CN102040601A - 1-N-(1-azabicyalo(2,2,2) octane ether compound and application thereof - Google Patents

Abstract

The invention relates to a 1-N-(1-azabicyalo(2,2,2) octane ether compound and application thereof. The compound comprises a 1-N-(1-azabicyalo(2,2,2) octane ether compound, a mixture of optical isomers, diastereoisomers and enantiomers of the quaternary ammonium salt of the 1-N-(1-azabicyalo(2,2,2) octane ether compound, pharmaceutically acceptable salt compounds and pharmaceutically acceptable medical compositions of the 1-N-(1-azabicyalo(2,2,2) octane ether compound. The compound provided by the invention can be used for treating diseases or symptoms related to the cholinergic systems of the central nervous system (CNS) and the peripheral nervous system (PNS), symptoms related to neurodegeneration, diseases or symptoms of the gastrointestinal tract, the respiratory tract, and the like related to smooth muscle contraction, endocrine diseases or symptoms, diseases or symptoms related to inflammations, abstinence symptoms caused by withdrawals of drug abuse as well as ocular diseases, anesthesia, septic shocks, biliary colic, urogenital tract renal colic, bladder irritation diseases, and the like.

Description

1-azabicyclo (2,2,2) octane ether compound and uses thereof

Technical field

The present invention relates to prepare 1-azabicyclo (2,2,2) octane ether compound and uses thereof.The compounds of this invention comprises optical isomer, diastereomer, the mixture of enantiomer, the pharmacologically acceptable salts compounds of 1-azabicyclo (2,2,2) octane ether compound and quaternary ammonium salt thereof, with and pharmacy acceptable drug composition.Compound involved in the present invention can be used for the treatment of and central nervous system (CNS), disease or illness that the cholinergic system of peripheral nervous system (PNS) is relevant, the illness relevant with nerve degeneration, disease or illnesss such as the gi tract relevant, respiratory tract with smooth muscle contraction, endocrinopathy or illness, disease relevant or illness with inflammation, Drug abuse give up the Withrawal symptom that causes and the application of ophthalmic diseases, anesthesia, anti-septic shock, anti-biliary colic, urogenital tract renal colic and irritative symptoms of bladder etc.

Background technology

1-azabicyclo (2,2,2) octane ether compound, especially some compound of its quaternary ammonium compound is verified has significant therapeutic action to some major diseases such as Parkinson, senile dementia, chronic obstructive pulmonary disease, urinary incontinence etc.Not only cholinolytic effect is strong for 1-azabicyclo (2,2,2) octane ether compound and quaternary ammonium salt thereof, and effect comprehensively, and longer duration is owing to it is widely used in clinical cholinolytic treatment to the selectivity that the choline hypotype has height.But how to guarantee that this compounds in the performance therapeutic action, stops it to pass through hemato encephalic barrier, make it not have the maincenter cholinolytic effect, simultaneously the side effect of heart is dropped to minimumly, be the focus of this compounds research always.

For example, recorded and narrated the 1-azabicyclo (2 that the benzyl ring amyl group replaces among the CN1475214,2,2) octane ether compound and disclose its clinical effect, patent disclosures such as CN1219513, CN1739511, CN1739517, CN1739518 this compound as the application of cholinolytic effect at aspects such as gi tract, ophthalmology, respiratory tract disease and central nervous system diseases.CN1951938 discloses the quaternary ammonium salt and the hyperfunction effect of treatment peripheral cholinergic nerve thereof of 1-azabicyclo (2,2,2) the octane ether compound of benzyl ring amyl group replacement.CN1824663 discloses the preparation method of 1-azabicyclo (2,2,2) the octane ether compound optical isomer that the benzyl ring amyl group replaces and as the purposes of cholinolytic compound.

The present invention is on the basis of a large amount of experiments, synthesized the 1-azabicyclo (2 that does not appear in the newspapers, 2,2) optical isomer of octane ethers and quaternary ammonium salt compound thereof, with and medicinal compositions, and studied described compound can be used for the treatment of with central nervous system (CNS), disease or illness that the cholinergic system of peripheral nervous system (PNS) is relevant, the illness relevant with nerve degeneration, the gi tract relevant with smooth muscle contraction, disease or illnesss such as respiratory tract, endocrinopathy or illness, disease relevant or illness with inflammation, Drug abuse give up Withrawal symptom that causes and ophthalmic diseases, anesthesia, anti-septic shock, anti-biliary colic, the application of urogenital tract renal colic and irritative symptoms of bladder etc.

Summary of the invention

The present invention relates to prepare 1-azabicyclo (2,2,2) octane ether compound and uses thereof.The compounds of this invention comprises optical isomer, diastereomer, the mixture of enantiomer, the pharmacologically acceptable salts compounds of 1-azabicyclo (2,2,2) octane ether compound and quaternary ammonium salt thereof, with and pharmacy acceptable drug composition.

Wherein, R ¹Be straight chain or the branched alkyl substituent that one or more 0-5 of having carbon atom is arranged; R ²Be aromatic heterocycle or the cycloaliphatic ring straight chain or that branched alkyl replaces that has one or more 0-10 of having carbon atom; R ³For hydrogen atom or have 1-10 carbon atom, can have 1 or 2 two key or triple-linked straight chain or branched aliphatics or aromatic group; X is heteroatomss such as N, O or S, n=0,1,2 etc.

Term as herein described " alkyl " is defined as comprising saturated monovalence hydrocarbon chain group; has straight chain; side chain or cyclic part or its combination; the non-annularity alkyl contains 1-10 carbon atom; preferred 1-6 carbon atom; cycloalkyl contains 3-8 carbon atom; also comprise such moieties; optionally replaced by 1 to 5 substituting group; substituting group is independently selected from by halogen; hydroxyl; sulfydryl; amino; nitro; cyano group; thiocyano; acyl derivative; sulfonyl-derivatives; the sulfinyl derivative; alkylamino; carboxyl; ester; ether; amido; azido-; sulfonic acid, sulfamyl; thio derivative; oxygen base ester; oxygen base amido; heterocycle; vinyl; C _1-5Alkoxyl group, C _6-10The group that aryloxy is formed.

Preferred alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl and 2, the 2-dimethyl propyl, replaced by at least one substituting group alternatively separately, substituting group is selected from the group of being made up of halogen, hydroxyl, sulfydryl, amino, nitro and cyano group.For example trifluoromethyl, trichloromethyl, 2,2,2-three chloroethyls, 1,1-dimethyl-2,2-two bromotrifluoromethanes, 1,1-dimethyl-2,2,2-three chloroethyls.

The alkoxyl group of herein mentioning, for containing 1-6 (preferably containing 1-4) carbon atom, hydrocarbon chain is side chain or straight chain.Preferred alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.

The alkenyl of herein mentioning that contains 2-7 carbon atom, for straight chain or branched, propenyl, butenyl, pentenyl, hexenyl or heptenyl for example vinyl, or straight chain or branched.Two keys can be in any position of alkenyl.

Mention herein contain 2-7 carbon atom alkynyl, for straight chain or branched, ethynyl for example, proyl, or straight chain or branched butynyl, pentynyl, alkynyl or heptyne base.Triple bond can be in any position of alkynyl.

Term used herein " cycloalkyl " expression derives from the monovalence 3-10 carbon-based group of saturated cyclic or polynuclear hydrocarbon, it can be alternatively replaced by the group that is fit to arbitrarily, comprises being not limited to one or morely be selected from alkyl or as above about the part of described other group of alkyl.Limiting examples has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclopentenyl, cyclopentyl base, suberyl, ring octyl group etc.

Term used herein " aromatic group " is defined as comprising from formed and contained the aromatic hydrocarbyl of 6-20 carbon atom by 1-3 ring; for example phenyl and naphthyl; replaced by a plurality of substituting groups alternatively separately; substituting group is independently selected from halogen, hydroxyl, sulfydryl, amino, nitro, cyano group, thiocyano, acyl derivative, sulfonyl-derivatives, sulfinyl derivative, alkylamino, carboxyl, ester, ether, amido, azido-, sulfonic acid, sulfamyl, thio derivative, oxygen base ester, oxygen base amido, heterocycle, vinyl, C _1-5Alkoxyl group, C _6-10Aryloxy, C _1-10Alkyl, C _1-10Thiazolinyl, C _1-10Alkynyl, C _1-10Haloalkyl, its condition be 2 or more multi-substituent can constitute a ring that adheres to aromatic ring.

When the ether compound of Chinese style of the present invention (I) representative and quaternary ammonium salt pharmacy acceptable salt compounds thereof, work as R ³During for hydrogen atom or other substituting groups, wherein said X ^-Represent pharmaceutically acceptable negatively charged ion.Wherein said X ^-Represent single or polyacid pharmaceutically acceptable negatively charged ion.X wherein ^-Be muriate, bromide, iodide, vitriol, nitrate, phosphoric acid salt, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate or tosilate.

Compound of the present invention can use separately, or with the effective other drug of treatment some diseases is used.For example, they can be simultaneously during respiratory system disease in treatment, respectively or sequentially with following medication combined dispensing: β ²-agonist, steroide, anti allergic drug, phosphodiesterase IN are faced upward preparation and or leukotriene D4 (LTD4) antagonist.Desired compound is at above-mentioned respiratory system disease of treatment and β ²-agonist, steroide, anti allergic drug, phosphodiesterase IN are faced upward preparation and are united that to use be useful.

Formula (I) compound is in their structure, the carbon atom that hydroxyl replaces is a chiral carbon atom, this solid center can exist R or S configuration, 1-azabicyclo (2,2,2) can there be configuration among R or the S two the 3-position in the octane structure, the raceme, diastereomer that the present invention comprises described compound with and independent isomer.

The present invention is by experimentation on animals and clinical observation, proposing above-claimed cpd can be used for the treatment of and central nervous system (CNS) in preparation, disease or illness that the cholinergic system of peripheral nervous system (PNS) is relevant, the illness relevant with nerve degeneration, the gi tract relevant with smooth muscle contraction, disease or illnesss such as respiratory tract, endocrinopathy or illness, disease relevant or illness with inflammation, Drug abuse give up Withrawal symptom that causes and ophthalmic diseases, anesthesia, anti-septic shock, anti-biliary colic, the application of urogenital tract renal colic and irritative symptoms of bladder etc.

Can be made into different modes of administration and formulation according to clinical needs, the administering mode of pharmaceutical preparation is whole body administration or topical, and that formulation comprises is oral, subcutaneous injection, intramuscular injection, intravenous drip, nasal drop or sprays.

Above-mentioned purpose of the present invention can realize by following synthetic route:

By (R)-or (S)-2-heterocycle-2-R ²-2-hydroxyl oxyethane with (R)-or (S)-reaction of 1-azabicyclo (2,2,2) octane, promptly obtain target compound 2 '-heterocycle-2 '-R ²-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether, its quaternary ammonium salt is by raceme or optical pure compound and excessive HX or R ³X (X=F ^-, Cl ^-, Br ^-, I ^-Deng) reaction obtains target compound.

Embodiment

Specify the present invention with embodiment below, these embodiment should not be construed as the limitation of the present invention that goes up in all senses.

Synthesizing of embodiment 12 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-1)

In the 250mL there-necked flask, add 1.94g (0.01mol) 2-pyrazine base-α-indyl-Alpha-hydroxy oxyethane and 1.27g (0.01mol) 3-1-azabicyclo (2,2,2) octane alcohol, anhydrous normal heptane of 50ml and 0.1g sodium hydride (content 80%).The oil bath heated and stirred slowly steams liquid, constantly replenishes normal heptane.Reaction 3h.Most of solvent is extracted in decompression out, splashes into 2N hydrochloric acid soln 5ml under the cooling, stirs, and separates out white solid.Solid filtering and dislocation in beaker, are added the strong aqua alkalization, ether extraction.With ether layer drying, steam desolventize the 1.8g title compound, productive rate 58%, fusing point: 67-69 ℃. ¹H-NMR(CDCl ₃)：δ(ppm，CD ₃Cl)，7.51(1H，m)，7.46(1H，m)，7.32(1H，m)，4.97(1H，s)，3.92(s，1H)，3.11(m，1H)，2.73(m，2H)，2.02(s，1H)，1.91-1.70(m，7H)，1.53(m，1H)，1.31(m，2H).

The preparation of embodiment 22 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether hydrochloride racemies (rac-1HCl)

With 2.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether is dissolved in the 5mL ether, the cooling of ether layer adds 2N hydrochloric acid soln 5ml, stirs and separates out solid.Filter collection solid, 95% ethyl alcohol recrystallization is used in the frozen water washing, gets the 1.5g title compound, white solid, productive rate 68%, fusing point: 101-103 ℃.H-NMR：δ(ppm，CD ₃Cl)，10.42(brs，1H)，7.57(1H，m)，7.41(1H，m)，7.34(1H，m)，4.92(1H，s)，3.96(s，1H)，3.15(m，1H)，2.72(m，2H)，2.09(s，1H)，1.99-1.75(m，7H)，1.52(m，1H)，1.39(m，2H).

The preparation of embodiment 32 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether bromate racemies (rac-1HBr)

With 2.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether is dissolved in the 5mL ether, the cooling of ether layer adds 60% bromic acid solution 4ml, stirs and separates out faint yellow solid.Filter collection solid, 95% ethyl alcohol recrystallization is used in the frozen water washing, gets the 1.7g title compound, faint yellow solid, productive rate 78%, fusing point: 94-98 ℃.H-NMR：δ(ppm，CD ₃Cl)，10.66(brs，1H)，7.34(1H，m)，7.23(1H，m)，7.09(1H，m)，4.90(1H，s)，3.91(s，1H)，3.12(m，1H)，2.74(m，2H)，2.02(s，1H)，1.91-1.77(m，7H)，1.58(m，1H)，1.33(m，2H).

Embodiment 42 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether mesylate raceme (rac-1HSO ₂CH ₃) preparation

With 2.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether is dissolved in the 5mL ether, methylsulfonic acid acid solution 3ml is gone in the cooling of ether layer, stirs and separates out faint yellow solid.Filter collection solid, 95% ethyl alcohol recrystallization is used in the frozen water washing, gets the 1.46g title compound, faint yellow solid, productive rate 72%, fusing point: 112-116 ℃.H-NMR：δ(ppm，CD ₃Cl)，10.21(br?s，1H)，7.43(1H，m)，7.23(1H，m)，7.02(1H，m)，4.94(1H，s)，3.95(s，1H)，3.65(s，3H)，3.14(m，1H)，2.72(m，2H)，2.06(s，1H)，1.94-1.71(m，7H)，1.55(m，1H)，1.37(m，2H).

Embodiment 5 Rac-N-methyl-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine salt compounded of iodine (Rac-1-CH ₃I) preparation

With 1.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether and excess iodine methane is dissolved in the 30mL acetonitrile, stirring and refluxing 5 days, the thin-layer chromatography detection reaction reaches balance, and the cooling room temperature boils off solvent, residue washs 3 times with ethyl acetate, ethyl alcohol recrystallization obtains target compound, gets yellow solid 0.56g, yield 46%, fusing point: 74-76 ℃.H-NMR：δ(ppm，DMSO)，7.45(1H，m)，7.27(1H，m)，7.04(1H，m)，4.96(1H，s)，3.99(s，1H)，3.23(s，3H)，3.15(m，1H)，2.72(m，2H)，2.04(s，1H)，1.92-1.78(m，7H)，1.54(m，1H)，1.39(m，2H).

Embodiment 6 Rac-N-ethyls-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt (Rac-1-CH ₃CH ₂Br) preparation

With 1.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether and excessive monobromethane be dissolved in the 50mL acetonitrile, stirring and refluxing 5 days, the thin-layer chromatography detection reaction reaches balance, and the cooling room temperature boils off solvent, residue washs 3 times with ethyl acetate, ethyl alcohol recrystallization obtains target compound, gets yellow solid 0.62g, yield 44%, fusing point: 104-106 ℃.H-NMR：δ(ppm，DMSO)，74-76℃。H-NMR：δ(ppm，DMSO)，7.42(1H，m)，7.23(1H，m)，7.09(1H，m)，4.95(1H，s)，3.93(s，1H)，3.24(m，3H)，3.13(m，1H)，2.77(m，2H)，2.44(m，2H)，2.07(s，1H)，1.92-1.79(m，7H)，1.52(m，1H)，1.33(m，2H).

Embodiment 7 Rac-N-sec.-propyls-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt (Rac-1-CH ₃CHBrCH ₃) preparation

With 1.0g 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether and excessive Iso-Propyl iodide be dissolved in the 50mL acetonitrile, stirring and refluxing 5 days, the thin-layer chromatography detection reaction reaches balance, and the cooling room temperature boils off solvent, residue washs 3 times with ethyl acetate, ethyl alcohol recrystallization obtains target compound, gets yellow solid 0.45g, yield 36%, fusing point: 76-79 ℃.H-NMR：δ(ppm，DMSO)，7.43(1H，m)，7.26(1H，m)，7.01(1H，m)，4.93(1H，s)，3.96(s，1H)，3.28(m，6H)，3.16(m，1H)，2.74(m，2H)，2.47(m，1H)，2.04(s，1H)，1.93-1.73(m，7H)，1.55(m，1H)，1.36(m，2H).

Embodiment 8 is optically pure 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether synthetic

Reaction conditions is with embodiment 1.

(1) (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, preparation 3R)-1): by 3R-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of R-α-carbazyl-α-indyl-Alpha-hydroxy methyl acetate.Colourless liquid, yield 44%,

(CHCl ₃, c=1.0).

(2) (2 ' R, 3S)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, preparation 3S)-1): by 3S-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of R-α-carbazyl-α-indyl-Alpha-hydroxy methyl acetate.Colourless liquid, yield 58%,

(CHCl ₃, c=1.0).

(3) (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, preparation 3S)-1): by 3R-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of R-α-carbazyl-α-indyl-Alpha-hydroxy methyl acetate.Colourless liquid, yield 41%,

(CHCl ₃, c=1.0).

(4) (2 ' S, 3S)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, preparation 3S)-1): by 3S-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of R-α-carbazyl-α-indyl-Alpha-hydroxy methyl acetate.Colourless liquid, yield 45%, (CHCl ₃, c=1.0).

Embodiment 9 is optically pure 2 '-carbazyl-2 '-indyl-2 '-preparation of oxyacetic acid-3-1-azabicyclo (2,2,2) octane ester hydrochlorides (1HCl)

Reaction conditions is with embodiment 2.

(2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether hydrochloride ((2 ' R, 3R)-1HCl): by (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, 3R)-1) and the synthetic gained of hydrochloric acid diethyl ether solution.White solid, yield 90%,

(CHCl ₃, c=1.0).

(2′R，3S)-1·HCl：

(CHCl ₃，c＝1.0)。

(2′S，3R)-1·HCl：

(CHCl ₃，c＝1.0)。

(2′S，3S)-1·HCl： (CHCl ₃，c＝1.0)。

Embodiment 10 is optically pure 2 '-pyrazinyl-2 '-indyl-2 '-preparation of hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether bromates (1HBr)

Reaction conditions is with embodiment 3.

(2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether bromate ((2 ' R, 3R)-1HBr): by (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, 3R)-1) and the synthetic gained of rare bromic acid solution.White solid, yield 80%,

(CHCl ₃, c=1.0).

(2′R，3S)-1·HBr：

(CHCl ₃，c＝1.0)。

(2′S，3R)-1·HBr：

(CHCl ₃，c＝1.0)。

(2′S，3S)-1·HBr： (CHCl ₃，c＝1.0)。

Embodiment 11 is optically pure 2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether mesylate (1HSO ₂CH ₃) preparation

Reaction conditions is with embodiment 3.

(2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether bromate ((2 ' R, 3R)-1HSO ₂CH ₃): by (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether ((2 ' R, 3R)-1) and the synthetic gained of rare bromic acid solution.White solid, yield 70%, (CHCl ₃, c=1.0).

(2′R，3S)-1·HSO ₂CH ₃： (CHCl ₃，c＝1.0)。

(2′S，3R)-1·HSO ₂CH ₃： (CHCl ₃，c＝1.0)。

(2′S，3S)-1·HSO ₂CH ₃：

(CHCl ₃，c＝1.0)。

Embodiment 12 optically pure N-methyl-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine salt compounded of iodine (1-CH ₃I) preparation

Reaction conditions is with embodiment 3.

(2 ' R, 3R)-N-methyl-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine salt compounded of iodine ((2 ' R, 3R)-1-CH ₃I) preparation: by (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether and the synthetic gained of excess iodine methane.Yellow solid, yield 68%,

(CHCl ₃, c=1.0).

(2′R，3S)-1-CH ₃I：

(CHCl ₃，c＝1.0)。。

(2′S，3R)-1-CH ₃I：

(CHCl ₃，c＝1.0)。

(2′S，3S)-1-CH ₃I：

(CHCl ₃，c＝1.0)。

Embodiment 13 optically pure N-ethyls-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt (1-CH ₃CH ₂Br) preparation

Reaction conditions is with embodiment 4.

(2 ' R, 3R)-N-ethyl-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt ((2 ' R, 3R)-1-CH ₃CH ₂Br) preparation: by (2 ' R, 3R)-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether (2 ' R, 3R)-1) and the synthetic gained of excessive monobromethane.Yellow solid, yield 67%,

(CHCl ₃, c=1.0).

(2′R，3S)-1-CH ₃CH ₂Br：

(CHCl ₃，c＝1.0)。

(2′S，3R)-1-CH ₃CH ₂Br：

(CHCl ₃，c＝1.0)。

(2′S，3S)-1-CH ₃CH ₂Br：

(CHCl ₃，c＝1.0)。

Embodiment 14 optically pure N-sec.-propyls-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt (1-CH ₃CHBrCH ₃) preparation

Reaction conditions is with embodiment 5.

(2 ' R, 3R)-N-sec.-propyl-2 '-pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether quaternary amine bromine salt ((2 ' R, 3R)-1-CH ₃CHBrCH ₃) preparation: by (2 ' R, 3R)-2 '-carbazyl-2 '-indyl-2 '-oxyacetic acid-3-1-azabicyclo (2,2,2) octane ester (synthetic gained of (2 ' R, 3R)-1) and excessive bromo propane.Yellow solid, yield 56%,

(CHCl ₃, c=1.0).

(2′R，3S)-1-CH ₃CHBrCH ₃)：

(CHCl ₃，c＝1.0)。

(2′S，3R)-1-CH ₃CHBrCH ₃)：

(CHCl ₃，c＝1.0)。

(2′S，3S)-1-CH ₃CHBrCH ₃)： (CHCl ₃，c＝1.0)。

Synthesizing of embodiment 152 '-(2-methyl) pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-2)

Reaction conditions is with embodiment 1.

2 '-(2-methyl) pyrazinyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether (rac-2) is by 3-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of α-(2-methyl) pyrazinyl-α-indyl base-Alpha-hydroxy oxyethane.White solid, fusing point: 72-74 ℃.Yield 58%.

The pharmacy acceptable salt such as hydrochloride of compound 2 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 162 '-pyrazinyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-3)

Reaction conditions is with embodiment 1.

2 '-pyrazinyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-3) are by the synthetic gained of 3-1-azabicyclo (2,2,2) octane cyclic alcohol and 2-pyrazine base-α-carbazyl-Alpha-hydroxy oxyethane.White solid, fusing point: 88-89 ℃.Yield 57%.

The pharmacy acceptable salt such as hydrochloride of compound 3 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 172 '-(2-methyl) pyrazinyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-4)

Reaction conditions is with embodiment 1.

2 '-(2-methyl) pyrazinyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ether (rac-4) is by 3-1-azabicyclo (2,2,2) octane cyclic alcohol and the synthetic gained of α-(2-methyl) pyrazinyl-α-carbazyl-Alpha-hydroxy oxyethane.White solid, fusing point: 82-84 ℃.Yield 42%.

The pharmacy acceptable salt such as hydrochloride of compound 4 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 18 2 '-pyridyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-5)

Reaction conditions is with embodiment 1,2 '-pyridyl-2 '-carbazyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-5) are by 3-1-azabicyclo (2,2,2) the synthetic gained of octane cyclic alcohol and α-carbazyl-α-pyridyl-Alpha-hydroxy oxyethane.White solid, fusing point: 61-63 ℃.Yield 53%.

The pharmacy acceptable salt such as hydrochloride of compound 5 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 19 2 '-pyridyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-6)

Reaction conditions is with embodiment 1.

2 '-pyridyl-2 '-indyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-6) are by the synthetic gained of 3-1-azabicyclo (2,2,2) octane cyclic alcohol and α-pyridyl-α-indyl-Alpha-hydroxy oxyethane.White solid, fusing point: 82-86 ℃.Yield 78%.

The pharmacy acceptable salt such as hydrochloride of compound 6 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 20 2 '-pyrazinyl-2 '-imidazolyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-7)

Reaction conditions is with embodiment 1.

2 '-pyrazinyl-2 '-imidazolyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-7) are by the synthetic gained of 3-1-azabicyclo (2,2,2) octane cyclic alcohol and 2-pyrazine base-α-cyclohexyl-Alpha-hydroxy oxyethane.White solid, fusing point: 92-94 ℃.Yield 67%.

The pharmacy acceptable salt such as hydrochloride of compound 7 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Synthesizing of embodiment 21 2 '-pyridyl-2 '-imidazolyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-8)

Reaction conditions is with embodiment 1.2 '-pyridyl-2 '-imidazolyl-2 '-hydroxyethyl-3-1-azabicyclo (2,2,2) octane ethers (rac-8) are by the synthetic gained of 3-1-azabicyclo (2,2,2) octane cyclic alcohol and α-pyridyl-α-cyclohexyl-Alpha-hydroxy oxyethane.White solid, fusing point: 128-130 ℃.Yield 58%.

The pharmacy acceptable salt such as hydrochloride of compound 8 with and the synthetic derivative with compound 1 of optical isomer, quaternary ammonium salt compound and optical isomer synthetic.

Embodiment 22: the experimental program of external medicine test of science

(1) people's M-ChR affinity

(1) cell cultures

The culture expression people Chinese hamster ovary cell (CHO) of M1, M2, M3, M4 and M5 acceptor of recombinating in Ham ' s F12 substratum, nutrient solution has 100IU/ml penicillin, 100ug/ml Streptomycin sulphate, 400ug/ml Geneticin and 5% foetal calf serum.Cell culture is supported in the humidifying incubator of 37 ℃ and 5%CO2.

(2) membrane prepare

Get the people who expresses the blue or green gill fungus alkali of M1, M2, M3, M4 and M5 acceptor and merge Chinese hamster ovary celI, be suspended in again in the phosphate buffered saline (PBS) that does not have calcium and magnesium.With cell suspension centrifugal 3 minutes (4 ℃) under 1500xg.Homogenize enchylema in 15mM Tris-HCl (Ph7.5) damping fluid contains 2mM MgCl2,0.3Mm EDTA and 1Mm EGTA in the damping fluid.Double under 40000xg centrifugal 25 minutes (4 ℃), the final solid of separating out is suspended in 7.5mM Tris-HCl (Ph7.5) damping fluid again, contain 12.5mM MgCl in the damping fluid ₂, 0.3mM EDTA, 1mM EGTA and 250mM sucrose, protein concn is 2 to 6mg/ml, is stored in the liquid nitrogen.

(3) in conjunction with measuring

According to Buckley N.J., Bonner T.l., Buckley C.M., Brann M.R., Mol.Pharmacol. (1989), 35, the described method of 469-476. is carried out combination and is measured.

25 to 50ug membranins are at room temperature cultivated in 1ml 50mM Tris-HCl (pH7.4) damping fluid, contain 2mM MgCl2 0.1nM[3H in the damping fluid]-NMS (N-methyl scopolamine, 85Ci/mmol, Apbiotech, UK) and the DMSO solution (ultimate density 1%) of the test compound of progressive concentration.In the presence of 1uM is atropinic, measure non-specific binding.Cultivate 60 (m2) or after 120 (m3) minutes, sample is passed through to soak in advance at least 2 hours glass fibre filter (Filtermat A in 0.3% polymine, Wallac, Belgium) carry out rapid vacuum filtration, stop measuring, sample is further used the flushing of the ice-cold 50mM Tris-HCl of 8mM (pH 7.4) damping fluid.Fall into a trap at Betaplate counter (Wallac) and to be captured in radioactivity on the filter.

Compound according to the present invention shows 7 to 10 Pic50 value to m3 and/or m2 acceptor.Especially compound (2 ' R, 3R)-1, (2 ' R, 3S)-4, (2 ' R, 3R)-5, (2 ' R, 3R)-1-CH3I, (2 ' R, 3S)-1-CH ₃CH ₂BrCH ₃, (2 ' R, 3S)-6-CH ₃CH ₂Br and (2 ' R, 3R)-7-CH ₃Compound exhibits such as I high affinity.

Compound according to the present invention shows 7 to 10 Pic50 value to the m4 acceptor.Especially compound (2 ' R, 3R)-2, (2 ' S, 3R)-4, (2 ' R, 3RB)-5,2 ' R, 3S)-3-CH ₃I, (2 ' S, 3S)-4-CH ₃CH ₂BrCH ₃, (2 ' R, 3S)-7-CH ₃CH ₂Br and (2 ' R, 3S)-8-CH ₃Compound exhibits such as I high affinity.

(2) to stomach, ileum, colon, gall-bladder, the spasmolysis of bladder

(1) The compounds of this invention can suppress the autonomous contraction of stripped cavy stomach, ileum, colon, gall-bladder, bladder, and stripped stomach, ileum, colon, gall-bladder, cystospasm contraction that antagonism Ach causes have tangible spasmolysis.The spasmolysis of bladder contracts obviously is better than coromegine due to its antagonism M-ChR.

(2) The compounds of this invention intravenous injection 0.01-0.05mg/kg, oral administration thing 0.1-2mg/kg all can suppress to anaesthetize the caused stomach of rabbit M-ChR, ileum, colon, gall-bladder, cystospasm contraction, the tangible spasmolysis of tool.Clinical effectiveness of the present invention is: all effective to the hyperfunction stomachache that causes of internal organ smooth muscle movement, diarrhoea, biliary colic, renal colic, the enuresis, the urinary incontinence and irritative symptoms of bladder; Tetanic and the symptom of trembling of Parkinson's disease patients can be alleviated, and hydrostomia and excessive sweating can be suppressed; Can alleviate the common cold initial stage symptom as having a stuffy nose, have a running nose etc. and acute and chronic rhinitis; Preanesthetic medication is effective; Effective to septic shock; At the expansion pupil of ophthalmology and regulate aspect the paralysis effective.

(3) application of the present invention in preparation treatment gastrointestinal tract disease medicine comprises: the treatment of A, peptide ulceration is used; B, alleviate GI tension force or move hyperfunction and be applicable to the treatment application of intestinal motility that excitation bowel syndrome, the pyridine of flesh second cause hyperfunction and dysentery and rectal distention stimulation symptom; C, inhibition salivation, the Parkinson's disease hydrostomia, the treatment of the saliva dysphagia that the esophagus mechanical obstruction is caused is used.

Application method can be selected for use oral or intramuscular injection or intravenous injection, optimum amount ranges 0.01-5mg/ time.

(4) the present invention's application in ophthalmic diseases in clinical comprises: A, expand pupil, fundoscopy and iritis, keratitis, prevent that the treatment of adhesion from using; B, be used for optometry and join the adjusting paralysis of mirror and use.

Drug formulation can be selected eye drops for use or be coated with an agent, and optimal concentration is 0.01-2%.

(5) the present invention's application in central nervous system disease in clinical mainly comprises: be used for the application of Parkinson's disease treatment.

Application method can be selected for use oral or intramuscular injection or intravenous injection, and optimum amount ranges is 0.01-10mg/ time.

(6) the present invention's application of anaesthetizing in clinical mainly is meant preanesthetic medication, and application method can be selected intramuscular injection or intravenous injection or subcutaneous injection for use, and optimum amount ranges is 0.01-10mg/ time.

(7) in the application of urogenital tract renal colic and irritative symptoms of bladder, application method can be selected for use oral or intramuscular injection or intravenous injection in clinical in the present invention, and optimum amount ranges is 0.01-10mg/ time.

(8) in the application of anti-septic shock, application method can be selected intramuscular injection or intravenous injection or subcutaneous injection for use in clinical in the present invention, and optimum amount ranges is 0.01-10mg/ time.

(9) the present invention's treatment and application aspect anti-biliary colic in clinical, application method can be selected for use oral or intramuscular injection or intravenous injection, and optimum amount ranges is 0.01-10mg/ time.

(3) experimental program of rat asthmatic model test

(1) animal is divided into 4 groups: normal control group, asthma group, Racemic isoproterenol treatment group and drug treating group at random before the laboratory animal grouping experiment after raising for 1 week under the condition of normal temperature control, illumination and free pickuping food, water.Every group is divided into again luring and breathes heavily 3 weeks, two time periods in 4 weeks and observe.

(2) the rat asthmatic model adopts the preparation of Protalbinic acid (OVA) sensitization method.1d, asthma group and each administration group rat are used 1ml suspension abdominal injection (OVA 10mg; Al (OH) ₃Dry powder 100mg) sensitization, 15d begins to lure and breathes heavily, and rat is placed in the homemade atomizing case, and the OVA solution with 1% atomizes and excites, about at every turn 30min, totally 21～28d.Carry out following experimental implementation respectively at 35d, 42d.Treatment group in lure at every turn breathe heavily before 1h give abdominal injection Racemic isoproterenol 1ml/kg, the medicine group in lure at every turn breathe heavily before 1h give injectable drug 1ml/kg body weight.Control group sucks 0.9% physiological saline in identical time abdominal injection, atomizing.

(3) to the overflow of sensitization induced lung influence last administration 1h after, rat is under vetanarcol (30mg/kg intraperitoneal injection) anesthesia, promoting the circulation of qi cannula art, interlock thing breathing apparatus (55 times/minute, ratio is 115: 1 during breathing, Tidal volume is 8ml) and self-control lung overflow device (the high 10cm of liquid level), piezotherapy is to eliminate autonomous respiration, link to each other with BL2420E+ biological function experimental system through pressure transmitter, after treating that overflow tolerance (curve) is stable, the jugular vein intubate is injected 100 μ g/m l vagusstoff 015ml to stimulate, and record gives the lung overflow value before and after the stimulant.Compare with spillway discharge difference before and after spillway discharge difference and the model control group administration before and after each administration group administration.Administration group and model control group compare, and the induced lung spillway discharge obviously reduces, and significant difference is arranged therebetween, and group is organized more obvious than three weeks all around.Illustrate the gas overflow amount is reduced, show the effect that it has the diastole tracheal smooth muscle, shown the effect similar to hormone.

The result shows from the whole animal research method, proved (2 ' R, 3R)-2, (2 ' S, 3S)-4, (2 ' R, 3S)-5, (2 ' S, 3R)-1-CH ₃I, (2 ' R, 3S)-2-CH ₃CH ₂BrCH ₃, (2 ' R, 3S)-4-CH ₃CH ₂Br and (2 ' R, 3S)-7-CH ₃Compounds such as I have the effect that airway reactivity is relievingd asthma, reduced to spasmolysis.

(4) to the effect of sensitization isolated rat lung bar

After treating that rat asthmatic model test experiments is finished, cut skin of neck rapidly, under thyroid cartilage, cut off, take out tracheae and lung tissue fast, wipe out cardiopulmonary immediately, be cut into 3mm * 3mm * 20mm lung bar along major axis at lobi inferior, place in the Magnus' bath that 10ml krebps liquid is housed, Magnus' bath is placed 37 ℃ water bath with thermostatic control and passes to the gas mixture that contains 95% oxygen, 5% carbonic acid gas.Keep per minute to feed 40～60 bubbles.The initial load of adjustment of tonicity transverter is 110g, allows tracheae spiral groove balance 60min in nutritive medium, changes liquid therebetween 3 times, adds equivalent krebps liquid 10ml at every turn.Treat that one section normal contraction curve of stable back elder generation's record as baseline, adds 100 μ g/ml vagusstoff 0.5ml then, observation and recording curve change.Each administration group rat tracheal smooth muscle relatively has significant difference to the reactive obviously reduction that vagusstoff stimulates with model group.And group is more more obvious than three week groups all around, illustrate tell compound can antagonism isolated rat tracheal smooth muscle to the reaction of vagusstoff, and result of treatment has time dependent.

Test-results shows: (2 ' R, 3R)-1, (2 ' S, 3S)-2, (2 ' R, 3S)-5, (2 ' S, 3R)-1-CH ₃I, (2 ' R, 3S)-4-CH ₃CH ₂BrCH ₃, (2 ' S, 3S)-6-CH ₃CH ₂Br and (2 ' R, 3R)-8-CH ₃Compounds such as I are attacked the contraction of sensitization isolated rat lung bar to vagusstoff also obvious antagonistic action.

Those skilled in the art's book according to the above description carry out various modifications and change to composition and method.All such modifications in the appended claims scope all are included in the scope of the present invention.

Claims (6)

1. 1-azabicyclo (2,2,2) the octane ether compound of formula (I) representative and optical isomer, diastereomer, the mixture of enantiomer, the pharmacologically acceptable salts compounds of quaternary ammonium salt thereof, with and pharmacy acceptable drug composition:

Wherein, R ¹Be straight chain or the branched alkyl substituent that one or more 0-5 of having carbon atom is arranged; R ²Be aromatic heterocycle or the cycloaliphatic ring straight chain or that branched alkyl replaces that has one or more 0-10 of having carbon atom; R ³For hydrogen atom or have 1-10 carbon atom, can have 1 or 2 two key or triple-linked straight chain or branched aliphatics or aromatic group; X is heteroatomss such as H, N, O or S, n=0,1,2 etc.

2. formula (I) compound comprises its pharmacologically acceptable salts compounds and carrier or mixing diluents compound: described X ^-Represent single or polyacid pharmaceutically acceptable negatively charged ion, be muriate, bromide, iodide, vitriol, nitrate, phosphoric acid salt, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate or tosilate; Carrier or thinner comprise β ²Agonist, steroidal, anti-allergy agent, phosphodiesterase IV inhibitors.

3. the medicine of aforementioned claim, wherein the carbon atom that replaces of hydroxyl be configured as R or S, dicyclo 3-position is configured as R or S, this compound is individual isomer, diastereomer or raceme.

4. the compound of claim 1 arbitrary claim to the claim 3 or pharmaceutical composition are used for the treatment of purposes in the medicine of uropoiesis or digestive tract diseases or illness in preparation, and described disease, obstacle or illness are relevant with smooth muscle contraction.

5. the compound of claim 1 arbitrary claim to the claim 3 or pharmaceutical composition are used for purposes with the medicine of inflammation related disease or illness in preparation, comprise inflammatory dermatosis for example acne and rosacea, enteritis, ulcerative colitis and diarrhoea, acute, chronic or recurrent is slight, moderate even serious pain, the pain, postoperative pain, the phantom limb pain that cause by migraine, neuropathic pain, chronic headache is with diabetic neuropathy, treatment back neurodynia or the relevant pain of outer nerve injury.

6. claim 1 each compound or pharmaceutical composition to the claim 3 is used for the preparation treatment, prevention or alleviate disease or obstacle or the illness that Mammals comprises the people: described disease, obstacle or illness are anxieties, cognitive disorder, study defective, memory impairment and dysfunction, presenile dementia, pseudodementia, attention deficit, attention deficit hyperactivity disorder, Parkinson's disease, the Heng Yandunshi chorea, schizophrenia, obsessional idea and behavior disorder, panic disorder, eating disorder is anorexia nervosa for example, Bulimia nerovsa and obesity, hypnolepsy, nociperception, peripheral neurophaty, autism, dislexia, tardive dyskinesia, supermotility, epilepsy, Bulimia nerovsa, posttraumatic syndrome, social phobia, somnopathy, syndrome before the menstruation, chronic fatigue syndrome, mutism etc.; Described disease, obstacle or illness are the neurodegeneration obstacles, comprise short-term hypoxia and bringing out property neurodegeneration, comprise the convulsions illness, stenocardia, and premature labor is twitched, diarrhoea, asthma, epilepsy, tardive dyskinesia, supermotility, the premature ejaculation and the difficulty of erecing; Described disease, obstacle or illness comprise the Withrawal symptom that causes with giving up of Drug abuse, and ophthalmic diseases, anesthesia, anti-septic shock, anti-biliary colic, urogenital tract renal colic and irritative symptoms of bladder are relevant.