CN101374803A - Cyclic amine derivatives and their uses - Google Patents
Cyclic amine derivatives and their uses Download PDFInfo
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- CN101374803A CN101374803A CNA2006800530020A CN200680053002A CN101374803A CN 101374803 A CN101374803 A CN 101374803A CN A2006800530020 A CNA2006800530020 A CN A2006800530020A CN 200680053002 A CN200680053002 A CN 200680053002A CN 101374803 A CN101374803 A CN 101374803A
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Abstract
Compounds of formula (I) have muscarinic M3 receptor modulating activity; formula (I) wherein R<1> is C1-C6-alkyl or a hydrogen atom; and R<2> is a hydrogen atom or a group -R<5>, or a group, -Z-Y-R<5>, or a group -Z-NR<9>R<10>, or a group -Z-N(R<9>)C(O)R<11>; and R<3> is a lone pair, or C1-C6-alkyl; R<4> is selected from one of the groups of formula (a), (b), (c) or (d); formulae (a), (b), (c), (d), Z is a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group; Y is a bond or oxygen atom; R<5> is an C1-C6-alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group; R<6> is C1-C6-alkyl or a hydrogen atom; R<7a> and R<7b> are a C1-C6- alkyl group or halogen; n and m are independently 0, 1 , 2 or 3; R<8a> and R<8b> are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl and hydrogen; R<8c> is -OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, or a hydrogen atom; R<8d> is C1-C6-alkyl or a hydrogen atom; R<9> and R<10> are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl- fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)- group; or R<9> and R<10> together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom; R<11> is C1-C6-alkyl or a hydrogen atom; Ar<1> is aryl, heteroaryl or cycloalkyl; Ar<2> are independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH2-, -CH2CH2- or a bond.
Description
Invention field
The present invention relates to two rings [2.2.1] heptan-2-yl amine derivatives, pharmaceutical composition, their preparation method and in treatment by the disease of the M3 M-ChR mediation purposes in the respiratory disease for example.
Background of invention
Anticholinergic agents stops through the passage of the various stimulations of parasympathetic nerve or the various effects that caused by this passage.This also is that this compounds can suppress vagusstoff (Ach) active result by blocking-up with combining of mAChR.
Have five kinds of muscarinic acetylcholine receptors (mAChRs) hypotype that is known as M1-M5, they are respectively heterogeneic products, demonstrate its unique pharmacological properties separately.MAChRs is distributed widely in the vertebrates organ, and these acceptors can be regulated inhibition and hormesis simultaneously.For example, in being found in air flue, bladder and GI unstriated muscle, M3mAChRs can regulate contractile response (relevant summary is referring to Caulfield, 1993, Pharmac.Ther., 58,319-379).
In lung, it is important that M-ChR M1, M2 and M3 have been proved to be, and be distributed in that (relevant summary is referring to Fryer and Jacoby, 1998 in tracheae, segmental bronchus, submucosal gland and the parasympathetic ganglion, AmJ Resp Crit Care Med., 158 (5 3) S 154-160).The M3 acceptor that is positioned at airway smooth muscle can be regulated contraction, thereby produces bronchoconstriction.Stimulate the M3 acceptor that is distributed in submucosal gland to cause mucus secretion.
Comprise among asthma and the COPD in multiple different pathological physiological status, have been noted that the signal by muscarinic acetylcholine receptor strengthens to some extent.In COPD, vagus nerve function may be enhanced (people .1989 such as Gross, Chest; 96:984-987), and/or because various geometry reasons also may cause greatly inaccessible (oedema occurs or be full of mucous airway walls surface if be applicable to) (people 1984 such as Gross, Am Rev Respir Dis; 129:856-870).In addition, inflammatory conditions may cause that inhibition M2 receptor active reduces, and this will cause the vagusstoff emission levels rising (people such as Fryer, 1999, LifeSci., 64, (6-7) 449-455) vagus nerve stimulation after.The M3 receptor active enhancing that is produced causes the air flue obturation more to become serious.Therefore, identifying potent muscarinic receptor antagonist can be used for therapeutic treatment and wherein relates to M3 receptor active enhanced morbid state.In fact, the present support of modern treatment strategy uses M3 antagonist bronchodilator to be used for COPD patient's first-line treatment (people .2001 such as Pauwels, Am Rev Respir Crit Care Med routinely; 163:1256-1276).
The incontinence that is caused by the bladder highly shrinkable equally also is proved to be to stimulate by M3mAChRs increases mediation.Therefore, the M3mAChR antagonist can be used as those treatment of diseases agent by the mAChR mediation.
Although a large amount of evidence supports use the treatment of Antimuscarinic acceptor can treat the airway disorders state, in clinical, almost there is not antimuscarinic compounds to can be used for lung's indication at present.Therefore, still need to cause at the M3 M-ChR new compound of blocking-up, particularly have long acting duration and the compound of the dosage of can realizing being administered once every day.Because M-ChR is distributed widely in the body, thereby anticholinergic agents directly can be delivered to respiratory tract, this is very favourable and can reduces the dosage that is applied medicine.Design is also used and to be had long acting duration and can be trapped in Topically active medicine on the acceptor or in the lung, uses same medicine and observed undesirable side effect if can alleviate general.
Tiotropium (Spiriva
TM) be a kind of long-acting muscarine antagonist of current listing, it is administered for the treatment chronic obstructive pulmonary disease by inhalation route.
Tiotropium
In addition, Rinovagos also is the muscarine antagonist that is used for the treatment of COPD of listing.
Rinovagos
Other modulators of muscarinic receptors is mentioned.For example, US4353922 has described the muscarine conditioning agent based on [2.2.1] azabicyclic heptane ring system.EP418716 and US005610163 have described multiple [3.2.1] azabicyclooctane ring system.WO06/017768 has described [3.3.1] azabicyclononane ring system.[2.2.2] azabicyclooctane ring system (quinoline rather encircles) for example before had been described among the US2005/0209272 and WO06/048225.[3.1.0] azabicyclo hexane system for example has been described among the WO06/035282.[3.2.1] azabicyclooctane for example has been described among the WO06/035303.
Summary of the invention
According to the present invention, provide formula (I) compound:
Wherein
R
1Be C
1-C
6-alkyl or hydrogen atom; And R
2Be hydrogen atom or group-R
5, or group-Z-Y-R
5, or group-Z-NR
9R
10, or group-Z-N (R
9) C (O) R
11And R
3Be lone-pair electron, or C
1-C
6-alkyl, coupled in this case nitrogen-atoms are quaternary nitrogen and have positive charge;
R
4Be selected from formula (a) and (b), (c) or (d) a kind of in the group;
Z is C
1-C
16-alkylidene group, C
2-C
16-alkylene group or C
2-C
16-alkynylene;
Y is chemical bond or Sauerstoffatom;
R
5Be C
1-C
6-alkyl, aryl, arylalkyl; Aryl-condensed-cycloalkyl, aryl-condensed-Heterocyclylalkyl, heteroaryl, aryl (C
1-C
8-alkyl)-, heteroaryl (C
1-C
8-alkyl)-, cycloalkyl or Heterocyclylalkyl;
R
6Be C
1-C
6-alkyl or hydrogen atom;
R
7aAnd R
7bBe C
1-C
6-alkyl or halogen;
N and m are 0,1,2 or 3 independently;
R
8aAnd R
8bBe independently selected from aryl, aryl-condensed-Heterocyclylalkyl, heteroaryl, C
1-C
6-alkyl, cycloalkyl and hydrogen;
R
8cFor-OH, C
1-C
6-alkyl, hydroxyl-C
1-C
6-alkyl or hydrogen atom;
R
9And R
10Be hydrogen atom, C independently
1-C
6-alkyl, aryl, aryl-condensed-Heterocyclylalkyl, aryl-condensed-cycloalkyl, heteroaryl, aryl (C
1-C
6-alkyl)-or heteroaryl (C
1-C
6-alkyl)-; Or R
9And R
10The nitrogen-atoms that links to each other with their forms the heterocycle of 4-8 atom, chooses wantonly and also contains other nitrogen or Sauerstoffatom;
R
11Be C
1-C
6-alkyl or hydrogen atom;
Ar
1Be aryl, heteroaryl or cycloalkyl;
Ar
2Be aryl, heteroaryl or cycloalkyl independently; And
Q be Sauerstoffatom ,-CH
2-,-CH
2CH
2-or chemical bond;
Or its pharmacologically acceptable salt, solvate, N-oxide compound or prodrug.
A son at The compounds of this invention is concentrated:
R
1Be C
1-C
6-alkyl or hydrogen atom, and R
2Be C
1-C
6-alkyl, hydrogen atom, or group-Z-Y-R
5, or group-Z-NR
9R
10
R
3Be lone-pair electron; Or C
1-C
6-alkyl, coupled in this case nitrogen-atoms are quaternary nitrogen and have positive charge;
R
4Be selected from formula (a) or a kind of (b) or in the group (c):
Z is C
1-C
8-alkylidene group;
Y is chemical bond or Sauerstoffatom;
R
5Be aryl or aryl (C
1-C
8-alkyl)-;
R
6Be C
1-C
6-alkyl or hydrogen atom;
R
7aAnd R
7bBe C independently
1-C
6-alkyl or halogen;
N and m are 0,1,2 or 3 independently;
R
8aAnd R
8bBe independently selected from aryl, heteroaryl, C
1-C
6-alkyl, cycloalkyl and hydrogen;
R
8cFor-OH, C
1-C
6-alkyl, hydroxyl-C
1-C
6-alkyl or hydrogen atom;
R
9And R
10Be hydrogen atom, C independently
1-C
6-alkyl, aryl, heteroaryl, aryl (C
1-C
6-alkyl)-or heteroaryl (C
1-C
6-alkyl)-; Or R
9And R
10The nitrogen-atoms that links to each other with their forms the heterocycle of 4-8 atom, chooses wantonly and also contains other nitrogen or Sauerstoffatom.
There is cis-or trans-form in The compounds of this invention;
Cis-trans-
Also there is group-NR in The compounds of this invention
1R
2R
3Form for outer or interior orientation;
In-outer-
Usually preferred compound of the present invention is mainly trans-Nei configuration.
Trans-, interior-
Because substituted bicyclic ring is possible lack symmetrical plane, so also may there be the optical isomer form in The compounds of this invention.Thereby the absolute configuration of molecule can use the Cahn-Ingold-Prelog rule definition to specify each position to be R or S.For fear of obscuring, the ring numbering below using.
Yet The compounds of this invention comprises the enantiomeric mixture of racemic modification, single enantiomer and arbitrary proportion, and this is because these forms all have muscarine M3 receptor modulating activities in various degree.
A preferred class The compounds of this invention comprises the quaternary ammonium salt of formula (I), and nitrogen is the quaternary nitrogen that has positive charge shown in its Chinese style (I).
The compounds of this invention can be used for treating or prevents wherein to relate to the disease that activates M-ChR, for example The compounds of this invention can be used for treating multiple indication, includes but not limited to respiratory tract obstruction for example chronic obstructive pulmonary disease, all types of chronic bronchitis (comprising relative expiratory dyspnea), asthma (supersensitivity and nonallergic; ' wheezy-infant syndrome (wheezy-infant syndrome) '), adult/adult respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperreactivity (bronchialhyperactivity), pulmonary fibrosis, pulmonary emphysema and allergic rhinitis, the airway hyperreactivity that caused by other medicines treatments (particularly other suction pharmacological agent) increase the weight of, pneumoconiosis (for example aluminosis, melanedema, asbestosis, silicosis, ostrich hair pneumoconiosis, siderosis, silicosis, tabacism and byssinosis); For example twitch or hyperperistalsis (hyperanakinesia), diverticulitis, follow the pain of gastrointestinal smooth muscle meat tissue spasm by irritable bowel syndrome, spastic colitis (spasmodic colitis), gastro-duodenal ulcer, gi tract for gastrointestinal tract disorder; Follow the urinary tract obstacle of dysuria to comprise nervosa frequent micturition, neurogenic bladder, nocturnal enuresis (nocturnal enuresis), psychosoma bladder (psychosomaticbladder), incontinence, urgent urination or the frequent micturition relevant with cystospasm or chronic cystitis; Motion sickness; And cardiovascular disorder vagus nerve inductive sinus bradycardia for example.
In order to treat the breathing illness, preferred usually by inhalation, usually preferred in this case administration is the compound (I) of quaternary ammonium salt.In most of situations, the acting duration of the quaternary ammonium salt of the present invention by inhalation can surpass 12, or above 24 hours.In order to treat gastrointestinal tract disorder and cardiovascular disorder, can be preferably with parenteral route administration, normally oral route.
The present invention relates to pharmaceutical composition on the other hand, and it comprises The compounds of this invention and pharmaceutically acceptable carrier or vehicle.
The present invention relates to The compounds of this invention on the other hand and is used for the treatment of or prevents wherein to relate to purposes in the medicine of the disease of muscarine M3 receptor active or illness in preparation.
Term
Unless point out in addition in the context of its application, following term has following implication:
" acyl group " is meant-the CO-alkyl that wherein alkyl is as described herein.Exemplary acyl group comprises-COCH
3With-COCH (CH
3)
2
" acyl amino " is meant-the NR-acyl group that wherein R and acyl group are as described herein.Exemplary acyl amino comprises-NHCOCH
3With-N (CH
3) COCH
3
" alkoxyl group " and " alkyl oxy " is meant-the O-alkyl that wherein alkyl is as described below.Exemplary alkoxyl group comprises methoxyl group (OCH
3) and oxyethyl group (OC
2H
5).
" carbalkoxy " is meant-the COO-alkyl that wherein alkyl is defined as follows.Exemplary carbalkoxy comprises methoxycarbonyl and ethoxycarbonyl.
" alkyl " is meant to have 1-12 in the chain, the straight or branched saturated hydrocarbyl of preferred 1-6 carbon atom during as a group or group part.Exemplary alkyl comprises methyl, ethyl, 1-propyl group and 2-propyl group.
" alkenyl " is meant to have 2-12 in the chain, the straight or branched alkyl of preferred 2-6 carbon atom and 1 carbon-carbon double bond during as a group or group part.Exemplary alkenyl comprises vinyl, 1-propenyl and 2-propenyl.
" alkynyl " is meant to have 2-12 in the chain, preferred 2-6 carbon atom and 1 carbon carbon triple-linked straight or branched alkyl during as a group or group part.Exemplary alkynyl comprises ethynyl, 1-proyl and 2-propynyl.
" alkylamino " is meant-the NH-alkyl, and wherein the alkyl definition is the same.Exemplary alkylamino comprises methylamino and ethylamino.
" alkylidene group " be meant-alkyl-and, wherein the alkyl definition is the same.Exemplary alkylidene group comprises-CH
2-,-(CH
2)
2-and-C (CH
3) HCH
2-.
" alkylene group " be meant-alkenyl-and, wherein the alkenyl definition is the same.Exemplary alkylene group comprises-CH=CH-,-CH=CHCH
2-and-CH
2CH=CH-.
" alkynylene " be meant-alkynyl-and, wherein the alkynyl definition is the same.Exemplary alkynylene comprises-CC-,-CCCH
2-and-CH
2CC-.
" alkyl sulphinyl " is meant-the SO-alkyl, and wherein the alkyl definition is the same.Exemplary alkyl sulphinyl comprises methylsulfinyl and ethyl sulfinyl.
" alkyl sulphonyl " is meant-SO
2-alkyl, wherein the alkyl definition is the same.Exemplary alkyl sulphonyl comprises methylsulfonyl and ethylsulfonyl.
" alkylthio " is meant-the S-alkyl, and wherein the alkyl definition is the same.Exemplary alkylthio comprises methylthio group and ethylmercapto group.
" aminoacyl " is meant-CO-NRR that wherein R is as described herein.Exemplary aminoacyl comprises-CONH
2With-CONHCH
3
" aminoalkyl group " is meant alkyl-NH
2, wherein alkyl as previously mentioned.Exemplary aminoalkyl group comprises-CH
2NH
2
" amino-sulfonyl " is meant-SO
2-NRR, wherein R is as described herein.Exemplary amino-sulfonyl comprises-SO
2NH
2With-SO
2NHCH
3
" aryl " is meant the optional substituted 6-14 of a having carbon atom during as a group or group part, preferably the monocycle of 6-10 carbon atom or encircle aromaticity isocyclic part, for example phenyl or naphthyl more.Aryl can be replaced by one or more substituting groups.
" arylalkyl " be meant aryl-alkyl-, wherein aryl and moieties are as mentioned above.The preferred aryl groups alkyl contains C
1-4Alkyl.Exemplary arylalkyl comprises benzyl, styroyl and menaphthyl.Wherein aryl moiety can be replaced by one or more substituting groups.
" alkoxy aryl " be meant aryl-alkoxyl group-, wherein aryl and alkoxyl group are as mentioned above.The preferred aryl groups alkoxyl group comprises C
1-4Alkyl.Exemplary alkoxy aryl comprises benzyloxy.Wherein aryl moiety can be replaced by one or more substituting groups.
" aryl-condensed-cycloalkyl " is meant and Cycloalkylfused monocyclic aryl ring (for example phenyl) that wherein aryl and cycloalkyl are as described herein.Exemplary aryl-condensed-cycloalkyl comprises tetralyl and indanyl.Aryl and cycloalkyl ring can be replaced by one or more substituting groups separately.Aryl-condensed-cycloalkyl can link to each other with the compound rest part by any possible carbon atom.
" aryl-condensed-Heterocyclylalkyl " is meant and Heterocyclylalkyl condensed monocyclic aryl ring (for example phenyl) that wherein aryl and Heterocyclylalkyl are as described herein.Exemplary aryl-condensed-Heterocyclylalkyl comprises tetrahydric quinoline group, indolinyl, benzo Dioxin base (benzodioxinyl), benzodioxole base (benzodioxolyl), dihydro benzo furyl and isoindole ketone group.This aryl and heterocycloalkyl ring can be replaced by one or more substituting groups separately.Aryl-condensed-Heterocyclylalkyl can link to each other with the compound rest part by any possible carbon atom or nitrogen-atoms.
" aryloxy " is meant-the O-aryl that wherein aryl as mentioned above.Exemplary aryloxy comprises phenoxy group.Wherein its aryl moiety can be replaced by one or more substituting groups.
" cyclic amine " is a class special " Heterocyclylalkyl " or " heterocycle ", and refer to optional substituted one of them ring carbon atom by nitrogen alternate 3-8 unit monocyclic cycloalkyl ring system, and it can be chosen and contains other heteroatoms that is selected among O, S or the NR (wherein R is as described herein) wantonly.Exemplary cyclic amine comprises tetramethyleneimine, piperidines, morpholine, piperazine and N methyl piperazine.The cyclic amine group can be replaced by one or more substituting groups.
" cycloalkyl " is meant the optional substituted 3-12 of a having carbon atom, preferred 3-8 carbon atom, the more preferably saturated monocycle of 3-6 carbon atom or bicyclic ring system.Exemplary monocyclic cycloalkyl ring comprises cyclopropyl, cyclopentyl, cyclohexyl and suberyl.Cycloalkyl can be replaced by one or more substituting groups.
" cycloalkylalkyl " be meant cycloalkyl-alkyl-, wherein cycloalkyl and alkyl are as previously mentioned.Exemplary monocyclic cycloalkyl alkyl comprises cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl and suberyl methyl.Its cycloalkyl moiety can be replaced by one or more substituting groups.
" dialkyl amido " is meant-N (alkyl)
2, wherein the alkyl definition is the same.Exemplary dialkyl amido comprises dimethylamino and diethylamino.
" halogen " or " halogen " is meant fluorine, chlorine, bromine or iodine.Preferred fluorine or chlorine.
" halogenated alkoxy " be meant alkyl wherein by one or more halogen atoms replace-the O-alkyl.Exemplary haloalkyl comprises trifluoromethoxy and difluoro-methoxy.
" haloalkyl " is meant the alkyl that is replaced by one or more halogen atoms.Exemplary haloalkyl comprises trifluoromethyl.
" heteroaryl " is meant optional substituted aromaticity monocycle or encircles organic group more that it has 5-14 annular atoms during as a group or group part, and preferably 5-10 annular atoms, and one or more annular atoms is non-carbon, for example nitrogen, oxygen or sulphur.This class examples of groups comprises benzimidazolyl-, benzoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, furyl, imidazolyl, indyl, indolizine base, isoxazolyl, isoquinolyl, isothiazolyl, oxazolyl, oxadiazole base, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, tetrazyl, 1,3,4-thiadiazolyl group, thiazolyl, thienyl and triazolyl.Its heteroaryl can be replaced by one or more substituting groups.Heteroaryl can link to each other with the compound rest part by any possible carbon atom or nitrogen-atoms.
" heteroarylalkyl " be meant heteroaryl-alkyl-, wherein heteroaryl and moieties are as previously mentioned.Preferred heteroarylalkyl contains the low alkyl group part.Exemplary heteroarylalkyl comprises pyridylmethyl.Its heteroaryl moieties can be replaced by one or more substituting groups.
" heteroaryl alkoxyl group " be meant heteroaryl-alkoxyl group-, wherein heteroaryl and alkoxyl group the part as mentioned above.Preferred heteroaryl alkoxyl group contains the low alkyl group part.Exemplary heteroaryl alkoxyl group comprises the pyridyl methoxyl group.Its heteroaryl moieties can be replaced by one or more substituting groups.
" heteroaryl oxygen base " is meant the wherein foregoing heteroaryl oxygen of heteroaryl base.Exemplary heteroaryl oxygen base comprises pyridyloxy.Its heteroaryl moieties can be replaced by one or more substituting groups.
" heteroaryl-condensed-cycloalkyl " is meant and Cycloalkylfused bicyclic heteroaryl (for example pyridyl or furyl) that wherein heteroaryl and cycloalkyl are as mentioned above.Exemplary heteroaryl-condensed-cycloalkyl comprises tetrahydric quinoline group and tetrahydrochysene benzfuran base.Heteroaryl and cycloalkyl ring can be replaced by one or more substituting groups separately.Heteroaryl-condensed-cycloalkyl can link to each other with the compound rest part by any possible carbon or nitrogen-atoms.
" heteroaryl-condensed-Heterocyclylalkyl " is meant and Heterocyclylalkyl condensed bicyclic heteroaryl (for example pyridyl or furyl) that wherein heteroaryl and Heterocyclylalkyl are as mentioned above.Exemplary heteroaryl-condensed-Heterocyclylalkyl comprises dihydro Dioxin and pyridyl (dihydrodioxinopyridinyl), pyrrolin and pyridyl, dihydrofuran and pyridyl and dioxole and pyridyl (dioxolopyridinyl).Heteroaryl and heterocycloalkyl ring can be replaced by one or more substituting groups separately.Heteroaryl-condensed-Heterocyclylalkyl can link to each other with the compound rest part by any possible carbon or nitrogen-atoms.
" Heterocyclylalkyl " or " heterocycle " is meant: (i) the optional substituted 4-8 of a having ring members and contain heteroatomic cycloalkyl among one or more O of being selected from, S or the NR; (ii) have 4-8 ring members and contain CONR and the cycloalkyl of CONRCO (this class examples of groups comprises succinimido and 2-oxo-pyrrolidine base).Heterocyclylalkyl can be replaced by one or more substituting groups.Heterocyclylalkyl can link to each other with the compound rest part by any possible carbon or nitrogen-atoms.
" Heterocyclylalkyl alkyl " or " heterocycle alkyl (heterocyclic alkyl) " be meant wherein Heterocyclylalkyl and the aforesaid Heterocyclylalkyl-alkyl of moieties-.
" low alkyl group " is meant to have 1-4 carbon atom in the chain and can be the aliphatic alkyl of straight or branched, i.e. methyl, ethyl, propyl group (propyl group or sec.-propyl) or butyl (butyl, isobutyl-or the tertiary butyl) as group unless otherwise defined.
" alkylsulfonyl " is meant-SO
2-alkyl, wherein alkyl is as described herein.Exemplary alkylsulfonyl comprises methylsulfonyl.
" sulfuryl amino " is meant-the NR-alkylsulfonyl that wherein R and alkylsulfonyl are as described herein.Exemplary sulfuryl amino comprises-NHSO
2CH
3R is meant alkyl as herein described, aryl or heteroaryl.
" pharmacologically acceptable salt " is meant the salt that can tolerate on physiology or the toxicology, comprises pharmaceutically acceptable base addition salt, pharmaceutically acceptable acid additive salt and pharmaceutically acceptable quaternary ammonium salt when suitable.For example: (i) contain one or more acidic-groups for example during carboxyl when The compounds of this invention, the pharmaceutically acceptable base addition salt that can form comprises sodium, potassium, calcium, magnesium and ammonium salt, perhaps with the organic amine salt that forms of diethylamine, N-methyl-glycosamine, diethanolamine or amino acid (for example Methionin) etc. for example; (ii) contain basic group when for example amino when The compounds of this invention, the pharmaceutically acceptable acid additive salt that can form comprises hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, Citrate trianion, lactic acid salt, tartrate, mesylate, maleate, fumarate, succinate etc.; (iii) when compound contains quaternary ammonium group, acceptable counter ion can be for example chlorion, bromide anion, sulfate radical, methanesulfonate, Phenylsulfonic acid root, tosylate, naphthalene disulfonic acid root, phosphate radical, acetate moiety, citrate, lactate, tartrate anion, methanesulfonate, maleate, fumaric acid radical, amber acid radical etc.Other salt form is described in detail in " Handbook of Pharmaceutical Salts.Properties, selection and use ", P.Heinrich Stahl ﹠amp; Camille G.Wermuth, Wiley-VCH, 2002.
It should be understood that The compounds of this invention used herein also comprises its pharmacologically acceptable salt.
" prodrug " is meant the compound that is converted into The compounds of this invention in vivo by metabolic way (for example hydrolysis, reduction or oxidation).For example, the ester prodrugs that contains the The compounds of this invention of hydroxyl can be converted into parent molecule by hydrolysis in the body.The suitable ester that contains the The compounds of this invention of hydroxyl has for example acetic ester, citrate, lactate, tartrate, malonic ester, barkite, salicylate, propionic ester, succinate, fumarate, maleic acid ester, methylene radical-bis-beta-hydroxyethyl base naphthoate, the rough gentian acid esters, isethionic acid ester (isethionates), two toluoyl tartrates (di-p-toluoyltartrates), methanesulfonates, esilate, benzene sulfonate, p-toluenesulfonic esters, cyclohexyl dithiocarbamic acid ester and quinate.The ester prodrugs that contains the The compounds of this invention of carboxyl can be converted into parent molecule by hydrolysis in the body.The example of ester prodrugs is F.J.Leinweber, Drug Metab.Res., those ester prodrugs of describing in 1987,18,379.
It should be understood that The compounds of this invention used herein also comprises its prodrug forms.
" saturated " is meant and do not contain any carbon-carbon double bond or carbon carbon triple-linked compound and/or group.
" optional being substituted " is meant optional by 4 substituting groups replacements at the most.Optional substituting group comprises that acyl group is (as-COCH
3), alkoxyl group is (as-OCH
3), carbalkoxy is (as-COOCH
3), alkylamino is (as-NHCH
3), alkyl sulphinyl is (as-SOCH
3), alkyl sulphonyl is (as-SO
2CH
3), alkylthio is (as-SCH
3) ,-NH
2, aminoacyl is (as-CON (CH
3)
2), aminoalkyl group is (as-CH
2NH
2), arylalkyl is (as-CH
2Ph or-CH
2-CH
2-Ph), cyano group, dialkyl amido is (as-N (CH
3)
2), halogen, halogenated alkoxy be (as-OCF
3Or-OCHF
2), haloalkyl is (as-CF
3), alkyl is (as-CH
3Or-CH
2CH
3) ,-OH ,-NO
2, aryl (optional alkoxy, halogenated alkoxy, halogen, alkyl or haloalkyl replace), heteroaryl (optional alkoxy, halogenated alkoxy, halogen, alkyl or haloalkyl replace), Heterocyclylalkyl, aminoacyl be (as-CONH
2,-CONHCH
3), amino-sulfonyl is (as-SO
2NH
2,-SO
2NHCH
3), acyl amino is (as-NHCOCH
3), sulfuryl amino is (as-NHSO
2CH
3), heteroarylalkyl, cyclic amine (as morpholine), aryloxy, heteroaryl oxygen base, arylalkyl oxygen base (as benzyloxy) and heteroaryl alkoxyl group.
Alkylidene group, alkylene group or alkynylene can be chosen wantonly and be substituted.Optional substituting group in the aforementioned group comprises that alkoxyl group is (as-OCH
3), alkylamino is (as-NHCH
3), alkyl sulphinyl is (as-SOCH
3), alkyl sulphonyl is (as-SO
2CH
3), alkylthio is (as-SCH
3) ,-NH
2, aminoalkyl group is (as-CH
2NH
2), arylalkyl is (as-CH
2Ph or-CH
2-CH
2-Ph), cyano group, dialkyl amido is (as-N (CH
3)
2), halogen, halogenated alkoxy be (as-OCF
3Or-OCHF
2), haloalkyl is (as-CF
3), alkyl is (as-CH
3Or-CH
2CH
3) ,-OH and-NO
2
The compounds of this invention can one or more geometrical isomers, optical isomer, enantiomer, diastereomer and tautomeric forms exist, and include but not limited to cis and trans forms, E-and Z-form, R-, S-and meso-form, ketone-and enol-form.Unless otherwise noted, for specific compound, comprise its all these isomeric forms, comprise its racemic modification and other mixture.When suitable, this class isomer can be by its mixture by use currently known methods (for example chromatographic technique and recrystallization technology) or it is carried out appropriate variations separate and obtain.When suitable, this class isomer can prepare by using currently known methods (for example asymmetric synthesis) or it being carried out appropriate variations.
Radicals R
1, R
2And R
3
R
1Be C
1-C
6-alkyl or hydrogen atom; And R
2Be hydrogen atom, or group-R
5, or group-Z-Y-R
5, or group-Z-NR
9R
10, or group-Z-N (R
9) C (O) R
11And R
3Be lone-pair electron, or C
1-C
6-alkyl, coupled in this case nitrogen-atoms are quaternary nitrogen and have positive charge;
Wherein at R
2In group-R
5, or group-Z-Y-R
5, or group-Z-NR
9R
10, or group-Z-N (R
9) C (O) R
11In:
Z can be, for example-and (CH
2)
1-16-, the latter's choosing wantonly by methyl substituted on 3 carbon atoms at the most in its chain;
Y be chemical bond or-O-;
R
5Can be, for example,
Optional aryl such as the phenyl or naphthyl that replaces, or aryl-condensed-Heterocyclylalkyl is as 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, or dihydro benzo furyl;
Optional heteroaryl such as pyridyl, pyrryl, pyrimidyl, oxazolyl, isoxazolyl, benzoisoxazole base, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl-, isothiazolyl, benzisothiazole base, pyrazolyl, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridazinyl, pyridazinyl, triazinyl, indyl and the indazolyl that replaces;
Optional aryl (the C that replaces
1-C
6-alkyl)-, aryl moiety is arbitrary aryl and the described-(C that the front is mentioned especially as described therein
1-C
6-alkyl)-partly be-CH
2-or-CH
2CH
2-those groups;
Optional aryl-condensed-cycloalkyl such as indanyl or 1,2,3 that replaces, the 4-tetralyl;
Optional heteroaryl (the C that replaces
1-C
8-alkyl)-, heteroaryl moieties is arbitrary heteroaryl and the described-(C that the front is mentioned especially as described therein
1-C
6-alkyl)-partly be-CH
2-or-CH
2CH
2-those groups;
Optional cycloalkyl that replaces such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group; Or
Optional Heterocyclylalkyl (the C that replaces
1-C
8-alkyl)-, for example wherein said Heterocyclylalkyl partly is the piperazinyl such as the methylpiperazine base of azetidinyl, piperidyl, piperazinyl, N-replacement, or pyrrolidyl and described-(C
1-C
6-alkyl)-partly be-CH
2-or-CH
2CH
2-those groups;
R
9And R
10Can be independently selected from hydrogen; C
1-C
6-alkyl such as methyl, ethyl or n-propyl or sec.-propyl; Or it is any at above-mentioned R
5Discussion in those optional aryl, aryl-condensed-Heterocyclylalkyl, aryl-condensed-cycloalkyl, heteroaryl or aryl (C that replace of mentioning especially
1-C
8-alkyl)-group; Or
R
9And R
10The nitrogen-atoms that links to each other with their forms has 4-8 annular atoms, the heterocycle of preferred 4-6 annular atoms, and optional other nitrogen or the Sauerstoffatom of also containing is as piperazinyl such as methylpiperazine base, pyrrolidyl, morpholinyl and the parathiazan base of azetidinyl, piperidyl, piperazinyl, N-replacement;
R
11Can be, for example methyl, ethyl or n-propyl or sec.-propyl.
Compound of the present invention is preferably wherein usually, at group-NR
1R
2R
3In, R
1Be methyl or ethyl, R
2Be aforesaid group-Z-Y-R
5, R wherein particularly
5Be ring-type lipophilic group such as phenyl, Y be chemical bond or-O-, and-Z-for the chain by (for example at the most 9) carbon atom that has 12 at the most with nitrogen and-YR
5The straight or branched alkylidene group that connects makes nitrogen by quaternized and have a positive charge.
Radicals R
4
R
4Be selected from a kind of in formula (a) and (b), (c) or the group (d);
In group (a), R
6Can be C
1-C
6-alkyl such as methyl or ethyl, or hydrogen atom; Ar
1Can be aryl such as phenyl, heteroaryl such as thienyl, particularly 2-thienyl, or cycloalkyl such as cyclohexyl, cyclopentyl, cyclopropyl or cyclobutyl; Ring substituents R
7aAnd R
7bCan be C independently
1-C
6-alkyl, as methyl, ethyl, n-propyl or sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, or halogen such as fluorine, chlorine or bromine; And m and n can be 1,2 or 3 independently.
At group (b) with (d), R
8aAnd R
8bCan be independently selected from above-mentioned R
5Those aryl of mentioning especially in the discussion, aryl-condensed-Heterocyclylalkyl, aryl-condensed-cycloalkyl, heteroaryl, C
1-C
6-alkyl, or arbitrary group of cycloalkyl.In addition, R
8bAlso can be hydrogen atom.R
8cCan be-OH, hydrogen atom, C
1-C
6-alkyl such as methyl or ethyl, or hydroxyl-C
1-C
6-alkyl such as hydroxymethyl.The present invention is R wherein preferably
8cSituation for-OH.R
8aAnd R
8bPreferably combination, particularly work as R
8cDuring for-OH, comprise wherein (i) R
8aAnd R
8bRespectively do for oneself and choose the bicyclic heteroaryl that replaces wantonly, as pyridyl, oxazolyl, thiazolyl, furyl and particularly thienyl such as 2-thienyl with 5 or 6 annular atomses; (ii) R
8aAnd R
8bBe the optional phenyl that replaces; (iii) R
8aAnd R
8bIn one be the optional phenyl that replaces, and another is cycloalkyl such as cyclopropyl, cyclobutyl, suberyl, ring octyl group, or particularly cyclopentyl or cyclohexyl; (iv) R
8aAnd R
8bIn one for the optional bicyclic heteroaryl that replaces, as pyridyl, thienyl, oxazolyl, thiazolyl or furyl with 5 or 6 annular atomses; And another is those combinations of cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group.
In group (c), R
8cCan be-OH, hydrogen atom, C
1-C
6-alkyl such as methyl or ethyl, or hydroxyl-C
1-C
6-alkyl such as hydroxymethyl.The present invention is R wherein preferably
8cSituation for-OH.Each Ar
2Be aryl, heteroaryl or cycloalkyl ring, and can be for example above-mentioned R
5Those aryl, heteroaryl, the C that mention in the discussion
1-C
6Arbitrary group of-alkyl or cycloalkyl.Preferred Ar
2Ring comprises phenyl.At two Ar
2Bridge-Q between the ring is-O-,-CH
2-or-CH
2CH
2-.
At R
4Selection (a) and (b), (c) and (d) in, the preferred R of the present invention
4For group (a) or (b) or (c).
The preferred SubClassing compound that the present invention relates to comprises formula (IA) compound
Wherein encircle A and be the optional phenyl ring that replaces, or have the monocyclic heterocycles of 5 or 6 annular atomses, or phenyl-condensed-Heterocyclylalkyl member ring systems, wherein this heterocycloalkyl ring is the monocyclic heterocycles with 5 or 6 annular atomses; R
8aBe phenyl, thienyl, cyclopentyl or cyclohexyl; R
8bBe phenyl; Thienyl, cyclopentyl or cyclohexyl; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10; Y be chemical bond or-O-, and X
-Be pharmaceutically acceptable negatively charged ion.In compound (IA), preferred usually ring A is the optional phenyl that replaces, and wherein Ren Xuan substituting group is selected from alkoxyl group, halogen particularly fluorine or chlorine, C
1-C
3-alkyl, amino C
1-C
3-acyl group, amino C
1-C
3-alkyl and amino-sulfonyl.
The preferred SubClassing compound of another that the present invention relates to comprises formula (IB) compound
Wherein encircle B and be the optional phenyl ring that replaces, or have the monocyclic heterocycles of 5 or 6 annular atomses, or aryl-condensed heterocycle alkyl ring; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10; Y be chemical bond or-O-; And R
6, Ar
1, R
7aAnd R
7bAs definition to above-mentioned group (a); And X
-Be pharmaceutically acceptable negatively charged ion.In compound (IB), preferred usually ring B is (i) optional phenyl that replaces, and wherein Ren Xuan substituting group is selected from alkoxyl group, halogen particularly fluorine or chlorine, C
1-C
3-alkyl, amino C
1-C
3-acyl group, amino C
1-C
3-alkyl and amino-sulfonyl;
The preferred SubClassing compound of another that the present invention relates to comprises formula (IC) compound
Wherein encircle C and be the optional phenyl ring that replaces, or have the monocyclic heterocycles of 5 or 6 annular atomses, or aryl-condensed heterocycle alkyl ring; Q be Sauerstoffatom ,-CH
2-,-CH
2CH
2-or chemical bond; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10, and Y be chemical bond or-O-; And X
-Be pharmaceutically acceptable negatively charged ion.In compound (IC), preferred usually ring C is the optional phenyl that replaces, and wherein Ren Xuan substituting group is selected from alkoxyl group, halogen particularly fluorine or chlorine, C
1-C
3-alkyl, amino C
1-C
3-acyl group, amino C
1-C
3-alkyl and amino-sulfonyl;
In subclass (IA), (IB) with (IC), s+t can be, for example 1,2,3,4,5,6 or 7, and can derive from the suitable combination of t and s, as t wherein be 0,1,2,3,4,5 or 6 and s be 1,2,3,4,5,6 or 7 combination.At compound (IA), (IB) with (IC), be preferably usually wherein that t is 0, s be 3 and Y be the t of-O-, the combination of Y and s.Also preferred wherein Y is that chemical bond and s+t are 2,3 or 4 combination.
In subclass of the present invention (IA), (IB) with (IC), usually preferred The compounds of this invention mainly exists with trans-Nei configuration form.
The example of The compounds of this invention comprises embodiment compound as herein described.
The invention still further relates to and wherein contain the pharmaceutical preparation of The compounds of this invention as activeconstituents.Other compound can be used for prevention and treatment pulmonary inflammation disease with the The compounds of this invention combination.Therefore, the invention still further relates to and be used to prevent and treat for example pharmaceutical composition of chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema and rhinallergosis of respiratory tract obstruction, it contains The compounds of this invention and one or more other therapeutical agents for the treatment of significant quantity.
Other compound and The compounds of this invention combination can be used for prevention and treatment pulmonary inflammation disease.Therefore, the present invention includes aforesaid medicament of the present invention and one or more anti-inflammatory agenies, bronchodilator, antihistaminic agent, separate the combination of congested agent or anti-cough agent, described aforesaid medicament of the present invention and described combination medicament may reside in same or the different pharmaceutical composition in, can separate or administration simultaneously.Preferred combination can have two or three different pharmaceutical composition.The therapeutical agent that suitable and The compounds of this invention is used for combined therapy comprises:
One or more other bronchodilator, for example PDE3 inhibitor;
Methyl xanthine, for example theophylline;
Other muscarinic receptor antagonist;
Reflunomide, for example fluticasone propionate, ciclesonide, health acid Mometasone or budesonide, the perhaps steroid of describing among WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181, WO03/62259, WO03/64445, WO03/72592, WO04/39827 and the WO04/66920;
The non-steroidal glucocoricoid receptor agonist;
Beta-2-adrenoreceptor agonists, salbutamol for example, Salmeterol, Orciprenaline, terbutaline, Partusisten, procaterol, carmoxirole, indenes Da Teluo, formoterol, Afromoterol, picumeterol, GSK-159797, GSK-597901, GSK-159802, GSK-64244, GSK-678007, TA-2005 and EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651, US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/016601, WO04/22547, WO04/32921, WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762, WO04/39766, WO04/45618, WO04/46083, WO04/71388, WO04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167, US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121, WO05/040103, WO05/044787, WO04/071388, WO05/058299, WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841, WO05/092860, WO05/092887, WO05/092861, WO05/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091, US20050171147, WO05/092870, WO05/077361, DE10258695, WO05/111002, WO05/111005, WO05/110990, US2005/0272769WO05/110359, WO05/121065, US2006/0019991, WO06/016245, WO06/014704, WO06/031556, WO06/032627, US2006/0106075, US2006/0106213, WO06/051373, compound among the WO06/056471;
Leukotrienes regulator, for example Singulair, Zafirlukast or pranlukast;
Proteinase inhibitor, for example inhibitor of matrix metalloproteinase such as MMP12 and tace inhibitor such as Marimastat, DPC-333, GW-3333;
People neutrophil's elastatinal, for example people neutrophil's elastatinal of describing among sivelestat and WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701, WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, the WO03/053930;
Phosphodiesterase-4 (PDE4) inhibitor, for example roflumilast, arofylline, cilomilast, ONO-6126 or IC-485;
Phosphodiesterase-7 inhibitor;
Antitussive, for example morphine monomethyl ether or dextramorphan;
Kinase inhibitor, particularly P38MAP kinase inhibitor;
The P2X7 antagonist;
The iNOS inhibitor;
Non-steroid class anti-inflammatory agent (NSAID), for example Ibuprofen BP/EP or Ketoprofen;
Dopamine-receptor antagonist;
TNF-alpha inhibitor, for example anti-TNF monoclonal antibody such as Remicade and CDP-870 and TNF receptor immunoglobulin molecule such as Enbrel;
The A2a agonist for example is described in the A2a agonist among EP1052264 and the EP1241176;
The A2b antagonist for example is described in the A2b antagonist among the WO2002/42298;
The conditioning agent of chemokine receptor function, the antagonist of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8 for example is as SB-332235, SB-656933, SB-265610, SB-225002, MCP-1 (9-76), RS-504393, MLN-1202, INCB-3284;
Regulate the compound of prostaglandin receptor effect, for example PGD
2(DP1 or CRTH2) or thromboxane A
2Antagonist such as ramatrobant;
Regulate the compound of Th1 or Th2 function, for example the PPAR agonist;
Interleukin 1 receptor antagonist, for example Kineret;
Interleukin-11 0 agonist, for example ilodecakin;
HMG-CoA reductase inhibitor (Statins), for example superstatin, mevastatin, lovastatin, Simvastatin, Pravastatin and fluvastatin;
The mucus conditioning agent for example INS-37217, overstate rope phosphorus, sibenadet, CS-003, Talnetant, DNK-333, MSI-1956, Gefitinib;
Anti-infection agent (microbiotic or antiviral agent) and anti-allergy medicine include but not limited to antihistaminic agent.
The part by weight of first and second activeconstituentss can change, and depends on the effective dose of each composition.Usually can use the effective dose of each composition.
Use the The compounds of this invention of effective dose, any suitable route of administration all can be used for offering Mammals, particularly people.In treatment is used, can be with active compound by any convenience, suitable or valid approach administration.Suitable route of administration is that those of ordinary skills are known, comprises in oral, intravenously, rectum, non-enteron aisle, part, intraocular, the nose, oral cavity and pulmonary administration.
The prevention of The compounds of this invention or therapeutic dose size depend on various factors certainly, comprise activity, patient age, body weight, diet, general health situation and sex, administration time, route of administration, discharge rate, employed any other medicines and the severity of disease to be treated of the specific compound that uses.Usually, the per daily dose that is used to suck can be single dose or multiple doses, is the extremely about 10mg/kg body weight for humans of about 0.1 μ g, and preferred 0.1 μ g is to about 0.5mg/kg, more preferably 0.1 μ g to 50 μ g/kg.On the other hand, also may need to use above-mentioned restriction dosage in addition in some cases.The composition that is fit to inhalation is known, wherein can contain known carrier and/or the thinner that can be used in this based composition.The active compound that can contain 0.01-99 weight % in the composition.Preferred unit dosage contains the active compound that consumption is 1 μ g to 10mg.For oral administration, appropriate dosage is 10 μ g/kg to 100mg/kg, is preferably 40 μ g/kg to 4mg/kg.
The present invention provides pharmaceutical composition on the other hand, and it contains The compounds of this invention and pharmaceutically acceptable carrier.Term in the pharmaceutical composition " composition " be meant contain (one or more) activeconstituents and (one or more) constitute carrier inert fraction product (pharmaceutically acceptable vehicle) and directly or indirectly by combination, complexing or assemble any two or more compositions or by any product that decomposes one or more compositions or obtain by other type reaction or the interaction of one or more compositions.Therefore, pharmaceutical composition of the present invention comprises by mixing any composition that The compounds of this invention, other activeconstituents and pharmaceutically acceptable vehicle make.
Pharmaceutical composition of the present invention contains The compounds of this invention or its pharmacologically acceptable salt as activeconstituents, also contains pharmaceutically acceptable carrier and other optional therapeutic component simultaneously.Term " pharmacologically acceptable salt " is meant by pharmaceutically acceptable nontoxicity alkali or acid and comprises mineral alkali or acid and organic bases or the sour salt that makes and the salt of quaternary ammonium compound and pharmaceutically acceptable counter ion.
For inhalation, active compound is preferably particulate form.It can comprise spraying drying, freeze-drying and micronization by various technology preparations.
For instance, the present composition can be prepared into the suspensoid sent by spraying gun or the gaseous solvents form in liquid propellant, for example in pressurised metered dose inhalers (PMDI), use.The propelling agent that is suitable among the PMDI is well known by persons skilled in the art, comprises CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl
2F
2) and HFA-152 (C
2H
4F
2) and Trimethylmethane.
In the preferred embodiment of the invention, the dry powdered form of the present composition for using Diskus (DPI) to send.The DPI of a lot of types is known.
The particulate sent by administration can be prepared with the vehicle that helps to send and disengage.For example, in dry powder formulations, particulate can use the larger vector particle formulation that helps to be flowed into by DPI lung.Suitable carrier is known, comprises lactose granule; They can have the piece average air kinetic diameter greater than 90 μ m.
In the situation of gaseous solvents matrix formulations, example as:
The compounds of this invention 24mg/ jar
Yelkin TTS, NF Liq.Conc. 1.2mg/ jar
The trichlorine methyl fuoride, NF 4.025g/ jar
Dichloro two fluoro methane, NF 12.15g/ jar.
According to employed suction system, active compound can be according to the above-mentioned dosage of carrying out.Except active compound, form of medication can contain vehicle in addition, and for example propelling agent (as contain freonll-11 in metering gaseous solvents situation), surfactant, emulsifying agent, stablizer, sanitas, seasonings, weighting agent (as contain lactose in the powder inhalator situation) or suitable words contain other active compound.
For inhalation, can use multiple system, the suction technology that is fit to the patient by these system utilizations can generate and use the gaseous solvents with optimum grain-diameter.Except use adapter (spacer, expander) and pear-shaped containers (as
) in addition, can also utilize emission to blow and spray
The metering gaseous solvents automatic gear, particularly in the powder inhalator situation, can utilize various solutions (as
Or the sucker of for example describing among the EP-A-0505321).In addition, The compounds of this invention can be sent with multi-layered devices, thereby be realized sending of combination medicament.
Synthetic method
The compounds of this invention can be according to the method among following proposal and the embodiment, uses suitable feedstock production, in the specific embodiment below with further exemplary illustration.In addition, by the method for describing in the included content of this paper, those of ordinary skills can prepare this paper other The compounds of this invention required for protection easily.Yet the compound of exemplary illustration can not be interpreted as and belong to a unique compounds of the present invention in an embodiment.The further exemplary illustration of these embodiment the preparation The compounds of this invention details.Those skilled in the art can understand easily, and the various known modification of carrying out at the condition and the method for following preparation step also can be used for preparing above-claimed cpd.
The compounds of this invention can separate for example foregoing pharmaceutical acceptable salt with its pharmaceutical acceptable salt.
May need the active function groups (as hydroxyl, amino, sulfydryl or carboxyl) of the intermediate that is used to prepare The compounds of this invention is protected, cause the formation of compound to avoid it undesirably to participate in reacting.Can use conventional blocking group for example T.W.Greene and P.G.M.Wuts at " Protectivegroups in organic chemistry " John Wiley and Sons, the blocking group of describing in 1999.
The compounds of this invention can be according to the exemplary path of preparing that provides in the scheme 1.
Scheme 1
General formula (I) compound, wherein R
a, R
bAnd R
cAnd R
4As in formula (I) compound to R
1, R
2, R
3And R
4Definition, can be from general formula (II) compound:
Prepare by reacting with general formula (III) compound:
R
c-X?(III)
Wherein X is leavings group such as halogen, tosylate, methanesulfonates.Reaction can be at a series of solvents such as acetonitrile, chloroform, DMF or DMSO, 0 ℃ to the scope of solvent refluxing temperature, preferably carry out in the scope from envrionment temperature to the solvent refluxing temperature.
There are two pairs of enantiomeric forms in general formula (I) compound, and it can be by preparing with the form with chirality from same chirality (XII).Perhaps, can the racemize material be carried out chiral separation by chirality HPLC.
General formula (II) compound, wherein R
4Be the group and the R of formula (a) as defined above
6Be H, can be from general formula (IV) compound:
R wherein
aAnd R
bAs above definition prepares by reacting with logical formula V compound:
R wherein
7a, R
7b, n and m such as mutual-through type (I) definition.Reaction can-nucleophilicity organic solvent non-in series such as DMF or toluene, and in temperature range, preferred 0 ℃ is carried out to solvent circulation temperature range.
Logical formula V compound is as known in the art, and can buy easily maybe and can prepare by currently known methods.
General formula (II) compound, wherein R
4Be the group of formula (b) as defined above, can prepare by reacting from general formula (IV) compound with general formula (VI) compound:
R wherein
8a, R
8bAnd R
8cFor as for the definition of general formula (I), and LG is leavings group, for example, O-alkyl, halogen or 1-imidazolyl.Be reflected under the existence of highly basic such as NaH in solvent such as toluene, THF or methylene dichloride in temperature range, preferred 0 ℃ is carried out to the scope of solvent refluxing temperature.
General formula (VI) compound, wherein R
8a, R
8bAnd R
8cAs the definition for general formula (I), and Y is O-alkyl, halogen or 1-imidazolyl, can prepare by currently known methods from general formula (VII) compound.
General formula (VII) compound is as known in the art, and can buy easily or by those methods preparation of currently known methods as describing in WO01/04118.
General formula (II) compound, wherein R
4Be the group of formula (c) as defined above, can prepare by reacting from general formula (IV) compound with general formula (VIa) compound:
Ar wherein
2, R
8c, Q and LG as above define, and uses those conditions that are similar to above-mentioned through type (IV) compound and formula (VI) compound prepared in reaction formula (II) compound.
Formula (VIa) compound can prepare by being similar to above-mentioned method from formula (VII) compound formula (VI) compound from formula (VIIa) compound.
General formula (VII) compound is as known in the art, and can buy easily or prepare by currently known methods.
General formula (IV) compound can be from general formula (VIII) compound:
By with hydrogen in the presence of the preferred palladium hydroxide/charcoal of catalyzer, in polar solvent such as MeOH or EtOAc, choose wantonly to react and prepare in the existence of protonic acid such as sulfuric acid or acetate.
General formula (VIII) compound can be from general formula (IX) compound:
By with the amine of general formula (X):
R
aR
bNH (X)
, in polar solvent such as THF or DCE, choose wantonly in the presence of acetate, to react and prepare at reductive agent such as sodium triacetoxy borohydride.
General formula (IX) compound can be from general formula (XI) compound:
By with the preferred Bu of tin reagent
3The preferred AIBN of SnH and radical initiator reacts and prepares.Reaction can be carried out to the scope of solvent refluxing temperature in the preferred room temperature of temperature range at the preferred toluene of serial solvent.
General formula (XI) compound can be from general formula (XII) compound:
Prepare by reacting with benzylalcohol.Be reflected under the existence of highly basic such as NaH and to the scope of envrionment temperature, carry out for preferred-78 ℃ in temperature range in preferred THF of a series of solvents or DMF.
Formula (XII) compound is as known in the art, and can from chirality initial two the ring [3.2.0] heptanone by bromination prepare (Synthesis (1977), 155-166).The fractionation of this two suberone is described among the EP0074856.
Following non-limiting example is carried out exemplary illustration to the present invention.
General experimental detail:
Unless otherwise noted, respond and all under nitrogen atmosphere, carry out.
When product when the column chromatography purifying, ' silicon-dioxide fast ' is meant chromatographic grade silica gel, 0.035-0.070mm (220-440 order) (as Fluka silica gel 60), and institute's nitrogen pressure of using at the most 10p.s.i to quicken the post wash-out.When using tlc (TLC), be meant the silica gel tlc that uses thin plate, normally have the 3 * 6cm silica gel (as Fluka60778) on the aluminium foil plate of fluorescent indicator (254nm).All solvents and commercial reagents are all used standard substance.
Unless otherwise noted, all compounds that contain (one or more) basic center by the HPLC purifying obtain with the tfa salt form.
LC-MS method 1
Waters Micromass ZQ has C18-reversed-phase column (30 * 4.6mm Phenomenex Luna, 3 μ m particle diameters), and wash-out uses A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid.Gradient:
Gradient-time flow velocity ml/ minute %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95
6.00 2.0 95 5
Detection-MS, ELS, UV (100 μ l crack MS have online UV detector)
MS ioning method-electron spray(ES) (positively charged ion and negatively charged ion)
LC-MS method 2
Waters Micromass ZQ has C18-reversed-phase column (5 microns C18 100x3.0mm of Higgins Clipeus or Equivalent), and wash-out uses A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid.Gradient:
Gradient-time flow velocity ml/ minute %A %B
0.00 1.0 95 5
1.00 1.0 95 5
15.0 1.0 5 95
20.0 1.0 5 95
22.0 1.0 95 5
25.0 1.0 95 5
Detection-MS, ELS, UV (100 μ l crack MS have online UV detector)
MS ioning method-electron spray(ES) (positively charged ion and negatively charged ion)
The abbreviation of in experimental section, using: DCM=methylene dichloride; EtOH=ethanol; DIPEA=two-sec.-propyl ethylamine; EDCI=1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; The DMAP=dimethyl aminopyridine; The RT=room temperature; HATU=O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate; The TFA=trifluoroacetic acid; The Rt=retention time.
Embodiment 1
Trans (±)-biphenyl-2-base-carboxylamine 2-dimethylamino-two ring [2.2.1] heptan-7-base ester (II): R
a, R
b=CH
3, R
4=biphenyl-2-base formamyl
A. (±)-7-benzyloxy-5-bromo-two ring [2.2.1] heptane-2-ketone (XI)
At N
2Down, to NaH (60% dispersion in oil; 433mg, 10.8mmol) suspension in anhydrous THF (7mL) drip benzylalcohol (1.07mL, 10.4mmol).This mixture was stirred 30 minutes, be cooled to-30 ℃ then, and with (±)-2, (1.32g, 4.9mmol) solution in anhydrous THF (6mL) drips processing to 3-two bromo-two ring [3.2.0] heptane-6-ketone, through 2 hours, reaction mixture is warmed to 0 ℃.This brown non-homogeneous mixture is diluted with ethyl acetate, uses 10% aqueous citric acid solution, water and salt water washing then, and uses dried over mgso, evaporation.Crude product uses 15% ether/pentane wash-out by the silica gel column chromatography purifying, obtains title compound, is colourless soup compound (609mg).
1H?NMR(CDCl
3，400MHz):δ?1.79(1H，ddd，J＝14.3Hz，4.2Hz，1.5Hz)，2.15(1H，m)，2.65(1H，m)，2.80(1H，m)，2.82(1H，d，J＝19.1Hz)，2.86(1H，m)，4.03(1H，q，J＝1.8Hz)，4.50(1H，d，J＝11.7Hz)，4.53(1H，d，J＝11.7Hz)，4.71(1H，m)，7.27-7.40(5H，m)。
B. (±)-7-benzyloxy-two ring [2.2.1] heptane-2-ketone (IX):
To (±)-7-benzyloxy-5-bromo-two ring [2.2.1] heptane-2-ketone (609mg, 2.06mmol) and AIBN (34mg, 0.21mmol) mixture that do not have in the toluene of water degasification in 30mL drips tributyl tin hydrogen (tributyltin hydride) (0.72mL, 2.68mmol), and this solution is heated to 80 ℃, continue 1.5 hours.Reaction mixture under reduced pressure concentrates, is adsorbed on the diatomite, and chromatography, use 1-15% ether/pentane wash-out, obtain title compound, be colourless jelly (446mg).
1H?NMR(CDCl
3，400MHz):δ?1.49(2H，m)，1.99(1H，d，J＝18.5Hz)，2.10(3H，m)，2.62(1H，m)，2.67(1H，m)，3.91(1H，s)，4.51(1H，d，J＝11.7Hz)，4.53(1H，d，J＝11.7Hz)，7.27-7.39(5H，m)。
C. (±)-(7-benzyloxy-two ring [2.2.1] heptan-2-yl)-dimethyl-(VIII): R
a
, R
b
=CH
3
R
4
=
Bn
To (±)-7-benzyloxy-two ring [2.2.1] heptane-2-ketone (262mg, 1.21mmol) and dimethylamine (the THF solution of 2M, 1.21mL, 2.42mmol) solution in the anhydrous DCE of 2mL adds acetate (69 μ L, 1.21mmol), (385mg is 1.82mmol) with a spot of 3 then to add sodium triacetoxy borohydride
Molecular sieve.This miscellany was stirred 6 hours at ambient temperature.Reaction is with the quencher of 10mL saturated sodium bicarbonate aqueous solution and stirred 10 minutes.Reaction mixture EtOAc extracting twice, the organic phase water of merging and salt water washing, anhydrous sodium sulfate drying, evaporation obtains title compound, is light yellow oil (259mg) that it need not be further purified direct use.LC-MS (method 1): Rt 1.73 minutes, m/z246.21[MH+].
D. (±)-2-dimethylamino-two ring [2.2.1] heptane-7-alcohol (IV): R
a
, R
b
=CH
3
With (±)-(7-benzyloxy-two ring [2.2.1] heptan-2-yl)-(236mg, 0.96mmol) solution in anhydrous MeOH (8mL) adds to 20wt% palladium hydroxide/charcoal (50mg) to dimethyl amine.Reaction vessel vacuumized and with nitrogen degasification three times, add then 25% vitriolic MeOH solution (320 μ L, 1.5mmol).To be reflected in the nitrogen atmosphere (hydrogen balloon) stirred 20 hours.Reaction 200mg solid sodium carbonate and the quencher of 3mL water, and evaporation.Resistates is distributed between DCM and the salt solution, and separates each layer.More than four times, evaporate by the organic phase dried over sodium sulfate of merging with the DCM extraction for water, obtains the miscellany of the 3:1 of title compound and recovery starting raw material, is colorless oil, and it need not be further purified direct use (105mg).
E. (±) trans-biphenyl-2-base-carboxylamine 2-dimethylamino-two ring [2.2.1] heptan-7-base ester
(II): R
a
, R
b
=CH
3
R
4
=biphenyl-2-formamyl
With the solution of miscellany in dry toluene (2mL) of the 3:1 of (±)-2-dimethylamino-two ring [2.2.1] heptane-7-pure and mild (±)-(7-benzyloxy-two ring [2.2.1] heptan-2-yl)-dimethyl-amine (96mg) with 2-biphenyl isocyanate (145mg, 0.74mmol) handle, and, continue 2.5 hours with mixture heating up to 80 ℃.Evaporate volatile matter, resistates uses 2-6% MeOH/DCM wash-out by the silica gel column chromatography purifying, obtains title compound, is colourless soup compound (125mg).LC-MS (method 1): Rt 7.05 minutes, m/z351.16[MH+].LC-MS (method 1): Rt 2.01 minutes and 2.09 minutes, m/z 351.27[MH+].
1H?NMR(CDCl
3，400MHz):δ?0.99(1H，dd，J＝12.7Hz，4.9Hz)，1.34(1H，m)，1.51(1H，m)，1.73(1H，m)，1.83(2H，m)，2.13(6H，s)，2.20(2H，m)，2.39(1H，m)，4.72(1H，s)，6.57(1H，s，br)，7.13(1H，td，J＝7.5，1.2Hz)，7.22(1H，dd，J＝7.5，1.7Hz)，7.36(3H，m)，7.40(1H，m)，7.48(2H，m)，8.06(1H，s，br)。
Embodiment 2
A. trans (1S, 2S) hydroxyl-two-thiophene-2-base-acetate 2-[methyl-(3-phenyl-propyl group)-amino]-two rings [2.2.1] heptan-7-base ester (II): R
a=CH
3R
b=3-phenyl-1-propyl group; R
4=hydroxyl-two thiophene-2-base carbonyl
B. trans (1S, 2S) 2-[methyl-(3-phenyl-propyl group)-amino]-two ring [2.2.1] heptane-7-alcohol (IV):
R
a
=CH
3
R
b
=3-phenyl-1-propyl group
Use is similar to those methods among the embodiment 1, and title compound is from (3R)-2,3-two bromo-, two ring [3.2.0] heptane-6-ketone and methyl-(3-phenyl propyl)-amine prepare for 1S, 2R.
1H?NMR(CDCl
3，400MHz):δ?0.91-0.95(1H，m)，1.32-1.38(1H，m)，1.54-1.62(2H，m)，1.68-1.89(6H，m)，1.98(1H，m)，2.08(3H，m)，2.26-2.29(3H，m)，2.59-2.63(2H，m)，3.97(1H，m)，7.15-7.19(3H，m)，7.25-7.29(2H，m)。
C.
Trans (1S, 2S) hydroxyl-two-thiophene-2-base-acetate 2-[methyl-(3-phenyl-propyl group)-amino]-two Ring [2.2.1] heptan-7-base ester (II): R a =CH 3 R b =3-phenyl-1-propyl group; R 4 =hydroxyl-two thiophene-2- The base carbonyl
Under envrionment temperature and nitrogen atmosphere, with trans (1S, 2S) 2-[methyl-(3-phenyl-propyl group)-amino] (165mg, 0.63mmol) solution in dry toluene (10mL) and sodium hydride (76mg, 60% the dispersion in mineral oil) stir two ring [2.2.1] heptane-7-alcohol.After stopping to emit gas, through 5 minutes, add hydroxyl-two-thiophene-2-base-acetate ethyl ester (205mg 0.76mmol), will react in the oil bath that is placed at 80 ℃ of following preheatings immediately then in batches.After 1 hour, will react cooling, use the saturated ammonium chloride solution quencher then.With reaction, extraction to ethyl acetate, the organic extract MgSO of merging
4Drying, and concentrate under the vacuum.By chromatography purification, use 0-3% methyl alcohol-CH
2Cl
2As elutriant, obtain title compound, be jelly (127mg).LC-MS (method 2): Rt 7.90 minutes, m/z 482[MH]+.
1H?NMR(CDCl
3，400MHz):δ?0.88-1.01(1H，m)，1.21-1.34(2H，m)，1.46-1.59(1H，m)，1.68-1.87(4H，m)，2.01-2.09(3H，s)，2.18-2.27(3H，m)，2.30-2.37(2H，m)，2.54-2.60(2H，m)，4.75-4.97(1H，m)，4.83(1H，m)，6.93-6.97(2H，m)，7.12-7.18(5H，m)，7.22-7.28(4H，m)。
Embodiment 3
Trans (1S, 2S) [7-(2-hydroxyl-2,2-two-thiophene-2-base-acetoxyl group)-two ring [2.2.1] heptan-2-yl]-dimethyl-(3-phenyl-propyl group)-ammonium bromide (I): R
a, R
b=CH
3R
b=3-phenyl-1-propyl group; R
4=hydroxyl-two thiophene-2-base carbonyl
In sealed tube, with trans (1S, 2S) hydroxyl-two-thiophene-2-base-acetate 2-[methyl-(3-phenyl-propyl group)-amino]-two rings [2.2.1] heptan-7-base ester, (33mg, 0.069mmol) solution in the acetonitrile solution (1mL) of the monobromomethane of 30% w/w was 50 ℃ of heating 2 days down.Remove and desolvate, and, use 0-10% methyl alcohol-CH by chromatography purification
2Cl
2As elutriant, obtain title compound, be foam-like material (33mg).LC-MS (method 2): Rt 7.45 minutes, m/z 496[M]+;
1H NMR (CDCl
3, 400MHz) δ 1.33-1.41 (1H, m), 1.45-1.56 (1H, m), 1.57-1.67 (2H, m), and 1.69-1.79 (1H, m), 2.04-2.21 (3H, m), 2.43 (1H, m), 2.64-2.79 (3H, m), 3.23 (3H, s), 3.25 (3H, s), and 3.43-3.55 (1H, m), 3.56-3.68 (1H, m), 4.31 (1H, m), 4.89-4.92 (1H, m), 5.02-5.05 (1H, m), and 6.93-6.99 (2H, m), 7.10-7.30 (9H, m).
The following examples are to be similar to the method preparation of describing among the embodiment 1-3.
Biology embodiment
The compounds of this invention is measured by following combination the restraining effect of M3 M-ChR:
The M-ChR radioligand is in conjunction with test
The application use [
3H]-N-methyl scopolamine ([
3H]-NMS) and the radioligand of the cytolemma of the expressing human M-ChR (M2 and M3) that is commercially available estimate the avidity of muscarine antagonist in conjunction with studying to M2 and M3 acceptor.Will in the cytolemma in the TRIS damping fluid in 96 orifice plates, use different concns [
3H]-NMS and M3 antagonist cultivated 3 hours.Cytolemma and binding radioactivity part by filtering results, are placed dried overnight subsequently.Add scintillating liquid then, the binding radioactivity part uses CanberraPackard Topcount scintillometer counting.
Antagonist to the transformation period of every kind of M-ChR use other radioligand [
3H]-modification of QNB and above-mentioned avidity test measures.Antagonist was cultivated 3 hours with the cytolemma of expressing human M-ChR under than the high 10 times concentration of its Ki value, the use of Ki value [
3H]-the QNB part is definite.During end, will [
3H]-QNB is added to than its high 25 times concentration of Kd value to the acceptor studied, continues to cultivate the different time sections between 15 minutes to 180 minutes.Cytolemma and binding radioactivity part by filtering results, are placed dried overnight subsequently.Add scintillating liquid subsequently, the binding radioactivity part uses Canberra Packard Topcount scintillometer counting.
The institute detect [
3H]-QNB is that the transformation period of antagonist on acceptor is relevant to M-ChR in conjunction with the dissociate ratio of acceptor of ratio and antagonist.
All embodiment compound exhibits of test go out binding affinity K in this test
iValue＜10nM, except embodiment compound 6, it demonstrates K
iValue＜100nM.
By calcium mobilization's analysis M3 acceptor active is suppressed
In the test of other M3 receptors bind, be that the density kind of 50000/75 μ l is gone into and overnight incubation in 96 orifice plates (black wall is put one's cards on the table) of collagen coating replenishing in can the substratum of 3% serum with the Chinese hamster ovary celI of expressing human M3 acceptor.Second day, in the HBSS damping fluid, prepare the quick dyestuff of calcium (Molecular Devices, Cat# R8041) by adding 5mM probenecid (pH7.4).Be added to isopyknic dye solution (75 μ l) in this cell and after cultivating 45 minutes, add 50 μ l muscarine antagonist or solvents then.After 15 minutes, with culture plate at FLEXstation
TM(excite 488nm, emission 525nm) goes up 15 seconds of reading to measure baseline fluorescence.Then with EC
80Concentration adds the muscarinic agonist carbechal, continues to measure 60 seconds of phosphor persistence.Calculate signal by deducting peak response by the average baselining fluorescence in the control wells that does not have antagonist.Calculate the peak response per-cent in the presence of antagonist subsequently, thereby generate IC
50Curve.
The compounds of this invention to the restraining effect of M3 M-ChR can be below external (ex-viva) and the body build-in test in estimate:
Exemplarily, embodiment 3 compounds demonstrate IC50 value＜10nM in this test.
Shrink by acetylmethyl choline inductive body entobronchus
To carry out mark separately with per 5 male guinea pigs (Dunkin Hartley) that are one group of weight of raising is 500-600g.Make animal adapt to its surrounding environment at least 5 days.During this period of time with research during, animal can arbitrarily drink water and take food.
Cavy is used suction narcotic fluothane (5%) anesthesia.To its intranasal administration test compounds or solvent (0.25-0.50mL/kg).Animal placed allow its recovery on the heating cushion, return in the cage then.
After administration reached 24 hours, cavy was finally used urethane (250 μ g/mL, 2mL/kg) anesthesia.When surgery anesthesia, jugular vein is inserted portex intravenous injection conduit, be used for intravenous administration acetylmethyl choline, wherein be filled with heparinization phosphate buffered saline (PBS) (hPBS) in the portex conduit (10U/mL).Expose tracheae, insert hard portex conduit, oesophagus uses flexible portex Infants'feeding test tube to insert conduit.
(EMMS, Hants UK) link to each other, and the latter is made up of respiration rate anemometer and pressure transmitter with the animal of this spontaneous respiration and lung measuring system then.Trachea cannula links to each other with the respiration rate anemometer, and the oesophagus intubate links to each other with pressure transmitter.
Placing the oesophagus intubate makes baseline drag (baseline resistance) be 0.1-0.2cmH20/mL/s.After writing down 2 minutes baseline reading, and intravenous administration acetylmethyl choline (30 μ g/kg at the most, 0.5mL/kg).Begin to start at from intravenous administration, write down 2 minutes the contraction of inducing.
During writing down in per 2 minutes, use drag area (AUC) under computed in software peak drag and the curve, it is used for the segmental bronchus provide protection of analytical test compound.
Exemplarily, embodiment 3 compounds after administration 1 hour for segmental bronchus protection, as showing in the accompanying drawings.
Description of drawings
Accompanying drawing is to show embodiment 3 compounds in cavy (3 μ g/kg are i.n.) to the histogram of the effect of acetylmethyl choline-inductive bronchoconstriction.
Claims (28)
1. formula (I) compound or pharmaceutically acceptable salt thereof, solvate, N-oxide compound or prodrug:
Wherein
R
1Be C
1-C
6-alkyl or hydrogen atom; And R
2Be hydrogen atom, or group-R
5, or group-Z-Y-R
5, or group-Z-NR
9R
10, or group-Z-N (R
9) C (O) R
11And R
3Be lone-pair electron, or C
1-C
6-alkyl, coupled in this case nitrogen-atoms are quaternary nitrogen and have positive charge;
R
4Be selected from formula (a) and (b), (c) or (d) a kind of in the group;
Z is C
1-C
16-alkylidene group, C
2-C
16-alkylene group or C
2-C
16-alkynylene;
Y is chemical bond or Sauerstoffatom;
R
5Be C
1-C
6-alkyl, aryl, arylalkyl; Aryl-condensed-cycloalkyl, aryl-condensed-Heterocyclylalkyl, heteroaryl, aryl (C
1-C
8-alkyl)-, heteroaryl (C
1-C
8-alkyl)-, cycloalkyl or Heterocyclylalkyl;
R
6Be C
1-C
6-alkyl or hydrogen atom;
R
7aAnd R
7bBe C independently
1-C
6-alkyl or halogen;
N and m are 0,1,2 or 3 independently;
R
8aAnd R
8bBe independently selected from aryl, aryl-condensed-Heterocyclylalkyl, heteroaryl, C
1-C
6-alkyl, cycloalkyl and hydrogen;
R
8cFor-OH, C
1-C
6-alkyl, hydroxyl-C
1-C
6-alkyl or hydrogen atom;
R
9And R
10Be hydrogen atom, C independently
1-C
6-alkyl, aryl, aryl-condensed-Heterocyclylalkyl, aryl-condensed-cycloalkyl, heteroaryl, aryl (C
1-C
6-alkyl)-or heteroaryl (C
1-C
6-alkyl)-; Or R
9And R
10The nitrogen-atoms that links to each other with their forms the heterocycle of 4-8 atom, chooses wantonly and also contains other nitrogen or Sauerstoffatom;
R
11Be C
1-C
6-alkyl or hydrogen atom;
Ar
1Be aryl, heteroaryl or cycloalkyl;
Ar
2Be aryl, heteroaryl or cycloalkyl independently; And
Q be Sauerstoffatom ,-CH
2-,-CH
2CH
2-or chemical bond.
2. the compound of claim 1, wherein
R
1Be C
1-C
6-alkyl or hydrogen atom and R
2Be C
1-C
6-alkyl, hydrogen atom or group-Z-Y-R
5, or group-Z-NR
9R
10
R
3Be lone-pair electron; Or C
1-C
6-alkyl, coupled in this case nitrogen-atoms are quaternary nitrogen and have positive charge;
R
4Be selected from formula (a) or (b) or (c) a kind of in the group:
Z is C
1-C
8-alkylidene group;
Y is chemical bond or Sauerstoffatom;
R
5Be aryl or aryl (C
1-C
8-alkyl)-;
R
6Be C
1-C
6-alkyl or hydrogen atom;
R
7aAnd R
7bBe C independently
1-C
6-alkyl or halogen;
N and m are 0,1,2 or 3 independently;
R
8aAnd R
8bBe independently selected from aryl, heteroaryl, C
1-C
6-alkyl, cycloalkyl and hydrogen;
R
8cFor-OH, C
1-C
6-alkyl, hydroxyl-C
1-C
6-alkyl or hydrogen atom;
R
9And R
10Be hydrogen atom, C independently
1-C
6-alkyl, aryl, heteroaryl, aryl (C
1-C
6-alkyl)-or heteroaryl (C
1-C
6-alkyl)-; Or R
9And R
10The nitrogen-atoms that links to each other with their forms the heterocycle of 4-8 atom, chooses wantonly and also contains other nitrogen or Sauerstoffatom.
3. claim 1 or 2 compound, wherein R
1Be methyl or ethyl, or hydrogen atom, and R
2Be methyl or ethyl, hydrogen atom or group-Z-Y-R
5, or group-Z-NR
9R
10
4. the compound of claim 3, wherein R
3Be methyl, make coupled nitrogen-atoms be quaternary nitrogen and have positive charge.
5. each compound in the aforementioned claim, wherein, at arbitrary group-R
5,-Y-R
5,-Z-Y-R
5,-Z-NR
9R
10In:
Z is-(CH
2)
1-16-, choosing wantonly by methyl substituted on 3 carbon atoms at the most in this chain;
Y be chemical bond or-O-;
R
5Be the optional following groups that replaces:
Phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, dihydro benzo furyl, naphthyl; Or
Pyridyl, pyrryl, pyrimidyl, oxazolyl, isoxazolyl, benzoisoxazole base, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl-, isothiazolyl, benzisothiazole base, pyrazolyl, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridazinyl, pyridazinyl, triazinyl, indyl or indazolyl; Or
Arylalkyl, wherein this aryl moiety is a phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, dihydro benzo furyl or naphthyl, and this moieties is-CH
2-or-CH
2CH
2-; Or
Heteroarylalkyl, wherein this heteroaryl moieties is pyridyl, pyrryl, pyrimidyl, oxazolyl, isoxazolyl, benzoisoxazole base, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl-, isothiazolyl, benzisothiazole base, pyrazolyl, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridazinyl, pyridazinyl, triazinyl, indyl or indazolyl, and this moieties is-CH
2-or-CH
2CH
2-; Or
Indanyl or 1,2,3, the 4-tetralyl; Or
Heterocyclylalkyl (C
1-C
6-alkyl)-, wherein this Heterocyclylalkyl partly is the piperazinyl such as the methylpiperazine base of azetidinyl, piperidyl, piperazinyl, N-replacement, or the Pyrrolidine base, and this moieties is-CH
2-or-CH
2CH
2-; Or
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group; And
R
9And R
10Be independently
Hydrogen; Methyl, ethyl or n-propyl or sec.-propyl;
Phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, dihydro benzo furyl, naphthyl;
Pyridyl, pyrryl, pyrimidyl, oxazolyl, isoxazolyl, benzoisoxazole base, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl-, isothiazolyl, benzisothiazole base, pyrazolyl, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridazinyl, pyridazinyl, triazinyl, indyl or indazolyl; Or
Arylalkyl, wherein this aryl moiety is a phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, dihydro benzo furyl or naphthyl, and this moieties is-CH
2-or-CH
2CH
2-; Or R
9And R
10The nitrogen-atoms that links to each other with them forms azetidinyl, piperidyl, piperazinyl, N methyl piperazine base, pyrrolidyl, morpholinyl or parathiazan basic ring.
6. claim 1 or 2 compound, wherein, at group-NR
1R
2R
3In, R
1Be methyl or ethyl, R
2Be group-Z-Y-R
5, and R
3Be methyl, make coupled nitrogen by quaternized and have a positive charge.
7. the compound of claim 6, wherein R
5Be the optional phenyl that replaces, Y be chemical bond or-O-, and-Z-is for being by having 12 at the most, or at the most the chain of 9 carbon atoms with nitrogen and-YR
5The straight or branched alkylidene group that connects.
8. each compound, wherein R in the aforementioned claim
4Be group (a), R
6Be methyl or ethyl or hydrogen atom; Ar
1Be phenyl, thienyl, cyclohexyl, cyclopentyl, cyclopropyl or cyclobutyl; R
7aAnd R
7bBe methyl, ethyl, n-propyl or sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, fluorine, chlorine or bromine independently; And m and n are 0,1,2 or 3 independently.
9. each compound, wherein R among the claim 1-7
4Be group (b), and R
8aAnd R
8bCan be independently selected from methyl, ethyl, n-propyl or sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl; Phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxy phenyl, dihydro benzo furyl, naphthyl; Pyridyl, pyrryl, pyrimidyl, oxazolyl, isoxazolyl, benzoisoxazole base, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl-, isothiazolyl, benzisothiazole base, pyrazolyl, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridazinyl, pyridazinyl, triazinyl, indyl or indazolyl; Indanyl and 1,2,3, the 4-tetralyl; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group and hydrogen atom; R
8cBe-OH, hydrogen atom, methyl, ethyl or hydroxymethyl.
10. the compound of claim 9, wherein R
8cFor-OH.
11. the compound of claim 9, wherein (i) R
8aAnd R
8bRespectively do for oneself and choose pyridyl, oxazolyl, thiazolyl, furyl, thienyl or the phenyl that replaces wantonly; Or (ii) R
8aAnd R
8bIn one be the optional phenyl that replaces, and another be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or encircles octyl group; Or (iii) R
8aAnd R
8bIn one be optional pyridyl, thienyl, oxazolyl, thiazolyl or the furyl that replaces, and another cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
12. the compound of claim 9 or 10, wherein R
8aAnd R
8bRespectively do for oneself 2-thienyl or phenyl; Or R
8aAnd R
8bIn one be phenyl, and another is the 2-thienyl.
13. the compound of claim 1, it has formula (IA)
Wherein encircle A and be the optional phenyl ring that replaces; R
8aBe phenyl, thienyl, cyclopentyl or cyclohexyl; R
8bBe phenyl; Thienyl, cyclopentyl or cyclohexyl; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10; Y be chemical bond or-O-, and X
-Be pharmaceutically acceptable negatively charged ion.
14. the compound of claim 1, it has formula (IB)
Wherein encircle B and be the optional phenyl ring that replaces; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10; Y be chemical bond or-O-; And R
6, Ar
1, R
7aAnd R
7bAs above-mentioned definition for group (a); And X-is pharmaceutically acceptable negatively charged ion.
15. the compound of claim 1, it has formula (IC)
Wherein encircle C and be the optional phenyl ring that replaces; Q be Sauerstoffatom ,-CH
2-,-CH
2CH
2-or chemical bond; S be 1,2,3,4,5,6 or 7 and t be 0,1,2,3,4,5,6 or 7, condition is that s+t is not more than 10, and Y be chemical bond or-O-; And X
-Be pharmaceutically acceptable negatively charged ion.
16. each compound in the claim 13,14 or 15, wherein the optional substituting group in ring A or B or C can be selected from alkoxyl group, halogen particularly fluorine or chlorine, C
1-C
3-alkyl, amino C
1-C
3-acyl group, amino C
1-C
3-alkyl and amino-sulfonyl.
17. each compound in the aforementioned claim, its for or be mainly trans-Nei configuration.
18. each compound in the aforementioned claim, it is used for the treatment of.
19. pharmaceutical composition, it comprises among the claim 1-18 each compound and pharmaceutically acceptable carrier or vehicle.
20. the pharmaceutical composition of claim 19, it is the form that is suitable for sucking.
21. each compound is used for the treatment of or prevents wherein to relate to purposes in the medicine of active disease of M3 M-ChR or illness in preparation among the claim 1-18.
22. a treatment wherein relates to the method for active disease of M3 M-ChR or illness, described method comprise to the object effective dosage that these needs are arranged as claim 1-18 in each described compound.
23. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness are respiratory tract obstructions.
24. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness are gastrointestinal tract disorders.
25. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness are cardiovascular disorders.
26. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness are chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperreactivity, pulmonary fibrosis, pulmonary emphysema or rhinallergosis.
27. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness be irritable bowel syndrome, spastic colitis, gastro-duodenal ulcer, gi tract tic or hyperperistalsis, diverticulitis, follow the pain of gastrointestinal smooth muscle meat tissue spasm; Follow the urinary tract obstacle of dysuria to comprise neurogenic frequent micturition, neurogenic bladder, nocturnal enuresis, psychosoma bladder, incontinence, urgent urination or the frequent micturition relevant with cystospasm or chronic cystitis; Motion sickness; And cardiovascular disorder vagus nerve inductive sinus bradycardia for example.
28. the purposes of claim 21 or the methods of treatment of claim 22, wherein said disease or illness are vagus nerve inductive sinus bradycardias.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0525675A GB0525675D0 (en) | 2005-12-16 | 2005-12-16 | Bicyclo[2.2.1]hept-2-ylamine derivatives and their uses |
| GB0525675.5 | 2005-12-16 | ||
| GB0619309.8 | 2006-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101374803A true CN101374803A (en) | 2009-02-25 |
Family
ID=35736293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800530020A Pending CN101374803A (en) | 2005-12-16 | 2006-12-14 | Cyclic amine derivatives and their uses |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101374803A (en) |
| GB (1) | GB0525675D0 (en) |
-
2005
- 2005-12-16 GB GB0525675A patent/GB0525675D0/en active Pending
-
2006
- 2006-12-14 CN CNA2006800530020A patent/CN101374803A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB0525675D0 (en) | 2006-01-25 |
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