CN1805935B - Piperidinium and pyrrolidinium derivatives as ligands for the muscarinic M3 receptor - Google Patents
Piperidinium and pyrrolidinium derivatives as ligands for the muscarinic M3 receptor Download PDFInfo
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- CN1805935B CN1805935B CN200480016629.XA CN200480016629A CN1805935B CN 1805935 B CN1805935 B CN 1805935B CN 200480016629 A CN200480016629 A CN 200480016629A CN 1805935 B CN1805935 B CN 1805935B
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Abstract
Compounds of formula (I) in salt or zwitterionic form wherein, wherein R<1>, R<2>, R<3>, R<4>, R<5>, J, L and M have the meanings as indicated in the specification, are useful for treating conditionsthat are mediated by the muscarinic M3 receptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
Description
The present invention relates to organic compound, their preparation and as the purposes of medicine.
On the one hand, the invention provides the compound of the formula I of salt or zwitterionic form:
Wherein:
R
1And R
3Be C independently of one another
3-C
15-carbocylic radical or have 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur;
R
2Be hydrogen, hydroxyl or the C that randomly replaced by hydroxyl
1-C
4-alkyl;
L and M be respectively (key and-CH
2-CH
2-), (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be C
1-C
2-alkylidene group,
Perhaps L and M are respectively (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be key; R
4Be C
1-C
4-alkyl;
R
5By-SO-R
6,-S (=O)
2-R
6,-CO-R
6,-CO-O-R
6,-CO-NH-R
6Or-R
7The C that replaces
1-alkyl,
Perhaps R
5By-O-R
6,-S-R
6,-SO-R
6,-S (=O)
2-R
6,-CO-R
6,-O-CO-R
6,-CO-O-R
6,-NH-CO-R
6,-CO-NH-R
6,-R
7Or-R
8The C that replaces
2-C
10-alkyl,
Perhaps R
5Be randomly by-R
7Or-R
8The C that replaces
2-C
10-alkenyl or C
2-C
10-alkynyl;
R
6Be C
3-C
15-carbocylic radical or have 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur,
Perhaps R
6Be randomly by C
1-C
10-alkoxyl group ,-O-R
7, C
3-C
15-carbocylic radical or have the C that 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur replaces
1-C
10-alkyl;
R
7It is 5-to 12-element heterocycle base with at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur; And R
8Be C
3-C
15-carbocylic radical.
Used term has following implication in this specification sheets:
" randomly be substituted " and refer to related group and can on one or more positions, be replaced by described any substituting group or described substituent any combination.
" halo " used herein or " halogen " expression belongs to the element of the periodic table of elements the 17th family (VII family in the past), and it can be for example fluorine, chlorine, bromine or iodine.Halo or halogen be fluorine, chlorine or bromine preferably.
" C used herein
1-C
10-alkyl " expression has the straight or branched alkyl of 1 to 10 carbon atom.C
1-C
10-alkyl is C preferably
1-C
5-alkyl, for example C
1-C
4-alkyl.
" C used herein
1-C
10-alkylidene group " expression has the straight or branched alkylidene group of 1 to 10 carbon atom.C
1-C
10-alkylidene group is C preferably
1-C
4-alkylidene group.
" C used herein
2-C
10-alkenyl " expression has the straight or branched alkenyl of 2 to 10 carbon atoms.C
2-C
10-alkenyl is C preferably
2-C
4-alkenyl.
" C used herein
2-C
10-alkynyl " expression has the straight or branched alkynyl of 2 to 10 carbon atoms.C
2-C
10-alkynyl is C preferably
2-C
8-alkynyl, for example C
2-C
4-alkynyl.
" C used herein
1-C
10-alkoxyl group " expression has the straight or branched alkoxyl group of 1 to 10 carbon atom.C
1-C
10-alkoxyl group is C preferably
1-C
4-alkoxyl group.
" C used herein
3-C
15-carbocylic radical " expression has the carbocylic radical of 3 to 15 ring carbon atoms, and for example monocyclic groups perhaps is alicyclic monocyclic groups such as C
3-C
8-cycloalkyl, for example cyclopentyl, cyclohexyl, suberyl or ring octyl group perhaps are aromatic monocyclic group such as phenyl, it can be by one or more, one or two C normally
1-C
4-alkyl replaces; Perhaps bicyclic groups is as C
8-bicyclic groups, C
9-bicyclic groups or C
10-bicyclic groups, it can be alicyclic or the aromatics bicyclic groups, as indanyl, indenyl or naphthyl, wherein any one group also can be by one or more, one or two C normally
1-C
4-alkyl replaces.C
3-C
15-carbocylic radical is C preferably
3-C
10-carbocylic radical, for example cyclopropyl, cyclopentyl, cyclohexyl, suberyl, phenyl, indanyl or naphthyl.Especially preferred is phenyl.C
3-C
15-carbocylic radical can be substituted or unsubstituted.Preferred substituted comprises halogen for example fluorine, cyano group, hydroxyl, amino, nitro, carboxyl, C
1-C
10-alkyl, C
1-C
10-haloalkyl, C
1-C
10-alkoxyl group, C
1-C
10-alkyl-carbonyl, C
1-C
10-alkyl sulphonyl ,-SO
2NH
2,-COO-C
6-C
10-aryl ,-COO-C
7-C
15-aralkyl, C
3-C
15-carbocylic radical and 5-to 12-element heterocycle base with at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur." C
3-C
15-carbocylic radical " the most unsubstituted phenyl.
" C used herein
3-C
8-cycloalkyl " expression has a cycloalkyl of 3 to 8 carbon atoms." C
3-C
8-cycloalkyl " " C preferably
3-C
6-cycloalkyl ".
" C used herein
1-C
10-haloalkyl " represent by the above defined C of one or more halogen atoms, preferred 1,2 or 3 halogen atom replacement
1-C
10-alkyl." C
1-C
10-haloalkyl " " C preferably
1-C
4-haloalkyl ".
" C used herein
1-C
10-alkyl-carbonyl " the above defined C that links to each other with carbonyl of expression
1-C
10-alkyl." C
1-C
10-alkyl-carbonyl " " C preferably
1-C
4-alkyl-carbonyl ".
" C used herein
1-C
10-alkyl sulphonyl " expression and-SO
2-continuous above defined C
1-C
10-alkyl." C
1-C
10-alkyl sulphonyl " " C preferably
1-C
4-alkyl sulphonyl ".
" 5-to the 12-element heterocycle base that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur " used herein represents single heterocycle, two heterocycles or three heterocyclic groups, and it can be saturated or unsaturated, has 5 to 12 annular atomses.Monocyclic heterocyclic group comprises furyl, pyrryl, pyrrolidyl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, thienyl, thiadiazolyl group, isothiazolyl, oxadiazole base, pyridyl, oxazolyl, isoxazolyl, piperidyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, piperazinyl, morpholinyl, triazinyl, oxazinyl or thiazolyl.Two heterocyclic groups comprise indyl, benzimidazolyl-, indazolyl and benzothiazolyl.5-to 12-element heterocycle base is 5-to 9-element heterocycle base preferably.Preferred 5-to 9-element heterocycle base comprises furyl, pyrryl, triazolyl, thienyl, thiadiazolyl group, oxazolyl, isoxazolyl, piperidyl, pyridyl, pyrazinyl, indyl, benzimidazolyl-, indazolyl and benzothiazolyl, especially thienyl.5-to 12-element heterocycle base can be unsubstituted or substituted, is for example replaced by 1,2,3 or 4 substituting group.Preferred substituted comprises halogen, cyano group, oxo, hydroxyl, carboxyl, nitro, C
1-C
10-alkyl, C
1-C
10-alkyl-carbonyl and the C that is randomly replaced by aminocarboxyl
1-C
10-alkoxyl group.
The amino that " aminocarboxyl " used herein expression links to each other with carbonyl by nitrogen-atoms.
" C used herein
6-C
10-aryl " expression comprises the unit price carbocyclic aromatic group of 6 to 10 carbon atoms, and it can be for example monocyclic groups such as phenyl or bicyclic groups such as naphthyl.C
6-C
10-aryl is C preferably
6-C
8-aryl, especially phenyl.
" C used herein
7-C
15-aralkyl " expression is by defined C above
6-C
10The above defined alkyl that-aryl replaces, for example C
1-C
5-alkyl.C
7-C
15-aralkyl is C preferably
7-C
10-aralkyl such as phenyl-C
1-C
4-alkyl.
Unless stated otherwise, otherwise word " comprises " or its various modification should be understood that to refer to and comprise described integer or step or integer or step group in this specification sheets and afterwards claim, but does not get rid of other integer or step or other integer or step group.
Preferred compound comprises the compound of the formula I of salt or zwitterionic form, wherein:
R
1And R
3Be C independently of one another
3-C
15-carbocylic radical or have 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur;
R
2It is hydroxyl;
L and M be respectively (key and-CH
2-CH
2-), (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be C
1-C
2-alkylidene group,
Perhaps L and M are respectively (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be key; R
4Be C
1-C
4-alkyl;
R
5By-CO-R
6Or-CO-NH-R
6The C that replaces
1-alkyl,
Perhaps R
5By-O-R
6,-S-R
6,-O-CO-R
6Or-R
8The C that replaces
2-C
10-alkyl,
Perhaps R
5Be randomly by-R
8The C that replaces
2-C
10-alkenyl or C
2-C
10-alkynyl; R
6Be C
3-C
15-carbocylic radical,
Perhaps R
6Be randomly by C
1-C
10-alkoxyl group, O-R
8Or C
3-C
15The C that-carbocylic radical replaces
1-C
10-alkyl; And
R
8Be C
3-C
15-carbocylic radical.
Especially preferred compound comprises the compound of the formula I of salt or zwitterionic form, wherein:
R
1And R
3Be C independently of one another
3-C
10-carbocylic radical, preferred phenyl; Or have 5-to a 9-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, preferred thienyl;
R
2It is hydroxyl;
L and M be respectively (key and-CH
2-CH
2-), (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be C
1-C
2-alkylidene group,
Perhaps L and M are respectively (CH
2-and-CH
2-CH
2-) or (CH
2-CH
2-and-CH
2-) and J be key;
R
4Be C
1-C
4-alkyl;
R
5By-CO-R
6Or-CO-NH-R
6The C that replaces
1-alkyl,
Perhaps R
5By-O-R
6,-S-R
6,-O-CO-R
6Or-R
8The C that replaces
2-C
5-alkyl,
Perhaps R
5Be randomly by-R
8The C that replaces
2-C
4-alkenyl or C
2-C
8-alkynyl;
R
6Be C
3-C
10-carbocylic radical, preferred phenyl,
Perhaps R
6Be randomly by C
1-C
4-alkoxyl group, O-R
8Or C
3-C
10The C that-carbocylic radical replaces
1-C
15-alkyl; And
R
8Be C
3-C
10-carbocylic radical, preferred phenyl.
Second aspect the invention provides the compound of the formula Ia of salt or zwitterionic form:
Wherein:
R
1And R
3Be C independently of one another
3-C
15-carbocylic radical or have 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur;
R
2Be hydrogen, hydroxyl or the C that randomly replaced by hydroxyl
1-C
4-alkyl;
J and K all are C independently
1-C
2-alkylidene group,
Perhaps among J and the K is a key, and another is C
1-C
2-alkylidene group;
L is C
1-C
2-alkylidene group;
R
4Be C
1-C
4-alkyl;
R
5By-OR
6,-O-CO-R
6Or-CO-O-R
6The C that replaces
1-C
8-alkyl; And
R
6Be C
1-C
8-alkyl, C
3-C
15-carbocylic radical or have 5-to the 12-element heterocycle base of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur.
Preferred compound also comprises the compound of the formula Ia of salt or zwitterionic form, wherein:
R
1And R
3Be C independently of one another
3-C
15-carbocylic radical;
R
2It is hydroxyl;
J is a key;
K is C
1-C
2-alkylidene group;
L is C
1-C
2-alkylidene group;
R
4Be C
1-C
4-alkyl;
R
5By-OR
6The C that replaces
1-C
8-alkyl; And
R
6Be C
3-C
15-carbocylic radical.
Especially preferred compound also comprises the compound of the formula Ia of salt or zwitterionic form, wherein:
R
1And R
3Be C independently of one another
3-C
10-carbocylic radical, preferred phenyl;
R
2It is hydroxyl;
J is a key;
K is C
1-C
2-alkylidene group;
L is C
1-C
2-alkylidene group;
R
4It is methyl;
R
5By-OR
6The C that replaces
1-C
4-alkyl; And
R
6Be C
3-C
10-carbocylic radical, preferred phenyl.
The compound of formula I is a quaternary ammonium salt.Suitable counter ion are pharmaceutically useful counter ion, for example comprise fluorion, chlorion, bromide anion, iodide ion, nitrate radical, sulfate radical, phosphate radical, formate, acetate moiety, trifluoroacetic acid root, propionate, butyric acid root, lactate, citrate, tartrate anion, malate, maleate, amber acid radical, benzoate anion, right-the chloro-benzoic acid root, phenylbenzene-acetate moiety or triphenylacetic acid root, neighbour-hydroxy-benzoic acid root, right-the hydroxy-benzoic acid root, 1-hydroxyl naphthalene-2-formate, 3-hydroxyl naphthalene-2-formate, methanesulfonate and Phenylsulfonic acid root.
The formula I compound that comprises basic center can form acid salt, particularly pharmaceutically useful acid salt.The pharmaceutically useful acid salt of formula I compound comprises mineral acid and organic acid salt, and described mineral acid is haloid acid such as hydrofluoric acid, hydrochloric acid, Hydrogen bromide or hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid for example; Described organic acid is aliphatic monocarboxylic acid such as formic acid, acetate, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acid such as lactic acid, citric acid, tartrate or oxysuccinic acid, di-carboxylic acid such as toxilic acid or succsinic acid, aromatic carboxylic acid such as phenylformic acid, right-chloro-benzoic acid, diphenyl acetic acid or triphenylacetic acid, aromatics hydroxy acid such as neighbour-hydroxy-benzoic acid, right-hydroxy-benzoic acid, 1-hydroxyl naphthalene-2-formic acid or 3-hydroxyl naphthalene-2-formic acid and sulfonic acid such as methylsulfonic acid or Phenylsulfonic acid for example.These salt can be with the compound of known salifying method by formula I.
Comprise acidic-group for example the formula I compound of carboxyl also can form salt with alkali, particularly pharmaceutically useful alkali as known in the art those; Such suitable salt comprises metal-salt, particularly basic metal or alkaline earth salt such as sodium, potassium, magnesium or calcium salt or the salt that forms with ammonia or pharmaceutically useful organic amine or heterocyclic bases such as thanomin, benzylamine or pyridine.These salt can be with the compound of known salifying method by formula I.
Exist therein in those compounds of one or more chiral centres, described compound can with the form of the form of each optically active isomer or its mixture for example the form of racemize or non-enantiomer mixture exist.For example the part shown in the J produces on the ring carbon atom that is connected in those compounds of a chiral centre therein, and this quaternary nitrogen atoms also is a chiral centre and therefore has four kinds of possible diastereomers.The present invention includes each optically active R and S isomer with and composition thereof, for example racemize or non-enantiomer mixture.The particularly preferred compound of the present invention is single isomer, and it can be single enantiomorph or single diastereomer.Surprisingly, these single isomer make can select in the mixture the most effective component and surprisingly it can provide the residence time on the M3 acceptor of improvement, is particularly suitable for the long material of acting duration that is administered once every day thereby can send.
Especially preferred specific compound of the present invention is hereinafter described in an embodiment those compounds.
The present invention also provides the method for preparation I compound, and it comprises:
(i) (A) make wherein R
1, R
2, R
3, R
4, J, L and M formula II as hereinbefore defined compound or its protected form
With R wherein
5As hereinbefore defined and X be the compound reaction of the formula III of chlorine, bromine or iodine
X-R
5 III；
(B) make wherein R
1, R
2, R
3, R
5, J, L and M formula IV as hereinbefore defined compound or its protected form
With R wherein
4As hereinbefore defined and X be the compound reaction of the formula V of chlorine, bromine or iodine
X-R
4 V；
(C) in order to prepare wherein R
5Be-Q-NH-CO-R
6Formula I compound, make wherein R
1, R
2, R
3, R
4, J, L and M as hereinbefore defined and Q be C
1-C
10The compound of the formula VI of-alkylidene group or its protected form
With R wherein
6The compound of formula VII as hereinbefore defined or its become the amide derivatives reaction
Perhaps
(D) in order to prepare wherein R
5By C
3-C
15The C that-carbocylic radical replaces
1-C
10-alkyl and described C
3-C
15-carbocylic radical is incited somebody to action wherein R by the formula I compound of carboxyl substituted
1, R
2, R
3, R
4, J, L and M as hereinbefore defined and R
5By C
3-C
15The C that-carbocylic radical replaces
1-C
10-alkyl and described C
3-C
15-carbocylic radical quilt-COO-C
6-C
10-aryl or-COO-C
7-C
15The formula I compound that-aralkyl replaces transforms; With
(ii) reclaim the product of salt or zwitterionic form.
Method modification (A) can realize with the currently known methods that saturated heterocyclic amine and halogenide are reacted or with the similar methods of method described in the embodiment hereinafter.This reaction is for example carried out in dimethyl sulfoxide (DMSO), dimethyl formamide, ether, acetonitrile or the acetone at organic solvent easily.This is reflected under 20 ℃ to 120 ℃ the temperature and carries out, and is easily to carry out under the temperature of room temperature to 80 ℃.
Method modification (B) can realize with the currently known methods that saturated heterocyclic amine and halogenide are reacted or with the similar methods of method described in the embodiment hereinafter.This reaction is for example carried out in dimethyl sulfoxide (DMSO), dimethyl formamide, ether, acetonitrile or the acetone at organic solvent easily.This is reflected under 20 ℃ to 120 ℃ the temperature and carries out, and is easily to carry out under the temperature of room temperature to 80 ℃.
Method modification (C) can be with making carboxylic acid (or it becomes amide derivatives such as acyl halide derivative) and the currently known methods of amine reaction or for example carrying out with the similar methods of method described in the embodiment hereinafter.This reaction is easily by carrying out the reaction of carboxylic acid and amine, for example dimethyl formamide of solvent is used in this reaction, in one or more coupling agents O-(7-azepine benzo triazol-1-yl)-1 for example, 1,3-, 3-tetramethyl-urea hexafluorophosphate (HATU) and alkali for example diisopropyl ethyl amine (DIPEA) carry out under existing.Suitable temperature of reaction is 10 ℃ to 40 ℃, for example room temperature.
Method modification (D) can realize with the currently known methods that ester is changed into corresponding carboxylic acid or with the similar methods of method described in the embodiment hereinafter.This reaction can be undertaken by catalytic hydrogenation easily, for example carries out catalytic hydrogenation with 10% palladium carbon, for example carries out in organic solvent such as dimethyl formamide.This reaction is at room temperature carried out easily.
When the compound of formula II was single enantiomorph or achirality form, the alkylation that is used to obtain the tertiary amine of formula I compound produced the mixture of two kinds of diastereomers.These isomer can for example fractional crystallization or column chromatography be separated with routine techniques.
The compound of formula II can with the form of each optically active isomer or with the form of its mixture for example the form of racemize or non-enantiomer mixture exist.Preferred formula II compound is compound or its protected form of formula IIa or IIb:
R wherein
1, R
2, R
3, R
4, J, L and M as hereinbefore defined.
The compound of formula II is known or can be by making wherein R
1, R
2And R
3As hereinbefore defined and R
aBe C
1-C
4The compound of the formula VIII of-alkyl or its protected form
With R wherein
4, J, L and M formula IX as hereinbefore defined compound react and prepare,
This reaction can be with making carboxylicesters and the currently known methods that reacts of alcohol or realizing with the similar methods of method described in the embodiment hereinafter.This reaction easily organic solvent for example in hexanaphthene or the toluene, preferably in basic metal for example in the presence of the sodium and under inert atmosphere such as argon gas, carry out.This reaction can be carried out under 40 ℃ to 120 ℃ temperature, but preferably under refluxad carries out.
R wherein
2The formula II compound that is hydroxyl can be by making wherein R
1, R
4, J, L and M formula X as hereinbefore defined compound or its protected form
With R wherein
3As hereinbefore defined and X be that the compound of the formula XI of chlorine, bromine or iodine reacts and prepares,
XMg-R
3 XI。
The compound of formula III be known or can with currently known methods or with the preparation of the similar methods of method described in the embodiment hereinafter.
The compound of formula IV can for example racemize or non-enantiomer mixture form exist with each optically active isomer form or its form of mixtures.Preferred formula IV compound is compound or its protected form of formula IVa or IVb,
R wherein
1, R
2, R
3, R
5, J, L and M as hereinbefore defined.
The compound of formula IV can be by making wherein R
1, R
2And R
3As hereinbefore defined and R
aBe C
1-C
4The compound of the formula VIII of-alkyl or its protected form and R wherein
5, J, L and M formula XII as hereinbefore defined compound react and prepare:
This reaction can be with making carboxylicesters and the currently known methods that reacts of alcohol or realizing with the similar methods of method described in the embodiment hereinafter.This reaction easily organic solvent for example in hexanaphthene or the toluene, be preferable over basic metal and for example for example carry out under the argon gas in the presence of the sodium and at inert atmosphere.This reaction can be carried out under 40 ℃ to 120 ℃ temperature, but preferably under refluxad carries out.
The compound of formula V be known or can with currently known methods or with the preparation of the similar methods of method described in the embodiment hereinafter.
The compound of formula VI is a new compound, and can be by making wherein R
1, R
2, R
3, R
4, J, M and L formula II as hereinbefore defined compound and X wherein be that chlorine, bromine or iodine, Q are C
1-C
10-alkylidene group and W are that the compound of the formula XIII of protecting group reacts and prepares:
This reaction can realize with the currently known methods that makes the reaction of heterocyclic amine and haloalkyl amine or with the similar methods of method described in the embodiment hereinafter.This reaction is for example carried out in the dimethyl formamide at organic solvent easily.This reaction can be under 40 ℃ to 80 ℃ the temperature, preferably carry out under 50 ℃ to 70 ℃, especially about 60 ℃ temperature.Described protecting group is uncle-butoxy carbonyl preferably.
The compound of formula VII or VIII be known or can with currently known methods or with the preparation of the similar methods of method described in the embodiment hereinafter.
The compound of formula IX and XII is known or can be by corresponding secondary amine alkylation is prepared.For example, R wherein
4The compound that is the formula IX of methyl can be by making the wherein compound of J, L and M formula XIV as hereinbefore defined
React under formic acid exists with formaldehyde and to prepare.This reaction is for example carried out under 40 ℃ to 120 ℃, preferred about 80 ℃ temperature in the water at solvent easily.Perhaps, compound that the compound of formula X can be by making wherein J, L and M formula XII as hereinbefore defined and R wherein
5As hereinbefore defined and X be that the compound of the formula III of chlorine, bromine or iodine reacts and prepares.This reaction easily organic solvent for example in the acetonitrile, under 40 ℃ to 120 ℃ the temperature, preferably refluxing under, for example carry out in the presence of the salt of wormwood in alkali.
The compound of formula X can be by making wherein R
4, J, L and M formula IX as hereinbefore defined compound and R wherein
1As hereinbefore defined and X be that the compound of the formula XV of chlorine, bromine or iodine reacts and prepares:
The compound of formula XI, XIII, XIV or XV be known or can with currently known methods or with the preparation of the similar methods of method described in the embodiment hereinafter.
Relate in the situation of protected functional group or protecting group at this paper, can select protecting group according to the character of functional group, for example can be as Protective Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; Sons Inc, the 3rd edition, selecting like that described in 1999, this reference is also to replacing the proper method of protecting group to be described with hydrogen.
The compound of formula I is quaternary ammonium salt and can it be changed between different salt forms with ion exchange chromatography.Described compound can with hydrate or to comprise the form of solvate of crystallization solvent for use obtained.Can be with currently known methods recovery type I compound and it is carried out purifying from reaction mixture.Can compound separation be come out with the form of non-enantiomer mixture at first, but in most of the cases, they preferably are used in the pharmaceutical composition of the present invention with single enantiomorph or diastereomeric form.
The formula I compound of pharmaceutically useful salt or zwitterionic form (being also referred to as promoting agent of the present invention hereinafter) useful as drug.Therefore, the present invention also provides as the pharmaceutically useful salt of medicine or the formula I compound of zwitterionic form.Promoting agent of the present invention can be used as muscarine antagonist, muscarine M3 receptor antagonist particularly, thus can be used as the inhibitor of bronchoconstriction.
Can use radiolabeled antagonist [
3H] competitiveness of n-epoxytropine tropate methyl chloride (NMS) filters in conjunction with measuring the avidity (Ki) of promoting agent of the present invention to people's muscarine vagusstoff M3 acceptor in measuring:
To carry out transfection with the concentration personnel selection M3 acceptor in 10 μ g albumen/holes by the film of the stable preparation of Chinese hamster ovary celI, then with its serial dilutions, Kd concentration (0.25nM) with promoting agent of the present invention [
3H] NMS and mensuration damping fluid (20mmol HEPES, 1mmol MgCl
2, pH 7.4) at room temperature hatched 17 hours.This mensuration is to carry out under 1% dimethyl sulfoxide (DMSO) exists with the final volume of 250 μ L, in final concentration.Under the situation that does not have promoting agent of the present invention, use the mensuration damping fluid of corresponding replacement volume to measure [
3H] total binding of NMS.In the presence of the 300nM ipratropium bromide, measure [
3H] non-specific binding of NMS.After incubation period, use Brandel
TMFilter harvesting device 9600 and film is collected the Unifilter that comprises 0.05% polymine
TMOn the GF/B filter plate.Filter plate was descended dry 2 hours at 35 ℃, add Microscint then
TM' O ' mixture is also used
3H-flicker scheme is at PackardTopcount
TMReading on the scintillator.Under the help of XL-Fit graphics package, calculate all IC50 and draw K with the Cheng-Prusoff correction
iValue (Cheng Y., Prusoff W.H. (1973) Biochem.Pharmacol.22 3099-3109).
In above mensuration, hereinafter the compound among the embodiment generally has the IC that is lower than 1 μ M
50Value.For example, the compound of embodiment 1a, 1b, 2,13,25,29,46b, 47b, 49,63,88,95,96a and 97b has 1.4,1.3,2.14,0.39,3.7,0.41,0.64,0.55,0.68,0.33,0.88,0.44,0.2 and the M3K of 0.75nM respectively
iValue.
Consider that it is to vagusstoff and M3 M-ChR bonded restraining effect, promoting agent of the present invention can be used for treating the receptor-mediated illness of muscarine M3, particularly increases relevant illness with the parasympathetic nerve tonus that causes body of gland excessive secretion for example or smooth muscle contraction.Treatment of the present invention can be symptomatic treatment or prophylactic treatment.
Consider its antimuscarinic activity, promoting agent of the present invention can be used for lax bronchial smooth muscle and alleviates bronchoconstriction.Can use such as people such as Chong J.Pharmacol.Toxicol.Methods1998,39,163, people such as Hammelmann, Am.J.Respir.Crit.Care Med., 1997, the alleviation that 156,766 body internal volume graphical method model and close copy are measured bronchoconstriction.Therefore, promoting agent of the present invention can be used for treating obstructive or airway inflammatory disease.Because its acting duration is long, so promoting agent of the present invention can be used once in one day in such treatment of diseases.On the other hand, promoting agent of the present invention shows usually and uses β
2Usually the side effect that runs into during agonist such as aroused in interestly overrun, tremble and characteristic that uneasy incidence is low, so such promoting agent is suitable for the formula that makes an immediate response (on demand) (rescue) treatment and the prophylactic treatment of obstructive or airway inflammatory disease.
Inflammatory that the present invention is suitable for or obstructive airway diseases comprise the asthma of any kind or cause, comprise endogenous (anallergic) asthma and exogenous (allergy) asthma.Treatment of asthma also is understood to include showing the roaring shape and being diagnosed as maybe the individuality for example 4 or treatment of individuality below 5 years old that can be diagnosed as " baby of stridulating " (a kind of definite patient's classification that causes important medical attention and usually be confirmed as the initial stage now or early stage asthma).(for convenience, this specific asthma is called " wheezy-infant syndrome (wheezy-infant syndrome) ".)
Prevention effects in the treating asthma will by reduce paresthesia epilepsy for example acute asthma or bronchoconstriction outbreak frequency or severity, improve pulmonary function or improve the air flue hyperergy and be proved to be.It can also be proved to be by the minimizing to other symptomatic treatment demand, described other symptomatic treatment promptly hour hands occur to the treatment of paresthesia epilepsy or be intended to limit or end the treatment of paresthesia epilepsy when paresthesia epilepsy, for example anti-inflammatory (for example reflunomide) or bronchodilator treatment.The prevention benefit of asthma may be tangible in the individuality that is easy to generation " fall morning " particularly." fall morning " is a kind of generally acknowledged asthma syndrome, accounts for sizable per-cent usually in asthma, it is characterized in that for example asthma attack of (time of the asthma symptomatic treatment long period of once carrying out before promptly common distance is any) between about 4 to 6 o'clock of morning.
Other inflammatory that the present invention is suitable for or obstructive airway diseases comprise the air flue hyperergy aggravation that adult type/adult respiratory distress syndrome (ARDS), the chronic obstructive pulmonary that comprises chronic bronchitis or airway disorders (COPD or COAD) or expiratory dyspnea, pulmonary emphysema and other medicines therapy, particularly other suction pharmacotherapy relevant with it cause with illness.The present invention also can be used for treating the bronchitis of any kind or cause, comprises for example acute bronchitis, arachidic bronchitis, catarrhal bronchitis, croupous bronchitis, chronic bronchitis or phthinoid bronchitis.Other inflammatory that the present invention is suitable for or obstructive airway diseases comprise pneumoconiosis (a kind of inflammatory, the normally professional lung disease of any kind or cause, no matter be acute or chronic, it is usually with obstruction of the air passage, and cause owing to repeat to suck dust), comprise for example aluminosis, anthracosis, asbestosis, chalicosis, cystic fibrosis, ostrich hair pneumoconiosis, arc-welder's disease, silicosis, tabacism and byssinosis.
Consider its antimuscarinic activity, promoting agent of the present invention also can be used for treating the illness of lax uterus, bladder or vascular system unstriated muscle of needs.Therefore, they can be used for preventing or alleviate too early labor pains in the gestation.They also can be used for treating chronic and acute urticaria, psoriatic, anaphylaxis conjunctivitis, actinitis, the rhinitis that comprises rhinallergosis, mast cell disease, urinary system illness such as the urinary incontinence (the particularly urinary incontinence that is caused by the bladder hyperactivity hyperkinesia), frequent micturition, neurogenic bladder or unstable bladder, cystospasm and chronic cystitis; Gastrointestinal disorder such as irritable bowel syndrome, spastic colitis, diverticulitis and peptide ulceration; With cardiovascular disorder such as vagus nerve inductive sinus bradycardia, and it also can be used for the ophthalmology interventional therapy.
Promoting agent of the present invention also can with the combination of other medicines in be used as the coupling therapeutical agent, described other medicines such as antiphlogiston, bronchodilator, antihistaminic, decongestant drug or cough medicine, particularly in obstructive or airway inflammatory disease those treatment of diseases as indicated above, for example as the active synergistic agent of such pharmacological agent or as reducing required dosage of such medicine or means that may side effect.Promoting agent of the present invention can mix with one or more other medicines in the fixed drug composition, perhaps can other medicines use preceding, use in or use the back used independently.Therefore, the present invention includes the combination of promoting agent of the present invention and antiphlogiston, bronchodilator, antihistaminic, decongestant drug or cough medicine mentioned above, described promoting agent of the present invention and described medicine are arranged in identical or different pharmaceutical composition.
This AID comprises steroide, for example glucocorticosteroid such as budesonide, beclometasone (beclamethasone), Fluticasone, ring shrinkage porosite or Mometasone or WO 02/88167, WO02/12266, steroide described in WO 02/100879 or the WO 02/00679, especially embodiment 3,11,14,17,19,26,34,37,39,51,60,67,72,73,90, the steroid agonist of those described in 99 and 101 and on-steroidal such as WO 00/00531, WO02/10143, WO 03/082280, WO 03/082787, WO 03/104195, described in the WO 04/005229 those; Described in LTB4 antagonist such as the US 5451700 those also have LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonist such as Singulair and Zafirlukast; PDE4 inhibitor such as cilomilast (Ariflo
GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), KW-4490 (KyowaHakko Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, described in WO04/000839 and WO 04005258 (Merck) and WO 98/18796 and the WO 03/39544 those; A2a agonist such as EP 1052264, EP 1241176, EP 409595A2, WO94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, described in WO 02/96462 and the WO03/086408 those; And described in A2b antagonist such as the WO 02/42298 those.
Promoting agent of the present invention can be used in the combination treatment with following material: chemokine receptor anagonists, calcium channel blocker, alpha-2-adrenoceptor antagonists, dopamine agonist, endothelin antagonist, P substance antagonist, 5-LO inhibitor, VLA-4 antagonist and theophylline.
Promoting agent of the present invention also especially can with the combination of beta-2-adrenoceptor agonist or reflunomide in be used as the coupling therapeutical agent.Suitable beta-2-adrenoceptor agonist comprises salbutamol, terbutaline, Salmeterol and especially formoterol and their pharmacologically acceptable salt, and the formula I compound among the WO0075114 (being introduced into this paper as a reference) (free or salt or solvate form thereof), the compound of compound, especially following formula in the preferred embodiment and their pharmacologically acceptable salt:
And the formula I compound among the WO 04/16601 (free or salt or solvate form thereof), the compound in the preferred embodiment 1,3,4,5 and 79.
The antihistaminic of combination therapy comprises cetrizine hcl, paracetamol, tavehil, promethazine, Loratadine, Desloratadine, diphenhydramine and hydrochloric acid Fei Suonading, activastine, astemizole, nitrogen
Si Ting, ebastine, epinastine, mizolastine and Te Fennading (tefenadine).
The combination of promoting agent of the present invention and one or more beta-2-adrenoceptor agonists, steroide, PDE4 inhibitor, A2a agonist, A2b antagonist and LTD4 antagonist can be used for for example treating airway disorders, comprises asthma and particularly COPD.Preferred triple combination comprises promoting agent of the present invention, beta-2-adrenoceptor agonist and steroide.
According to foregoing, the present invention also provides the method for treatment obstructive or airway inflammatory disease, it comprise to the individuality that needs are arranged particularly the human individual use formula I compound mentioned above or its pharmaceutically useful salt or solvate.On the other hand, the invention provides formula I compound mentioned above or its pharmaceutically useful salt or the solvate that is used to prepare the medicine for the treatment of obstructive or airway inflammatory disease.
Promoting agent of the present invention can be used by any suitable approach, and is for example Orally administered, for example Orally administered with the form of tablet or capsule; Parenteral is used, and for example intravenously is used; Be locally applied to skin, for example in psoriatic treatment; Intranasal administration is for example in the treatment of spring fever; Perhaps, preferably suck and use, particularly in the treatment of obstructive or airway inflammatory disease.Promoting agent of the present invention can be sent with treatment COPD and asthma with the form of inhalative solution formulation especially.
On the other hand, the present invention also provides pharmaceutical composition, and it comprises the formula I compound of free form or its pharmaceutically useful salt or solvate form thereof, and randomly comprises suitable acceptable diluents or carrier.This based composition can prepare with known technology in conventional thinner or vehicle and the Galenic formula field.Therefore, oral dosage form can comprise tablet and capsule.The preparation that is used for topical application can be taked for example form of patch of ointment, ointment, gelifying agent or transdermal drug delivery system.The composition that is used to suck can comprise aerosol or other aerosolizable preparation or dry powder formulations.
When composition comprises aerosol formulation, it preferably comprises the mixture of hydrogen-fluoro-alkane (HFA) propellent for example such as HFA134a or HFA227 or these materials, and can comprise one or more solubility promoters as known in the art such as ethanol (by weight at the most 20%) and/or one or more tensio-active agents such as oleic acid or sorbitan trioleate and/or one or more weighting agents such as lactose.When composition comprises dry powder formulations, it for example comprises preferably that particle diameter is no more than 10 microns formula I compound, and randomly comprises diluent or carrier such as the lactose with required size distribution and help to prevent product performance because moisture and the compound such as the Magnesium Stearate of variation.When composition comprised atomization preparation, it preferably comprised and for example dissolves or be suspended in formula I compound in the matrix, and described matrix comprises water, solubility promoter such as ethanol or propylene glycol and stablizer, and described stablizer can be a tensio-active agent.
The present invention comprises that also (A) can suck the free form of form or the formula I compound mentioned above of its pharmaceutically useful salt or solvate form thereof; (B) medicine that can suck, pharmaceutically acceptable carrier that it comprises this compounds of the form that can suck and can suck form; (C) medicament production, it comprises this compounds and the suction apparatus of the form that can suck; (D) comprise the suction apparatus of this compounds of the form that can suck.
The dosage of used promoting agent of the present invention will change according to the concrete illness of for example being treated, required effect and method of application certainly when enforcement is of the present invention.Generally speaking, use for suction, suitable per daily dose is 0.0001 to 30mg/kg, is generally 0.01 rank to 10mg/ patient, and for Orally administered, suitable per daily dose is 0.01 to 100mg/kg rank.
With following embodiment the present invention is illustrated.
Embodiment
All compounds among these embodiment all are separated with the form of the non-enantiomer mixture on quaternary nitrogen atoms at first.Provide in these embodiments in the situation of each diastereomer, it is separated by such mixture is carried out fractional crystallization.The stereochemistry of these single isomer is determined with nmr and/or X-ray crystallography.
Especially preferred formula I compound comprises the compound of formula XVI:
Wherein T is as shown in following table 1, and its preparation method is as mentioned below.All compounds all are quaternary ammonium salts.This table gives mass-spectrometric data.Relevant counter ion are determined in relevant preparation method.
Table 1
Also especially preferred formula I compound is the compound of the formula XVI of T as shown in following table 2 and 3 wherein, and its preparation method is as mentioned below.All compounds all are quaternary ammonium salts.This table gives mass-spectrometric data.Relevant counter ion are determined in relevant preparation method.
Table 2
Table 3
Also especially preferred formula I compound comprises the wherein compound of the formula XVII of T as shown in following table 4 and 5:
Its preparation method is as mentioned below.All compounds all are quaternary ammonium salts.This table gives mass-spectrometric data.Relevant counter ion are determined in relevant preparation method.
Table 4
Table 5
The preparation of midbody compound
Used abbreviation is as follows: DCM is a methylene dichloride, and DMF is a dimethyl formamide, and DMSO is a dimethyl sulfoxide (DMSO), and THF is a tetrahydrofuran (THF).
Hydroxyl-phenylbenzene-acetate-1-methyl-piperidin-4-yl-ester
This compound is to prepare with the method described in the US Patent specification US 3252981.
Hydroxyl-phenylbenzene-acetate 1-methyl-piperidin-4-yl methyl ester
With (1-methyl-piperidin-4-yl)-methyl alcohol (2.58g, 20mmol) and hydroxyl-phenylbenzene-methyl acetate (9.69g 40mmol) is suspended in the toluene (65ml).Add molecular sieve 4A (1g) and mixture was at room temperature stirred 10 minutes.Add sodium (0.08g) and reaction mixture is descended stirring 3 hours at 80 ℃.Then, add other sodium (0.1g) and with it 80 ℃ of heating 18 hours down.Reaction mixture is cooled to room temperature, solid is leached, wash with ethyl acetate.Filtrate is used saturated NaHCO
3The aqueous solution (50ml) washing is once used HCl aqueous solution 1M washed twice (each 25ml).With the saturated NaHCO of acid water layer that merges
3The aqueous solution and solid NaHCO
3Alkalization is taken out the gained precipitation by filtering, and with its vacuum-drying, obtains the title product (M+H) of white solid form
+: 340.09.
Hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester
A) oxo-thiophene-2-base-Acetyl Chloride 98Min.:
In being suspended in DCM (80ml) and be cooled to the solution of oxo-thiophene-2-base-acetate of 5 ℃ (8g, (5.3ml 61.5mmol), adds DMF (0.1ml) then to add oxalyl chloride in 51.2mmol).Continuation was stirred 1 hour down at 5 ℃, at room temperature stirred 18 hours.Reaction mixture is evaporated to dried, adds toluene and this mixture is evaporated once more then, obtain the title compound of dark oily matter form.
B) oxo-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester:
Under agitation, in the oxo-thiophene under 0 to the 5 ℃-solution of 2-base-Acetyl Chloride 98Min. (29mmol) in chloroform (60ml), drip 1-methyl-piperidines-4-alcohol (5.87g, 29mmol) solution in chloroform (60ml).The gained mixture was at room temperature stirred 2 hours.With 10% solution of potassium carbonate, water (* 2) washing, use dried over mgso, filter and evaporation, obtain title compound.
C) hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester:
With the 2-bromothiophene (3.2ml, 33mmol) drips of solution in THF (30ml) be added to magnesium (0.8g, 33mmol) and the mixture of monocrystalline iodine in THF (30ml) in.After just adding half 2-bromothiophene, stop to add until reaction beginning (judging) by heat release.In that being maintained, temperature of reaction finishes this interpolation under the situation that is lower than 40 ℃.After adding fully, reaction mixture is heated to 70 ℃ reaches 1 hour.Then with the cooling of this mixture and join oxo-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester (6.48g is 25.6mmol) in the solution in THF (80ml).After adding fully, reaction mixture was at room temperature stirred 1 hour, being heated to then refluxes reaches 2 hours.After being cooled to room temperature, add saturated aqueous ammonium chloride (100ml).With this solution extracted with diethyl ether, use dried over mgso, filter and concentrate.With quick silica gel column chromatography purifying, obtain title product.
Hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl methyl ester
A) oxo-thiophene-2-base-Acetyl Chloride 98Min.:
In being suspended in DCM (80ml) and be cooled to the solution of oxo-thiophene-2-base-acetate of 5 ℃ (8g, (5.3ml 61.5mmol), adds DMF (0.1ml) then to add oxalyl chloride in 51.2mmol).Continuation was stirred 1 hour down at 5 ℃, at room temperature stirred 18 hours.This reaction mixture is evaporated to dried, adds toluene and this mixture is evaporated once more then, obtain the title compound of dark oily matter form.
B) oxo-thiophene-2-base-acetate 1-methyl-piperidin-4-yl methyl ester:
In the oxo-thiophene under 0 to the 5 ℃-solution of 2-base-Acetyl Chloride 98Min. (31.5mmol) in chloroform (60ml), drip (1-methyl-piperidin-4-yl)-methyl alcohol (4.07g, 31.5mmol) solution in chloroform (60ml), simultaneously temperature maintenance is being lower than 5 ℃.The gained mixture was at room temperature stirred 2 hours.With 10% solution of potassium carbonate, water washing, use dried over mgso then, filter and evaporation, obtain title compound.
C) hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl methyl ester:
With the 2-bromothiophene (2.15ml, 22.2mmol) drips of solution in THF (15ml) be added to magnesium (0.54g, 22.2mmol) and the mixture of monocrystalline iodine in THF (15ml) in.After just adding half 2-bromothiophene, stop to add until reaction beginning (judging) by heat release.In that being maintained, temperature of reaction finishes this interpolation under the situation that is lower than 40 ℃.After adding fully, reaction mixture is heated to backflow reaches 20 minutes.Then with the cooling of this mixture and join oxo-thiophene-2-base-acetate 1-methyl-piperidin-4-yl methyl ester (4.6g is 17.2mmol) in the solution in THF (40ml).After adding fully, reaction mixture was at room temperature stirred 1 hour, being heated to then refluxes reaches 2.5 hours.After being cooled to room temperature, add saturated aqueous ammonium chloride (100ml) and ether.With this solution extracted with diethyl ether, use dried over mgso, filter and concentrate.With quick silica gel column chromatography purifying, obtain title product.
Hydroxyl-phenylbenzene-acetate (R)-1-methyl-piperidines-3-base ester
A) (R)-3-hydroxy piperidine-1-formic acid uncle-butyl ester:
Under agitation, (6.574g 0.048mol) is dissolved in the 2M aqueous sodium hydroxide solution (65ml) and with it and is cooled to 0 ℃ with (R)-3-hydroxyl piperidine hydrochloric acid salt.(11.44g, 0.525mol) 1, the solution in the 4-diox (65ml) also at room temperature stirred reaction mixture 90 minutes to drip two carbonic acid di-tert-butyls.(3 * 150ml) extractions also wash the organic layer that merges once with water, with the salt water washing once, use dried over mgso, filter and be evaporated to dried, obtain title compound with chloroform with reaction mixture.
B) (R)-1-methyl-piperidines-3-alcohol:
Under inert atmosphere, (10g 0.05mol) is dissolved in the dry THF (50ml) and with it and is cooled to 0 ℃ with (R)-3-hydroxy piperidine-1-formic acid uncle-butyl ester.Under 0 to 5 ℃, and the solution of the lithium aluminum hydride that in this solution, adds 1M in THF (80ml, 0.08mol).After adding, make reaction mixture be warming up to room temperature and stir and spend the night.Reaction mixture cooled off in ice bath and add Rochelle salt (Rochelle ' s salt) and (5g), will react and stir 30 minutes.Then, to wherein dripping water (10ml) and evaporating solvent.Resistates absorbed with chloroform (70ml) and Virahol (30ml) and with its stirring 1 hour.Solid is leached and extracts once more.The organic extract merging is evaporated, obtain the title compound of pale asphyxia oily matter form.
C) hydroxyl-phenylbenzene-acetate (R)-1-methyl-piperidines-3-base ester:
To (R)-1-methyl-piperidines-3-alcohol (4.61g, 0.040mol) and hydroxyl-phenylbenzene-methyl acetate (9.63g 0.040mol) adds in advance activatory 4A molecular sieve and with this mixture heating up to 50 ℃ in the mixture in hexanaphthene (50ml).Add sodium metal (50mg) then and with the gained mixture heating up to refluxing.After 1 hour, refluxed 5 hours to wherein adding sodium (50mg) and continuing again.Concentrate, be dissolved in again in the chloroform, water, wash with salt solution then, use dried over mgso, filter, evaporate, obtain crude product.With vacuum fast silica gel chromatogram method purifying (gradient elution: DCM to DCM: methyl alcohol 20: 1), after evaporation, obtain the title product of form of foam.
Hydroxyl-two-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-base ester
A) oxo-thiophene-2-base-Acetyl Chloride 98Min.:
In being suspended in DCM (80ml) and be cooled to the solution of oxo-thiophene-2-base-acetate of 5 ℃ (8g, (5.3ml 61.5mmol), adds DMF (0.1ml) then to add oxalyl chloride in 51.2mmol).Continuation was stirred 1 hour down at 5 ℃, at room temperature stirred then 18 hours.Reaction mixture is evaporated to dried, adds toluene and this mixture is evaporated once more then, obtain the title compound of dark oily matter form.
B) oxo-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-base ester:
Under agitation, during 20 minutes, (8.9g 51.2mmol) drips (R)-1-methyl-piperidines-3-alcohol (5.87g, 51mmol) solution in DCM (50ml) in the solution in DCM (50ml) to the oxo-thiophene under 5 ℃-2-base-Acetyl Chloride 98Min..The gained mixture was at room temperature stirred 18 hours.With 1 mole of sodium hydrogen carbonate solution washing, use dried over mgso, filter and evaporation, obtain the title compound of dark oily matter form.
C) hydroxyl-two-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-base ester:
(0.092ml, (0.576g 23.7mmol), adds monocrystalline iodine then 0.94mmol) to add magnesium in the solution in THF (2ml) to the 2-bromothiophene.Then, (2.2ml 22.8mmol), keeps gentle reflux simultaneously to wherein dripping other 2-bromothiophene in THF (48ml).After adding fully, reaction mixture is heated to backflow reaches 1 hour.Then, under agitation, this mixture is added drop-wise to the basic ester of oxo-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-, and (6g is 23.7mmol) in the solution in THF.After adding fully, reaction mixture is heated to backflow reaches 2 hours.After being cooled to room temperature, add saturated aqueous ammonium chloride (100ml), add entry (100ml) then.Gained solution is extracted with 1 mole hydrochloride (100ml) with ethyl acetate (200ml) extraction and with the gained organic phase.With yellow soda ash water layer is alkalized, use ethyl acetate extraction, use dried over mgso, filter and concentrate, obtain the title product of brown oil form, it is placing post crystallization.
Hydroxyl-phenylbenzene-acetate (S)-1-methyl-tetramethyleneimine-2-ylmethyl ester
With ((S)-1-methyl-tetramethyleneimine-2-yl)-methyl alcohol (2.38ml, 20mmol) and hydroxyl-phenylbenzene-methyl acetate (7.27g 30mmol) is suspended in the toluene (20ml).Add molecular sieve 4A (3g) and this suspension under agitation is heated to 80 ℃.(0.46g 20mmol) and with reaction mixture stirred 3 hours down at 80 ℃ to wherein adding sodium.Reaction mixture is cooled to room temperature, solid is leached and uses toluene wash.Filtrate is used saturated NaHCO
3The aqueous solution (50ml) washing is once used twice of 1M HCl solution washing (each 30ml).Use saturated NaHCO
3The acid water layer that the aqueous solution will merge is adjusted to pH 8.This emulsion is extracted with ethyl acetate (50ml).With the ethyl acetate layer dried over sodium sulfate that merges, filter and be evaporated to dried, obtain the product of yellow oil form, it is at the placement post crystallization.(M+H)
+：326.2
Prepared hydroxyl-phenylbenzene-acetate (R)-1-methyl-tetramethyleneimine-2-base-methyl ester similarly.
Hydroxyl-two-thiophene-2-base-acetate (S)-1-methyl-tetramethyleneimine-2-ylmethyl ester
To molecular sieve 4A, ((S)-1-methyl-tetramethyleneimine-2-yl)-methyl alcohol (3.71g, 31.2mmol) and hydroxyl-two-thiophene-2-base-methyl acetate (3.96g 15.6mmol) adds sodium (65mg) and this suspension under agitation is heated to 80 ℃ reaches 3.5 hours in the mixture in toluene (40ml).Then, add other sodium (65mg) and reaction mixture stirred 16 hours down at 80 ℃.Reaction mixture is cooled to room temperature, and (2 * 100ml) extract with ether (100ml) dilution and with HCl 1M.The acid water layer that merges is washed with ether (50ml), in ice, carry out refrigerative and alkalize with 4M sodium hydroxide simultaneously.Then, with this solution ethyl acetate and extracted with diethyl ether.With the organic layer dried over mgso that merges, filter and be evaporated to dried, obtain title product.
The preparation of specific embodiment
Used abbreviation is as follows: DCM is a methylene dichloride, and DMF is a dimethyl formamide, and DMSO is a dimethyl sulfoxide (DMSO), and HPLC is a high performance liquid chromatography.
Embodiment 1
Cis and trans-4-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperazine
The pyridine bromide (1a, 1b)
With hydroxyl-phenylbenzene-acetate-1-methyl-piperidin-4-yl-ester (0.5g, 1.5mmol) and (2-bromo-oxyethyl group)-benzene (0.37g 1.8mmol) is dissolved among the DMF and is heated to 40 ℃ and reaches 24 hours.(0.18g 0.9mmol) continues to stir 24 hours under 40 ℃ with 100mg salt of wormwood and with it again to add other (2-bromo-oxyethyl group)-benzene.Temperature is risen to 60 ℃ and add (2-bromo-oxyethyl group)-benzene (0.1g 0.5mmol), continues to stir 24 hours under this temperature.(0.1g 0.5mmol) and with it continues to stir 16 hours down at 60 ℃ to add another part (2-bromo-oxyethyl group)-benzene.Reaction mixture is filtered and evaporating solvent.Gained oily matter with the acetonitrile absorption and with the product crystallization, is obtained the mixture (1a) of cis and trans-isomer(ide).Solid leached and with acetonitrile recrystallization twice, obtain the trans diastereomer (1b) of white solid form.
Embodiment 2
(S)-2-(2-hydroxyl-2,2-phenylbenzene-acetoxy-methyl)-1-methyl isophthalic acid-Xin-2-alkynyl-tetramethyleneimine trifluoro
Acetate
In 96 orifice plates, the 1-bromine suffering-solution of 2-alkynes in DMSO of 200 μ l1.1M is joined in hydroxyl-phenylbenzene-acetate (the S)-1-methyl-tetramethyleneimine-solution of 2-ylmethyl ester in DMSO of 200 μ l 0.368M with the mechanical liquid treater.Placed 48 hours down in 40 ℃ with this pore plate by sealing and in baking oven.This orifice plate is cooled to room temperature and with (mass directed) preparation HPLC purification reaction mixture of quality orientation, uses acetonitrile: water: the trifluoroacetic acid wash-out obtains the title compound of oily matter form.This product is separated with the form that has different stereochemical non-enantiomer mixtures on quaternary nitrogen atoms.The counter ion that preparation HPLC is handled the back existence are different mixtures of bromine and trifluoroacetic acid root.
Use suitable initial compounds to prepare the compound of embodiment 3 to 24 and 49 to 62 similarly.
Embodiment 25
4-(2-hydroxyl-2,2-phenylbenzene-acetoxy-methyl)-1-methyl isophthalic acid-(2-oxo-2-phenyl-ethyl)-piperidines
Trifluoroacetate
In 96 orifice plates, the solution of 2-bromo-1-phenyl-ethyl ketone in DMSO of 200 μ l1.1M is joined in the hydroxyl-phenylbenzene-acetate 1-methyl-solution of piperidin-4-yl methyl ester in DMSO of 200 μ l 0.368M with the mechanical liquid treater.Placed 48 hours down in 40 ℃ with this pore plate by sealing and in baking oven.This orifice plate is cooled to room temperature and with the preparation HPLC purification reaction mixture of quality orientation, uses acetonitrile: water: the trifluoroacetic acid wash-out obtains the title compound of oily matter form.This product is separated with the form that has different stereochemical non-enantiomer mixtures on quaternary nitrogen atoms.The counter ion that preparation HPLC is handled the back existence are different mixtures of bromine and trifluoroacetic acid root.
Use suitable initial compounds to prepare the compound of embodiment 26 to 42 and 63 to 93 similarly.
Embodiment 43 and 44
Cis and trans 4-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(3-phenoxy group-propyl group)-piperazine
The pyridine bromide
(2.44g, 7.52mmol) (1.78ml 11.3mmol) is dissolved among the DMF (16ml) and with it to descend to stir 20 hours at 50 ℃ with (3-bromo-propoxy-)-benzene with hydroxyl-phenylbenzene-acetate-1-methyl-piperidin-4-yl-ester.Concentrate, obtain white solid, it is ground and drying under vacuum with acetonitrile.Use the acetonitrile recrystallization, make and from formed crystallization, mainly isolate a kind of diastereomer.After further concentrating, from filtrate, mainly be settled out another kind of diastereomer.Cis and trans-isomer(ide) that these two kinds of solids are title compounds.
Embodiment 45
1-[2-(4-benzyloxycarbonyl-phenyl)-ethyl]-4-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl-piperazine
The pyridine bromide
With hydroxyl-phenylbenzene-acetate-1-methyl-piperidin-4-yl-ester (1.56g, 4.8mmol) and 4-(2-bromo-ethyl)-peruscabin (2.3ml, 7.21mmol) be dissolved among the DMF (5ml) and with it and stirred 20 hours down at 50 ℃, heated 5 hours down at 60 ℃ then.Concentrate and with twice (eluent: water/acetonitrile), obtain the title compound of non-enantiomer mixture form of C-18 reverse-phase chromatography purifying.
Embodiment 46
(1S/R, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperidines
Bromide (46a), (1S, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(2-benzene oxygen
Base-ethyl)-piperidines bromide (46b) and (1R, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperidines bromide (46c)
With hydroxyl-phenylbenzene-acetate (R)-1-methyl-piperidines-3-base ester (2.25g, 0.00692mol) and (2-bromo-oxyethyl group)-benzene (2.08g, 0.0103mol) be dissolved in the acetonitrile (3ml) and with it and stirred 72 hours down at 60 ℃, obtain (1S/R, 3R) mixture (46a).Reaction mixture is cooled to room temperature and is evaporated to driedly, obtain white foam.Grind by in this foam, adding acetone then, then it is carried out sonication, be heated to backflow and make it to be cooled to room temperature.With this suspension filter dry doubling with the gained solid with the acetonitrile recrystallization twice that comprises less water, obtain the white solid form (1S, 3R)-diastereomer (46b).Then, obtain mother liquor and, obtain solid from initial acetone grinding its evaporation.With this resistates C18 silica gel (70g) purified by flash chromatography, the speed water/acetonitrile 100/0 to 0/100 with 20ml/ minute in 40 minutes carries out gradient elution.The fraction that will comprise product merges and, obtains mainly that (1R 3R)-diastereomer (46c), is white solid with its evaporation.
Embodiment 47
(1S/R, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(3-phenyl-propyl group)-piperidines
Bromide (47a) and (1R, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(the 3-phenyl-
Propyl group)-piperidines bromide (47b)
(3.0g, 0.00923mol) (2.12ml 0.0138mol) is dissolved in the acetonitrile (3ml) and with it to descend to stir 24 hours at 60 ℃ with (3-bromo-propyl group)-benzene with hydroxyl-phenylbenzene-acetate (R)-1-methyl-piperidines-3-base ester.At this moment, HPLC/MS shows and has formed (1S/R, 3R) mixture (47a).It was at room temperature placed 72 hours, produce the white solid precipitation.Carry out twice recrystallization continuously with acetonitrile, obtain (1R, 3R)-title compound (47b).
Embodiment 48
(1R/S, 3R)-3-(2-hydroxyl-2,2-phenylbenzene-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-propyl group)-piperidines
Bromide
With hydroxyl-phenylbenzene-acetate (R)-methyl-piperidines-3-base ester (1.7g, 0.00523mol) and (3-bromo-propoxy-)-benzene (1.2ml 0.00781mol) is dissolved in the acetonitrile (2ml) and it is stirred down at 60 ℃ and spends the night.Reaction mixture is cooled to room temperature and is evaporated to dried.Absorbing also with DCM resistates, water extracts.With water layer with DCM (3 * 20ml) wash and be evaporated to dried.Resistates is carried out purifying with C18 silica gel (70g) flash chromatography, and the speed water/acetonitrile 100/0 to 0/100 with 20ml/ minute in 25 minutes carries out gradient elution.The fraction that will comprise product merges and evaporation, obtains the title compound of 700mg white foam form.
Embodiment 94
Trans 4-(2-hydroxyl-2,2-two-thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(3-phenyl-propyl group)-piperidines
Bromide
(1.5g, 4.44mmol) (1.4ml 8.88mmol) is dissolved among the DMF (5ml) and with it to descend to stir 16 hours at 50 ℃ with (3-bromo-propyl group)-benzene with hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester.By filtering to isolate the gained solid,, obtain 1: 1 cis/trans non-enantiomer mixture (perhaps as among the embodiment 67, separating) with DMF (5ml) washing and dry under high vacuum.Further carry out recrystallization twice, obtain title compound (trans diastereomer) with DMF.
Embodiment 95
Trans-4-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperidines
Bromide
(1.5g, 0.00444mol) (1.79g 0.00888mol) is dissolved among the DMF (5ml) and with it to descend to stir 16 hours at 50 ℃ with 2-phenoxy group monobromoethane with hydroxyl-two-thiophene-2-base-acetate 1-methyl-piperidin-4-yl ester.Reaction mixture is evaporated to dried, obtains this cis/trans mixture, this resistates is absorbed with acetonitrile (10ml) and at room temperature stirred 10 minutes.With the suspension filtration and with solid acetonitrile recrystallization, obtain the trans-isomer(ide) (139) of white solid form.
Embodiment 96
(1R, 3R)-3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(3-phenyl-propyl group)-piperidines
Bromide (96a) and (1S, 3R)-3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(3-
Phenyl-propyl group)-piperidines bromide (96b)
Under 60 ℃, with hydroxyl-two-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-base ester (2.1g, 0.00623mol) be dissolved in the acetonitrile (5ml) and to wherein drip 1-bromine 3-phenyl-propane (1.43ml, 0.00934mol).60 ℃ down stir 18 hours after, white solid smashed and under this temperature, continued restir 8 hours.This suspension is cooled to room temperature and leaches solid.Solid is comprised the 2 acetonitrile recrystallizations that drip with 3ml, obtain the white solid form (1R, 3R)-3-(2-hydroxyl-2,2-two-thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(3-phenyl-propyl group)-piperidines bromide (96a).With the reaction mixture mother liquid evaporation to dry doubling with resistates with C18 silica gel (70g) purified by flash chromatography, in 25 minutes with speed water/acetonitrile 100/0 to 0/100 gradient elution of 20ml/ minute.The fraction that will comprise product merge and be evaporated to dried, obtain white amorphous solid (1S, 3R)-3-(2-hydroxyl-2,2-two-thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(3-phenyl-propyl group)-piperidines bromide (96b).
Embodiment 97
(1R/S, 3R)-3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-
Piperidines bromide (97a) and (1R, 3R)-3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl
-1-(2-phenoxy group-ethyl)-piperidines bromide (97b)
Under 60 ℃, with hydroxyl-two-thiophene-2-base-acetate (R)-1-methyl-piperidines-3-base ester (0.57g, 0.00169mol) be dissolved in the acetonitrile (3ml) and to wherein drip 2-phenoxy group monobromoethane in acetonitrile (1ml) (0.51g, 0.00254mol).With reaction mixture refluxed 96 hours, be cooled to room temperature and place it in the refrigerator.Obtain about 1: 1 isomer (1R/S, 3R)-mixture of 3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperidines bromide (97a).This suspension is filtered and washs with cold acetonitrile, obtain the white solid form (1R, 3R)-3-(2-hydroxyl-2,2-two thiophene-2-base-acetoxyl group)-1-methyl isophthalic acid-(2-phenoxy group-ethyl)-piperidines bromide (97b).
Claims (7)
1. the compound of formula XVI:
Wherein T is as shown in the table:
2. the compound of formula XVI:
Wherein T is as shown in the table:
3. the compound of formula XVII:
Wherein T is as shown in the table:
4. pharmaceutical composition, it comprises compound any in the claim 1 to 3 as activeconstituents.
5. any one compound purposes in the medicine of the receptor-mediated illness of preparation treatment muscarine M3 in the claim 1 to 3.
6. any one compound purposes in the medicine of preparation treatment inflammatory or allergic conditions in the claim 1 to 3.
7. the described purposes of claim 6, wherein said inflammatory or allergic conditions are inflammatory or obstructive airway diseases.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0314697A GB0314697D0 (en) | 2003-06-24 | 2003-06-24 | Organic compounds |
| GB0314697.4 | 2003-06-24 | ||
| GB0327526.0 | 2003-11-26 | ||
| GB0327526A GB0327526D0 (en) | 2003-11-26 | 2003-11-26 | Organic compounds |
| PCT/EP2004/006795 WO2005000815A2 (en) | 2003-06-24 | 2004-06-23 | Piperidinium and pyrrolidinium derivatives as ligands for the muscarinic m3 receptor |
Publications (2)
| Publication Number | Publication Date |
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| CN1805935A CN1805935A (en) | 2006-07-19 |
| CN1805935B true CN1805935B (en) | 2010-06-09 |
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| CN200480016629.XA Expired - Fee Related CN1805935B (en) | 2003-06-24 | 2004-06-23 | Piperidinium and pyrrolidinium derivatives as ligands for the muscarinic M3 receptor |
Country Status (3)
| Country | Link |
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| CN (1) | CN1805935B (en) |
| ES (1) | ES2351602T3 (en) |
| GB (1) | GB0314697D0 (en) |
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| CN103965178B (en) * | 2013-02-06 | 2018-03-02 | 中国药科大学 | Purposes as the pyrrolidin derivatives of M3 muscarinic receptor antagonists and its in pharmacy |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0073645B1 (en) * | 1981-08-26 | 1986-11-12 | Dainippon Pharmaceutical Co., Ltd. | 2-cyclic amino-2-(1,2-benzisoxazol-3-yl)acetic acid ester derivatives, process for the preparation thereof and composition containing the same |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
-
2003
- 2003-06-24 GB GB0314697A patent/GB0314697D0/en not_active Ceased
-
2004
- 2004-06-23 ES ES04740214T patent/ES2351602T3/en active Active
- 2004-06-23 CN CN200480016629.XA patent/CN1805935B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0073645B1 (en) * | 1981-08-26 | 1986-11-12 | Dainippon Pharmaceutical Co., Ltd. | 2-cyclic amino-2-(1,2-benzisoxazol-3-yl)acetic acid ester derivatives, process for the preparation thereof and composition containing the same |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
Non-Patent Citations (9)
| Title |
|---|
| pharmaceutical bulletin32 3.1984,32(3),1126-34页,尤其试验部分. * |
| pharmaceutical bulletin32 3.1984,32(3),977-85页,尤其表1. * |
| pharmaceutical bulletin33 2.1985,33(2),818-22页,尤其表1. * |
| SUGAI,SABURO et al.Studies on spasmolytics. II. Synthesisandanticholinergicactivitiesof4-acyloxy-1-alkyl-1-(1,3-dioxolan-4-ylmethyl)piperidiniumcompounds.Chemical & * |
| SUGAI,SABURO et al.Studies on spasmolytics. II. Synthesisandanticholinergicactivitiesof4-acyloxy-1-alkyl-1-(1,3-dioxolan-4-ylmethyl)piperidiniumcompounds.Chemical &pharmaceutical bulletin32 3.1984,32(3),977-85页，尤其表1. |
| SUGAI,SABURO et al.Studies on spasmolytics.III. Synthesisandanticholinergicactivityof4-acyloxy-1-alkyl-1-(1,3-dioxolan-4-ylmethyl)piperidinesandtheir quaternary salts.Chemical & * |
| SUGAI,SABURO et al.Studies on spasmolytics.III. Synthesisandanticholinergicactivityof4-acyloxy-1-alkyl-1-(1,3-dioxolan-4-ylmethyl)piperidinesandtheir quaternary salts.Chemical &pharmaceutical bulletin32 3.1984,32(3),1126-34页，尤其试验部分. |
| YOSHIDA,SEIICHIRO et al.Structure-activity relationship of 3-and4-acyloxy-1-(1,3-dioxolan-4-ylmethyl)piperidine derivatives.Chemical & * |
| YOSHIDA,SEIICHIRO et al.Structure-activity relationship of 3-and4-acyloxy-1-(1,3-dioxolan-4-ylmethyl)piperidine derivatives.Chemical &pharmaceutical bulletin33 2.1985,33(2),818-22页，尤其表1. |
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| Publication number | Publication date |
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| CN1805935A (en) | 2006-07-19 |
| GB0314697D0 (en) | 2003-07-30 |
| ES2351602T3 (en) | 2011-02-08 |
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