JPH1081684A - Substituted 3-aminoquinuclidine drug compositions - Google Patents

Abstract

(57) [Summary] (Modified) [Problem] To provide a substituted 3-aminoquinuclidine drug composition [Solution] Compound represented by the following formula (A) or (B) (In the formula (A), Ar ¹ , Ar ² and Ar ³ are each independently an optionally substituted aryl;
X is an optionally substituted alkoxy having 1 to 6 carbon atoms, an optionally substituted aryl and the like; (B)
In the case of R ¹ , R ² and R ³ are each independently hydrogen, alkyl having 1 to 6 carbon atoms which may be substituted,
Y is an optionally substituted alkoxy having 1 to 6 carbons and the like; Y is an optionally substituted alkyl having 1 to 6 carbons, an alkenyl having 2 to 6 carbons optionally substituted or An optionally substituted cycloalkyl having 3 to 8 carbon atoms; n is 0 to 6; X (CH ₂ ) _n
Is substituted at the 4,5 or 6 position of the quinuclidine ring; Y is substituted at the 4 or 6 position of the quinuclidine ring. ) Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to new and useful quinuclidine derivatives of interest to those in the fields of medicinal chemistry and chemotherapy. More particularly, the present invention relates to substituted 3-aminoquinuclidines and pharmaceutically acceptable salts thereof, which are particularly useful in terms of antagonism to substance P. Therefore, these compounds are used for the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain or migraine.

[0002]

2. Description of the Related Art J. Warawa discloses in U.S. Pat. No. 3,560,510 that certain 3-amino-
It discloses that 2-benzhydrylquinuclidine is effective as a diuretic with the corresponding unsubstituted 3-benzylamino form, which is the intermediate. Also, E.I. J. War
awa et al., Journal of Medicine
1 Chemistry, Vol. 18, p. 587 (1
975), this work was compared to others in the same line, that is, where the 3-amino moiety was either ethylamino, β-phenylethylamino, β-isopropylamino, 2-furfurylamino and However, the phenyl group itself is not substituted, and the 2-benzhydryl group is always symmetrically substituted (or unsubstituted).

However, none of the above references teaches or suggests that any of these compounds is effective as a substance P antagonist.

[0004] Substance P is a peptide belonging to tachykinin, which is a naturally occurring undecapeptide. Tachykinin is named because its stimulating action on smooth muscle tissue is immediate. More specifically,
Substance P is a pharmacologically active neuropeptide produced in mammals (first isolated from the gastrointestinal tract). F. U.S. Pat. No. 4,680, Veber et al.
283 has a characteristic amino acid sequence. It is well known that substance P and other tachykinins are widely involved in the pathology of many diseases. For example, substance P has recently been implicated in the transmission of pain or migraine (BEB Sandbe).
rg et al., Journal of Medicinal.
Chemistry, Vol. 25, p. 1009 (1
982)) Others, central nervous system disorders such as anxiety and schizophrenia, respiratory diseases such as asthma and inflammatory diseases such as rheumatoid arthritis, gastrointestinal disorders and gastrointestinal disorders such as ulcerative colitis and Crohn's disease. It has been reported that it is also related to diseases of the ducts (D. Regoli “Trends in
Cluster Headache ", F. Sicu
edited by teri et al., Elsevier Scientific
c Publishers, Amsterdam, 19
87 pp. 85-95).

[0005] In recent years, efforts have been made to develop peptide-like substances that act as antagonists to tachykinin peptides, including substance P, for the purpose of more effectively treating the above disorders and diseases. Was. Such a substance has a problem that it is easily metabolized due to its peptide-like property, and lacks stability as a practical therapeutic agent for treating diseases. On the other hand, the non-peptide antagonist of the present invention does not have such a problem, and is much more metabolically stable than the above-mentioned conventional one.

[0006]

DISCLOSURE OF THE INVENTION The present inventors intend to provide compounds useful as antagonists of substance P, and to synthesize a series of compounds described below. .

[0007]

SUMMARY OF THE INVENTION The present invention provides a therapeutically effective amount of a novel 3-aminoquinuclidine compound or a pharmaceutically acceptable salt thereof represented by the following formula: Gastrointestinal disorders, central nervous system disorders,
It is intended to provide a pharmaceutical composition for treating inflammatory diseases, asthma, pain and migraine.

[0008]

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(Wherein, Ar ¹ , Ar ² and Ar ³ are each independently an optionally substituted aryl; X is an optionally substituted alkoxy having 1 to 6 carbon atoms; Good aryl, CONR ¹ R ² , CO ₂
R ¹ , CHR ¹ OR ² , CHR ¹ NR ² R ³ , COR ¹
Or CONR ¹ OR ² ; R ¹ , R ² and R ³
Each independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms which may be substituted, and 1 to 5 carbon atoms which may be substituted.
6 alkoxy, which may have 3 to 8 carbon atoms which may be substituted
A cycloalkyl having 1 to 1 carbon atoms which may be substituted
5 is a heterocyclic group or an optionally substituted aryl; Y is an optionally substituted alkyl having 1 to 6 carbons, an alkenyl having 2 to 6 carbons optionally substituted or substituted. X is a cycloalkyl having 3 to 8 carbon atoms; n is 0 to 6; X (CH ₂ ) _n is substituted at the 4, 5, or 6-position of the quinuclidine ring; Or it is substituted at the 6-position. In the above formula, "halogen" means a group derived from fluorine, chlorine, bromine and iodine.

"Alkyl" is used as a term to refer to monovalent linear and branched hydrocarbon radicals and includes methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, t-butyl and the like, but are not limited thereto.

"Alkenyl" is a term used to represent monovalent straight-chain and branched-chain hydrocarbon groups having a double bond, and includes ethenyl, 1- and 2-propenyl, and 2-methyl. Includes, but is not limited to, -1-propenyl, 1- and 2-butenyl and the like.

"Alkoxy" is used as a term representing -OR (R is an alkyl group), and includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like. It is not limited.

"Alkylthio" is used as a term representing -SR (R is an alkyl group) and includes methylthio, ethylthio, n-propylthio, isopropylthio, n-
Examples include, but are not limited to, butylthio, isobutylthio, t-butylthio, and the like.

"Cycloalkyl" is used as a term representing a cyclic hydrocarbon group and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The above alkyl, alkoxy, alkenyl,
Substituents on alkylthio and cycloalkyl include halogen, nitro, cyano, and the like, and their substitutions include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

"Aryl" is used as a broad term for aromatic groups, including those which may be treated as "heteroaryl", and includes phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazole, tetrazole , Thiazole, imidazole, pyrazole and the like, but are not limited thereto.

Among the substituents on the aryl group represented by Ar ¹ , Ar ² and Ar ³ , some of the substituents on the aryl group have a halogen and a carbon number of 1 to 1.
Alkyl having 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, alkylsulfinyl having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, trifluoromethyl, trifluoromethoxy and the like , But
It is not limited to these.

"Heterocyclic group" refers to pyrrolidino, piperidino,
Includes, but is not limited to, morpholino, piperazinyl, thiamorpholino, and the like.

The substituents on the nitrogen atom and sulfur atom on the heterocyclic group include, but are not limited to, oxygen and alkyl having 1 to 4 carbon atoms. Certain of the compounds of the above formula may be in the form of an acid salt. Pharmaceutically acceptable acid salts are salts of acids that can form non-toxic salts.

The present invention relates to a pharmaceutical composition for use in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain and migraine in mammals. And a pharmaceutically acceptable carrier or diluent.

General Description of the Synthesis The novel compounds of the present invention can be prepared by the following methods.

[0022]

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The target compound is synthesized by various methods.
In the synthetic diagram, Ar ¹ , Ar ² and Ar ³ are as defined above, and W and W ′ are respectively — (CH ₂ ) _n X or Y in the formulas (A) and (B), or Wherein P and Q are each a protecting group.

The substituted quinuclidin-3-one (i) can be obtained from a substituted isonicotinate by the method of Org. Synth. Col
l. Vol. V, 989 (1973), in the same manner as in the method for producing unsubstituted quinuclidin-3-one. For example, 5-methyl- and 5-methoxycarbonyl-quinuclidin-3-one have already been synthesized in this way (J. Chem. So.
c. Perkin Trans. , 1,409 (199
1)).

[0025]

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In position 2 of quinuclidin-3-one (i),
J. Med. Chem. 18,587 (1975) to introduce benzhydryl or a group equivalent thereto. The compound (i) is subjected to aldol condensation by heating to reflux with an aromatic aldehyde (Ar ² CHO) in a protic solvent (for example, ethanol) in the presence of a basic catalyst such as sodium hydroxide to give ^2- aldehyde.
Converted to benzylidene compound (ii).

Another aryl group (Ar ³ ) is introduced by a Grignard reaction in an aprotic solvent such as tetrahydrofuran, ether or toluene. Good results are obtained by adding a catalytic amount of cuprous halide, such as cuprous bromide or cuprous iodide, to improve the yield of the 1,4-addition product. The reaction is usually
It is performed at a low temperature such as 78 to 0 ° C. In addition, it has been reported by Kwajima et al. That selectivity may be improved when trimethylsilyl chloride, HMPA and CuBr-DMS are used (Tetrahedron,
45, 349 (1989)). Further, the obtained compound (i
ii) can be converted to the corresponding carboxylic acid by hydrolysis with an acid, which can be further converted to another amide by alkylation using a commonly used method.

[0028]

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Compound (iii) is converted to target compound (vi) by two separate routes. The first route involves an arylmethylamino group (Ar ¹ CH) at the 3-position of quinuclidine.
₂ NH-) is directly introduced. This transformation first forms an imine from the benzylamine corresponding to (iii). This reaction often involves the use of an acid (eg, CSA)
It is carried out under dehydrating conditions in hot toluene in the presence of a catalyst. Next, the imine is reduced to obtain the compound (vi). This reduction is carried out by catalytic reduction or using a hydrogenating reagent such as an aluminum-based reagent, borons, borohydrides or trialkylsilane. Often, trialkylboranes (eg, 9-BBN) or sodium triacetoxyborohydride (NaBH (O
Good results are obtained by reacting Ac) ₃ ) in tetrahydrofuran at room temperature for 30 minutes to several days.

The second route is a step-wise conversion of the 3-amino compound (v), followed by alkylation of the compound to give (vi). Compound (iv) is an oxime,
Imino-type compounds such as hydrazone or imine, which is, Q-NH _2, corresponding to (iii) (e.g.,
(Hydroxylamine, N, N-dimethylhydrazine, ammonia or benzylamine). The resulting compound (iv) is reduced by various reducing agents such as LAH, boron-based reagent, catalytic reduction or a combination thereof. In the case of imines derived from ammonia, formic acid is used as reducing agent.
The formed 3-amino compound (v) is then purified using appropriate benzaldehyde (Ar ¹ CHO) under normal reductive amination conditions (eg, in the presence of sodium cyanoborohydride in methanol: J. Am Chem.S
oc. , 93, 2897 (1971)). Other reducing agents such as NaBH ₄ , Na
BH (OAc) ₃ or trialkylsilane can also be used for this reaction.

[0031]

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The functional group present in W of compound (vi) can be converted to another functional group (W '). Some of the target compounds (ix) are obtained as follows. For example, a compound (vi) having a group W containing an amide group is represented by L
It can be converted to the corresponding amine by treatment with a reducing agent such as AH, or can be converted to the corresponding carboxylic acid by hydrolysis. The resulting carboxylic acid is
It can be converted to the corresponding ester by a usual method. The compound (vi) having a group W containing an ester or a carboxylic acid can be prepared by using a suitable reducing agent (for example, LA
By using H), it can be converted to the corresponding hydroxymethyl. If the benzylamine moiety hinders such conversion, it is necessary to protect the NH of the benzylamine compound (vi) with a suitable protecting group. Such protecting groups include Cbz or Bo
c is suitable (TW Greene, Protec)
five Groups in Organic Sy
nthesis, J. et al. Wiley & Sons (19
81)). After the conversion of the functional group is completed, the protecting group is eliminated by a usual method to obtain the desired compound (ix).

Since the quinuclidine compounds of the present invention all have at least two asymmetric centers, various stereoisomeric types or coordinations can be obtained. Thus, the compounds of the present invention may exist as separate optically active forms of (+)-and (-)-and as a racemic or (±) -mixture. Various diastereomers may also be present. The present invention includes all these forms in its scope. For example, the diastereomer
The optically active substance can be separated by a method well known to those skilled in the art, for example, a fractional crystallization method, etc. Can be obtained by

The 3-arylmethylamino-2- of the present invention
Since most of the benzhydrylquinuclidine compounds are basic compounds, they can form various salts with various organic or inorganic acids.

While such salts must be pharmaceutically acceptable for administration to animals, in practice, even if they are pharmaceutically unacceptable salts, the quinuclidine base compound will be removed from the reaction mixture. After isolation as such a salt, it may be converted back to the free base by treatment with an alkaline reagent and the free base converted to a pharmaceutically acceptable acid addition salt. The acid addition salt of the quinuclidine base compound of the present invention can be easily prepared by treating the base compound with a substantially equivalent amount of a predetermined mineral acid or organic acid in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. Can be manufactured. Careful evaporation of the solvent readily affords the desired solid salt.

The acids used in the preparation of the pharmaceutically acceptable acid addition salts of the quinuclidine base compound of the present invention as described above include non-toxic acid addition salts, ie, hydrochloride, hydrobromide, iodine and the like. Hydride, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate , Fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, pamoate (i.e., 1,
Acids which form salts with pharmaceutically acceptable anions such as 1'-methylene-bis- (2-hydroxy-3-naphthoate)) and the like.

The quinuclidine compounds of the present invention, which also have acidic properties, can form base salts with various pharmaceutically acceptable cations. Such salts include alkali metal salts and alkaline earth metal salts, and particularly include sodium and potassium salts. All of these salts can be produced by conventional techniques. The chemical base used in the preparation of the pharmaceutically acceptable base salts of the present invention should form non-toxic base salts with the acidic quinuclidine derivatives described above. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium. These salts can be readily prepared by treating the acidic quinuclidine compound with an aqueous solution containing the desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. . As another method, a lower alkanol solution of an acidic compound and a desired alkali metal alkoxide are mixed,
The obtained solution may be produced by a method of evaporating to dryness as in the above case. In each case, it is desirable to have a complete reaction with stoichiometric amounts of reagents and to maximize the yield of the final product.

[0038]

The active quinuclidine compound of the present invention exhibits an excellent P substance receptor binding action, and is therefore effective for treating various conditions characterized by excessive action of the P substance. Some of these conditions include gastrointestinal disorders such as ulcers and colitis and other central nervous system disorders such as gastrointestinal disorders, anxiety and psychiatric disorders, inflammatory diseases such as rheumatoid arthritis and inflammatory enteritis, asthma, etc. In addition to the respiratory diseases described above, pain associated with the above-mentioned conditions including migraine is included. Therefore, the compound of the present invention is intended to suppress and / or treat the above-mentioned disease states of mammals including humans,
It can be used as a substance P antagonist. When the compounds of the present invention are tested as anti-inflammatory agents, the standard rat paw carrageenan-induced edema test (CA Winte
r, Proceedings of the Soc
iety of Experimental Biol
ogy and Medicine, Vol. 111,
p. 544 (1962)) and mustard oil-induced plasma leakage test (G. Jansco et al., Natur
e, Vol. 270, 22/29, p. 741-743 (1977) and F.M. Lembeck et al., Brit. J. Pharmac
ol. , 105, 527 (1992)).

The radiolabeled compounds of formulas (A) and (B) are useful as research and diagnostic tools in the study of the rate of drug metabolism and in the analysis of drug binding in humans and animals. is there. In the field of research, it is used in particular for radioligand binding analysis, automated radiographic studies, and in vivo studies of binding,
In the field of diagnostics, in particular, the study of substance P receptors in the human brain, eg up / down regulation in disease states, and tissues involved in inflammation in the body, such as immune-type cells or inflammatory bowel disorders It is used to study binding in cells directly related to E.g. In particular, tritiated and ¹⁴ C-isomers of substituted 3-aminoquinuclidine are used as radiolabeled forms of the quinuclidine compounds of the present invention.

The active quinuclidine compounds described above are:
Administration may be by any of oral, parenteral and topical routes. Generally, the most desirable doses of these compounds will be between about 2.8 mg and about 1500 mg per day, but will naturally vary with the weight and condition of the patient and the particular route of administration.
However, dosages will also vary depending on the type of animal being treated and the difference in sensitivity of the animal to the drug, as well as the type of drug formulation, the duration and interval of administration. In some cases, a dose lower than the lower limit of the above range may be appropriate, and even if the dose is larger than the above range, it may cause harmful side effects if it is divided into several times a day and administered in small amounts. Not always.

The compounds of the present invention can be administered with a pharmaceutically acceptable carrier or diluent by any of the above three routes of administration, and can be administered in one or more divided doses. it can. More specifically, the novel therapeutic agents of the present invention can be administered in various types of dosage forms, such as tablets, capsules, medicinal drops, in combination with various pharmaceutically acceptable inert carriers. Lozenges, hard candy, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups and the like can be provided. These carriers include solid diluents or excipients, sterile aqueous media, various non-toxic organic solvents, and the like. In the case of a drug for oral administration, sweetening and / or flavoring may be appropriately performed. Generally, the therapeutically effective compounds of the present invention will comprise from about 5.0% to 70% by weight.
The dosage form has a concentration in the range of weight%.

For oral administration, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate,
Various excipients such as glycine are combined with various disintegrants such as starch, preferably corn, potato or tapioca starch, alginic acid and certain silicic acid double salts, and polyvinylpyrrolidone, sucrose, gelatin, It can be used with a granulating binder such as gum arabic. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are also often very effective for tablet formation. The same kind of solid composition can be used by filling it into a gelatin capsule. Suitable substances in this connection include, in addition to lactose or milk sugar, high molecular weight polyethylene glycols. When it is desired to prepare aqueous suspensions and / or elixirs for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring agents or dyes, and if necessary, emulsifiers and / or
Alternatively, a suspending agent may be used in combination with water, ethanol, propylene glycol, glycerin and the like, and a diluent obtained by combining them.

For parenteral administration, solutions of the compounds of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solution is appropriately buffered as necessary (preferably p
H> 8), the liquid diluent must first be made isotonic.
Such aqueous solutions are suitable for intravenous injection, and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The production of all these solutions under sterile conditions can be readily achieved by standard pharmaceutical techniques well known to those skilled in the art. Further, when the compounds of the present invention are used for treating skin inflammation, they may be administered topically. In this case, it is desirable to apply topically in the form of creams, jellies, gels, pastes, ointments and the like according to standard pharmaceutical practices.

In order to measure the action of the compound of the present invention as a substance P antagonist, the P-tail of the cow tail tissue or IM-9 cells was determined.
The ability to block the binding of substance P at the substance receiving site,
It is measured using a radioligand. The substance P antagonistic effect of the quinuclidine compound described above is expressed in Journal of B
iological Chemistry, Vol. 2
58, p. 5158 (1983). A. Ca
Evaluation is performed using the standard assay described in the paper of Scieri et al. The method essentially comprises determining the concentration of the individual compound required to reduce the amount of radiolabeled P substance ligand at the P substance receiving site of the isolated bovine tissue or IM-9 cells by 50%. To determine a characteristic IC ₅₀ value for each test compound.

In this test, some preferred compounds have 0.1-60 nM for inhibition of substance P binding at the receptor site.
Showed IC ₅₀ values in the range of (nanomolar).

The anti-inflammatory effect of the compounds of the present invention has been demonstrated in the standard rat leg carrageenan-induced edema test described above. In this study, male white rats weighing 150-190 g in response to subplantar injection of carrageenin
The anti-inflammatory effect is measured as the rate of suppressing edema occurring in the hind paw. Injection of carrageenan is performed as a 1% aqueous solution. Edema formation is then assessed by measuring paw volume before carrageenin injection and paw volume 3 hours after injection. A 3 hour volume increase after carrageenan injection is an individual response. Differences in response between drug-treated rats (6 per group) and control groups injected with vehicle only are obtained when 33 mg / kg of a standard compound such as phenylbutazone is administered orally If it is significant compared to the result, it is judged as an active compound.

Further, the anti-inflammatory effect of the present invention is the same as that of L
It is also demonstrated in a mustard oil-induced plasma leakage test in standard rat paws such as embeck. This test measures the anti-inflammatory effect by controlling the rate of plasma leakage occurring in the hind paws of female SD rats (weighing 100 to 150 g) in response to application of mustard oil to the instep. The compound of the present invention is dissolved in an aqueous solution containing 0.1% methylcellulose and orally administered 1 hour before applying mustard oil. Evans blue injection solution (50 mg / kg dissolved in physiological saline containing 0.02% bovine serum albumin) was injected intravenously, and mustard oil diluted to 5% concentration with liquid paraffin was applied to the hind paws of rats I do. Twenty minutes later, the feet are amputated and frozen. After grinding the feet, Evans Blue is extracted and colorimetrically determined. The difference in response between the group treated with the compounds of the invention and the untreated group is
If it is statistically significant, it is considered an active compound.

The antipsychotic effect of the compounds of the present invention as a neuroleptic agent used for treatment of various psychiatric disorders is measured mainly by a method for examining the ability of those compounds to suppress substance P-induced hyperactivity in rats. This investigation is performed by first administering a control compound or an appropriate test compound of the present invention to rats, then injecting substance P into the brain via a cannula, and measuring the motor response of each rat to the stimulus.

[0049]

EXAMPLES Examples of the present invention will be described below. However, the invention is not limited to the description of these examples. Nuclear magnetic resonance spectrum (NMR) was measured at 270 MHz unless otherwise specified.
The position of the peak is shown in the unit (ppm) of one millionth of a downfield from tetramethylsilane. The shape of the peak is indicated by the following symbol.

S: single, d: double, t: triple, g: quadruple, m: multiple, br: wide.

Synthetic drawing of Examples 1, 2 and 3

[0052]

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Methyl 2-chloroisonicotinate, 2- isonicotinic acid N-oxide (50.0 g, 0.359
mol) 1, 5 phosphorus chloride (120g, 0.576mol) and phosphorous oxychloride (160 ml, 1.72 mol) were mixed with stirring at room temperature. The mixture was heated at reflux for 2 hours, distilled at 1 Torr pressure to remove excess phosphorous kiosichloride and then evaporated in vacuo. While carefully cooling the residue, dry methanol was added to cause an exothermic reaction. Mix the mixture with NaHC
It was made basic with an aqueous solution of O ₃ and extracted with ethyl acetate. The extract was dried over MgSO ₄ and concentrated by evaporation. The crude product was distilled under reduced pressure to obtain methyl 2-chloroisonicotinate (136-144 ° C / 36 mmHg, 41.6 g). It still contains impurities ( ¹ H N
(18% mol according to MR), there is no effect on the next step.

¹ H NMR (270 MHz, CDC
l ₃ ): 8.54 (br d, J = 5 Hz, 1H);
89 (br s, 1H), 7.77 (dd, J = 5, 1
Hz, 1H), 3.97 (s, 3H).

[0055] 2- (2-phenylethynyl) isonicotinate, (19.08G as 100% purity, 0.111 mol) 3 2-chloro-isonicotinic acid methyl 2, phenylacetylene (13.6 g, 0.133 mol) , Cuprous iodide (1.0
0g, 5.25mmol) and triethylamine (30m
l) was mixed with stirring at room temperature, and bis (triphenylphosphine) palladium (II) chloride (2.0 g, 2.85 mmol) was added to the mixture. The reaction mixture was
Heated to reflux for an hour. The solvent was evaporated off and the residue was chromatographed (silica gel, 10-30% ethyl acetate-).
Hexane) and crystallized from ether-hexane to give methyl 2- (2-phenylethynyl) isonicotinate
3 (11.25 g, 43%) was obtained.

¹ H NMR (270 MHz, CDC
l ₃ ): 8.77 (br d, J = 5 Hz, 1H);
08 (m, 1H), 7.78 (dd, J = 5.2 Hz, 1
H), 7.62 (m, 2H), 7.38 (m, 3H),
3.98 (s, 3H).

[0057] (N- ethoxycarbonylmethyl-2-phenethyl-piperidin) -4-carboxylate, 4 3 isonicotinate (12.75 g, 53.8 mmol)
Was dissolved in acetic acid (18 ml), and Pt was added in an autoclave.
It was catalytically reduced with O ₂ (459 mg) at 50 kg / cm ² for 15 hours. The catalyst was removed by passing through Celite and washed with toluene. The filtrate was concentrated to give a cis / trans mixture of piperidine isomers (16.36 g,
5: 1).

This crude product and ethyl bromoacetate (10.
8 g, 64.7 mmol) were dissolved in toluene (150 ml), and K ₂ CO ₃ (15 g, 109 mmol) was added to the resulting solution.
l) was suspended. The mixture was heated at reflux for 5 hours and NH ₄ C
The reaction was stopped by the addition of 1 aqueous solution. The resulting mixture was extracted with ethyl acetate, washed with brine, Na ₂ SO ₄
And dried. Evaporation of the solvent gave a mixture of 4 cis / trans isomers (18.91 g).

¹ H NMR (270 MHz, CDC
l ₃ ), 4 -cis (low polarity, major) isomer: 7.3
1-7.16 (m, 5H), 4.14 (quart, J
= 7 Hz, 2H), 3.69 (s, 3H), 3.47
(D, J = 17 Hz, 1H), 3.39 (d, J = 17H
z, 1H), 3.00 (m, 1H), 2.77-2.5
3 (m, 4H), 2.38 (tt, J = 12, 4 Hz, 1
H), 2.03 (m, 1H), 1.96-1.64.
(M, 3H), 1.52 (quart, J = 12 Hz, 2
H), 1.25 (t, J = 7 Hz, 3H): 4 -trans (high polarity, minor) isomer: 3.36 (d, J = 17)
Hz, 1H), 3.29 (d, J = 17 Hz, 1H).

6-phenethylquinuclidin-3-one,
5, a mixture of 6 potassium t- butoxide and toluene (50ml) in which was heated to reflux, was added the crude mixture of 4 dissolved in toluene (100ml) in portions. The addition took 3 hours, then the resulting mixture was heated for another hour.
The reaction was quenched with 6N HCl and the solvent was evaporated off.
12N HCl (40 ml) was added to the residue and the mixture was
Heated to 20 ° C. overnight. The reaction mixture was concentrated to remove undesired components, which were filtered off. The filtrate was basified with NaOH and NaHCO ₃ until pH 8.5 and extracted with ethyl acetate. The extract was washed with brine and dried over Na ₂ SO _4. Evaporation of the solvent gave a diastereomeric mixture of 5 and 6 (8.36).
g). By ¹ H NMR analysis of this sample, 5 (α-
The presence of a 2: 1 mixture of phenethyl; high polarity) and 6 (β-isomer; low polarity) was confirmed. The mixture of 5 and 6 was chromatographed (silica gel, 50-70% ethyl acetate-hexane) to give the 5 rich fraction (0.68
g, 8: 1), a portion rich in 6 (0.58 g, 1: 1)
0) and an inseparable part (5.24 g).

¹ H NMR (270 MHz, CDC
_{l 3), 5: 7.32-7.17 (} m, 5H), 3.4
7 (d, J = 19 Hz, 1H), 3.11 (d, J = 19
Hz, 1H), 3.05-2.80 (m, 3H), 2.6.
9 (m, 2H), 2.42 (m, 1H), 2.18
(M, 1H), 1.96 (m, 2H), 1.89-1.
49 (m, 3H).

[0062] ^{_{13 C NMR (CDCl 3),}} 5: 21
9.0, 141.4, 127.86, 127.93, 1
25.3, 56.1, 53.7, 48.6, 40.2,
36.2, 32.0, 31.9, 24.6.

¹ H NMR (270 MHz, CDC
l ₃ ), 6 : 7.32-7.14 (m, 5H), 3.3
8 (d, J = 18 Hz, 1H), 3.23 (d, J = 18
Hz, 1H), 2.86-2.65 (m, 4H), 2.4
0 (m, 1H), 2.17 (m, 1H), 2.05-
1.76 (m, 4H), 1.54 (m, 1H).

[0064] ^{_{13 C NMR (CDCl 3),}} 6: 21
9.1, 141.4, 127.8, 125.3, 63.
8, 54.8, 40.1, 39.4, 36.2, 32.
5,32.4,25.1.

(2R ^* , 4R ^* , 6R ^* )-2-diphenylmethyl-6-phenethylquinuclidin-3-one,
7 Compound 5 (577 mg, 2.52 mmol), benzaldehyde (328 mg, 3.09 mmol) and NaOH (7.6
mg, 0.19 mmol) was dissolved in ethanol (8 ml), and the resulting solution was heated to reflux for 1 day. After evaporating off the solvents, the residue was diluted with ether -NH ₄ Cl aqueous solution.
The organic layer was washed with brine and dried over Na ₂ SO _4.
After evaporating the solvent, the residual oil was purified by chromatography (silica gel, 5-20% ethyl acetate / hexane) to give the 2-benzylidene compound of 5 (738 mg, 9).
2%).

CuBr dimethyl sulfide (27 m
g, 0.13 mmol) in a cold suspension of toluene (6 ml) (-6
Phenylmagnesium bromide (3.0 M in ether, 1.25 ml). To this reagent was added the 2-benzylidene compound (738 mg, 2.33 mmol),
Chlorotrimethylsilane (0.71 ml, 5.6 mmol),
A mixture of HMPA (0.98 ml, 5.6 mmol) and toluene (6 ml) was added while keeping the internal temperature below -60 <0> C. After 1 hour, the reaction mixture was gradually warmed to 0 ° C. The reaction was quenched at −60 ° C. with acetic acid (0.43 ml), to which ether and water were added. The pH of the solution was adjusted to 4 and the organic layer was washed with brine, Na ₂ SO ₄
And dried. The solvent was evaporated off and the crude product was purified by chromatography (silica gel, 13-50%, ethyl acetate-hexane) to give 7 (357 mg, 39%).

¹ H NMR (270 MHz, CDC
_{l 3): 7.42-7.10 (m,} 15H), 4.44
(D, J = 9.2 Hz, 1H), 4.18 (d, J = 9.
2Hz, 1H), 2.95-2.78 (m, 2H), 2.
69-2.47 (m, 3H), 2.39 (m, 1H),
2.15-0.52 (m, 6H).

¹³ C NMR (CDCl ₃ ): 220.
1, 143.1, 142.6, 141.7, 128.
3,128.2,128.14,128.07,12
6.1, 125.6, 65.2, 56.1, 50.0,
44.0, 41.9, 35.6, 32.3, 31.6,
27.1.

(2R ^* , 3R ^* , 4R ^* , 6R ^* )-2
-Diphenylmethyl-3- (2-methoxybenzyl) amino-6-phenethyl-1-azabicyclo [2.2.
2] Octane, 8 Compound 7 (357 mg, 0.904 mmol), 2-methoxybenzylamine (189 mg, 1.38 mmol) and camphorsulfonic acid (2.0 mg) were dissolved in toluene (30 ml), and the resulting mixture was dissolved. And heated under reflux for 3 hours under dehydration conditions using MS 4A.

After replacing the solvent with tetrahydrofuran, 9-BBN (0.5M in tetrahydrofuran, 5.
4 ml) was added and the resulting mixture was stirred at room temperature for 4 days. After evaporation of the solvent, the residue was brought to pH 13 with base, extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and concentrated. The crude product is subjected to column chromatography (silica gel, methanol-CH ₂ Cl ₂ ), preparative T
LC (silica gel, 10% methanol-CH ₂ Cl ₂ )
And purified by a combination of crystallization from methanol to give pure compound 8 (109 mg, 23%).

(2R ^* , 3R ^* , 4R ^* , 6S ^* )-and (2R ^* , 3R ^* , 4S ^* , 6R ^* )-2-diphenylmethyl-3- (2-methoxybenzyl) amino-6
- phenethyl-1-azabicyclo [2.2.2] octane, in the same manner as in the method for producing the 10 and 11 5 to 8, the compound of 6 9
To a mixture of 10 and 11 .

¹ H NMR (270 MHz, CDC
l ₃ ), 9- exo (low polarity) isomer: 4.44 (d,
J = 9.2 Hz, 1H), 3.83 (d, J = 9.2 Hz,
1H); 9- endo (highly polar) isomer: 4.52
(D, J = 7.5 Hz, 1H), 4.04 (d, J = 7.
5Hz, 1H).

¹³ C NMR (CDCl ₃ ), 9- ex
o: 219.9, 74.2, 57.3, 50.8, 4
1.8, 35.7, 34.3, 33.4, 32.7, 2
6.0; 9- endo: 220.6, 72.6, 50.
3,49.2,41.6,41.4,35.5,32.
3,24.8.

Compound name of Example 1 : (2R ^* , 3R ^* , 4R ^* , 6R ^* )-2-diphenylmethyl-3- (2-methoxybenzyl) amino-
6-phenethyl-1-azabicyclo [2.2.2] octane structural formula:

[0075]

Embedded image

Mp: 107.1-107.9 ° C. IR (nujol) cm ⁻¹ : 1493,1243.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 7.35-6.95 (m, 16H), 6.78-
6.67 (m, 2H), 6.58 (dd, J = 7.3,
1.5 Hz, 1 H), 4.52 (d, J = 12 Hz, 1
H), 3.63 (dd, J = 12, 8 Hz, 1H);
58 (d, J = 13 Hz, 1H), 3.53 (s, 3
H), 3.38 (m, 1H), 3.27 (d, J = 13
Hz, 1H), 2.81 (dd, J = 8, 4.4 Hz, 1
H), 2.59-2.47 (m, 2H), 2.06
(M, 1H), 1.96 (m, 2H), 1.85 (m,
1H), 1.74 (m, 1H), 1.62-1.37.
(M, 2H), 1.21 (m, 1H), 0.99 (m,
1H).

Compound name of Example 2 : (2R ^* , 3R ^* , 4R ^* , 6S ^* )-2-diphenylmethyl-3- (2-methoxybenzyl) amino-
6-phenethyl-1-azabicyclo [2.2.2] octane structural formula:

[0079]

Embedded image

Mp: 110.0-114.7 ° C. IR (nujol, cm ⁻¹ ): 1599, 1587, 12
32.

¹ H NMR (270 MHz, CDC
_{l 3): 7.35-7.06 (m,} 14H), 6.77
−6.67 (m, 4H), 6.59 (dd, J = 7.
4, 1.6 Hz, 1H), 4.61 (d, J = 12 Hz, 1
H), 3.59 (d, J = 13 Hz, 1H), 3.53
(S, 3H), 3.42 (m, 1H), 3.27 (d,
J = 13 Hz, 1H), 3.14 (m, 1H), 2.86
(Dd, J = 8.4 Hz, 1H), 2.68 (m, 1
H), 2.50 (m, 1H), 2.42-2.20
(M, 2H), 2.04 (m, 1H), 1.88 (m,
2H), 1.63-1.42 (m, 2H), 1.25-
1.09 (m, 2H).

Compound name of Example 3 : (2R ^* , 3R ^* , 4S ^* , 6R ^* )-3- (2
-Methoxybenzyl) amino-2-diphenylmethyl-
6-phenethyl-1-azabicyclo [2.2.2] octane structural formula:

[0083]

Embedded image

Mp: 122.4-125.3 ° C. IR (nujol) cm ⁻¹ : 1494, 1243, 105
2.

¹ NMR (270 MHz, CDCl ₃ ) δ:
7.37-7.00 (m, 16H), 6.77 (t, J
= 7.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1
H), 6.63 (dd, J = 7.4, 1.5 Hz, 1
H), 4.49 (d, J = 12 Hz, 1H), 3.69
(Dd, J = 12, 7.6 Hz, 1H), 3.59 (d,
J = 14 Hz, 1H), 3.55 (s, 3H), 3.32
(D, J = 14 Hz, 1H), 3.32-3.26 (m,
1H), 2.91-2.80 (m, 2H), 2.48
(M, 1H), 2.33 (t, J = 8.4 Hz, 2H),
2.07 (m, 2H), 1.60-1.41 (m, 4
H), 0.82 (m, 1H).

Synthetic drawing of Example 4

[0087]

Embedded image

The compound of Example 4 is (2R ^* , 4R ^* ,
6R ^* )-2-Diphenylmethyl-6-phenethylquinuclidin-3-one and 2,5-dimethoxybenzylamine were obtained by reacting in the same manner as in Example 1.

Compound name of Example 4 : (2R ^* , 3R ^* , 4R ^* , 6R ^* )-3-
(2,5-dimethoxybenzyl) amino-2-diphenylmethyl-6-phenethyl-1-azabicyclo [2.
2.2] Octane Structural formula:

[0090]

Embedded image

Mp: 123.5-124.8 ° C. IR (nujol) cm ⁻¹ : 1499, 1492, 122
6.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 7.35-6.95 (m, 15H), 6.67 (d
d, J = 9, 3 Hz, 1H), 6.60 (d, J = 9 Hz,
1H) 6.37 (d, J = 3 Hz, 1H), 4.52
(D, J = 13 Hz, 1H), 3.73 (s, 3H),
3.63 (m, 1H), 3.53 (d, J = 13 Hz, 1
H), 3.49 (s, 3H), 3.37 (m, 1H),
3.18 (d, J = 13 Hz, 1H), 2.84 (dd,
J = 7.5, 4.3 Hz, 1H), 2.60-2.44
(M, 2H), 2.10-1.68 (m, 5H), 1.
50 (m, 2H), 1.20 (m, 1H), 1.01
(M, 1H).

Synthetic diagram of Examples 5, 6, 7 and 8

[0094]

Embedded image

Cis-3- (diethylcarbamoyl) -1
Methyl-(methoxycarbonylmethyl) piperidine-4-carboxylate, 12 cis-3- (diethylcarbamoyl) -1- (methoxycarbonylmethyl) piperidine-4-carboxylate, 12 was prepared according to Tetrahedron Lett. 19
89, 30, 5795-5798; Che
m. Soc. , PERKIN TRANS. 1. , 19
91, 409-420.

(3R ^* , 4R ^* )-N, N-diethyl-
5-oxo-1-azabicyclo [2.2.2] octane-3-carboxamide, 13 12 (159g, 0.503mol) in toluene (700 meters
l) The solution was mixed with potassium t-butoxide (169 g, 1.
51 mol) in a toluene (1.9 l) solution under nitrogen conditions.
It was added dropwise at 10 ° C. over 2.5 hours. The mixture was heated at reflux for 1 hour and cooled to room temperature. Water was added and both layers were heated at reflux for 2 hours. The organic layer was separated and the aqueous layer was neutralized and extracted with ethyl acetate for 15 hours using a continuous extraction device. The combined extracts were dried over MgSO _4, and concentrated. Recrystallization from ethanol gave 13 as colorless crystals (34.
6g, 31%). X-ray, ¹³ C and DEPT NMR
Determined the three-dimensional structure.

IR (KBr) cm ^-1 : 2975, 291
5,2875,1726,1629,1483,146
2,1454,1434,1410,1382,136
8,1296,1253,1141,1081,105
2.

¹ H NMR (CDCl ₃ ) δ: 3.6
(D, J = 8 Hz, 1H), 3.5-3.1 (m, 8
H), 3.0-2.9 (m, 2H), 2.5 (dd, J
= 6, 3 Hz, 1H), 2.2 (dd, J = 8, 3 Hz, 2
H), 1.2 (t, J = 7 Hz, 3H), 1.1 (t, J
= 8 Hz, 3H).

¹³ C NMR (CDCl ₃ ) δ: 215.
4,173.2,62.5,51.5,45.9,4
2.3, 42.0, 41.3, 40.5, 25.9, 1
5.0, 12.9.

(3R ^* , 4R ^* )-N, N-diethyl-
5-oxo-6-benzylidene-1-azabicyclo [2.2.2] octane-3-carboxamide, 14 13 (34.6g, 154mmol) , benzaldehyde (17.4 g, 164 mmol) and NaOH (6.5
g, 164 mmol) in ethanol (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystals were collected by filtration, washed with cold ethanol and dried in vacuo to give 14 (38.4 g, 128 mmol). The filtrate was concentrated under reduced pressure to give the second crystal (3.3 g, 11 mmol)
I got (Total 41.7 g, 139 mmol, 90%).

IR (KBr) cm ^-1 : 2960, 293
0,2875,1706,1640,1453,144
5,1427,1315,1260,1136,109
4,694.

¹ H NMR (CDCl ₃ ) δ: 8.0
(Dd, J = 8.6 Hz, 2H), 7.3 (m, 3H),
7.1 (s, 1H), 3.4-3.0 (m, 6H),
2.7 (dd, J = 5.0, 3.0 Hz, 2H), 1.2
(T, J = 7 Hz, 3H), 1.1 (t, J = 8 Hz, 3
H).

¹³ C NMR (CDCl ₃ ) δ: 202.
5, 172.9, 143.8, 134.1, 132.
0, 129.3, 128.2, 125.2, 52.3
47.7, 46.4, 43.5, 42.0, 41.9,
40.5, 25.9, 15.1, 13.1.

(3R ^* , 4R ^* , 6R ^* )-N, N-diethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide, 15 and (3R ^* , 4R ^* , 6S ^* )-N, N-
Diethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide, flamed a 1 liter 4-neck flask equipped with a 16 mechanical stirrer and thermometer. Dry and pass a stream of nitrogen. Cu
Br.CH ₃ SCH ₃ (3.1 g, 15 mmol) was placed in the flask and dried tetrahydrofuran (400 ml)
And cool to -50 ° C. To this suspension was added 3M (as ether solution) phenylmagnesium bromide (5
0 ml, 150 mmol) was added dropwise over 20 minutes and stirred at -60 ° C for 30 minutes. 14 (45 g, 15
(0 mmol) in 400 ml of dry tetrahydrofuran (slightly heated to dissolve) was added dropwise over 1 hour under a nitrogen atmosphere. After the addition, the reaction mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was added to a saturated aqueous solution of NH ₄ Cl (100
ml) and the organic layer was washed with a saturated aqueous solution of NH ₄ Cl until the blue color disappeared. The blue aqueous layer is ethyl acetate (100
ml × 2). The combined organic layers were washed with brine, dried over MgSO _4, and concentrated. The crude product solid is subjected to silica gel chromatography (hexane: ethyl acetate =
Purified with 1: 1 to 1: 2) to give the 1,2 adduct (1.
2 g, 3.1 mmol, 2%) and 1,4 adduct 15, 1
6 (54 g, 138 mmol, 92%) were obtained. In the product
The ratio of 15/16 was changed by quenching temperature.

¹ H NMR (CDCl ₃ ) δ; 15 :
7.43 (d, J = 7 Hz, 2H), 7.3-7.1
(M, 8H), 4.7 (d, J = 7 Hz, 1H), 4.4
(D, J = 7 Hz, 1H), 3.4-3.1 (m, 7
H), 2.5-2.4 (m, 3H), 1.9-1.8.
(M, 2H), 1.2 (t, J = 3 Hz, 3H), 1.1
(T, J = 7.3 Hz, 3H). 16 : 7.4-7.2
(M, 10H), 4.8 (d, J = 11 Hz, 1H),
3.96 (d, J = 11 Hz, 1H), 3.6-3.5
(M, 1H), 3.4-2.8 (m, 8H), 2.5-
2.4 (m, 1H), 1.9-1.8 (m, 2H),
1.2-1.1 (m, 6H).

(3R ^* , 4R ^* , 5S ^* , 6S ^* )-
N, N-diethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide, 17 4 CH ₂ titanium chloride (1M Cl ₂ 3.99 ml of solution,
The 3.99 mmol), 2,5-dimethoxybenzyl amine (1.31g, 7.84mmol), was dissolved in triethylamine (2.14 ml, 15.4 mmol) and 15 and 16 the mixture dried of CH ₂ Cl ₂ (20ml) To the solution
C. under a nitrogen atmosphere and stirred at room temperature for 4 days. The reaction mixture was poured into a 1N aqueous solution of NaOH (10 ml) at 5 ° C. and extracted with CH ₂ Cl ₂ . After separating the organic layer,
The aqueous layer was extracted with CH ₂ Cl _2. The combined organic layers are
Dried over SO ₄ and concentrated to give 4.54 g of crude imine. The crude imine was used in the next step without further purification. A solution of the crude imine in tetrahydrofuran (15 ml) was added at 10 ° C. to a suspension of NaBH (OAc) ₃ (4.9 g, 23 ml) in a mixed solution of acetic acid (13 ml) and tetrahydrofuran (10 ml). . After stirring at room temperature for 1 hour, the reaction mixture was added to a 1N aqueous NaOH solution (30 ml) for 5 hours.
℃ poured in, and extracted with _{CH 2 Cl 2 (10ml × 3} ). The combined organic extracts were washed with brine, dried over MgSO _4, and concentrated. Silica gel chromatography of the crude oil (CH ₂ Cl ₂ : ethyl acetate = 2: 1, CH ₂ Cl
₂ : methanol = 100: 0.5 to 100: 3) to give 17 (1.44 g, 27 mmol, 35%).

Mp: 143.7 to 145.6 ° C. (3R ^* , 4R ^* , 5S ^* , 6S ^* )-N, N-diethyl-5- (2-methoxybenzyl) amino-6-diphenylmethyl-1- Azabicyclo [2.2.2] octane-3-carboxamide, 18 Compound 18 was prepared according to the method of compound 17 . The configuration of compound 18 was determined by ¹ H NMR and H-
H COSY determined by NMR.

Mp: 121.2-122.6 ° C. (3R ^* , 4S ^* , 5R ^* , 6R ^* )-N, N-diethyl-5- (2,5-dimethoxybenzyl) amino-6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide, 19 17 (506mg, 0.93mmol) and heated under reflux for 3 hours a mixture of 20% sodium methoxide / methanol (140 ml) under a nitrogen atmosphere did. After cooling the reaction mixture, the resulting white suspension was poured onto ice chips and CH ₂ Cl ₂
(80 ml × 3). The combined organic layers were washed with brine, dried over MgSO _4, and concentrated. The obtained crude solid is subjected to silica gel chromatography (CH ₂ C
Purification with l ₂ : methanol = 10: 1) gave 19 (0.46 g, 0.8 mmol, 92%). mp: 167.8-168.2 ° C (2R ^* , 3R ^* , 4S ^* , 5S ^* )-5- (N, N-
Drying of diethylaminomethyl) -3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [2.2.2] octane monomethanesulfonate, 20 19 (300 mg, 0.55 mmol) A solution of tetrahydrofuran (2 ml) was added to LiAlH ₄ (105 mg, 2.7).
5 mmol) in dry tetrahydrofuran (5 ml) suspension.
C. and stirred at room temperature for 1 hour. Na ₂ was added to the reaction mixture.
SO ₄ · 10H ₂ O and (2 g) was added and stirred for 15 hours at room temperature. The suspension was filtered and the solid was washed with dry tetrahydrofuran. The filtrate was concentrated under reduced pressure. The oil obtained was dissolved in 2 ml of acetone and CH ₃ SO ₃ H (159 m
g, 1.65 mmol) with the crude oil in acetone (2 ml)
Added to the solution. The resulting precipitate was collected by filtration and dried in vacuo to give 20 (254 mg, 0.31 mmol, 57%).

Mp: 239.7-242.2 ° C. Decomposition.

Compound name of Example 5 : (3R ^* , 4R ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-3-carboxamide Structural formula:

[0111]

Embedded image

Mp: 143.7 to 145.6 ° C. IR: ν (KBr): 2965, 2935, 2885,
1621, 1494, 1483, 1475, 1465,
^{1453,1431,1214cm -1 1 H NMR: δ (} CDCl 3): 7.3-6.9
(M, 10H), 6.6 (s, 2H), 6.4 (s, 1
H), 4.65 (d, J = 11 Hz, 1H), 3.9-
3.05 (m, 8H), 3.7 (s, 3H), 3.6
(S, 3H), 2.9-2.6 (m, 4H), 2.5-
2.35 (m, 2H), 1.75-1.45 (m, 2
H), 1.2 (t, J = 7 Hz, 3H), 1.1 (t, J
= 7 Hz, 3H).

Compound name of Example 6 : (3R ^* , 4R ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (2-methoxybenzyl) amino-6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide Structural formula:

[0114]

Embedded image

Mp: 121.2-122.6 ° C. IR: ν (KBr): 3325, 2980, 2940,
2890, 1616, 1491, 1460, 1452,
1440,1431,1269,1244,1103
^{1046,1032cm -1 1 H NMR: δ (} CDCl 3): 7.3-7.0
(M, 10H), 6.7-6.6 (m, 2H), 6.3
(D, J = 7 Hz, 1H), 4.6 (d, J = 12 Hz, 1H)
H), 3.9-3.1 (m, 6H), 3.6 (s, 3
H), 2.8-2.65 (m, 4H), 2.5-2.3.
(M, 2H), 1.8-1.4 (m, 2H), 1.2
(T, J = 7 Hz, 3H), 1.1 (t, J = 7 Hz, 3
H).

Compound name of Example 7 : (3R ^* , 4S ^* , 5R ^* , 6R ^* )-N, N-
Diethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-3-carboxamide Structural formula:

[0117]

Embedded image

Mp: 167.8-168.2 ° C. IR: ν (KBr): 2980, 2940, 2800,
1632, 1503, 1463, 1451, 1431,
^{1268,1048cm -1 1 H NMR: δ (} CDCl 3): δ7.33-7.0
5 (m, 10H), 6.67-6.24 (m, 2H),
6.26 (d, J = 3 Hz, 1H), 4.38 (d, J =
12Hz, 1H), 3.80-3.01 (m, 11H),
3.03 (dd, J = 8, 4 Hz, 1H), 3.73
(S, 3H), 3.55 (s, 3H), 2.69-2.
60 (m, 1H), 2.23 (brs, 1H), 1.
90-1.80 (m, 1H), 1.40-1.28
(M, 1H), 1.28-1.08 (m, 6H).

Compound name of Example 8 : (2R ^* , 3R ^* , 4S ^* , 5S ^* )-5
(N, N-diethylaminoethyl) -3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1
-Azabicyclo [2.2.2] octane monomethanesulfonate Structural formula:

[0120]

Embedded image

Mp: 239.7 to 242.2 ° C. decomposition IR: ν (KBr): 3455, 2980, 2950,
1504, 1466, 1227, 1203, 1196,
^{1059,1051,1044cm -1 1 H NMR: δ (} CDCl 3) ( free): δ7.3
3-7.04 (m, 11H), 6.68 (dd, J =
9,3 Hz, 1H), 6.61 (d, J = 9 Hz, 1H),
4.45 (br, d, J = 12 Hz, 1H), 3.80 −
3.68 (m, 11H), 3.74 (s, 3H),
64 (br d, J = 13 Hz, 1H), 3.47-3.4
3 (m, 1H), 3.47 (s, 3H), 3.27 (b
rd, J = 13 Hz, 1H), 3.80 (dd, J = 8,
4Hz, 1H), 2.86-2.53 (m, 6H), 2.
39 (br s, 1H), 2.23 (br d, J = 1
4Hz, 1H), 1.92-1.81 (m, 1H), 1.
51-1.34 (m, 1H), 1.26-1.10.
(M, 6H).

Synthetic drawing of Example 9 and Example 10

[0123]

Embedded image

(3R ^* , 4R ^* )-N, N-diethyl-
6-diphenylmethyl-5,5-ethylenedioxy-1
-Azabicyclo [2.2.2] octanefoafocarboxamide, 21 (3R ^* , 4R ^* )-N, N-diethyl-6-diphenylmethyl-5-oxo-1-azabicyclo [2.2.
2] Octane-3-carboxamide (10 g, 26 mmol
l) 1,1,2-bis (trimethylsiloxy) ethane (6
g, 29 mmol), trimethylsilyl chloride (20 ML)
And a mixture of ethylene glycol (50 ml)
Heat to 20 ° C. for 20 hours then reflux for 3 hours. After distilling off the by-products (93 ° C./atmospheric pressure), the mixture is
Ph ₂ cold aqueous solution (250 ml) of aHCO ₃ C H C
H), 4.33 and 4.28 (pair of d, J = 12H
z; Ph ₂ of the other isomer C H CH and Ph ₂ CHC
H ) MS (DI-EI); M / z = 434 (M ⁺ ) (3R ^* , 4S ^* )-N, N-diethyl-6-diphenylmethyl-5,5-ethylenedioxy-1-azabicyclo [2 .2.2] octane-3-carboxamide, 22 21 (9.8g, 22mmol) of sodium methoxide (28% in methanol; 400 g) a suspension was heated to reflux for 9 hours. Ice solution (300m
l) was poured on top, and extracted 3 times with CH ₂ Cl ₂ (150ml). The combined extracts were dried over Na ₂ SO _4, and concentrated. The crude product was purified by recrystallization from ethanol, 22
(1: 4 mixture for position 6; 8.4 g, 19
mmol, 87%).

¹ H NMR (CDCl ₃ ) δ4.40
(D, J = 12.1Hz; Ph 2 of one isomer C H C
H), 4.34 and 3.93 (pair of d, J = 12.
5 Hz; Ph ₂ of the other isomer C H CH and Ph ₂ CH
CH ) MS (DI-EI); M / z = 434 (M ^<+> ) (3R ^* , 4S ^* )-N, N-diethyl-6-diphenylmethyl-5-oxo-l-azabicyclo [2.2.
2] octane-3-carboxamide, 23 22 (6.5g, 15mmol) and aqueous 6N HCl (1
(00 ml) was heated to reflux for 10 hours. The resulting solution was neutralized with a solution of NaOH (24 g) in water (100 ml) and extracted four times with CH ₂ Cl ₂ (100 ml). The combined extracts were dried and concentrated Na ₂ SO _4. The crude product is purified by recrystallization from ethanol, 2
3 (1: 1 mixture for position 6; 4.0 g, 1
0 mmol, 68%).

[0126]¹H NMR (CDCl_Three) Δ 4.71
And 3.95 (pair of d, J = 5.7 Hz; one isomer)
Ph_TwoCHCH and Ph_TwoCHCH), 4.47
And 4.03 (a pair of d, J = 8.4 Hz; the other isomer)
Ph_TwoCHCH and Ph _TwoCHCH) (3R^*, 4S^*, 5S^*, 6S^*) -N, N-diethyl
Ru-5- (2,5-dimethoxybenzyl) amino-6
Diphenylmethyl-1-azabicyclo [2.2.2]
Butane-3-carboxamide,24 23 (3.9 g, 10 mmol), 2,5-dimethoxyben
Jilamine¹⁾(1.9 g, 11 mmol), and camphor
-Add sulfonic acid (120mg) to toluene (40ml)
The mixture was heated to reflux for 8 hours while removing water,
The solvent was removed with. Remove the residue with a small amount of tetrahydrofuran.
(Approximately 5 ml), and the solution was added to sodium triacetate.
Toxiborohydride (5.3 g, 25 mmol) in acetic acid (1
00 ml) solution at room temperature. The mixture is stirred at room temperature for 4 hours.
Stir and remove the solvent. Water (25 ml) was added and the mixture was
NaHCO_ThreeAnd extracted three times with ethyl acetate. Combination
The extracted extract is_TwoSO_FourAnd concentrated. Crude
The product is purified by recrystallization from ethyl acetate,24Get
(2.4 g, 4.4 mmol, 44%).

Note 1) Acta. Chem. Scan
d. , 25 . 2629 (1971) (2R ^* , 3R ^* , 4R ^* , 5R ^* )-5- (N, N-
Diethylaminomethyl) -3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [2.2.2] octane, 25 lithium aluminum hydride (80 mg, 2.1 mmol)
Is suspended in tetrahydrofuran (10 ml)
24 (220 mg, 0.41 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours and Na ₂ SO ₄ .10H ₂ O
(320 mg, 1 mmol) was added and then stirred for 10 minutes. After removing the precipitate, the solution was concentrated. The residue was dissolved in hexane (20 ml), filtered and concentrated to give 25 as a colorless oil (210 mg, 0.39 mmol, 95
%).

Compound name in Example 9 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-3-carboxamide Structural formula:

[0129]

Embedded image

Mp: 153.1 to 154.1 ° C. IR: ν (KBr): 1634, 1501, 1466,
1447, 1432, 1266, 1227 cm ^-1 NMR: δ (CDCl ₃ ): 7.03-7.37 (m,
10H), 6.68 (dd, J = 8.8, 2.5 Hz, 1
H), 6.62 (d, J = 8.8 Hz, 1H), 6.38
(D, J = 2.5 Hz, 1H), 4.51 (d, J = 1
2.1Hz, 1H), 3.73 (s, 3H), 3.49
(S, 3H), 3.05-3.77 (m, 9H), 2.
92 (dd, J = 8.1, 4.4 Hz, 1H), 2.54
-2.89 (m, 3H), 2.11 (br, 1H),
1.70-1.79 (m, 2H), 1.15 (t, J =
7.3 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3
H).

Compound name of Example 10 : (2R ^* , 3R ^* , 4R ^* , 5R ^* )-5-
(N, N-diethylaminomethyl) -3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1
-Azabicyclo [2.2.2] octane structural formula:

[0132]

Embedded image

Mp:-IR: ν (KBr): 3430, 2935, 1499,
1467, 1459, 1450, 1226, 1050,
702 cm ^-1 NMR: δ (CDCl ₃ ): 7.03-7.41 (m,
10H), 6.68 (dd, J = 8.8, 3.0 Hz, 1
H), 6.62 (d, J = 8.8 Hz, 1H), 6.43
(D, J = 2.8 Hz, 1H), 4.47 (d, J = 1
2.1 Hz, 1H), 3.74 (s, 3H), 3.68
(Dd, J = 12.7, 7.9 Hz, 1H), 3.58
(D, J = 12.2 Hz, 1H), 3.51 (s, 3
H), 3.23 (d, J = 13.2 Hz, 1H), 3.1
0-3.25 (m, 1H), 2.85-2.95 (m, 1H)
2H), 2.35-2.60 (m, 7H), 2.29
(Dd, J = 13.2, 2.5 Hz, 1H), 2.12
(Br, 1H), 1.70-1.90 (m, 2H),
1.26-1.43 (m, 1H), 1.01 (t, J =
7.1 Hz, 6H).

Synthetic diagram of Examples 11 and 12

[0135]

Embedded image

The compounds of Examples 11 and 12 were obtained in the same manner as in Example 1.

Compound name of Example 11 : (2R ^* , 3R ^* , 4S ^* , 6R ^* )-3-
(2,5-dimethoxybenzyl) amino-2-diphenylmethyl-6-phenethyl-1-azabicyclo [2.
2.2] Octane dimesylate Structural formula:

[0138]

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Mp: 228.4-232.3 ° C. IR (nujol) cm ⁻¹ : 1154, 1039.

¹ NMR (270 MHz, CDCl ₃ ) δ
(Free amine): 7.37-7.01 (m, 15H),
5.69 (dd, J = 8.9, 2.5 Hz, 1H);
63 (d, J = 8.9 Hz, 1H), 6.42 (d, J =
2.5 Hz, 1 H), 4.50 (d, J = 12.4 Hz, 1
H), 3.74 (s, 3H), 3.70 (dd, J = 1)
2.4, 7.9 Hz, 1H), 3.57-3.52 (m,
1H), 3.52 (s, 3H), 3.33-3.21.
(M, 1H), 3.23 (d, J = 13 Hz, 1H),
2.91-2.80 (m, 2H), 2.48 (m, 1
H), 2.32 (m, 2H), 2.12-1.97
(M, 2H), 1.59-1.30 (m, 4H), 0.
81 (m, 1H).

Compound name of Example 12 : (2R ^* , 3R ^* , 4R ^* , 6S ^* )-3-
(2,5-dimethoxybenzyl) amino-2-diphenylmethyl-6-phenethyl-1-azabicyclo [2.
2.2] Octane dimesylate Structural formula:

[0142]

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Mp: 207.5-212.0 ° C. IR (nujol) cm ^-1 : 1502, 1163, 103
9.

¹ H NMR (270 MHz, CDCl ₃ )
δ (free form): 7.34-7.06 (m, 13H),
6.72-6.53 (m, 4H), 6.37 (d, J =
2.8 Hz, 1H), 4.61 (d, J = 11.8 Hz, 1
H), 3.73 (s, 3H), 3.53 (dd, J = 1
3.2 Hz, 1H), 3.49 (s, 3H), 3.43
(M, 1H), 3.20 (d, J = 13.2 Hz, 1
H), 3.13 (m, 1H), 2.89 (m, 1H),
2.67 (m, 1H), 2.50-2.26 (m, 3
H), 2.03 (br s, 1H), 1.88 (m, 2
H), 1.65-1.43 (m, 2H), 1.20-
1.05 (m, 2H).

Synthetic drawing of Example 13 and Example 14

[0146]

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4-methoxycarbonylpyridine-2-carboxylic acid 26 Compound 26 was prepared according to the method described in J. Am. DE PHARMACIE DE
BELGIQUE, 24, 3-21 (1969).

2-dimethylcarbamoylpyridine-4-
Methyl carboxylate 28 Compound 26 (73 g, 0.4 mol) and thionyl chloride (88
ml, 1.2 mol) in toluene (200 ml) was heated under reflux for 3 hours. After removing excess thionyl chloride at normal pressure, toluene was removed under reduced pressure. The resulting light green acid chloride 27 was used in the next step without further purification. Dimethylamine hydrochloride (98.6 g, 1.2 mol) and triethylamine (1.3 mol) in methylene chloride (2
(00 ml), a solution of 27 in methylene chloride (100 ml) was added dropwise at 0 ° C. over 10 minutes. The mixture was stirred at room temperature for 1 hour. After water (200 ml) was added to the reaction solution, the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N-NaOH, and further washed with brine, dried over MgSO _4, and concentrated. The obtained crude solid was purified by silica gel chromatography (eluent: ethyl acetate) to give Compound 28 (47 g, 226 mmol, 56
%).

¹ H NMR (CDCl ₃ ) δ: 8.74
(Dd, J = 5, 1 Hz, 1H), 8.19 (m, 1
H), 7.90 (dd, J = 5.2 Hz, 1H), 3.9
7 (s, 3H), 3.16 (s, 3H), 3.08
(S, 3H).

Methyl 2-dimethylcarbamoyl-1- (methoxycarbonylmethyl) piperidine-4-carboxylate 29 Compound 28 (55.4 g, 0.27 mol), concentrated hydrochloric acid (16
ml) and methanol (62 ml) were hydrogenated with platinum dioxide (1 g) at 8 kg / cm ² for 24 hours. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained oil was used in the next step without further purification. Hydrochloride of crude intermediate compound and methyl bromoacetate (61
g, 0.4 mol) and potassium carbonate (73.5 g, 0.53
mol) in toluene (200 ml) was heated at 70 ° C. for 3 hours. After cooling, water (200 ml) was added to the reaction mixture,
Further, it was extracted with ethyl acetate (200 ml × 2). The combined organic layers were dried over MgSO ₄ and concentrated. The obtained crude oil was purified by silica gel chromatography (eluent: ethyl acetate) to give Compound 29 (69.8 g,
0.26 mol, 97%).

IR (neat) cm ^-1 : 3455,295
5,1735,1726,1648,1636,149
8,1435,1249,1205,1198,116
9, 1138, 1094.

(2R ^* , 4S ^* )-2-benzylidene-
6-dimethylcarbamoyl-3-oxo-1-azabicyclo [2.2.2] octane 32 and (2R ^* , 4R
^* )-2-benzylidene-6-dimethylcarbamoyl-
3-oxo-1-azabicyclo [2.2.2] octane
33 Compound 29 (30 g, 111 mmol) in toluene (150
ml) solution with potassium t-butoxide (37.4 g, 33
3 mmol) in toluene (400 ml) under nitrogen conditions.
It was added dropwise at 0 ° C. over 30 minutes. The mixture was heated at reflux for 30 minutes and then cooled to room temperature. After removal of the solvent, water (200 ml) was added to the residue. The pH of the resulting mixture was adjusted to pH = 7 with concentrated hydrochloric acid. The brown residue obtained by concentration was purified by silica gel chromatography (ethyl acetate: methanol = 10: 1 as eluent) to obtain a brown oil (11.9 g). A solution of the obtained crude oil and brine (1 ml) in DMSO (10 ml) was added to 1
Heated at 00 ° C. for 1.5 hours. Residue obtained by concentration,
Benzaldehyde (11.8 g, 111 mmol) and N
aOH (4.44 g, 111 mmol) in ethanol (30
ml) The solution was heated to reflux for 1.5 hours. After adding water to the mixture obtained by concentration, methylene chloride (50 ml × 3) was added.
Extracted. The combined organic layers were dried over MgSO _4.
The crude oil obtained by concentration was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1 as eluent) to give Compound 32 (7.56 g, 26.9 mmol, 2
4.2%) and compound 33 (200 mg, 0.7 mmol, 0.1%).
6%).

Physical Properties Data of Compound 32 ¹ H NMR (CDCl ₃ ) δ: 7.82-7.79
(M, 2H), 7.37-7.29 (m, 3H), 7.
11 (s, 1H), 3.91 (dd, J = 10, 6 Hz,
1H), 3.33-3.07 (m, 2H), 3.03.
(S, 3H), 2.96-2.81 (m, 1H), 2.
72-2.68 (m, 1H), 2.45 (s, 3H),
2.11-2.04 (m, 2H), 1.93-1.84
(M, 1H).

¹³ C NMR (CDCl ₃ ) δ: 204.
2,169.1,141.1,133.5,131.
4,129.2,127.8,56.8,47.8,3
9.6, 36.8, 35.3, 25.8, 25.4.

Physical Properties Data of Compound 33 ¹ H NMR (CDCl ₃ ) δ: 7.97-7.93
(M, 2H), 7.42-7.34 (m, 3H), 7.
08 (s, 1H), 3.83-3.76 (m, 1H),
3.31-3.20 (m, 1H), 3.02-2.90
(M, 2H), 3.02 (s, 3H), 2.97 (s,
3H), 2.73-2.69 (m, 1H), 2.21-
2.11 (m, 1H), 1.98-1.88 (m, 2
H).

¹³ C NMR (CDCl ₃ ) δ: 205.
3, 168.9, 143.7, 132.9, 131.
6,129.4,128.0,124.6,56.4,
42.4, 40.1, 37.3, 35.8, 25.8,
25.0.

(2R ^* , 4S ^* , 6S ^* )-N, N-dimethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide
34 Compound 34 is Compound 15 ((3R ^* , 4R ^* , 6R ^* )
-N, N-diethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide).

[0158] ^{IR (KBr): 1723,1644cm -1 1} H NMR (CDCl 3) δ: 7.29-7.07
(M, 10H), 4.29 (d, J = 10 Hz, 1H),
4.18 (d, J = 10 Hz, 1H), 3.59 (m, 1
H), 3.01-2.81 (m, 2H), 2.97.
(S, 3H), 2.66-2.46 (m, 2H), 2.
62 (s, 3H), 2.05-1.75 (m, 3H).

¹³ C NMR (CDCl ₃ ) δ: 218.
5, 169.9, 143.6, 142.8, 128.
21, 128.0, 127.8, 127.7, 126.
1,125.9,66.8,56.6,49.8,4
2.9, 41.1, 36.4, 36.1, 28.9, 2
4.2.

(2R^*, 4S^*, 5S^*, 6S^*)-
N, N-dimethyl-5- (2,5-dimethoxybenzyl
L) amino-6-diphenylmethyl-1-azabicyclo
[2.2.2] Octane-2-carboxamide35And
And (2R^*, 4S^*, 5R^*, 6R^*) -N, N-dimension
Tyl-5- (2,5-dimethoxybenzyl) amino-6
-Diphenylmethyl-1-azabicyclo [2.2.2]
Octane-2-carboxamide36 Compound34(2.22 g, 6.13 mmol), 2,5-di
Methoxybenzylamine (1.23 g, 7.36 mmol)
Of toluene and CSA (camphor sulfonic acid) (20 mg)
(50 ml) solution into Dean Stark
ark) Heated to reflux using a water separator for 24 hours. Dissolution
The medium was removed under reduced pressure. The obtained crude imine is further refined.
Used in the next step without preparation. Dry T of crude imine
The HF (20 ml) solution was added to NaBH (OAc)_Three(3.9
g, 18.4 mmol) and acetic acid (3 ml) in THF (20
ml) solution was added at 5 ° C. and stirred at room temperature for 15 hours.
After adjusting the pH to 10 with 1N-NaOH, ethyl acetate was added.
(20 ml × 3). Brine combined organic layers
After washing with MgSO_FourAnd dried. Obtained by concentrating
The crude oily substance was subjected to silica gel chromatography (ethyl acetate).
Hexane = 1: 1) to give a colorless oil.
The oil was recrystallized from methanol to give the compound35
(Colorless crystals, 2.21 g, 4.3 mmol, 70%) were obtained.
Was. Also, compounds36(Colorless crystal, 224mg, 0.5mm
ol, 8%) was obtained from another fraction of a colorless oil and recrystallized.
Purified. Compound35And compounds36Standing
The body configuration is H—H COSY, C—H COSY, DE
PT and¹³C Determined by NMR.

Compound name of Example 13 : (2R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-2-carboxamide Structural formula:

[0162]

Embedded image

Mp: 171.3 to 174.5 ° C. IR (KBr) cm ⁻¹ : 2490, 2875, 2835,
2800, 1644, 1504, 1463, 1450,
1307,1225,1049,825,705.

NMR (270 MHz, CDCl ₃ ) δ:
7.29-7.00 (m, 10H), 6.67 (dd,
J = 9, 3 Hz, 1H), 6.60 (d, J = 9 Hz, 1
H), 6.37 (d, J = 3 Hz, 1H), 4.38
(D, J = 12 Hz, 1H), 3.73 (s, 3H),
3.55-3.43 (m, 2H), 3.47 (s, 3
H), 3.36-3.20 (m, 3H), 2.96 (d
d, J = 8.4 Hz, 1H), 2.72 (s, 3H),
2.59-2.51 (m, 1H), 2.43-2.35
(M, 1H), 2.22 (brs, 1H), 2.15
(S, 3H), 1.97-1.89 (m, 1H), 1.
59-1.49 (m, 1H), 1.29-1.81
(M, 1H).

Compound name of Example 14 : (2R ^* , 4S ^* , 5R ^* , 6R ^* )-N, N-
Dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-2-carboxamide Structural formula:

[0166]

Embedded image

Mp: 176.2-178.9 ° C. IR (KBr) cm ⁻¹ : 2945, 2860, 2835,
1635, 1597, 1493, 1459, 1281,
1220, 1053, 1027, 704.

NMR (270 MHz, CDCl ₃ ) δ (free form): 7.35-6.97 (m, 10H), 6.70
−6.61 (m, 3H), 4.30 (d, J = 13 Hz,
1H), 3.86-3.67 (m, 1H), 3.76.
(S, 3H), 3.71 (s, 3H), 3.52 (d,
J = 14 Hz, 1H), 3.32 (dd, J = 11.5 H)
z, 1H), 3.25 (d, J = 14 Hz, 1H), 3.
05-2.98 (m, 1H), 2.79-2.61
(M, 3H), 2.75 (s, 3H), 2.15 (s,
3H), 2.14 (brs, 1H), 1.66-1.
50 (m, 2H), 1.25-1.11 (m, 3H).

Synthetic drawing of Examples 15, 16 and 17

[0170]

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(2R ^* , 4R ^* , 6S ^* )-N, N-dimethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide
37 and (2R ^* , 4R ^* , 6R ^* )-N, N-dimethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide 3
Mixture Compound 37 as a mixture of compounds 38 8, Compound 15 ((3
R ^* , 4R ^* , 6R ^* )-N, N-diethyl-5-oxo-6-diphenylmethyl-1-azabicyclo [2.
2.2] Octane-3-carboxamide).

IR (KBr): 2935, 1733, 1
726, 1634, 1493, 1452 cm ^-1 (2R ^* , 4R ^* , 5R ^* , 6R ^* )-N, N-dimethyl-5- (2,5-dimethoxybenzyl) amino-6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide 39 and (2R ^* , 4R
^* , 5S ^* , 6S ^* )-N, N-dimethyl-5- (2,
5-Dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide 40 Compound 39 and Compound 40 were synthesized by the same method as Compound 35 and Compound 36. Was done. The yield of compound 39 was 22% and that of compound 40 was 7%. Compound 39 was isolated as the dihydrochloride salt.

The configuration of compound 39 and compound 40 was determined by H—H COSY, C—H COSY, DEPT and ¹³ C NMR.

Compound name of Example 15 : (2R ^* , 4R ^* , 5R ^* , 6R ^* )-N, N-
Dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-2-carboxamide dihydrochloride Structural formula:

[0175]

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Mp: 224.6-228.0 ° C. IR (KBr) cm ⁻¹ : 3435, 3175, 2960,
2925,1663,1575,1510,1235
1040,715.

NMR (270 MHz, CDCl ₃ ) δ (free form): 7.35-6.97 (m, 10H), 6.67
(Dd, J = 9, 3 Hz, 1H), 6.60 (d, J = 9
Hz, 1H), 6.39 (d, J = 3 Hz, 1H), 4.5
2 (d, J = 12 Hz, 1H), 3.72 (s, 3H),
3.57-3.50 (m, 2H), 3.46 (s, 3
H), 3.35 (br d, J = 9 Hz, 1H), 3.2.
4 (d, J = 13 Hz, 1H), 3.19-3.03
(M, 1H), 2.96 (dd, J = 8.4 Hz, 1
H), 2.78 (s, 3H), 2.67-2.59
(M, 1H), 2.30-2.21 (m, 1H), 2.
17 (s, 3H), 1.81-1.72 (m, 1H),
1.45-1.36 (m, 2H).

Compound name of Example 16 : (2R ^* , 4R ^* , 5S ^* , 6S ^* )-N, N-
Dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-2-carboxamide Structural formula:

[0179]

Embedded image

Mp: IR (KBr) cm ^-1 : 2940, 1634, 1495,
1226.

NMR (270 MHz, CDCl ₃ ) δ (free form): 7.37-7.01 (m, 10H), 6.72
−6.64 (m, 2H), 6.39 (d, J = 2 Hz, 1
H), 4.52 (d, J = 12 Hz, 1H), 4.03.
(Brt, J = 8 Hz, 1H), 3.99 (dd, J =
12,7 Hz, 1H), 3.74 (s, 3H), 2.77
(S, 3H), 2.39 (s, 3H), 2.29-2.
12 (m, 2H), 1.79-1.71 (m, 2H),
1.55-1.43 (m, 1H).

(2R ^* , 3R ^* , 4R ^* , 6S ^* )-3
-(2,5-Dimethoxybenzyl) amino-2-diphenylmethyl-6-hydroxymethyl-1-azabicyclo [2.2.2] octane 41 LiAlH ₄ (92 mg, 2.4 mmol) in dry THF (1
Compound 35 (417 mg, 0.8 ml) was added to the suspension at 0 ° C.
mmol) in dry THF (10 ml) and then heated to reflux for 1 hour. Sodium sulfate 10
The hydrate was added and stirred for 30 minutes. After cooling, the solids were removed by filtration and washed with THF. After concentrating the obtained filtrate, an excess amount of 10% hydrochloric acid-methanol was added.
Concentrated again. The obtained oil was purified by recrystallization from methanol-ether. The white crystals were collected by filtration and dried in vacuo to give the dihydrochloride of compound 41 (240 mg, 0.44 mmol, 55%).

The steric configuration of compound 41 is H—H COS
Determined by Y, CH COSY, DEPT and ¹³ C NMR.

Compound name of Example 17 : (2R ^* , 3R ^* , 4R ^* , 6S ^* )-6-hydroxymethyl-3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [ 2.
2.2] Octane dihydrochloride Structural formula:

[0185]

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Mp: 206.2-207.9 ° C. IR (KBr) cm ^-1 : 3490, 3430, 3210,
3130, 1595, 1587, 1505, 1450,
1229, 1047, 1040.

NMR (270 MHz, CDCl ₃ ) δ (free form): 7.33-7.05 (m, 10H), 6.67
(Dd, J = 9, 3 Hz, 1H), 6.60 (d, J = 9
Hz, 1H), 6.37 (d, J = 3 Hz, 1H), 4.5
1 (d, J = 12 Hz, 1H), 3.72 (s, 3H),
3.56-3.40 (m, 3H), 3.46 (s, 3
H), 3.27-3.18 (m, 3H), 2.89-
2.75 (m, 2H), 2.60-2.51 (m, 1
H), 2.19-2.13 (m, 1H), 1.96-
1.88 (m, 1H), 1.72-1.62 (m, 1
H), 1.37-1.25 (m, 1H), 0.94-
0.86 (m, 1H).

Synthetic drawing of Example 18

[0189]

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5-Isopropyl-2-methoxybenzylamine 44 Compound 42 was synthesized according to the method described in JP-T-58-501127. Compound 42 obtained by the above method
(80 g, 0.37 mol) and NaN ₃ (28.6 g,
(0.44 mol) in DMF (200 ml) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with diethyl ether. After washing the combined extracts with water, brine, dried over MgSO _4. After distilling off the solvent, the obtained azide 43 was used for the next step without further purification. The crude azide 43 was hydrogenated in methanol in the presence of platinum oxide (1 g) for 3 days (2 kg / cm
_² H ^2). The catalyst was removed by filtration through Celite. The resulting crude amine was purified by distillation (0.2 mmHg, 93-98 ° C) to give a colorless oil 44 (21.6 g,
0.12 mol, 33%).

[0191] property data IR of compound 43 ^{(neat): 2105cm -1 1 H NMR (} 270MHz, CDCl 3) δ: 7.18
(Dd, J = 8, 2 Hz, 1H), 7.15 (d, J = 2
Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 4.3
4 (s, 2H), 3.84 (s, 3H), 2.87 (h
ep, J = 7 Hz, 1H), 1.22 (d, J = 7 Hz, 6
H).

Physical data of compound 44 IR (neat): 2960, 1498, 1458, 12
^{94,1250,1032cm -1 1 H NMR (270MHz,} CDCl 3) δ: 7.10
−7.07 (m, 2H), 6.82-6.78 (m, 1
H), 3.83 (s, 3H), 3.80 (s, 2H),
2.86 (hep, J = 7 Hz, 1H), 1.22 (d,
J = 7 Hz, 6H).

(2R ^* , 4S ^* , 5S ^* , 6S ^* )-
N, N-dimethyl-5- (5-isopropyl-2-methoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide 45 Compound 45 is Synthesized according to the same preparation method as for compound 35 . Compound 45 was isolated as the dihydrochloride pentahydrate.

Compound name of Example 18 : (2R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Dimethyl-5- (5-isopropyl-2-methoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane dihydrochloride Structural formula:

[0195]

Embedded image

Mp: 168.9 to 174.6 ° C. IR (KBr) cm ⁻¹ : 3410, 3190, 2965,
1656, 1505, 1454, 1257, 1029,
710.

NMR (270 MHz, CDCl ₃ ) δ (free form): 7.31-6.98 (m, 11H), 6.64
−6.59 (m, 2H), 4.41 (br d, J = 1
2Hz, 1H), 3.63-3.18 (m, 5H), 3.
49 (s, 3H), 3.00 to 2.95 (m, 1H),
2.80-2.69 (m, 1H), 2.73 (s, 3
H), 2.60-2.51 (m, 1H), 2.40-
2.35 (m, 1H), 2.22 (br s, 1H),
2.15 (s, 3H), 2.00-1.89 (m, 1
H), 1.60-1.50 (m, 1H), 1.30-
1.18 (m, 7H).

Synthetic diagram of Example 19 and Example 20

[0199]

Embedded image

(3R ^* , 4S ^* )-6-Diphenylmethyl-5-oxo-1-azabicyclo [2.2.2] octane-3-carboxylic acid hydrochloride 46 Compound 22 (5.2 g, 12 mmol) The 6N hydrochloric acid solution was heated under reflux for 18 hours. The resulting precipitate was collected and dried to give Compound 46 (1.7 g, 4.6 mmol, 3
8%, 46 : (3R ^* , 4R ^* ) isomer = 4: 1) was obtained. This compound was used for the next step without further purification.

¹ H NMR (DMSO-d ₆ ) δ: 5.
70 and 4.81 (pair of d, J = 11 Hz; Ph ₂ C
H CH and ^{_{Ph 2 CHC H) (3R *}} , 4S *) -N, N- dimethyl-6-diphenylmethyl-5-oxo-1-azabicyclo [2.2.
2] Octane-3-carboxamide 47 compound 46 (2.1 g, 6.6 mmol) and dimethylamine hydrochloride (0.65 g, 8.0 mmol) in DMF (30
ml) suspension at room temperature with triethylamine (1.3 g, 13 g).
mmol). To this suspension was added diethylcyanophosphonic acid (1.2 g, 7.3 mmol) followed by triethylamine (0.67 g, 6.7 mmol) at room temperature.
After the resulting mixture was stirred at room temperature for 5 hours, aqueous sodium hydrogen carbonate (5.
0 ml). The solution was extracted three times with ethyl acetate. The combined extracts were dried over Na ₂ SO _4, and concentrated. The mixture was purified by silica gel chromatography (hexane: ethyl acetate = 1: 4) to give the compound
27 is the single isomer for the 3-position (1.4 g, 3.9 mm
ol, 60%).

¹ H NMR (CDCl ₃ ) δ: 4.49
And 4.02 (pair of _{d, J = 8Hz; Ph 2} C H CH and Ph ₂ CHC H of one isomer), 4.66 and 3.96 (pair of d, J = 8 Hz; other isomer Ph
₂ C H CH and Ph ₂ CHC H).

(3R ^* , 4S ^* , 5S ^* , 6S ^* )-
N, N-dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide 49 Compound 47 (3.9 g, 10 mmol), 2 , 5-Dimethoxybenzylamine (1.9 g, 11 mmol) and CSA
(Camphor sulfonic acid) (120 mg) in toluene (40 ml)
The solution was heated to reflux for 8 hours under dehydrating conditions. The residue obtained by removing the solvent was dissolved in a small amount of THF (5 ml), and the solution was added to a solution of NaBH (OAc) ₃ (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. After the mixture was stirred at room temperature for 4 hours, the solvent was removed. Water (25 ml) was added to the obtained residue, neutralized with sodium bicarbonate, and extracted three times with ethyl acetate. The combined extracts were washed with Na ₂ SO ₄
And dried. The crude product obtained by concentration was recrystallized from ethyl acetate to give Compound 49 (2.4 g, 4.
(4 mmol, 44%).

Compound name of Example 19 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Dimethyl-5- (2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-3-carboxamide Structural formula:

[0205]

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Mp: 142.0-142.9 ° C IR (KBr) cm ^-1 : 1637,1499.

NMR (270 MHz, CDCl ₃ ) δ:
7.03-7.37 (m, 10H), 6.68 (dd,
1H, J = 2.5, 8.8 Hz), 6.64 (d, 1H,
J = 8.8 Hz), 6.39 (d, 1H, J = 2.5H)
z), 4.51 (d, 1H, J = 12.1 Hz), 3.7
3 (s, 3H), 3.49 (s, 3H), 3.05-
3.82 (m, 5H), 2.96 (s, 6H), 2.6
2-2.95 (m, 4H), 2.17 (br, 1H),
1.62-1.77 (m, 2H).

(3R ^* , 4S ^* )-6-Diphenylmethyl-5-oxo-1-azabicyclo [2.2.2] octane-3-carboxamide 48 Compound 46 (1.1 g, 3.3 mmol) in THF (1.1 g, 3.3 mmol) 10m
l) The suspension was added at room temperature to triethylamine (0.66 g,
6.6 mmol). To this suspension was added ethyl chloroformate (0.36 g, 3.3 mmol) at 0 ° C.
After the mixture was stirred at room temperature for 1 hour, it was poured into aqueous ammonia and further extracted three times with ethyl acetate. The combined extracts were dried over Na ₂ SO _4. Concentrate to 48
(1.2 g, 3.0 mmol, 90%, 48 : isomer for position 3 = 4: 1) was obtained. This compound was used for the next step without further purification.

¹ H NMR (CDCl ₃ ) δ: 4.43
And 3.98 (pair of _{d, J = 9Hz; Ph 2} C H CH and Ph ₂ CHC H of one isomer), 4.51 and 4.28 (pair of d, J = 8 Hz; other isomer Ph
₂ C H CH and Ph ₂ CHC H).

(3R ^* , 4S ^* , 5S ^* , 6S ^* )-5
-(2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide 50 compound 48 (1.2 g, 3 mmol), 2,5-dimethoxybenzylamine ( 0.6 g, 3.3 mmol) and CSA
A solution of (camphorsulfonic acid) (45 mg) in toluene (15 ml) was heated to reflux for 3 hours under dehydrating conditions. The residue obtained by removing the solvent was dissolved in a small amount of THF (3 ml), and the solution was added to a solution of NaBH (OAc) ₃ (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. After stirring the mixture at room temperature for 3 hours, the solvent was removed. Water was added to the obtained residue, neutralized with sodium bicarbonate, and extracted three times with ethyl acetate. The combined extracts were dried over Na ₂ SO _4. The residue obtained by concentration was recrystallized from methanol-acetone to obtain a by-product. The residue obtained by concentrating the mother liquor was recrystallized from methanol-ethyl acetate to obtain compound 50 (0.27 g, 0.56 mmol, 19%).

Compound name in Example 20 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5
(2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-
3-carboxamide structural formula:

[0212]

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Mp: 127.0-129.0 ° C. IR (KBr) cm ⁻¹ : 3350, 1686, 1493.

NMR (270 MHz, CDCl ₃ ) δ:
7.05-7.32 (m, 10H), 6.69 (dd,
1H, J = 2.5, 8.8 Hz), 6.64 (d, 1H,
J = 8.8 Hz), 6.36 (d, 1H, J = 2.5H)
z), 5.36 (br, 2H), 4.47 (d, 1H,
J = 12.1 Hz), 3.74 (s, 3H), 3.53
(S, 3H), 3.48-3.75 (m, 2H), 2.
95-3.26 (m, 6H), 2.11 (br, 1
H), 2.59-2.62 (m, 1H), 2.37-
2.50 (m, 2H), 1.76-1.89 (m, 1
H).

Synthetic drawing of Example 21

[0216]

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(3R ^* , 4S ^* , 5S ^* , 6S ^* )-5
-(2,5-Dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid hydrochloride 51 Compound 50 (100 mg, 0.2 mmol) in concentrated hydrochloric acid (2 ml) )
The solution was heated at reflux for 15 hours. After cooling to room temperature, the mixture was basified with aqueous ammonia and extracted twice more with methylene chloride. The combined extracts were dried.
10% hydrochloric acid-methanol was added to the residue obtained by concentration, and the mixture was concentrated again. The resulting precipitate was recrystallized from methanol-ether to give Compound 51 (30 mg, 0.054
mmol, 27%).

Compound name of Example 21 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5
(2,5-dimethoxybenzyl) amino-6-diphenylmethyl-1-azabicyclo [2.2.2] octane-
3-carboxylic acid dihydrochloride structural formula:

[0219]

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Mp: 230.0 ° C. (decomposition) IR (KBr) cm ⁻¹ : 2945, 1726, 1502
1451.

NMR (270 MHz, CDCl ₃ ) δ (free base): 6.95-7.32 (m, 10H), 6.6
5 (dd, 1H, J = 2.5, 8.8 Hz), 6.61
(D, 1H, J = 8.8 Hz), 6.49 (d, 1H, J
= 2.5 Hz), 4.41 (d, 1H, J = 12.1H)
z), 3.68 (s, 3H), 3.53 (s, 3H),
2.70-3.70 (m, 7H), 2.31-2.60
(M, 3H), 1.67-1.85 (m, 1H), 1.
33-1.49 (m, 1H).

Synthetic diagram of Example 22

[0223]

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Compound 52 was synthesized from compound 23 in the same manner as in Example 9 and isolated as the dihydrochloride.

Compound name of Example 22 : (3R ^* , 4S ^* , 5S ^* , 6S ^* ) N, N-diethyl-5- (5-isopropyl-2-methoxybenzyl) amino-6-diphenylmethyl-1- Azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0226]

Embedded image

Mp: 155 to 158 ° C. IR (KBr) cm ⁻¹ : 3450, 1633, 1499,
1443, 1248, 700.

¹ H NMR (270 MHz, CDCl ₃ )
δ (free form): 7.37-7.04 (m, 10H),
5.01 (dd, J = 2.8, 6.7 Hz, 1H);
65 (d, J = 6.7 Hz, 1H), 6.60 (d, J =
2.8 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1
H), 3.70-3.50 (m, 4H), 3.53.
(S, 3H), 3.38-3.07 (m, 5H), 2.
96 (dd, J = 4.2, 7.9 Hz, 1H), 2.90
−2.56 (m, 4H), 2.17 (br s, 1
H), 1.84-1.73 (m, 2H), 1.20
(D, J = 7.3 Hz, 6H), 1.17 (t, J = 7.
0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H).

Synthetic drawing of Example 23 and Example 24

[0230]

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Ethyl N-Boc-isonipecotate 54 Compound 53 (25.83 g, 164 mmol) in THF (2
0 ml) solution with di-tert-butyl carbonate (37.2 g, 170
mmol) in THF (30 ml) at room temperature. The solvent was removed and the residue was distilled under vacuum. 80
After removing the fraction at ~ 100 ° C, 120 ° C, 1.5mmHg
Compound 54 (38.3 g,
151 mmol, 92%).

¹ H NMR (270 MHz, CDCl ₃ )
δ: 4.14 (quart, J = 7 Hz, 2H), 4.0
2 (br d, 2H), 2.83 (br t, 2H),
2.43 (tt, J = 10.9, 3.9 Hz, 1H),
1.87 (m, 2H), 1.64 (m, 2H), 1.4
6 (s, 9H), 1.26 (t, J = 7 Hz, 3H).

4-Allyl-1-azabicyclo [2.2.
2] Octan-3-one 57 diisopropylamine (25.2 ml, 179 mmol) and n-butyllithium (1.59 M in hexane, 96
ml, 153 mmol) of LDA in THF (30
Compound 54 (33.56 g, 131 mmol) was added to the solution.
A solution of l) in THF (15 ml) was added slowly at -60 ° C. After the addition is completed, raise the temperature to -25 ° C and again
Cool to 60 ° C. Allyl bromide (12.4 ml, 143 mm) was added to the enolate solution kept at -60 ° C or lower.
ol) was added and the temperature of the mixture was raised to -5 ° C. After quenching the reaction with acetic acid (17.6 ml) at -60 ° C, the solvent was removed. The residue was extracted with ethyl acetate at pH = 6.0, the extract was washed with brine, and then extracted with Na ₂
Dried over SO _4. A crude product of compound 55 (40.13 g) was obtained by concentration.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 5.68 (m, 1H), 5.08-5.00 (m,
2H), 4.17 (quart, J = 7.1 Hz, 2
H), 3.86 (br d, J = 13 Hz, 2H), 2.
90 (m, 2H), 2.27 (d, J = 7.3 Hz, 2
H), 2.07 (m, 2H), 1.45 (s, 9H),
1.38 (m, 2H), 1.26 (t, J = 7.1 Hz,
3H).

The obtained crude product was dissolved in ethyl acetate (20 ml).
And mixed with trifluoroacetic acid (60 ml). After standing at room temperature for 4 hours, the mixture was concentrated and subsequently azeotropically dehydrated with toluene. As a result, a TFA salt of ethyl 4-allylinisonipecotate was obtained.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 8.60 (brs, 1H), 8.30 (br
s, 1H), 5.68-5.56 (m, 1H), 5.1
5-5.06 (m, 2H), 4.22 (quart, J
= 7.1 Hz, 2H), 3.39 (br d, J = 12H)
z, 2H), 2.99 (m, 2H), 2.36-2.3
1 (m, 4H), 1.73 (m, 2H), 1.29
(T, J = 7.1 Hz, 3H). Anhydrous potassium carbonate (70.7 g, 512 mmol) was added to a toluene solution of a crude TFA salt of ethyl 4-allylinisonipecotate and ethyl bromoacetate (23.5 g, 141 mmol).
Was added and the resulting suspension was warmed at 80 ° C. for 15 minutes. After cooling the reaction mixture, pH = 8 with dilute hydrochloric acid.
Adjusted to zero. The resulting solution was extracted with ethyl acetate, after washing the extract with brine, dried over Na ₂ SO _4,
The crude product of compound 56 (37.4
g) was obtained.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 5.68 (m, 1H), 5.06-4.99 (m,
2H), 4.22-4.12 (m, 4H), 3.19.
(S, 2H), 2.83 (m, 2H), 2.35-2.
21 (m, 4H), 2.15 (d, J = 13 Hz, 2
H), 1.61 (m, 2H), 1.264 (t, J = 7
Hz, 3H), 1.256 (t, J = 7 Hz, 3H).

Potassium t-butoxide (35.84 g,
(320 mmol) in toluene (100 ml) was heated to reflux. Crude compound 56 was gradually added to the suspension. The reaction was quenched with water (120 ml) and heated at 80 ° C. overnight. 6N-hydrochloric acid (54 ml) was added and stirred for 15 minutes. The reaction mixture was cooled to room temperature, followed by NaO
The pH was adjusted to 13.5 with aqueous solutions of H and Na ₂ CO ₃ . The resulting solution was extracted with methylene chloride, and the extract was washed with brine and dried over Na ₂ SO ₄ . The crude quinuclidine compound was obtained by concentration. The crude product was distilled under vacuum, and the fraction at 122 ° C. and 15 mmHg was collected to obtain Compound 57 (15.35 g, 72% yield from Compound 54 ).

¹ H NMR (270 MHz, CDCl ₃ )
δ: 5.78 (m, 1H), 5.08-4.98 (m,
2H), 3.26 (s, 2H), 3.01 (m, 4
H), 2.20 (d, J = 7.4 Hz, 2H), 1.95
-1.65 (m, 4H).

¹³ C NMR (CDCl ₃ ) δ: 218.
4,133.6,117.1,62.0,47.0,4
2.3, 37.2, 29.4.

4-Allyl-2-diphenylmethyl-1-
Azabicyclo [2.2.2] octan-3-one 58 compound 57 (17.66 g, 107 mmol), benzaldehyde (12.49 g, 117 mmol) and NaOH
(0.46 g, 11.5 mmol) of ethanol (80 ml)
The solution was heated at reflux for 1 hour. After cooling the reaction mixture,
The yellow solid is collected and 4-allyl-2-benzylidene-1-
Azabicyclo [2.2.2] octan-3-one (2
(6.66 g, 98%).

¹ H NMR (270 MHz, CDCl ₃ )
δ: 8.04-8.01 (m, 2H), 7.40-7.
32 (m, 3H), 7.03 (s, 1H), 5.87
(M, 1H), 5.09-5.02 (m, 2H), 3.
24-2.96 (m, 4H), 2.32 (d, J = 7.
4 Hz, 2H), 1.97-1.74 (m, 4H).

The CuBr-DMS complex (1.06 g, 5.
Phenylmagnesium bromide (3.0 M in ether, 42 m 2) while immersing a solution of toluene (100 mmol) in a dry ice-acetone bath at −60 ° C.
1, 126 mmol) was added slowly. 4-Allyl-2-benzylidene-1-azabicyclo [2.2.2] octan-3-one (25.9 g, 10
3 mmol), trimethylsilyl chloride (31.4 ml, 247
mmol) and HMPA (43 ml, 247 mmol) in toluene (120 ml) were added while keeping the temperature below -60 ° C. After the addition was completed, the temperature was raised to 0 ° C. Acetic acid (1
(4.5 ml). After water was added to the mixture, it was neutralized with Na ₂ CO ₃ . The resulting mixture is p
Extracted with ether at H = 6.5 and pH = 8.0 and washed with brine. After drying over Na ₂ SO ₄ and concentration, a crude product of compound 58 was obtained. The crude product was triturated with ether to give compound 58 (23.
04g, 68%).

¹ H NMR (270 MHz, CDCl ₃ )
δ: 7.39-7.15 (m, 10H), 5.72
(M, 1H), 5.04-4.95 (m, 2H), 4.
47 (d, J = 8.4 Hz, 1H), 3.96 (d, J =
8.4 Hz, 1H), 3.11 (m, 2H), 2.65
(M, 2H), 2.16 (m, 2H), 1.94-1.
6 (m, 4H).

¹³ C NMR (CDCl ₃ ) δ: 219.
3, 143.1, 142.2, 134.3, 128.
3,126.5,126.4,117.5,72.3
50.6, 50.0, 44.0, 42.4, 37.9,
31.1, 29.9.

4-Allyl-3N- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [2.2.2] octane 61 and 62 Compound 58 (4.00 g, 12.1 mmol) Ammonium formate (8.00 g, 127 mmol) in formamide (2
4 ml) The solution was heated at 170 ° C. bath temperature for 5 hours. The solvent was removed and water was added to the residue. The obtained solid was purified by recrystallization from methanol to give Compound 59 (2.0
3 g, 70%, cis: trans = 1: 1) was obtained.

¹ H NMR (270 MHz, CDCl ₃ )
δ: 6.69 (d, J = 11.4 Hz), 6.52 (d, J = 11.7H)
z).

MS: 360 (M ⁺ ), 319.

A solution of compound 59 in 4N hydrochloric acid (20 ml) was heated at 80 ° C. overnight. The reaction was quenched with aqueous Na ₂ CO ₃ . The resulting mixture was extracted with methylene chloride, and the extract was dried over Na ₂ SO ₄ . Compound 60 (1.95 g, cis-trans mixture) was obtained by concentration under reduced pressure.

MS: 332 (M ⁺ ), 291,166.

To a methanol solution of the crude compound 60 and 2,5-dimethoxybenzaldehyde (1.19 g, 6.99 mmol) were added bromocresol green and NaBH ₃ CN.
(380 mg, 6.05 mmol) was added and the pH was adjusted with acetic acid.
Was adjusted to be acidic. After standing overnight, it was basified with aqueous Na ₂ CO ₃ . The resulting mixture was extracted with methylene chloride, and the extract was washed with brine and dried over Na ₂ SO ₄ . Concentration under reduced pressure gave a crude mixture of compound 61 (cis isomer) and compound 62 (trans isomer). The crude mixture was partially separated by silica gel chromatography (0-10% methanol-methylene chloride). The more polar isomer-enriched fraction was recrystallized from methanol to give pure compound 61 (280 ml,
The cis isomer) was obtained. The less polar fraction was converted to the dimesylate salt and further purified by recrystallization from acetone to give compound 62 (395 mg, trans isomer).

Compound name of Example 23 : cis-4-allyl-3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [2.2.2] octane Structural formula:

[0253]

Embedded image

Mp: 163.7-164.8 ° C. IR (nujol) cm ⁻¹ : 1594, 1498, 102
9.

NMR (270 MHz, CDCl ₃ ) δ:
7.40-7.02 (m, 10H), 6.70 (m, 2
H), 6.40 (brs, 1H), 5.77 (m, 1
H), 5.04-4.97 (m, 2H), 4.59
(D, J = 11.9 Hz, 1H), 3.77-3.68.
(M, 7H, 3.77 (s, 3H) and 3.72
(S, 3H), 3.34 (d, J = 11.4H)
z, 1H), 2.98 (m, 1H), 2.88-2.5
6 (m, 4H), 2.25-2.04 (m, 3H),
1.57-1.40 (m, 3H), 1.25 (m, 1
H).

Compound name of Example 24 : trans-4-allyl-3- (2,5-dimethoxybenzyl) amino-2-diphenylmethyl-1-azabicyclo [2.2.2] octane dimesylate Structural formula:

[0257]

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Mp: 245.0-246.1 ° C. IR (nujol) cm ^-1 : 1609, 1502, 104
4.

¹ H NMR (270 MHz, CDCl ₃ )
δ (free form): 7.44-7.09 (m, 10H),
6.71-6.63 (m, 2H), 6.52 (d, J =
1.5 Hz, 1H), 5.76 (m, 1H), 5.05-
4.94 (m, 2H), 3.90 (d, J = 11.9H)
z, 1H), 3.75 (s, 3H), 3.71 (s, 3
H), 3.31 (dd, J = 11.9, 3.5 Hz, 1
H), 3.00 (d, J = 12.4 Hz, 1H), 2.9
6-2.83 (m, 3H), 2.52-2.40 (m,
1H), 2.40 (d, J = 12.4 Hz, 1H), 2.
24 (br s, 1H), 2.18-2.02 (m, 2
H), 1.66-1.13 (m, 4H).

Embodiments 25, 26, 27, 28, 29, 3
Compounds 0, 31, 32, 33 and 34 were synthesized by the same preparation method as in Example 9.

Compound name of Example 25 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (5-ethyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0262]

Embedded image

Mp: 190.0 to 193.0 ° C. IR (KBr) cm ⁻¹ (free form): 3450, 1635,
1499, 1443, 1249, 1030, 822, 7
49,698.

NMR (270 MHz, CDCl ₃ , free form): δ7.39-7.04 (m, 10H), 6.98
(Dd, J = 2.0, 8.4 Hz, 1H), 6.63
(D, J = 8.4 Hz, 1H), 6.50 (d, J = 2.
0 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1
H), 3.83-3.46 (m, 3H), 3.51.
(S, 3H), 3.35-3.08 (m, 6H), 2.
96 (q, J = 4.0 Hz, 1H), 2.92-2.83
(M, 1H), 2.78-2.62 (m, 2H), 2.
50 (q, J = 7.4 Hz, 2H), 2.15 (br.
s, 1H), 1.85-1.73 (m, 2H), 1.2
0-1.08 (m, 3x3H).

Compound name of Example 26 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (2-methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0266]

Embedded image

Mp: 158.0-163.0 ° C. IR (KBr) cm ^-1 (free form): 3450, 1630,
1597, 1487, 1443, 1244, 1029,
813,750,701,696.

NMR (270 MHz, CDCl ₃ (free form)): δ7.35-7.04 (m, 11H), 6.7
6 (d, J = 2.2 Hz, 1H), 6.65 (d, J =
8.8 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1
H), 3.68-3.52 (m, 4H), 3.50.
(S, 3H), 3.33-3.06 (m, 5H), 2.
90 (q, J = 4.0 Hz, 1H), 2.87-2.56
(M, 3H), 2.42 (s, 3H), 2.11 (b
r. s, 1H), 1.80-1.65 (m, 2H)
17 (t, J = 7.0 Hz, 3H), 1.11 (t, J =
7.0 Hz, 3H).

Compound name of Example 27 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (2-methoxy-5-trifluoromethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide Structural formula:

[0270]

Embedded image

Mp: 122.0-125.0 ° C. IR (KBr) cm ⁻¹ : 3450, 1634, 1499,
1465, 1454, 1252, 1153, 1031,
752, 704, 604.

NMR (270 MHz, CDCl ₃ ): δ
7.36-6.99 (m, 11H), 6.66 (d, J
= 9.2 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1
H), 4.48 (d, J = 12.1 Hz, 1H), 3.7
0-3.47 (m, 4H), 3.56 (s, 3H),
3.33-3.05 (m, 5H), 2.91 (dd, J
= 4.0, 7.9 Hz, 1H), 2.85-2.58
(M, 3H), 2.11 (br.s, 1H), 1.90
−1.55 (m, 2H), 1.15 (t, J = 7.1H)
z, 3H), 1.10 (t, J = 7.1 Hz, 3H).

Compound name of Example 28 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (5-chloro-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0274]

Embedded image

Mp: 190.0-194.0 ° C IR (KBr) cm ^-1 (free form): 3430, 1631,
1486, 1449, 1247, 1025, 821, 7
51,701,693.

NMR (270 MHz, CDCl ₃ (free form)): δ 7.58 (d, J = 6.9 Hz, 2H), 7.
40-7.19 (m, 8H), 7.14 (dd, J =
2.5, 8.9 Hz, 1H), 6.63 (d, J = 8.9)
Hz, 2H), 5.24 (br.s, 1H), 4.49
(D, J = 11.9 Hz, 1H), 3.85-3.06
(M, 12H), 3.47 (s, 3H), 2.24 (b
r. s, 1H), 2.15-1.90 (m, 2H),
1.23 (t, J = 7.2 Hz, 3H), 1.02 (t,
J = 7.2 Hz, 3H).

Compound name of Example 29 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (5-t-butyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0278]

Embedded image

Mp: 180.0 to 183.0 ° C. IR (KBr) cm ⁻¹ (free amine): 3450,163
0, 1500, 1457, 1450, 1250, 75
1,702.

NMR (270 MHz, CDCl ₃ (free amine)): δ7.36-7.03 (m, 11H), 6.
89 (d, J = 2.6 Hz, 1H), 6.64 (d, J =
8.8 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1
H), 3.71-3.48 (m, 4H), 3.52.
(S, 3H), 3.35-3.03 (m, 5H), 2.
98 (dd, J = 4.0, 7.7 Hz, 1H), 2.91
-2.60 (m, 3H), 2.19 (br.s, 1
H), 1.87-1.75 (m, 2H), 1.27
(S, 9H), 1.16 (t, J = 7.3 Hz, 3H),
1.11 (t, J = 7.3 Hz, 3H).

Compound name of Example 30 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5- (2
-Methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid dihydrochloride Structural formula:

[0282]

Embedded image

Mp: 170.0-175.0 ° C. IR (KBr) cm ^-1 (hydrochloride): 3420, 1725,
1490.

NMR (270 MHz, CDCl ₃ (free amine)): δ 7.40-7.10 (m, 11H), 6.
75 (br s, 1H), 6.41 (d, J = 8.4H
z, 1H), 4.40 (d, J = 11.7 Hz, 1H),
4.05 (br s, 1H), 3.48 (s, 3H),
3.60-3.40 (m, 2H), 3.34-2.50
(M, 8H), 2.38 (s, 3H), 1.95-1.
56 (m, 2H).

Compound name of Example 31 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5- (5
-Isopropyl-2-methoxybenzylamino) -6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0286]

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Mp: 247 ° C. IR (KBr) cm ⁻¹ (hydrochloride): 3310, 1685,
1505.

NMR (270 MHz, CDCl ₃ (free form)): δ7.35-7.00 (m, 11H), 6.6
6 (d, J = 8.4 Hz, 1H), 6.57 (d, J =
2.2 Hz, 1, H), 5.39 (brs, 2H),
4.48 (d, J = 12.1 Hz, 1H), 3.70 −
3.64 (m, 1H), 3.63 (d, J = 12.8H
z, 1H), 3.55 (3H, s), 3.20 (d, J
= 12.8 Hz, 1H), 3.19-2.93 (m, 4
H), 2.83-2.60 (m, 2H), 2.49-
2.42 (m, 2H), 1.95-1.81 (m, 1
H), 1.60-1.50 (m, 1H), 1.20
(D, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6.
6 Hz, 3H).

Compound name of Example 32 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5- (5
-Isopropyl-2-methoxybenzylamino) -6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid dihydrochloride Structural formula:

[0290]

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Mp: 150.0 to 155.0 ° C. IR (KBr) cm ^-1 (hydrochloride): 3400, 1730,
1510.

NMR (270 MHz, CDCl ₃ (free amine type)): δ7.36-7.00 (m, 11H),
6.63 (d, J = 8.8 Hz, 1H), 6.57 (d,
J = 1.8 Hz, 1H), 4.47 (d, J = 12.4H)
z, 1H), 4.00 (br s, 1H), 3.51
(S, 3H), 3.70-3.45 (m, 2H), 3.
40-2.40 (m, 8H), 2.00-1.55
(M, 2H), 1.19 (d, J = 6.9 Hz, 3H),
1.18 (d, J = 6.9 Hz, 3H).

Compound name of Example 33 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5- (2
-Methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0294]

Embedded image

Mp: 220.0-225.0 ° C. IR (KBr)) cm ⁻¹ (hydrochloride): 3300, 320
0, 1685, 1495.

NMR (270 MHz, CDCl ₃ (free form)): δ7.34-7.06 (m, 11H), 6.7
2 (d, J = 2.6 Hz, 1H), 6.67 (d, J =
8.4 Hz, 1H), 5.48 (brs, 2H), 4.
45 (d, J = 12.1 Hz, 1H), 3.80-3.6
4 (m, 1H), 3.62-3.50 (m, 4H),
3.28-2.95 (m, 6H), 2.63-2.76
(M, 1H), 2.57-2.45 (m, 1H), 2.
42 (s, 3H), 1.95-1.50 (m, 2H).

Synthetic diagram of Example 34

[0298]

Embedded image

Compound 63 (0.30 g, 0.77 mmol
l), 4-methoxybenzylamine (0.12 ml, 0.1 mL).
89 mmol) and CSA (camphorsulfonic acid) (9.2 m
g, 0.04 mmol) in a dry toluene solution (5.0 ml) was heated to reflux overnight under dehydration while stirring. The solvent was removed under reduced pressure. The obtained crude imine (compound 64 )
Was used in the next step without further purification. A solution of the crude imine in dry THF (1.0 ml) was added to NaBH (OA
c) A solution of ₃ (0.41 g, 1.93 mmol) in acetic acid (8.
0 ml) at room temperature and stirred at room temperature for 8 hours. The mixed solution was concentrated under reduced pressure. The residue was adjusted to basic with NaOH and extracted with methylene chloride. After washing the combined organic layers with brine and dried over K ₂ CO _3. The pale yellow viscous oil (0.52 g) obtained by concentration was subjected to silica gel chromatography (methylene chloride: methanol = 100:
Purification in 1) gave the title compound (colorless viscous oil) containing trace amounts of the endo isomer. The oil was recrystallized from isopropanol to give the pure title compound 65 as colorless crystals.
(65.5 mg, 17% yield) was obtained.

Compound name of Example 34 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N-
Diethyl-5- (4-methoxybenzylamino) -6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide Structural formula:

[0301]

Embedded image

Mp: 131.0 to 133.0 ° C. (isopropanol) IR (nujol) cm ^-1 (free form): 3380 (m),
1645 (s), 1610 (m), 1510 (s), 1
243 (s), 1030 (s), 810 (m), 750
(M), 745 (m), 710 (m), 690 (m).

NMR (270 MHz, CDCl ₃ ): δ
7.43-7.15 (m, 9H), 7.15-7.04
(M, 1H), 6.68 (d, J = 8.8 Hz, 2H),
6.50 (d, J = 8.8 Hz, 2H), 4.43 (d,
J = 12.1 Hz, 1H), 3.78 (s, 3H), 3.
77-3.62 (m, 1H), 3.56 (d, J = 1
3.0 Hz, 1H), 3.56-3.44 (m, 1H),
3.16 (d, J = 13.0 Hz, 1H), 3.35 −
3.04 (m, 6H), 2.84 (dd, J = 4.0,
7.7 Hz, 1H), 2.80-2.65 (m, 1H),
2.59 (dd, J = 8.6, 8.6 Hz, 1H);
08 (br.s, 1H), 1.86-1.68 (m, 2
H), 1.63 (br.s, 1H), 1.15 (t, J
= 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3
H).

Synthetic drawing of Examples 35, 36 and 37

[0305]

Embedded image

(3R ^* , 4S ^* , 5S ^* , 6S ^* )-5
-(2-methoxy-5-methylthiobenzylamino)-
6-diphenylmethyl-1-azabicyclo [2.2.
2] Octane-3-carboxylic acid (the compound of Example 30,
A solution of 0.40 g (0.65 mmol) in 10% hydrochloric acid / methanol (5 ml) was heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed. Aqueous sodium bicarbonate was added to the residue to adjust the pH to 8
And the organic layer was extracted with ethyl acetate (2 × 70 ml). After washing the combined extracts with brine, MgSO
It dried with ₄ and concentrated under reduced pressure further. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 2) to give compound 66 (0.20 g, yield 56%).

Compound name of Example 35 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-5- (2
-Methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylate Structural formula:

[0308]

Embedded image

Mp: 70-73 ° C. IR (KBr) cm ⁻¹ : 3440, 2950, 1730,
1495.

NMR (270 MHz, CDCl ₃ (free form)): δ 7.05-7.30 (m, 11H), 6.7
2 (d, J = 2.2 Hz, 1H), 6.65 (d, J =
8.4 Hz, 1H), 4.43 (d, J = 12.1 Hz, 1
H), 3.71 (s, 3H), 3.55 (s, 3H),
3.52-3.65 (m, 3H), 3.24 (d, J =
13.2 Hz, 1H), 2.92-3.20 (m, 4
H), 2.43-2.66 (m, 3H), 2.42.
(S, 3H), 1.75-1.92 (m, 1H), 1.
32-1.50 (m, 1H).

Compound 66 (66 mg, 0.1 mg) was added to a suspension of LiAlH ₄ (12 mg, 0.39 mmol) in ether (5 ml).
3 mmol) at 0 ° C. and stirred at room temperature for 1 hour. Aqueous sodium bicarbonate (2 drops) and ethyl acetate (20 ml) were added to
Stir for 5 minutes. The organic layer was separated, dried over MgSO ₄ and concentrated under reduced pressure. The obtained crude product was treated with 10% hydrochloric acid / methanol to obtain Compound 67 (43 mg, yield 55%).

Compound name of Example 36 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-3-hydroxymethyl-5- (2-methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1- Azabicyclo [2.2.2] octane dihydrochloride Structural formula:

[0313]

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Mp: 178-182 ° C IR (KBr) cm ^-1 : 3400, 1575, 1495.

NMR (270 MHz, CDCl ₃ (free form)): δ7.34-7.07 (m, 11H), 6.7
3 (d, J = 2.2 Hz, 1H), 6.64 (d, J =
8.4 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1
H), 3.54 (s, 3H), 3.76-3.52.
(M, 5H), 3.20 (d, J = 12.8 Hz, 1
H), 3.20-3.10 (m, 1H), 2.98-
2.86 (m, 2H), 2.60-2.47 (m, 1
H), 2.42 (s, 3H), 2.30-2.19
(M, 2H), 2.00-1.72 (m, 2H), 1.
39-1.30 (m, 1H).

To a solution of compound 66 (141 mg, 0.25 mmol) in dry methanol (3 ml) was added 60% NaH (20 mg,
0.50 mmol) was added at room temperature. The mixture was heated at 50 ° C. for 2 hours. The solvent was removed and ethyl acetate (100m
Extracted in l). After washing the organic layer with brine, Mg
Dried over SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain Compound 68 (28 mg, yield: 20%).

Compound name of Example 37 : (3R ^* , 4R ^* , 5R ^* , 6R ^* )-5- (2
-Methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylate dihydrochloride Structural formula:

[0318]

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Mp: 144 to 147 ° C. IR (KBr) cm ⁻¹ : 3420, 1730, 1495.

NMR (270 MHz, CDCl ₃ (free form)): δ 7.29-7.05 (m, 11H), 6.7
4 (d, J = 2.2 Hz, 1H), 6.61 (d, J =
8.4 Hz, 1H), 4.41 (d, J = 12.1 Hz, 1
H), 3.84 (dd, J = 7.3 and 12.1 Hz, 1
H), 3.72-3.62 (m, 1H), 3.68.
(S, 3H), 3.48 (s, 3H), 3.58-3.
49 (m, 2H), 3.31 (dt, J = 2.7 and 1
3.6 Hz, 1 H), 3.15 (d, J = 13.6 Hz, 1
H), 2.87-2.75 (m, 2H), 2.70-
2.62 (m, 1H), 2.60-2.48 (m, 2
H), 2.41 (s, 3H), 2.11-1.97
(M, 1H).

The compound of Example 38 was synthesized in the same manner as the compound of Example 18.

Compound name of Example 38 : (2R ^* , 4R ^* , 5R ^* , 6R ^* )-N, N-
Dimethyl-5- (2-methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxamide Structural formula:

[0323]

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Mp: 156 to 158 ° C. IR (KBr) cm ⁻¹ : 3450, 2920, 1645,
1495.

NMR (270 MHz, CDCl ₃ (free form)): δ7.36-6.98 (m, 11H), 6.7
4 (d, J = 2.6 Hz, 1H), 6.63 (d, J =
8.4 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1
H), 3.55 (d, J = 13.2 Hz, 1H), 3.5
2-3.49 (m, 1H), 3.49 (s, 3H),
3.35 (d, J = 8.4 Hz, 1H), 3.21 (d,
J = 13.2 Hz, 1H), 3.19-3.00 (m, 1
H), 2.97-2.92 (m, 1H), 2.79
(S, 3H), 2.66-2.59 (m, 1H), 2.
41 (s, 3H), 2.20-2.10 (m, 1H),
2.17 (s, 3H), 1.82-1.67 (m, 1
H), 1.48-1.30 (m, 2H).

The compound of Example 39 was synthesized from the compound of Example 38 by the synthesis method of Example 21.

Compound name of Example 39 : (2R ^* , 4R ^* , 5R ^* , 6R ^* )-5- (2
-Methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid dihydrochloride Structural formula:

[0328]

Embedded image

Mp: 162 to 167 ° C. IR (KBr) cm ⁻¹ : 3430, 1740, 1495.

NMR (270 MHz, CDCl ₃ (free form)): δ7.36-7.25 (m, 10H), 7.1
4 (dd, J = 2.6 and 8.4 Hz, 1H), 6.71
(D, J = 2.6 Hz, 1H), 6.67 (d, J = 8.
4 Hz, 1 H), 4.65 (d, J = 12.1 Hz, 1
H), 4.26 (dd, J = 8.4 and 12.1 Hz, 1
H), 3.79-3.67 (m, 1H), 3.53.
(S, 3H), 3.50-3.20 (m, 3H), 3.
10-2.80 (m, 1H), 2.70-2.57
(M, 1H), 2.42 (s, 3H), 2.33-2.
15 (m, 1H), 1.72-1.60 (m, 1H).

The compounds of Examples 40, 41 and 42 were synthesized by the same method as in Examples 19 and 20.

Compound name of Example 40 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N-methoxy-N-methyl-5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1 -Azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0333]

Embedded image

Mp: 174-176 ° C IR (KBr) cm ^-1 : 3415, 2945, 1658,
1504, 1454, 1436, 1391, 1232
1041,711.

NMR (270 MHz, CDCl ₃ (free form)): δ 7.05-7.35 (m, 10H), 6.6
7 (dd, J = 8.8, 2.9 Hz, 1H), 6.60
(D, J = 8.8 Hz, 1H), 6.42 (d, J = 2.
9 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1
H), 3.73 (s, 3H), 3.67 (s, 3H),
3.47 (s, 3H), 3.20 (s, 3H), 2.8
0-3.83 (m, 8H), 2.60-2.71 (m, 8H)
1H), 2.36 (br, 1H), 1.25-1.85
(M, 2H).

Compound name of Example 41 : (3R ^* , 4S ^* , 5R ^* , 6R ^* )-N-ethyl-5- (2,5-dimethoxybenzylamino) -6
Diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride Structural formula:

[0337]

Embedded image

Mp: 248 to 249 ° C. IR (KBr) cm ⁻¹ : 3480, 3430, 3250,
3195, 2975, 1675, 1594, 1506
1453, 1436, 1238, 712.

NMR (270 MHz, CDCl ₃ (free form)): δ 7.03-7.39 (m, 10H), 6.6
0-6.75 (m, 2H), 6.41 (d, J = 2.2
Hz, 1H), 5.44 (br, 1H), 4.40 (d,
J = 12.5 Hz, 1H), 3.53-3.81 (m, 2
H), 3.74 (s, 3H), 3.59 (s, 3H),
2.91-3.33 (m, 8H), 2.62-2.74
(M, 1H), 2.22 (br, 1H), 1.76 −
1.90 (m, 1H), 1.25-1.42 (m, 1
H), 1.12 (t, J = 7 Hz, 3H).

Compound name of Example 42 : (3R ^* , 4S ^* , 5S ^* , 6S ^* )-N, N
(3-oxa-1,5-pentylene) -5- (2,5-
Dimethoxybenzylamino) -6-diphenylmethyl-
1-azabicyclo [2.2.2] octane-3-carboxamide Structural formula:

[0341]

Embedded image

Mp: 164-165 ° C IR (KBr) cm ^-1 : 2935, 1645, 1498,
1450,1432,1268,1232,1112
1048, 1023, 704.

NMR (270 MHz, CDCl ₃ ): δ
7.05-7.36 (m, 10H), 6.68 (dd,
J = 8.8, 2.9 Hz, 1H), 6.62 (d, J =
8.8 Hz, 1H), 6.36 (d, J = 2.9 Hz, 1
H), 4.51 (d, J = 12.1 Hz, 1H), 3.7
3 (s, 3H), 3.48 (s, 3H), 3.00-
3.80 (m, 13H), 2.89 (dd, J = 7.
7, 4.1 Hz, 1H), 2.57-2.86 (m, 3
H), 2.08 (br, 1H), 134-1.83.
(M, 2H).

Compound name of Example 43 : (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane −
3-carboxamide dihydrochloride (3R ^* , 4R ^* )-N, N-diethyl-5-oxo-
Optical Resolution of 1-Azabicyclo [2.2.2] octane-3-carboxamide 13 Compound 13 (180 g, 0.84 mol) and (−)-dibenzoyl-L-tartaric acid monohydrate (211 g, 0.561
mol) was added to ethanol (3.65 L), and the resulting mixture was heated to reflux to dissolve. The solution was quenched to 40 ° C. and left overnight at room temperature to give (3R, 4R) -N, N
-Diethyl-5-oxo-1-azabicyclo [2.2.
2] (-)-Dibenzoyl-L-tartrate salt of octane-3-carboxamide 69 was obtained as crystals. (10
0.5 g, 21.5%, 97% ee). In the mother liquor (-)-
Dibenzoyl-L-tartaric acid monohydrate (90.6 g, 0.
241 mol) and concentrated to about 3.5 L. The resulting mixture is dissolved by heating under reflux and left for 2 days at room temperature to give (3S, 4S) -N, N-diethyl-5-oxo-1-
The (-)-dibenzoyl-L-tartrate salt of azabicyclo [2.2.2] octane-3-carboxamide 70 was obtained as crystals. (117 g, 25%, 92% ee).
The same operation was repeated using 220 g of 13 to give 69 -(-)-dibenzoyl-L-tartrate (180 g, 31
%, 95% ee) and 70 (-)-dibenzoyl-L-
The tartrate salt (91 g, 16%, 97% ee) was obtained.

The (-)-of 70 obtained by the above two operations
The dibenzoyl-L-tartrate salt was combined, suspended in 1.5 L of ethanol, and dissolved by heating under reflux for 3 hours. The mixture was left overnight at room temperature, and the precipitated crystals were collected by filtration. The salt was removed with aqueous sodium bicarbonate, extracted with methylene chloride, dried, and concentrated to give 70 . (73 g, 18%,> 99% ee). The salt was removed by the same operation to obtain 69 (83 g, 21%,> 99% ee). Here, the optical purity (% ee) was determined by an HPLC method using an optically active column, and the absolute configuration was determined by X-ray crystallography of 70 (-)-dibenzoyl-L-tartrate.

(3R, 4R) -N, N-diethyl-5-
Oxo-1-azabicyclo [2.2.2] octane-3
-(-)-Dibenzoyl-L-tartrate salt of carboxamide 69 mp: 120-135 ° C (decomposition, no clear melting point) Elemental analysis: (1 ethanol 0.5H ₂ O) theoretical C, 60.27%; H, 6.48%; N, 4.39%,
Found C, 60.10%; H, 6.43%; N, 4.4.
5% (3S, 4S) -N, N-diethyl-5-oxo-1-
Azabicyclo [2.2.2] octane-3-carboxamide 70 (-)-dibenzoyl-L-tartrate mp: 158.7-159.3 ° C (decomposition) Elemental analysis: theoretical C , 61.85%; H, 5.88.
%; N, 4.81% Found C, 61.54%;
N, 4.81% (+)-(3R, 4R) -N, N-diethyl-5-oxo-1-azabicyclo [2.2.2] octane-3-carboxamide 69

[0347]

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Mp: 108.6-112.1 ° C. (recrystallized from ethyl acetate) Elemental analysis: theoretical, C, 64.26%; H, 8.99
%; N, 12.49% found C, 63.96%; H,
9.24%; N, 12.38% [α] _D = + 59.0 ° (c = 1.00, ethanol) (−)-(3S, 4S) -N, N-diethyl-5-oxo-1 -Azabicyclo [2.2.2] octane-3-carboxamide 70

[0349]

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Mp: 108.6-111.5 ° C. (recrystallized from ethyl acetate) Elemental analysis: theoretical C, 64.26%; H, 8.99
%; N, 12.49% found C, 63.90%; H,
9.24%; N, 12.33% [α] _D = -58.8 ° (c = 1.00, ethanol) (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-methoxy) Benzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride

[0351]

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[0352] This compound is an optical isomer of the compound of Example 31, Example 5,9 and the compound 70 as a starting material,
It could be synthesized by the same method as 19 and 20.

Mp: 215-219 ° C. IR (KBr): 3320, 3200, 1685, 15
^{05 cm -1 1 HNMR (270 MHz} , CDCl 3) δ: 7.35-
7.00 (m, 11H), 6.67 (d, J = 2.8H)
z, 1H), 5.57-5.36 (m, 2H), 4.4
8 (d, J = 11.7 Hz, 1H), 3.70-3.6
2 (m, 2H), 3.55 (s, 3H), 3.26-
2.90 (m, 5H), 2.80-2.26 (m, 2
H), 2.51-2.40 (m, 2H), 1.92-
1.80 (m, 1H), 1.70-1.66 (m, 1
H), 1.21 (d, J = 7.0 Hz, 3H) 1.18
(D, J = 7.0 Hz, 3H).

[Α] _D = + 15.5 ° (c = 1.00,
DMSO) Compound of Example 44 (3R, 4S, 5S, 6S) -5- (5-Isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3- Carboxylic acid dihydrochloride

[0355]

Embedded image

This compound is an optical isomer of the compound of Example 32 and could be synthesized from the compound of Example 43 in the same manner as in Example 21.

Mp:> 230 ° C IR (KBr): 3400, 3200, 1735, 15
^{00 cm -1 1 HNMR (270 MHz} , CDCl 3) δ ( free):
7.40-6.98 (m, 11H), 6.63 (d, J
= 8.8 Hz, 1H), 6.57 (s, 1H), 4.4
5 (d, J = 12.4 Hz, 1H), 3.50 (s, 3
H), 3.97-3.80 (m, 1H), 3.64.
(D, J = 12.4 Hz, 1H), 3.50-3.00
(M, 6H), 2.90-2.50 (m, 4H), 1.
97-1.82 (m, 1H), 1.70-1.52
(M, 1H), 1.19 (d, J = 7.0 Hz, 3H)
1.17 (d, J = 7.0 Hz, 3H).

[Α] _D = + 9.90 ° (c = 1.00,
ethanol).

Compound of Example 45 (3R, 4S, 5S, 6S) -5- (2-methoxy-5
-Methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide dihydrochloride

[0360]

Embedded image

[0361] This compound is an optical isomer of the compound of Example 33, Example 5,9 and the compound 70 as a starting material,
It could be synthesized by the same method as 19 and 20.

Mp: 218-225 ° C. IR (KBr): 3300, 3200, 1690, 14
^{95 cm -1 1 HNMR (270 MHz} , CDCl 3): 7.33-
7.10 (m, 11H), 6.72 (d, J = 2.6H
z, 1H), 6.67 (d, J = 8.4 Hz, 1H),
5.76 (1H, s), 5.42 (br s, 1H),
4.46 (d, J = 12.1 Hz, 1H), 3.85 −
3.74 (m, 1H), 3.61-3.56 (m, 1
H), 3.55 (s, 1H), 3.28-2.98
(M, 5H), 2.80-2.43 (m, 3H), 2.
42 (s, 3H), 1.92-1.65 (m, 2H) [α] _D = + 20.8 ° (c = 0.5, DMSO).

Compound of Example 46 (3R, 4S, 5S, 6S) -5- (5-methoxy-2
-Methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid dihydrochloride

[0364]

Embedded image

This compound is an optical isomer of the compound of Example 30 and could be synthesized from the compound of Example 45 in the same manner as in Example 21.

Mp: 212-215 ° C. IR (KBr): 3400, 3200, 1720, 14
^{95 cm -1 1 HNMR (270 MHz} , CDCl 3) δ ( free):
7.45-7.10 (m, 11H), 6.72 (s, 1
H), 6.65 (d, J = 8.8 Hz, 1H), 4.4
7 (d, J = 11.0 Hz, 1H), 3.53 (s, 3
H), 3.62-2.62 (m, 11H), 2.41.
(S, 3H), 2.04-1.90 (m, 1H), 1.
82-1.62 (m, 1H) [α] _D = + 12.0 ° (c = 1.00, DMSO).

Compound of Example 47 (3R, 4S, 5S, 6S) -5- (2,5 Dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide Hydrochloride

[0368]

Embedded image

[0369] This compound is an optical isomer of the compound of Example 20, Example 5,9 and the compound 70 as a starting material,
It could be synthesized by the same method as 19 and 20.

Mp: 191 ° -196 ° C. IR (KBr): 3300, 3200, 1685, 15
^{05 cm -1 1 HNMR (270 MHz} , CDCl 3): 7.33-
7.08 (m, 10H), 6.71-6.62 (m, 2
H), 6.35 (d, J = 2.9 Hz, 1H), 5.4
4 (br s, 2H), 4.46 (d, J = 12.1H
z, 1H), 3.73 (s, 3H), 3.53 (s, 3
H), 3.70-3.45 (m, 2H), 3.30-
2.93 (m, 5H), 2.75-2.60 (m, 1
H), 2.54-2.38 (m, 2H), 1.93-
1.77 (m, 1H), 1.70-1.55 (m, 1
H) [α] _D = + 18.6 ° (c = 0.5, DMSO).

Compound of Example 48 (3R, 4S, 5S, 6S) -5- (2,5 Dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid Dihydrochloride

[0372]

Embedded image

This compound is an optical isomer of the compound of Example 21 and could be synthesized from the compound of Example 47 in the same manner as in Example 21.

Mp: 238-245 ° C. IR (KBr): 3500, 1720, 1505, 14
^{40cm -1 1 HNMR (270 MHz,} CDCl 3) δ ( free):
7.32-7.02 (m, 10H), 6.71-6.5
6 (m, 2H), 6.41 (br s, 1H), 4.3
8 (d, J = 11.0 Hz, 1H), 3.68 (s, 3
H), 3.90-3.45 (m, 2H), 3.44.
(S, 3H), 3.25-2.95 (m, 4H), 2.
74-2.20 (m, 5H), 1.90-1.55
(M, 2H) [α] _D = 12.7 ° (c = 1.00, DMSO)

Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/435 ACJ A61K 31/435 ACJ (72) Inventor Masami Nakane 6-28 Kawanahonmachi, Showa-ku, Nagoya-shi, Aichi Prefecture

Claims (1)

[Claims] 1. A compound represented by the following formula (A) or (B): (Wherein Ar ¹ , Ar ² and Ar ³ are each independently an optionally substituted aryl; X is an optionally substituted alkoxy having 1 to 6 carbon atoms, an optionally substituted aryl, CONR ¹ R ² , CO ₂ R ¹ , CHR
¹ OR ² , CHR ¹ NR ² R ³ , COR ¹ or CON
Be ^{R 1 OR 2; R 1,} R 2 and R ³ are each independently hydrogen, optionally substituted carbon atoms even if the 1-6 alkyl, optionally substituted carbon atoms even if the 1-6 alkoxy Y is a substituted or unsubstituted cycloalkyl having 3 to 8 carbon atoms, an optionally substituted heterocyclic group having 1 to 5 carbon atoms or an optionally substituted aryl; Is alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons which may be substituted or cycloalkyl having 3 to 8 carbons which may be substituted; Yes; X (CH ₂ ) _n is substituted at the 4,5 or 6 position of the quinuclidine ring; Y is substituted at the 4 or 6 position of the quinuclidine ring. ) Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and a gastrointestinal disorder, a central nervous system disorder, an inflammatory disease,
Pharmaceutical compositions for the treatment of asthma, pain and migraine.