AU651641B2 - 2-amino-mono-methoxycyclohexyl amides useful as analgesics - Google Patents

Description

-iS i---r 1 651641

AUSTRALIA

PATENTS ACT 1990 rn M U T. R' rR P F C T FT A T I O N Q Q M D T.E T E S PE C T F T A T T 0 FOR A STANDARD PATENT

ORIGINAL

S0 o 4000c 4 0440 Name of Applicant: Actual Inventors: 0 Address for Service: oe WARNER-LAMBERT COMPANY David Christopher Horwell, David Charles Rees and Om Prakash Goel SHELSTON WATERS Clarence Street SYDNEY NSW 2000

A

0403 '3 #0 Invention Title: "2-AMINO-MONO-METHOXYCYCLOHEXYL AMIDES USEFUL AS ANALGESICS" The following statement is a full description of this invention, including the best method of performing it known to us:- -la- 2-AMINO-MONO-METHOXYCYCLOHEXYL AMIDES USEFUL AS ANALGESICS CROSS REFERENCE This invention relates to United States Application 612,636, filed November 9, 1990, which is a division of 503,067, filed March 29, 1990, now U.S. 5,051,428, which is a continuation of 280,759, filed December 6, 1988, now abandoned. The instant invention covers two compounds not specifically exemplified in the related case. Compounds substituted on the cyclohexyl moiety by a methoxy group at the 6 position are-the instant invention.

The compounds with the 6-methoxy substituent exhibit a particularly high selectivity for the kappa versus mu opioid receptor in the in vitro receptor binding assay.

ti BACKGROUND OF THE INVENTION The search for strong analgesics which also possess minimal potential for dependency has been among the highest priority efforts in pharmaceutical research. These research efforts have, to a great extent, involved chemical modification of the opiate structure and the discovery of novel compounds which possess niorphine-like activity.

i 30 The concept of multiple opioid receptors has been supported by studies with nalorphine and a series of benzomorphans which display unusual pharmacological properties dissimilar from morphine, yet blocked by the selective opioid antagonists.

cs~7 i

I

-2- [See, for example, W. R. Martin, et al, J. Pharmacol.

Exp. Ther., 197: 517-532 (1976).] The existence of multiple types of opioid receptors is of importance because it suggests the possibility of separating the desirable analgesic and psychotherapeutic effects of a drug compound from the undesirable abuse potential or habituating effects.

United States Patent 4,098,904 discloses certain cis- and trans-N-(2-aminocycloaliphatic) benzamide compounds having analgesic activity.

United States Patent 4,145,435 describes certain 2-amino-cycloaliphatic amide compounds as analgesics.

o0 In particular, trans-3,4-dichloro-N-[2- (1-pyrrolidinyl)-cyclohexyl]benzacetamide is reported 15 to possess selective kappa agonist activity, and therefore, to possess analgesic activity without 4"*o attendant dependence liability. [See P. V. Vonvoigtlander, et al, J. Pharmacol. Exp. Ther., 224: 7-12 (1983).] United States Patent 4,212,878 discloses certain N-[(4-mono- or di-oxygen-group-substituted-l-amino- 'cyclohex-1-yl)methyl)phenylacetamides, particularly 2-(3,4-dichlorophenyl)-N-[[8-(1-pyrrolidinyl)-1,4o" dioxaspiro[4.5]dec-8-yl]methyl]acetamide having 25 analgesic properties.

United States Patent 4,359,476 and its o' .continuation-in-part 4,460,600 disclose certain N-[2- I amino(oxy or thio group) substituted cycloaliphatic]benzeneacetamide and -benzamide compounds having the oxy- or thio group substituents on a cycloaliphatic ring carbon adjacent to either of the nitrogen-bearing carbon atoms of the cycloaliphatic ring. These compounds, having analgesic activity are typified by 4-bromo--[3p-v 1 -3methoxy-2-(1-pyrrolidinylcyclohexyl]-Nmethylbenzamide.

United States Patent 4,598,087 and its divisional, United States Patent 4,677,122, disclose certain oxy- or thioacetamides of trans-1,2-diaminocyclohexane having analgesic activity. These compounds are typified by trans-2-(2,3-dichlorophenoxy)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide.

United States Patent 4,656,182 discloses certain trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzoo"b [b]thiophene acetamides having analgesic activity.

o United States Patent 4,663,343 discloses certain t^ trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- 15 naphthalenyloxy- and naphthalenylthioacetamides having analgesic activity.

United States Patent 4,737,493 discloses certain t a substituted phenoxy-, and 2-naphthalenyloxy, indenyl-, indolyl-, benzofuranyl-, and benzo[b]thiofuranylcarboxamides of 7,8-(substituted-diamino)-1oxaspiro[4.5]decanes useful as analgegia agents.

United States Patent 4,463,013 discloses certain 0 0 oxygen substituted amino-cyclohexyl-benzeneacetamides S°as diuretics.

25 United States Patent 4,438,130 discloses certain mono-axa-, thiaspiro-cyclic-benzeneacetamide and ct^ benzamide compounds useful as analgesics.

I l United States Patents 4,906,655 and 5,019,588 disclose certain 1, 2 -cycloheixylaminoaryl amides useful as analgesic agents.

-4- SUMMARY OF THE INVENTION The invention relates to a novel series of monomethoxycyclohexyl amides which possess selective kappa receptor analgesic activity. The compounds show a surprising increase in activity in the nociceptive assay of the rat paw pressure test of M.

B. Tyers, Brit. J. Pharmacol., 69:503-512 (1980) when compared with compounds known in the art.

The invention covers novel amides (la,2a,68)-N- [2-methoxy-6-(1-pyrrolidinyl)cyclohexyl]-N-methyl-4benzofuranacetamide monohydrochloride and (la,21,3a)- 0o 0 N-[3-methoxy-2-(1-pyrrolidinyl)-cyclohexyl]-N-methyl- 0 4-benzofuranacetamide monohydrochloride and the pharmaceutically acceptable acid addition salts.

The invention also includes pharmaceutical compositions comprising an analgesically effective amount of the above compounds in admixture with a pharmaceutically acceptable carrier or excipient and a method of treating pain in a patient suffering .Q00 therefrom comprising administering to said patient 0e° the pharmaceutical composition in unit dosage form.

The invention further includes pharmaceutical ocompositions comprised of a neuroprotective amount of 25 the above compounds in admixture with a pharmaceutically acceptable cairier or excipient as well as a method of treating stroke and/or cerebral ischemia in a patient suffering therefrom.

The invention further includes methods for 30 preparing the compounds recited above.

IL~ n A method for preparing compounds of the invention wherein a substituent is or So and the methoxy moiety is attached at 3- or 6- position comprises epoxidizing 3-methoxycyclohexene to produce a mixture of the trans and cis epoxides in a ratio of 2:1 and separating them by fractional distillation.

So ~The trans epoxide is reacted with pyrrolidine to produce a mixture of two isomeric amino alcohols.

,,,The mixture is treated with methanesulfonyl chloride 15 and then N-methylbenzylamine to produce 4444 N-benzyldiamine which is converted to the salt and catalytically hydrogenated. The diamine is then reacted with a benzofuran or benzothiophene acetic acid to produce a compound of the invention.

The cis epoxide undergoes the same reaction sequence.

Alternatively the trans epoxide is first reacted with N-benzylmethylamine to produce an amino alcohol which is converted to the salt; the mixture crystal 25 resulting is mechanically separated, the largest crystal is catalytically debenzylated and the product reacted with 4-benzofuranacetyl chloride to produce a compound of the invention.

The compounds of the present invention include 30 solvates, hydrates, and pharmaceutically acceptable acid addition salts of the basic compounds of formula I above.

By virtue of the basic nitrogen on the cyclohexane moiety, pharmaceutically acceptable salts

I

C~

i -i :I -6- 6 0 *o 0 I *P 6UI~ f0D 0*I 0 064 61 rt' of compounds of the present invention may be prepared by reaction with appropriate acids. Suitable acids for the formation of pharmaceutically acceptable salts of the compounds of this invention form a class well known to practitioners of the pharmaceutical formulation arts (cf. S. M. Berge, et al, "Pharmaceutical Salts" in J. Pharm. Sci., 66: 1-19 (1977)), and include such acids as hydrochloric, hydrobromic, hydriodic, sulfuric, nitric, phosphoric, acetic, benzoic, citric, maleic, tartaric, succinic, gluconic, ascorbic, sulphamic, oxalic, pamoic, methanesulfonic, benzenesulfonic, ethanesulfonic, hydroxyethanesulfonic, and related acids and mixtures thereof.

15 The salts are generally prepared by reacting the free base with one equivalent of the desired acid in an appropriate unreactive solvent, followed by collection of the salt by filtration or recovery upon removal of the solvent. The free base may be 20 regenerated, if desired, by reaction of the salt with one equivalent of a base such as sodium hydroxide, sodium bicarbonate, sodium carbonate, and the like.

The salts may differ from the free base form of compounds of this invention in properties such as melting point and solubility in polar solvents, but are otherwise considered equivalent for the purposes of this invention.

The compounds of the present invention contain three or more asymmetric carbon atoms. The compounds exist in various stereo- and regio-isomeric forms and mixtures thereof. The present invention contemplates all stereo- and regio-isomeric forms of the compounds of formula I above. Both the and and the are contemplated by the invention.

~i~a~a~i~ -7- The individual stereo compounds are obtained, if desired, from a mixture of different forms by known methods of resolution such as the formation of diastereomers followed by recrystallization.

The compounds of the present invention possess significant analgesic activity with the potential for minimum dependence liability due to their selective kappa opioid receptor binding properties. In addition to producing analgesia, compounds which are selective kappa antagonists, such as the compounds of this invention, also cause opioid receptor-mediated 0 sedation, diuresis, and corticosteroid elevation.

0 "o Accordingly, the compounds of this invention may also .qao be useful as diuretics and psychotherapeutic agents 15 as well as analgesics.

The compounds of the present invention also have application in congestive heart failure, advanced hepatic cirrhosis, nephrotic syndrome, chronic renal failure, trauma associated with surgery, emotional and physical stress, endocrine disorders, syndrome of S° inappropriate antidiuretic hormone secretion and O o therapy with certain pharmacologic drug agents such Sas certain sulphonyl ureas, certain biguanides such as phenformin and metformin, clofibrate, certain o 0 25 tricycles such as carbamazepine, amitriptyline, 44 thiothixene, fluphenazine and-'hioridazine, certain antineoplastic agents, certain analgesics and certain natriuretic diuretics.

The compounds of the present invention also have neuroprotective indications. As such they are useful in the treatment of stroke and the treatment of cerebral ischemia F. Von Voightlander in Brain Research 435: 174-180 (1987)) and A. H. Tang, et al.

in Brain Research 403: 52-57 (1987)).

-8- Representative compounds of the present invention demonstrate positive activity in standard laboratory analgesic tests in animals such as mice.

The MPE 50 doses for several representative compounds of this invention in the standard rat paw pressure analgesia test M. B. Tyers, Brit. J. Pharmacol., (1980), 69: 503-512 are presented in Table I below.

Conpounc 17 in the table exhibits a particularly high selectivity for the kappa versus mu opioid receptor in the in vitro binding assay.

0 t 0 o 0a o CC w 0 0 .0 I I 0 00,i

I,,

-i Li i i.n -9- TABLE I H2

HC

00* o o *r 000 Compound Structure (position of OMe) OQioid Binding (klnM) Kappa mu Rat Paw Pressure mu/k MPE 5 0

IV

MPE

5 0 mg/kg

PO

PO/IV

Ratio

A

B

C

D

E

F

G, Compound 7(sch:) H, Compound 12(sch3) I, Compound 17(sch4) 7.1 4 1.72 4.13 24 4 0.84 0.9 6.7 1.3 7.36 253 3.45 3300 1900 210 2020 4300 400 28 1.3 2130 176 2220 359 5100 18.4 13 20.2 10.6 1.4 1480

K

i values represent the mean (standard error of the mean) from concentration-response curves performed in triplicate from each of the least two separate experiments.

MPE

5 0 values represent the dose required to produce 50% of the maximum possible analgesic effect. They are derived from a single experiment with six animals per dose level.

p? Representative compounds of the present invention were also tested in vitro to determine the extent of opioid receptor binding, and were found to bind selectively to the kappa opioid receptor site with evidence of little or no binding to the mu or delta opioid receptors.

Measurement of the kappa opioid receptor binding activity of compounds of the present invention was made by the following method. Guinea pig brain homogenates were prepared fresh daily utilizing the method of Gillan et al, Br. J. Pharmacol. (1980) 70: 481-490.

The binding of tritiated etorphine to brain o° homogenates was measured in the presence of unlabeled o competitor compounds of the present invention with 200 nanomolar D-alanine-D-leucine-enkephalin (acrox.,t to DADLE) and 200 nanomolar D-ala-MePheGly-ol-enkephalin (acronym DAGO) added to saturate the delta and mu opioid receptors, respectively. The reaction was terminated by rapid filtration and the radioactivity bound to the filters counted by liquid scintillatil spectrophotometry.

oa o Measurement of the mu and delta opioid receptor binding activity of the compounds of this invention was made by the following method. Guinea pig brain 25 homogenates were freshly prepared daily by the method of Gillan, et al, cited above.' Homogenates were incubated for 150 minutes at 0 C Swith either tritiated DAGO to measure mu receptor binding activity, or with tritiated DADLE in the presence of a ten-fold excess of unlabeled DAGO to measure delta opioid receptor binding. Nonspecific binding was determined in the presence of 10-6 molar DAGO and 10- 6 molar DADLE.

-ll-~

M

-11- Reactions were terminated by rapid filtration and the radioactivity bound to the filters counted by liquid scintillation spectrophotometry.

The data were analyzed by the methods of Scatchard, Ann. N.Y. Acad. Sci., 51: 660-672 (1949) and Hill, J. Physiol., 40: IV-VIII (1910). The inhibition of the binding of tritiated etorphine, DAGO and DADLE by cold ligands was determined from the regression of log percentage inhibition of specific binding or log concentration of cold ligand. The inhibition constant, Ki, was calculated from the equation: o o K o O i 1 /KD where is the concentration of the labeled ligand and KD is the equilibrium dissociation constant.

Schemes 2-4 below illustrate chemical syntheses of SooI some of the compounds of the present invention. All compounds are racemic mixtures. They are prepared by 0 0 epoxidizing commercially available 3-methoxycyclohexene So (also named 2-cyclohexene-l-ol, methyl ether) by the action of m-chloroperbenzoic acid in dichloromethane to yield a mixture of trans and.cis 3-methoxycyclohexane epoxides 1 and 2 in a ratio of 2:1. The trans and cis epoxides were carefully separated by fractional distillation to greater than 95% isomeric purity. In Synthetic Scheme 2, the trans epoxide 1, is reacted with pyrrolidine to give a mixture of two isomeric amino alcohols 3 and 3a. This mixture of amino alcohols is treated with methanesulfonyl chloride and subsequently with N-methylbenzylamine to yield N- L SHELSTON WATERS CLARENCE STREET, SYDNEY, AUSTRALIA -12benzyldiamine 4. The compound 4 is converted to the hydrochloride salt 5 and catalytically hydrogenated to afford 97% pure 6. The diamine 6 was reacted with benzofuran acetic acid in presence of carbonyldiimidazole to afford Compound 7 of this invention.

In Scheme 3 the cis epoxide 2 was reacted in the same sequence as above which afforded the Compound 12 of shown stereochemistry.

In Scheme 4, the trans epoxiea 1 is first reacted with N-benzylmethylamine to give amino alcohol 13.

This amino alcohol is treated with methanesulfonyl o"9 .chloride and subsequently with pyrrolidine to yield 14 o, as a mixture of four components as determined by GC in a ratio of 1:4:7:4. When 13 was converted to the 15 hydrochloride salt, a mixture of crystals was formed from which the largest brown color crystals were mechanically separated and found to be a single isomer based on spectroscopic evidence. On catalytic debenzylation with hydrogen 16 was formed. This was reacted with 4-benzofuranacetyl chloride to yield 17 04 a o o° 6L- I I I_ I II 1 -13- SCHEME 2 (all compounds are racemic)

OCH

3 b

MCPBA

CH

2 C1 2

OCH

3

OCH

3 01, a~ a 4", a a 00 a ~,a a aaa ~a a a a

OCH

3 CNNi 2-propanol

A

CH

3

SO

2 C1 Et 3

N

PhCH 2

NHCH

3 a a $0 a 0 a a Ph) HC1 I1) H 2 /Pd/C- MeOH 2) NaOH dOH OdE 3 1) carbonyl diimidazole 2) HUi eHC1 -14- SCHEME 3 (all compounds are racernic)

OCH

3 o4

QNH

2 -propanol

A

4; 4; 4; 44; 4; ~4 4; 4; 4,4 4; 4; p

OCH

3 I OCH 3 or

HO%)

(I isomer)

CH

3 S0 2 C1 SEt 3

N

IPhCH 2

NHCH

3 QN OCH3 H3C, <:NOCH 3 H3C,~~ N:

.H

Ph)-

Q

HU1

I

$1 4

I,

I

4,4 $4 4; 4; 4; 4; 4; 4; 44$ 4; 4; .44 1) H 2 /Pd/C H 2 MeOH Pd/C 2) NaCH C0 2

H

OCH

3 1)

O\

carbonyl diimidazole

TRF

N

H

3

H

11.

2) HUJ *HC1 ~C b A..

SCHEE 4 (all compounds are racemic)

OCH

3 HhN ICH 3 2-propanol c4 0 0 o 0 0 C) r tt 0 0 04 0 @009 0 49 C) CH3SO2C1 Et3N

'N'

I

H

HU2

CH

3

OCH

3 Ph *HC1

L

0 40 ~0 I 0 00 a 00 4 OQ a 90 0cj '0 I1) NaCH 2) Pd/C; H 2

)CH

3 Et 3 N, DMAP (cat.)

THF

L6 2) HU1 3 isomers )4 OCH 3

HC

nontoxic, pharmaceutically acceptable salts may be -16administered to mammals orally in combination with conventional compatible carriers in solid or in liquid form. These oral pharmaceutical compositions may contain conventional ingredients such as binding agents selected from syrups, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, and mixtures thereof.

The compositions may further include fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof.

These oral compositions may also contain lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high o 15 molecular weight fatty acids such as stearic acid, ,silica, or agents to facilitate disintegration of the solid formulation such as starch, and wetting agents Z o 44o such as sodium lauryl sulfate.

The solid oral compositions may take any convenient form such as tablets, lozenges, capsules, or dry powders which may be reconstituted with water or other suitable liquid prior to administration.

Liquid form pharmaceutical c, -_,itions may take the form of solutions, suspensions, or emulsions. The liquid forms may contain flavorants, sweeteners, and/or preservatives such as alkyl p-hydroxybenzoates. They S 9 may further contain suspending agents such as sorbitol, glucose, or other sugar syrups, methyl-, hydroxymethylor carboxymethylcellulose, and gelatin, emulsifying agents such as lecithin or sorbitol monooleate, and conventional thickening agents.

Liquid compositions may optionally be encapsulated in, for example, gelatin capsules in an effective amount.

i I

EL

-17- The compounds of the invention may also be administered to mammals rectally in the form of suppositories. For preparing suppositories, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the melt. The mixture is then poured into convenient sized molds and allowed to cool and solidify.

Preferably, the pharmaceutical compositions of this invention are in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component.

The unit doses can be a packaged preparation with the package containing discrete quantities of the a0 15 preparation. For example, the package may take the 4° °o form of packaged tablets, capsules, and powders in envelopes, vials, or ampoules. The unit dosage form I, can also be a capsule, cachet, or tablet itself or can be the appropriate number of any of these in package caGo o 20 form.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.5 mg to about 350 mg according to the particular application ouoo and the potency of the active ingredient.

25 When employed systematically in therapeutic use as analgesic agents in the pharmadeutical method of this invention, the compounds are administered at doses of from about 0.05 mg to about 2.0 mg of active compound per kilogram of the recipient.

The following examples are provided to enable one skilled in the art to practice the present invention.

These examples are not intended in any way to limit the scope of the invention but are intended as illustrative thereof.

-18- EXAMPLE 1 4-Methoxycyclohexene epoxide (1) m-Chloroperoxybenzoic acid (3.5 g, 20 mmol) in 1:1 dichloromethane-carbon tetrachloride (70 ml) was added over 25 minutes to a stirred solution of 4-methoxycyclohexene (2.0 g, 18 mmol) in carbon tetrachloride (10 ml) at -50C. After 5 hours the mixture was allowed to warm to room temperature and after 2 hours the slurry was filtered. The filtrate was washed with 5% aqueous sodium bisulphite (40 ml) then saturated aqueous sodium carbonate (2 x 40 ml).

The resulting solution was dried (K 2

CO

3 and distilled using a vigreaux column at atmospheric pressure to give the epoxides as a mixture of two diastereoisomers S 15 (1.0 g, 7.8 mmol), bp 175-176 0 C (760 mm Hg); i.r.

(neat) 2938, 1104 cm- 1 8 (CDC1 3 300 MHz) 3.22 (1H,m); 3.24 and 3.22 together 3.05 (2H,m), 2.3-1.2 m/e 129 111 97 58 (100%); 20 Anal. C 7

H

1 2 0 2 requires C, 65.60; H, 9.44. Found C, 65.57; H, 9.60%.

EXAMPLE 2 Amino alcohols (2) The epoxides (2.0 g, 15.6 mmol) and N-benzylmethylamine (3.0 g, 25-mmol) were dissolved in propan-2-ol (10 ml) and heated under reflux for hours. The resulting solution was distilled to give the amino alcohols as a mixture of three isomers 30 (3.2 g, 13 mmol, bp 133-134 0 C/ 0.05 mbar; i.r.

(neat) 3460, 2939, 2866 cm-l; 6 (CDCl 3

D

2 0) 7.3 4.0-2.7 (7H,m, strong s at 3.36, 3.30, 3.29); 2.4-1.2 strong s at 2.19, 2.18, 2.15); m/e (EIl) 249 218 190 Anal. C1 5

H

23

NO

2 requires C, -1.9- 72.25; H, 9.30; N, 5.62. Found C, 72.13; H, 9.22; N, 5.56%. 1 H nmr spectra of the individual isomers were obtained after separation by silica gel chromatography using 20:1 dichioromethane-methanol. 8 (CDC1 3

D

2 0) Isomer A: 7.24 3.61 (1H,d,J 14); 3.45 (lH,J 14); 3.43 3.36 3.18 2.36 2.19 2.27-1.99 1.22 (3H,m).

Isomer B: 7.28 3.70 (lH,d,J 15 Hz); 3.65 3.45 3.44 (1H,d,J 15 Hz); 3.30 2.83 2.15 2.20-1.85 1.60 1.30 Isomer C: 7.28 3.79 3.74 (1H,d,J 15 Hz); 3.55 3.45 (1H,d,J 15 Hz); 3.29 2.42 2.18(3H,s); 2.05 1.55 1.30 (2H,m).

iv, EXAMPLE 3 N-benzyl diamines (3) The diastereoisomeric mixture of amino alcohols (8.0 g, 32 mmol) was dissolved in dichioromethane 00 20 (105 ml) and triethylamine (7.1 ml), cooled to and treated with methenesulphonyl chloride (2.7 ml, mmol) dropwise such that the temperature remained below -5 0 C. After 1.5 hours the mixture was U concentrated in vacuo to a volume of 20 ml arnd treated with pyrrolidine (22 ml, 260 mmol) under reflux for hours. The resulting mixtiire was poured into aqueous sodium carbonate (700 ml) and extracted with dichloromethane (3 x 100 ml) to give, after concentration, an orange oil (15 g) which was distilled to give the N-benzyl diamines as a mixture of three O (racemic) isomers (9.3 g, 31 mmol, 97%); bp 122-155-C/0.2 mbar; i.r. (neat) 2936, 2 791 cm-1, M/e 303 287 270 84 (100%); (CDC1 3

D

2 0, 300 MHz); 7.30 3.65 (2H,s); 3.75-3.50 3.36 and 3.32 and 3.29 (s) together are 2.19 and 2.17 and 2.15 (s) together are 3.10-1.00 (16H,m); Anal.

ClgH 30

N

2 0*0.33H 2 0 requires C, 74.00; H, 10.02; N, 9.08.

Found C, 73.97; H, 9.78; N, 8.82%.

EXAMPLE 4 Diamines (4) The N-benzyl diamines (3.5 g, 12 mmol) were dissolved in ethanol (50 ml) and treated with palladium hydroxide on carbon (0.94 g) and hydrogen at psi at 60°C for 2 hours. The mixture was filtered through kieseleguhr and distilled to give the diamines as a mixture of three (racemic) isomers (1.4 g, 15 6.6 mmol, bp 84-85 0 C/0.3 mbar; i.r. (neat) 3402, S2942 cm-l; m/e 197 180 84 (100%); t (CDC1 3

D

2 0, 300 MHz), 3.36 and 3.31 and 3.28 together are 2.38 and 2.37 together are 3.7-3.2 2.8-0.9 (17H,m). An 20 analytically pure sample was obtained by treating (4) (212 mg, 1.0 mmol) with p-toluene sulphonic acid (190 mg, 1.0 mmol) in propan-2-ol (1 ml) to give a white solid which was recrystallized from propan-2ol/diethyl ether to give the mono-R-toluenesulphonate 25 salt (200 mg, 0.50 mmol, mp 120-1360C. Anal.

Ci 2

H

2 4

N

2 0*C 7 HsS0 3 requires C, 59.35; H, 8.39; N, 7.29; S, 8.34. Found C, 58.95; H, 8.24; N, 6.99; S, 8.42%.

4y -21- EXAMPLE (la,2a, 6a)-2-methoxy-7-oxobicyclo[4.1.0]heptane and (la, 2B, 6a) isomer (2)

OCH

3

OCH

3

OCH

3

MCPBA

K> CH 2 C1 2 1 2 A solution of 3-methoxycyclohexene (258.11 g, 2.3 mol, Aldrich) in 9.4 L of methylene chloride was cooled in an ice/acetone bath. Solid m-chloroperbenzoic acid 884.6 g, 2.56 mol) was added in small portions over 30 minutes, keeping the temperature below 3'°C The reaction was allowed to warm'to room 'temperature overnight. The reaction was then cooled to 150, and 4 L of 5% sodium bisulfite was added slowly.

After 15 minutes, 205 g of NaOH in 2 L of water was added, and the mixture was stirred for 20 minutes. The aqueous layer was removed, 5 L of saturated NaHCO 3 was added, and the mixture was stirred for 20 minutes. The 1--ers were separated and the organic layer was dried o K 2

CO

3 The solution was filtered and the solvent removed under vacuum. The remaining oil was distilled S° (80 0 -90°C, 25 mm Hg) to yield 242.8 g of a 2:1 mixture of 1 and 2. The isomers were separated by vacuum distillation through a 4-ft fractionating column 4 4 30 to give a 76% combined overall yield of material with o' >95% isomeric purity. Anti-isomer (major isomer) 1 H-NMR (CDC13) 8 3.5-3.4 1H), 3.45 3H), 3.2 (br s, 1H), 3.1 J=3.7 Hz, 1H), 2.1-2.0 1H), 1.9-1.7 2H), 1.5-1.3 1H), 1.4-1.1 2H).

I

-22- EFTIR (neat): cm- 1 2943, 1460, 1101, 933, 802.

Syn-isomer 2 H-NMR (CDC13): 5 3.7-3.6 1H), 3.46 3H), 3.4-3.2 2H), 1.9-1.8 2H), 1.7-1.1 (mn, 4H). FTIR 1459, 1113, 931, 864 cm'l. m/e (CI CH 4 129 111 97 85 The structurj of the an.tiisomer was confirmed by COSY and NOESY experiments.

NOE Observed EXAMPLE 6 (la,21,6B)-2-methoxy-6-(1-pyrrolidinyl)-cyclohexanol (3)

OCH

3

OCH

3

OCH

3 200 2-propanol No\\, 12 (major) Oxirane (20.0 g, 0,156 mol) and pyrrolidine (20.1 g, 0.283 mol) were refluxed in 100 mL of 2propanol for 6.5 hours. The solvent was removed under vacuum, and the resulting oil tas distilled (112-116 0

C,

1.1 mm Hg) to give 3 (28.85 g, 0.145 mol, 93%) as a yellow oil. GC showed a 95:5 ratio of isomers. 1

H-NMR

(d 6 -DMSO): 8 4.15 (br s, 1H), 3.32 3H), 3.2-3.1 (in, 1H), 2.96-2.8 1H), 2.7-2.65 4H), 2.5-2.3 .0

A'

q-l iI I

II

1,

VI

ji -i -II._ 11.23- 1H), 2.0-1.8 1H), 1.7-1.5 5H), 1.3-0.9 (m, 3H). FTIR (neat): cm 1 -3300 (br)r 1462, 1353, 1298, 1101, 1071, 883. m/e 201 199 184 168 110 70 Analysis requires: C, 66.29%; H, 10.62%; N, 7.03%. Found: C, 65.96%; H, 10.68%; N, 6.85%. Structure of 3 was verified by COSY and NOESY experiments.

OCHr3

H

CH

2J"

H

NOE OBSERVED

C-

COUPLING OBSERVED Irro 1 44 1(01 iQIQ D p O

O

(tL OLlrl*

O

~llnd 9 O O IO IC

I

O 1 11(11

L

I

I

I

EXAMPLE 7 (1c*,2B,33)-N-[3-methoxy-2-(l-pyrrolidinyl)-cyclohexyl)- N-methylbenzenezuethanamine (4)

OCH

3 0:

OCH

3 CH3S 0 2 C1 O.Nd Et 3 N PhCH 2

NHCH

3 H3C,

NI

Ph The aminoalcohol 3 (27.47 g, 0.138 mol) was dissolveC in 270 mL CH 2 C1 2 and 23 mL triethylamine. The r- B 'P

~I

Tlrrr~lr-pi i~ -24solution was cooled to and 10 mL methanesulfonyl chloride was added in one portion. The temperature rose rapidly to 280. When the temperature returned to 200, 2.6 mL more methanesulfonyl chloride was added dropwise with cooling. A solid precipitate formed, and mL more CH 2 Cl 2 was added to facilitate stirring.

After 4 hours, the reaction was complete by GC. The reaction mixture was poured into 450 mL CH 2 C12 and washed three times with 450 mL water. The organic layer was dried over magnesium sulfate, in the cold, overnight. The solution was filtered and the solvent removed under vacuum, to give 28.68 g of a solid. This solid was dissolved in 64 mL of N-benzylmethylamine and heated to 93 0 C for 4 hours. The reaction mixture was poured into 100 mL 10% K 2

CO

3 and extracted three times with CH 2 C1 2 The organic layer was dried over K 2 C0 3 filtered, and the solvent removed under vacuum. The product was vacuum distilled to give a yellow oil, 4 (28.83 g, 0.095 mol, 69%) bp 140-1600/2.8 mm Hg.

S 20 1 H-NMR (CDC1 3 6 7.5-7.1 5H), 4.0-3.8 (br m, 1H), 3.63 2H), 3.30 3H), 3.15 (td, J=3.7, 11 Hz, 1H), 3.1-2.7 (br m, 5H), 2.07 3H), 2.05-2.85 (m, 2H), 2.85-2.65 (br, 4H), 1.6-1.4 2H), 1.4-1.0 (m, 2H). Analysis requires: C, 75.45%; H, 10.00%; N, o: 25 9.26%. Found: C, 75.30%; H, 9.98%; N, 8.99%.

EXAMPLE 8 (la, 28, [3-methoxy-2- (-pyrrolidinyl)cyclohexyl] N-methylbenzene methanamine monohydrochloride (7 OCH 3 C'N OCH 3 CT b H c l Hb HHC1 Ph A Ph. The diamine 4 (21.96 g, 0.0726 mol) was dissolved in 210 mL anhydrous ether and 28 mL of 2.6 M HCI (in 2propanol) was added dropwise. After addition was complete, the reaction was stirred 10 minutes at room temperature, strongly cooled (dry ice acetone bath), filtered, and the filter cake washed with cold anhydrous ether. The monohydrochloride salt (16.40 g, 0.0484 mol) was obtained as a white powder after drying. The mother liquor was washed with 15% NaOH, dried over MgS0 4 filtered, and the solvent removed under vacuum, to give 6.71 g of 4. The yield of mono 4 4 t HCl salt was 96% after recovery of 4. The crude salt was used for the next step. 1 H-NMR (d 6

-DMSO):

10.0 (br, 1H), 7.4-7.2 5H), 4.14 3.8-3.5 Sn(m, 3H), 3.4-3.1 8H; includes s, 3H at 3.27, and br S 30 at 2.03 (s+br, 4H), 1.9( br, m, 4H), 1.6-1.0 (m, 4H). FTIR (KBr): cm 1 3454, 2938, 2603, 1476, 1087, 1020, 752, 706. m/e 303 302 287 160 134 123 110 91 84 Analysis requires: C, 67.33%; H, xZ"-F

\A

p 1; -4

J

-26- 9.22%; N, 8.27%; Cl, 10.46%. Found: C, 66.90%; H, 9.18%; N, 7.98%; Cl, 10.65%; H20, 0.17%. GC showed that this material was 94% pure.

EXAMPLE 9 (la, 21, 313) -3-methoxy-N-methyl.-2- (1-pyrrolidinyl) cyclohexanamine N OCH 3 1) H/Pd/

OCH

3 MeOH

C

N HC 2) NaH H 3

C

*HCl 2) NaOH 20 *4 25 t a 306 I i t [i+ 6 3o The crude salt 5 (16.40 g, 0.0487 mol) was reduced with 1.5 g 20% Pd/C in 500 mL MeOH. The catalyst was filtered off and the solvent removed under vacuum.

Dilute NaOH and ether were added to the resulting solid, and the layers were separated. The aqueous base was washed twice with ether, and the combined ether washings were dried over Na 2

SO

4 The solution was filtered and the solvent removed under vacuum, to give the diamine 6 (9.45 g, 0.0445 mol, 91% yield). The crude amine was taken on to the next step, since by GC the material was 97% pure. A portion of the material was purified by Kulgelrohr distillation (100 0

C,

1.2 mm Hg). 1 H-NMR (CDC1 3 8 3.8 1H), 3.24 (s, 3H), 2.8-2.6 5H), 2.6-2.45 2H), 2.40 3H), 2.2-1.9 2H), 1.8-1.4 6H), 1.3-0.9 2H).

FTIR (neat): cm 1 3319 2932 1459, 1437, 1360, 1095 m/e 212 197 180 123 108 84 Analysis ,^^r~04 s i

"-I

J

4 i 4 Ul pi? -27requires: C, 67.88%, H, 11.39%; N, 13.20%. Found: C, 68.17%; H, 11.84%; N, 13.27%. GC showed the product to be 94% pure.

EXAMPLE (la,21,318)-N-[3-methoxy-2-(1-pyrrolidinyl)-cyclohexyl]- N-methyl-4-benzofuranacetamide monohydrochloride

CO

2

H

Kl OCH 3 1) 7OCH

H

3

CNI

S

H3C Ns' carbonyl diimidazole H3C HTHF *HC1 S 2) HC1 20 Benzofuranacetic acid (1.95 g, 0.0111 mol) was 0 0 dissolved in 35 mL THF. Carbonyldiimidazole (1.81 g, 0.0112 mol) was added in one portion and the reaction S 25 was stirred under nitrogen for 2.5 hours. The amine 6 S: (2.13 g, 0.0100 mol) in 10 mL-THF was then added and the solution was stirred overnight. The solvent was removed under vacuum and 80 mL CH 2 Cl 2 was added. This solution was washed with 30 mL H 2 0, twice with 30 mL S 30 NaOH, and finally with 30 mL H 2 0. The solution was dried over MgS0 4 filtered, and the solvent removed under vacuum. The resulting viscous yellow oil gradually solidified to give 2.22 g, (54% yield).

1 H-NMR (CDC1 3 8 7.6 J=2.2 Hz, 1H), 7.4-7.36 (d, L -28- J=8.1 Hz, 1H), 7.25-7.1 2H), 7.0-6.9 (dd, J=2.7 Hz, 15.5 Hz, 1H), 4.4-4.2 1H), 4.18-4.1 J=15 Hz, 1H), 4.0-3.8 2H), 3.28 3.21 (two singlets, 3H), 2.81 2.76 (two singlets, 3H), 2.76-2.5 8H), 2.1-1.9 1H), 1.9-0.9 9H). FTIR (KBr): cm 1 -3500 (H 2 2936, 1638 1434, 1138, 1100, 761 m/e CH 4 399 371 338 213 181 Analysis requires: C, 71.32%; H, 8.16%; N, 7.56%. Found: C, 70.99%; H, 8.40%; N, 7.87%. This material was dissolved in isopropanol and 3 mL of 7.3 M HC1 in isopropanol was added. Dry ether was added until the solution became cloudy. This material was allowed to stand at room temperature for 3 hours and placed in a freezer overnight. The So 15 resulting solid was filtered, washed with dry ether, and dried under vacuum at 50 0 C. The solid was recrystallized in isopropanol and then lyophilized from water to give 0.80 g of 7. Analysis requires: C, 64.93%; H, 7.68%; N, 6.89%; Cl, 8.71%. Found: C, 20 63.32%; H, 7.70%; N, 6.53%; Cl, 8.59%; H 2 0, 3.85%.

1 H-NMR (d 6 -DMSO): 6 10.35 (br, 1H), 7.93-7.91 (d, J=2 Hz, 1H), 7.47-7.42 J=8.2 Hz, 1H), 7.27-7.18 (m, 2H), 7.1-7.0 J=7.3 Hz, 1H), 4.9-4.7 (br, 1H), 4.27o" 4.2 J=16 Hz, 1H), 4.96-3.88 J=16 Hz, 1H), 4 25 3.7-3.3 4H), 3.3-3.1 (m and s at 3.19, 4H), 3.1-2.9 (m and s at 3.00, 4H), tI j c i i- I I i 'I r

I

r L? -29- EXAMPLE 11 (la, 2a 6B) -2-methoxy-6- (1-pyrrolidinyl) cyclohexanol or (la, 23, 3a) -3-methoxy72- (1-pyrrolidinyl) cyclohexanol O NH 2-propanol

A

OCH3 or v

HO

oaaB (I O O r) 0" O Ub 000

D

DB

IOID

(r The oxirane 2 (16.78 g, 0.131 mol) was dissolved in 178 mL 2-propanol, and pyrrolidine (11.94 g, 0.168 mol) was added. The solution was refluxed under

N

2 for 20 hours. The solvent was removed under vacuum.

Only one product was seen by GC. The yellow oil was kugelrohr distilled (80-1200C, 1.2 mm Hg) to. yield 8 (23.61 g, 0.118 mol, 1 H-NMR (CDC1 3 8 3.8-3.7 1H), 3.7 (br, 1H), 3.6-3.45 1H), 3.41 3H), 3.0-2.8 (td, J=3.5, 10 Hz, 1H), 2.7-2.5 4H), 2.0-1.85 1H), 1.85-1.1 8H). m/e 200 199 184 168 110 ri D ri

(ODO

c r pO

O

1 01B I L 1I11

/F

t S/v I i:V EXAMPLE 12 (la, 21, 3a) -N-[3-methoxy-2- (1-pyrrolidinyl) cyclohexyl] N-methylbenzenemethanamine 1) CH 3

SO

2 Cl Et 3

N

2) PhCH 2

NHCH

3

N,

OCH

3 4 44 *4 *444 o 44 *4 44 4 0 44 4 The alcohol 8 (23.38 g, 0.120 mol) was dissolved in CH 2 Cl 2 and triethylamine (20 mL) was added. The solution was cooled to -5°C under N 2 and methanesulfonyl chloride was added dropwise, keeping the temperature between 0°C and 5 0 C. The reaction was allowed to warm to room temperature overnight. The reaction mixture was then poured into 700 mL CH 2 Cl 2 and washed with 350 mL H 2 0, and then 700 mL H 2 0. The organic layer was dried over MgS0 4 filtered, and the solvent removed under vacuum. N-benzylmethylamine mL) was added, and the mixture was heated to (under N 2 for 20 hours. The reaction mixture was poured into 300 mL 10% K 2

CO

3 The product was extracted 25 into CH 2 C1 2 dried over MgS0 4 filtered, and the solvent removed under vacuum. The ye-llow oil was kugelrohr distilled, collecting the fraction boiling from 110-160°C (1.0 mm Hg). The diamine 9 (25.80 g, 0.0853 mol, 71% yield) was obtained as a viscous yellow oil. 1 H-NMR (CDC1 3 5 7.5-7.1 5H), 3.73 2H), 3.36 3H), 3.3-3.1 1H), 3.0-2.7 4H), 2.6-2.5 1H), 2.22 3H), 2.2-2.0 1H), 1.9-1.0 (m, 9H).

I

-31- EXAMPLE 13 (la,28,3a)-N--[3-methoxy-2-(pyrrolidinyl)cyclohexyl]- N-methylbenzenemethanamine monohydrochloride O0CH3 O, 0 CH3 N~ HC1

H

3 C H3C N *HC1 Ph Ph 0 00 o e 15 The crystalline diamine 9 (3.75 g, 12.4 mmol) was dissolved in 75 mL of methanol with 0.5 g 20% Pd/C, and 0 reduced with 50 psi of H 2 for 18 minutes at ambient temperature. The crude product showed a single peak by GC. The catalyst was filtered off and the solvent S 20 removed under vacuum to give 11 (2.62 g, 12.3 mmol, 99% yield). H-NMR (CDC3) 3.45-3.35 1H), 3.31 (s, 3H), 3.0-2.8 2H), 2.8-2.6 2H), 2.6-2.4 2H), 2.38 3H), 2.3-1.9 3H), 1.9-1.6 5H), 1.3-0.9 3H). FTIR (neat): cm 1 3304, 2935, 1440, 1105 25 850. m/e 123 110 108 84 71 70 55 42 The structure of 11 was verified by decoupling, COSY, and NOESY experiments.

Alternatively the monohydrochloride salt 10 (19.73 g, 0.0586 mol), was dissolved in 500 mL methanol, with g 20% Pd/C, and reduced at 50 psi H 2 for 19 hours at ambient temperature. The reaction mixture was filtered, and the solvent removed under vacuum.

Aqueous base (250 mL 15% NaOH) was added to the i L i -32resulting solid, and the mixture was extracted twice with 150 mL CH 2 C1l and once with 200 mL ether. The combined organic layers were dried over MgSO 4 filtered, and the solvent was removed under vacuum.

The product was kugelrohr distilled collecting the fraction 80 0 -120°C (0.1 mm Hg) to give 11 (8.38 g, 0.0395 mol, 67% yield) spectrally identical to material resulting from debenzylation of the free base.

EXAMPLE 14 (la, 2,3a)-3-methoxy-M-methyl-2- (l-pyrrolidinyl) cyclohexanamine o250 mL of anhdous ether, was treated with 11.2 mL of

S

00 0 o Pd/C H H N-C MeOH H3C" N washed with 15% NaoH, dried, and evaporated as before, to give a yellow oil. On standing for three days, the S 20 ph o0 The diamine free base 9 (25.11 g, 0.0830 mol) in ^°"250 mL of anhydrous ether, was treated with 11.2 mL of 25 HC1 in isopropanol (0.267 g HCl/mL). The resulting monohydrochloride salt, 10, a hygroscopic white powder, was collected by filtration. A second crop of 10 was obtained by washing the mother liquor with 15% NaOH, drying over MgSO 4 evaporating to an oil, and similar treatment with HC1. The combined yield of 10 was 19.78 g. Compound 10 was hygroscopic.

The mother liquor from the second crop of 10 was washed with 15% NaOH, dried, and evaporated as before, to give a yellow oil. On standing for three days, the L 1 I -33free base, (3.81 crystallized from this oil, mp 59*-60*C. 1 H-NMR. (CDC1 3 8 7.4-7.1 3.72 2H), 3.35 3H), 3.3-3.0 1H), 3.0-2.7 5H), 2.6-2.5 (td, J=3.6, 11.5 Hz, 1H), 2.22 (s, 3H), 2.2-2.0 1H), 1.9-1.7 (mn, 6H), 1.5-1.0 3H).

13C-NMR (ppm) 141.2, 128.5, 128.0, 126.4, 81,3, 63.8, 62.8, 59.4, 56.2, 47.9, 36.7, 30.6, 27.8, 24.1, 21.7.

FTIR (KBr): cm 1603, 1496, 1042, 956, 903, 833, 747.

m/I 303 302 287 160 123 91 84 Both the free base 9 and the monohydrochloride 10 were successfully used in the next step.

EXAMPLE (la,21,3a)-N-[3-methoxy-2-(1-pyrrolidinyl)-cyclohexyl]- N-methyl-4-benzofuranacetamide monohydrochloride C02H R3 N carbonyl diimidazole H3C.

H HC1 2 ~1 HC10

*HC

0 So NL0 Benzofuranacetic acid (1.51 g, 8.57 mmol) was dissolved in 20 mL anhydrous THF (under N2), and H30 carbonyldiimidazole (1.39 g 8.57 mmol) was added in one portion. Gas evolution was observed. The reaction was stirred overnight at ambient temperature. The amine 11 (1.40 g, 6.59 mmol) in 10 mL THF was then added, and the reaction was stirred for 6 hours. The -34reaction mixture was poured into CH 2 C12, and washed once with water, twice with 15% NaOH, and a final time with water. The combined aqueous layers were extracted twice with ether. All organic layers were combined and dried over MgSO 4 filtered, and the solvents removed under vacuum. A white solid (2.22 g, 6.0 mmol, yield) mp 97-101 0 C was obtained. 1 H-NMR (CDCl 3 6 7.63 1H), 7.4 J=8 Hz, 1H), 7.35-7.0 2H), 6.9-6.8 IH), 4.7-4.5 (br m, 1H), 4.1-3.8 2H), 3.6-3.1 4H; includes s at 8 2.4-2.2 1H), 1.8-0.8 9H) FTIR (KBr): cm 1 3500 2854, 1636, 1533 1431, 1250, 1086, 765 (water was evident in the IR). m/e 371 355 338 0° 181 149 131 110 84 70 Analysis requires: C, 71.32%; H, 8.16%; N, 7,56%. Found: C, 70.58%; H, 8.18%; N, 7.83%. HPLC, (210 nm) showed that the compound was 99.3% pure. This material (2.13 g, 5.7 mmol) was dissolved in 50 mL ether and 10 mL acetonitrile. Then 2.43 g of 16% HCl/ether solution was added dropwise. A precipitate gradually formed. The solution was cooled on ice and filtered. The solid was recrystallized in isopropanol/ether, and lyophilized in water to give the hydrochloride salt as a glassy solid (1.4 g, mp.

600-70°C, 97.3% pure by GC). 1 H-NMR (d 6 -DMSO) 9.4 (br, 1H), 7.95-7.9 J=2.2 7.5-7.4 (d, J=8 Hz, 1H), 7.3-7.1 2H), 7.1-7.0 J=7.3 Hz, 1H), 4.6 (br, 1H), 4.3-4.1 J=16 Hz, 1H), 4.0-3.9 J=16 Hz, 1H), 3.9-3.6 4H), 3.5-3.1 includes s at 3.40 (water), and s at 3.31), 3.0 3H), 2.3-2.1 1H), 2.05-1.1 9H). Analysis requires: (corrected for 5.5% water) C, 61.35%; H, 7.87%; N, 6.50%; Cl, 8.23%. Found: C, 61.2%; H, 8.10%; N, 6.47%; Cl, 8.43%; H 2 0, 5.46%.

Example 16 (la ,20,60)-2-methoxy-6-[methyl(phenylmethyl)amino]cyclohexano (13) or (lac,2,30)-3-methoxy-2-[methyl(phenylmethyl)amino]cyclohexanol (13a)

OCH

3

OCH

3

CH

3

OCH

3

N

CH

3 Ph H NHO 1 2-propanol 13 13a Ph Oxirane 1 (20.08 g, 0.157 mol) and Nmethylbenzylamine (30.24 g, 0.25 mol) were dissolved in 110 mL of 2-propanol and heated to reflux, under N 2 for 18 hours. The solvent was removed under vacuum, and the product was Kugelrohr distilled, removing the material that distilled below 1000C at 1.0 mm Hg, and collecting the fraction boiling between 100 0 C-140 0 C at 1.0 mm Hg. A colorless oil (35.42 g, 90%) was obtained. The product showed a single peak by GC.

H-NMR (d 6 -DMSO): 7.4-7.1 5H), 4.17 18), a 3.74-3.68 J=13.4 Hz, 1H), 3.55-3.45 J=13.4 Hz, 1H), 3.33 3H), 3.3-3.2 1H), 3.0-2.85 1H), 2.4-2.3 1H), 2.13 3H), 2.0-1.8 1H), 2.8-2.6 2H) 1.4-0.9 3H) 13C-NMR (d 6 -DMSO): 6 140.1, 128.7, 128.4, 126.9, 83.7, 73.9, 65.9, 58.1, 57.1, 36.6, 29.4, 22.9, 21.4. FTIR (neat): cm 1 3400 (br), 2938, 2864, 1496, 1454, 1121, 1096, 881, 743, 701. m/e 249 234 218 160 120 91 65 42 Analysis requires: C, 72.25%; H, 9.30%; N, 5.62%. Found: C, c

PT

-36- 72.231s, H, 9.22%; N, 5.127%. Structure was ve= 4ed 'by COSY, :ETCOR, L-F-ETCOR, and D ET N1x-R t es Example 17 (1 a,2a,63)-N-[2-methoxy-6-( 1-pyrrolidinyl)cyclohexyl]-N-methylbenizenemethanamine

CH

3

OCH

3 aMsC 3

NCH

3 OCH3 b) pyrmhldine[ Ph 3 isomers HO c) HCIN 0 13a Ki~i) 14 Amino alcohol 13a (35.08g, 0.141 mol) was added to 460 mL CE4 2 Cl 2 and 32 mL triethylamine, under N 2 Th e resulting solution was cooled to -101C. M et ha ne sulf'onylchloride (13 rn'i) was added dropwise, mainzanannga temperature below Aft-er= the= 00addition wscomplete, the cold bath was remnoved, and the reaction stirred for 5 hours, at which ti.me all the starting material was consumed, as show.n by GC. Th e :00.:reaction mixture was Poured Into a sepoaratory fu~nnel wit 5 00 mLT 2 C1 2 The organic layer was washaed thnree timfes With 250 mL H 2 0, dried over MogSO 4 filtered, and the total -volume of the solution'reduced to approximately 250 mL under -vacuum. To this solution, 97 mL of pyrrolidine was added, and allowed to stand at room tezroerature for 16 hours, then heated to reflu.x for 1.5 hours. The react -on mixture was poured into 800 mL of 10% Na 2

CO

3 and extracted with 500 mL CH 2 Cl 2 -37then 400 mL CH 2 C1 2 then 500 mL CH 2 C1 2 The combined organic layers were dried over MgSO 4 filtered, and the solvent removed under vacuum. The crude oil was Kugelrohr distilled to remove colored irmurities to give 18.21 g of a pale yellow oil. A GC on the distillate showed a mixture of four products in a ratio of 1:4:7:4 in order of increasing retention time.

This crude oil was dissolved in 95 mL ether and treated with 3 mL of 2.6 N HC1 in isopropanol. The solution was decanted away from the brown solids that formed and additional 50 mL of ether was added to the o 'o solution and 6 mL more of the HCl/isopropanol solution oo, was added dropwise, and the resulting solution placed oo. in a freezer for 3 weeks. The crystals that formed were filtered, and several crystal forms were observed.

The largest brown color crystals were mechanically separated. These were treated with dilute NaOH and extracted with ether. The organic layer was dried over Na 2

SO

4 filtered, and the solvent removed under vacuum.

The oil obtained was purified by flash chromatography (SiO 2 using 1.5% MeOH/CHC13 and saturated with NH 4 0H) 'to yield 14 (0.45 g, 0.0015 mol). 1 H-NMR (CDC1 3 7.5-7.1 5H); 4.0-3.8 J=13.5 Hz, 1H); 3.86-3.80 1H); 3.77-3.72 J=13.5 Hz, 1H); 3.3 25 3H); 3.3-3.2 (td, J 11.3 Hz, 1H); 2.8-2.6 (m, 4H); 2.6-2.5 (dd, J=2.3, 10.8RHz); 2.37 3H); 2.0-1.8 2H); 1.8-1.6 4H); 1.6-1.4 2H); 1.4-1.0 2H). 1C-NMR '(d-DMSO) 141.9, 128.2, 127.8, 126.2, 79.0, 66.2, 58.0, 54.2, 46.2, 27.4, 23.4, 22.9, 19.0. m/e 302 287 211 173 160 150 134 110 91 84 44 Analysis requires: C, 75,45%; H, 10.00%; N, 9.26%. Found: C, 75.40%; H, 9.97%; N, _e i -38- 9.17%. Stereochemica1 and regiochemical assignments were detsiu.ned by COSY, NOESY, and HETCOR NMR experimnelts.

EXAMPLE 18 (1lx, 2ax, 6.B) -2-methoxy-N-methyl-6- (1-pyrrolidinyl) cyclohexanamine Pd/C

H

2

N

H

3 C H n

I

L

2

ESSQ

30 The N-benzyldiamine, 14 (0.45 g, 1.49 mmol) was treated with 0.05 g 20% Pd/C in 75 mIL methanol and 50 psi hydrogen at room temaperature. The product was filtered and the solvent removed under vacuum. The crude oil was chromatographed MeOH/2% conc.

NH

4 OH/96% CHCl 3 to yield 15 (0.23 g, 73% yield).

1 H-NMR (CDCl 3 3.7-3.6 (mi iH), 3.35 3H), 2.76-2.6 (in, 1H), 2.6-2.5 (mn, 5H), 2.42 3H), 2.4-2.2 (br, 1H), 1.9-1.3 (mn, 10H). m/ef 212 181 150 112 111 110 97 96 84 70 44 42 i )rA

B

-39- EXAMPLE 19 (la,2a, 68) -N-[2-methoxy-6-(1-pyrrolidinyl)cyclohexyl]- N-methyl-4-benzofuranacetamide monohydrochloride

CO

2

H

C

2 0 2 C1 2 S DMF (cat.)

CH

2 C1 2

OCH

3 1) Et 3

N

THF

*HC1 2) HC1 r i 1 20 o o t I o ft o o Soa o 6 m 0 01 6 1 30 1 4-Benzofuranacetic acid (1.01 g, 5.73 mmol) was placed in a 100 mL boiling flask, and dissolved in 50 mL CH 2 Cl 2 under N 2 Oxalyl chloride (1.6 mL) and dimethyl formamide (0.04 g) were added, and gas evolution was observed. The reaction was stirred at 25°C for 18 hours, and the solvent removed under vacuum. The resulting oil was Kugelrohr distilled (0.07 mm Hg, 90 0 C-100 0 C) to yield 1.04 g of a yellow oil. This oil was shown by 1 H-NMR to be a 1:1 mixture of the acid and the acid chloride. This mixture (0.20 g) was dissolved in 10 mL anhydrous THF, and cooled to 0°C under N 2 Then the diamine 15 (0.11 g, 0.52 mmol, dissolved in 2.5 mL THF) and triethylamine mL) were added to the acid chloride solution.

Then 4 -(dimethylamino)pyridine (0.01 g) was added, and the solution stirred at room temperature for 24 hours.

I.

c The solvent was removed under vacuum, and the crude oil was chromatographed MeOH/1% conc. NH 4 OH/CHCl 3 twice to yield 1 (0.11 g, 0.30 rnmol), as the free base.

1 H-NMR (CDCl 3 5 7.6 J=4.9 Hz, IH), 7.4-7.38 (d, J=7.9 Hz, 1H), 7.25-7.20 J=8 Hz, 1H), 7.11-7.08 (d, J=7.3 Hz, 1H), 6.95 (br s, 1H), 4.6-4.5 (br, 1H), 4.1-3.9 (in, 2H), 3.6 (br s, 1H), 3.3-3.2 (br, 1H), 3.19 3H), 3.07 (br s, 3H), 2.7-2.5 (br, 2H), 2.1-1.1 (mn, 12H). in/ef 372 371 100%), 369 300 181 150 110 This product was dissolved in anhydrous diethyl ether, and treated with 20% HCl/MeOH to form the ionohydrochloride salt. This was filtered, and lyophilized to give 16 03 g, 0. 08 mmol). 1 H-NxR (d 6 -DMSO): 9.6 (br, 7.94-7.92 J=2.4 Hz, IIH), 7. 5-7. 4 J=8. 6 Hz, lH) 7. 3-7. 2 J=8 Hz, 1H), 7.18-7.15 L72.4 Hz, 1H), 7.1-7.0 J=7.3 Hz, 1H), 4.8-4.6 (dd, J=2.4, 12 Hz, 1H), 4.25-4.1 (d, J=16.5 Hz, 1H), 4.05-3.8 (in, 2H), 3.6-2.8 (mn, includes

H

2 0 peak), 2.2-1.2 (in, 10H) rn/if 1% NH 3 in OH 4 372 23%) 371 100%), 300 182 181 150 131 110 FTIR (KBr): cm 1 l, 3432 (br) 2945, 1734, 1647 1457, 1432, 1246, 1124, 1102, 1045, 1009, 765 HRMS

C

2 2

H

3 0

N

2 0 3 Requires: 370.2256. Found: 004411370.2246.

Claims (4)

1. A compound named (la,2a,6)-N-[2-methoxy-6- (1-pyrrolidinyl)cyclohexyl]-N-methyl-4-benzofuran- acetamide monohydrochloride.

2. A method of treating pain in a mammal which comprises administering to said mammal a pharmaceutical composition comprising an effective amount of a compound as claimed in claim 1.

3. A method of treating stroke in mammal which comprises administering to said mammal a pharmaceutical composition comprising an effective amount of a compound as claimed in claim 1. DATED this 8th day of March, 1994 WARNER-LAMBERT COMPANY Attorney: IAN T. ERNST S° Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS ao ooo o o o i r; i -I i i -42- ABSTRACT The invention concerns novel 2-amino-3- or

6-methoxycyclohexyl amides having analgesic and neuroprotective activity. The compounds bind selectively to the kappa opioid receptor. Pharmaceutical compositions containing the compounds, methods of using them, and processes for preparing them are also disclosed. aa L 0 0 0 s> B o 0 4 a a 0 CC ua 04 a cC 4 .1 f