydrochloride. Yield 29.7 g. The pro- duct was recrystallized from a mixture of 120 ml acetone and 38 ml methanol. Yield 29.1 g, m.p. 215-215.8°C, [ ] ²⁰ = -68.66°C. ^D

EXAMPLE 13

The following compounds were prepared from compound (41) and an alkylhalide by reflux in abs. ethanolic solution under the presence of K~C0~ as described for compound (42). Rinse up as described for compound (7).

(+-) trans l-cyclopropylmethyl-4-(4-dimethylaminophenyl)- 3-(4-trifluoromethylphenoxymethyl)piperidine, hydro¬ chloride (66)

Was prepared from (41) (1 g) cyclopropylmethyl bromide (1.17 g) and K ₂ C0 ₃ (1 g) reflux for 11 h yield 59% of (66). M.p. 211.3-212.5°C.

(+-) trans l-allyl-4-(4-dimethylaminophenyl)-3-(4-trifluoro- methylphenoxymethyl)piperidine, hydrochloride (67)

From (41) (1 g), allylbromide (0.35 g) and K ₂ C0 ₃ (1 g). Heating to 50°C for 4 h. Yield of (67) 35%. M.p. 211.0 -

212.8°C.

SUBSTITUTESHEET

(+-) trans l-cyclopentyl-4-(4-dimethylaminophenyl)-3-(4- trifluoromethylphenoxymethyl)piperidine, hydrochloride (68)

Prepared from (41) (1.5 g), bromocyclopentane (0.80 g) and K ₂ C0 ₃ (1 g). Reflux for 21 h. Purification of the crude product on silica gel column. Yield of (68) 11%.

M.p. 205.8 - 206.2°C.

(+-) trans 4-(4-dimethylaminophenyl)-l-(3-methylbutyl)-3- (4-trifluoromethylphenoxymethylJpiperidine, hydrochloride (69)

Prepared from (41) (0.5 g), 3-methyl-l-bromobutane (0.4 g) and K ₂ C0 ₃ (0.5 g). Reflux for 8 h. Purification on silica gel. Yield of (69) 51%. M.p. 223.9 - 225.1°C.

(+-) trans l-acetyl-4-(4-dimethylaminophenyl)-3-(4-tri- fluoromethylphenoxymethylpiperidine), hydrochloride (70)

Mixing of (41) (0.5 g) with acetylchloride (0.5 ml), 2-bromopropane (0.5 ml) and K ₂ C0 ₃ (0.5 g) with subsequent heating to 70 C for 4 days and purification on a silica gel column gave 0.08 g of (70) identified by

H, ¹³ C NMR and MS. M.p. 188.4 - 190.0°C.

(+-) trans 4-(4-dimethylaminophenyl)-l-isopropyl-3-(4-tri- fluoromethylphenoxymethyl)piperidine, hydrochloride (71)

0.32 g (71) was isolated from the crude mixture from the preparation of (70). M.p. 227.0 - 229.0 °C.

(+-) trans 4-(4-dimethylaminophenyl)-l-(2-propynyl)-3-(4- trifluoromethylphenoxymethyl)piperidine, hydrochloride (72)

From (41) (0.5 g), 2-bromo-l-propyn (0.31 g) and ₂ C0 ₃ (0.5 g). Reflux for 2 days. Purification on a silica gel column. Yield of (72) 20%. M.p. 198.0 - 199.2°C.

EXAMPLE 14

The following compounds were prepared using the method described for the preparation of compounds (47) and (48).

(+-) trans l-butyl-4-(4-dimethylaminophenyl)3-(4-methyl- phenoxymethyl)piperidine, hydrochloride (73)

from (47) (1 g) and 4-methylphenol (0.33 g) by standing at RT overnight, yield of (73) 21%. M.p. 216.0 - 218.0°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl)-3-(2-methyl- phenoxymethyl)piperidine, hydrochloride (74)

From (47) (1 g) and 2-methylphenol (0.33 g) by standing at RT overnight. Purification on silica gel column using CH ₂ C1 ₂ /CH ₃ 0H (9/1) and pentane/triethyl amine (15/1) as eluents. Yield of (74) 21%. M.p. 130-131°C.

(+-) trans l-butyl-4-(4-dimethylaminophenyl)-3-(4-trifluoro- methoxyphenoxymethyl)piperidine, hydrochloride (75)

From (47) (1 g) and 4-trifluoromethoxyphenol (0.54 g) by standing at RT overnight. Purification on silica gel.

SUBSTITUTESHEET

Yield of (75) 0.1 g. M.p. 171-185°C.

EXAMPLE 15

(+-) trans 4-(4-aminophenyl)-l-butyl-3-(4-trifluoromethyl phenoxymethyl)piperidine, hydrochloride (76)

(+-) trans 4-(4-aminopheny1)-1-butyl-3-hydroxymethy1 piperidine (77) (2.4 g), 4-trifluoromethylphenol (1.49 g), triphenylphosphine (2.4 g) and diethyl azodicarboxylate (1.6 g) were reacted in dry THF according to the method described by 0. Mitsunobu (Synthesis 1981, 1). After reaction at RT for 3 days the solvent was evaporated, the residue extracted with 4M 0H~ / ether and the dried evaporated ether phases were purified on silicagel (eluent CH ₂ C1 ₂ /CH ₃ 0H 9/1) yield of (76) 59%. M.p. 189-191°C.

(+-) cis l-butyl-4-(4-nitrophenyl)-3-(4-trifluoromethyl¬ phenoxymethyl) piperidine, hydrochloride (78)

was prepared from (+-) cis l-butyl-3-hydroxymethyl-4-nitro- phenylpiperidine (12.6 g) analogous to the preparation of (76). Yield of (78) 33% as a hard glass identified by ¹ H and ¹³ C NMR.

(+-) trans l-butyl-4-(4-formylaminophenyl)-3-(4-trifluoro- methylphenoxymethyl) piperidine, hydrochloride (79)

Compound (76) (1 g) was dissolved in ethyl formiate (10 ml) reflux for 1 h followed by addition of 1 M NaOH to pH 5. Heating to 50°C overnight followed by evaporation to dryness. The residue was partitioned between CH ₂ C1 ₂ /0H , the organic layer dried, evaporated to

SUBSTITUTE SHEET

dryness and precipitated as the hydrochloride from acetone/ether. Yield 45% of (79). M.p. 165-170°C.

(+-) trans l-butyl-4-(4-N-ethyl-N-methylaminophenyl)-3- (4- trifluoromethylphenoxymethyl)piperidine, hydrochloride (80)

(79) (2.7 g) was dissolved in dioxan (50 ml). NaBH. (0.71 g) and CH ₃ C00H (1.12 g) was added (at 14°C). Reflux for 8 h. The solvent was evaporated and the residue purified on a silica gel column using

CH ₂ C1 ₂ /CH ₃ 0H (9/1) as eluent. 0.22 g (80) was isolated. M M..pp.. 223366--223377°°CC.. IInn aaddddiittion to (80) the following two compounds were isolated.

(+-) trans l-butyl-4-( -ethylaminophenyl)-3-(4-trifluoro¬ methylphenoxymethyl)piperidine, hydrochloride (81)

0.11 g. M.p. 130-135 C dec.

(+-) trans l-butyl-4-(4-methylaminophenyl)-3-(4-trifluoro¬ methylphenoxymethyl)piperidine, hydrochloride (82)

Yield 0.45 g. M.p. 180°C dec.

(+-) trans 4-(4-acetamidophenyl)-l-butyl-3-(4-trifluoro- methylphenoxymethyl)piperidine, hydrochloride (83)

(76) (0.5 g) was dissolved in toluene (30 ml) acetyl chloride (176 μl) and triethyl amine (0.5 ml) were added. Stirring at RT for 3 h. 4 M NaOH was added and the mixture extracted with 2 x toluene. The combined organic phases was evaporated and the residue precipitated as the hydro-

chloride from acetone/ether. Yield 0.52 g of (83). M.p. 212-214°C.

(+-) trans l-butyl-4-(4-succinimidophenyl)-3-(4-trifluoro- methylphenoxymethyl)piperidine, hydrochloride (84)

(76) (0.6 g) and succinic anhydride (0.15 g) were mixed in toluene. Heating to 160°C for 2 h after evaporation of the solvent. Cooling to RT, addition of abs. ethanol and subsequent heating to reflux until complete dissolution. Evaporation gave a yellow oil which was purified on silica gel (3 times) yield 50% of (84) M.p.

151.5 - 152°C after precipitation as hydrochloride salt.

(+-) trans l-butyl-4-(4-methylsulfonylamidophenyl)-3-(4- trifluoromethylphenoxymethyl)piperidine, hydrochloride (85)

(76) (0.5 g) was dissolved in toluene (30 ml) methanesul- fonyl chloride (0.3 g) and triethyl amine (0.5 ml) were stirred at RT overnight. Extraction with 0H~/ether/toluene. The organic phases were collected, dried over MgSO., and evaporated. Purification on silica gel gave 27% of (85). M.p. 130-135°C decomp.

l-butyl-4-(4-morpholinophenyl)-3-(4-trifluoromethylphenox y¬ methyl)piperidine, hydrochloride (86)

(76) (0.7 g), bis-(2,2 dichloroethyl)ether (0.2 ml) and ^K 2 ^C0 ₃ ( 9) were dissolved in abs. ethanol, crystals of I ₂ and KI were added and the mixture refluxed for 1 week. Evaporation was followed by partition between OH and ether and evaporation of the organic phase gave a yellow oil which was purified on silica gel. 0.3 g of

(86) was isolated. M.p. 105°C dec.

l-butyl-4-(4-N'-ethylureidophenyl)-3-(4-trifluoromethyl¬ phenoxymethyl)piperidine, hydrochloride (87)

(76) (0.46 g) was dissolved in touene (30 ml) ethyl isocyanate (250 μl) was added. Stirring at RT for 2 days. Evaporation to dryness followed by extraction with 4 M NaOH/ether. The ether phases were combined, dried, evaporated and the residue precipitated as the hydrochloride salt. Yield of (87) 96%. M.p. 197.0 - 198.4°C.

(+-) trans 4-(4-dimethylaminophenyl)-l-methyl-3-(4-trifluoro¬ methylphenoxymethyl)piperidine, hydrochloride (88)

(41) (1 g) and formic acid (0.56 ml) were mixed in abs. ethanol at 0°C. Formaldehyde (0.25 g 35% solution) was added. The mixture was stirred at RT overnight and heated to 80°C for 7 h. Addition of further formic acid (0.23 ml) was followed by heating to 80°C for 20 h. Eva¬ poration of the mixture was followed by extraction of the residue with NaOH(4M)/ether. The etheral layer was eva¬ porated and the residue was purified on silica gel and subsequently precipitated from acetone/ether as the hydro¬ chloride. Yield 33%. M.p. 238-239.6°C.

EXAMPLE 16

(-) trans 4-(4-fluorophenyl)-l-pentyl-3-(2-trifluoromethyl■ benzyloxymethyl)piperidine, hydrochloride (89)

(37) (1 g) was reacted with 2-trifluoromethylbenzyl alcohol (1 g) as described for compound (36). Yield 8% of (89).

SUBSTITUTESHEET

M. p. 87-88°C.

(-) trans 3-benzyloxymethyl-4-(4-fluorophenyl)-l-pentyl- piperidine, hydrochloride (90)

(37) (1 g) was reacted with benzyl alcohol (1.5 g) and NaH (0.2 g). Heating to 70°C overnight was followed by rinse up as described for (36) and gave 0.5 g (90). M.p. 142.8-143.1°C.

(-) trans l-butyl-3-(4-methoxybenzylaminomethyl)-4-phenyl- piperidine, hydrochloride (91)

(-) trans (21) (2 g) was reacted with 4-methoxybenzyl amine (0.66 ml) by heating at 90°C for 1 h. The crude product was purified on silica gel using ethyl acetate/triethyl amine 10/1 as eluent. Yield of (91) 0.5 g. M.p. 260-262°C.

(+-) cis l-butyl-3-(4-methoxybenzylaminomethyl)-4-phenyl- piperidine, hydrochloride (92)

(+-) cis (21) (0.3 g) was heated with 4-methoxy benzyl amine (0.1 ml) at 70°C for 6 h. Purification on column as described for (91) yield of (92) 0.025 g.

EXAMPLE 17 (+-) trans 4-(4-trifluoromethyl)-3-hydroxymethyl-l-pentyl- piperidine (93)

231 mmol of trans 4-trifluoromethylcinnamic acid was converted to 4-trifluoromethylcinnamoyl chloride by reflux with 577 mmol thionyl chloride in chloroform, and the solvents was subsequently evaporated. The cinnamoyl

chlori in 100 ml methylene chloride was slowly added to a suspension of 231 mmol 1-pentyl amine and 138 mmol potassium carbonate in 250 ml methylene chloride under reflux. After 60 min another 231 mmol of 1-pentyl amine was added, refluxing was continued for 60 min, and the reaction mixture left at room temperature overnight. 500 ml methylene chloride was added, and washings with water aqeuous acid and base, followed by evaporation from toluene afforded 4-trifluoromethylcinnamoyl-N-pentylamide 48 g. M.p. 114.5- 114.8°C.

105 mmol 4-trifluoromethylcinnamoyl-N-pentylamide, 116 mmol diethyl malonate, and 285 mmol sodium ethoxide were refluxed in a 1:1 touene/diglyme mixture for 7 h, cooled and washed with dilute HCl and water. Evaporation at 2 torr gave a dark red oil, which was purified by column chromatography on silica to give 23 g 4-(4-trifluoromethyl- phenyl)-3-ethoxycarbonyl-l-pentylpiperidine-2,6-dione as a reddish oil. 57 mmol 4-(4-trifluoromethylphenyl)-3- ethoxycarbonyl-l-pentylpiperidine-2,6-dione in 100 ml THF was slowly added with stirring to a suspension of 260 mmol LiAlH. in 100 ml THF maintaining the temperature at 10°C, followed by stirring at room temperature overnight. Excess hydride was destroyed by addition of water, followed by 500 ml 4 N HCl. The THF was removed by evaporation, the aqueous phase was extracted by methylene chloride, and the organic phase was washed with 4 N NaOH, dried, and evapo¬ rated. Column chromatography on silica yielded the pure compound, which was crystallized from EtOAc. Compound (93). Yield 3.7 g. M.p. 112-115°C.

(+-) trans 4-(3-trifluoromethyl)-3-hydroxymethyl-l-pentyl- piperidine (94)

This compound was prepared from 3-trifluoromethylcinnamic acid in the same manner as described above for the 4-

SUBSTITUTE SHEET

isomer. Compound (94). Yield 2.9 g. M.p. 125-126°C.

EXAMPLE 18

(+-) trans 4-(4-bromophenyl)-3-(ethoxycarbonyl)-1-pentyl- 2,6-piperidinedione (95)

This compound was prepared essentially as described in US patent 4,902,801. 540 mmol 4-bromobenzaldehyde in 500 ml

EtOAc was slowly added to a suspension of 1351 mmol sodium ethylate in 500 ml EtOAc with stirring, maintaining the temperature below 10°C. Stirring was continued for one hour while the temperature was allowed to increase to room temperature. A solution of 648 mmol ethyl-N-pentyl- amidomalonate in 250 ml EtOAc was slowly added, and the stirring continued for 3 days. 360 ml of 25% acetic acid in water was added, and the organic phase was washed with brine and evaporated. Re-evaporation from 500 ml of toluene gave a mass which was crystallized from 1400 ml of 80% EtOH in water. Compound (95) yield 150. M.P. 61-65°C.

(+-) trans 4-(4-bromophenyl)-3-(hydroxymethyl)-l-pentyl- piperidine (96)

244 mmol (+-) trans 4-(4-bromophenyl)-3-(ethoxycarbonyl)- -l-pentyl-2,6-piperidine-dion in 500 ml dry THF, was drop- wise added to a suspension of 448 mmol LiAlH. in 500 ml THF, with stirring and maintaining the temperature at

-20°C. Stirring was continued at -20°C for 1 h, and then at room temperature overnight. Residual hydride was de¬ stroyed by addition of water, followed by 350 ml 6N HCl. The phases were separated, and the aqueous phase extracted by 4 x 250 ml methylene chloride. The organic phases were combined and evaporated. Dried by re-evaporation from to¬ luene, and triturated by ether. The product was released

SUBST ^I TUTESHEET

from the hydrochloride by partitioning between methylene chloride and 2N NaOH, and recrystallized from EtOAc. Compound (96) yield 35 g. M.p. 128-130°C.

The following compounds were prepared essentially in the same manner. The cooling to -20°C, during the addition to the LiAlH.-suspension, was only employed with the bromo compounds, the other diones were reduced at 10°C. None of the diones were crystallized. Instead the oils obtained from the evaporation were dissolved in toluene, dried with K ₂ C0 ₃ , and reduced without further purification.

(+-) trans 4-(3-bromophenyl)-3-hydroxymethyl-l-butyl- piperidine (97)

From 50 g 3-bromobenzaldehyde. Compound (97) yield 25 g.

(+-) trans 4-(2-bromophenyl)-3-hydroxymethyl-l-pentyl- piperidine (98)

From 15 g 2-bromobenzaldehyde. Compound (98) yield 7.36 g. M.p. 119-120 ^U C.

(+-) trans 4-(2-trifluoromethylphenyl)-3-hydroxymethyl-l- pentylpiperidine (99)

From 20 g 2-trifluoromethylbenzaldehyde. Compound (99) yield 14.29 g. M.p. 109.5-110°C.

(+-) trans 4-(2-chlorophenyl)-3-hydroxymethyl-l-pentyl- piperidine (100)

From 10 g 2-chlorobenzaldehyde. Compound (100) yield

8.89 g. M.p. 101-102°C.

( +- ) trans 4- ( 4-chlorophenyl ) -3-hydroxymethyl-l-pentyl- piperidine ( 101 )

From 10 g 4-chlorobenzaldehyde . Compound ( 101 ) yield 5.48 g. M.p. 125-128°C.

EXAMPLE 19

(+-) trans 4-(4-bromophenyl)-3-(4-trifluoromethylphenoxy¬ methyl)-l-pentylpiperidine, HCl (102)

73.5 mmol of compound (96) and 147 mmol 4-trifluoromethyl- fluorobenzene was dissolved in 250 ml dry DMF and poured over 81 mmol of potassium tert-butoxide, with vigorous stirring and while cooled in an ice/water bath. Stirring was continued for 30 min. at room temperature, and then the solution was poured into a mixture of 1000 ml ice/water and 750 ml ether. Brine was added, the phases were separated, and the aqueous phase extracted by 3 x 150 ml portions of ether. The combined ether phases were washed extensively with water, dried and evaporated. The product was isolated as the hydrochloride by precipitation from acetone/ether. Compound (102) yield 31 g. M.p. 135-137°C.

The following compounds were prepared essentially in the same manner.

(+-) trans 4-(3-bromophenyl)-3-(4-trifluoromethylphenoxy¬ methyl)-l-butylpiperidine, HCl (103)

From 59 mmol of compound (97), reaction time 40 minutes, triturated from ether. Compound (103) yield 26.3 g. M.p.

SUBSTITUTESHEET

lll-113 ^ω C.

(+-) trans 4-(2-bromophenyl)-3-(4-trifluoromethylphenoxy¬ methyl)-l-pentylpiperidine, HCl (104)

From 20.6 mmol of compound (98), reaction time 60 min. Triturated from ether. Compound (104) yield 7.5 g. M.p. 147.5-148.5°C.

(+-) trans 4-(2-trifluoromethylphenyl-3-(4-trifluoromethyl¬ phenoxymethyl)-l-pentylpiperidine, HCl (105)

From 15 mmol of compound (99), reaction time 40 min., crystallization unsuccessful. Obtained as a hard glass by evaporation from EtOAc at 120°C, 0.5 torr. Compound (105) yield 2.2 g. M.p. 135-138°C.

EXAMPLE 20

(+-) trans 4-(4-cyanophenyl)-3-(4-trifluoromethylphenoxy¬ methyl)-l-pentylpiperidine, HCl (107)

19.2 mmol of compound (102) in 100 ml methylene chloride was washed with 2 x 20 ml 2N NaOH, 20 ml brine, evaporated, and reevaporated from 50 ml DMF. The product was dissolved in 20 ml DMF, 40 mmol of CuCN(I) was added and the suspen- sion was refluxed for 8 h., protected from moisture by a CaCl ₂ -guard tube. The resulting mixture was dissolved in 80 ml 30% vol/vol ethylenediamine plus 100 ml ether, with stirring during one hour. The phases were separated, and the ether phase was extracted by 2 x 40 ml 10% NaCN- solution, 2 x 40 ml water, dried and evaporated. Column chromatography on silica with EtOAc yielded 5.3 g of the product as a brown oil. 3.1 g of this material was preci-

SUBSTITUTESHEET

pitated as the hydrochloride from acetone/ether. Compound (107) yield 2.88 g. M.p. 110-115°C.

(+-) trans 4-(4-carboxyphenyl)-3-(4-trifluoromethylphenoxy¬ methyl)-l-pentylpiperidine, HCl (108)

5.1 mmol of compound (107) was hydrolyzed by refluxing, in a mixture of 25 ml EtOH and 15 ml 2N NaOH, for 12 hours. The ethanol was evaporated, the solution neutralized by addition of dilute HCl, brine was added and the product extracted into methylene chloride, washed with water and evaporated. The product was crystallized as the hydro¬ chloride by slow evaporation from acetone. Compound (108) yield 1.4 g. M.p. 250°C d.

(+-) trans 4-(4-carbamoylphenyl)-3-(4-trifluoromethylphen- oxy-methyl)-1-pentylpiperidine, HCl (109)

1.9 mmol of compound (107) was suspended in 10 ml 2N NaOH, 10% H ₂ 0 ₂ , refluxed for 3 hours, and left at room temperature for 3 days. The solution was acidified (to avoid foaming) and evaporated, partitioned between 2N NaOH and ether, and the ether phase washed with water, dried and evaporated to a yellow powder which was recrystallized from 1:1 EtOAc/heptane. Compound (109) yield 170 mg. M.p. 167.5 - 168.5°C.

EXAMPLE 21

(+-) trans 4-(4-ethylcarbamoylphenyl)-3-(4-trifluoromethyl¬ phenoxymethyl)-1-pentylpiperidine, HCl (110)

2 mmol of compound (108) was refluxed in a mixture of 5 ml chloroform and 3.7 ml thionyl chloride for 80

min., evaporated, and re-evaporated 3 times from chloroform, dissolved in 10 ml dry methylene chloride, and cooled in an ice/water bath. A solution of 50 mmol of ethylamine in 10 ml 4N NaOH was added with vigorous stirring, and the mixture stirred for 1 hour at room temperature. The chloroform phase was separated, washed with base, water, dried and evaporated. The product was then isolated by precipitation of the hydrochloride from acetone/ether. Compound (110) yield 760 mg. M.p. 211-214°C.

(+-) trans 4-(4-phenethylcarbamoylphenyl)-3-(4-trifluoro¬ methylphenoxymethyl)-1-pentylpiperidine, HCl (111)

1 mmol of compound (108) was refluxed in a mixture of 5 ml chloroform and 2 ml thionyl chloride for 80 minutes, evaporated, and re-evaporated 3 times from methylene chloride and dissolved in 10 ml dry methylene chloride. 2.5 mmol of phenethyl amine was dropwise added with stirring, and the solution stirred for 30 min. The methylene chloride solution was then washed with water, dried, and evaporated to give a mass which was precipi¬ tated from acetone/ether. Compound (111) yield 400 mg. M.p. 192-195°C.

(+-) trans 4-(4-(N-(2-hydroxy-2-phenylethyl)carbamoyl)- phenyl)-3-(4-trifluoromethylphenoxymethyl)-1-pentyl- piperidine, HCl (112)

1 mmol of compound (108) was refluxed in a mixture of 5 ml chloroform and 2 ml thionyl chloride, and dissolved in 10 ml dry methylene chloride. 2.5 mmol of 2-hydroxy-2- phenyl-ethyl amine was dropwise added with stirring, and the solution stirred for 30 minutes. The methylene chloride solution was then washed with water, dried and evaporated,

SUBSTITUTESHEET

to give a mass which was precipitated from acetone/ether. Compound (112). Yield 350 mg. M.p. 179-181°C.

EXAMPLE 22

(+-) trans 4-(4-hydroxymethylphenyl)-3-(4-trifluoromethyl¬ phenoxymethyl)-1-pentylpiperidine, oxalate (113)

To a suspension of 1.23 mmol of LiAlH. in 10 ml diglyme, was dropwise added a suspension of compound (108) with stirring at 0°C, and the stirring continued for one hour. Another 1.23 mmol portion of LiAlH. was added, and the stirring continued for 2 h at room temperature. Excess hydride was destroyed by addition of water, allow¬ ing the temperature to rise to 50°C, and the solution filtrated. The precipitate was extracted by ether, and the combined filtrate and extracts evaporated. The product was isolated by column chromatography on silica with MeOH/methylene chloride 1:9, and the oxalate salt isolated as a hard glass. Compound (113) yield 290 mg. M.p. 68-70°C.

(+-) trans 4-(4-aminomethylphenyl)-3-(4-trifluoromethyl- phenoxymethyl)-l-pentylpiperidine, HCl (114)

3.2 mmol of compound (107) was partitioned between 10 ml methylene chloride and 10 ml 2N NaOH, 10 ml of toluene was added to the methylene chloride phase and evaporated, and the product re-evaporated from 25 ml toluene and dis¬ solved in 10 ml dry ether. This solution was dropwise added to a suspension of 3.2 mmol of LiAlH. in 10 ml ether, the mixture refluxed for 10 minutes, and further stirred for 30 min. at room temperature. 10 ml of 4N NaOH solu¬ tion was added, the ether phase separated, and the aqueous phase extracted with 2 x 10 ml ether. The combined gelly

ether solutions was dried with MgSO., extracted with stir¬ ring, filtered through a column of MgSO., and the MgSO. was extracted with ether. The combined extracts and fil¬ trate were evaporated, and the hydrochloride isolated by evaporation from acetone. The compound was then dissolved in water, washed with EtOAc, basified and extracted into ether, dried and evaporated. The product was then isolated as the hydrochloride by evaporation from acetone as a hard glass. Compound (114) yield 1.2 g. M.p. 140-160°C.

EXAMPLE 23

(+-) trans 4-(5-N-methylindolinyl)-3-hydroxymethyl-l-pentyl- piperidine (115)

186 mmol of N-methylindolin-5-carbaldehyde in 300 ml EtOAc was slowly added over 30 minutes to a suspension of 465 mmol sodium ethylate in 300 ml EtOAc with stirring, maintaining the temperature below 10°C. Stirring was con¬ tinued for one hour while the temperature was allowed to increase to room temperature. A solution of 204 mmol of ethyl N-pentylamidomalonate in 100 ml EtOAc was slowly added, and the stirring continued overnight. 123 ml of 25% acetic acid water was added, and the organic phase washed with brine and evaporated. The residue was dissolved in 300 ml toluene, dried with K ₂ C0 ₃ with stirring for one hour, filtered and evaporated to give 60 g of oil, which was dissolved in 100 ml THF.

This solution was slowly added to a stirred suspension of 271 mmol of LiAlH. in 200 ml THF plus 150 ml toluene, maintaining the temperature below 10°C. Stirring was con¬ tinued at room temperature overnight. Residual hydride was destroyed by addition of water, followed by 500 ml 6N HCl, maintaining the temperature below 20°C with an ice/- water bath. The phases were separated, and the aqueous

SUBSTITUTESHEET

phase extracted with 8 x 300 ml methylene chloride. 120 g solid NaOH was slowly added to the aqueous phase, and the precipitate filtered through hyflo. The precipitate was twice extracted with ether, combined with the filtrate, and washed with water, dried, and evaporated to give an oil, which was triturated by 50 ml EtOAc overnight. The precipitate was filtered, and washed extensively with icecold EtOAc until almost colorless. Compound (115) yield 8.3 g. M.p. 97-99.5°C.

(+-) trans 4-(5-N-methylindolinyl)-3-(4-trifluoromethyl¬ phenoxymethyl)-1-pentylpiperidine, HCl (116)

This compound was prepared as in example 19, from 15.8 mmol of compound (115). Reaction time 45 min. Compound (116) yield 8 g. M.p. 70-75°C d.