JPH05194465A - 2-aminomonomethoxycyclohexylamide useful as analgesic - Google Patents

Abstract

PURPOSE: To provide the novel subject compd. which exhibits high selectivity to a κ-μ opioid receptor and is useful for pain treatment and fit treatment.

CONSTITUTION: The (1α, 2α, 6β)-N-[2-methoxy-6-(1-pyrolidinyl)cyclohexyl]-N- methyl-4-benzofuran acetoamido monohydrochloride of formula I is obtd. by reacting the transepoxide of formula II with N-benzylmethylamine to obtain an aminoalcohol of formula III. This compd. is treated with a methanesulfonylchloride, then a pyrroidine to obtain a 4-component mixture, which is converted into hydrochloride. This hydrochloride is mechanically separated to obtain a compd. of formula IV. The compd. is then subjected to catalytic debenzylation by using hydrogen and the production is brought into reaction with 4-benzofuranacetyl chloride, by which the compd. described above is obtd.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[Cross-reference] The present invention, November 9, 1990
It relates to date-filed U.S. Patent Application No. 612,636.
The application is a divisional application of application No. 503,067, dated March 29, 1990, which is now US Pat. No. 5,051,428, which is now withdrawn 1.
It is a continuation application of application No. 280,759 dated December 6, 988.

The present invention includes two compounds not specifically exemplified in the relevant case. The present invention is a compound in which the 3- or 6-position in the cyclohexyl moiety is substituted with a methoxy group. Compounds having 3- or 6-methoxy substituents were tested in an in vitro receptor binding assay,
It shows a particularly high selectivity for the kappa vs. mu opioid receptors.

[0003]

BACKGROUND OF THE INVENTION The search for potent analgesics with minimal reliance has been the focus of highest priority in pharmaceutical research. Most of these research efforts have involved the chemical modification of opiate structure as well as the discovery of new compounds with morphine-like activity.

The concept of many opioid receptors has been confirmed by studies on nalorphine and a series of benzomorphans that differ from morphine and exhibit unusual pharmacological properties that are blocked by selective opioid antagonists. For example WR Martin, et
al, J. Pharmacol. Exp. Ther., 197: 517-532 (1976)].

It is important that there are multiple types of opioid receptors. It is because its presence suggests that it may be able to separate the desired analgesic and psychotherapeutic effects of the drug compound from the abusable or undesired effects of habit.

[0006]

U.S. Pat. No. 4,098,904 discloses certain cis- and trans - N- (2 having analgesic activity.
-Aminoalicyclic) benzamide compounds are disclosed.

US Pat. No. 4,145,435 describes certain 2-aminoalicyclic amide compounds as analgesics. In particular, trans -3,4-dichloro- N-
[2- (1-pyrrolidinyl) cyclohexyl] benzacetamide has been reported to have selective kappa agonist activity and therefore analgesic activity without concomitant addiction burden [PV Vonvoigtlander, et al, J. .
Pharmacol. Exp. Ther. , 244: 7-12 (1983)].

US Pat. No. 4,212,878 discloses certain N -[(4-mono- or di-oxygen group-substituted-1-aminocyclohex-1-yl) methyl) phenyls having analgesic properties. Acetamides, especially 2- (3.4-diglycone
Lorophenyl) -N -[[8- (1-pyrrolidinyl)-
1,4-Dioxaspiro [4,5] dec-8-yl] methyl] acetamide is disclosed.

US Pat. No. 4,359,476 and its continuation-in-part No. 4,460,600 disclose oxy on an alicyclic ring carbon adjacent to any of the nitrogen-bearing carbon atoms of the alicyclic ring. Certain N- , having substituents on the radicals or thio groups
[2-Amino (oxy or thio group) substituted alicyclic] benzeneacetamide and -benzamide compounds are disclosed. These compounds have analgesic activity, 4
It is represented by -bromo- N- [3-methoxy-2- (1-pyrrolidinylcyclohexyl] -N -methylbenzamide.

US Pat. No. 4,598,087 and its divisional application US Pat. No. 4,677,122 disclose certain oxy- or thios of trans -1,2-diaminocyclohexane having analgesic activity. Acetamides have been disclosed. These compounds are trans- 2- (2,
3-dichlorophenoxy) -N -methyl- N- [2-
It is represented by (1-pyrrolidinyl) cyclohexyl] acetamide.

US Pat. No. 4,656,182 describes certain trans - N -methyl- N- [2-
(1-Pyrrolidinyl) cyclohexyl] benzo [b] thiophenacetamides are disclosed.

US Pat. No. 4,663,343 discloses certain trans - N -methyl- N- [2-
(1-Pyrrolidinyl) cyclohexyl] naphthalenyloxy- and naphthalenylthioacetamides are disclosed.

US Pat. No. 4,737,493 discloses certain 7,8- (substituted diamino) -1's useful as analgesics.
-Substituted phenoxy of oxaspiro [4.5] decane-,
1- and 2-naphthalenyloxy, indenyl-, indolyl-, benzofuranyl-, and benzo [b] thiofuranylcarboxamides are disclosed.

US Pat. No. 4,463,013 discloses certain oxygen substituted amino-cyclohexyl-benzeneacetamides as diuretics.

US Pat. No. 4,438,130 discloses certain mono-oxa-, thiaspiro-cyclic-benzeneacetamide and benzamide compounds useful as analgesics.

US Pat. Nos. 4,906,655 and 5,019,588 disclose certain 1,2-cyclohexylaminoarylamides useful as analgesics.

SUMMARY OF THE INVENTION The present invention relates to a series of novel monomethoxycyclohexyl amides having selective kappa receptor analgesic activity. The compound is MB Tyer
s, Brit. J. Pharmacol., 69: 503-512 (1980), the nociceptive assay (nociceptive assa) of the rat paw pressure test.
In y) there is a surprising increase in activity when compared to compounds known in the art.

The present invention provides a novel amide (1α, 2α, 6β)
-N- [2-methoxy-6- (1-pyrrolidinyl) cyclohexyl] -N-methyl-4-benzofuranacetamide monohydrochloride and (1α, 2β, 3α) -N- [3-
Methoxy-2- (1-pyrrolidinyl) -cyclohexyl] -N-methyl-4-benzofuranacetamide monohydrochloride as well as pharmaceutically acceptable acid addition salts thereof.

The present invention also provides a pharmaceutical composition containing an analgesic effective amount of the compound together with a pharmaceutically acceptable carrier or excipient, as well as administering the pharmaceutical composition to a patient with pain in a unit dosage form. A method of treating pain in a patient, comprising:

The present invention further provides a pharmaceutical composition containing a neuroprotective amount of the compound together with a pharmaceutically acceptable carrier or excipient, and a method of treating stroke and / or cerebral ischemia in a patient suffering from a nerve. Include.

The present invention further includes methods of making the above compounds. Replacement

[Chemical 1] And a methoxy moiety is attached to the 3- or 6-position by epoxidizing 3-methoxycyclohexene to give a 2: 1 ratio of trans.
To produce a mixture of the scan and cis epoxides then consists of fractional distillation them.

Reaction of the trans epoxide with pyrrolidine produces a mixture of the two isomeric amino alcohols. The mixture was treated with methanesulfonyl chloride then N-
Treatment with methylbenzylamine gives N-benzyldiamine, which is converted into a salt and catalytically hydrogenated. The diamine is then reacted with benzofuran or benzothiophene acetic acid to produce the compounds of this invention. The cis epoxide goes through the same reaction steps.

Alternatively, the trans epoxide is first reacted with N-benzylmethylamine to give the amino alcohol, which is converted to the salt. The crystals of the resulting mixture are mechanically separated and the largest crystals are catalytically debenzylated and the product is reacted with 4-benzofuran acetyl chloride to produce the compounds of the present invention.

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

Due to the basic nitrogen present in the cyclohexane moiety, pharmaceutically acceptable salts of the compounds of this invention can be prepared by reaction with the appropriate acid. Suitable acids to form pharmaceutically acceptable salts of compounds of the present invention are of the type well known to those skilled in the pharmaceutical formulation arts (SM B
erge, et al, “Pharmaceutical Salts” in J. Pharm.
Sci., 66: 1-19 (1977)), examples of which include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid,
Benzoic acid, citric acid, maleic acid, tartaric acid, succinic acid,
There are gluconic acid, ascorbic acid, sulfamic acid, oxalic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid and related acids and mixtures thereof.

Salts are generally prepared by reacting the free base with 1 equivalent of the desired acid in a suitable non-reactive solvent, then collecting the salt by filtration or by recovery after removal of the solvent. If desired, the free base can be regenerated by reacting the salt with 1 equivalent of a base such as sodium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like. These salts differ from the free base of the compounds of the invention in properties such as melting point and solubility in polar solvents,
However, it is otherwise considered equivalent for the purposes of the present invention.

The compounds of the present invention contain 3 or more asymmetric carbon atoms. The compound has various stereo- and position (regi
o) -exists in the form of isomers as well as mixtures thereof.
The present invention contemplates all stereoisomeric and regioisomeric forms of the compounds of formula I above. In the present invention, both (+) to (-) and (±) are considered.

If desired, the individual stereocompounds may be obtained from the mixture of different forms by known resolution techniques such as formation of diastereomers and subsequent recrystallization.

Pharmacological Properties Due to their selective kappa opioid receptor binding properties, the compounds of the present invention have significant analgesic activity that can minimize addiction burden. In addition to producing analgesia, compounds that are selective kappa antagonists, such as compounds of the invention, also include
It causes opioid receptor-mediated sedation, diuresis, and elevated corticosteroids. Therefore, the compounds of the present invention can also be useful as diuretics and psychotherapeutic agents as well as analgesics.

The compounds of the invention are also syndromes of congestive heart attack, acquired liver cirrhosis, nephrotic syndrome, chronic renal failure, surgery-related trauma, emotional and psychological stress, endocrine disorders, and inappropriate antidiuretic hormone secretion. And certain pharmacological agents such as certain sulfonylureas, certain biguanides such as phenformin and metformin, clofibrate, certain tricyclic compounds such as carbamazepine, amitriptyline, thiothixene,
It is also indicated for treatment with fluphenazine and thioridazine, certain antitumor agents, certain analgesics and certain natriuretic diuretics.

The compounds according to the invention are also indicated for neuroprotection. They are useful in seizures and cerebral ischemia by themselves (PF Von Voightlander in Brain Researc
h 435: 174-180 (1987) and AH Tang, et al., in Br .
ain Research 403: 52-57 (1987)).

Representative compounds of the present invention show positive activity in standard laboratory analgesic tests in animals such as mice. MB Tyers, Brit. J. Pharmacol. , (1980), 69: 5.
MPE ₅₀ for some representative compounds of the invention in the standard rat paw pressure analgesia test described in 03-512.
The dose is as shown in Table I below.

Compound 17 in tablets shows a particularly high selectivity for the kappa to mu opioid receptor in the in vitro binding assay.

[0034]

[Table 1] K ₁ values represent the mean ± (standard error of the mean) from the concentration-response curves obtained from 3 replicates of each of at least 2 separate experiments. The MPE ₅₀ value indicates the dose required to obtain 50% of the maximum possible analgesic effect. They are derived from a single experiment performed with 6 animals per dose level.

Representative compounds of the invention were also tested in vitro to determine the extent of opioid receptor binding, and apparently no or little binding to mu or delta opioid receptors. It was found to bind selectively to the kappa opioid receptor site.

The kappa opioid receptor binding activity of the compound of the present invention was measured by the following method. Guinea pig brain homogenates were prepared using Gillan et al, Br. J. Pharmacol. (1
980) 70: 481-490, freshly prepared daily.

Binding of tritium-labeled etorphine to brain homogenates resulted in 200 nanomolar D to saturate the delta and mu opioid receptors, respectively.
-Alanine-D-leucine-enkephalin (acronym
DADLE) and 200 nmol of D-ara-MePhe
Gly-all-enkephalin (acronym DAGO) was added and measured in the presence of the unlabeled competitor of the compound of the invention. The reaction was terminated by rapid filtration and the radioactivity bound to the filter was counted by liquid scintillation spectrophotometry.

The mu and delta opioid receptor binding activity of the compound of the present invention was measured by the following method. Guinea pig brain homogenate was prepared as described in Gillan, et al,
It was freshly prepared every day by the method of.

The homogenate was incubated at 0 ° C. with tritium labeled DAG0 for measuring mu receptor binding activity, or with tritium labeled DADLE in the presence of a 10-fold excess of unlabeled DAGO for measuring delta opioid receptor binding. And incubated for 150 minutes. Non-specific binding was determined in the presence of 10 ⁻⁶ mol DAGO and 10 ⁻⁶ mol DADLE.

The reaction was terminated by rapid filtration and the radioactivity bound to the filter was counted by liquid scintillation spectrophotometry.

Data are Scatchard, Ann. NY Acad. Sc
i. , 51: 660-672 (1949) and Hill, J. Physiol. , 40:
It was analyzed by each method described in IV-VIII (1910). Binding inhibition of tritium-labeled etorphin, DAGO and DADLE by cold ligand was determined by regression of log inhibition% of specific binding or log concentration of cold ligand. The inhibition constant, K _i, was calculated from the following formula.

[0042]

[Equation 1] [Where [L] is the concentration of labeled ligand and K _D is the equilibrium dissociation constant].

[Synthesis of Compound of the Present Invention] Scheme 2 below
~ 4 describe the chemical synthesis of some compounds of the invention. All compounds are racemic mixtures. They are commercially available 3-methoxycyclohexene (2-
Cyclohexen-1-ol, also referred to as methyl ether) is epoxidized by the action of m-chloroperbenzoic acid in dichloromethane to give a 2: 1 ratio of trans and cis 3-methoxycyclohexane epoxide 1. Manufactured by obtaining a mixture of 1 and 2 . The tran
Careful separation of the s- and cis- epoxides by fractional distillation yields isomer purity greater than 95%. In the synthetic scheme 2, reacting the trans epoxide 1 with pyrrolidine 2 isomers amino alcohol 3 and 3a
A mixture of Treatment of this mixture of amino alcohols with methanesulfonyl chloride followed by N-methylbenzylamine provides N-benzyldiamine 4 . The compound 4 is converted to the hydrochloride 5 and then catalytically hydrogenated to give 97% of pure 6 . Reaction of the diamine 6 with benzofuran acetic acid in the presence of carbonyldiimidazole gives compound 7 of the invention.

Reaction of cis epoxide 2 in Scheme 3 in the same steps as above gives compound 12 having the stereochemistry shown.

The trans-epoxide 1 in Scheme 4
Is first reacted with N-benzylmethylamine to give amino alcohol 13 . Treatment of this amino alcohol with methanesulfonyl chloride followed by pyrrolidine in a ratio of 1: 4: 7: 4 as determined by GC,
14 is obtained as a four-component mixture. A mixture of crystals is obtained when 13 is converted to the hydrochloride salt. The largest brown crystals from this are mechanically separated and are found to be the single isomer 15 based on spectroscopic evidence. Catalytic debenzylation with hydrogen gives 16 . Reaction of this with 4-benzofuran acetyl chloride gives 17 .

[0046]

[Chemical 2]

[0047]

[Chemical 3]

[0048]

[Chemical 4]

Pharmaceutical Compositions The compounds of the present invention and / or their non-toxic pharmaceutically acceptable salts may be orally administered to mammals in combination with conventional compatible carriers in solid or liquid form. These oral pharmaceutical compositions may contain a binder selected from conventional ingredients such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone and mixtures thereof. The composition may further contain fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methylcellulose and mixtures thereof.

These oral compositions also contain lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, or solid formulation disintegration promoters such as starch, and lubricants such as sodium lauryl sulphate. Can be included.

Oral solid compositions can be in any convenient form, such as tablets, troches, capsules or dry powders, which can be reconstituted with water or other suitable liquid prior to administration.

The liquid form of the pharmaceutical composition may take the form of a solution, suspension or emulsion. The liquid form may contain flavoring agents, sweetening agents and / or preservatives such as alkyl p-hydroxybenzoates. They also include suspending agents such as sorbitol, glucose or other sugar syrups, methyl-, hydroxymethyl- or carboxymethylcellulose, and gelatin,
Emulsifying agents such as lecithin or sorbitol monooleate, as well as conventional thickening agents can be included.

The liquid composition can optionally be encapsulated in effective amounts, for example in gelatin capsules.

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

The pharmaceutical composition of the present invention is preferably in unit dosage form. In the dosage form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dose can be a packaged preparation, in the package containing discrete quantities of preparation. For example, the package may take the form of a drug packet, packaged preparation in vials or ampoules, capsules and powders. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active compound in a unit dose of preparation is about 0., depending on the individual application and the potency of the active ingredient.
It can be varied or adjusted from 5 mg to about 350 mg.

For systemic use as an analgesic in the formulation procedure of the present invention, the compound is administered at a dose of from about 0.05 mg to about 2.0 mg of active compound per kg body weight of the recipient.

The following examples are provided to enable one of ordinary skill in the art to practice the invention. These examples are in no way intended to limit the scope of the invention, but to illustrate the invention.

Example 1 4-Methoxycyclohexene epoxide (1) 1: 1 m in dichloromethane-carbon tetrachloride (70 ml)
-Chloroperoxybenzoic acid (3.5 g, 20 millimolar
For 25 minutes at -5 ° C carbon tetrachloride (10 m
4-methoxycyclohexene (2.0 g, 18
Limol) to the stirred solution. After 5 hours, allow the mixture to
Warm to warm and after 2 hours filter the slurry. Filter
The solution was added to 5% aqueous sodium acid sulfite (40 ml),
Rinse with saturated aqueous sodium carbonate (2 x 40 ml)
It The resulting solution is dried (K₂CO₃) And at atmospheric pressure
Distillation of two diastereomers using a Vigreaux column
Epoxide (1) as a mixture of isomers (1.0 g, 7.
8 mmol, 43%). Boiling point 175-176 ° C
(760 mmHg). I.R. (neat) 2938, 1104cm^-1Δ (CDC
l₃, 300MHz) 3.22 (1H, m), 3.24 (s) and 3.22 (s) [together
(3H)], 3.05 (2H, m), 2.3-1.2 (6H, m); m / e (E
I⁺) 129 (11%), 111 (35%), 97 (65%), 58 (100%). C₇H
₁₂O₂Analytical value for: Calculated: C 65.60, H 9.44. Actual measurement
Value: C 65.57, H 9.6%.

Example 2 Amino alcohol (2) The above epoxide (1) (2.0 g, 15.6 mmol) and N-benzylmethylamine (3.0 g, 25 mmol) were added to propan-2-ol (10 ml). And is heated under reflux for 20 hours. The resulting solution was distilled to give the amino alcohol (2) as a mixture of three isomers.
(3.2 g, 13 mmol, 83%) is obtained. Boiling point 13
3-134 ° C / 0.05 mbar. IR (neat) 3460,
2939, 2866cm ^-1 ; δ (CDCl ₃ , D ₂ O) 7.3 (5H, m), 4.0-2.7
(7H, m, 3.36,3.30, strong at 3.29), 2.4-1.2 (10H, m, 2.19,2.1
8 / 2.15); m / e (EI ⁺ ) 249 (10%), 218 (8%), 190 (100
%). Analytical value for C ₁₅ H ₂₃ NO ₂ : calculated value: C 72.25, H
9.30, N 5.62. Found: C 72.13, H 9.22, N 5.56%.
The individual isomers were obtained after separation by silica gel chromatography using 20: 1 dichloromethane-methanol. ¹ H NMR of these isomers is as follows.
δ (CDCl ₃ , D ₂ O) isomer A: 7.24 (5H, m), 3.61 (1H, d, J = 1
4), 3.45 (1H, J = 14), 3.43 (1H, m), 3.36 (3H, s), 3.18 (1
H, m), 2.36 (1H, m), 2.19 (3H, s), 2.27-1.99 (3H, m), 1.2
2 (3H, m). Isomer B: 7.28 (5H, m), 3.70 (1H, d, J = 15Hz),
3.65 (1H, m), 3.45 (1H, m), 3.44 (1H, d, J = 15Hz), 3.30 (3
H, s), 2.83 (1H, m), 2.15 (3H, s), 2.20-1.85 (3H, m), 1.6
0 (1H, m), 1.30 (2H, m). Isomer C: 7.28 (5H, m), 3.79 (1
H, m), 3.74 (1H, d, J = 15Hz), 3.55 (1H, m), 3.45 (1H, d, J = 1
5Hz), 3.29 (3H, s), 2.42 (2H, m), 2.18 (3H, s), 2.05 (1H,
m), 1.55 (2H, m), 1.30 (2H, m).

Example 3 N-Benzyldiamine (3) The above diastereoisomeric mixture of amino alcohols (2) (8.0 g, 32 mmol) was dissolved in dichloromethane (105 ml) and triethylamine (7.1 ml). , -10 ° C and then keeping the temperature below -5 ° C, methanesulfonyl chloride (2.7ml,
(35 mmol). After 1.5 hours, the mixture was concentrated in vacuo to a volume of 20 ml and treated under reflux with pyrrolidine (22 ml, 260 mmol) for 1.5 hours. The resulting mixture was treated with aqueous sodium carbonate (700 m
l) and extracted with dichloromethane (3 x 100 ml) to give an orange oil (15 g) after concentration.
This oil was distilled to give N-benzyldiamine (3) (9.3 g, 31 mmol, 97%) as a mixture of three (racemic) isomers. Boiling point 122-155 ° C / 0.2
Millibar. IR (neat) 2936, 2791 cm ^-1 . m / e (EI ⁺ ) 30
3 (5%), 287 (10%), 270 (10%), 84 (100%); δ (CDCl ₃ ,
_{D 2 O, 300MHz) 7.30 (} 5H, m), 3.65 (2H, s), 3.75-3.50 (1H,
m), 3.36 (s) and 3.32 (s) and 3.29 (s) (together (3H)), 2.19 (s) and 2.17 (s) and 2.15 (s) (together (3H)) , 3.10-1.00 (16H, m). C ₁₉ H ₃₀ N ₂ O ・ 0.33H ₂
Analytical value for O: Calculated value: C 74.00, H 10.02, N 9.0
8. Found: C 73.97, H 9.78, N 8.82%.

Example 4 Diamine (4) N-benzyldiamine (3) above (3.5 g, 12 mi).
Limol) is dissolved in ethanol (50 ml) and 50
20% palladium on carbon (0.94 at 60 psi, 60 ° C)
g) and hydrogen for 2 hours. Porous diatom with a mixture
Filter through soil and then distill to give 3 (racemic) isomers
Diamine (4) as a body mixture (1.4 g, 6.6 mm
Mol, 55%). Boiling point 84 ~ 85 ℃ / 0.3mm
bar. I.R. (neat) 3402, 2942cm^-1. m / e (EI⁺) 197 (5
%), 180 (10%), 84 (100%). (CDCl₃, D₂O, 300MHz) 3.36
(s) and 3.31 (s) and 3.28 (s) (in together (3H)
2.38 (s) and 2.37 (s) [together (3H)
], 3.7-3.2 (1H, m), 2.8-0.9 (17H, m). (4) (21
2 mg, 1.0 mmol) was added to propan-2-ol (1 m
l) p-toluenesulfonic acid (190 mg, 1.0 mm) in
Analytical by treatment with
Obtain a pure sample. This white solid was converted to propan-2-o.
Recrystallized from methanol / diethyl ether and mono-p-tolu
Ensulfonate salt (200 mg, 0.50 mmol, 5
0%). Melting point 120-136 [deg.] C. C ₁₂H_{twenty four}N₂O ・ C₇H₈
SO₃Analytical value for: Calculated value: C 59.35, H 8.39, N 7.2
9, S 8.34. Measured value: C 58.95, H 8.24, N 6.99, S 8.42
%.

Example 8 (1α, 2α, 3α) -2-Methoxy-7-oxobicyclo [4.1.0] heptane (1) and (1α, 2β, 6)
α) isomer (2)

[Chemical 5]

A solution of 3-methoxycyclohexene (258.11 g, 2.3 mol, Aldrich) in 9.4 liters of methylene chloride is cooled in an ice / acetone bath. Solid m-chloroperbenzoic acid (50%, 884.6 g, 2.56 mol) is added portionwise over 30 minutes while maintaining the temperature below 3 ° C. The reaction mixture is warmed to room temperature overnight. The reaction mixture is then cooled to 15 ° C. and 4 liters of 5% sodium acid sulfite are added slowly. After 15 minutes 205 g of NaOH in 2 l of water are added and the mixture is stirred for 20 minutes. The aqueous layer is removed and saturated Na
5 liters of HCO ₃ are added and the mixture is stirred for 20 minutes. The layers are separated and the organic layer is dried over K ₂ CO ₃ .
The solution is filtered and the solvent removed in vacuo. The residual oil is distilled (80-90 ° C, 25 mmHg) to give 242.8 g (82%) of a 2: 1 mixture of (1) and (2). Isomers were separated by vacuum distillation through a 4ft fractionation column to yield 76% of material with> 95% isomer purity.
A total yield of Anti - isomer (major ^{isomer) - 1 H-NMR (CDCl} 3): δ3.5-3.4 (m, 1H), 3.45 (s, 3H),
3.2 (brs, 1H), 3.1 (d, J = 3.7Hz, 1H), 2.1-2.0 (m, 1H), 1.
9-1.7 (m, 2H), 1.5-1.3 (m, 1H), 1.4-1.1 (m, 2H). FTIR (neat): cm ^-1 , 2943, 1460, 1101, 933, 802. Syn-isomer- ¹ H-NMR (CDCl ₃ ): δ 3.7-3.6 (m, 1H), 3.46 (s, 3H),
3.4-3.2 (m, 2H), 1.9-1.8 (m, 2H), 1.7-1.1 (m, 4H). FTIR-
1459, 1113, 931, 684 cm ^-1 . _{m / e (CI + CH 4} ) 129 (23%), 1
11 (99%), 97 (100%), 85 (25%). The structure of the anti-isomer was confirmed by COSY and NOESY experiments.

[Chemical 6]

Example 9 (1α, 2β, 6β) -2-Methoxy-6- (1-pyrrolidinyl) -cyclohexanol (3)

[Chemical 7] Oxirane (1) (20.0 g, 0.156 mol) and pyrrolidine (20.1 g, 0.283 mol) are refluxed in 100 ml 2-propanol for 6.5 hours. The solvent was removed in vacuo and the resulting oil was distilled (112-116 ° C,
(3) (28.85g, 1.1mmHg) as a yellow oil
0.145 mol, 93%). GC shows the isomers in a ratio of 95: 5. ¹ H-NMR (d ₆ -DMSO): δ4.15 (brs, 1H),
3.32 (s, 3H), 3.2-3.1 (m, 1H), 2.96-2.8 (m, 1H), 2.7-2.
65 (m, 4H), 2.5-2.3 (m, 1H), 2.0-1.8 (m, 1H), 1.7-1.5 (m,
5H), 1.3-0.9 (m, 3H). FTIR (neat): cm ^-1 , ~ 3300 (b
r), 1462, 1353, 1298, 1101, 1071, 883. m / e (EI ⁺ ) 20
1 (41%), 199 (42%), 184 (61%), 168 (100%), 110 (99
%), 70 (62%). Analytical value: Calculated value: C 66.29%, H 10.62
%, N 7.03%. Found: C 65.96%, H 10.68%, N 6.85
%. The structure of (3) was verified by COSY and NOESY experiments.

[Chemical 8]

Example 10 (1α, 2β, 3β) -N- [3-methoxy-2- (1-
Pyrrolidinyl) -cyclohexyl] -N-methylbenzenemethanamine (4)

[Chemical 9] Amino alcohol (3) (27.47 g, 0.138 mol) is dissolved in 270 ml CH ₂ Cl ₂ and 23 ml triethylamine. The solution is cooled to 0 ° and 10 ml of methanesulfonyl chloride are added at once. The temperature is
It rapidly rises to 28 °. When the temperature has returned to 20 °, another 2.6 ml of methanesulfonyl chloride are added dropwise with cooling. A solid precipitate forms. CH ₂ C
Add 50 ml of l ₂ to facilitate stirring. After 4 hours, the reaction is shown to be complete by GC. The reaction mixture is
Pour into 450 ml of CH ₂ Cl ₂ and wash 3 times with 450 ml of water. The organic layer is dried over magnesium sulfate over night. The solution is filtered and the solvent removed in vacuo to give 28.68 g solid. This solid is dissolved in 64 ml of N-benzylmethylamine and heated to 93 ° C. for 4 hours.
The reaction mixture is poured onto 100 ml of 10% K ₂ CO ₃ and extracted 3 times with CH ₂ Cl ₂ . The organic layer is dried over K ₂ CO ₃ , filtered and the solvent is removed under vacuum. The product was vacuum distilled to give oil (4) (28.83 g, 0.095 mol, 69
%). Boiling point 140-160 ° / 2.8 mmHg. ¹ H-NM
R (CDCl ₃ ): δ7.5-7.1 (m, 5H), 4.0-3.8 (br m, 1H), 3.63
(s, 2H), 3.30 (s, 3H), 3.15 (td, J = 3.7,11Hz, 1H), 3.1-2.
7 (br m, 5H), 2.07 (s, 3H), 2.05-2.85 (m, 2H), 2.85-2.65
(br, 4H), 1.6-1.4 (m, 2H), 1.4-1.0 (m, 2H). Analytical values: Calculated values: C 75.45%, H 10.00%, N 9.26%. Found: C 7
5.30%, H 9.98%, N 8.99%.

Example 11 (1α, 2β, 3β) -N- [3-methoxy-2- (1-
Pyrrolidinyl) cyclohexyl] -N-methylbenzenemethanamine monohydrochloride

[Chemical 10]Diamine (4) (21.96 g, 0.0726 mol),
Dissolve in 210 ml of anhydrous ether and 2.6M HCl
28 ml (in 2-propanol) are added dropwise. Addition complete
Afterwards, the reaction mixture was stirred at room temperature for 10 minutes and was stirred (drier
Ice-acetone bath) cooled, filtered and filter cake
Is washed with cold anhydrous ether. White powder after drying
Monohydrochloride as powder (16.40 g, 0.0484 mol)
To get The mother liquor was washed with 15% NaOH and MgSO 4._Four
Dried over, filtered, and the solvent removed under vacuum.
(4) (6.71 g) is obtained. Yield of mono HCl salt (5)
The rate is 96% after recovery of (4). This crude salt is
It is used for the process of. ¹H-NMR (d₆-DMSO): δ10.0
(br, 1H), 7.4-7.2 (m, 5H), 4.14 (s, 1H), 3.8-3.5 (m, 3H),
 3.4-3.1 (m, 8H; s, 3H in 3.27 and b in 3.4
including r), 2.03 (s ＋ br, 4H), 1.9 (br, m, 4H), 1.6-
1.0 (m, 4H). FTIR (KBr): cm^-1， 3454，2938，2603，147
6, 1087, 1020, 752, 703. m / e (EI⁺) 303 (14%), 302 (23
%), 287 (42%), 160 (32%), 134 (33%), 123 (76%), 1
10 (35%), 91 (71%), 84 (100%). Analytical value: Calculated value: C 6
7.33%, H 9.22%, N 8.27%, Cl 10.46%. Measured value: C
66.90%, H9.18%, N 7.98%, Cl 10.65%, H₂O 0.17
%. GC shows this material to be 94% pure.

Example 12 (1α, 2β, 3β) -3-methoxy-N-methyl-2-
(1-pyrrolidinyl) -cyclohexanamine

[Chemical 11] The crude salt (5) (16.40 g, 0.0487 mol) was added to
Reduction with 1.5 g of 20% Pd / C in 500 ml of MeOH. The catalyst is filtered off and the solvent is removed under vacuum.
Dilute NaOH and ether are added to the solid obtained and the layers are separated. The aqueous base is washed twice with ether and then the combined ether washes are dried over Na ₂ SO ₄ . The solution is filtered and the solvent removed under vacuum to diamine (6)
(9.45 g, 0.0445 mol, 91% yield) is obtained.
The crude amine is 97% pure by GC and is used in the next step. A part of the substance,
Purify by Kulgelrohr distillation (100 ° C, 1.2 mmHg). ¹ H-NMR (CDCl ₃ ): δ3.8 (m, 1H), 3.24 (s, 3H), 2.8-2.
6 (m, 5H), 2.6-2.45 (m, 2H), 2.40 (s, 3H), 2.2-1.9 (m, 2
H), 1.8-1.4 (m, 6H), 1.3-0.9 (m, 2H). FTIR (neat): cm
^-1 , 3319 (br), 2932 (s), 1459, 1437, 1360, 1095 (s).
m / e (EI ⁺ ) 212 (2.5%), 197 (8.6%), 180 (6.1%), 123 (10
0%), 108 (22%), 84 (65%). Analytical value: Calculated value: C 67.88
%, H 11.39%, N 13.20%. Found: C 68.17%, H 11.
84%, N 13.27%. GC shows the product to be 94% pure.

Example 13 (1α, 2β, 3β) -N- [3-methoxy-2- (1-
Pyrrolidinyl) -cyclohexyl] -N-methyl-4-
Benzofuran acetamide monohydrochloride

[Chemical 12] Benzofuran acetic acid (1.95 g, 0.0111 mol)
Dissolve in 35 ml of THF. Carbonyldiimidazole (1.81 g, 0.0112 mol) is added in one portion and the reaction mixture is stirred under nitrogen for 2.5 hours. Then THF 1
Amine (6) in 0 ml (2.13 g, 0.0100 mol)
Is added and the solution is stirred overnight. The solvent is removed under vacuum and 80 ml CH ₂ Cl ₂ is added. This solution was added to H ₂
2 times with 30 ml O, 30 ml 5% NaOH and finally H
Wash with 30 ml of ₂ O. Dry the solution over MgSO ₄ ,
Filter and then remove the solvent under vacuum. The viscous yellow oil obtained gradually solidifies to give 2.22 g (54% yield). ¹ H-NMR (CDCl ₃ ): δ7.6 (d, J = 2.2Hz, 1H), 7.4-
7.36 (d, J = 8.1Hz, 1H), 7.25-7.1 (m, 2H), 7.0-6.9 (dd, J =
2.7Hz, 15.5Hz, 1H), 4.4-4.2 (m, 1H), 4.18-4.1 (d, J = 15H
z, 1H), 4.03-3.8 (m, 2H), 3.28 ＋ 3.21 (2 single wires, 3
H), 2.81 + 2.76 (2 single wires, 3H), 2.76-2.5 (m, 8H),
2.1-1.9 (m, 1H), 1.9-0.9 (m, 9H). FTIR (Kbr): cm ^-1 , 〜 3
500 (H ₂ O), 2936, 1368 (vs), 1434, 1138, 1100, 761
(s). m / e (CI +, CH ₄ ) 399 (12%), 371 (100%), 338 (5
%), 213 (9%), 181 (7%). Analytical value: Calculated value: C 71.32
%, H 8.16%, N 7.56%. Measured value: C 70.99%, H 8.40
%, N 7.87%. This material is dissolved in isopropanol and 3 ml of 7.3M HCl in isopropanol are added. Dry ether is added until the solution becomes cloudy. The material is left at room temperature for 3 hours and placed in the freezer overnight. The solid obtained is filtered, washed with dry ether and then vacuum dried at 50 ° C. The solid was recrystallized in isopropanol and then freeze dried from water (7) 0.80 g.
To get Analytical value: Calculated value: C 64.93%, H 7.68%, N 6.8
9%, Cl 8.71%. Found: C 63.32%, H 7.70%, N 6.53
%, Cl 8.59%, H ₂ O 3.85%. ¹ H-NMR (d ₆ -DMSO): δ 10.3
5 (br, 1H), 7.93-7.91 (d, J = 2Hz, 1H), 7.47-7.42 (d, J = 8.2
Hz, 1H), 7.27-7.18 (m, 2H), 7.1-7.0 (d, J = 7.3Hz, 1H), 4.
9-4.7 (br, 1H), 4.27-4.2 (d, J = 16Hz, 1H), 4.96-3.88 (d, J
= 16Hz, 1H), 3.7-3.3 (m, 4H), 3.3-3.1 (m and s at 3.19,
4H), 3.1-2.9 (m and s at 3.00, 4H), 2.1-1.3 (m, 10H).

Example 14 (1α, 2β, 6β) -2-Methoxy-6- (1-pyrrolidinyl) cyclohexanol or (1α, 2β, 3α)
-3-Methoxy-2- (1-pyrrolidinyl) cyclohexanol

[Chemical 13] 2 oxiranes (2) (16.78 g, 0.131 mol)
-Dissolved in 178 ml of propanol and pyrrolidine (1
1.94 g, 0.168 mol) is added. The solution is refluxed under N ₂ for 20 hours. The solvent is removed under vacuum. Only one product is seen by GC. Kugelroh with yellow oil
r Distill (80-120 ℃, 1.2mmHg) and (8) (2
3.61 g, 0.118 mol, 90%) is obtained. ¹ H-NMR (C
DCl ₃ ): δ3.8-3.7 (m, 1H), 3.7 (br, 1H), 3.6-3.45 (m, 1
H), 3.41 (s, 3H), 3.0-2.8 (td, J = 3.5,10Hz, 1H), 2.7-2.5
(m, 4H), 2.0-1.85 (m, 1H), 1.85-1.1 (m, 8H). m / e (EI ⁺ ) 20
0 (77%), 199 (27%), 184 (38%), 168 (54%), 110 (100
%), 70 (76%).

Example 15 (1α, 2β, 3α) -N- [3-methoxy-2- (1-
Pyrrolidinyl) cyclohexyl] -N-methylbenzenemethanamine

[Chemical 14] Alcohol (8) (23.38 g, 0.120 mol) as C
Dissolve in H ₂ Cl ₂ and add triethylamine (20 ml). The solution is cooled to −5 ° C. under N ₂ and methanesulfonyl chloride is added dropwise keeping the temperature between 0 ° and 5 ° C. The reaction mixture is warmed to room temperature overnight.
The reaction mixture is then poured onto 700 ml of CH ₂ Cl _{2 and} washed with 350 ml of H ₂ O and then 700 ml of H ₂ O.
The organic layer is dried over MgSO ₄ , filtered and the solvent removed under vacuum. N-benzylmethylamine (55 ml)
Is added and the mixture is heated under N ₂ to 95 ° C. for 20 hours. The reaction mixture is poured onto 300 ml of 10% K ₂ CO ₃ . The product is extracted into CH ₂ Cl ₂ , dried over MgSO ₄ , filtered and then the solvent is removed under vacuum. Yellow oil
Kugelrohr Distill and collect the fraction boiling at 110-160 ° C (1.0 mmHg). Diamine (9) (25.
80 g, 0.0853 mol, 71% yield) are obtained as a viscous yellow oil. ¹ H-NMR (CDCl ₃ ): δ7.5-7.1 (m, 5
H), 3.73 (s, 2H), 3.36 (s, 3H), 3.3-3.1 (m, 1H), 3.0-2.7
(m, 4H), 2.6-2.5 (m, 1H), 2.22 (s, 3H), 2.2-2.0 (m, 1H),
1.9-1.0 (m, 9H).

Example 16 (1α, 2β, 3α) -3-methoxy-N-methyl-2-
(1-pyrrolidinyl) -cyclohexanamine

[Chemical 15] Crystalline diamine (9) (3.75 g, 12.4 mmol)
Is dissolved in 75 ml methanol with 0.5 g 20% Pd / C and reduced using 50 psi H ₂ at ambient temperature for 18 minutes. The crude product shows a single peak by GC. The catalyst was filtered off and the solvent removed under vacuum (1
1) (2.62 g, 12.3 mmol, yield 99%) is obtained. ¹ H-NMR (CDCl ₃ ): δ3.45-3.35 (m, 1H), 3.31 (s, 3H),
3.0-2.8 (m, 2H), 2.8-2.6 (m, 2H), 2.6-2.4 (m, 2H), 2.38
(s, 3H), 2.3-1.9 (m, 3H), 1.9-1.6 (m, 5H), 1.3-0.9 (m, 3
H). FTIR (neat): cm ^-1 , 3304, 2935, 1440, 1105 (s),
850. m / e (EI +) 123 (67%), 110 (16%), 108 (17%), 84
(100%), 71 (11%), 70 (25%), 55 (15%), 42 (39%).
The structure of (11) has decoupling, COSY and N
Proved by OESY experiment. In addition, monohydrochloride (1
0) (19.73 g, 0.0586 mol) with 20% Pd / C
Together 1.5g, it was dissolved in methanol 500ml and 19 hours reduced at ambient temperature by using H ₂ of 50 psi.
The reaction mixture is filtered and the solvent removed under vacuum. Aqueous base (250% 15% NaOH) is added to the solid obtained and the mixture is extracted twice with 150 ml CH ₂ Cl ₂ and once with 200 ml ether. The combined organic layer is M
Dry over gSO ₄ , filter and then remove the solvent under vacuum. The product was distilled by Kugelrohr to obtain fractions [80-
120 ° C. (0.1 mmHg) was collected and spectroscopically identical (11) (8.3) to the material obtained from debenzylation of the free base.
8 g, 0.0395 mol, yield 67%) is obtained.

Example 17 (1α, 2β, 3α) -N- [3-methoxy-2- (1-
Pyrrolidinyl) cyclohexyl] -N-methyl-benzenemethanamine monohydrochloride

[Chemical 16]Diamine free base (9) (2) in 250 ml of anhydrous ether.
5.11 g, 0.0830 mol) in isopropanol
Treatment with 11.2 ml of HCl (HCl 0.267 g / ml)
Make sense. Obtained monohydrochloride as a hygroscopic white powder
(10) is collected by filtration. Mother liquor 15% NaOH
Rinse with MgSO_FourDry on top and evaporate to an oil
Second treatment of (10) by the same treatment with HCl.
Get the gain of. The combined yield of (10) is 19.78 g.
Is. Compound (10) is hygroscopic. No. 10
The mother liquor from yield 2 was washed with 15% NaOH and dried.
And evaporated as above to give a yellow oil. 3 days
The free base (9) (3.81
g) precipitates from the oil. Melting point 59-60 [deg.] C.
(9):¹H-NMR (CDCl₃): Δ7.4-7.1 (m, 5H), 3.72 (s, 2
H), 3.35 (s, 3H), 3.3-3.0 (m, 1H), 3.0-2.7 (m, 5H), 2.6-
2.5 (td, J = 3.6,11.5Hz, 1H), 2.22 (s, 3H), 2.2-2.0 (m, 1
H), 1.9-1.7 (m, 6H), 1.5-1.0 (m, 3H).¹³C-NMR (ppm) 141.
2, 128.5, 128.0, 126.4, 81.3, 63.8, 62.8, 59.4, 5
6.2, 47.9, 36.7, 30.6, 27.8, 24.1, 21.7. FTIR (KB
r): cm ^-1, 1603, 1496, 1042, 956, 903, 833, 747. m /
e (EI +) 803 (M + 1, 33%), 302 (M, 39%), 287 (31%), 16
0 (33%), 123 (56%), 91 (64%), 84 (100%). Free base
Both (9) and the monohydrochloride (10) are preferably
Used in the process.

Example 18 (1α, 2β, 3α) -N- [3-methoxy-2- (1-
Pyrrolidinyl) -cyclohexyl] -N-methyl-4-
Benzofuran acetamide monohydrochloride

[Chemical 17] Benzofuran acetic acid (1.51 g, 8.57 mmol)
Dissolve in 20 ml anhydrous THF under N ₂ and add carbonyldiimidazole (1.39 g, 8.57 mmol) in one portion. Gas evolution is observed. The reaction mixture is stirred overnight at ambient temperature. Then amine (11) (1.40 g, 6.59 mmol) in 10 ml of THF is added and the reaction mixture is stirred for 6 hours. The reaction mixture was added to CH ₂ Cl ₂
And washed once with water, twice with 15% NaOH and finally once with water. The combined aqueous layers are extracted twice with ether. Combine all organic layers and MgSO ₄
Dry on, filter and remove the solvent under vacuum. A white solid (2.22 g, 6.0 mmol, 90% yield) with a melting point of 97-101 ° C. is obtained. ¹ H-NMR (CDCl ₃ ): δ7.63
(s, 1H), 7.4 (d, J = 8Hz, 1H), 7.35-7.0 (m, 2H), 6.9-6.8
(m, 1H), 4.7-4.5 (brm, 1H), 4.1-3.8 (m, 2H), 3.6-3.1 (m,
4H, including s at δ2.8), 2.4-2.2 (m, 1H), 1.8-0.8
(m, 9H). FTIR (KBr): cm ^-1 , 3500 (br), 2854, 1636, 153
3 (w), 1431, 1250, 1086, 765 (water is evident in IR). m / e (EI +) 371 (1%), 355 (6%), 338 (5%), 181
(37%), 149 (89%), 131 (28%), 110 (21%), 84 (100
%), 70 (29%). Analytical value: Calculated value: C 71.32%, H 8.16
%, N 7.56%. Found: C 70.58%, H 8.18%, N 7.83
%. HPLC (210 nm) shows the compound to be 99.3% pure. This material (2.13 g, 5.7 mmol) was treated with 50 ml of ether and 10 ml of acetonitrile.
Dissolve in. Then a 16% HCl / ether solution 2.4
3 g are added dropwise. A precipitate gradually forms. The solution is 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 60-70).
A purity of 97.3% is obtained by deg. ¹ H-NMR (d ₆ -DMS
O): δ9.4 (br, 1H), 7.95-7.9 (d, J = 2.2Hz, 1H), 7.5-7.4
(d, J = 8Hz, 1H), 7.3-7.1 (m, 2H), 7.1-7.0 (d, J = 7.3Hz, 1
H), 4.6 (br, 1H), 4.3-4.1 (d, J = 16Hz, 1H), 4.0-3.9 (d, J =
16Hz, 1H), 3.9-3.6 (m, 4H), 3.5-3.1 (m, s at 3.40
(Water) and s in 3.31), 3.0 (s, 3H), 2.3-2.
1 (m, 1H), 2.05-1.1 (m, 9H). Analytical value: Calculated value: (corrected for 5.5% water), C 61.35%, H 7.87%, N 6.50%, C
l 8.23%. Found: C 61.2%, H 8.10%, N 6.47%, Cl
8.43%, H ₂ O 5.46%.

Example 19 (1α, 2β, 6β) -2-Methoxy-6- [methyl (phenylmethyl) amino] -cyclohexanol (17)

[Chemical 18] Oxirane (1) (20.08g, 0.157 mol) and N- methylbenzylamine (30.24g, 0.25 mol) was dissolved in 2-propanol 110ml and N ₂
Heat under reflux for 18 hours. The solvent was removed under vacuum and the product was Kugelrohr distilled to 100 ° C (1.0 mmHg).
Remove the material that distills below and from 100 ° C to 140 ° C
Collect the fraction boiling between (1.0 mmHg).
A colorless oil (13) (35.42 g, 90%) is obtained. The product shows a single peak by GC. ¹ H-NMR
(d ₆ -DMSO): δ7.4-7.1 (m, 5H), 4.17 (s, 1H), 3.74-3.68
(d, J = 13.4Hz, 1H), 3.55-3.45 (d, J = 13.4Hz, 1H), 3.33 (s,
3H), 3.3-3.2 (m, 1H), 3.0-2.85 (m, 1H), 2.4-2.3 (m, 1H),
2.13 (s, 3H), 2.0-1.8 (m, 1H), 2.8-2.6 (m, 2H), 1.4-0.9
(m, 3H). ¹³ C-NMR (d ₆ -DMSO): δ 140.1, 128.7, 128.4, 1
26.9, 83.7, 73.9, 65.9, 58.1, 57.1, 36.6, 29.4, 2
2.9, 21.4. FTIR (neat): cm ^-1 , 3400 (br), 2938, 286
4, 1496, 1454, 1121, 1096, 881, 743, 701. m / e (EI
+) 249 (m, 17%), 234 (20%), 218 (22%), 160 (22%), 1
20 (5%), 91 (100%), 65 (7%), 42 (13%). Analytical values: Calculated values: C 72.25%, H 9.30%, N 5.62%. Found: C 72.
23%, H 9.22%, N 5.47%. Structure is COSY, HETCOR, LR
Proven by HETCOR and DEPT NMR techniques.

Example 20 (1α, 2α, 6β) -N- [2-methoxy-6- (1-
Pyrrolidinyl) cyclohexyl] -N-methylbenzenemethanamine

[Chemical 19] Amino alcohol (13) (35.08 g, 0.141 mol) is added to 460 ml CH ₂ Cl ₂ and 32 ml triethylamine under N ₂ . The resulting solution is cooled to -10 ° C. Methanesulfonyl chloride (13 ml) is added dropwise keeping the temperature below -5 ° C. After the addition is complete
The cooling bath is removed and the reaction mixture is stirred for 5 hours. At this time all starting material has been consumed as seen by GC. The reaction mixture is poured into a separating funnel with 500 ml of CH ₂ Cl ₂ . The organic layer was mixed with 250 ml of H ₂ O 3
Wash once, dry over MgSO ₄ , filter and then reduce the total volume of the solution under vacuum to about 250 ml. To this solution is added 97 ml of pyrrolidine and left at room temperature for 16 hours, then heated to reflux for 1.5 hours. 10% of reaction mixture
Poured into 800 ml of Na ₂ CO ₃ and 500 of CH ₂ Cl ₂
ml, then 400 ml CH ₂ Cl _{2 and} then CH ₂ Cl ₂
Extract with 500 ml. The combined organic layers are dried over MgSO ₄ , filtered and the solvent removed in vacuo. Kugelr crude oil
ohr Distilled to remove colored impurities 18.21g pale yellow oil
(43%) is obtained. The GC to distillate shows a mixture of the four products in a 1: 4: 7: 4 ratio in order of increasing retention time.

The crude oil is dissolved in 95 ml of ether and treated with 3 ml of 2.6N HCl in isopropanol. The solution is decanted from the brown solid that has formed and a further 50 ml of ether are added to the solution and more than 6 ml of HCl / isopropanol solution are added dropwise and the resulting solution is left in the freezer for 3 weeks. The crystals that formed are filtered and some crystalline morphology is observed. The largest brown crystals are mechanically separated. These crystals are treated with dilute NaOH and extracted with ether. The organic layer is dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum. The oil obtained is purified by flash chromatography (SiO ₂ ) (using 1.5% MeOH / CHCl ₃ and saturated with NH ₄ OH) (1
4) (0.45 g, 0.0015 mol) is obtained. ¹ H-NMR (C
DCl ₃ ): δ7.5-7.1 (m, 5H), 4.0-3.8 (d, J = 13.5Hz, 1H), 3.
86-3.80 (m, 1H), 3.77-3.72 (d, J = 13.5Hz, 1H), 3.3 (s, 3
H), 3.3-3.2 (td, J = 3.3,11.3Hz, 1H), 2.8-2.6 (m, 4H), 2.
6-2.5 (dd, J = 2.3,10.8Hz), 2.37 (s, 3H), 2.0-1.8 (m, 2H),
1.8-1.6 (m, 4H), 1.6-1.4 (m, 2H), 1.4-1.0 (m, 2H). ¹³ C-
NMR (d ₆ -DMSO): 14.9, 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 (E
I +) 302 (11.4%), 287 (7.9%), 211 (35.5%), 173 (28.1
%), 160 (12.2%), 150 (15.5%), 134 (64.5%), 110 (3
6.0%), 91 (100%), 84 (23.3%), 70 (21.4%), 44 (30.9
%). Analytical value: Calculated value: C 75.45%, H 10.00%, N 9.26
%. Found: C 75.40%, H 9.97%, N 9.17%. Stereochemical and regiochemical designations are COSY, NOESY and HET
It was measured by a COR NMR experiment.

Example 21 (1α, 2α, 6β) -2-methoxy-N-methyl-6-
(1-pyrrolidinyl) cyclohexanamine

[Chemical 20] N-benzyldiamine (14) (0.45 g, 1.49 mmol) was added at room temperature in 75 ml of methanol and at 50 psi.
Under hydrogen, using 0.05 g of 20% Pd / C.
The product is filtered and the solvent is removed under vacuum. Chromatography of crude oil (2% MeOH / 2% concentrated NH
₄ OH / 96% CHCl ₃ ) (15) (0.23 g,
Yield 73%). ¹ H-NMR (CDCl ₃ ): δ3.7-3.6 (m, 1
H), 3.35 (s, 3H), 2.76-2.6 (m, 1H), 2.6-2.5 (m, 5H), 2.4
2 (s, 3H), 2.4-2.2 (br, 1H), 1.9-1.3 (m, 10H). m / e (EI +)
212 (8.1%), 181 (22%), 150 (26%), 112 (23%), 111 (2
4%), 110 (100%), 97 (21%), 96 (21%), 84 (63%), 70
(50%), 55 (22%), 44 (33%), 42 (33%).

Example 22 (1α, 2α, 6β) -N- [2-methoxy-6- (1-
Pyrrolidinyl) cyclohexyl] -N-methyl-4-benzofuranacetamide monohydrochloride

[Chemical 21] 4-Benzofuran acetic acid (1.01 g, 5.73 mmol)
The, CH ₂ in put and under N ₂ to the boiling flask 100ml
Dissolve in 50 ml of Cl ₂ . Oxalyl chloride (1.6 ml)
And dimethylformamide (0.04 g) are added.
Gas evolution is observed. The reaction mixture is stirred at 25 ° C. for 18 hours and then the solvent is removed under vacuum. The obtained oil is Ku
Gelrohr distillation (0.07 mmHg, 90-100 ° C) gives 1.04 g of a yellow oil. This oil was analyzed by ¹ H-NMR to
It was found to be a 1: 1 mixture of acid and acid chloride. This mixture (0.20 g) is dissolved in 10 ml of anhydrous THF and cooled to 0 ° C. under N ₂ . Then diamine (15) (0.11 g, 0.52 mmol, THF
Dissolved in 2.5 ml) and triethylamine (1.0 ml)
Is added to the acid chloride solution. Then 4- (dimethylamine) pyridine (0.01 g) is added and the solution is stirred at room temperature for 24 hours. The solvent was removed under vacuum and the crude oil was chromatographed twice (3% MeOH).
/ 1% conc. NH ₄ OH / CHCl ₃₎ to give the free base (16) (0.11 g, 0.30 mmol). ¹ HN
MR (CDCl ₃ ): δ7.6 (d, J = 4.9Hz, 1H), 7.4-7.38 (d, J = 7.9H
z, 1H), 7.25-7.20 (t, J = 8Hz, 1H), 7.11-7.08 (d, J = 7.3Hz,
1H), 6.95 (br, s, 1H), 4.6-4.5 (br, 1H), 4.1-3.9 (m, 2H),
3.6 (brs, 1H), 3.3-3.2 (br, 1H), 3.19 (s, 3H), 3.07 (br
s, 3H), 2.7-2.5 (br, 2H), 2.1-1.1 (m, 12H). m / e (CI +) 37
2 (M + 2, 25%), 3.71 (M + 1,100%), 369 (13%), 300 (24
%), 181 (63%), 150 (21%), 110 (9%).

The product is dissolved in anhydrous diethyl ether and treated with 20% HCl / MeOH to form the monohydrochloride salt. It is filtered and lyophilized (1
6) (0.03 g, 0.08 mmol) is obtained. ¹ H-NMR (d _6-
DMSO): δ9.6 (br, 1H), 7.94-7.92 (d, J = 2.5Hz, 1H), 7.5-
7.4 (d, J = 8.6Hz, 1H), 7.3-7.2 (t, J = 8Hz, 1H), 7.18-7.15
(d, J = 2.4Hz, 1H), 7.1-7.0 (d, J = 7.3Hz, 1H), 4.8-4.6 (dd,
J = 2.4,12Hz, 1H), 4.25-4.1 (d, J = 16.5Hz, 1H), 4.05-3.8
(m, 2H), 3.6-2.8 (include m, H ₂ O peak), 2.2-1.2 (m, 10
H). m / e (CI +, CH 4 in _{1% NH 3): 372 (} M + 2, 23%), 371 (M
+1, 100%), 300 (32%), 182 (17%), 181 (81%), 150
(37%), 131 (11%), 110 (22%). FTIR (KBr): cm ^-1 ,, 343
2 (br), 2945, 1734, 1647 (s), 1457, 1432, 1246, 112
4, 1102, 1045, 1009, 765 (s). HRMS (EI +) C ₂₂ H ₃₀ N ₂ O ₃ −
Calculated: 370.2256. Found: 370.2246.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor David Chillards Lease Cambridge, England. Seeb 2 2 The Bee. Noritsuji Street 33 (72) Inventor Aum Prakashiyu Gale 48103, Michigan, USA. Unover. Holden Drive 3995

Claims (6)

[Claims] 1. (1α, 2α, 6β) -N- [2-methoxy-6- (1-pyrrolidinyl) cyclohexyl] -N-
A compound designated as methyl-4-benzofuranacetamide monohydrochloride. 2. (1α, 2β, 3α) -N- [3-Methoxy-2- (1-pyrrolidinyl) -cyclohexyl] -N
A compound named as methyl-4-benzofuranacetamide monohydrochloride. 3. A pharmaceutical composition useful in the treatment of pain in mammals, containing an analgesic effective amount of a compound of claim 1 or 2 together with a pharmaceutically acceptable carrier. 4. A method for treating pain in a mammal, which comprises administering the pharmaceutical composition according to claim 3 to the mammal. 5. A pharmaceutical composition useful in the treatment of stroke in mammals, comprising an effective amount of one of the compounds of claims 1 and 2 together with a pharmaceutically acceptable carrier. 6. A method for treating stroke in a mammal, which comprises administering the pharmaceutical composition according to claim 5 to the mammal.