CN1140447A - Novel carbamate deriv. and medicinal composition contg. the same - Google Patents

Abstract

A carbamate derivative represented by general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof, said derivative having a muscarine M3 receptor antagonism and being useful as a preventive or remedy for digestive, respiratory or urologic diseases.

Description

New carbamate derivatives and pharmaceutical composition thereof

Technical field

The present invention relates to medicine, be specifically related to have the carbamate derivatives of M-ChR antagonistic action, its esters, its hydrate or its solvate, and the pharmaceutical composition that contains described compound.Background technology

On the basis of the research of up to now M-ChR being done, people have known can cause when compound has the M-ChR antagonistic action that bronchiectasis, gastrointestinal motility suppress, inhibition of the inhibition of gastric acid secretion, dry, platycoria, bladder contracts, hypohidrosis, tachycardia or the like.Well-known M-ChR exists with three kinds of hypotypes at least.That main is M ₁Acceptor is present in brain etc., M ₂Acceptor is present in heart etc., M ₃Acceptor is present in unstriated muscle and glandular tissue.

Known chemical compound lot has avidity to M-ChR.Especially (p.138) mainly as spasmolytic, this is because it has the height avidity and suppress its function M-ChR to coromegine for Merck Index, 11th ed..Yet, because coromegine is to the M-ChR M of all hypotypes ₁, M ₂And M ₃Avidity almost equal, and antagonistic action non-selectivity (Seitai-no Kagaku (Medical Science), 42 (5), 381 (1991)), it can cause such as palpitaition, dry, feel sick, the side effect of platycoria etc., and these side effects seemingly M-ChR antagonistic action (except required effect) cause.In these side effects, people are concerned about and M especially ₂The improvement of receptor related cardiac side effects.

In recent years, the compound of antagonism M-ChR is optionally studied.For example, Britain does not examine publication application No.2, and 249,093 have disclosed the ester derivative of the piperidines-4-alcohol of the N-replacement with following general formula: (R in following formula ₁To R ₅Definition referring to above-mentioned disclosed application.)

Yet these compounds are for muscarine M ₃The selectivity of acceptor is inadequate, and these compounds are obviously different with compound of the present invention on structural performance, and these compounds have ester bond in its basic structure.

As the patent that discloses carbamate derivatives, can quote not examination disclosed Japanese patent application (disclosing) No.4-95071.The patent application of the disclosure has disclosed the compound with following structure: (R, R in following formula ¹, R ², X and Y definition referring to above-mentioned disclosed application.)

Though this patent has usually disclosed in the compound of representing with above-mentioned general formula, can have at least one substituent phenyl as R ²Example, but embodiment 13 has only disclosed and has had the 4-xenyl compound of (having phenyl as substituent phenyl in contraposition).

On the other hand, compound of the present invention is obviously different on its structure, and as in the described formula (I) below, the X that is connected with the A ring and Y are (being the ortho position that Y always is positioned at X) that is connected with adjacent carbon atom on the A ring.

And the above-claimed cpd that is disclosed is as the compound with anti-forgetful effect, and does not disclose and the M-ChR function associated, so these compounds are also obviously different with compound of the present invention in pharmacological action.

In addition, examination disclosed Japanese patent application (disclosing) No.62-209077 has not disclosed the compound that is expressed from the next:

(L, X, R in following formula ¹, R ²With the definition of Z referring to above-mentioned disclosed application.)

That is, from this general formula broadly, this patent has disclosed (definition of each symbol is referring to above-mentioned disclosed application in the formula) is as Z and the portion C-OR that can be connected with the NH group by hydrogen bond ⁵(definition of each symbol is referring to above-mentioned patent in the formula) is as X.

The compound of property as an illustration, it has disclosed a kind of urea derivatives, wherein Z is 1-azabicyclic (2.2.2) oct-3-yl group, the aromatic ring that contains X is 2-p-methoxy-phenyl (embodiment E 14 in above-mentioned disclosed application), and carbamate derivatives, wherein Z is 8-methyl-8-azabicyclic (3.2.1) oct-3-yl group, and the aromatic ring that contains X is 2-Phenoxyphenyl (embodiment E 27 in above-mentioned disclosed application).

Yet compound of the present invention is structurally obviously different, and wherein the Y in the general formula is not a Sauerstoffatom below, and 2-p-methoxy-phenyl or 2-Phenoxyphenyl can not encircle as A-Y-R ¹Do not disclose above-claimed cpd in addition as having the compound and the M-ChR antagonistic action thereof of 5-HT antagonistic activity, so these compounds are also obviously different with compound of the present invention in pharmacological action yet.

Summary of the invention

Inventor of the present invention is for can be to muscarine M ₃Acceptor shows that optionally the compound of antagonistic action has carried out extensive studies, and successfully develops the novel carbamate derivatives with following general formula (I), and they are for muscarine M ₃Acceptor has good selectivity antagonistic action, has finished the present invention on the basis of this discovery.

Therefore, the present invention relates to carbamate derivatives, its esters, its hydrate or its solvate, and the muscarine M3 receptor antagonist that contains described compound or its pharmacy acceptable salt class by following general formula (I) expression:

Wherein each symbol has following meanings:

The A ring: phenyl ring or pyridine ring,

The B ring: on nitrogen-atoms, can have the nitrogenous saturated heterocyclic that substituting group also can be crosslinked,

R ¹: substituent phenyl be can have, cycloalkyl or cycloalkenyl group or five Yuans or six Yuans nitrogen heterocycles of 3 to 8 carbon atoms contained,

X: singly-bound or methylene radical,

Y: singly-bound, carbonyl, the methylene radical that can be replaced by hydroxyl or by formula-S (O) _lThe group of-expression, and

L:0,1 or 2 integer.

The preferred embodiment of compound of the present invention is carbamate derivatives or its esters, and wherein in above-mentioned general formula (I), the B ring is any represented group by following general formula (IIa), (IIb) and (IIc): Wherein each symbol has following meanings (hereinafter identical):

Z: by

Or The group of expression,

Z ': by

Or

Q ^-: negatively charged ion,

R ²: hydrogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl-low alkyl group, can have substituent aralkyl or be contained the low alkyl groups that the heteroatomic heterocyclic radical of 1 or 2 replaces, can have substituting group and can condense.

R ³: low alkyl group, low-grade alkenyl, low-grade alkynyl, can have substituent aralkyl or be contained the low alkyl groups that the heteroatomic heterocyclic radical of 1 or 2 replaces, can have substituting group and can condense.

R ⁴: low alkyl group, low-grade alkenyl or low-grade alkynyl,

R ⁵: low alkyl group, low-grade alkenyl, low-grade alkynyl or aralkyl,

M and n: can be identical or different, respectively be 1 to 4 integer (condition is that m+n is 3 to 5 integer),

The integer of p:1 to 3 (condition is that m+p is 3 to 5 integer),

Q:0 or 1, and

R, s and t: can be identical or inequality, respectively be 0 to 3 integer (condition is that r+s+t is 2 or 3).

Preferred example comprises carbamate derivatives or its esters, and wherein the B ring is the group by general formula (IIb) expression,

Carbamate derivatives or its esters, wherein the B ring is the group by general formula (IIc) expression,

Carbamate derivatives or its esters, wherein R ¹Be to have substituent phenyl or five Yuans nitrogen heterocycles, perhaps

Carbamate derivatives or its esters, wherein the B ring is that wherein Z is the group that is expressed from the next by the group of general formula (IIa) expression:

In addition, contain of the present invention by above-mentioned general formula (I) expression carbamate derivatives or its esters as the muscarine M of active ingredient ₃Receptor antagonist is to be used for prevention or treatment various diseases as medicine, especially with muscarine M ₃Receptor related disease (comprises respiratory tract disease, as chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis etc., urinary tract disorder, as in nervosa pollakiuria, neurologic bladder dysfunction, enuresis nocturna, unstable bladder dysfunction, cystospasm, the isochronous urinary incontinence of chronic cystitis, pollakiuria etc., and gastrointestinal tract disease, as irritable bowel syndrome, spastic colitis, diverticulitis or the like) muscarine M3 receptor antagonist.

Be described in detail compound of the present invention below.

Examples of groups by the expression of A ring comprises phenyl ring and pyridine ring, and X is adjacent on the A ring with Y bonded carbon atom.It is the ortho position that Y always is connected X.

By " having substituting group and nitrogenous saturated heterocyclic that can be crosslinked on the nitrogen-atoms " of B ring expression is by above-mentioned general formula (IIa), (IIb) or (IIc) contain the saturated rings of nitrogen-atoms in the ring structure of expression.In general formula (IIa) or the ring of B (IIb), m+n or m+p are 3 to 5 integer, so it is five Yuans to seven Yuans rings.The B ring of general formula (IIc) will be described below.

The following describes the compound (Ia when the B ring is represented by general formula (IIa) ¹) (wherein Z by

Represent) and compound (Ia ²) (wherein Z by

Expression).The illustrative example that the B that is represented by general formula (IIa) encircles comprises five Yuans to seven Yuans rings, as pyrrolidine ring, piperidine ring and hexahydroazepine ring.

When B ring by general formula (IIb) or (IIc) during expression, on the B ring, all exist crosslinked.In general formula (IIb), a nitrogen-atoms and a carbon atom are ends of the bridge, and in general formula (IIc), two carbon atoms are ends of the bridge.When B ring by general formula (IIb) or (IIc) during expression, the carbon atom that is connected with Sauerstoffatom can be any carbon atom on the ring.

The following describes the compound (Ib when the B ring is represented by general formula (IIb) ¹) (wherein Z ' by Represent) and compound (Ib ²) (wherein Z ' by Expression).The illustrative example that the B that is represented by general formula (IIb) encircles comprises five Yuans to seven Yuans rings, as quinuclidinyl, 1-azabicyclic [2.2.1] heptyl, 1-azabicyclic [3.2.1] octyl group or the like, bridge carbon atom or the carbon atom that is adjacent are the positions that is connected with Sauerstoffatom preferably.

The following describes the compound (Ic when the B ring is represented by general formula (IIc) ¹) (wherein Z by

Represent) and compound (Ic ²) (wherein Z by

Expression).

The following describes the B ring by general formula (IIc) expression, wherein the summation of r, s and t is 3.P is that 1 situation is listed in the left side one row, and p is row in the middle of 2 situation is listed in, and p is that 3 situation is listed in the right side one row.For the summation of r, s and t is that 2 situation also describes with identical method. Following group is preferably as the B ring by general formula (IIc) expression.

Though for by " Q ^-" expression the quaternary ammonium salt negatively charged ion have no particular limits; its illustrative example comprises halogen atom ion, trifluoromethanesulfonic acid root, tosic acid root, methanesulfonate or the like, and wherein the halogen atom ion is that halogen ion (as chlorion, bromide anion, iodide ion etc.) is particularly preferred.Other anionic illustrative example comprises inorganic anion, and as nitrate ion, sulfate ion, phosphate anion, carbanion or the like, carboxylic acid ion is as formate (HCOO ^-), acetate moiety (CH ₃COO ^-), propionate, oxalate, malonate or the like, and amino acid negatively charged ion is as L-glutamic acid or the like.In above-mentioned halogen ion, bromide anion or iodide ion are preferred.Like this, a kind of negatively charged ion can change into another kind of better negatively charged ion by common ion exchange reaction.

Be meant the straight or branched alkyl that contains 1 to 6 carbon atom at this used term " low alkyl group ".The illustrative example of low alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl butyl, 1, the 2-dimethyl propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl or the like.In these groups, the alkyl (as methyl, ethyl, propyl group, sec.-propyl, butyl etc.) that contains 1 to 4 carbon atom is preferred, and methyl and ethyl are preferred, and methyl is most preferred.

" low-grade alkenyl " is meant the straight or branched thiazolinyl that contains 2 to 6 carbon atoms, and its illustrative example comprises vinyl, propenyl, butenyl, methylpropenyl, ethyl propylene base, dimethyl vinyl, pentenyl, methyl butene base, dimethyl propylene thiazolinyl, ethyl propylene base, hexenyl, dimethyl butyrate thiazolinyl, methylpent thiazolinyl or the like.Propenyl and butenyl are preferred, and propenyl is preferred.

" low-grade alkynyl " is meant the straight or branched alkynyl that contains 2 to 6 carbon atoms, and its illustrative example comprises ethynyl, proyl, butynyl, methyl-prop alkynyl, pentynyl, methyl butynyl, hexin base or the like.Wherein, ethynyl and proyl are preferred, and ethynyl is preferred.

Be meant the group that the arbitrary hydrogen atom on the above-mentioned low alkyl group is substituted by cycloalkyl at this used term " cycloalkyl-low alkyl group ", as cyclohexyl methyl, cyclohexyl ethyl, cyclohexyl propyl group, cyclopentyl-methyl or the like, wherein cyclohexyl methyl and cyclopentyl-methyl are preferred.The illustrative example of " cycloalkyl " comprises the cycloalkyl that contains 3 to 8 carbon atoms, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group or the like.Wherein, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred.And cyclobutyl, cyclopentyl and cyclohexyl are preferred.

" aralkyl " is that arbitrary hydrogen atom is replaced the group that obtains by aryl in above-mentioned " low alkyl group ", and its illustrative example comprises benzyl, phenylethyl, phenyl propyl, 2-phenyl propyl or the like, and wherein benzyl and phenylethyl are preferred.Be meant aromatic hydrocarbyl at this used term " aryl ", preferably contain the aryl of 6 to 14 carbon atoms.Its illustrative example comprises phenyl, naphthyl, indenyl, anthryl and phenanthryl, and wherein phenyl or naphthyl is preferred.

" can have substituent aralkyl " at this used term and be meant that the aryl moiety in the above-mentioned aralkyl can be replaced by one or more substituting groups.Its illustrative example comprises halogen atom; carboxyl; nitro; cyano group; hydroxyl; trihalomethyl group; low alkyl group; lower alkoxy; lower alkoxycarbonyl; lower acyl; sulfydryl; lower alkylthio; alkylsulfonyl; the low alkyl group alkylsulfonyl; sulfinyl; the low alkyl group sulfinyl; sulfamyl; the lower alkane sulfoamido; formamyl; thiocarbamoyl; one or the two elementary alkyl amido formyl radical; amino; one or two elementary alkyl amido; pyrrolidyl; lower acyl amino; amidino groups; methylene-dioxy; ethylenedioxy; phenyl or the like.For low alkyl group, can with one or more hydroxyls, lower alkoxy, amino and one or two elementary alkyl amido replace.

The example of " halogen atom " comprises fluorine, chlorine, bromine and iodine.When two or more halogen atoms replace, can use any combination of these atoms.In addition, when substituting group is halogen atom, have no particular limits for substituent number.

The illustrative example of " trihalomethyl group " comprises trifluoromethyl, trichloromethyl, trisbromomethyl, three iodomethyls, dichloro brooethyl or the like.Wherein trifluoromethyl is preferred.

The illustrative example of " lower alkoxy " comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen, 2-methyl butoxy, 1,2-dimethyl propoxy-, 1-ethyl propoxy-, hexyloxy or the like.Wherein, the lower alkoxy (as methoxyl group, oxyethyl group, propoxy-, butoxy or the like) that contains the alkyl of 1 to 4 carbon atom is preferred, and methoxyl group and oxyethyl group are preferred.

The illustrative example of " lower alkoxycarbonyl " comprises methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, isopentyloxy carbonyl, tert-pentyloxy carbonyl, neopentyl oxygen carbonyl, 2-methyl butoxy carbonyl, 1,2-dimethyl propoxycarbonyl, 1-ethyl propoxycarbonyl, hexyloxy carbonyl or the like.

The illustrative example of " lower acyl " comprises formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, valeryl or the like, and wherein formyl radical, ethanoyl and propionyl are preferred.

Be meant the group that the hydrogen atom of sulfydryl is replaced by above-mentioned low alkyl group at this used term " lower alkylthio ", its illustrative example comprises methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, penta sulfenyl, own sulfenyl or the like.

" low alkyl group alkylsulfonyl " comprises methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl, butyl alkylsulfonyl, amyl group alkylsulfonyl, hexyl alkylsulfonyl or the like.

The illustrative example of " low alkyl group sulfinyl " comprises methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, sec.-propyl sulfinyl, butyl sulfinyl, amyl group sulfinyl, hexyl sulfinyl or the like.

The illustrative example of " lower alkane sulfoamido " comprises methylsulfonyl amido, ethanesulfonamide group, third sulfoamido, different third sulfoamido, fourth sulfoamido, penta sulfoamido, own sulfoamido or the like.

Be meant one or two formamyls that hydrogen atom is replaced by above-mentioned low alkyl group on the formamyl at this used term " one or two elementary alkyl amido formyl radical ", its illustrative example comprises methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, formyl-dimethylamino or the like.

Be meant one or two amino that hydrogen atom is replaced by above-mentioned low alkyl group on the amino at this used term " one or two elementary alkyl amido ", its illustrative example comprises methylamino, ethylamino, propyl group amino, dimethylamino, diethylamino, dipropyl amino or the like.

At this used term " lower acyl amino " is amino last one or two acyl aminos that hydrogen atom is replaced by above-mentioned lower acyl, and its illustrative example comprises acetamido, propionamido-, amide-based small, isobutyl amide, valeryl amido, hexanoyl amido or the like.

Be meant that at this used term " quilt is contained or two low alkyl groups that heteroatomic heterocyclic radical replaces, and can have substituting group and also can condense " above-mentioned low alkyl group is replaced the group that forms by unsaturated or saturated monocycle or annelated heterocycles base.The preferred embodiment of described heterocyclic group has and has one or two heteroatomic monocycles or two ring unsaturated heterocycle groups, and described heteroatoms is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms.Its illustrative example comprises furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, isothiazolyl isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, draw the diindyl base, indazolyl, indolizine base (indozinyl), quinolyl, quinazolyl, quinolizinyl, quinoxalinyl, the cinnolines base, benzimidazolyl-, imidazopyridyl, benzofuryl, dihydro benzo furyl, naphthyridinyl (naphthylidinyl), 1,2-benzoisoxazole base benzoxazolyl, benzothiazolyl oxazole pyridyl, isothiazole and pyridyl, benzothienyl or the like.Wherein, furyl, thienyl, pyrryl, imidazolyl, pyridyl, pyrazinyl, benzimidazolyl-, quinolyl, dihydro benzo furyl etc. are preferred.

These heterocyclic groups can have substituting group, as low alkyl group, amino, nitro, cyano group, halogen atom, trityl or the like.

Substituent example on " can have substituent phenyl " comprises halogen atom, nitro, cyano group, trihalomethyl group, amino, one or two elementary alkyl amido, hydroxyl, sulfydryl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy or the like.Wherein, nitro, amino, hydroxyl, low alkyl group and lower alkoxy are preferred.

The illustrative example of " cycloalkenyl group " comprises the cycloalkenyl group that contains 3 to 8 carbon atoms, as the l-cyclopropenyl radical, the 2-cyclopropenyl radical, 1 cyclobutene base, 2-cyclobutene base, the 1-cyclopentenyl, the 2-cyclopentenyl, the 3-cyclopentenyl, the 1-cyclohexenyl, the 2-cyclohexenyl, the 3-cyclohexenyl, the 1-cycloheptenyl, the 2-cycloheptenyl, the 3-cycloheptenyl, 1-cyclooctene base, 2-cyclooctene base, 3-cyclooctene base, 4-cyclooctene base, 2, the 4-cyclopentadienyl, 2, the 5-cyclohexadienyl, 2,4-cycloheptadiene base, 2,6-cycloheptadiene base or the like, wherein, 2-cyclopentenyl and 2-cyclohexenyl are preferred.

Be meant the group that contains the ring atom of at least one nitrogen-atoms conduct except that carbon atom at this used term " five Yuans or six Yuans nitrogen heterocycles ", this group also can contain the another kind of atom that is selected from oxygen and sulphur, its illustrative example comprises saturated heterocyclyl (as piperidyl, pyrrolidyl, morpholinyl or the like) and aromatic heterocyclic radical (as pyrryl (pyrolyl), pyridyl, thiazolyl, imidazolyl, oxazolyl or the like), and wherein piperidyl and pyrryl are preferred.

In some cases, compound of the present invention (I) can contain one or more unsymmetrical carbons, so can have optical isomer (as (R) type, (S) type or the like) and racemic modification, diastereomer or the like.Owing to exist and depend on substituent pair of key, so also can there be geometrical isomer form (as (Z) type, (E) type or the like).These mixture of isomers and isolating form include within the scope of the invention.

In the compound of the present invention (I) some can form salt with acid.The example of these salts comprises the acid salt with mineral acid (example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid or the like) or organic acid (as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, citric acid, tartrate, carbonic acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, L-glutamic acid or the like).In addition, compound of the present invention (I) can be segregated into hydrate, with the solvate or the polymorphic form of ethanol etc.(preparation method)

Compound of the present invention (I) can be prepared with various preparation methods.Described below is its typical preparation method.First kind of preparation method

(in the superincumbent reaction formula, A ring, B ring, R ¹, X and Y as defined above.)

Compound of the present invention (I) can obtain by making the isocyanate compound of being represented by general formula (III) carry out condensation reaction with the alkylol cpd of being represented by general formula (IV).

This reaction is to carry out with this compound (III) and compound (IV) that reacts corresponding quantity by stirring under the temperature that room temperature extremely refluxes in inert solvent.

The example of inert solvent comprises dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE, tetrachloroethane, methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), diox, glycol dimethyl ether, ethyl acetate, benzene, toluene, acetonitrile, methyl-sulphoxide or the like, and the mixture of these solvents, can be according to any selective solvent of various reaction conditionss.Second kind of preparation method

(in the superincumbent reaction formula, A ring, B ring, R ¹, X and Y as defined above, T ¹Expression leavings group (as halogen atom, lower alkoxy, phenoxy group, imidazolyl or the like).)

Method A: compound of the present invention (I) can obtain by making compound of being represented by logical formula V and the alkylol cpd reaction of being represented by general formula (IV).

This reaction is by stirring down and carry out with this compound (V) and compound (IV) that reacts corresponding quantity in ice-cooled temperature to room temperature (or heating when needing) in above-mentioned inert solvent.

For accelerated reaction, preferably add Lewis acid (as aluminum isopropylate or the like) or alkali (as sodium, sodium hydride, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide or the like).

Method B: compound of the present invention (I) can obtain with the compound reaction of being represented by general formula (VII) by making the compound by general formula (VI) expression.This reaction uses the processing identical with method A to carry out.The third preparation method (in the superincumbent reaction formula, A ring, B ring, R ¹, X and Y as defined above.)

Compound of the present invention (I) can obtain with the alkylol cpd reaction of being represented by general formula (IV) by making the compound by general formula (VIII) expression.

This reaction is to carry out with this compound (VIII) and compound (IV) that reacts corresponding quantity by stirring under heating in above-mentioned inert solvent.

For accelerated reaction, preferably add alkali (as sodium, sodium hydride or the like).The 4th kind of preparation method (in the superincumbent reaction formula, A ring, R ¹, R ², X and Y as defined above, B ' ring is that the Z on the B ring is the ring of NH, T ²Be above-mentioned leavings group or formyl radical.)

The 4th kind of preparation method is that a N-alkylated reaction has low alkyl group, low-grade alkenyl, low-grade alkynyl or aralkyl as B ring substituents R with preparation ²Compound (this is reflected at and hereinafter is called the N-alkylated reaction).

Compound of the present invention (Ie) obtains with the compound reaction of being represented by general formula (IX) by making the compound by general formula (Id) expression.

This reaction can be carried out according to common N-alkylated reaction.

(1) when compound (IX) is alkyl halide or alkyl sulfonic ester: this reaction is to carry out with this compound (Id) and compound (IX) that reacts corresponding quantity by stirring under the temperature that extremely heats with ice-cooled temperature in above-mentioned inert solvent.For accelerated reaction, preferably add alkali (mineral alkali for example is as salt of wormwood, yellow soda ash or the like, or organic bases, as triethylamine or the like).

(2) when compound (IX) is aldehyde: this reaction is a kind of dehydration condensation, wherein makes the compound (Id) and aldehyde (R that react corresponding quantity with this ²-CHO (IX)) and a kind of reductive agent reaction.By this alkylated reaction, the compound N-R in the above-mentioned reaction formula does not appear ², but generate compound N-CH ₂-R ²

As reductive agent, use sodium borohydride, sodium cyanoborohydride, nitrilotriacetic base sodium borohydride or the like.This reaction is by carrying out in ice-cooled temperature (under refluxing) reaction stirred to the temperature of heating in alcohol or above-mentioned inert solvent.In addition, also can be by finishing in the presence of catalyzer (as palladium-carbon, platinum oxide or the like), carrying out catalytic hydrogenation under normal pressure or the high pressure.The 5th kind of preparation method

By a kind of compound of the present invention (R wherein ²For having substituent aralkyl or, can having substituting group, and can condense by the low alkyl groups that had the heteroatomic heterocyclic radical of 1 or 2 to replace) the preparation another kind of compound of the present invention (R on the B ring wherein ²Be hydrogen atom).In a kind of preparation method, in inert solvent, stir under in room temperature to Heating temperature and react the compound (R of the present invention of corresponding quantity with this ²Be above-mentioned substituting group) and chloro-formic ester (as chloroformic acid 1-chloroethene ester), the solvolysis of using always then.In another kind of preparation method, compound of the present invention (wherein above-mentioned R ²Be benzyl, can have substituting group) in the presence of catalyzer (as palladium-charcoal, platinum oxide, palladium hydroxide or the like), carry out common hydrogenation.The 6th kind of preparation method

(in the superincumbent reaction formula, A ring, B ring, R ¹, R ³, R ⁴, R ⁵, X, Y and Q as defined above.)

In this preparation method, the N-alkylated reaction by compound (If) (wherein the amine on the B ring of compound of the present invention is secondary amine or tertiary amine) prepares quaternary ammonium compound (Ig), and the B endless belt in the compound promptly of the present invention has the compound of the group of following formula

Or As Z or Z ' like this, (condition is q=0), compound (If) is by general formula (Ia ¹), (Ib ¹) or (Ic ¹) compound of expression, and compound (Ig) is by general formula (Ia ²), (Ib ²) or (Ic ²) expression compound.When compound (If) when being secondary amine, quaternary ammonium compound (Ig) obtains by making 1mol compound (If) and 2mol alkylating agent (XI) reaction at least.

This reaction is by stirring down and carry out with this compound (If) and alkylating agent (XI) that reacts corresponding quantity in ice-cooled temperature to room temperature (or heating when needing) in inert solvent (as dimethyl formamide, chloroform, benzene, 2-butanone, acetone, tetrahydrofuran (THF) or the like).

The example of alkylating agent comprises elementary alkyl halide, low alkyl group-trifluoromethayl sulfonic acid ester, low alkyl group-p-toluenesulfonic esters, low alkyl group-methanesulfonates or the like.Elementary alkyl halide preferably wherein.The 7th kind of preparation method

(in above-mentioned reaction formula, A ring, B ring, l, R ¹, X and Y as defined above.)

In this preparation method, the amine of the B ring by the oxidation The compounds of this invention is that tertiary amine compound (If) or sulfide (Ii) make N-oxide compound (Ih) or sulfoxide or sulfone (Ij).

This reaction is at inert solvent such as chloroform, methylene dichloride etc., alcohol is as methyl alcohol, ethanol etc., in water or their mixed solvent, in ice-cooled temperature to room temperature or in case of necessity under Heating temperature, by agitate compounds (If) or (Ii) and an amount of or excessive oxygenant react.

The example of oxygenant has: organic peroxide acid such as metachloroperbenzoic acid etc., sodium periodate, hydrogen peroxide etc.The 8th kind of preparation method

(in above-mentioned reaction formula, A ring, B ring, R ¹, X and Y as defined above, Alk refers to aralkyl R ²Or R ³The low alkyl group part, D fourth finger aryl moiety.)

This preparation method is used to prepare a kind of compound, can have the aryl moiety of a substituent aralkyl to be replaced by amidino groups in this compound.That is, methods availalbe (i), (ii) or (iii) synthetic compound (Ij) with amidino groups.

(i) a kind of nitrile is changed into imidoether, then with the method for amine condensation.

At-40-0 ℃, in the presence of hydrogen chloride gas, make nitrile compound (Ii) and alcohol (as methyl alcohol, ethanol etc.) reaction, make it to change into imidoether, this product and ammonia, amine or ammonium salt (as volatile salt, ammonium chloride, ammonium acetate etc.) are reacted.With regard to solvent, can use methyl alcohol, ethanol, acetone, tetrahydrofuran (THF) etc.

(ii) a kind of nitrile is changed into thioamides, change into thioimido ester then, again with the method for amine condensation.

In the presence of organic bases (as methylamine, triethylamine, pyridine, picoline etc.), make nitrile compound (Ii) and hydrogen sulfide reaction, make thioamide compound.Also can in the presence of hydrogenchloride, make phosphorodithioic acid (O, O-diethyl ester) and nitrile compound (Ii) reaction make thioamide compound.

Make the reaction of thioamides and rudimentary alkyl halide (as methyl iodide, iodoethane etc.) generate thioimido ester, make this product and ammonia, amine or ammonium salt (as volatile salt, ammonium chloride, ammonium acetate etc.) reaction subsequently.With regard to solvent, can use methyl alcohol, ethanol, acetone, tetrahydrofuran (THF) and ethyl acetate etc.

(iii) a kind of with amine, ammonium salt, metal amide and Grignard reagent (Grignard ' s reagent) direct addition in the method for nitrile.

In suitable solvent, or under the solvent-free situation, with all ingredients (as ammonia, ammonium chloride, ammonium thiocyanate, thiocyanic acid alkylammonium (alkyl ammonium thiocyanate), MeAl (Cl) NH ₂, NaNH ₂, (CH ₃) 2NMgBr etc. adds and be formed in nitrile compound (Ii) thereby synthetic effectively compound of interest.With regard to solvent, can use chloroform, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), toluene, dimethyl formamide etc.Sometimes, can add the speed of fast response during as catalyzer significantly as aluminum chloride, tosic acid etc. when adding alkali such as sodium hydride etc. or acid.This reaction can be carried out to room temperature or under Heating temperature in the refrigerative temperature.(other preparation method)

A kind of R ²The The compounds of this invention that this aryl moiety that substituent aralkyl can be arranged is an aminophenyl can be that the The compounds of this invention of nitrophenyl makes by the described aryl moiety of another kind.In a kind of preparation method, this compound of interest is under room temperature or Heating temperature, in the presence of catalyzer (as Raney nickel, palladium charcoal, palladium, palladous oxide, palladium hydroxide etc.), be that the hydrogenation of the The compounds of this invention of nitrophenyl makes by described aryl moiety.In another preparation method, this compound of interest is to room temperature in ice-cooled temperature, or in case of necessity under Heating temperature, in strong solvent, in the presence of the metal (as iron powder, tin, zinc etc.) of the required a great deal of of reaction, by being that the reduction of the The compounds of this invention of nitrophenyl makes with described aryl moiety.

A kind of The compounds of this invention that the methylene radical Y that hydroxyl replaces arranged can be that the The compounds of this invention of carbonyl makes by Y.That is, in strong solvent (as alcohol etc.), in the presence of reductive agent (as sodium borohydride etc.), make by reducing the compound that contains carbonyl of the present invention in the refrigerative temperature to room temperature.

When producing compound of the present invention, need in some cases functional group is protected.In this case, can increase suitable going protects step to be prepared with conventional method.

The The compounds of this invention that generates is separable to become free form with purifying, or makes salt with salifying method commonly used.This separation and purifying are to be undertaken by the chemical operation of routine, as extraction, concentrate, evaporation, crystallization, filtration, recrystallization, various chromatographic processes etc.Industrial usability

The compounds of this invention is to muscarine M ₃Acceptor has avidity and selectivity.And as M ₃Receptor antagonist is used to prevent and treats various and M ₃The disease that acceptor is relevant, especially respiratory tract disease, as chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis etc., the urethral disease of oozing, as in nervosa pollakiuria, neurologic bladder dysfunction, enuresis nocturna, unstable bladder dysfunction, cystospasm, the isochronous urinary incontinence of chronic cystitis, pollakiuria etc., and gastrointestinal tract disease, as irritable bowel syndrome, spastic colitis, diverticulitis or the like.

Particularly The compounds of this invention is to being present in the M of unstriated muscle, glandular tissue etc. ₃Acceptor has higher selectivity, has surpassed the M that is present in heart etc. ₂So acceptor is as the M that heart etc. is had side effects hardly ₃Receptor antagonist, especially as chronic bronchitis, asthma, rhinitis, and the prevention and the medicine of the above-mentioned urinary incontinence, pollakiuria, enuresis nocturna, irritable bowel syndrome, chronic obstructive pulmonary disease etc., they are quite useful.

Confirm avidity and the antagonistic action thereof of The compounds of this invention with following test to M-ChR.M-ChR is in conjunction with the preparation of test a. film

Respectively from 200-350g heavy Wistar male rat (available from Japanese SLC) excision heart and lower jaw gland, each (contains 100mM sodium-chlor and 10mM magnesium chloride with 5 volume 20mM HEPES damping fluids, pH=7.5 is called the HEPES damping fluid below) mix mutually, and in the ice-cooled homogenate of formation down.Filter through gauze then, and at 4 ℃,, the granular substance that obtains is suspended in the HEPES damping fluid, again at 4 ℃, with 50,000 * g ultracentrifugation 10 minutes with 50,000 * g ultracentrifugation 10 minutes.The granular substance that obtains is suspended in the HEPES damping fluid and is kept at-80 ℃.Melt resulting sample during use and carry out following test.B. muscarine M2 receptor binding assays

The method (J.Pharmacol.Exp.Ther., 242,257-262,1987) through improved Doods etc. is used in this test.At 25 ℃ heart film, tritium-labeled quinuclidinyl benzilate and every kind of test compound are incubated 45 minutes in 0.5ml HEPES damping fluid, mix with 5ml HEPES damping fluid then, with glass filter (Whatman GF/B) suction filtration, filter washs three times with 5ml HEPES damping fluid.Be adsorbed on the radioactivity of the tritiated quinuclidinyl benzilate on the filter with liquid scintillation counter measurement.In this case, measure non-specific binding by the coromegine that adds 1 μ M.The compounds of this invention and muscarine M with dissociation constant (Ki) expression ₂The avidity of acceptor can be according to the method (Biochem.Pharmacol., 22,3099,1073) of Cheng and Prusoff, suppresses tritium-labeled part quinuclidinyl benzilate from each test compound and calculates in conjunction with 50% concentration (IC50).C. muscarine M ₃Receptor binding assays

Carry out this test with the method that is same as above-described muscarine M2 receptor binding assays, but the part that uses lower jaw gland film and use tritium-labeled N-methyl scopolamine to serve as a mark this moment.

The result: table 1 has been listed the result that the typical sample that uses The compounds of this invention carries out above-mentioned test.By table 1 as seen, The compounds of this invention (I) is to M ₃The Ki value of acceptor is 10 ^-8-10 ^-10M, so its binding ability compares M ₂Situation exceed more than 10 times.

Table 1

Embodiment	????????????Ki(nM)		????M 2/M 3
				??M 2In conjunction with test	?M 3In conjunction with test
	????1 ????2 ????3 ????4 ????7	?????25.9 ?????100 ?????14.4 ?????5.89 ?????14.7				????0.94 ????4.89 ????0.56 ????0.39 ????0.57	????27.6 ????20.4 ????25.7 ????15.2 ????25.8
Comparative example compd A coromegine			?????400 ?????0.98	????95 ????0.39	????4.2 ????2.5

Compd A: be disclosed in compound (I) coromegine among the GB2249093: (11 editions, P138) M-ChR antagonistic effect (in the body) a. carries out the test of bronchospasm to Merck Index to cavy

This test is the method (Arch.Exp.Path.Pharmak. according to Konzett etc., 195,77-74,1940) carry out, anesthesia (1.5g/kg at urethanum, i.p.) under, will be connected in the tracheae of an intubate insertion Hartley male guinea pig (400-700g) and with a breathing apparatus.In order to stop its spontaneous breathing, to its use gallamine (2mg/kg, i.v.).Use the bronchospasm sensor measurement bronchospasm of Ugo Basile system.Through methacholine chloride (methacholine) administration (5 μ g/kg, i.v.) bring out reproducible bronchospasm for twice after, each test compound after 3 minutes, once more brings out bronchospasm with methacholine chloride by being inserted in the catheter drug delivery in the external jugular vein.Calculate after each test compound administration inhibiting rate, bronchospasm before the administration is suppressed 50% compound dosage as ID bronchospasm ₅₀Value.

The result: the value of typical compound is listed in table 2.The compounds of this invention (I) demonstrates outstanding ID ₅₀Value.

Table 2

Embodiment	Bronchospasm test ID 50(mg/kg?i.v.)
		???1 ???3 ???4 ???7	????????0.0045 ????????0.0038 ????????0.0082 ????????0.0054
Coromegine	????????0.00080

B. the rhythmicity bladder contracts of rat test

(1.0g/kg under anesthesia s.c.), just carries out ligation at the end away from kidney with the both sides ureter of every Wistar female rats (140-200g) at urethanum.The conduit that inserts bladder by per urethra injects bladder bringing out the rhythmicity bladder contracts with the physiological saline of 0.5-1ml, and measures intravesical pressure with pressure transmitter.When observing 5 minutes or after the stable rhythmicity of longer time shrinks, gave each each test compound cumulatively, measured intravesical pressure after the administration in 5-10 minute through external jugular vein.Calculate after the test compound administration inhibiting rate, bladder contracts peak value before the administration is suppressed 30% compound dosage as ED the bladder contracts peak value ₃₀Value.

Typical compound the results are shown in table 3.The compounds of this invention demonstrates outstanding ED ₃₀Value.C. the salivation of rat test

With urethanum (0.8g/k, i.p.) anesthesia Wistar male rat (6 age in week).With after each test compound (control group is a solvent) administration 15 minutes, give oxotremorine with the dosage of 0.8 μ mol/kg.Every kind of medicine all passes through femoral vein (femural vein) administration.Collect and weigh and give 5 minutes endocrine salivas behind the oxotremorine.Calculating is with respect to the inhibiting rate of the salivation amount of control group, and the dosage that control group salivation amount is suppressed 50% compound is as ID ₅₀Value.

The result: the value of typical compound is listed in table 3.The ID of coromegine and OXYBUTYNIN HYDROCHLORIDE ₅₀ED during value is tested with above-mentioned rat rhythmicity bladder contracts ₃₀Be worth similar, but the ID of The compounds of this invention ₅₀Value is than above-mentioned ED ₃₀Be worth little 5-10 doubly, demonstrate it thus salivation is had more weak effect relatively.

Table 3

Embodiment	Rhythmicity bladder contracts test ED 30(mg/kg?i.v.)	Salivation test ED 50(mg/kg?i.v.)
			????2 ????4 ????15 ????61	???????0.018 ???????0.014 ???????0.058 ???????0.029	??????????0.11 ??????????0.10 ??????????0.36 ??????????0.14
The coromegine Oxybutynin	???????0.009 ???????0.24	??????????0.0084 ??????????0.18

From above-mentioned muscarine M ₃Test of acceptor avidity and muscarine M ₃Receptor antagonist test (in the body) result, The compounds of this invention (I) is to M ₃Acceptor demonstrates selectivity and higher avidity, and the muscarine M of interior rhythmicity bladder contracts of outstanding antibody and bronchospasm ₃Receptor antagonism.Therefore, can determine optionally antagonism muscarine M of The compounds of this invention (I) ₃Acceptor.In addition, its side effect (as common side effects of conventional anticholinergic such as drys) is very little.

Carrier, vehicle and other additive that use is generally used for pharmaceutical preparation can prepare the pharmaceutical composition that contains a kind of the present invention itself or its salt as active ingredient at least.

With regard to pharmaceutical carrier and vehicle, can use nontoxic solid or liquid, medicinal material.Their example comprises: lactose, Magnesium Stearate, starch, talcum powder, gelatin, agar, pectin, gum arabic, sweet oil, sesame oil, theobroma oil, ethylene glycol and other material commonly used.

Preparation of the present invention can be with the form oral administration of formulations such as tablet, pill, capsule, particle, pulvis, solution, or with formulations such as injection such as intravenous injection, intramuscular dose etc., suppository, transdermal absorption formulation, inhalation, intravesical injections without enterally administering.Although the dosage that uses depends on particular cases such as each patient's disease symptoms, age, sex, but under case of oral administration, the dosage of each grownup every day is generally 0.05-100mg, and per daily dose can be in one day single administration or in a day, divide 2-4 administration.When according to symptom needs intravenously administrable, the dosage of each grownup every day is generally 0.007-l0mg, can be in one day single administration or be divided into administration several times.

The solids composition that the present invention is used for oral administration can be made into formulations such as inert tablet, pulvis, particle.In this solids composition, at least a active ingredient is mixed mutually with at least a inert diluent, and the example of this thinner has lactose, N.F,USP MANNITOL, glucose, hydroxypropylcellulose, Microcrystalline Cellulose, starch, polyvinylpyrrolidone, silicoaluminate magnesium etc.Usually, said composition also contains additive except inert diluent, for example, and lubricant such as Magnesium Stearate etc., disintegrating agent such as calcium carboxymethylcellulose etc., stablizer such as lactose etc. and solubilizing agent such as L-glutamic acid, aspartic acid etc.Sometimes need tablet or pill are coated with the molten or enteric film of last layer stomach such as sucrose, gelatin, hydroxypropylcellulose, Hydroxypropyl Methylcellulose Phathalate etc.

The liquid composition that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension agent, syrup, elixir etc., and generally contains inert diluent such as pure water, ethanol etc.Except inert diluent, this composition also can contain auxiliary agent such as wetting agent, suspension agent etc., sweetener, spices, perfume compound, sanitas etc.

The injection that is used for parenteral admin comprises the aqueous solution or non-aqueous solution, suspension agent and the emulsion of sterilization.The example of the aqueous solution and aqueous suspension agent has distilled water for injection and physiological saline.The example of non-aqueous solution and suspension agent thereof has propylene glycol, polyoxyethylene glycol, vegetables oil such as olive wet goods, alcohol as ethanol etc. and tween 80 (Polysor-bate80).This composition also can contain auxiliary agent such as sanitas, wetting agent, emulsifying agent, dispersion agent, stablizer (as lactose), solubility promoter (as L-glutamic acid and aspartic acid) etc.This composition through as Sterile Filtration, mix sterilant or radiation carries out disinfection.The solids composition of previously prepared sterilization can be dissolved in earlier in sterile water for injection or the sterilization solvent before use.

Implement best mode of the present invention

Provide embodiments of the invention below and be used to illustrate the present invention.Compound of the present invention is not limited to the compound that the following example is described, and The compounds of this invention not only comprises the compound of above-mentioned general formula (I) expression, but also comprises their salt, hydrate, solvate, geometry and optically active isomer and their polymorphic form.Comparative example 1

Splashed into the 3.28g methyl-chloroformate down in 5 minutes in the dichloromethane solution (50ml) of 5.02g 1-(2-aminophenyl) pyrroles and 3.83g triethylamine ice-cooled, the mixture that obtains at room temperature stirs and spends the night.In mixture, add the 3.83g triethylamine again and in 5 minutes, splash into the 3.28g methyl-chloroformate down ice-cooled, then the mixture that obtains was at room temperature stirred 6 hours.In mixture, add the 3.83g triethylamine down and in 5 minutes, splash into the 3.28g methyl-chloroformate ice-cooled again.At room temperature the mixture that obtains is stirred then and spend the night.Reaction mixture mixes with the 100ml water, isolates the organic layer of formation and uses anhydrous magnesium sulfate drying, under reduced pressure boils off solvent then.The residue that obtains obtains 1.34g 1 with silica gel column chromatography (hexane/ethyl acetate=4/1) purifying, two [2-(1H-pyrroles-1-yl) phenyl] the urea colorless solids of 3-.

Infrared absorption spectrum ν _Max(KBr) cm ^-1: 3320,1662,1550

Nuclear magnetic resonance spectrum (CDCl ₃, mark in the TMS)

δ：6.30(4H，dd，J＝2.5Hz，1.8Hz)，6.46(2H，s)，

6.71(4H，dd，J＝2.4Hz，1.9Hz)，7.10-7.16(2H，m)，7.20-7.26(2H，

m)，7.32-7.38(2H，m)，8.04(2H，d，J＝7.3Hz)

Make following compounds with the method identical with comparative example 1.Comparative example 2

1, two [2-(2-tetrahydrobenzene-1-yl) phenyl] ureas of 3-;

Starting compound: 2-(2-tetrahydrobenzene-1-yl) aniline, Vinyl chloroformate;

Mass-spectrometric data (m/z, FAB): 373 (M ⁺+ 1) nuclear magnetic resonance spectrum (DMSO-d ₆, mark in the TMS)

δ：1.35-1.50(2H，m)，1.50-1.75(4H，m)，1.90-2.20(6H，m)，3.65-3.75

(2H，m)，5.63(2H，dm，J＝10.3Hz)，5.94(2H，dm，J＝10.3Hz)，7.00-

7.20 (6H, m), (2H, m), 8.18 (1H, s) embodiment 1 for 7.55-7.65

At room temperature in the toluene solution (50ml) of 1.98g 2-xenyl carboxylic acid and 1.11g triethylamine, splash into 2.89g diphenyl phosphate acylazide, stirred 1.5 hours at 60 ℃ then.Adding 1.27g 3-quinine cyclol post-heating again refluxed 6 hours.Reaction mixture is cooled to room temperature and water, saturated aqueous solution of sodium bicarbonate, water and salt water washing successively, the organic layer anhydrous sodium sulfate drying that obtains.Under reduced pressure boil off solvent.Residue obtains 2.47g N-(2-xenyl) carboxylamine (3-rubane) ester colorless solid with silica gel column chromatography (chloroform/methanol=9/1) purifying.This solid is dissolved in the 30ml ethanol and with 4ml 4N hydrogenchloride-dioxane solutions mixes, under reduced pressure boil off solvent, residual solid recrystallization in Virahol-diethyl ether obtains 2.23g one hydrochloric acid N-(2-xenyl) carboxylamine (3-rubane) ester clear crystal.Fusing point: 137-138 ℃ (i-PrOH-Et ₂O) ultimate analysis is (to C ₂₀H ₂₃N ₂O ₂Cl0.8H ₂O)

C (%) H (%) N (%) Cl (%) theoretical value 64.35 6.64 7.50 9.50 measured values 64.38 6.62 7.36 9.50 embodiment 2

To 1.00g 1, add 30mg sodium hydride (60%, in mineral oil), reaction mixture reflux 6 hours in two [2-(1H-pyrroles-1-yl) phenyl] ureas of 3-and the solution of 1.05g 3-quinine cyclol in toluene (30ml) and dimethyl formamide (1ml).After the cooling, reaction mixture washes the organic layer anhydrous magnesium sulfate drying with water again with the dilution of 30ml ethyl acetate.After under reduced pressure boiling off solvent, residue obtains 0.58g N-[2-(1H-pyrroles-1-yl) phenyl with silica gel column chromatography (chloroform/methanol=9/1) purifying] the faint yellow oily thing of carboxylamine (3-rubane) ester.This oily matter is dissolved in the 5ml ethanol and with 1ml 4N hydrogenchloride ethyl acetate solution mixes, under reduced pressure boil off solvent then, residue is recrystallization in ethanol-diethyl ether, obtains 0.35g one hydrochloric acid N-[2-(1H-pyrroles-1-yl) phenyl] carboxylamine (3-rubane) ester clear crystal.Fusing point: 183-185 ℃ (EtOH-Et ₂O) ultimate analysis is (to C ₁₈H ₂₂N ₃O ₂Cl0.2H ₂O)

C (%) H (%) N (%) Cl (%) theoretical value 61.52 6.42 11.96 10.09 measured values 61.59 6.37 11.95 10.36 embodiment 3

Add the 0.16ml methyl iodide in 2-butanone (5ml) solution of 0.46g N-(2-xenyl) carboxylamine (3-rubane) ester, mixture had been lower than in stirring at room to place under 5 ℃ the temperature and is spending the night in 5.5 hours then.Filter then and obtain sedimentary crystal, this crystal obtains 0.58g iodate 3-[[N-(2-xenyl) carbamyl with the diethyl ether washing] the oxygen base]-1-methyl quinuclidine ring light yellow crystal.

Fusing point: 220-221 ℃ of (2-butanone) ultimate analysis is (to C ₂₁H ₂₅N ₂O ₂I)

C (%) H (%) N (%) I (%) theoretical value 54.32 5.43 6.03 27.33 measured values 54.16 5.43 5.89 27.36 embodiment 4

At room temperature splash into 3.10g diphenyl phosphate acylazide in the toluene solution (30ml) of 2.00g 2-xenyl carboxylic acid and 1.22g triethylamine, reaction mixture stirred 20 minutes at 90 ℃.Then, this mixture is mixed with the dimethyl formamide solution (10ml) of 4.00g tosic acid (4-rubane) ester and 1.50g triethylamine, reheat refluxed 3 hours.After air cooling, add the 30ml ethyl acetate, wash with water again twice.With after the saturated aqueous solution of sodium bicarbonate washing, use the anhydrous magnesium sulfate drying organic layer, and under reduced pressure boil off solvent at last.(chloroform/methanol=29/1-9/1) purifying obtains 1.82gN-(2-xenyl) carboxylamine (4-rubane) ester light brown solid to residue with silica gel column chromatography.This solid is dissolved in the 30ml ethanol and with 3ml 4N hydrogenchloride ethyl acetate solution mixes, under reduced pressure boil off solvent then, gained solid recrystallization in ethanol-diethyl ether obtains 0.91g one hydrochloric acid N-(2-xenyl) carboxylamine (4-rubane) ester clear crystal.

Fusing point: 225-226 ℃ (EtOH-Et ₂O)

Ultimate analysis is (to C ₂₀H ₂₃N ₂O ₂Cl0.2H ₂O)

C (%) H (%) N (%) Cl (%) theoretical value 66.27 6.51 7.73 9.78 measured values 66.25 6.53 7.73 9.76 embodiment 5

Add the 0.11ml methyl iodide in the 2-butanone solution (5ml) of 0.57g N-(2-xenyl) carboxylamine (4-rubane) ester, reaction mixture at room temperature stirs and spends the night.After under reduced pressure boiling off solvent, add acetone residue is solidified, recrystallization obtains 0.49g iodate 4-[[N-(2-xenyl) carbamyl in acetonitrile then] the oxygen base]-1-methyl quinuclidine ring clear crystal.

Fusing point: 123-125 ℃ (acetonitrile)

Ultimate analysis is (to C ₂₁H ₂₅N ₂O ₂I1.8H ₂O)

C (%) H (%) N (%) I (%) theoretical value 50.77 5.80 5.64 25.55 measured values 50.39 5.48 5.64 25.76 embodiment 6

Use monobromethane to 2-butanone solution (10ml) bubbling of 0.97g N-(2-xenyl) carboxylamine (4-rubane) ester 20 minutes while stirring, and restir 1 hour at room temperature.Leach the crystal of separating out then, wash this crystal with 2-butanone and obtain 1.06g bromination 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1-methyl quinuclidine ring clear crystal.

Fusing point: 243-244 ℃ (2-butanone)

Ultimate analysis is (to C ₂₁H ₂₅N ₂O ₂Br)

C (%) H (%) N (%) Br (%) theoretical value 60.44 6.04 6.71 19.15 measured values 60.34 6.14 6.61 19.01 embodiment 7

Splash into the 0.11ml methyl iodide in room temperature in the acetonitrile suspension of 0.50g N-(2-xenyl) carboxylamine (4-piperidines) ester and 0.23g salt of wormwood, reaction mixture was stirring at room 23 hours.The elimination insolubles also under reduced pressure boils off solvent.Residue with silica gel column chromatography (purifying of chloroform/methanol=20/7-5/1) obtains 0.36g iodate 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1,1-lupetidine colorless solid.This solid recrystallization in methyl alcohol-diethyl ether is obtained 0.13g iodate 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1,1-lupetidine clear crystal.

Fusing point: 223-224 ℃ (methyl alcohol-diethyl ether)

Ultimate analysis is (to C ₂₀H ₂₅N ₂O ₂I0.3H ₂O)

C (%) H (%) N (%) I (%) theoretical value 52.48 5.64 6.12 27.72 measured values 52.12 5.46 6.02 28.05

The compound for preparing the following example 8-10 with the method identical with embodiment 1.Embodiment 8

One Hydrogen bromide N-(2-benzyl phenyl) carboxylamine (3-rubane) ester

Starting compound: 2-benzylbenzoic acid

Fusing point: 170-172 ℃ (acetonitrile-Virahol)

Ultimate analysis is (to C ₂₁H ₂₅N ₂O ₂Br)

C (%) H (%) N (%) Br (%) theoretical value 60.44 6.04 6.71 19.15 measured values 60.33 6.02 6.71 19.06 embodiment 9

One oxalic acid N-(2-phenyl-3-pyridyl) carboxylamine (3-rubane) ester

Starting compound: 2-phenyl nicotinic acid

Form: colourless amorphous substance

Ultimate analysis is (to C ₂₁H ₂₃N ₃O ₆1.75H ₂O)

C (%) H (%) N (%) theoretical value 56.69 6.00 9.44 measured values 56.88 5.74 9.12 mass-spectrometric data (m/z, FAB): 324 (M++1) infrared absorption spectrum ν vmax (KBr) cm-1:1724,1636,1442,1246 embodiment 10

One oxalic acid N-(2-xenyl methyl) carboxylamine (3-rubane) ester

Starting compound: 2-biphenyl acetic acid

Fusing point: 73-76 ℃ (EtOH-i-Pr ₂O)

Ultimate analysis is (to C ₂₃H ₂₆N ₂O ₆0.75H ₂O)

C (%) H (%) N (%) theoretical value 62.79 6.30 6.37 measured values 62.67 6.43 6.06 embodiment 11

Add 8.67g diphenyl phosphate acylazide in the toluene solution (150ml) of 5.95g 2-Phenylbenzoic acid and 3.34g triethylamine, reaction mixture stirred 1.5 hours at 60 ℃.Add 6.51g 1-benzyl-4-piperidines alcohol then, mixture stirring and refluxing 6 hours.Reaction soln is cooled to room temperature, and water, saturated aqueous solution of sodium bicarbonate, water and salt solution wash successively then, use anhydrous sodium sulfate drying again.Removal of solvent under reduced pressure.(chloroform/methanol=100/7-50/1) purifying obtains 11.27g N-(2-xenyl) carboxylamine (1-benzyl-4-piperidines) ester to residue with silica gel column chromatography.The above-mentioned product of 0.54g is dissolved in the 20ml ethanol, add 0.5ml 4N hydrogenchloride dioxane solution, removal of solvent under reduced pressure, residue recrystallization in ethanol-diethyl ether obtains 0.46g hydrochloric acid N-(2-xenyl) carboxylamine (1-benzyl-4-piperidines) ester clear crystal.

Fusing point: 183-184 ℃ ((EtOH-Et ₂O)

Ultimate analysis is (to C ₂₅H ₂₇N ₂O ₂Cl)

C (%) H (%) N (%) Cl (%) theoretical value 70.99 6.43 6.62 8.38 measured values 70.86 6.46 6.59 8.49

Prepare following compounds embodiment 12 with the method identical with embodiment 11

One hydrochloric acid N-(2-benzyl phenyl) carboxylamine (1-benzyl-4-piperidines) ester.

Starting compound: 2-benzylbenzoic acid

Fusing point: 218-222 ℃ (EtOH-CH ₃CN)

Ultimate analysis is (to C ₂₆H ₂₉N ₂O ₂Cl)

C (%) H (%) N (%) Cl (%) theoretical value 71.46 6.69 6.41 8.11 measured values 71.43 6.70 6.47 8.07 embodiment 13

To 1 of 11.0g N-(2-xenyl) carboxylamine (1-benzyl-4-piperidines) ester, splash into 9.2ml chloroformic acid (1-chloroethene) ester in the 2-dichloroethane solution (70ml), mixture stirring and refluxing 3 hours in room temperature.Reaction soln is cooled to room temperature and removal of solvent under reduced pressure.Residue and 70ml methanol mixed and stirring and refluxing are spent the night.Removal of solvent under reduced pressure adds the 200ml saturated aqueous solution of sodium bicarbonate, and uses chloroform extraction in residue.The organic layer that obtains is with the salt water washing and use anhydrous magnesium sulfate drying, under reduced pressure boils off solvent then.Residue solidifies with acetonitrile-diethyl ether, obtains 5.96g N-(2-xenyl) carboxylamine (4-piperidines) ester colorless solid.The above-mentioned solid of 0.76g recrystallization in acetonitrile is obtained 0.40gN-(2-xenyl) carboxylamine (4-piperidines) ester colourless crystallization.

Fusing point: 147-149 ℃ (CH ₃CN)

Ultimate analysis is (to C ₁₈H ₂₀N ₂O ₂)

C (%) H (%) N (%) theoretical value 72.95 6.80 9.45 measured values 72.91 6.75 9.49 embodiment 14

To 1 of 0.50g N-(2-xenyl) carboxylamine (4-piperidines) ester and 0.20ml 4-tolyl aldehyde, adding in a small amount the 0.72g sodium triacetoxy borohydride in batches, mixture was stirring at room 3 days in the 2-dichloroethane solution (15ml).This mixture is mixed with salt solution, solution is adjusted to pH=9, use chloroform extraction again with saturated aqueous solution of sodium bicarbonate.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying, under reduced pressure boils off solvent then.Residue obtains 0.60g N-(2-xenyl) carboxylamine [1-(4-methyl-benzyl)-4-piperidines] ester colorless oil with silica gel column chromatography (chloroform/methanol=50/1) purifying.This oily matter is dissolved in the methyl alcohol and with the 0.14g oxalic acid mixes removal of solvent under reduced pressure.To solidify the solid product recrystallization in acetonitrile-diisopropyl ether that obtains with ethanol-diethyl ether then and obtain 0.45g one oxalic acid N-(2-xenyl) carboxylamine [1-(4-methyl-benzyl)-4-piperidines] ester clear crystal.

Fusing point: 103-107 ℃ (CH ₃CN-i-Pr ₂O)

Ultimate analysis is (to C ₂₈H ₃₀N ₂O ₆0.2H ₂O)

C (%) H (%) N (%) theoretical value 68.06 6.20 5.67 measured values 68.36 6.59 5.33

The compound for preparing the following example 15-21 with the method identical with embodiment 14.Embodiment 15

One oxalic acid N-(2-xenyl) carboxylamine [1-(3-hydroxybenzyl)-4-piperidines] ester

Starting compound: 3-hydroxy benzaldehyde

Fusing point: 167-170 ℃ (CH ₃CN-EtOH)

Ultimate analysis is (to C ₂₇H ₂₈N ₂O ₇)

C (%) H (%) N (%) theoretical value 65.84 5.73 5.69 measured values 65.79 5.68 5.73 embodiment 16

Half oxalic acid N-(2-xenyl) carboxylamine [1-(4-hydroxybenzyl)-4-piperidines] ester

Starting compound: 4-hydroxy benzaldehyde

Fusing point: 140-142 ℃ (H ₂O-EtOH)

Ultimate analysis is (to C ₂₆H ₂₇N ₂O ₅1.75H ₇2O)

C (%) H (%) N (%) theoretical value 65.19 6.42 5.85 measured values 65.18 6.28 5.84 embodiment 17

One oxalic acid N-(2-xenyl) carboxylamine [1-(3-methoxy-benzyl)-4-piperidines] ester

Starting compound: meta-anisaldehyde 99

Fusing point: 136-138 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₂₈H ₃₀N ₂O ₇)

C (%) H (%) N (%) theoretical value 66.39 5.97 5.53 measured values 66.25 5.94 5.47 embodiment 18

One oxalic acid N-(2-xenyl) carboxylamine [1-(4-methoxy-benzyl)-4-piperidines] ester

Starting compound: p-anisaldehyde

Fusing point: 137-134 ℃ (CH ₃CN-i-Pr ₂O)

Ultimate analysis is (to C ₂₈H ₃₀N ₂O ₇)

C (%) H (%) N (%) theoretical value 66.39 5.97 5.53 measured values 66.06 5.92 5.48 embodiment 19

One oxalic acid N-(2-xenyl) carboxylamine [1-(4-methylthio group benzyl)-4-piperidines] ester

Starting compound: to methylthio phenyl formaldehyde

Fusing point: 149-150 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₂₈H ₃₀N ₂O ₆S)

C (%) H (%) N (%) S (%) theoretical value 64.35 5.79 5.36 6.14 measured values 64.43 5.75 5.35 6.22 embodiment 20

One fumaric acid N-(2-xenyl) carboxylamine [1-(3, the 4-methylenedioxy benzyl)-4-piperidines] ester

Starting compound: piperonylaldehyde

Fusing point: 167-162 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₃₀H ₃₀N ₂O ₈)

C (%) H (%) N (%) theoretical value 65.92 5.53 5.13 measured values 65.63 5.52 5.08 embodiment 21

Dioxalic acid N-(2-xenyl) carboxylamine [1-(4-dimethylamino benzyl)-4-piperidines] ester

Starting compound: Paradimethylaminobenzaldehyde

Fusing point: 149-152 ℃ (CH ₃CN-i-Pr ₂O)

Ultimate analysis is (to C ₃₁H ₃₅N ₃O ₁₀)

C (%) H (%) N (%) theoretical value 61.08 5.79 6.89 measured values 60.97 5.76 6.86 embodiment 22

Add chloromethyl oil of mirbane between 0.93g salt of wormwood and 0.58g in room temperature in the acetonitrile solution (15ml) of 1.0g N-(2-xenyl) carboxylamine (4-piperidines) ester, reaction mixture was stirring at room 30 hours.Elimination insolubles, and concentrated filtrate under reduced pressure use silica gel column chromatography (chloroform/methanol=98/2) purifying residue to obtain yellow unbodied N-(2-xenyl) carboxylamine [1-(the nitrobenzyl)-4-piperidines] ester of 1.5g then.The above-mentioned product of 0.62g recrystallization in ethanol is obtained 0.20g N-(2-xenyl) carboxylamine [1-(nitrobenzyl)-4-piperidines] ester clear crystal.

Fusing point: 93-94 ℃ (EtOH)

Ultimate analysis is (to C ₂₅H ₂₅N ₃O ₄)

C (%) H (%) N (%) theoretical value 69.59 5.84 9.74 measured values 69.63 5.82 9.68

The compound for preparing the following example 23-32 with the method identical with embodiment 22.Embodiment 23

N-(2-xenyl) carboxylamine [1-(to nitrobenzyl)-4-piperidines] ester.

Starting compound: to brooethyl oil of mirbane

Fusing point: 117-118 ℃ (EtOH)

Ultimate analysis is (to C ₂₅H ₂₅N ₃O ₄)

C (%) H (%) N (%) theoretical value 69.59 5.84 9.74 measured values 69.46 5.82 9.70 embodiment 24

One oxalic acid N-(2-xenyl) carboxylamine [1-(bromobenzyl)-4-piperidines] ester.

Starting compound: a bromine toluene bromide

Fusing point: 158-160 ℃ (MeOH-i-Pr ₂O)

Ultimate analysis is (to C ₂₇H ₂₇N ₃O ₆Br)

C (%) H (%) N (%) Br (%) theoretical value 58.39 4.90 5.04 14.39 measured values 58.33 4.86 5.03 14.13 embodiment 25

One oxalic acid N-(2-xenyl) carboxylamine [1-(a cyano group benzyl)-4-piperidines] ester.

Starting compound: a brooethyl benzonitrile

Fusing point: 180-184 ℃ (MeOH-EtOH)

Ultimate analysis is (to C ₂₈H ₂₇N ₃O ₆)

C (%) H (%) N (%) theoretical value 67.06 5.43 8.38 measured values 66.90 5.39 8.41 embodiment 26

One oxalic acid N-(2-xenyl) carboxylamine [1-(luorobenzyl)-4-piperidines] ester.

Starting compound: a fluorine toluene bromide

Fusing point: 185-186 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₂₇H ₂₇N ₂O ₆F)

C (%) H (%) N (%) F (%) theoretical value 65.58 5.50 5.66 3.84 measured values 65.54 5.54 5.68 3.82 embodiment 27

One oxalic acid N-(2-xenyl) carboxylamine [1-(o-chlorobenzyl)-4-piperidines] ester.

Starting compound: adjacent chlorine toluene(mono)chloride

Fusing point: 197-198 ℃ (H ₂O-EtOH)

Ultimate analysis is (to C ₂₇H ₂₇N ₂O ₆Cl)

C (%) H (%) N (%) Cl (%) theoretical value 63.47 5.33 5.48 6.94 measured values 63.55 5.31 5.51 6.88 embodiment 28

One oxalic acid N-(2-xenyl) carboxylamine [1-(m-chloro benzyl)-4-piperidines] ester.

Starting compound: m-chloro toluene bromide

Fusing point: 158-159 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₂₇H ₂₇N ₂O ₆Cl)

C (%) H (%) N (%) Cl (%) theoretical value 63.47 5.33 5.48 6.94 measured values 63.60 5.36 5.45 7.17 embodiment 29

One oxalic acid N-(2-xenyl) carboxylamine [1-(2-methyl-benzyl)-4-piperidines] ester.

Starting compound: adjacent monobromomethane toluene

Fusing point: 185-186 ℃ (Et ₂O-EtOH)

Ultimate analysis is (to C ₂₈H ₃₀N ₂O ₆):

C (%) H (%) N (%) theoretical value 68.56 6.16 5.71 measured values 68.43 6.26 5.72 embodiment 30

One oxalic acid N-(2-xenyl) carboxylamine [1-(methyl-benzyl)-4-piperidines] ester

Starting compound: a methyl chloride toluene

Fusing point: 180-181 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₈H ₃₀N ₂O ₆):

C (%) H (%) N (%) theoretical value 68.56 6.16 5.71 measured values 68.52 6.16 5.68 embodiment 31

One oxalic acid N-(2-xenyl) carboxylamine [1-(m-trifluoromethyl benzyl)-4-piperidines] ester

Starting compound: m-trifluoromethyl toluene bromide

Fusing point: 150-151 ℃ (EtOH)

Ultimate analysis: (to C ₂₈H ₂₇N ₂O ₆F ₃):

C (%) H (%) N (%) F (%) theoretical value 61.76 5.00 5.14 10.47 measured values 61.76 5.03 5.12 10.76 embodiment 32

One oxalic acid N-(2-xenyl) carboxylamine [1-(meta-methoxy carbonyl benzyl)-4-piperidines] ester

Starting compound a: bromomethyl-benzoic acid methyl ester

Fusing point: 115-116 ℃ (EtOH-Et2O)

Ultimate analysis: (to C ₂₉H ₃₀N ₂O ₈0.25H ₂O):

C (%) H (%) N (%) theoretical value 64.61 5.70 5.20 measured values 64.66 5.59 5.21 embodiment 33

1.1g N-(2-xenyl) carboxylamine [1-(nitrobenzyl)-4-piperidines] ester is dissolved in the 50ml methane, in nitrogen atmosphere, in the presence of Raney nickel, carries out catalytic reduction.The elimination Raney nickel also removes and desolvates, and residue obtains the faint yellow unbodied N-of 0.68g (2-xenyl) carboxylamine [1-(aminobenzyl)-4-piperidines] ester with silica gel column chromatography (chloroform/methanol=50/1) purifying.Above-mentioned product is dissolved in the 10ml methyl alcohol and with 2ml 4N hydrogenchloride-ethyl acetate solution mixes, under reduced pressure boil off solvent, the faint yellow solid recrystallization in ethanol-diisopropyl ether that obtains is obtained 0.15g two hydrochloric acid N-(2-xenyl) carboxylamine [1-(aminobenzyl)-4-piperidines] ester clear crystal.

Fusing point: 189-193 ℃ (EtOH-i-Pr2O)

Ultimate analysis: (to C ₂₅H ₂₉N ₃O ₂Cl ₂H ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 60.98 6.35 8.53 14.40 measured values 61.25 6.16 8.32 14.06

Prepare following compounds with being same as embodiment 33 described methods.Embodiment 34

Dioxalic acid N-(2-xenyl) carboxylamine [1-(PAB)-4-piperidines] ester

Starting compound: N-(2-xenyl) carboxylamine [1-(to nitrobenzyl)-4-piperidines] ester

Fusing point: 117-114 ℃ (CH ₃CN-i-Pr ₂O)

Ultimate analysis: (to C ₂₉H ₃₁N ₃O ₁₀0.25H ₂O):

C (%) H (%) N (%) theoretical value 59.43 5.42 7.17 measured values 59.43 5.34 7.22 embodiment 35

To with ice-cooled 0.64g N-[4-(methylol) benzyl] splash into the 0.23ml methylsulfonyl chloride in the dichloromethane solution (12ml) of trifluoroacetamide and 0.33g triethylamine, reaction mixture was stirring at room 3 hours, then reaction mixture is poured into and also used dichloromethane extraction in the water, organic layer is water and salt water washing successively, and use anhydrous sodium sulfate drying, under reduced pressure boil off solvent then.Residue is dissolved in the 5ml dimethyl formamide, this mixture is splashed into 0.74g N-(2-xenyl) carboxylamine (4-piperidines) ester and the suspension of 0.37g salt of wormwood in ice-cooled dimethyl formamide (20ml), and with reaction mixture in stirred overnight at room temperature.Then reaction mixture is poured in the water and also used ethyl acetate extraction, organic layer is water and salt water washing successively, and uses anhydrous sodium sulfate drying, under reduced pressure boils off solvent then.Residue obtains N-(2-xenyl) carboxylamine [1-(to trifluoroacetyl aminomethyl the benzyl)-4-piperidines] ester of the faint yellow oily of 1.19g with silica gel column chromatography (chloroform/methanol=100/1) purifying.Above-mentioned product is dissolved in the 20ml methyl alcohol, and mixes, then in stirred overnight at room temperature with 4ml water and 0.20g salt of wormwood.Under reduced pressure boil off solvent and residue is mixed usefulness chloroform-2-propyl alcohol extraction with water.Organic layer under reduced pressure boils off solvent again with the salt water washing and with anhydrous sodium sulfate drying.Residue is dissolved in the 20ml ethanol and with 1.5ml 4N hydrogenchloride-dioxane solutions and mixes, then removal of solvent under reduced pressure.The residue that obtains crystallization in ethanol-diethyl ether, recrystallization in ethanol-diethyl ether obtains 0.47g two hydrochloric acid N-(2-xenyl) carboxylamine [1-(to the amino methyl benzyl)-4-piperidines] ester clear crystal again.

Fusing point: 225-229 ℃ (EtOH-Et ₇2O)

Ultimate analysis: (to C ₂₆H ₃₁N ₃O ₂Cl ₂0.75H ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 62.21 6.53 8.37 14.13 measured values 62.57 6.30 8.36 13.84

Prepare following compounds with the method that is same as embodiment 3 descriptions.Embodiment 36

Iodate 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1-ethyl rubane

Starting compound: iodoethane

Fusing point: 243-245 ℃ of (decomposition) (2-butanone)

Ultimate analysis: (to C ₂₂H ₂₇N ₂O ₂I):

C (%) H (%) N (%) I (%) theoretical value 55.24 5.69 5.86 26.53 measured values 55.08 5.61 5.82 26.80

The compound for preparing the following example 37-40 with the method that is same as embodiment 22 descriptions.Embodiment 37

One oxalic acid N-(2-xenyl) carboxylamine [1-(cyclohexyl methyl)-4-piperidines] ester

Starting compound: brooethyl hexanaphthene

Fusing point: 180-181 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₇H ₃₄N ₂O ₆):

C (%) H (%) N (%) theoretical value 67.20 7.10 5.80 measured values 66.99 6.97 5.82 embodiment 38

One hydrochloric acid N-(2-xenyl) carboxylamine [1-styroyl-4-piperidines] ester

Starting compound: bromine ethylbenzene

Fusing point: 137-139 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₆H ₂₉N ₂O ₂Cl0.5H ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 70.02 6.78 6.28 7.95 measured values 70.34 7.00 6.08 7.72 embodiment 39

N-(2-xenyl) carboxylamine [1-[(1-trityl-1H-benzoglyoxaline-5-yl) methyl]-4-piperidines] ester and N-(2-xenyl) carboxylamine [1-[(1-trityl-1H-benzoglyoxaline-6-yl) methyl]-4-piperidines] mixture of ester

Starting compound: 5-chloromethyl-1-trityl-1H-benzoglyoxaline and 6-chloromethyl-1-trityl-1H-benzoglyoxaline

Mass-spectrometric data (m/z, FAB): 669 (M ⁺+ 1)

Nuclear magnetic resonance spectrum (DMSO-d ₆, mark in the TMS)

δ：1.15-1.30(1H，m)，1.35-1.50(0.5H，m)，1.50-1.60(1H，m)，

1.65-1.85(1.5H，m)，2.05-2.30(1.5H，m)，

2.50-2.65(0.5H，m)，3.20-3.45(2H，m)，4.30-4.50(1H，m)，

6.35-6.40(1H，m)，6.80-7.25(7H，m)，7.25-7.65(19H，m)，

7.80 (0.5H, s), 7.86 (0.5H, s), 8.61 (J=8.8Hz) embodiment 40 for 1H, d

Two hydrochloric acid N-(2-xenyl) carboxylamine [1-(2-pyridylmethyl)-4-piperidines] ester

Starting compound: hydrochloric acid 2-chloromethylpyridine

Fusing point: 144-150 ℃ (EtOH-CH ₃CN)

Ultimate analysis: (to C ₂₄H ₂₇N ₃O ₂Cl ₂H ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 60.25 6.11 8.78 14.82 measured values 60.51 5.85 8.81 14.75

The compound for preparing the following example 47-45 with the method that is same as embodiment 14 descriptions.Embodiment 41

Oxalic acid N-(2-xenyl) carboxylamine [1-furfuryl group-4-piperidines] ester

Starting compound: 2-furfural

Fusing point: 163-164 ℃ (EtOH-AcOEt)

Ultimate analysis: (to C ₂₅H ₂₆N ₂O ₇):

C (%) H (%) N (%) theoretical value 64.37 5.62 6.01 measured values 64.28 5.61 5.96 embodiment 42

One oxalic acid N-(2-xenyl) carboxylamine [1-(p-chlorobenzyl)-4-piperidines] ester

Starting compound: 4-chloro-benzaldehyde

Fusing point: 172-173 ℃ (EtOH)

Ultimate analysis: (to C ₂₇H ₂₇N ₂O ₆Cl0.25H ₇2O):

C (%) H (%) N (%) Cl (%) theoretical value 62.91 5.38 5.43 6.88 measured values 62.88 5.21 5.42 7.00 embodiment 43

One oxalic acid N-(2-xenyl) carboxylamine [1-(3-furyl methyl)-4-piperidines] ester

Starting compound: 3-furfural

Fusing point: 165-166 ℃ (EtOH)

Ultimate analysis: (to C ₂₅H ₂₆N ₂O ₇):

C (%) H (%) N (%) theoretical value 64.37 5.62 6.01 measured value 64.15 5.68 5.88 embodiment, 44 1 oxalic acid N-(2-xenyl) carboxylamine [1-(2-thenyl)-4-piperidines] esters

Starting compound: 2 thiophene carboxaldehyde

Fusing point: 103-105 ℃ (EtOH-Et2O)

Ultimate analysis: (to C ₂₅H ₂₆N ₂O ₆S0.25H ₂O):

C (%) H (%) N (%) S (%) theoretical value 61.65 5.48 5.75 6.58 measured values 61.69 5.52 5.59 6.56 embodiment 45

One oxalic acid N-(2-xenyl) carboxylamine [1-(3-thenyl)-4-piperidines] ester

Starting compound: 3-thiophenecarboxaldehyde

Fusing point: 147-149 ℃ (AcOEt-CH ₃CN)

Ultimate analysis: (to C ₂₅H ₂₆N ₂O ₇6S):

C (%) H (%) N (%) S (%) theoretical value 62.23 5.43 5.81 6.65 measured values 62.20 5.42 5.77 6.65

The compound for preparing the following example 46-48 with the method that is same as embodiment 1 description.Embodiment 46

One hydrochloric acid N-(2-benzoyloxy phenyl) carboxylamine (3-rubane) ester

Starting compound: 2-benzoylbenzoic acid

Fusing point: 236-238 ℃ (decomposition) (EtOH)

Ultimate analysis: (to C ₂₁H ₂₃N ₂O ₃Cl0.1H ₇2O):

C (%) H (%) N (%) Cl (%) theoretical value 64.89 6.02 7.21 9.12 measured values 64.84 5.97 7.19 8.97 embodiment 47

One hydrochloric acid N-(2 '-methyl-2-xenyl) carboxylamine (3-rubane) ester

Starting compound: 2 '-methyl-2-xenyl carboxylic acid

Fusing point: 195-196 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₁H ₂₅N ₂O ₂Cl):

C (%) H (%) N (%) Cl (%) theoretical value 67.64 6.76 7.51 9.51 measured values 67.41 6.75 7.50 9.39 embodiment 48

One fumaric acid N-(2 '-nitro-2-xenyl) carboxylamine (3-rubane) ester

Starting compound: 2 '-nitro 72-xenyl carboxylic acid

Fusing point: 156-157 ℃ (CH ₃CN-Et ₂O)

Ultimate analysis: (to C ₂₄H ₂₅N ₃O ₈):

C (%) H (%) N (%) theoretical value 57.77 5.07 9.19 measured values 57.78 5.13 9.32 embodiment 49

In the acetone soln (30ml) of the mixture 0.97g of N-(2-xenyl) carboxylamine [1-[(1-trityl-1H-benzoglyoxaline-5-yl) methyl-4-piperidines] ester and N-(2-xenyl) carboxylamine [1-[(1-trityl-1H-benzoglyoxaline-6-yl) methyl-4-piperidines] ester, add 15ml 1N hydrochloric acid, reaction mixture was stirring at room 18 hours, under reduced pressure reaction mixture is concentrated then, add saturated aqueous solution of sodium bicarbonate its pH value is adjusted to 9, use chloroform extraction again.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying.Under reduced pressure boil off solvent then and obtain N-(2-xenyl) carboxylamine [1-(1H-benzoglyoxaline-5-the ylmethyl)-4-piperidines] ester of 0.71g colorless oil.The above-mentioned product of 0.55g is dissolved in the 20ml ethanol and with 0.11g oxalic acid mixes, under reduced pressure boil off solvent then.(chloroform/methanol=10/1-5/1) purifying obtains 0.20g sesquialter oxalic acid N-(2-xenyl) carboxylamine [1-(1H-benzoglyoxaline-5-ylmethyl)-4-piperidines] ester colorless solid to residue with silica gel column chromatography.Above-mentioned product recrystallization in ethanol-diethyl ether is obtained 0.1g sesquialter oxalic acid N-(2-xenyl) carboxylamine [1-(1H-benzoglyoxaline-5-ylmethyl)-4-piperidines] ester clear crystal.

Fusing point: 197-193 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₉H ₂₉N ₄O ₈H ₂O):

C (%) H (%) N (%) theoretical value 60.10 5.39 9.67 measured values 60.12 5.17 9.66 embodiment 50

Dichloromethane solution (6ml) with 0.60g N-(2 '-methoxyl group-2-xenyl) carboxylamine (3-rubane) ester under argon gas is cooled to-60 ℃, under-50 ℃ or lower temperature, drip 3.7ml 1M boron tribromide-dichloromethane solution, reaction mixture was stirred 3 hours, during churning make temperature rise to-10 ℃ gradually.Reaction mixture is cooled to-50 ℃ and successively with 3.0ml triethylamine and 1.5ml methanol mixed, make temperature return to room temperature then, mix with water and use dichloromethane extraction.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying, under reduced pressure boils off solvent again, and (purifying of chloroform/methanol=30/1-10/1) obtains 0.25g N-(2 '-hydroxyl-2-xenyl) carboxylamine (3-rubane) ester to residue with silica gel column chromatography.Be dissolved in above-mentioned product in the 10ml ethanol and add 63mg oxalic acid, under reduced pressure boil off solvent then, residual solid recrystallization in methyl alcohol obtains 0.18g one oxalic acid N-(2 '-hydroxyl-2-xenyl) carboxylamine (3-rubane) ester clear crystal.

Fusing point: 153-155 ℃ (MeOH)

Ultimate analysis: (to C ₂₂H ₂₄N ₂O ₇0.75H ₂O):

C (%) H (%) N (%) theoretical value 59.79 5.82 6.34 measured values 59.64 5.94 6.36 embodiment 51

In the ethanolic soln (150ml) of 7.40g N-(2 '-nitro-2-xenyl) carboxylamine (3-rubane) ester, add 0.80g 10% palladium charcoal and in nitrogen atmosphere, carry out catalytic hydrogenation.The elimination catalyzer under reduced pressure boils off solvent, and residue is with silica gel column chromatography (chloroform/methanol/28% ammoniacal liquor=10/1/0.1) purifying, obtains 6.27g N-(2 '-amino-2-xenyl) carboxylamine (3-rubane) ester weak yellow foam shape material.The above-mentioned product of 2.53g is dissolved in the 50ml ethanol and with 4ml 4N hydrogenchloride-dioxane solutions mixes, under reduced pressure boil off solvent, residue adds ethanol-diethyl ether and solidifies, with the 1.69g solid product recrystallization twice in ethanol that obtains, obtain the clear crystal of the salt that N-(2 '-amino-2-xenyl) carboxylamine (3-rubane) ester and 1.9 molecule hydrochloric acid generate.

Fusing point: 156-158 ℃ (EtOH)

Ultimate analysis: (to C ₂₀H ₂₃N ₃O ₂1.9HClH ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 56.56 6.38 9.89 15.86 measured values 56.19 6.61 9.89 15.67 embodiment 52

Add the 0.21g sodium borohydride at the ice-cooled aliquot that in the ethanolic soln (40ml) of 1.91g N-(2-benzoyloxy phenyl) carboxylamine (3-rubane) ester, divides down, reaction mixture at room temperature stirred 3 hours, after boiling off solvent under the decompression, the residue dilute with water is also used ethyl acetate extraction.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying, under reduced pressure boils off solvent then.Residue obtains 1.08g N-[2-(Alpha-hydroxy benzyl) phenyl with silica gel column chromatography (chloroform/methanol=20/1-chloroform/methanol/28% ammoniacal liquor=10/1/0.1) purifying] carboxylamine (3-rubane) ester weak yellow foam shape thing.This product is dissolved in the 20ml ethanol, and mixes, under reduced pressure boil off solvent again with 0.8ml 4N hydrogenchloride-dioxane solutions.Residue adds ethanol-diethyl ether and solidifies, and recrystallization obtains 0.34g one hydrochloric acid N-[2-(Alpha-hydroxy benzyl) phenyl in ethanol then] carboxylamine (3-rubane) ester clear crystal.

Fusing point: 202-203 ℃ (EtOH)

Ultimate analysis: (to C ₂₁H ₂₅N ₂O ₃Cl):

C (%) H (%) N (%) Cl (%) theoretical value 64.86 6.48 7.20 9.12 measured values 64.76 6.53 7.22 9.12 embodiment 53

To 0.93g N-[2-(2-cyclopentenes-1-yl) phenyl] add 0.05g sodium hydride (60%) in the toluene solution (30ml) of urethanum and 0.76g 3-quinine cyclol, reaction mixture spends the night 135 ℃ of stirrings and simultaneously the ethanol that forms is removed.Reaction mixture is cooled to room temperature and mixes, use ethyl acetate extraction then with salt solution.The organic layer anhydrous sodium sulfate drying under reduced pressure boils off solvent then.Residue obtains N-[2-(2-cyclopentenes-1-yl) phenyl of the faint yellow oily of 1.10g with silica gel column chromatography (chloroform/methanol=30/1) purifying] carboxylamine (3-rubane) ester.This product is dissolved in the 30ml ethanol, and mixes, under reduced pressure boil off solvent again with 1.4ml 4N hydrogenchloride-dioxane solutions.Residue adds acetonitrile-ethyl acetate and solidifies, and recrystallization obtains 0.44g hydrochloric acid N-[2-(2-cyclopentenes-1-yl) phenyl in ethanol-ethyl acetate then] carboxylamine (3-rubane) ester clear crystal.

Fusing point: 187-182 ℃ (EtOH-AcOEt)

Ultimate analysis: (to C ₁₉H ₂₅N ₂O ₂Cl0.25H ₂O):

C (%) H (%) N (%) Cl (%) theoretical value 64.58 7.27 7.93 10.03 measured values 64.78 7.14 7.90 10.20 embodiment 54

To 0.23g N-[2-(2-tetrahydrobenzene-1-yl) phenyl] add 0.2ml 4N hydrogenchloride dioxane solution and 0.20g 10% palladium charcoal in the ethanolic soln (5ml) of carboxylamine (3-rubane) ester, in nitrogen atmosphere, carry out catalytic hydrogenation then.Behind the elimination catalyzer, under reduced pressure boil off solvent, residue mixes with sodium bicarbonate aqueous solution, uses chloroform extraction then.The organic layer anhydrous sodium sulfate drying under reduced pressure boils off solvent then.Residue is dissolved in the 5ml ethanol, adds 26mg oxalic acid, under reduced pressure boils off solvent, and recrystallization obtains 0.08g oxalic acid N-(2-cyclohexyl phenyl) carboxylamine (3-rubane) ester clear crystal in acetonitrile-diethyl ether then.

Fusing point: 102-103 ℃ (Et ₂O-CH ₃CN)

Ultimate analysis: (to C ₂₂H ₃₀N ₂O ₆0.75H ₂O):

C (%) H (%) N (%) theoretical value 61.17 7.35 6.48 measured values 61.29 7.33 6.50 embodiment 55

0.64g N-(2-xenyl) carboxylamine (3-rubane) ester is dissolved in the 15ml methylene dichloride, then at the ice-cooled 0.47g metachloroperbenzoic acid that adds down, reaction mixture at room temperature stirred 3.5 days, mixed with aqueous sodium carbonate in the reaction soln, used chloroform extraction then.The organic layer anhydrous sodium sulfate drying under reduced pressure boils off solvent then.Obtain 0.4g N-(2-xenyl) carboxylamine (1-oxidation-3-rubane) ester colorless solid, this product recrystallization in ethanol-diethyl ether obtains 0.29g N-(2-xenyl) carboxylamine (1-oxidation-3-rubane) ester clear crystal.

Fusing point: 190-191 ℃ of (decomposition) (Et ₂O-EtOH)

Ultimate analysis: (to C ₂₀H ₂₂N ₂O ₃0.2H ₂O):

C (%) H (%) N (%) theoretical value 70.24 6.60 8.19 measured values 70.41 6.56 8.05 embodiment 56

1.00g N-(2-thiophenyl phenyl) carboxylamine (3-rubane) ester is dissolved in the 30ml ethanol, and the solution that obtains mixes mutually with 0.80ml 4N hydrogenchloride-ethyl acetate solution, under reduced pressure boils off solvent then.Residue is dissolved in the 25ml ethanol, the ethanolic soln that obtains is at room temperature dripped to the 1.80g sodium periodate aqueous solution (24ml), the mixture that obtains at room temperature stirred 2 days, mixed with the 1.20g sodium periodate aqueous solution (12ml) then, at room temperature stirred 2 days again.Concentrated reaction solution under reduced pressure, the residue that obtains mix with water and use chloroform extraction.Organic layer is used anhydrous sodium sulfate drying after using the salt water washing, under reduced pressure boils off solvent then.Residue obtains 0.56g N-(2-benzene sulfonyl phenyl) carboxylamine (3-rubane) ester with silica gel column chromatography (chloroform/methanol=20/1) purifying.This product is dissolved in the 10ml ethanol, and mix with 0.4ml 4N hydrogenchloride-dioxane solutions, under reduced pressure boil off solvent, add ethyl acetate residue is solidified, recrystallization obtains 0.35g hydrochloric acid N-(2-benzene sulfonyl phenyl) carboxylamine (3-rubane) ester clear crystal in ethanol-ethyl acetate then.

Fusing point: 167-162 ℃ (AcOEt-EtOH)

Ultimate analysis: (to C ₂₀H ₂₃N ₂O ₄SCl0.25H ₂O):

C (%) H (%) N (%) S (%) Cl (%) theoretical value 56.20 5.54 6.55 7.50 8.29 measured values 56.18 5.43 6.52 7.39 8.23 embodiment 57

In ethanol (20ml) solution of 1.0g N-(2-thiophenyl phenyl) carboxylamine (3-rubane) ester, add 0.8ml 4N hydrogenchloride-ethyl acetate solution, under reduced pressure boil off solvent.Residue is dissolved in the 25ml ethanol, and the solution that obtains at room temperature drips to the 0.60g sodium periodate aqueous solution (8ml), and reaction mixture at room temperature stirs and spends the night.Concentrated reaction mixture under reduced pressure alkalizes residue with saturated aqueous solution of sodium bicarbonate then, uses chloroform extraction then.Organic layer under reduced pressure boils off solvent then with anhydrous sodium sulfate drying.Residue is dissolved in the 30ml methyl alcohol, and adds the 0.30g fumaric acid, under reduced pressure boils off solvent.Residue is crystallization in methyl alcohol-acetonitrile, and in ethanol recrystallization, obtain 0.34g one fumaric acid N-(2-phenylsulfinyl phenyl) carboxylamine (3-rubane) ester.

Fusing point: 178-179 ℃ (EtOH)

Ultimate analysis: (to C ₂₄H ₂₆N ₂O ₇S):

C (%) H (%) N (%) S (%) theoretical value 59.25 5.39 5.76 6.59 measured values 59.02 2.35 5.73 6.68

Use the method for describing in the embodiment 1 to prepare following compounds.Embodiment 58

One hydrochloric acid N-(2-xenyl) carboxylamine (3 α-8-methyl azabicyclic [3.2.1] oct-3-yl) ester.

Starting compound: tropine

Fusing point: 262-263 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₁H ₂₅N ₂O ₂Cl):

C (%) H (%) N (%) Cl (%) theoretical value 67.64 6.76 7.51 9.51 measured values 67.34 6.83 7.41 9.59

Use the method for describing in the embodiment 53 to prepare the compound of the following example 59,60.Embodiment 59

One hydrochloric acid N-(2-thiophenyl phenyl) carboxylamine (3-rubane) ester.

Starting compound: N-(2-thiophenyl phenyl) Urethylane.

Fusing point: 237-233 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₀H ₂₃N ₂O ₂SCl):

C (%) H (%) N (%) S (%) Cl (%) theoretical value 61.45 5.93 7.17 8.20 9.07 measured values 61.32 5.90 7.14 8.25 9.33 embodiment 60

Dioxalic acid N-(2-piperidino-(1-position only) phenyl) carboxylamine (3-rubane) ester.

Starting compound: N-(2-piperidino-(1-position only) phenyl) urethanum.

Fusing point: 172-173 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₃H ₃₁N ₃O ₁₀0.25H ₂O):

C (%) H (%) N (%) theoretical value 53.74 6.18 8.17 measured values 53.72 6.15 7.97

Use the method for describing similar in appearance to embodiment 2 to prepare the compound of the following example 61 and 62.Embodiment 61

Half oxalic acid N-[2-(2-tetrahydrobenzene-1-yl) phenyl] carboxylamine (3-rubane) ester.

Starting compound: 1, two [2-(2-tetrahydrobenzene-1-yl) phenyl] ureas of 3-

Fusing point: 98-100 ℃ (CH ₃CN)

Ultimate analysis: (to C ₂₁H ₂₇N ₂O ₄H ₂O):

C (%) H (%) N (%) theoretical value 64.76 7.51 7.19 measured values 64.58 7.29 7.09 embodiment 62

Oxalic acid N-[2-(2-tetrahydrobenzene-1-yl) phenyl] carboxylamine (1-benzyl-4-piperidines) ester.

Starting compound: 1, two [2-(2-tetrahydrobenzene-1-yl) phenyl] urea and the 1-benzyl-4-hydroxy piperidines of 3-

Fusing point: 118-121 ℃ (EtOH-Et ₂O)

Ultimate analysis: (to C ₂₇H ₃₂N ₂O ₆0.25H ₂O):

C (%) H (%) N (%) theoretical value 66.86 6.75 5.78 measured values 66.81 6.74 5.76 embodiment 63

Add 0.14g 3-bromopropylene in two butanone (3ml) solution of 0.30g N-(2-xenyl) carboxylamine (4-rubane) ester, reaction mixture stirred 3 hours at 60 ℃.After the cooling, filter and collect the crystal of separating out, and wash this crystal, obtain 0.40g bromination 1-allyl group-4-[[N-(2-xenyl) carbamyl with diethyl ether] the oxygen base] the rubane clear crystal.

Fusing point: 182-183 ℃ (2-butanone)

Ultimate analysis: (to C ₂₃H ₂₇N ₂O ₂Br):

C (%) H (%) N (%) Br (%) theoretical value 62.31 6.14 6.32 18.02 measured values 62.28 6.15 6.28 17.89

Use the method for describing in the embodiment 3 to prepare the compound of the following example 64-66.Embodiment 64

Iodate 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1-sec.-propyl rubane.

Starting compound: 2-iodopropane.

Fusing point: 236-239 ℃ (2-butanone)

Ultimate analysis: (to C ₂₃H ₂₉N ₂O ₂I):

C (%) H (%) N (%) I (%) theoretical value 56.10 5.94 5.69 25.77 measured values 56.22 6.02 5.64 25.52 embodiment 65

Iodate 4-[[N-(2-xenyl) carbamyl] the oxygen base]-1-propyl group rubane.

Starting compound: propyl iodide.

Fusing point: 217-218 ℃ of (decomposition) (2-butanone)

Ultimate analysis: (to C ₂₃H ₂₉N ₂O ₂I):

C (%) H (%) N (%) I (%) theoretical value 56.10 5.94 5.69 25.77 measured values 56.02 5.92 5.70 25.84 embodiment 66

Iodate 1-benzyl-3-[[N-(2-xenyl) carbamyl] the oxygen base] rubane.

Starting compound: toluene bromide.

Fusing point: 208-210 ℃ (2-butanone)

Ultimate analysis: (to C ₂₇H ₂₉N ₂O ₂Br0.25H ₂O):

C (%) H (%) N (%) Br (%) theoretical value 65.13 5.97 5.63 16.05 measured values 64.98 5.88 5.65 16.18

During the structural formula of the The compounds of this invention for preparing among the embodiment 7-66 is listed in the table below:

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Embodiment A Y R ¹X B salt

Except the compound of embodiment above-mentioned, below other The compounds of this invention is listed in.These compounds can synthesize according to route of synthesis and method that above-mentioned preparation technology and embodiment describe, also can according to those of skill in the art not the needs improved method of specifically testing with regard to the aforesaid method that can grasp synthesize.

Compd A Y R ¹X B

Compd A Y R ¹X B

Compd A Y R ¹X B

Compd A Y R ¹X B

Preparation embodiment 1

The compounds of this invention 5.0

Lactose 113.6

Microcrystalline Cellulose 28.4

Light silicon dioxide 1.5

Magnesium Stearate 1.5

With DC type mixing tank the 15g The compounds of this invention is mixed mutually with 340.8g lactose and 85.2g Microcrystalline Cellulose.With this mixture compression molding, obtain compressed flap with the roll-type compressor.With hammer mill this flap is pulverized, the meal that obtains sieves through 20 screen clothes.Material after sieving adds 4.5g light silicon dioxide and 4.5g Magnesium Stearate then, and mixes with DC type mixing tank.Mixture obtains 3000 tablets of tablets of every weight 150mg with the tabletting machine compressing tablet of punch die/punch systems with 7.5mm diameter.Preparation embodiment 2

The compounds of this invention 5.0

Lactose 95.2

W-Gum 40.8

Polyvinylpyrrolidone K25 7.5

Magnesium Stearate 1.5

METHOCEL E15LV 2.3

Polyethylene glycol 6000 0.4

Titanium dioxide 1.1

Pure talc powder 0.7

Use fluidized bed pelletizer, the 15g The compounds of this invention is mixed mutually with 285.6g lactose and 122.4g rice starch.In addition, the 22.5g polyvinylpyrrolidone is dissolved in makes a kind of binder solution in the 127.5g water.Use fluidized bed pelletizer that binder solution is sprayed on and prepare particle on the said mixture.In this particle, add the 4.5g Magnesium Stearate and use DC type mixing tank to mix.Mix products obtains sheet and heavily is 3000 tablets of tablets of 150mg with the tabletting machine compressing tablet of the punch die/punch systems with 7.5mm diameter.

In 24.2g water, add 2.3g METHOCEL E15LV, 0.4g polyethylene glycol 6000,1.1g titanium dioxide and 0.7g pure talc powder in addition and form suspension, make coating liquid.Use high speed dressing machine (High Coater) with above-mentioned 3000 tablet coatings, makes the film coating tablet of every heavy 154.5mg with coating liquid.Preparation embodiment 3 (liquid inhalant)

The 10mg The compounds of this invention is dissolved in the 90ml physiological saline, overall solution volume is adjusted to 100ml, every part of 1ml of this solution is divided in the ampoule of 1ml capacity, made liquid inhalant in 30 minutes 115 ℃ of sterilizations then with identical physiological saline.Preparation embodiment 4 (powder inhalation)

The compounds of this invention 50 μ g

Lactose 450 μ g

Amount to 500 μ g

With 5g The compounds of this invention and 45g lactose uniform mixing, and this mixture of 200mg packed into make powder inhalation (at every turn sucking 500 μ g) in the powder inhalator.

Claims (12)

1. carbamate derivatives by following general formula (I) expression, its salt, its hydrate or its solvate:

Wherein each symbol has following meanings:

The A ring: phenyl ring or pyridine ring,

The B ring: on nitrogen-atoms, can have the nitrogenous saturated heterocyclic that substituting group also can be crosslinked,

R ¹: substituent phenyl be can have, cycloalkyl or cycloalkenyl group or five Yuans or six Yuans nitrogen heterocycles of 3 to 8 carbon atoms contained,

X: singly-bound or methylene radical,

Y: singly-bound, carbonyl, the methylene radical that can be replaced by hydroxyl or by formula-S (O) ₁The group of-expression, and

1:0,1 or 2 integer.

2. carbamate derivatives as claimed in claim 1 or its salt is characterized in that wherein B ring is any represented group by following general formula (IIa), (IIb) and (IIc): Wherein each symbol has following meanings:

Z: by

Or

The group of expression,

Z ': by

Or The group of expression,

Q ^-: negatively charged ion,

R ²: hydrogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl-low alkyl group, can have substituent aralkyl or be contained the low alkyl groups that the heteroatomic heterocyclic radical of 1 or 2 replaces, can have substituting group and can condense.

R ³: low alkyl group, low-grade alkenyl, low-grade alkynyl, can have substituent aralkyl or be contained the low alkyl groups that the heteroatomic heterocyclic radical of 1 or 2 replaces, can have substituting group and can condense.

R ⁴: low alkyl group, low-grade alkenyl or low-grade alkynyl,

R ⁵: low alkyl group, low-grade alkenyl, low-grade alkynyl or aralkyl,

M and n: can be identical or different, respectively be 1 to 4 integer (condition is that m+n is 3 to 5 integer),

The integer of p:1 to 3 (condition is that m+p is 3 to 5 integer),

Q:0 or 1, and

R, s and t: can be identical or inequality, respectively be 0 to 3 integer (condition is that r+s+t is 2 or 3).

3. carbamate derivatives as claimed in claim 2 or its salt is characterized in that wherein the B ring is the group of being represented by general formula (IIb).

4. carbamate derivatives as claimed in claim 2 or its salt is characterized in that wherein the B ring is the group of being represented by general formula (IIc).

5. carbamate derivatives as claimed in claim 1 or 2 or its salt is characterized in that wherein R ¹Be to have substituent phenyl, this substituting group is selected from halogen atom, nitro, cyano group, trihalomethyl group, amino, one or two elementary alkyl amido, hydroxyl, sulfydryl, low alkyl group, low-grade alkenyl, low-grade alkynyl and lower alkoxy, perhaps five Yuans nitrogen heterocycles.

6. carbamate derivatives as claimed in claim 2 or its salt is characterized in that wherein the B ring is that wherein Z is the group that is expressed from the next by the group of general formula (IIa) expression:

7. carbamate derivatives as claimed in claim 6 or its salt is characterized in that R ³And R ⁴Can be identical or different, each represents low alkyl group.

8. a pharmaceutical composition contains carbamate derivatives as claimed in claim 1 or its pharmacy acceptable salt as active ingredient.

9. muscarine M ₃Receptor antagonist contains carbamate derivatives as claimed in claim 1 or its esters as active ingredient.

10. muscarine M as claimed in claim 9 ₃Receptor antagonist is characterized in that it is to be used for prevention or treatment and muscarine M as medicine ₃Receptor related disease, comprise respiratory tract disease, as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis, urinary tract disorder, as the urinary incontinence and the pollakiuria when nervosa pollakiuria, neurologic bladder dysfunction, enuresis nocturna, unstable bladder dysfunction, cystospasm and the chronic cystitis, and gastrointestinal tract disease, as irritable bowel syndrome, spastic colitis and diverticulitis.

11. muscarine M as claimed in claim 10 ₃Receptor antagonist, it is characterized in that it is used to prevent or the treatment of urinary tract disease as medicine, as the urinary incontinence and the pollakiuria when nervosa pollakiuria, neurologic bladder dysfunction, enuresis nocturna, unstable bladder dysfunction, cystospasm and the chronic cystitis.

12. muscarine M as claimed in claim 10 ₃Receptor antagonist is characterized in that it is used to prevent or treat respiratory tract disease as medicine, as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis.