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CN101163673A - New muscarinic receptor antagonists - Google Patents

New muscarinic receptor antagonists Download PDF

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Publication number
CN101163673A
CN101163673A CNA2006800136147A CN200680013614A CN101163673A CN 101163673 A CN101163673 A CN 101163673A CN A2006800136147 A CNA2006800136147 A CN A2006800136147A CN 200680013614 A CN200680013614 A CN 200680013614A CN 101163673 A CN101163673 A CN 101163673A
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alkyl
compound
independently
halogen
formula
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安德鲁·贝利
戴维·唐纳德
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AstraZeneca AB
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AstraZeneca AB
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Abstract

The invention provides compounds of formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5>, n and X are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.

Description

New muscarinic receptor antagonist
Technical field
The present invention relates to used intermediate in method, their purposes in treatment and their preparations of the substituted alkyl ester of cyclic amino alcohols, their preparation method, the pharmaceutical composition that contains them, pharmaceutical compositions.
Background technology
Muscarinic receptor (Muscarinic receptor) is G-protein linked receptor (GPCR) family, has 5 family member M 1, M 2, M 3, M 4And M 5In 5 muscarine hypotypes, known three hypotype (M 1, M 2And M 3) human lung tissue is had physiological effect.
Parasympathetic nerve is the main path of reflectivity bronchoconstriction in the human airway, regulates air flue tonus (airway tone) by discharging vagusstoff to muscarinic receptor.The air flue tonus for example increases among the patient of asthma and chronic obstructive pulmonary disease (COPD) to some extent suffering from respiratory disorder, has therefore developed muscarinic receptor antagonist to be used for the treatment of airway disorders.Muscarinic receptor antagonism profit so-called Anticholinergics in clinical practice.As the first-line treatment at the COPD individuality, muscarinic receptor antagonist has obtained extensive approval, and its purposes in depth be set forth in the relevant document (people such as Lee for example, Current Opinion in Pharmacology 2001,1,223-229).
When using muscarinic receptor antagonist treatment respiratory disorder, muscarinic receptor antagonist passes through inhalation usually.Yet when when the inhalation, significantly the muscarinic receptor antagonist of ratio is inhaled in the systemic circulation usually, causes the side effect that occurs having reported, for example dry.In addition, most of muscarine antagonists have short relatively acting duration, and this requires administration every day for several times.This every day, the multiple dosing scheme was not only brought inconvenience to the patient, and because the patient to not the complying with of frequent repeat administration scheme, causes treating inadequate substantial risk.
Therefore, still need to block the new compound of muscarinic receptor.Particularly, still need when inhalation, to have the new muscarine antagonist of efficient and the side effect of low system.In addition, still need when inhalation acting duration long and allow the new muscarine antagonist of administration every day 1 time or 2 times.
By for example EP 1302458 known hydroxyaryl cycloalkyl carboxylicesterss with cyclic amino alcohols of muscarine antagonism.
Summary of the invention
According to the present invention, provide formula (I) compound:
Figure S2006800136147D00021
Wherein:
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus (heteroaromatic ring) of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
R 5Expression hydrogen or C 1-6Alkyl;
N is 1 or 2;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace;
And X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
Formula (I) compound comprise with quaternary nitrogen atoms on the associating negatively charged ion X of positive charge Equivalent.Negatively charged ion X can be the pharmaceutically acceptable negatively charged ion of unit price or multivalence (for example divalence) acid arbitrarily.In embodiment of the present invention, X can be an inorganic anion, for example chlorion, bromide anion, iodide ion, sulfate ion, nitrate ion or phosphate anion; Perhaps suitable organic anion, for example acetate ion, maleate ion, fumarate ion, citrate ion, oxalate denominationby, succinate ion, tartrate anion ion, methanesulfonate ion or tosic acid radical ion.
It should be understood that some The compounds of this invention can for example hydration and non-solvent form exist with solvation.Should be appreciated that the present invention contains these all solvation forms.Some formula (I) compound can exist with stereoisomeric forms in any ratio.It should be understood that the present invention contain formula (I) compound all how much and optical isomer and composition thereof, comprise racemoid.The same formation of tautomer and composition thereof one aspect of the present invention.
In this context, term ' assorted fragrance ' is meant that containing at least one is selected from heteroatomic aromatic nucleus in nitrogen, oxygen and the sulphur.According to the present invention, the example of the assorted aromatic nucleus of 5-6 unit comprises thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl,  azoles base,  di azoly, imidazolyl, different  azoles base, isothiazolyl, pyrazolyl and triazolyl.Term ' aliphatic heterocycle ' is meant that containing at least one is selected from heteroatomic non-aromatic ring in nitrogen, oxygen and the sulphur.According to the present invention, the aliphatic heterocyclic example of 4-8 unit comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, high piperazinyl (homopiperazinyl), homopiperidinyl (homopiperidinyl) and azetidinyl.
Unless description is arranged in addition, in this context, alkyl group and part can be straight or brancheds, comprise methyl, ethyl, just-propyl group, different-propyl group or tert-butyl.Cycloalkyl is a monocyclic groups, for example cyclopentyl or cyclohexyl.Halogen is for example fluorine, chlorine or bromine.
In this context, when pointing out that certain group can choose wantonly when being replaced by one or more substituting groups, this group can be that replace or unsubstituted; This moment, then described group was replaced by 1,2 or 3 substituting group usually if replace.
In embodiment of the present invention, R 1Expression phenyl, described phenyl can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.Advance on the one hand R in this embodiment 1The expression phenyl, it can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.
In embodiment of the present invention, R 2The representative ring amyl group, it can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.Advance on the one hand R in this embodiment 2The representative ring amyl group, it can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.
In embodiment of the present invention, R 3Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 3The expression methyl.
In embodiment of the present invention, R 4Expression hydrogen, methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 4The expression methyl.
In embodiment of the present invention, R 5Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 5The expression methyl.
In embodiment of the present invention, R 4And R 5Represent methyl or ethyl independently of one another.
In embodiment of the present invention, n is 1.
In embodiment of the present invention, n is 2.
In embodiment of the present invention, X represents chlorion, bromide anion, iodide ion or fumarate ion.In advancing on the one hand of this embodiment, X represents bromide anion or iodide ion.
In embodiment of the present invention, R 1The expression phenyl, it can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace; R 2The representative ring amyl group, it can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) the one or more substituting groups in 2 replace; R 3The expression methyl; R 4And R 5Represent methyl or ethyl independently of one another; N is 1 or 2; And X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.In advancing on the one hand of this embodiment, X represents chlorion, bromide anion, iodide ion or fumarate ion.
The compounds of this invention has at least two chiral centres.The position of these two chiral centres as shown in the formula the asterisk in (I) ( *) shown in.One of them chiral centre is positioned at and each R 1, R 2And R 3On the carbon atom (2 ') that links to each other, and another chiral centre is positioned at connection and contains on the carbon atom (3) of azo-cycle and carboxyl.Because this compound has two chiral centres, therefore there are 4 kinds of possible steric isomers (3R, 2 ' R), (3S, 2 ' S), (3R for each compound, 2 ' S) and (3S, 2 ' R), two kinds of enantiomorphs are to (3R, 2 ' R)/(3S, 2 ' S) and (3R, 2 ' S)/(3S, 2 ' R)].All optical isomers of formula (I) compound and composition thereof are contained in the present invention, comprise racemoid.
In embodiment of the present invention, the chiral centre that is positioned on 3 has the R configuration.In another embodiment of the present invention, the chiral centre that is positioned on 3 has the S configuration.Advance in the embodiment in the present invention, the chiral centre that is positioned on 2 ' has the R configuration.In yet another embodiment of the invention, the chiral centre that is positioned on 2 ' has the S configuration.
In embodiment of the present invention, formula (I) compound has (3R, 2 ' R) configuration.In another embodiment of the present invention, formula (I) compound has (3S, 2 ' S) configuration.Advance in the embodiment in the present invention, formula (I) compound has (3R, 2 ' S) configuration.In yet another embodiment of the invention, formula (I) compound has (3S, 2 ' R) configuration.
In advancing an embodiment, the invention provides optically pure formula (I) compound.In this context, the term optical purity defines with enantiomeric excess (e.e.), is calculated by the difference of existing two kinds of enantiomorph content and the ratio of these content summations, represents with per-cent.For instance, the product that contains the another kind of enantiomorph of a kind of enantiomorph of 95% and 5% has 90% enantiomeric excess [i.e. (95-5)/(95+5) * 100].Optical pure compound of the present invention has the e.e. at least 90%.In embodiment of the present invention, optical pure compound has the e.e. at least 95%.Advance in the embodiment in the present invention, optical pure compound has the e.e. at least 98%.When compound had diastereomer, optical pure compound had and is at least 90% e.e. and at least 90% diastereomeric excess (d.e) [diastereomeric excess defines with reference to enantiomeric excess].In embodiment of the present invention, optical pure compound has and is at least 95% e.e. and at least 95% d.e..Advance in the embodiment in the present invention, optical pure compound has and is at least 98% e.e. and at least 98% d.e..
In embodiment of the present invention, provide optically pure formula (I) compound with (3R, 2 ' R) configuration.
In embodiment of the present invention, provide optically pure formula (I) compound with (3S, 2 ' S) configuration.
In embodiment of the present invention, provide optically pure formula (I) compound with (3R, 2 ' S) configuration.
In embodiment of the present invention, provide optically pure formula (I) compound with (3S, 2 ' R) configuration.
In one aspect of the present invention, providing is (IB) compound:
Figure S2006800136147D00061
Wherein
R 1The expression phenyl, described phenyl can be chosen wantonly by halogen, hydroxyl, C 1-6Alkyl or C 1-6Alkoxyl group replaces; Perhaps R 1Expression thienyl or furyl, described thienyl or furyl can be chosen wantonly by halogen or C 1-6Alkyl replaces;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
R 5Expression C 1-6Alkyl;
N is 1 or 2;
And X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
In embodiment of the present invention, in formula (IB), R 1The expression phenyl.
In embodiment of the present invention, in formula (IB), R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace.When cycloalkyl ring was replaced by halogen, it can be replaced by more than halogenic substituent, and each carbon atom in the cycloalkyl ring can be chosen wantonly and carries 1 or 2 halogenic substituent.
In embodiment of the present invention, in formula (IB), R 2Represent unsubstituted C 3-8Cycloalkyl ring.Advance on the one hand R in this embodiment 2Represent unsubstituted cyclopentyl.
In embodiment of the present invention, in formula (IB), R 2Representative ring amyl group, described cyclopentyl can be chosen wantonly by fluorine and replace.
In embodiment of the present invention, in formula (IB), R 3Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 3The expression methyl.
In embodiment of the present invention, in formula (IB), R 4Expression hydrogen, methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 4The expression methyl.
In embodiment of the present invention, in formula (IB), R 5Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 5The expression methyl.
In embodiment of the present invention, in formula (IB), n is 1.
In embodiment of the present invention, in formula (IB), R 4And R 5Represent methyl or ethyl independently of one another, and n is 1.
In embodiment of the present invention, in formula (IB), X represents chlorion, bromide anion, iodide ion or fumarate ion.In advancing on the one hand of this embodiment, X represents bromide anion or iodide ion.
In embodiment of the present invention, in formula (IB), R 1The expression phenyl; R 2The representative ring amyl group; R 3The expression methyl; R 4And R 5Represent methyl or ethyl independently of one another; N be 1 and X represent monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.In advancing on the one hand of this embodiment, X represents chlorion, bromide anion, iodide ion or fumarate ion.
Advancing on the one hand, the invention provides formula (IC) compound:
Figure S2006800136147D00071
Wherein:
R 1Expression phenyl, thienyl or furyl;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
R 5Expression C 1-6Alkyl;
N is 1 or 2;
And X -Expression monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
In embodiment of the present invention, in formula (IC), R 1The expression phenyl.
In embodiment of the present invention, in formula (IC), R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace.When cycloalkyl ring was replaced by halogen, it can be replaced by more than halogenic substituent, and each carbon atom in the cycloalkyl ring can be chosen wantonly and carries 1 or 2 halogenic substituent.
In embodiment of the present invention, in formula (IC), R 2Represent unsubstituted C 3-8Cycloalkyl ring.Advance on the one hand R in this embodiment 2Represent unsubstituted cyclopentyl.
In embodiment of the present invention, in formula (IC), R 2Representative ring amyl group, described cyclopentyl can be chosen wantonly by fluorine and replace.
In embodiment of the present invention, in formula (IC), R 3Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 3The expression methyl.
In embodiment of the present invention, in formula (IC), R 4Expression hydrogen, methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 4The expression methyl.
In embodiment of the present invention, in formula (IC), R 5Expression methyl, ethyl or just-propyl group.Advance on the one hand R in this embodiment 5The expression methyl.
In embodiment of the present invention, in formula (IC), n is 1.
In embodiment of the present invention, in formula (IC), R 4And R 5Represent methyl or ethyl independently of one another; And n is 1.
In embodiment of the present invention, in formula (IC), X -Expression chlorion, bromide anion or fumarate ion.Advance on the one hand X in this embodiment -The expression bromide anion.
In embodiment of the present invention, in formula (IC), R 1The expression phenyl; R 2The representative ring amyl group; R 3The expression methyl; R 4And R 5Represent methyl or ethyl independently of one another; N is 1 and X -Expression monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.Advance on the one hand X in this embodiment -Expression chlorion, bromide anion or fumarate ion.
In embodiment of the present invention, formula (I) compound is selected from:
(3S)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  X, and
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  X, wherein X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
According to this embodiment, pharmaceutically acceptable negatively charged ion comprises chlorion, bromide anion, iodide ion and fumarate ion.
Advancing on the one hand, the invention provides the method for preparation formula (I) compound, described method comprises: make formula (IV) compound or its C 1-6Alkyl ester, acid anhydrides or acyl halide and the reaction of formula V compound obtain formula (II) compound,
Figure S2006800136147D00081
In the formula (IV), R 1, R 2And R 3Define suc as formula (I),
Figure S2006800136147D00091
In the formula V, R 4Define suc as formula (I) with n,
Figure S2006800136147D00092
Then with (II) and formula R 5(wherein Y is leavings group (for example halogen) and R to-Y (III) compound 5Define suc as formula (I)) reaction, and
Randomly carry out step of one in following or multistep:
● compound is converted into other formula (I) compound,
● form pharmacologically acceptable salt with monovalent acid or polyacid negatively charged ion.
Compound (IV) and reaction (V) can be easily suitable solvent for example toluene or methylene dichloride in the presence of, carry out in the temperature of 0-100 ℃ of scope.In one embodiment of this invention; compound (IV) can be acyl halide (for example acyl chlorides) form easily, and the latter can be by with acid and suitable agent (for example thionyl chloride or oxalyl chloride) at suitable solvent for example in methylene dichloride or the toluene, carry out in the thermotonus of 0-100 ℃ of scope.
Compound (II) and reaction (III) can be easily at suitable solvent for example in the presence of methylene dichloride or the acetonitrile, carry out in the temperature of 0-100 ℃ of scope.
It should be appreciated by those skilled in the art that in the method for the invention, may need for example hydroxyl, carboxyl or amino with some functional group in protecting group protection raw material reagent (starting reagent) or the midbody compound.Therefore, the preparation of the compound of formula (I) can be included in certain stage interpolation and/or remove one or more protecting groups.The protection of functional group and deprotection are at " Protective Groups in Organic Synthesis "; 2nd edition; T.W.Greene and P.G.M. Wuts; Wiley-Interscience (1991) and " Protecting Groups "; P.J.Kocienski has description among the Georg Thieme Verlag (1994).
Formula (IV) compound can adopt the method for this area description or prepare with reference to these class methods.For example, the preparation of α-cycloalkyl-α-phenylpropionic acid is described in Zhurnal Obshchei Khimii, and (1964), 34 (5), among the 1618-1621.
The formula V compound can be commercially available, and also can adopt the method preparation of describing in the document, for example referring to Chemische Berichte/Recueil (1997), and 130 (3), 385-397 and Journal ofMedicinal﹠amp; Pharmaceutical Chemistry (1959), 1,73-94.
Optically pure formula (I) compound for example can be prepared as follows: with optically pure formula (IV) compound and the reaction of optically pure formula V compound, obtain the ester of formula (II), then with (II) and the reaction of formula (III) compound.Optically pure formula V compound can be commercially available, and also can adopt the method for describing in the document to prepare.
Optically pure formula (IV) compound can be prepared as follows: with corresponding racemic acid or its C 1-6Alkyl ester, acid anhydrides or acyl halide and suitable ancillary compound (for example (R)-4-benzyl-2- oxazolidone) reaction; the mixture of the diastereomeric ester of resulting separation (for example passing through chromatographic separation) is then removed formula (IV) acid that ancillary compound obtains enantiomer-pure.
Optically pure formula (IV) compound did not before prepare.Therefore, optically pure formula (IV) compound or its C have been the present invention further provides 1-6Alkyl ester, acid anhydrides or acyl halide, described formula (IV) compound is
Figure S2006800136147D00101
Wherein,
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace.
In embodiment of the present invention, optically pure formula (IV) compound or its C are provided 1-6Alkyl ester, acid anhydrides or acyl halide, R in described formula (IV) compound 1The expression phenyl, described phenyl can be chosen wantonly by halogen, hydroxyl, C 1-6Alkyl or C 1-6Alkoxyl group replaces; Perhaps R 1Expression thienyl or furyl, described thienyl or furyl can be chosen wantonly by halogen or C 1-6Alkyl replaces; R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace;
R 3Expression C 1-6Alkyl.
Optically pure formula (IV) compound has the e.e. at least 90%.In embodiment of the present invention, optically pure formula (IV) compound has the e.e. at least 95%.Advance in the embodiment in the present invention, optically pure formula (IV) compound has the e.e. at least 98%.
Optically pure formula of the present invention (IV) examples for compounds comprises:
(2R)-2-cyclopentyl-2-phenylpropionic acid and
(2S)-2-cyclopentyl-2-phenylpropionic acid.
Formula (II) compound did not before prepare.In addition, these not quaternised compounds demonstrate the anticholinergic agents activity equally, for treatment urinary tract illness for example the bladder hyperactivity hyperkinesia be favourable.Therefore, the present invention further provides formula (II) compound
Figure S2006800136147D00111
Wherein,
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
N is 1 or 2;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace.
In embodiment of the present invention, provide formula (II) compound, wherein
R 1The expression phenyl, described phenyl can be chosen wantonly by halogen, hydroxyl, C 1-6Alkyl or C 1-6Alkoxyl group replaces; Perhaps R 1Expression thienyl or furyl, described thienyl or furyl can be chosen wantonly by halogen or C 1-6Alkyl replaces; R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by halogen and replace; R 3Expression C 1-6Alkyl; R 4Expression hydrogen or C 1-6Alkyl; And n is 1 or 2.
Comprise according to formula of the present invention (II) compound:
(3S)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester,
(3R)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester,
(3S)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester,
(3R)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester,
(3R)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester and
(3S)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester.
The compounds of this invention has pharmaceutical activity, particularly as anticholinergic agents, comprises muscarinic receptor (M1, M2 and M3) antagonist, the particularly activity of M3 antagonist.Can use the disease and the illness of The compounds of this invention treatment to comprise:
1. respiratory tract: airway obstructive disease, comprise: asthma, comprise that bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (comprising what acetylsalicylic acid and NSAID-brought out) and dust bring out asthma, intermittent and persistence, all are severities; Airway hyperreactivity with other reason; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises CFA, idiopathic interstitial pneumonia, concurrent antineoplaston and chronically infected fibrosis, comprises tuberculosis and aspergillosis and other fungi infestation; Complication of transplanted lung; Lung vascular system vasculitis and thrombotic disease; And pulmonary hypertension; Antitussive activity comprises for a long time cough and iatrogenic cough relevant with the secretion symptom of treatment and airway inflammation; Acute and chronic rhinitis comprises medicamentous rhinitis and vasomotor rhinitis; Perennial rhinitis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis); Nasal polyposis; Acute viral infection comprises flu and the infection that causes because of respiratory syncytial virus, influenza, coronavirus (comprising SARS) and adenovirus;
2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise their sacroiliitis, not only comprised idiopathic but comprise insecondary, congenital hip dysplasia for example; Neck and lumbar spine scorching and lumbago and backache and cervicodynia; Rheumatoid arthritis and Still disease (Still ' s disease); Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA (undifferentiated spondarthropathy); Septic arthritis infects relevant joint disease (arthopathies) and osteopathia with other, such as tuberculosis, comprises Pott's disease (Potts ' disease) and Poncet syndrome (Poncet ' s syndrome); The synovitis that acute and chronic crystal brings out comprises gout, tendon, mucous bursa and synovia inflammation that calcium pyrophosphate deposition disease is relevant with apatite calcium; Behcet's disease (Behcet ' sdisease); Primary and Secondary cases xerodermosteosis (Sjogren ' s syndrome); Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, MCTD and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; The rheumatic polymyopathy; Juvenile arthritis (juvenile arthritis) comprises primary inflammatory arthritis and related syndromes and rheumatic fever and whole body complication thereof that no matter which kind of joint distributes; Vasculitis (vasculitide), comprise giant cell arteritis, aortic arch syndrome (Takayasu ' s arteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microcosmic polyarteritis, with the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome (Muckle-Wells syndrome) and familial Ireland heat (Familial Hibernian Fever), Kikuchi disease (kikuchi); Drug-induced arthrodynia, tendonitis (tendonititides) and myopathy;
3. because the flesh skeleton illness that pain that damage [for example sport injury] or disease cause and reticular tissue reproduce: sacroiliitis (rheumatoid arthritis for example, osteoarthritis, gout or crystal joint disease), other joint disease (for example disc degenerates or temporomandibular degenerative joint), bone remodelling disease (for example osteoporosis, scleromalacia or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease disease, spondyloarthropathy or periodontopathy (for example periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas dermatitis and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, skin tag disease, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, epidermis eosinophilia, alopecia areata, male pattern baldness disease, sweet's syndrome (Sweet ' ssyndrome), Wei-Ke syndrome (Weber-Christian syndrome), erythema multiforme; Cellulitis comprises communicable and noninfectious; Pimelitis; Lymphoma cutis; Non-melanoma skin cancer and other dysplasia infringement; Drug-induced disease comprises fixed drug eruption;
The eye: blepharitis; Conjunctivitis comprises property and spring allergic conjunctivitis for many years; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmune disorder; Influence amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise virus, fungi and infectation of bacteria;
6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome and can have food related allergic (for example migraine, rhinitis or eczema) away from the intestines effect;
7. belly: hepatitis comprises autoimmunity, alcohol and viral hepatitis; Hepatic fibrosis and liver cirrhosis; Cholecystitis; Pancreatitis comprises acute pancreatitis and chronic pancreatitis;
8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer (Hunner ' s ulcer); Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Peyronie disease (Peyronie ' s disease); Erectile dysfunction (masculinity and femininity);
9. allograft rejection: acute and chronic allograft rejection, for example after kidney, heart, liver, lung, marrow, skin or the corneal transplantation or the acute and chronic allograft rejection after the blood transfusion; Or chronic graft versus host disease;
10.CNS: alzheimer's disease and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis (vasculitis); Temporal arteritis; Myasthenia gravis; Acute and chronic pain be (acute, intermittence or persistence, no matter derive from maincenter or periphery), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade pain, the neuropathic pain syndrome that causes, comprise after diabetes, the bleb and the DPN relevant with HIV-because of cancer and tumour; Neurosarcoidosis; The maincenter and the peripheral nervous system complication of pernicious, infectivity and self-immunprocess;
11. other autoimmune disorder and allergic disorder comprise Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Graves disease (Graves ' disease), bronzed disease (Addison ' sdisease), diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, height-IgE syndrome, antiphospholipid syndrome;
12. the disease that other has inflammatory or immunity composition comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, malignant cutaneous reticulosis syndrome (ezary syndrome) and paraneoplastic syndrome;
13. it is cardiovascular; Atherosclerosis, influence the pericarditis of coronary artery and peripheral circulation; Myocarditis, inflammatory and autoimmunity myocardosis comprise myocardial sarcoisosis; The ischemic reperfusion injury; Endocarditis, cardiovalvulitis and aortitis comprise communicable (for example plum is toxic); Vasculitis; Nearly vein and peripheral vein disease comprise phlebitis and thrombosis, comprise that dvt forms and the varix complication;
14. tumour: treatment common cancer, the malignant tumour that comprises prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and infringement marrow (comprising leukemia) and lymphadenosis system is such as hodgkin lymphoma (Hodgkin ' s lymphoma) and non-hodgkin lymphoma (non-Hodgkin ' s lymphoma); Comprise prevention and treatment metastatic disease and tumor recurrence and paraneoplastic syndrome; With
15. gi tract: coeliac disease, rectitis, acidophilia gastroenteritis, mast cell disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (irritable bowel disorder), irritable bowel syndrome (irritable bowel syndrome), non-inflammatory diarrhoea or have the relevant allergy of food away from the effect of intestines, for example, migraine, rhinitis and eczema.
Therefore, defined formula (I) compound during the present invention also provides as mentioned, it is used for the treatment of.
On the other hand, the purposes of defined formula (I) compound in the medicine that preparation is used for the treatment of in the invention provides as mentioned.
In the context of the present specification, term " treatment " also comprises " prevention " is unless exist opposite specific description.Term " treatment " and " remedially " are also answered respective explanations.
The invention provides into provides treatment to suffer from described disease on the one hand or has faced the method for this illness in the Mammals of described disease danger, and described method comprises above-mentioned formula (I) compound to the Mammals drug treatment significant quantity that these treatment needs are arranged.
The present invention also provides above-mentioned formula (I) compound to be used for the treatment of purposes in the medicine of chronic obstructive pulmonary disease (COPD) (for example irreversible COPD) in preparation.
The present invention also provides above-mentioned formula (I) compound to be used for the treatment of purposes in the medicine of asthma in preparation.
The present invention further provides for example method of philtrum chronic obstructive pulmonary disease (COPD) (for example irreversible COPD) of treatment warm-blooded animal, described method comprises above-mentioned formula (I) compound to the Mammals effective dosage that these treatment needs are arranged.
The present invention further provides for example method of philtrum asthma of treatment warm-blooded animal, described method comprises above-mentioned formula (I) compound to the Mammals effective dosage that these treatment needs are arranged.
For with being used for the treatment of property of The compounds of this invention processing warm-blooded animal people for example, usually described composition is mixed with pharmaceutical compositions according to the standard pharmaceutical practice.
Therefore on the other hand, the invention provides pharmaceutical composition, wherein contain above-mentioned The compounds of this invention and pharmaceutically acceptable assistant agent, diluent or carrier.Advancing on the one hand, the invention provides the described method for compositions of preparation, described method comprises mixes activeconstituents with pharmaceutically acceptable assistant agent, diluent or carrier.According to mode of administration, pharmaceutical composition can contain 0.05-99%w (weight percentage), 0.05-80%w for example, and 0.10-70%w for example, 0.10-50%w activeconstituents for example, all wt percentage ratio calculates based on whole composition.
Pharmaceutical composition of the present invention can be administered for the illness that hope is treated according to standard manner, for example by local (for example to lung and/or air flue or skin), oral, rectum or administered parenterally.To achieve these goals, The compounds of this invention can be mixed with for example gaseous solvents, dry powder formulations, tablet, capsule, syrup, powder, granule, water or oily solution agent or suspensoid, (liquid) emulsion, can disperse powder, suppository, ointment, creme, drops and aseptic injection water or oily solution agent or suspensoid by manner known in the art.
Suitable drug composition of the present invention is fit to be used for oral administration with unit dosage, and for example tablet or Capsule form oral administration wherein contain the 0.1mg-1g activeconstituents.
On the other hand, pharmaceutical composition of the present invention is suitable for intravenously, subcutaneous or intramuscularly.Each patient's acceptable for example intravenously, subcutaneous or intramuscular dosage is 0.01mgkg -1To 100mgkg -1Compound, for example be 0.1mgkg -1To 20mgkg -1The compounds of this invention, said composition administration every day 1-4 time.Intravenously, subcutaneous and intramuscular dosage can pass through the administration of bolus injection mode.Perhaps, intravenous dosages can give by the mode of continuous infusion in for some time.Perhaps, each patient can take the oral per daily dose that is about as much as non-enteron aisle per daily dose, described composition administration every day 1-4 time.
Other suitable pharmaceutical composition of the present invention is suitable for inhalation, and for example when chronic obstructive pulmonary disease (COPD) or asthma, inhalation is to use the useful especially method of The compounds of this invention in the treatment respiratory tract disease.When by inhalation, formula (I) compound is effective under the dosage of μ g scope, for example 0.1-500 μ g, 0.1-50 μ g, 0.1-40 μ g, 0.1-30 μ g, 0.1-20 μ g, 0.1-10 μ g, 5-10 μ g, 5-50 μ g, 5-40 μ g, 5-30 μ g, 5-20 μ g, 5-10 μ g, 10-50 μ g, 10-40 μ g, 10-30 μ g or 10-20 μ g activeconstituents.
Pharmaceutical composition is provided in embodiment of the present invention, and it comprises above-mentioned The compounds of this invention and is combined with pharmaceutically acceptable assistant agent, diluent or carrier, they is mixed be used for inhalation.
When inhalation, can use metered-dose inhaler device to use the activeconstituents that is scattered in the suitable propelling agent, and add or do not add other excipient for example ethanol, tensio-active agent, lubricant or stablizer.Suitable propelling agent comprises the mixture of hydrocarbon, chlorine hydrofluoric ether and hydrofluoroalkane (for example Sevoflurane) propelling agent or any above-mentioned propelling agent.Preferred propelling agent is P134a and P227, and they can use or unite other propelling agent and/or tensio-active agent and/or other excipient separately and use.Can use atomized water suspensoid or preferred solution agent with single dose or multiple doses dosage form, regulate or do not regulate suitable pH and/or Zhang Du.
Can use Diskus use separately or with pharmaceutically acceptable carrier bonded activeconstituents, back one situation can be fine dispersive powder or ordered mixture form.Diskus can be single dose or multiple doses, can use dry powder or contain the capsule of dry powder.
Metered dose inhaler, spraying gun and powder inhaler are well-known, and can use various these class devices.
The invention further relates to combination therapy, wherein with The compounds of this invention or comprise the pharmaceutical composition of The compounds of this invention or the administration or as the combination preparation administration, to be used for the treatment of one or more cited illnesss simultaneously or sequentially of preparation and another kind of or multiple therapeutical agent.
Especially, with regard to the treatment of inflammatory diseases, for example (but being not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel, The compounds of this invention can with following reagent coupling:
Non-steroidal anti-inflammatory agents (hereinafter referred to as NSAID) comprises nonselective cyclooxygenase COX-1/COX-2 inhibitor, no matter part or whole body are used (piroxicam for example, diclofenac, propionic acid is Naproxen Base for example, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP, fragrant that acid is mefenamic acid for example, INDOMETHACIN (Indomethacin), sulindac, azapropazone (azapropazone), pyrazolone is Phenylbutazone for example, salicylate is Asprin for example); Selective COX-2-2 inhibitor (meloxicam for example, celecoxib, rofecoxib, valdecoxib, Lu Makao former times (lumarocoxib), former times examined by handkerchief and support is examined former times); Cyclooxygenase suppresses nitric oxide donors (CINOD); Glucocorticosteroid (no matter by local, oral, intramuscular, intravenously or the administration of IA path); Methotrexate, leflunomide; Oxychloroquine, d-Trolovol, auranofin or other parenteral or oral gold preparation; Anodyne; Diacerein (diacerein); The intraarticular therapy is derivatives of hyaluronic acids for example; With accessory substance glycosamine for example.
The present invention further relates to the coupling of compound of the present invention and following cytokine or cytokine function agonist or antagonist (comprise and act on for example medicine of SOCS system modifier of cytokine signaling pathway): comprise α-, β-and gamma-interferon; Insulin-like growth factor I type (IGF-1); Interleukin (IL) comprises for example Kineret of IL1 to 17 and interleukin antagonist or inhibitor; Tumor necrosis factor alpha (TNF-α) inhibitor is anti-tumor necrosis factor monoclonal antibody (infliximab (infliximab) for example for example; Adalimumab (adalimumab), and CDP-870) and the TNF receptor antagonist comprise for example pentoxifylline (pentoxyfylline) of immunoglobulin molecules (for example etanercept) and low-molecular-weight drug.
In addition, the present invention relates to the coupling of the monoclonal antibody of The compounds of this invention and target B-lymphocyte (for example CD20 (Rituximab (rituximab)), MRA-aIL16R) and T-lymphocyte (CTLA4-Ig, HuMax Il-15).
The invention further relates to the coupling of The compounds of this invention and following chemokine receptor function conditioning agent, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); And CX 3CR1 (C-X 3-C family) antagonist.
The present invention further relates to the coupling of The compounds of this invention and following inhibitor: matrix metallo-proteinase inhibitor, the inhibitor of instant stromatin enzyme (stromelysins), collagenase and gelatinase and proteoglycan enzyme (aggrecanase); Collagenase-1 (MMP-1) particularly, collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and molten stromatin enzyme-3 (MMP-11) and MMP-9 and MMP-12 comprise Vibravenos etc.
The present invention further relates to compound of the present invention and following drug combination: leukotrienes biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonist for example: abandon stay logical; ABT-761; Fenleuton; Tepoxalin; Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfonamide; 2,6-two-tert-butyl phenol hydrazone; The methoxyl group tetrahydropyrans is Zeneca ZD-2138 for example; Compound S B-210661; The 2-cyano group naphthalene compound of pyridyl-replacement is L-739 for example, and 010; 2-cyano quinolines compound is L-746 for example, and 530; Indoles and quinoline compound be MK-591 for example, MK-886, and BAY * 1005.
The present invention further relates to The compounds of this invention or its pharmacologically acceptable salts and the combination that is selected from the receptor antagonist of following leukotrienes (LT) B4, LTC4, LTD4 and LTE4: thiodiphenylamine-3-ketone is L-651 for example, and 392; Amidino compounds is CGS-25019c for example; Benzo  amine (benzoxalamine) is Ontazolast for example; Benzenyl amidine (benzenecarboximidamides) is BIIL 284/260 for example; Compound is Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY * 7195 for example.
The present invention further relates to the coupling of The compounds of this invention and following medicine: phosphodiesterase (PDE) inhibitor for example methyl xanthine (methyl xanthanines) comprises theophylline and aminophylline; Optionally PDE isozyme inhibitor comprises the inhibitor of PDE4 inhibitor and isoform PDE4D and the inhibitor of PDE5.
The present invention further relates to the coupling of The compounds of this invention and following medicine: histamine 1 receptor antagonist, alerlisin for example, Loratadine, Desloratadine, fexofenadine, Acrivastine, terfenadine, astemizole, azelastine, levocabastine, Toldrin, promethazine, marezine (cyclizine), or mizolastine; Oral, part or parenteral are used.
The present invention further relates to the coupling of The compounds of this invention and proton pump inhibitor (for example omeprazole) or stomach protection histamine 2 receptor antagonist.
The invention further relates to the coupling of The compounds of this invention and histamine 4 receptor antagonists.
The present invention further relates to the coupling of The compounds of this invention and following medicine: α-1/ α-2 adrenoceptor agonists, vasoconstrictor, sympathomimetic drug, propylhexedrine (propylhexedrine) for example, synephrine, Phenylpropanolamine, ephedrine, pseudo-ephedrine, naphcon, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorephinephrine hydrochloride.
The present invention further relates to the coupling of The compounds of this invention and following medicine: receptor, agonist (comprising beta receptor hypotype 1-4), Racemic isoproterenol for example, salbutamol (salbutamol), formoterol, Salmeterol, terbutaline (terbutaline), Metaprel, bitolterol mesilate (bitolterol mesylate), pirbuterol or indacaterol, or its chirality enantiomorph.
The present invention further relates to for example coupling of sodium cromoglycate or sodium nedocromil of compound of the present invention and chromone.
The present invention further relates to the coupling of this compound of the present invention and following medicine: glucocorticosteroid, flunisolide for example, Triamcinolone Acetonide, Viarox, budesonide, fluticasone propionate, ciclesonide, or furancarboxylic acid Mo Meisong.
The present invention further relates to compound of the present invention and regulates for example coupling of the medicine of PPAR of nuclear hormone receptor.
The present invention further relates to the coupling of compound of the present invention and following medicine: immunoglobulin (Ig) (Ig) or Ig preparation or antagonist or antibody are regulated for example anti-IgE of Ig function (horse pearl monoclonal antibody for example difficult to understand).
The present invention further relates to compound of the present invention and other system or topical application for example coupling of Thalidomide (thalidomide) or derivatives thereof, retinoid, anthratriol (dithranol) or calcipotriol (calcipotriol) of anti-inflammatory agent.
The present invention further relates to the coupling of compound of the present invention and following medicine: aminosalicylate and sulfapyridine be sulfasalazine for example, mesalazine, Balsalazide, and olsalazine; With immunoregulation druge thio-purine (thiopurines) and cortex steroid budesonide for example for example.
The present invention further relates to the coupling of compound of the present invention and following medicine: antiseptic-germicide comprises penicillin derivative, tsiklomitsin, macrolide, beta-lactam, fluoroquinolone, metronidazole and suction aminoglycoside; And antiviral drug, comprise acyclovir, Famciclovir, valacyclovir, ganciclovir, cidofovir; Amantadine, Rimantadine; Virazole; Zanamivir (zanamavir) and special quick clothes (oseltamavir); Proteinase inhibitor, Indinavir for example, viracept see nelfinaivr, ritonavir, and Saquinavir; Nucleoside reverse transcriptase inhibitor, didanosine for example, Lamivudine, stavudine (stavudine), zalcitabine or zidovudine; Or non-nucleoside reverse transcriptase inhibitor, for example nevirapine (nevirapine) or efavirenz (efavirenz).
The present invention further relates to the coupling of compound of the present invention and following medicine: cardiovascular agent, calcium channel blocker for example, receptor, blocker, angiotensin-converting enzyme (ACE) inhibitor, Angiotensin-2 receptor antagonist; Lipid reduces medicine, for example the special class (fibrates) of statin or shellfish; The blood cell shape conditioning agent is for example joined the appropriate western film; Thrombolytics, and anti-coagulant comprise anticoagulant.
The present invention further relates to the coupling of compound of the present invention and following medicine: the CNS medicine, thymoleptic (for example Sertraline) for example, antiparkinsonian medicine (selegiline for example, levodopa, Ropinirole, pramipexole, the MAOB inhibitor is Si Lanjilan (selegine) and rasagiline for example, the comp inhibitor is tolcapone (tasmar) for example, A-2 inhibitor, dopamine reuptake inhibitor, nmda antagonist, or anti-Alzheimer medicine E2020 (donepezil) for example nicotinic agonist, the inhibitor of dopamine agonist or neuronal nitric oxide synthase (inhibitors of neuronal nitric oxide synthase)),, Li Fansi's is bright, tacrine, cox 2 inhibitor, propentofylline or metrifonate.
The present invention further relates to compound of the present invention and treatment is acute and the coupling of the medicine of chronic pain, as maincenter and peripheral action pain killer (for example opioid or derivatives thereof), Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline) or other thymoleptic, Paracetamol or non-steroidal anti-inflammatory agents.
The present invention further relates to for example coupling of lignocaine (lignocaine) or derivatives thereof of local anesthetic of compound of the present invention and parenteral or topical application (comprising suction).
Compound of the present invention also can comprise for example Reynolds former times sweet smell of hormonal medicaments with anti-osteoporosis agents, or for example coupling of alendronate (alendronate) of diphosphonate (biphosphonate).
The present invention further relates to the coupling of compound of the present invention and following medicine: (i) tryptase inhibitors; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin is changed enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) the adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) kinase inhibitor, comprise tyrosine kinase inhibitor (Btk for example, Itk, Jak3 MAP, the example of inhibitor can comprise Gefitinib (Gefitinib), imatinib mesylate), the serine/threonine kinase inhibitor (for example, map kinase is the inhibitor of p38, JNK, protein kinase A, B and C and IKK for example), or relate to the inhibitor of the kinases (for example, cell cycle protein dependent kinase) of Cycle Regulation; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin-B1-or B2-receptor antagonist body; (x) antigout agent, for example, colchicine; (xi) xanthine oxidase inhibitor, for example, Zyloric; (xii) uricosuric agent, for example probenecid or sulphur arsenic ketone or benzbromarone; (xiii) tethelin succagoga; (xiv) transforming growth factor (TGF β); (xv) Thr6 PDGF BB (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) rHuGM-CSF (GM-CSF); (xviii) capsicum vegetable oil (capsaicin cream); (xix) tachykinin NK-1 1 or NK3 receptor antagonist for example are selected from NKP-608C, SB-233412 (Talnetant) or D-4418; (xx) elastase inhibitor is selected from UT-77 or ZD-0892; (xxi) TNF-α converting enzyme inhibitor (TACE); (xxii) inductive nitric oxide synthase inhibitor activity (iNOS); Or the chemoattractant receptor homolog molecule (CRTH2 antagonist) of (xxiii) expressing on the TH2 cell; (xxiv) inhibitor of P38; (xxv) medicine of adjusting Toll receptoroid (TLR) function and (xxvi) the active medicine of adjusting purinergic receptor, for example P2X7; Or (xxvii) transcription factor activatory inhibitor, for example NFkB, API or STATS.
Compound of the present invention can also with the coupling of existing therapeutical agent of treatment cancer, for example suitable therapeutical agent comprises:
(i) antiproliferative/antitumour drug or its combination as being used for the medical science oncology, for example alkylating agent (as cis-platinum, carboplatin, endoxan, mustargen, L-PAM, Chlorambucil, busulfan or nitrosourea); (antifol for example is as fluorinated pyrimidine such as 5 FU 5 fluorouracil or Tegafur, Raltitrexed, Rheumatrex, cytosine arabinoside, hydroxyurea, gemcitabine or taxol for metabolic antagonist; Antitumor antibiotics (for example anthracycline antibiotics, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu or Plicamycin); Antimitotic agent (catharanthus alkaloid class for example, as vincristine(VCR), vincaleucoblastine, vindesine or vinorelbine, or taxanes, as taxol or docetaxel); Or topoisomerase enzyme inhibitor (for example epipodophyllotoxin class, as Etoposide and teniposide, Amsacrine, topotecan or camptothecin);
(ii) cytostatic agent such as antiestrogen (tamoxifen for example, toremifene, raloxifene, droloxifene or iodoxyfene), estrogen receptor is born conditioning agent (as fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide or cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide or buserelin), progestogens (as Magace), aromatase inhibitor (anastrozole for example, letrozole, vorozole (vorazole) or Exemestane) or 5 inhibitor such as finasteride;
The (iii) medicine (for example inhibitor of inhibitors of metalloproteinase such as Marimastat or UPA function of receptors) of anticancer invasion;
(iv) somatomedin depressant of functions, for example such as following inhibitor: growth factor antibodies (for example anti--erbb2 antibody trastuzumab or anti--erbb1 antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor or serine/threonine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor for example, as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) or 6-acryl amino-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), the inhibitor of the inhibitor of platelet-derived growth factor family or pHGF family;
(v) anti-angiogenic agent, for example those suppress the medicine of vascular endothelial growth factor effect, (for example anti-VEGF antibody rhuMAb-VEGF, for example those disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354) or the compound (for example inhibitor or the angiostatin of linomide, beta 2 integrin alpha v β 3 functions) that works with other mechanism;
(vi) vascular damages disclosed compound among agent such as combretastatin A4 or International Patent Application WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or the WO 02/08213;
(those materials of target spot such as ISIS 2503, anti--ras antisense thing are listed in vii) antisense therapy agent above for example being oriented to;
(the viii) medicament that uses in the gene therapy method, the medicament that uses in for example following method: for example those use the method for Isocytosine deaminase, thymidine kinase or bacterium nitroreductases and increase the method for example multidrug resistance gene treatment of patient to chemotherapy or radiotherapy tolerance to replace method, GDEPT (the enzyme prodrug treatment of the gene orientation) method of aberrant gene such as unusual p53 or unusual BRCA1 or BRCA2; Perhaps
(ix) be used in medicine in the following immunotherapy method, comprise the method that for example increases the patient tumors cell immunogenicity in vitro and in vivo, as with cytokine such as interleukin-22, interleukin 4 or rHuGM-CSF transfection, the method that reduces T-cell anergy, the immunocyte that uses transfection such as transfection cytokine dendritic cell method, use cytokine transfection tumor cell line method and use the method for antiidiotypic antibody.
Be used for the treatment of respiratory tract disease for example the particularly advantageous combination of asthma, COPD or allergic rhinitis be above-mentioned formula (I) compound and the combination that is selected from one or more following medicines:
● the PDE4 inhibitor, comprise isoform PDE4D inhibitor,
● selectivity beta 2 adrenoreceptor agonists, for example Metaprel (metaproterenol), Racemic isoproterenol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline (orciprenaline), bitolterol mesilate, pirbuterol or indacaterol;
● the conditioning agent of chemokine receptor function (for example CCR1 receptor antagonist);
● the inhibitor of p38 kinase function;
● glucocorticosteroid, for example flunisolide, Triamcinolone Acetonide, Viarox, budesonide (budesonide), fluticasone propionate, ciclesonide (ciclesonide) or furancarboxylic acid Mo Meisong (mometasonefuroate); And
● the non-steroid glucocorticoid receptor antagonist.
In embodiments, the invention provides a kind of pharmaceutical product, wherein combination contain above-mentioned formula (I) compound as first activeconstituents and beta 2 adrenoreceptor agonists as second activeconstituents, for example Metaprel (metaproterenol), Racemic isoproterenol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline (orciprenaline), bitolterol mesilate, pirbuterol or indacaterol;
In embodiments, the invention provides a kind of pharmaceutical product, wherein combination contain above-mentioned formula (I) compound as first activeconstituents and glucocorticosteroid as second activeconstituents, glucocorticosteroid is flunisolide, Triamcinolone Acetonide, Viarox, budesonide, fluticasone propionate, ciclesonide or Mometasone for example;
In embodiments, the invention provides a kind of pharmaceutical product, wherein combination contain above-mentioned formula (I) compound as first activeconstituents and non-steroid glucocorticoid receptor antagonist as second activeconstituents.
Non-limiting example below utilizing is carried out exemplary illustration to the present invention.
In an embodiment, NMR spectrum on Varian Unity Inova spectrograph, with 300 or the proton frequency of 400MHz measure.MS spectrum is measured on Agilent 1100 MSD G1946D spectrographs or Hewlett Packard HP1100 MSD G1946A spectrograph.Preparation HPLC separates use Waters Symmetry Or Xterra Post carries out, and uses 0.1% trifluoroacetic acid aqueous solution: acetonitrile, 0.1% ammonia soln: acetonitrile or 0.1% ammonium acetate: acetonitrile is as eluent.SCX and NH 2Resin is obtained by Varian Incorporated.
Embodiment 1
(3S)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00241
A) cyclopentyl (phenyl) methyl acetate
Use chlorine trimethyl silyl (20mL) to handle methyl alcohol (200mL) solution of α-benzyl ring pentane acetate (10g), mixture heating up was refluxed 3 hours.Removal of solvent under reduced pressure, resistates with 25% ether/isohexane wash-out, obtain subtitle compounds (10.5g) through the silica column chromatography purification, are oily matter.
1H NMR(400MHz，CDCl 3)δ 7.35-7.22(m，5H)，3.64(s，3H)，3.28(d，1H)，2.60-2.50(m，1H)，1.95-1.85(m，1H)，1.70-1.40(m，5H)，1.30-1.20(m，1H)，1.03-0.97(m，1H)。
B) 2-cyclopentyl-2-phenylpropionic acid methyl esters
Figure S2006800136147D00252
Heptane/tetrahydrofuran/ethylbenzene (40.1mL) solution of 1.8 moles of lithium diisopropylamines is added in the anhydrous tetrahydro furan (60mL), under-78 ℃ and nitrogen, stir.Last 25 minutes then and in said mixture, drip cyclopentyl (phenyl) methyl acetate (embodiment 1a, anhydrous tetrahydro furan 10.5g) (30mL) solution.Reaction mixture was stirred 15 minutes at-78 ℃, be warmed to-30 ℃ then.Last anhydrous tetrahydro furan (15mL) solution that added methyl-iodide (13.68g) in 10 minutes then.Mixture, is distributed between ethyl acetate and the saturated aqueous ammonium chloride after 1 hour 0 ℃ of stirring.Separate organic layer, use anhydrous magnesium sulfate drying, filter the back removal of solvent under reduced pressure, obtain subtitle compounds (10.4g), be oily matter.
1H NMR(400MHz，CDCl 3)δ 7.36-7.19(m，5H)，3.64(s，3H)，2.83-2.76(m，1H)，1.77-1.69(m，1H)，1.60-1.30(m，9H)，0.95-0.85(m，1H)。
C) 2-cyclopentyl-2-phenyl-propionic acid
Figure S2006800136147D00261
(embodiment 1b, 10.4g) mixture in the methyl alcohol (150mL) and the 2 molar sodium hydroxide aqueous solution (100mL) refluxed 18 hours with 2-cyclopentyl-2-phenylpropionic acid methyl esters.Reduction vaporization is removed methyl alcohol, and resistates distributes between water and ether, separates behind the water layer with ice-cooled.Aqueous solution concentrated hydrochloric acid acidifying, resulting precipitation ethyl acetate extraction.Organic layer is used the salt water washing subsequently, separates, and uses anhydrous magnesium sulfate drying, and removal of solvent under reduced pressure obtains subtitle compounds (7.7g).
m/e 217(M-H +，100％)
D) (4R)-the 4-benzyl-3-[(2R)-2-cyclopentyl-2-phenyl propionyl]-1,3- azoles alkane-2-ketone
Figure S2006800136147D00262
(embodiment 1c, toluene 4.93g) (100mL) solution use thionyl chloride (30mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with 2-cyclopentyl-2-phenyl-propionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times.Resistates is dissolved in the anhydrous tetrahydro furan (20mL), in anhydrous tetrahydro furan (100mL) solution of-78 ℃ of disposable adding to (R)-4-benzyl-2- oxazolidone (4.00g), with it-78 ℃ of hexane (14.1mL) solution-treated of using 1.6 moles of n-Butyl Lithiums in advance.Reaction mixture stirred 30 minutes at-78 ℃, then stirring at room 1 hour.During end, mixture distributes between ethyl acetate and saturated aqueous ammonium chloride, organic layer anhydrous magnesium sulfate drying, reduction vaporization.By the silica gel chromatography purifying, with the isohexane eluant solution of 10% tetrahydrofuran (THF), resulting then solid grinds with isohexane, obtains subtitle compounds 2.97g, is white solid.
m/e 378(M+H +，100％)
1H NMR(400MHz，DMSO-D 6)δ 7.33-7.22(m，7H)，7.15-7.09(m，3H)，4.85-4.81(m，1H)，4.24(t，1H)，4.09(q，1H)，3.04-2.90(m，2H)，2.55(t，1H)，1.78-1.71(m，1H)，1.69(s，3H)，1.42-1.20(m，6H)，1.15-1.05(m，1H)。
E) (2R)-2-cyclopentyl-2-phenylpropionic acid
Figure S2006800136147D00271
To (the 4R)-4-benzyl that under 0 ℃ and nitrogen, stirs-3-[(2R)-2-cyclopentyl-2-phenyl propionyl]-1; 3- azoles alkane-2-ketone (embodiment 1d; 2.9g) in the solution in the mixture of tetrahydrofuran (THF) (80mL) and water (20mL), water (2.69mL) solution of Dropwise 35 wt.% hydrogen peroxide.Mixture is dropwise used water (7mL) solution-treated of lithium hydroxide monohydrate (516mg) subsequently, again stirring at room 4 hours.During end, reaction mixture cools off in ice bath, with water (30mL) solution-treated of Sodium Pyrosulfite (4g).The mixture reduction vaporization is removed tetrahydrofuran (THF), and resistates distributes between ether and excessive dilute sodium hydroxide aqueous solution.After the water layer cooling, by dripping concentrated hydrochloric acid acidifying, resulting precipitation ethyl acetate extraction.The acetic acid ethyl ester extract salt water washing that merges, anhydrous magnesium sulfate drying, reduction vaporization.Crude product with the isohexane eluant solution of 20% ethyl acetate, obtains subtitle compounds (1.7g) by the silicon-dioxide purified by flash chromatography.By with isohexane/2-propyl alcohol (9/1) wash-out, use the chirality HPLC of Chiralpak  AD-H post to record this sour enantiomeric excess and be higher than 98%.
m/e 217.7(M-H +，100％)
1H NMR(400MHz，CDCl 3)δ 7.42-7.39(m，2H)，7.32(t，2H)，7.26-7.22(m，1H)，2.84-2.80(m，1H)，1.80-1.77(m，1H)，1.60-1.36(m，9H)，1.14-1.09(m，1H)。
F) (3S)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00272
(embodiment 1e, toluene 0.8g) (20mL) solution use thionyl chloride (5mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2R)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times obtain the 0.87g acyl chlorides.Methylene dichloride (7mL) solution of acyl chlorides (0.43g) is handled with S-(+)-3-hydroxy-n-crassitude (556mg) (available from Lancaster SynthesisLimited, the e.e. that marks is 99%), and reaction mixture was 40 ℃ of heating 20 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, reduction vaporization after the organic layer drying.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains the 0.21g product.
m/e 302(M+H +，100％)
G) (3S)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
With (3S)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester (embodiment 1f, acetonitrile 100mg) (1mL) solution methylene dichloride (0.5mL) solution-treated of methyl-iodide (50mg).Solvent removed by evaporation at reduced pressure, resistates are ground with ether and are obtained title compound, are white solid (90mg).
m/e 316(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ7.35-7.34(m，4H)，7.27-7.24(m，1H)，5.36(s，1H)，3.79(q，1H)，3.59-3.54(m，2H)，3.51-3.46(m，1H)，3.12(s，3H)，2.93(s，3H)，2.79-2.75(m，1H)，2.65-2.60(m，1H)，2.05-2.00(m，1H)，1.69-1.66(m，1H)，1.53-1.33(m，9H)，1.12-1.09(m，1H)。
Embodiment 2
(3R)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00281
A) (3R)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00282
(embodiment 1e, toluene 0.8g) (20mL) solution use thionyl chloride (5mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2R)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times obtain the 0.87g acyl chlorides.Methylene dichloride (7mL) solution of acyl chlorides (0.43g) is handled with (R)-1-methyl-3-hydroxyl pyrrolidine (556mg) (available from Lancaster Synthesis Limited, the e.e that marks is 99%), and reaction mixture was 40 ℃ of heating 20 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, reduction vaporization after the organic layer drying.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains subtitle compounds (0.26g).
m/e 302(M+H +，100％)
B) (3R)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00291
Adopt embodiment 1 step g), (embodiment 2a, method 100mg) prepares title compound, obtains the 50mg title compound by (3R)-1-methylpyrrolidin-3-base (2R)-2-cyclopentyl-2-phenylpropionic acid ester.
m/e 316(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ 7.35-7.31(m，4H)，7.27-7.22(m，1H)，5.36(s，1H)，3.78(q，1H)，3.59-3.54(m，2H)，3.51-3.46(m，1H)，3.12(s，3H)，2.91(s，3H)，2.79-2.75(m，1H)，2.66-2.60(m，1H)，2.06-2.00(m，1H)，1.69-1.66(m，1H)，1.53-1.33(m，9H)，1.12-1.07(m，1H)。
Embodiment 3
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00292
A) (4R)-4-benzyl-3-[(2S)-2-cyclopentyl-2-phenyl propionyl]-1,3- azoles alkane-2-ketone
Figure S2006800136147D00301
(embodiment 1c, toluene 4.93g) (100mL) solution use thionyl chloride (30mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with 2-cyclopentyl-2-phenyl-propionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times.Resistates is dissolved in the anhydrous tetrahydro furan (20mL), in anhydrous tetrahydro furan (100mL) solution of-78 ℃ of disposable adding to (R)-4-benzyl-2- oxazolidone (4.00g), the latter is in advance in-78 ℃ of hexanes with 1.6 moles of n-Butyl Lithiums (14.1mL) solution-treated.Reaction mixture stirred 30 minutes at-78 ℃, then stirring at room 1 hour.During end, mixture distributes between ethyl acetate and saturated aqueous ammonium chloride, organic layer anhydrous magnesium sulfate drying, reduction vaporization.By flash chromatography on silica gel method purifying,, obtain subtitle compounds (3.30g) with the isohexane eluant solution of 10% tetrahydrofuran (THF).
1H NMR(400MHz，DMSO-D 6)δ 7.32-7.24(m，7H)，7.18-7.12(m，3H)，4.72-4.70(m，1H)，4.20(t，1H)，4.01(q，1H)，3.20(q，1H)，2.81-2.74(m，2H)，1.78-1.72(m，1H)，1.59(s，3H)，1.49-1.17(m，7H)。
B) (2S)-2-cyclopentyl-2-phenylpropionic acid
Figure S2006800136147D00302
Adopt the method for embodiment 1 step e), by (4R)-4-benzyl-3-[(2S)-2-cyclopentyl-2-phenyl propionyl]-1, (embodiment 3a, 3.25g) the preparation subtitle compounds obtains the 1.7g subtitle compounds to 3- azoles alkane-2-ketone.By with isohexane/2-propyl alcohol (9/1) wash-out, use the chirality HPLC of Chiralpak  AD-H post to record this sour enantiomeric excess and be higher than 98%.
m/e 217.7(M-H +，100％)
1H NMR(400MHz，CDCl 3)δ7.42-7.39(m，2H)，7.32(t，2H)，7.26-7.22(m，1H)，2.84-2.79(m，1H)，1.80-1.77(m，1H)，1.59-1.38(m，9H)，1.1 4-1.11(m，1H)。
C) (3S)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00311
(embodiment 3b, toluene 0.85g) (100mL) solution use thionyl chloride (15mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2S)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times obtain the 0.87g acyl chlorides.Use S-(+)-3-hydroxy-n-crassitude (556mg) (available from LancasterSynthesis Limited methylene dichloride (7mL) solution of resulting acyl chlorides (0.43g), the e.e. that marks is 99%) to handle, reaction mixture was 40 ℃ of heating 20 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, reduction vaporization after the organic layer drying.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains subtitle compounds (0.2g).
m/e 302(M+H +，100％)
D) (3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00312
Adopt embodiment 1 step g), prepare title compound, obtain the 90mg title compound by the method for (3S)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester (100mg).
m/e 316(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ7.35-7.34(m，4H)，7.26-7.22(m，1H)，5.36(s，1H)，3.77(q，1H)，3.60-3.43(m，3H)，3.12(s，3H)，2.91(s，3H)，2.79-2.74(m，1H)，2.67-2.63(m，1H)，2.07-2.04(m，1H)，1.69-1.66(m，1H)，1.53-1.33(m，9H)，1.12-1.07(m，1H)。
Embodiment 4
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Figure S2006800136147D00321
A) (3R)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00322
(embodiment 3b, toluene 0.85g) (100mL) solution use thionyl chloride (15mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2S)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times obtain the 0.87g acyl chlorides.Methylene dichloride (7mL) solution of acyl chlorides (0.43g) is handled with (R)-1-methyl-3-hydroxyl pyrrolidine (556mg) (available from Lancaster Synthesis Limited, the e.e. that marks is 99%), and reaction mixture was 40 ℃ of heating 20 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, and organic layer separates back anhydrous magnesium sulfate drying, reduction vaporization.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains subtitle compounds (0.23g).
m/e 302(M+H +，100％)
B) (3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  iodide
Adopt the method for embodiment 1 step g), (embodiment 4a, 100mg) the preparation title compound obtains the 110mg title compound by (3R)-1-methylpyrrolidin-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester.
m/e 316(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ 7.35-7.33(m，4H)，7.27-7.24(m，1H)，5.37(s，1H)，3.79(q，1H)，3.60-3.55(m，2H)，3.51-3.44(m，1H)，3.12(s，3H)，2.93(s，3H)，2.80-2.75(m，1H)，2.66-2.61(m，1H)，2.04-2.00(m，1H)，1.71-1.67(m，1H)，1.54-1.33(m，9H)，1.12-1.07(m，1H)。
Embodiment 5
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  iodide
Figure S2006800136147D00331
A) (3R)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00332
(embodiment 3b, toluene 246mg) (20mL) solution use thionyl chloride (5mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2S)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times.Resistates is dissolved in the methylene dichloride (3mL), ((R)-(+) that 130mg-is available commercially-3-hydroxyl piperidine hydrochloric acid salt is by EuropeanJournal of Medicinal Chemistry (1976) with (R)-3-hydroxy-n-methyl piperidine, 11 (5), the method preparation of summarizing among the 461-6) handle, reaction mixture was 40 ℃ of heating 18 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, the organic layer anhydrous magnesium sulfate drying after the separation, reduction vaporization.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains subtitle compounds (77mg).
m/e 316(M+H +，100％)
B) (3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  iodide
Adopt the method for embodiment 1 step g),, obtain the 85mg title compound by (3R)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester (77mg) preparation title compound.
m/e 330.3(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ7.37-7.31(m，4H)，7.28-7.24(m，1H)，5.15(s，1H)，3.56-3.51(m，1H)，3.39-3.36(m，1H)，3.07(s，3H)，2.88(s，3H)，2.77-2.73(m，1H)，1.82-1.58(m，4H)，1.58-1.33(m，10H)，1.14-1.07(m，1H)。
Embodiment 6
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  iodide
Figure S2006800136147D00341
A) (3S)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester
Figure S2006800136147D00342
(embodiment 3b, toluene 250mg) (20mL) solution use thionyl chloride (5mL) to handle, and resulting mixture was 100 ℃ of heating 2 hours with (2S)-2-cyclopentyl-2-phenylpropionic acid.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic 3 times.Resistates is dissolved in the methylene dichloride (3mL), ((S)-(-) that 250mg-is available commercially-3-hydroxyl piperidine hydrochloric acid salt is by EuropeanJournal of Medicinal Chemistry (1976) with (S)-3-hydroxy-n-methyl piperidine, 11 (5), the method preparation of summarizing among the 461-6) handle, reaction mixture was 40 ℃ of heating 18 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, the organic layer anhydrous magnesium sulfate drying after the separation, reduction vaporization.Crude product is by the silicon-dioxide purified by flash chromatography, and ethyl acetate/isohexane (1/1) eluant solution with 1% triethylamine obtains subtitle compounds (80mg).
m/e 316(M+H +，100％)
B) (3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  iodide
Figure S2006800136147D00351
Adopt the method for embodiment 1 step g), (embodiment 6a, 80mg) the preparation title compound obtains the 90mg title compound by (3S)-1-methyl piperidine-3-base (2S)-2-cyclopentyl-2-phenylpropionic acid ester.
m/e 330(M +，100％)
1H NMR(400MHz，DMSO-D 6)δ 7.38-7.33(m，4H)，7.28-7.23(m，1H)，5.18-5.14(m，1H)，3.58-3.53(m，1H)，3.35-3.31(m，1H)，3.08(s，3H)，2.89(s，3H)，2.81-2.75(m，1H)，1.81-1.75(m，2H)，1.75-1.65(m，2H)，1.58-1.30(m，10H)，1.17-1.11(m，1H)。
Pharmacology is analyzed
With scintillation proximity assay (SPA) form, by [ 3H] N-epoxytropine tropate (NMS) is to expressing human muscarine vagusstoff M 3Acceptor (M 3-ACh) the competitiveness of CHO-K1 (Chinese hamster ovary) cytolemma is in conjunction with determining that compound is to M 3Avidity (the pIC of acceptor 50).
With cytolemma in advance with the coupling of SPA pearl, 5 μ g membranin/mg SPA, then with the concentration in 2mg/ hole use The compounds of this invention serial dilution, 0.2nM [ 3H] NMS, (20mM HEPES pH7.4 contains 5mM MgCl for half Kd (dissociation constant that test records) and mensuration damping fluid 2) cultivate.To be determined at final volume be 200 μ L, carry out in the presence of 1% (v/v) methyl-sulphoxide (DMSO).Under the situation that does not have competitive compound, measure [ 3H] total binding of NMS, measure existing under the atropinic situation of 1 μ M [ 3H] non-specific binding of NMS.Culture plate adopts normalization method then incubated at room temperature 16 hours 3The H rules are at Wallac Microbeta TMLast reading.With pIC 50Be defined as specificity [ 3H]-NMS reduces the negative logarithm of 50% needed compound concentration, according to experience record suppress per-cent respectively above and below two kinds of compound concentrations of 50% between interpolation obtain pIC 50Following table shows the pIC of each embodiment 50Numerical value.
The compound of embodiment pIC 50
1 7.9
2 8.9
3 8.9
4 8.8
5 8.9
6 7.7
1f 7.7
2a 8.1
3c 8.5
4a 9.1

Claims (18)

1. formula (I) compound:
Figure S2006800136147C00011
Wherein:
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
R 5Expression hydrogen or C 1-6Alkyl;
N is 1 or 2;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace; And
X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
2. the compound of claim 1, wherein R 1Expression phenyl, described phenyl can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.
3. claim 1 or 2 compound, wherein R 2The representative ring amyl group, it can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-4Alkyl), N (C 1-4Alkyl) 2And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, NH 2, NH (C 1-4Alkyl) and N (C 1-4Alkyl) 2In one or more substituting groups replace.
4. each compound, wherein R among the claim 1-3 3The expression methyl.
5. each compound, wherein R among the claim 1-4 4And R 5Represent methyl or ethyl independently of one another.
6. each compound among the claim 1-5, wherein n is 1.
7. each compound among the claim 1-5, wherein n is 2.
8. each compound among the claim 1-7, wherein X represents bromide anion or iodide ion.
9. the compound of claim 1 is selected from:
(3S)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2R)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-dimethyl pyrrolidine  X,
(3R)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  X, or
(3S)-3-{[(2S)-and 2-cyclopentyl-2-phenyl propionyl] the oxygen base }-1,1-lupetidine  X,
Wherein X represents monovalent acid or polyacid pharmaceutically acceptable negatively charged ion.
10. prepare the method for formula (I) compound described in the claim 1, described method comprises:
Make formula (IV) compound or its C 1-6Alkyl ester, acid anhydrides or acyl halide and the reaction of formula V compound obtain formula (II) compound,
Figure S2006800136147C00031
In the formula (IV), R 1, R 2And R 3Define suc as formula (I) is middle,
Figure S2006800136147C00032
In the formula V, R 4Define suc as formula (I) is middle with n,
Figure S2006800136147C00033
Then with (II) and formula R 5The reaction of-Y (III) compound, formula R 5Y is leavings group and R among-the Y (III) 5Define suc as formula (I), and
Randomly carry out step of one in following or multistep:
● compound is converted into other formula (I) compound,
● form pharmacologically acceptable salt with monovalent acid or polyacid negatively charged ion.
11. a pharmaceutical composition, it comprises each described formula (I) compound among the claim 1-9, and is combined with pharmaceutically acceptable assistant agent, diluent or carrier.
12. the method for the pharmaceutical composition described in the preparation claim 11, described method comprise each described formula (I) compound and pharmaceutically acceptable assistant agent, diluent or carrier among the claim 1-9 are mixed.
13. each described formula (I) compound among the claim 1-9, it is used for the treatment of.
14. each described formula (I) compound is used for the treatment of purposes in the medicine of chronic obstructive pulmonary disease in preparation among the claim 1-9.
15. the treatment warm-blooded animal is the method for philtrum chronic obstructive pulmonary disease for example, described method comprises each described formula (I) compound in the claim 1-9 of the Mammals effective dosage of this treatment of needs.
16. pharmaceutical product, wherein combination contains first activeconstituents of each described formula (I) compound among the claim 1-9 and is selected from the second following activeconstituents:
The PDE4 inhibitor;
The selectivity beta 2 adrenoreceptor agonists;
The conditioning agent of chemokine receptor function;
The inhibitor of p38 kinase function;
Glucocorticosteroid; With
The non-steroid glucocorticoid receptor antagonist.
17. formula (II) compound
Wherein,
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 4Expression hydrogen or C 1-6Alkyl;
N is 1 or 2;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace.
18. optically pure formula (IV) compound or its C 1-6Alkyl ester, acid anhydrides or acyl halide, described compound is
Figure S2006800136147C00051
Wherein,
R 1Expression phenyl, benzimidazolyl-, benzothiazolyl, the assorted aromatic nucleus of benzoxazol base or 5-6 unit, wherein each can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 6, NR 7R 8, S (O) 2NR 9R 10, C (O) NR 11R 12, C (O) 2R 13, NR 14S (O) 2R 15, NR 16C (O) R 17, NR 18C (O) 2R 19, NR 20C (O) NR 21R 22, OR 23And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 2Expression C 3-8Cycloalkyl ring, described cycloalkyl ring can be chosen wantonly by one or more and independently be selected from following substituting group and replace: halogen, S (O) 0-2R 24, NR 25R 26, S (O) 2NR 27R 28, C (O) NR 29R 30, NR 31S (O) 2R 32, NR 33C (O) R 34, OR 35And C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 3Expression C 1-6Alkyl;
R 6, R 13, R 15, R 17, R 19, R 23, R 24, R 32, R 34And R 35Represent hydrogen or C independently of one another 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
R 7, R 8, R 9, R 10, R 11, R 12, R 14, R 16, R 18, R 20, R 21, R 22, R 25, R 26, R 27, R 28, R 29, R 30, R 31And R 33Represent hydrogen, C independently of one another 2-6Hydroxyalkyl or C 1-6Alkyl, described C 1-6Alkyl can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkoxyl group, NH 2, NH (C 1-6Alkyl) and N (C 1-6Alkyl) 2In one or more substituting groups replace;
Perhaps R 7And R 8, R 9And R 10, R 11And R 12, R 21And R 22, R 25And R 26, R 27And R 28Or R 29And R 30In the arbitrarily a pair of nitrogen-atoms that both connect with them can form the aliphatic heterocycle of 4-8 unit, described heterocycle can be chosen wantonly and independently is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Hydroxyalkyl and C 1-6One or more substituting groups in the haloalkyl replace.
CNA2006800136147A 2005-04-20 2006-04-18 New muscarinic receptor antagonists Pending CN101163673A (en)

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