CN1286831C - N-ureido-piperidines as antagonists viii for CCR-3 receptor - Google Patents
N-ureido-piperidines as antagonists viii for CCR-3 receptor Download PDFInfo
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- CN1286831C CN1286831C CNB028239784A CN02823978A CN1286831C CN 1286831 C CN1286831 C CN 1286831C CN B028239784 A CNB028239784 A CN B028239784A CN 02823978 A CN02823978 A CN 02823978A CN 1286831 C CN1286831 C CN 1286831C
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention relates to compounds of Formula (I), wherein R1 R5, A, L, and X are as defined in the specification. The compounds are useful as CCR-3 receptor antagonists, and therefore, may be used for treatment of CCR-3 mediated diseases.
Description
The present invention relates to belong to the piperidine derivative of CCR-3 receptor antagonist, the pharmaceutical composition that contains these derivatives, its application and preparation method thereof.
Organizing eosinophilia is the feature of many pathologic conditions, such as asthma, rhinitis, eczema and parasitic infection (referring to Bousquet, J etc. " New England's medicine magazine " are 323:1033-1039 (1990) and Kay (N.Eng.J.Med.), A.B. and Corrigan, C.J. " Britain medicine bulletin " is 48:51-64 (1992) (Br.Med.Bull)).In asthma, eosinophilic granulocyte accumulation and activation and bronchiolar epithelium infringement and relevant to the hyperergy of constrictor mediator.Known such as the such chemokine of RANTES, eotaxin and MCP-3 activate eosinophilic granulocyte (referring to Baggiolini, M. and Dahinden, C.A. " immunology today " is 15:127-133 (1994) (Immunol.Today); Rot, A.M. etc. " experiment medicine magazine " (J.Exp.Med.) 176,1489-1495 (1992); And Ponath, P.D. " Journal of Clinical Investigation " is the 97th volume (J.Clin.Invest.), #3:604-612 (1996)).Yet, different with the RANTES and the MCP-3 that also induce other white corpuscle type migration, eotaxin has selection chemotaxis (referring to Griffith-Johnson, D.A. etc. " biological chemistry and biophysical studies communication " are 207:788 (1994) (Biochem.Biophy.Res.Commun.)) to eosinophilic granulocyte.No matter be to suck by percutaneous injection or peritoneal injection or by aerosol all on the medicine-feeding part of eotaxin, to have observed specific eosinophilic granulocyte and accumulate that (referring to Griffith-Johnson, D.A. etc. " biological chemistry and biophysical studies communication " are 197:1167 (1993) (Biochem.Biophy.Res.Commun.); Jose, P.J. etc. " experiment medicine magazine " (J.Exp.Med.) 179,881-887 (1994); Rothenberg, M.E. etc. " experiment medicine magazine " (J.Exp.Med.) 181,1211 (1995); And Ponath, P.D. " Journal of Clinical Investigation " is the 97th volume (J.Clin.Invest.), #3:604-612 (1996)).
Many diseases relevant have been used for the treatment of such as dexamethasone, methylprednisolone (methprednisolone) and the such glucocorticosteroid of hydrocortisone with eosinophilic granulocyte, comprise bronchial asthma (R.P.Schleimer etc. " U.S. respiratory disease look back " (Am.Rev.Respir.Dis.) 141,559 (1990)).Think that glucocorticosteroid suppresses the eosinophilic granulocyte survival of IL-5 and IL-3 mediation in these diseases.Yet, prolong and use glucocorticosteroid in the patient, to have side effects, such as glaucoma, osteoporosis and retarded growth (referring to Hanania, N.A. etc. " transformation reactions and clinical immunology magazine " (J.Allergy and Clin.Immunol.) the 96th rolls up, 571-579 (1995) and Saha, M.T. etc. " paediatrics journal " (Acta Paediatrica) the 86th rolls up #2,138-142 (1997)).Therefore, need have the another kind of treatment disease relevant and can not cause the therapeutic modality of these bad side effects with eosinophilic granulocyte.
Recently, the CCR-3 acceptor is accredited as eosinophilic granulocyte and is used for it eotaxin, RANTES and the aitiogenic main Chemokine Receptors of MCP-3.Before being transfected into mouse-β lymphoma system in the time, CCR-3 bonded eotaxin, RANTES and MCP-3 have produced chemotactic response to eotaxin, RANTES and MCP-3 (referring to Ponath on these cells, P.D. " experiment medicine magazine " (J.Exp.Med.) 183,2437-2448 (1996)).Expression CCR-3 acceptor and this receptor have high selectivity to eotaxin on eosinophilic granulocyte, T-cell (hypotype Th-2), basophil and mastocyte surface.Studies confirm that with anti--CCR-3 mAb pretreat eosinophilic granulocyte suppressed fully eosinophilic granulocyte to the chemotaxis of eotaxin, RANTES and MCP-3 (referring to heath, H. etc. " Journal of Clinical Investigation " (J.Clin.Invest.) the 99th rolls up #2:178-184 (1997)).The U.S. Pat of being authorized 6 that the applicant obtains, 140,344 and US 6,166,015 and all disclose among the disclosed European application EP903349 on March 24th, 1999 and to suppress the CCR-3 antagonist raised by the eosinophilic granulocyte that causes such as the such chemokine of eotaxin.
Therefore, the ability of blocking-up CCR-3 receptors bind RANTES, MCP-3 and eotaxin and prevent that thus eosinophilic granulocyte from raising the inflammatory diseases that should be the eosinophilic granulocyte mediation treatment means is provided.
The present invention relates to suppress the novel piperidine derivative of eotaxin and CCR-3 receptors bind and disease that anti-eosinophilic granulocyte brings out is provided thus, such as the means of asthma.
The present invention provides racemize and the non-racemic mixture and the pharmaceutically acceptable salt thereof of the compound of general formula (I) or its prodrug, each isomer, isomer in aspect first:
Wherein:
R
1Be (C
1-C
2) alkylidene group;
R
2It is the optional phenyl that replaces;
R
3Be hydrogen, alkyl, acyl group, aryl or aralkyl;
Ring A is cycloalkyl, heterocyclic radical or the optional phenyl that replaces;
L is-C (=O)-,-C (=S)-,-SO
2-,-C (=O) N (R
a)-,-C (=S) N (R
a)-,-SO
2N (R
a)-,-C (=O) O-,-C (=S) O-,-S (=O)
2O-;
R wherein
aBe hydrogen, alkyl, acyl group, aryl, aralkyl, carbalkoxy or carbobenzoxy-(Cbz);
X do not exist, for-(CR ' R ") O-,-(CR ' R ") S-,-(CR ' R ") NR
b-or alkylidene group;
Wherein " independent is hydrogen or alkyl and R for R ' and R
bIt is hydrogen or alkyl;
R
4Be aryl or heteroaryl; And
R
5It is hydrogen or alkyl;
Condition is to work as R
1Be-CH
2-, R
2Be phenyl, R
3Be hydrogen, R
5Be hydrogen, A be phenyl, L be-C (=when O) NH-and X do not exist, R then
4Not 2, the 5-difluorophenyl.
In addition, in above-mentioned defined compound, [they are called hereinafter (i)], preferred following compounds:
The (ii) compound of (i) is the compound of general formula (II):
R wherein
1-R
5, A, L and X such as in (i) definition.
The (iii) compound of (i) is the compound of general formula (III):
R wherein
1-R
5, A, L and X such as in (i) definition.
(iv) any one compound, wherein R in (i)-(iii)
1It is methylene radical.
(v) any one compound, wherein R in (i)-(iii)
2Be 4-chloro-phenyl-or 3, the 4-dichlorophenyl.
(vi) any one compound, wherein R in (i)-(iii)
3Be hydrogen.
(vii) any one compound in (i)-(iii), wherein L be-C (=O)-,-SO
2-,-C (=O) N (R
a)-,-C (=S) N (R
a)-or-C (=O) O-.
(viii) (and compound vii), wherein L be-C (=O)-.
(ix) compound (i) is the compound of general formula (IV):
R wherein
3, R
4, A, L and X such as in (i) definition.
(x) compound (i) is the compound of general formula (VI):
Wherein X and R
4Such as in (i) definition.
(xi) (compound vii), wherein X does not exist, is methylene radical, 1,2-second two bases, 1,3-glyceryl or 1,4-fourth two bases.
(xii) compound (xi), wherein R
4Be 3; the 4-dichlorophenyl; 3; 4; the 5-trimethoxyphenyl; 4-methylsulfonyl phenyl; 3-methylsulfonyl phenyl; 4-methoxynaphthalene-2-base; 5-(3; the 4-Dimethoxyphenyl) pyrimidine-2-base; phenyl; the 3-fluorophenyl; the 4-ethylphenyl; the 3-p-methoxy-phenyl; 2; the 4-difluorophenyl; the 3-trifluoromethyl; the 4-aminomethyl phenyl; the 4-fluorophenyl; the 2-fluorophenyl; 4-formamyl phenyl; 3-formamyl phenyl; the 4-acetylphenyl; the 4-nitrophenyl; the 2-aminomethyl phenyl; 2-chloro-4-fluorophenyl; 3; the 4-Dimethoxyphenyl; 2; the 5-Dimethoxyphenyl; 2; the 3-dichlorophenyl; 2; the 4-dichlorophenyl; the 4-bromophenyl; 4-chloro-3-nitrophenyl; the 2-nitrophenyl; 2-nitro-4-trifluoromethyl; the 4-chloro-phenyl-; the 3-chloro-phenyl-; the 2-chloro-phenyl-; the 3-aminomethyl phenyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; the 3-bromophenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; 3; 5-pair-trifluoromethyl; the 4-tert-butyl-phenyl; the 4-ethoxyl phenenyl; the 3-cyano-phenyl; the 4-cyano-phenyl; the 4-p-methoxy-phenyl; the 3-nitrophenyl; 3; the 5-Dimethoxyphenyl; the 4-iodophenyl; the 4-isopropyl phenyl; 3-methoxycarbonyl phenyl; the 3-acetylphenyl; the 2-aminomethyl phenyl; indoles-2-base; 5-methoxyl group indoles-2-base; 5-chloro-indole-2-base; 2-methoxycarbonyl phenyl; 3; the 5-dichlorophenyl; the 1-naphthyl; 3-chloro-2-aminomethyl phenyl; 2; the 5-3,5-dimethylphenyl; the 2-thienyl; the 3-ethoxyl phenenyl; the 3-isoquinolyl; 2-toluquinoline-6-base; 3-methylamino-phenyl; the 3-quinolyl; the 2-quinolyl; 5-hydroxyl naphthalene-2-base; oxine-2-base; 5; 7-dimethyl-[1; 8] naphthyridine-2-base; the 6-quinolyl; 3-(kharophen) phenyl or 2; 3, the 4-trimethoxyphenyl.
(xiii) compound (xii), wherein R
4Be 3,4,5-trimethoxyphenyl, 4-ethanoyl-phenyl, 3-formamyl phenyl, 4-formamyl phenyl, 3-methylsulfonyl phenyl or 4-methylsulfonyl-phenyl.
(xiv) (compound viii) and salt thereof, wherein X is-CH
2S-and R
4Be 5-(3, the 4-Dimethoxyphenyl)-pyrimidine-2-base, 5-(3, the 4-methylenedioxyphenyl)-pyrimidine-2-base or 5-(4-p-methoxy-phenyl) pyrimidine-2-base.
(xv) compound (i), wherein encircling A is the phenyl of cycloalkyl or heterocyclic radical or replacement.
(xvi) compound (xv), wherein encircling A is cycloalkyl or heterocyclic radical.
(xvii) compound (i), wherein R
2It is the phenyl that replaces.
The present invention provides in aspect second and has contained general formula (I) compound for the treatment of significant quantity or the pharmaceutical composition of its pharmaceutically acceptable salt and pharmaceutically acceptable vehicle.
The present invention provides the preparation method of general formula disclosed herein (I) compound in aspect the 3rd.
The present invention provides the new intermediate that is used to prepare general formula (I) compound disclosed herein in aspect the 4th.
The present invention provides general formula (I) compound or its pharmaceutically acceptable salt that is used for therapeutic treatment or diagnosis (for example being used for the treatment of asthma) in aspect the 5th.
The present invention provides in aspect the 6th general formula (I) compound or its pharmaceutically acceptable salt to be used for the treatment of application in the medicine of mammalian diseases (for example asthma) that can be by giving the treatment of CCR-3 receptor antagonist in preparation.
Except as otherwise noted, used following term has the following implication that provides in this specification sheets and the claim.
" acyl group " refers to group-C (O) R, and wherein R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, and wherein alkyl, cycloalkyl, cycloalkylalkyl and phenylalkyl are as defined herein.Representational example is including, but not limited to formyl radical, ethanoyl, cyclohexyl-carbonyl, cyclohexyl methyl carbonyl, benzoyl, benzyloxycarbonyl group.
" acyl group alkyl " refers to group-alkylidene group-C (O) R, and wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, optional phenyl, benzyl, hydroxyl, alkoxyl group, amino, an alkylamino or the dialkylamino that replaces.Representational example comprises methyl carbonyl-methyl, 2-(ethoxycarbonyl) ethyl, 2-(methoxycarbonyl) ethyl, 2-propyloic.
" amido " refers to group-NR ' C (O) R, and wherein R ' is that hydrogen or alkyl and R are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, and wherein alkyl, cycloalkyl, cycloalkylalkyl and phenylalkyl are as defined herein.Representational example is including, but not limited to formamido group, kharophen, cyclohexyl-carbonyl amino, cyclohexyl methyl-carbonylamino, benzamido, benzyloxycarbonyl group amino.
" alkoxyl group " refers to group-OR, and wherein R is alkyl, for example methoxyl group, oxyethyl group, propoxy-, butoxy as herein defined.
" carbalkoxy " refers to group-C (O)-R, and wherein R is as above-mentioned defined alkoxyl group.
" alkenyl " refers to straight chain monovalence alkyl or the side chain monovalence alkyl of 3-6 carbon atom, for example vinyl, the propenyl of 2-6 the carbon atom that contains two keys at least.
" alkyl " refers to the saturated monovalence alkyl of straight chain of 1-6 carbon atom or the saturated monovalence alkyl of side chain of 3-6 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group.
" alkylamino " or " alkylamino " refers to group-NHR, and wherein R represents alkyl, cycloalkyl or cycloalkyl-alkyl as herein defined.Representational example is including, but not limited to methylamino-, ethylamino, isopropylamino, hexamethylene amino.
" alkylidene group " refers to the saturated bivalent hydrocarbon radical of straight chain of 1-6 carbon atom or the saturated bivalent hydrocarbon radical of side chain of 3-6 carbon atom, for example methylene radical, ethylidene, 2,2-dimethyl ethylidene, propylidene, 2-methyl propylidene, butylidene, pentylidene.
" alkynyl " refers to the straight chain monovalence alkyl that contains at least one triple-linked 2-6 carbon atom or the side chain monovalence alkyl of 3-6 carbon atom.For example, ethynyl, proyl.
" alkyl sulphonyl " refers to group-S (O)
2R, wherein R is alkyl, cycloalkyl or cycloalkyl-alkyl, for example methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl, cyclohexyl alkylsulfonyl as herein defined.
" alkyl sulphinyl " refers to group-S (O) R, and wherein R is alkyl, cycloalkyl or cycloalkyl-alkyl, for example methanesulfinyl, second sulfinyl, third sulfinyl, fourth sulfinyl, cyclohexyl sulfinyl as herein defined.
" alkylthio " refers to group-SR, and wherein R is an alkyl as hereinbefore defined, for example methylthio group, ethylmercapto group, rosickyite base, butylthio.
" aryl " refers to the monocycle or the di pah group of a preferred 6-10 annular atoms; it is optional to be replaced by one or more substituting groups substituting group, preferred 1,2 or 3 substituting groups, described substituting group preferably from alkyl, haloalkyl, hydroxyalkyl, the alkyl of mixing, acyl group, amido, amino, alkylamino, dialkylamino, alkylthio, alkyl sulphinyl, alkyl sulphonyl ,-S (O)
2NR ' R " (wherein R ' and R " is independent be hydrogen or alkyl), the group of alkoxyl group, halogenated alkoxy, carbalkoxy, formamyl, hydroxyl, halogen, nitro, cyano group, sulfydryl, methylene-dioxy or ethylenedioxy composition.In particular, term aryl is including, but not limited to phenyl, chloro-phenyl-, fluorophenyl, p-methoxy-phenyl, 1-naphthyl, 2-naphthyl and derivative thereof.
" arylidene " refers to divalent aryl as hereinbefore defined.
" aralkyl " refers to alkyl as herein defined, and wherein one of hydrogen atom of alkyl is replaced by aryl.Typical aralkyl is including, but not limited to benzyl, 2-benzene second-1-base, naphthyl methyl, 2-naphthalene second-1-base, naphtho-benzyl, 2-naphtho-benzene second-1-base.
" aryloxy " refers to group-O-R-, and wherein R is an aryl as herein defined.
" formamyl " refers to group-C (=O) NH
2
" cycloalkyl " refers to the saturated monovalence cyclic hydrocarbon radical of 3-7 ring carbon, for example cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl.
" cycloalkyl-alkyl " refers to group-R
xR
y, R wherein
xBe alkylidene group and R
yBe cycloalkyl, for example cyclohexyl methyl as herein defined.
" dialkylamino " refers to group-NRR ', and wherein R and R ' represent alkyl, cycloalkyl or cycloalkylalkyl as herein defined independently.Representational example is including, but not limited to dimethylamino, methyl ethylamino, two (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl group) amino, amino, (cyclohexyl methyl) (ethyl) amino of (cyclohexyl methyl) (methyl).
" halogen " refers to fluorine, bromine, chlorine or iodine, preferred fluorine and chlorine.
" haloalkyl " refers to the alkyl that is replaced by one or more identical or different halogen atoms, for example-and CH
2Cl ,-CF
3,-CH
2CF
3,-CH
2CCl
3
" heteroaryl " refers to the monovalence monocycle or the bicyclic groups that contain at least one aromatic ring of 5-12 annular atoms, wherein on described aromatic ring, contain 1,2 or 3 ring hetero atoms that are selected from N, O or S, remaining annular atoms is C, and the tie point that should understand described heteroaryl is positioned on the aromatic ring.This hetero-aromatic ring is optional to be replaced by one or more substituting groups, preferred 1 or 2 substituting groups independently, described substituting group be selected from alkyl, haloalkyl, hydroxyalkyl, assorted alkyl, acyl group, amido, amino, alkylamino, dialkylamino, alkylthio, alkyl sulphinyl, alkyl sulphonyl ,-SO
2NR ' R " (wherein R ' and R " is independent be hydrogen or alkyl), the phenyl of alkoxyl group, halogenated alkoxy, carbalkoxy, formamyl, hydroxyl, halogen, nitro, cyano group, sulfydryl, methylene-dioxy, ethylenedioxy or optional replacement.In particular, the term heteroaryl comprises, but be not limited to pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl isoxazolyl, pyrryl, pyrazolyl, pyrimidyl, 5-(3, the 4-Dimethoxyphenyl)-pyrimidine-2-base, 5-(4-p-methoxy-phenyl)-pyrimidine-2-base, 5-(3, the 4-methylenedioxyphenyl)-pyrimidine-2-base, benzofuryl, the tetrahydrochysene benzfuran base, isobenzofuran-base, benzothiazolyl, the benzisothiazole base, the benzotriazole base, indyl, pseudoindoyl benzoxazolyl, quinolyl, tetrahydric quinoline group, isoquinolyl, benzimidazolyl-, benzoisoxazole base or benzothienyl and derivative thereof.
" inferior heteroaryl " refers to divalence heteroaryl as hereinbefore defined.
" heteroaralkyl " refers to alkyl as herein defined, and wherein one of hydrogen factor of alkyl is replaced by heteroaryl.
" assorted alkyl " refers to alkyl as herein defined, and wherein 1,2 or 3 hydrogen atoms are independently selected from-OR
a,-NR
bR
cWith-S (O)
nR
dThe substituting group of the group that (wherein n is the integer of 0-2) formed replaces, and the tie point that should understand described assorted alkyl is by carbon atom, wherein R
aBe hydrogen, acyl group, alkyl, cycloalkyl or cycloalkylalkyl; R
bAnd R
cIndependently of one another is hydrogen, acyl group, alkyl, cycloalkyl or cycloalkylalkyl; When n is 0, R
dBe hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; And when n is 1 or 2, R
dBe alkyl, cycloalkyl, cycloalkylalkyl, amino, amido, an alkylamino or dialkylamino.Representational example is including, but not limited to 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyl-1-hydroxymethyl ethyl, 2; 3-dihydroxypropyl, 1-hydroxymethyl ethyl, 3-hydroxyl butyl, 2,3-dihydroxy butyl, 2-hydroxyl-1-methyl-propyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonyl ethyl, aminosulfonyl ylmethyl, amino-sulfonyl ethyl, amino-sulfonyl propyl group, methylamino-alkylsulfonyl methyl, methylamino-alkylsulfonyl ethyl, methylamino-alkylsulfonyl propyl group.
" heterocyclic radical " refers to the saturated or undersaturated non-aromatic ring shape group of 3-8 annular atoms, and one of them or two annular atomses are to be selected from NR
x{ R wherein
xIndependent separately is hydrogen, alkyl, acyl group, alkyl sulphonyl, amino-sulfonyl, (alkylamino) alkylsulfonyl, (dialkylamino) alkylsulfonyl, formamyl, (alkylamino) carbonyl, (dialkylamino) carbonyl, (formamyl) alkyl, (alkylamino) carbonylic alkyl or dialkylamino carbonylic alkyl }, O or S (O)
nThe heteroatoms of (wherein n is the integer of 0-2), remaining annular atoms is C.This heterocycle can be chosen wantonly independently by 1,2 or 3 substituting groups and replace, described substituting group be selected from alkyl, haloalkyl, assorted alkyl, halogen, nitro, cyano group alkyl, hydroxyl, alkoxyl group, amino, an alkylamino, dialkylamino, aralkyl ,-(X)
n(wherein X is O or NR ' to-COR, n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, amino, an alkylamino, dialkylamino or the optional phenyl that replaces, and R ' is a hydrogen or alkyl) ,-alkylidene group-COR (wherein R is hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, amino, an alkylamino, dialkylamino or the optional phenyl that replaces) or-S (O)
nR
d(wherein n is the integer of 0-2, and R
dBe hydrogen (condition is that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, an alkylamino, dialkylamino or hydroxyalkyl).In particular, the term heterocyclic radical is including, but not limited to THP trtrahydropyranyl, piperidino-(1-position only), N-methyl piperidine-3-base, Piperazino, N-methylpyrrolidin-3-base, 3-pyrrolidino, morpholino, thiomorpholine generation, thiomorpholine generation-1-oxide compound (thiomorpholino-1-oxide), thiomorpholine generation-1,1-dioxide (thiomorpholino-1,1-dioxide), tetrahydro-thienyl-S, S-dioxide (tetrahydrothiophenyl-S, S-1,1-dioxide), pyrrolinyl, imidazolinyl and derivative thereof.
" hydroxyalkyl " refers to the alkyl that replaced by one or more, preferred 1,2 or 3 hydroxyls as hereinbefore defined, and condition is not carry an above hydroxyl on the same carbon atom.Representational example is including, but not limited to 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(methylol)-2-methyl-propyl, 2-hydroxyl butyl, 3-hydroxyl butyl, 4-hydroxyl butyl, 2,3-dihydroxypropyl, 2-hydroxyl-1-hydroxymethyl ethyl, 2,3-dihydroxy butyl, 3,4-dihydroxy butyl and 2-(methylol)-3-hydroxypropyl, preferred 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(methylol)-2-hydroxyethyl.Therefore, term used herein " hydroxyalkyl " is used to define the subclass of assorted alkyl.
" leaving group " has usually and its implication relevant in synthetic organic chemistry, i.e. atom that can be replaced by nucleophile or group and comprise: halogen (such as chlorine, bromine, iodine), alkane sulfonyloxy, arylsulfonyloxy, alkyl carbon acyloxy (for example acetoxyl group), aryl-carbonyl oxygen, mesyloxy, tosyloxy, trifluoro-methanesulfonyl oxy, aryloxy (for example 2,4-2,4-dinitrophenoxy base), methoxyl group, N, O-dimethyl hydroxyl amino.
" optional replace phenyl " refers to optional by one or more substituting groups, preferred 1,2 or 3 phenyl that substituting group replaces, described substituting group preferably from alkyl, haloalkyl, hydroxyalkyl, assorted alkyl, acyl group, amido, amino, alkylamino, dialkylamino, alkylthio, alkyl sulphinyl, alkyl sulphonyl ,-SO
2NR ' R " (wherein R ' and R " is independent be hydrogen or alkyl), the group of alkoxyl group, halogenated alkoxy, carbalkoxy, formamyl, hydroxyl, halogen, nitro, cyano group, sulfydryl, methylene-dioxy or ethylenedioxy composition.In particular, this term is including, but not limited to phenyl, chloro-phenyl-, fluorophenyl, bromophenyl, aminomethyl phenyl, ethylphenyl, p-methoxy-phenyl, cyano-phenyl, 4-nitrophenyl, 4-trifluoromethyl, 4-chloro-phenyl-, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-aminomethyl phenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl and derivative thereof.
" choose wantonly " or " randomly " refers to that described result in back or situation can take place but and nonessential will take place and this description comprises the example that example that described result or situation take place and they do not take place.For example, " optional replaced or dibasic aryl by the alkyl list " refers to that alkyl can exist but and the situation that nonessential existence and this description comprise that aryl is replaced by the alkyl list or dibasic situation and aryl are not replaced by alkyl.
" pharmaceutically acceptable vehicle " refers to the vehicle that is used for pharmaceutical compositions, it generally be safe, avirulent and both abiotic on also non-others unwanted and comprising veterinary drug is used and people's medicine is used acceptable vehicle.This class vehicle that comprises one or more at this specification sheets and used " the pharmaceutically acceptable vehicle " of claim.
" the pharmaceutically acceptable salt " of compound refers to pharmaceutically acceptable and has the salt of the pharmacologically active of required parent compound.This class salt comprises: the salt of the sour addition that (1) and mineral acid form, and described mineral acid is all if any hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Or the salt of the sour addition that forms with organic acid, described organic acid is all if any acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, 4-methyl bicyclic [2.2.2]-oct-2-ene-1-formic acid, glucoheptonic acid, the 3-phenylpropionic acid, trimethylacetic acid, tetrabutyl acetate, dodecyl sulphate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.; Or the salt of (2) formation when the acid proton that exists on the parent compound is replaced by metal ion, for example alkalimetal ion, alkaline-earth metal ions or aluminum ion; Or the ligand that forms with organic bases, such as thanomin, diethanolamine, trolamine, Trometamol, N-methylglucosamine.
" phenylalkyl " refers to alkyl as herein defined, and wherein the phenyl that is optionally substituted of one of hydrogen atom of alkyl replaces.
" protecting group " refers to when covering, reduce when reactive group on the molecule is connected or stoping its reactive atomic group.The example of protecting group can be rolled up in (John Wiley and Sons.1971-1996) and find " protecting group in the organic chemistry " (Protective Groups in Organic Chemistry) (Wiley, the 2nd edition 1999) of T.W.Greene and P.G.Futs and " synthetic organic method summary " (Compendium of SyntheticOrganic Methods) 1-8 of Harrison and Harrison etc.Representational amino protecting group comprises trityl, allyloxy carbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), the nitro-veratryl oxygen base carbonyl (NVOC) of formyl radical, ethanoyl, trifluoroacetyl group, benzyl, carbobenzoxy-(Cbz) (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethylsulfonyl (SES), trityl and replacement.Representational hydroxyl protecting group comprises those acylated hydroxies or alkylating group, such as benzyl and trityl ethers and alkyl ether, THP trtrahydropyranyl ethers, trialkylsilyl ethers class and allyl ether series.
Disease " treatment " or " therapy " comprising: (1) preventing disease, that is: making may contact or susceptive disease but do not take place as yet or the mammiferous disease clinical symptom that demonstrates disease symptoms does not take place; (2) suppress disease, that is: stop or slow down disease or the development of its clinical symptom; Or (3) palliate a disease, that is: disease or its clinical symptom are disappeared.
" treatment significant quantity " refers to when the Mammals administration is enough to carry out the compound amount of this class to treatment of diseases when treating disease." treatment significant quantity " is with compound, disease and severity thereof different change the with treat mammiferous age, body weight etc.
" prodrug " refers to any compound that discharges the active parent drug of general formula (I) when giving mammalian subject with this class prodrug in vivo.Be present in the prodrug that functional group on general formula (I) compound prepares general formula (I) compound by modification, can make modifier cleaved in vivo and discharge parent compound according to this class mode.Prodrug comprises the compound of general formula (I), and hydroxyl, amino or the sulfhedryl on its formula of (I) compound is connected and regenerates free hydroxyl group, amino or sulfhedryl respectively with any group of cracked in vivo.The example of prodrug is including, but not limited to the ester class (for example acetic ester, manthanoate and benzoate derivatives) of the hydroxyl-functional base on general formula (I) compound, amino formate (for example N, N-dimethylamino carbonyl).
Has the same molecular formula but the order of connection of character or its atom or its atoms in space are arranged different compounds and be called " isomer ".The isomer that the atom spatial disposition is different is called " steric isomer ".Each other for the steric isomer of non-mirror image is called " diastereomer ", and those are be called " enantiomorph " of non-superimposable mirror image each other.When compound had asymmetric center, if for example the different groups with 4 of carbon atom connect, it was right then may to form enantiomorph.Enantiomorph is characterised in that the absolute configuration of its asymmetric center and the R-by Cahn and Prelog and S-sequence rule or describes and called after dextrorotation or left-handed (promptly being respectively (+) or (-)-isomer) around the mode of polarization plane rotation by molecule.The form that chipal compounds can be used as each enantiomorph or its mixture exists.The mixture that contains the equal proportion enantiomorph is called " racemic mixture ".
Compound of the present invention can have one or more asymmetric centers; This compounds can be used as each (R)-and (S)-steric isomer thus or produces as its mixture.Except as otherwise noted, in this specification sheets and the claim to the description of specific compound or name in order to comprising each enantiomorph and mixture, otherwise be exactly its racemoid.The stereochemical mensuration of steric isomer and separation method are well-known (referring to the discussion in the 4th edition the 4th chapter of " senior organic chemistry " (" Advanced Organic Chemistry ") in the art, J.March, John Wiley and Sons, New York, 1992).The nomenclature that used nomenclature is generally recommended based on IUPA among the application.For example, incite somebody to action wherein R
1Be methylene radical, R
2It is the 4-chloro-phenyl-; L is C (=O) NH; X does not exist; A is a cyclopentyl; R
3Be hydrogen; And R
4Be compound called after (±)-anti-form-1-{ 2-[4-(4-chloro-phenyl-) piperidines-1-yl] the cyclopentyl }-3-quinoline-2-base-urea of the general formula (I) of 2-quinolyl (compound in the table 1).
Representational general formula (I) compound is as shown in following table.
Table I
Although above described extensive definition of the present invention, some in the compound of preferred formula (I).
The preferred compound of the present invention is the compound of general formula (I), wherein R
1It is methylene radical.
One aspect of the present invention relates to the compound of general formula (I), and wherein encircling A is the phenyl of cycloalkyl, heterocyclic radical or replacement.The preferred compound of another kind of the present invention is the compound of general formula (I), and wherein encircling A is cyclopentyl.The ring A be cyclopentyl compound unexpectedly forcefully with the CCR-3 receptors bind.Other preferred compound of the present invention is: the compound of general formula (I), wherein encircle A and be heterocyclic radical (particularly THP trtrahydropyranyl, S, S-dioxo-tetrahydro-thienyl, tetrahydro-thienyl or pyrrolidyl); Or the compound of general formula (I), wherein encircling A is the phenyl that replaces.
Preferred compounds of the invention are the compound of general formula (I), wherein R
2By 1 or 2 phenyl ring that substituting group replaces, described substituting group is selected from: alkyl, alkoxyl group, haloalkyl, halogen, cyano group or nitro; Preferable methyl, ethyl, methoxyl group, trifluoromethyl, chlorine, fluorine or bromine; Most preferably 4-nitrophenyl, 4-trifluoromethyl, 4-chloro-phenyl-, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-aminomethyl phenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl.Particularly preferably be 4-chloro-phenyl-or 3, the 4-dichlorophenyl.
The preferred compound of the present invention is the compound of general formula (I), wherein R
3Be hydrogen or methyl, preferred hydrogen.
The preferred compound of the present invention is the compound of general formula (I), wherein L be-C (=O)-,-SO
2-,-C (=O) N (R
a)-,-C (=S) N (R
a)-or-C (=O) O-.More preferably wherein L be-C (=) O-,-C (=O) N (R
a)-compound; Most preferably L is-C (=O) N (R
a)-compound.Hereinbefore, R
aPreferably hydrogen or methyl, most preferably hydrogen.
The preferred compound of the present invention is the compound of general formula (I), and wherein X does not exist, is methylene radical, 1,2-second two bases, 1,3-glyceryl or 1,4-fourth two bases.
The preferred compound of the present invention is the compound of general formula (I), wherein R
4Be the optional phenyl that replaces, the optional heteroaryl that replaces, wherein said hetero-aromatic ring is the pyrimidine-2-base of indyl, thienyl, quinolyl, replacement, for example (5-(3, the 4-Dimethoxyphenyl) pyrimidine-2-base, 5-(3, the 4-methylene-dioxy) 8-phthalazinyl pyrimidine-2-base or 5-(4-p-methoxy-phenyl) pyrimidine-2-base) or 1.Preferred R
4Be selected from 3; the 4-dichlorophenyl; 3; 4; the 5-trimethoxyphenyl; 4-methylsulfonyl-phenyl; 3-methylsulfonyl phenyl; 4-methoxynaphthalene-2-base; 5-(3; the 4-Dimethoxyphenyl) pyrimidine-2-base; phenyl; the 3-fluorophenyl; the 4-ethylphenyl; the 3-p-methoxy-phenyl; 2; the 4-difluorophenyl; the 3-trifluoromethyl; the 4-aminomethyl phenyl; the 4-fluorophenyl; the 2-fluorophenyl; 4-formamido group phenyl; the 4-acetylphenyl; the 4-nitrophenyl; the 2-aminomethyl phenyl; 2-chloro-4-fluorophenyl; 3; the 4-Dimethoxyphenyl; 2; the 5-Dimethoxyphenyl; 2; the 3-dichlorophenyl; 2; the 4-dichlorophenyl; the 4-bromophenyl; 4-chloro-3-nitrophenyl; the 2-nitrophenyl; 2-nitro-4-trifluoromethyl; the 4-chloro-phenyl-; the 3-chloro-phenyl-; the 2-chloro-phenyl-; the 3-aminomethyl phenyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; the 3-bromophenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; 3; 5-pair-trifluoromethyl; the 4-tert-butyl-phenyl; the 4-ethoxyl phenenyl; the 3-cyano-phenyl; the 4-cyano-phenyl; the 4-p-methoxy-phenyl; the 3-nitrophenyl; 3; the 5-Dimethoxyphenyl; the 4-iodophenyl; the 4-isopropyl phenyl; 3-methoxycarbonyl phenyl; the 3-acetylphenyl; the 2-aminomethyl phenyl; indoles-2-base; 5-methoxyl group indoles-2-base; 5-chloro-indole-2-base; 2-methoxycarbonyl phenyl; 3; the 5-dichlorophenyl; the 1-naphthyl; 3-chloro-2-aminomethyl phenyl; 2; the 5-3,5-dimethylphenyl; the 2-thienyl; the 3-ethoxyl phenenyl; the 3-isoquinolyl; 2-toluquinoline-6-base; 3-methylamino-phenyl; the 3-quinolyl; the 2-quinolyl; 5-hydroxyl naphthalene-2-base; oxine-2-base; 5; 7-dimethyl-[1; 8] naphthyridine-2-base; the 6-quinolyl; 3-(kharophen) phenyl or 2; 3, the 4-trimethoxyphenyl.Preferred especially R
4Be trimethoxyphenyl, for example 3,4,5-trimethoxyphenyl, 4-ethanoyl-phenyl, 4-formamido group-phenyl and 4-methylsulfonyl-phenyl.
Preferably so in addition compounds, wherein X is-CH
2S-,-CH
2O-,-CH
2CH
2-and R
4Be heteroaryl, preferred optional pyrimidyl, pyrazolyl or the thienyl that replaces.Preferred especially some compounds like this, wherein X is-CH
2S-and R
4Be 5-(3, the 4-Dimethoxyphenyl) pyrimidine-2-base, 5-(3, the 4-methylenedioxyphenyl) pyrimidine-2-base, 5-(4-p-methoxy-phenyl) pyrimidine-2-base.
The specific compound of general formula (I) is the compound of general formula (II):
R wherein
1-R
5, A, L and X have any implication as described herein.
The specific compound of general formula (I) is the compound of general formula (III):
R wherein
1-R
5, A, L and X have any implication as described herein.
The specific compound of general formula (I) is the compound of general formula (IV):
R wherein
3, R
4, A, L and X have any implication as described herein.
The specific compound of general formula (I) is the compound of logical formula V:
Wherein X and R
4Has any implication as defined herein.
The specific compound of general formula (I) is the compound of general formula (VI):
Wherein X and R
4Any implication with this paper definition.
The specific compound of general formula (I) is the compound of general formula (VII):
Wherein X and R
4Any implication with this paper definition.
The specific compound of general formula (I) is the compound of general formula (VIII):
Wherein X and R
4Any implication with this paper definition; And R
xBe hydrogen, alkyl, acyl group, alkyl sulphonyl, amino-sulfonyl, (alkylamino) alkylsulfonyl, (dialkylamino) alkylsulfonyl, formamyl, (alkylamino) carbonyl, (dialkylamino) carbonyl, (formamyl) alkyl, (alkylamino) carbonylic alkyl or dialkylamino carbonylic alkyl.
The specific compound of general formula (I) is the compound of general formula (IX):
Wherein X and R
4Any implication with this paper definition.
The specific compound of general formula (I) is the compound of general formula (X):
Wherein X and R
4Any implication with this paper definition.
The particularly preferred compound of the present invention is:
Anti-form-1-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-(3,4,5-trimethoxy-phenyl) urea hydrochloride;
Anti-form-1-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetrahydrochysene-furans-3-yl }-3-(3,4,5-trimethoxy-phenyl) urea;
(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxyl-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) urea;
(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-methylol-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) urea; With
(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-methoxymethyl-cyclopentyl }-3-(3,4,5-trimethoxy-phenyl) urea;
Or
The racemize of its prodrug, each isomer, isomer and non-racemic mixture and pharmaceutically acceptable salt thereof.
Compound of the present invention is that CCR-3 receptor antagonist and the eosinophilic granulocyte that suppresses to cause by the CCR-3 chemokine, such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4 are raised.Compound of the present invention is used for the treatment of the disease that eosinophilic granulocyte brings out with the composition that contains them, such as inflammatory diseases or anaphylactic disease and comprise: the respiratory tract anaphylaxis disease, such as asthma, allergic rhinitis, hypersensitivity tuberculosis, hypersensitivity pneumonitis, eosinophilic pneumonia (for example chronic eosinophilic pneumonia); Inflammatory bowel (for example regional ileitis and ulcerative colitis); And psoriatic and inflammatory dermatosis, such as dermatitis and eczema.
Can be by in vitro tests, such as the part more specifically described in embodiment 45,46 and 47 CCR-3 antagonistic activity in conjunction with test and chemotaxis test determination The compounds of this invention.As the asthma Balb/c mouse model test activity in vivo of more specifically describing among the embodiment 48 that brings out at ovalbumin.
In general, can treat the The compounds of this invention of significant quantity by any acceptable mode that is used for the promoting agent of similar application.The compounds of this invention, be that the actual amount of active ingredient depends on many factors, such as the severity of treatment disease, experimenter's age and effect, route of administration and mode and the other factors of relative health condition, compound used therefor.
The treatment significant quantity of general formula (I) compound can be in about 0.01-20mg/ kg body weight recipient/sky, preferred about 0.1-10mg/kg/ days scope.Therefore, with regard to regard to people's administration of 70kg, dosage range is most preferably about 7mg-0.7g/ days scope.
In general, can be with compound of the present invention as pharmaceutical composition by the administration of one of following any route of administration: oral, through skin, suction (for example in the nose or oral cavity sucks) or non-enteron aisle (for example intramuscular, intravenously or subcutaneous) administration.Preferred administering mode is to use that every day, dosage was oral easily, and this dosage can be adjusted according to the degree of sufferer.These compositions can adopt tablet, pill, capsule, semisolid, pulvis, sustained release preparation, solution, suspensoid, liposome, elixir or other suitable compositions form arbitrarily.The another kind of preferred administering mode of The compounds of this invention is to suck.This is a kind of promoting agent directly to be transported to respiratory tract with treatment such as the effective means (referring to U.S. Pat 5,607,915) of asthma and other similar with respiratory tract disease or relevant sample disease.
Various factors is depended in selection to preparation, such as the bioavailability of administering mode and drug substance.In order to transport by suction, the administrable dispenser that described compound is mixed with liquor or suspension, aerosol propellant or dry powder and packs into suitable.Three types medicinal inhalation devices-nebulizer, metered-dose inhaler (MDI) and Diskus (DPI) are arranged.The nebulizer device produces high velocity air, and this air-flow makes therapeutical agent (being mixed with liquid form) be the atomizing ejection and carries respiratory tract into the patient.MDI ' s generally has the preparation of packing with pressurized gas.When opening, this device discharges quantitative therapeutical agent by pressurized gas, and the reliable method that can give quantitative promoting agent is provided thus.DPI ' s gives therapeutical agent with free-pouring powder type, and this powder can be dispersed in respiratory in the air-flow of patient's suction by described device.For the mobile powder that gains freedom, with vehicle, such as lactose preparation therapeutical agent.Quantitative therapeutical agent is stored in the capsule and when each the startup, distributes to the patient.Recently, especially to the medicine of bioavailability extreme difference based on having researched and developed pharmaceutical preparation by the principle that increases surface-area, promptly reduces granular size and increase bioavailability.For example, U.S. Pat 4,107 has been described in 288 and has been had 10-1, and the pharmaceutical preparation of 000nm magnitude range wherein makes active substance be fixed on the cross-linked macromolecular matrix.U.S. Pat 5,154, described the production method of pharmaceutical preparation in 684, wherein under the situation that has surface-modifying agent to exist, drug substance has been ground into nano particle (mean particle size is 400nm) and makes them be dispensed into the pharmaceutical preparation that liquid medium obtains showing high bioavailability then.
Composition generally is made up of the compound and at least a pharmaceutically acceptable vehicle of general formula (I).Acceptable vehicle is that avirulent, auxiliary administration and treatment beneficial effect that can mutual-through type (I) compound produce detrimentally affect.This class vehicle can be solid, liquid, semisolid or be the general available gaseous state vehicle of those skilled in the art with regard to aerosol composition arbitrarily.
The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, skim-milk.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and various oil, comprise those oil that derive from oil, animal, plant or synthetic source, for example peanut oil, soybean oil, mineral oil, sesame wet goods.Preferred liquid vehicle, the liquid vehicle of particularly using Injectable solution comprise water, salt solution, D/W and glycols.
Coercible gas can be used for the The compounds of this invention of dispersed gas solation.The rare gas element that is suitable for this purpose is nitrogen, carbonic acid gas etc.
With regard to the liposomal pharmaceutical preparation that is used for non-enteron aisle or oral transhipment, medicine and lipid are dissolved in appropriate organic solvent, for example the trimethyl carbinol, hexanaphthene (1% ethanolic soln).With this solution freeze-drying and make lipid mixtures be suspended in the water-containing buffering liquid and make it to form liposome.If necessary, can reduce the liposome size by sonication.(referring to Frank Szoka, Jr. with Demetrios Papahadjopoulos, " relative nature and the preparation method of lipid vesicle (liposome) " (" Comparative Properties andMethods of Preparation of Lipid Vescles (Liposomes) ")-" biophysics is looked back in the biotechnology yearbook " (Ann.Rev.Biophys Bioeng), 9:467-508 (1980); And D.D.Lasic, " the new application of liposome " (" Novel Applications of Liposomes ")-" biotechnology trend " (Trends in Biotech), 16:467-608 (1998)).
Drug excipient that other is suitable and preparation thereof are described among " RemingtonShi pharmaceutical science " (Remington ' s Pharmaceutical Sciences) (Mack PublishingCompany, the 18th edition, 1990) that E.W.Martin edits.
The concentration of compound in preparation can change in the wide region that those skilled in the art use.In general, preparation contains by weight general formula (I) compound that (wt%) accounts for total weight of formulation 0.01-99.99%, and equipoise is one or more suitable drug excipients.The content of preferred described compound is about the level of 1-80%.The representational pharmaceutical preparation that contains general formula (I) compound is described among the embodiment 44.
Can prepare compound of the present invention according to many modes known in those skilled in the art.Preferable methods is including, but not limited to following general synthesis step.
The raw material and the reagent merchant that are used to prepare these compounds are enough in goods providers, such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, CA), EnikaChemie or Sigma (St.Louis, MO, USA), Maybridge (Dist:Ryan Scientific, P.O.Box 6496, Columbia, S.C.92960), Bionet Research Ltd., (Cornwall PL32 9QZ, UK), Menai Organics Ltd., (Gwynedd, N.Wales, UK), Butt Park Ltd., (Dist.Interchim, Montlucon Cedex is France) or by method known in those skilled in the art, prepare according to the step described in the following reference: such as " organic synthesis reagent " (Reagents for Organic Synthesis) of Fieser and Fieser, 1-17 rolls up (John Wiley and Sons, 1991); " chemistry of carbon compound " of Rodd (Chemistry of Carbon Compounds), 1-5 volume and supplementary issue (Elsevier Science Publishers, 1989); " organic reaction " (Organic Reactions), 1-40 rolls up (John Wiley and Sons, 1991); " senior organic chemistry " (AdvancedOrganic Chemistry) of March, (John Wiley and Sons, 1992); " comprehensive organic transformation " (Comprehensive Organic Transformations) (VCH Publishers Inc., 1989) with Larock.These synthetic schemess only are the illustrating and for reference the disclosure of the specification those skilled in the art, can carry out various improvement and can expect these improvement these synthetic schemess of method that can synthesize The compounds of this invention concerning some.
If desired, can use routine techniques, separate and the raw material and the intermediate of purification reaction including, but not limited to filtration, distillation, crystallization, chromatogram.Use usual manner, comprise that physical constant and spectroscopic data characterize this class raw material.
Synthesizing of general formula (I) compound
The compound that generally prepares general formula (I) as follows by the precursor amine of general formula (Ia).
Below synthetic schemes 1-8 middle distance the preparation of general formula (Ia) compound has been described and to the conversion of compound of Formula I.
Synthetic schemes 1-5 represents to have the preparation method of the compound of Formula I of different rings A.Concrete typical example, wherein R are provided in preparation 1-6
1-R
2It is 4-benzyl chloride base.Those skilled in the art are easy to prepare similar compounds according to the reference of this specification sheets and introducing, wherein R
1And R
2In four corner of the present invention, change.
Synthetic-ring A=the phenyl of synthetic schemes 1. ring butylamine classes
Synthetic-ring A=the cyclopentyl and the cyclohexyl of synthetic schemes 2. cis two amines
Synthetic-ring A=cyclopentyl, tetrahydrofuran base, pyrrolidyl or the tetrahydro-thienyl of synthetic schemes 3. trans two amines
The amino-alkylation that general method A:(uses epoxide to carry out)
Under 80-95 ℃ with amine R
2NH (1 equivalent) and concrete epoxide 3a (1.1-10 is quantitative) are dissolved in the resulting 0.5-1.5M solution stirring of ethanol 2-4.5 days, and this system is cooled to room temperature and concentrated.By chromatography or the thick amino alcohol of recrystallization method purifying.
General method B:(uses methylsulfonyl chloride and ammonium hydroxide to form amine)
Under 0 ℃, use Et
3N (2 equivalent) and MeSO
2Cl (2 equivalent) handles described amino alcohol (1 equivalent) successively and is dissolved in CH
2Cl
2Resulting 0.2-0.3M solution, this system was stirred 1-2 hour down and makes it be distributed in CH at 0 ℃
2Cl
2With 10-15%NH
4Between the OH.Use CH
2Cl
2Extract water and drying and concentrated extract.Under 70-80 ℃, resistates is dissolved in 2.5: 1 dioxs: 28-30wt%NH
4The resulting 0.13M solution stirring of OH 2.5-18 hour is cooled to room temperature and concentrated with this system.Resistates is distributed between EtOAc and the 1N NaOH, extracts water and use salt water washing extract, drying also to concentrate with EtOAc.By the chromatography purification crude product or without being further purified use.
(is this correct for the A=tetramethylene sulfone that synthesizes-encircle of synthetic schemes 4. sulfones?)
Synthetic-ring A=the phenyl of synthetic schemes 5. aniline
R
2NH=4-(4-benzyl chloride base) piperidyl
The preparation method of synthetic schemes 6 and the substituted general formula I a of 7 representative ring A compound.Synthetic schemes 6 expression contains the preparation method of general formula I a compound of the cyclopentyl ring A of replacement.Synthetic schemes 7 expressions produce the general formula I a compound that the tetramethyleneimine 7b preparation that replaces contains the pyrrolidine ring A of replacement by handle unsubstituted tetramethyleneimine 7a (R=H) with suitable reagent.
Synthesizing of synthetic schemes 6. cycloalkyl derivatives
Synthesizing of synthetic schemes 7. pyrrolidin derivatives
Synthetic schemes 8 and 9 represents the compound of general formula (Ia) is changed into the method for the compound of general formula (I), and wherein L and A are variable.
Synthetic schemes 8. primary amine classes are to the conversion of ureas and benzamides
(typical situation is R with synthetic schemes as follows 8
4Be 3,4,5-trimethoxyphenyl) and general method C and D prepare the compound of general formula (I), wherein L is-C (=O) NR
aAnd X does not exist.(typical situation is R with synthetic schemes as follows 8
4Be 3,4,5-trimethoxyphenyl) and general method E and F prepare the compound of general formula (I), wherein L be-C (=O)-and X do not exist.
General method C:(uses isocyanates to form urea)
Be dissolved in CH with concrete isocyanic ester (1.1-2 equivalent) processing described amine (1 equivalent) under 0-20 ℃
2Cl
2Or CH
2Cl
2With the resulting 0.1-0.6M solution of DMF, this system was stirred 0.5-1.5 hour and make it be distributed in CH
2Cl
2With NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.Be used for next step by column chromatography or preparation type TLC purifying urea crude product or without being further purified.
General method D:(uses isocyanates to form urea, salify subsequently)
Be dissolved in CH with concrete isocyanic ester (1.1-2 equivalent) processing described amine (1 equivalent) under 0-20 ℃
2Cl
2Or CH
2Cl
2With the resulting 0.1-0.6M solution of DMF, this system was stirred 0.5-1.5 hour and make it be distributed in CH
2Cl
2With NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.Be used for next step by column chromatography or preparation type TLC purifying urea crude product or without being further purified.Et with 1N HCl
2The described free alkali of O solution-treated is dissolved in CH
2Cl
2Resulting solution also is concentrated into and obtains hydrochloride.
General method E:(uses I-hydroxybenzotriazole and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride to form acid amides)
With I-hydroxybenzotriazole hydrate (HOBt) (0.2-0.5 equivalent) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (DEC) (1.3-2 equivalent) handles successively that down described amine (1 equivalent) and concrete carboxylic acid (1.2-1.5 equivalent) are dissolved in CH at 0 ℃
2Cl
2Resulting 0.1-0.4M solution descended this system stirring 2-72 hour and made it be distributed in CH at 0-20 ℃
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By column chromatography and/or the described acid amides crude product of preparation type TLC purifying.
General method F:(uses I-hydroxybenzotriazole and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride to form acid amides, salify subsequently)
With I-hydroxybenzotriazole hydrate (HOBt) (0.2-0.5 equivalent) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (DEC) (1.3-2 equivalent) handles successively that down described amine (1 equivalent) and concrete carboxylic acid (1.2-1.5 equivalent) are dissolved in CH at 0 ℃
2Cl
2Resulting 0.1-0.4M solution descended this system stirring 2-72 hour and made it be distributed in CH at 0-20 ℃
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By column chromatography and/or the described acid amides crude product of preparation type TLC purifying.Et with 1N HCl
2The described free alkali of O solution-treated is dissolved in CH
2Cl
2Resulting solution also is concentrated into and obtains hydrochloride.
Synthetic schemes 9 and the following step G-O have described the different methods that is used for the compound of general formula (Ia) is changed into the compound of general formula (I), and wherein L is variable.
The parallel of general method G:(sulfonamides synthesized)
Needed amine Ia (1 equivalent), suitable SULPHURYL CHLORIDE (1.5 equivalent) and Amberlite IRA67 (2 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture rotation is spent the night.(CA USA) handles this mixture and rotation is spent the night for Argonaut Technologies Inc., San Carlos with PS-triamine (1.2 equivalent).By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to obtaining product.
General method H:(is by the parallel synthesizing amide class of chloride of acid class)
Needed amine Ia (1 equivalent), suitable chloride of acid (1.5 equivalent) and Amberlite IRA67 (2 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture rotation is spent the night.(CA USA) handles this mixture and rotation is spent the night for Argonaut Technologies Inc., San Carlos with PS-triamine (1.2 equivalent) and MP-carbonic ether (2 equivalent).By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to obtaining product.
General method I:(is by the parallel synthesizing amide class of carboxylic-acid)
(CA USA) is dissolved in CH for Argonaut Technologies Inc., San Carlos with needed amine Ia (1 equivalent), the carboxylic acid (1.5 equivalent) that suits and PS-carbodiimide (2 equivalent)
2Cl
2(2ml) resulting mixture rotation is spent the night.With MP-carbonic ether (2 equivalent) handle this mixture and the rotation spend the night.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to obtaining product.
General method J:(is by the parallel synthetic ureas of isocyanates and by parallel chromatography purification)
Needed amine Ia (1 equivalent) and suitable isocyanic ester (1.2 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture stirs and spends the night.Concentrate this compound to obtaining crude product, by using step gradient (2.5%MeOH/CH
2Cl
2, 10%MeOH/CH
2Cl
2) this crude product of parallel chromatography purification.
General method K:(is by the parallel synthetic ureas of isocyanates and with capturing and release scavenging agent purifying (Catch and Release Scavenger))
Needed amine Ia (1 equivalent) and suitable isocyanic ester (1.2 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture stirs and spends the night.Handle this mixture and rotated 3 hours with MP-TsOH.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.With this solid and 2M NH
3MeOH solution rotated together 2 hours.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to the product that obtains purifying.
General method L:(uses the Phoxime resin by the parallel synthetic ureas of phenyl amines)
Suitable aniline (3 equivalent) and Phoxime resin (1 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture rotation is 3 hours.If aniline does not dissolve, then add triethylamine (3.5 equivalent).This mixture rotation is spent the night.By solid collected by filtration and use CH
2Cl
2, MeOH, CH
2Cl
2, MeOH and CH
2Cl
2Washing.This solid and needed amine IA (1.1 equivalent) are dissolved in CH
2Cl
2(0.5ml) and the resulting mixture of toluene (1.5ml) 80 ℃ of down heating, jolting is simultaneously spent the night and this system is cooled to room temperature.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to obtaining product.
General method M:(uses triphosgene by the parallel synthetic ureas of phenyl amines)
Suitable aniline (1.2 equivalent), triphosgene (0.4 equivalent) and triethylamine (1.4 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture heated 1 hour down at 35 ℃.After being cooled to room temperature, add needed amine Ia (1 equivalent).H is spent the night, uses in this mixture stirring
2O and salt water washing, make this system pass through Na
2SO
4And be concentrated into and obtain crude product, with it by parallel chromatography purification.
General method N:(is by the parallel synthesizing thiourea class of isothiocyanic acid ester class)
Needed amine Ia (1 equivalent) and suitable isothiocyanic acid ester (1.2 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture stirs and spends the night.Handle this mixture and rotated 3 hours with MP-TsOH.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.With this solid and 2M NH
3MeOH solution rotated together 2 hours.By solid collected by filtration and use CH
2Cl
2, MeOH and CH
2Cl
2Washing.Concentrated filtrate is to the product that obtains purifying.
The parallel of general method O:(amino formate synthesized)
Needed amine Ia (1 equivalent) and suitable succinimide (1.5 equivalent) are dissolved in CH
2Cl
2(2ml) resulting mixture stirs and spends the night.If reaction not exclusively, is then heated this system 1 hour down at 38 ℃.Use H
2O and this mixture of salt water washing, make this system pass through Na
2SO
4And be concentrated into and obtain crude product, it is carried out purifying (step gradient 5%MeOH/CH by the parallel purification method
2Cl
2, 10%MeOH/CH
2Cl
2).
Experimental section
General remark
Except as otherwise noted, all non-aqueous reaction all carries out in nitrogen environment and with Na
2SO
4Be used for dry all organic layers.Generally pass through silica gel (230-400 order) hurried chromatography or use from Analtech, Inc., Newark, the preparation type TLC of the Uniplate Silica Gel GF PLC Plates (20 * 20cm, 1000 microns) of DE carries out purifying.Used aluminum oxide is for containing 6wt%H
2The alkali of O (Brockmann III).Do not calibrate with the fusing point that kapillary is obtained.Measure IR spectrum with KBr.Except as otherwise noted, all in CDCl3, test NMR spectrum.Record on the 300MHz instrument
1H NMR spectrum and under 75.5MHz record
13C NMR spectrum.Use electrospray ionization to carry out mass spectroscopy.Diode array spectrometer (scope 190-300nm has been installed in use; Hewlett Packard) Shimadzu system carries out the analysis mode reversed-phase HPLC.Stationary phase is that Zorbax SB-Phenyl differentiates post (4.6mm * 50mm fast; Hewlett Packard), mobile phase A is that 0.1% trifluoroacetic acid and Mobile phase B are CH
3CN.The flow velocity that uses is 2.5ml/ minute, and linear gradient is 20-55%B5 minute, and is 55-20%B5 minute then.Obtain other physics and analytical data by physics and analysis bank at Roche Bioscience.All parallel building-up reactionss are all carried out in sealed tube, and at the rotation front-seat air body that spends the night.Use CH continuously
2Cl
2, MeOH, CH
2Cl
2, MeOH and CH
2Cl
2(Wis. USA) and after dry in a vacuum then uses washing AmberliteIRA67 for Aldrich Chemical Co., Milwaukee.Characterize all products that derive from parallel building-up reactions (parallel synthesis reaction) by HPLC-MS.
Embodiment
Following preparation method (1-6) is used to prepare the synthetic intermediate that can be prepared as follows the The compounds of this invention described in the row embodiment.
Preparation 1:(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of hexahydroaniline
Steps A: (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of hexalin
After the steps A, (0.25ml, (52mg, 0.25mmol) alkylation is 3 days 2.5mmol) to make 4-(4-benzyl chloride base)-piperidines (referring to preparation 7) with 7-oxa--two ring [4.1.0] heptane down and among the EtOH (0.5ml) at 80 ℃.Crude product was used 90: 9.5: 0.5-80: 19: 1 CH
2Cl
2: MeOH: NH
4The chromatography of OH obtains product (68mg, 88%), is tawny oily matter, leaves standstill to be solidified into milk oil sample solid:
Mp 100-101.3 ℃; IR 3379,2929cm
-1 1H NMR δ 1.05-1.76 (m, 12H), 2.02 (dt, J=2.4,11.6Hz, 1H), 2.06-2.20 (m, 2H), 2.49 (d, J=7.0Hz, 2H), 2.51-2.64 (m, 2H), 2.79 (m, 1H), 3.34 (m, 1H), 4.05 (m, 1H), 7.06 (m, 2H), 7.24 (m, 2H); MS m/z308 (M+H)
+. analyze. (C
18H
26ClNO) C, H, N.
Step B:(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of hexahydroaniline
Use Et
3N (350 μ l, 2.53mmol) and MeSOCl
2(194 μ l 2.53mmol) handle (±)-trans-2-[4-under 0 ℃ (4-benzyl chloride base) piperidines-1-yl successively]-(390mg 1.27mmol) is dissolved in CH to hexalin
2Cl
2(6ml) resulting solution, this system was stirred 2 hours down and makes it be distributed in CH at 0 ℃
2Cl
2With 10%NH
4Between the OH.Use CH
2Cl
2Extract water and use salt water washing extract, drying also to concentrate.Under 70 ℃, resistates is dissolved in THF (3ml) and 28-30wt%NH
4The resulting solution stirring of OH (1.2ml) 24 hours, make it be cooled to room temperature and be distributed in EtOAc and 1N NaOH between.Extract water and use salt water washing extract, drying also to concentrate with EtOAc.To resistates use the alumina chromatography of 1: 3 EtOAc: MeOH-100%MeOH and use 20: 1 hexanes: EtOAc-100%MeOH subsequently, be the alumina chromatography of 3: 1 EtOAc: MeOH-100%MeOH and obtain product (260mg subsequently, 67%), be tawny oily matter, leave standstill curing:
mp?69.1-70.4℃；
1H?NMRδ1.03-1.34(m，6H)，1.37-1.52(m，1H)，1.57-1.77(m，5H)，1.92-2.05(m，3H)，2.48(d，J＝7.0Hz，2H)，2.45-2.64(m，3H)，2.73(m，1H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?307(M+H)
+。
Preparation 2:(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Steps A: (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentanol
Press general method A, under 95 ℃ with 4-(4-benzyl chloride base)-piperidines (17.86g, 85.05mmol) and 6-oxa--two encircles [3.1.0] hexane, and (50g 0.6mol) is dissolved in the resulting solution stirring of EtOH (170ml) 40 hours, and this system is cooled to room temperature and concentrated.Make resistates at hot CH
2Cl
2Crystallization (80ml) is concentrated into this crystalline mixture half volume and obtains product (18.2g, 73%) with remaining on to spend the night under 0 ℃ and filter and wash to be precipitated to cold hexane, is the tawny solid.Mother liquor is concentrated into half volume, uses CH
2Cl
2Dilution also kept 1 hour down and uses cold CH at-10 ℃
2Cl
2With hexane flushing precipitation and the product of getting back (1.8g, 7%) is the tawny solid:
mp?104.1-105.5℃；IR?3436，2928cm
-1；
1H?NMRδ1.19-1.75(m，8H)，1.81-1.99(m，4H)，2.06(dt，J＝2.5，11.7Hz，1H)，2.47(m，1H)，2.50(d，J＝7.0Hz，2H)，2.90(m，1H)，3.07(m，1H)，4.10(m，1H)，7.06(m，2H)，7.23(m，2H)；
13C?NMRδ21.63，27.35，32.01，32.15，34.31，37.87，42.47，50.47，52.97，75.15，75.22，128.27，130.43，131.55，139.04；MS?m/z?294(M+H)
+.Anal.(C
17H
24ClNO·0.1H
2O)C，H，N。
Step B:(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Press general method B, use Et
3N (190 μ l, 1.4mmol) and MeSOCl
2(110 μ l 1.4mmol) handle (±)-trans-2-[4-under 0 ℃ (4-benzyl chloride base) piperidines-1-yl successively]-(205mg 0.697mmol) is dissolved in CH to cyclopentanol
2Cl
2(2.8ml) resulting solution, this system was stirred 1 hour down and makes it be distributed in CH at 0 ℃
2Cl
2With 10%NH
4Between the OH.Use CH
2Cl
2Extract water and drying and be concentrated into and obtain 220mg oily matter.Under 70-80 ℃, resistates (110mg) is dissolved in diox (2ml) and 28-30wt%NH
4The resulting solution stirring of OH (0.8ml) spends the night, makes it to be cooled to room temperature to concentrate.Resistates is distributed between EtOAc and the 1N NaOH, extracts water and use salt water washing extract, drying also to concentrate with EtOAc.Resistates is used 10: 1 hexanes: EtOAc-100%EtOAc, is 95: 4.75 subsequently: 0.25-60: 38: 2 CH
2Cl
2: MeOH: NH
4The alumina chromatography of OH and obtain product (87mg, 85%) is oily matter: (insertion spectroscopic data)
1H?NMRδ1.18-1.71(m，9H)，1.76-2.00(m，3H)，2.07(dt，J＝2.4，11.5Hz，1H)，2.31(m，1H)，2.50(d，J＝6.9Hz，2H)，2.86-2.99(m，2H)，3.19(m，1H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?293.2(M+H)
+。
Preparation 3:(±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Steps A: the preparation of (±)-trans-4-nitro-Phenylsulfonic acid 2-azido--ring pentyl ester
With pyridine (0.88ml, 10.9mmol) (2.22g 10.0mmol) handles (±)-trans-2-azido--cyclopentanol (1.27g, 10.0mmol) (Zhang, Z.da under 0 ℃ successively with 4-nitro-benzene sulfonyl chloride; Scheffold, R.Helv.Chim.Acta 1993,76,2602) be dissolved in CH
2Cl
2(14ml) resulting solution and make this system be slowly to warm to room temperature.This reaction system was stirred 4 days, in this process, add again pyridine (0.9ml, 11mmol) and 4-nitro-Phenylsulfonic acid (2.2g, 10mmol) and make this system be distributed in CH
2Cl
2And between the 1N HCl.Use CH
2Cl
2Extract water and use saturated NaHCO
3Washing extract, dry and concentrated.Resistates is used 10: 1-4: the chromatography of 1 hexane: EtOAc and obtain product (2.63g, 84%) is yellow oil:
1H?NMRδ1.61-1.90(m，4H)，2.00-2.16(m，2H)，3.96(m，1H)，4.72(m，1H)，8.14(m，2H)，8.43(m，2H)。
Step B:(±)-preparation of cis-1-(2-azido--cyclopentyl)-4-(4-benzyl chloride base)-piperidines
At room temperature with (±)-trans-4-nitro-Phenylsulfonic acid 2-azido--ring pentyl ester (630mg, 2.0mmol), 4-(4-benzyl chloride base)-piperidines (420mg, 2.0mmol) and Et
3(280 μ l 2.0mmol) are dissolved in CH to N
3The resulting turbid solution of CN (4ml) stirred 10 days and stirred 2 days down at 65 ℃, and this system is cooled to room temperature and concentrated.Make resistates be distributed in CH
2Cl
2And between the 1N NaOH.Use CH
2Cl
2Extract water and drying and concentrated extract.Resistates is used 20: 1-1: the chromatography of 1 hexane: EtOAc, use 100%CH subsequently
2Cl
2-95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (145mg, 22%) is tawny oily matter:
1H NMR δ 1.32-1.90 (m, 13H), 2.33 (m, 1H), 2.49 (d, J=6.4Hz, 2H), 2.96 (m, 1H), 3.06 (m, 1H), 4.04 (t, J=4.0Hz, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 319.2 (M-H)
-
Two C:(of step ±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Use PPh
3(514mg, 1.96mmol) and H
2O (141 μ l, 7.83mmol) handle (±)-cis-1-(2-azido--cyclopentyl)-4-(4-benzyl chloride base)-piperidines (210mg successively, 0.65mmol) be dissolved in the resulting solution of THF (2.5ml), this system was refluxed 3 hours, make it to be cooled to room temperature and concentrated.Resistates was used 90: 9.5: 0.5-75: 23.75: 1.25CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (183mg, 95%) is colorless oil, leaves standstill to be solidified into milk oil sample solid:
mp?69.6-71.3℃；
1H?NMRδ1.20-1.35(m，2H)，1.43-1.93(m，11H)，2.17(m，1H)，2.49(d，J＝6.9Hz，2H)，2.89-3.02(m，2H)，3.34(t，J＝4.4Hz，1H)，7.06(m，2H)，7.23(m，2H)；
13C?NMRδ20.72，27.08，32.48，32.61，38.32，42.95，52.14，53.09，53.61，71.49，128.63，130.80，131.88，139.58；MS?m/z?293.2(M+H)
+。
Preparation 4:(±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of hexahydroaniline
Steps A: the preparation of (±)-trans-4-nitro-Phenylsulfonic acid 2-azido--cyclohexyl
With pyridine (14.2ml, 176mmol) (35.6g 160mmol) handles (±)-trans-2-azido-hexamethylene-1-alcohol (11.3g, 80.0mmol) (Zhang, Z.da under 0 ℃ successively with 4-nitro-benzene sulfonyl chloride; Scheffold, R.Helv.Chim.Acta 1993,76,2602) be dissolved in CH
2Cl
2(110ml) resulting solution makes this system be slowly to warm to room temperature, this reaction system was stirred 4 days and makes this system be distributed in CH
2Cl
2And between the 1N HCl.Use CH
2Cl
2Extract water and use saturated NaHCO
3Washing extract, dry and concentrated.Resistates is used 10: 1-1: the chromatography of 1 hexane: EtOAc and obtain product (19g, 72%) is a milk oil sample solid:
1H?NMRδ1.19-1.39(m，3H)，1.53-1.82(m，3H)，2.00-2.10(m，1H)，2.26(m，1H)，3.36(m，1H)，4.35(ddd，J＝4.7，9.2，10.8Hz，1H)，8.17(m，2H)，8.41(m，2H)。
Step B:(±)-preparation of cis-1-(2-azido--cyclohexyl)-4-(4-benzyl chloride base)-piperidines
At room temperature with (±)-trans-4-nitro-Phenylsulfonic acid 2-azido--cyclohexyl (1.77g, 5.41mmol), 4-(4-benzyl chloride base)-piperidines (1.14g, 5.43mmol) and Et
3(0.75ml 5.4mmol) is dissolved in CH to N
3The resulting turbid solution of CN (11.2ml) stir 17 hours, stirred 31 hours down and stirred 5 days down at 65 ℃ at 80 ℃, this system be cooled to room temperature and concentrate.Make resistates be distributed in CH
2Cl
2And between the 1NNaOH.Use CH
2Cl
2Extract water and drying and concentrated extract.Resistates was used 98: 1.9: 0.1-95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH-100%EtOAc and use the chromatography of 95: 5 EtOAc: MeOH subsequently, obtain raw material (±)-trans-4-nitro-Phenylsulfonic acid 2-azido--cyclohexyl (1.2g according to elution order, 68%) required product (155mg,, 9%) and raw material 4-(4-benzyl chloride base)-piperidines (810mg, 71%).Product:
1H?NMRδ1.19-1.81(m，12H)，1.92-2.08(m，3H)，2.22(m，1H)，2.48(d，J＝7.0Hz，2H)，3.02(m，2H)，4.05(m，1H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?333.2(M+H)
+。
Step C:(±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of hexahydroaniline
Use PPh
3(364mg, 1.39mmol) and H
2O (141 μ l, 5.56mmol) handle (±)-cis-1-(2-azido--cyclohexyl)-4-(4-benzyl chloride base)-piperidines (155mg successively, 0.463mmol) be dissolved in the resulting solution of THF (1.8ml), this system was refluxed 3 hours, make it to be cooled to room temperature and concentrated.Resistates was used 95: 4.75: 0.25-75: 23.75: 1.25CH
2Cl
2:: MeOH: NH
4The chromatography of OH and obtain product (121mg, 85%) is a milk oil sample solid:
1H?NMRδ1.14-1.93(m，15H)，1.96(dt，J＝11.8，3.5Hz，1H)，2.48(d，J＝7.0Hz，2H)，3.03-3.13(m，2H)，3.30(m，1H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?307.2(M+H)
+。
The preparation 5:(±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-ring butylamine preparation
Steps A: (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclobutanone
In 15 minutes, use 4-(4-benzyl chloride base) piperidines (4.56g, 21.7mmol) be dissolved in the resulting solution of MeOH (10.9ml) and dropwise handle and be in 0 ℃ down and 1 in the Ar environment, two (front three is for the siloxy-) cyclobutenes of 2-(5.0g, 22mmol) and with this system temperature to room temperature.This reaction system is stirred 5 hour time limit, add 1 again in this process, (0.99g 4.3mmol) also concentrates two (front three is for the siloxy-) cyclobutenes of 2-.Resistates was used 95: 4.75: 0.25CH
2Cl
2:: MeOH: NH
4The chromatography of OH and obtain product (4.8g, 80%) is yellow oil:
1H?NMRδ1.20-1.35(m，2H)，1.43-1.64(m，3H)，1.93-2.18(m，4H)，2.49(d，J＝6.9Hz，2H)，2.64-2.91(m，3H)，3.14(m，1H)，3.90(m，1H)，7.05(m，2H)，7.23(m，2H)；MS?m/z?278.1(M+H)
+。
Step B:(±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclobutanone O-methyl-oxime
65 ℃ down and in the Ar environment with (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclobutanone (1.74g, 6.26mmol) and MeONH
2(2.63g 31.3mmol) is dissolved in the resulting solution stirring of MeOH (20ml) 3 hours to HCl, and this system is cooled to room temperature and concentrated.Make resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between, use CH
2Cl
2Extract water and drying and concentrated extract.Resistates used 95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (1.5g, 78%), for brown oil and be mainly a kind of steric isomer:
1H?NMRδ1.05-1.65(m，4.5H)，1.92-2.11(m，4H)，2.45-2.65(m，3H)，2.73-2.96(m，2H)，3.22(m，1H)，3.73(m，1H)，3.82(m，3H)，4.57(m，0.5H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?307.1(M+H)
+。
Step C:(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-ring butylamine preparation
(1.23ml 16.0mmol) dropwise is in NaBH in the Ar environment with trifluoroacetic acid
4(604mg, 16.0mmol) be dissolved in the resulting mixture of THF (13ml), this mixture is stirred 5 minutes, usefulness (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(985mg 3.21mmol) is dissolved in the resulting solution of THF (35ml) and dropwise handled and at room temperature stir 5 hours cyclobutanone O-methyl-oxime.With this mixture with 6N HCl (1.5ml) exercise due diligence to pH～2, stir 10 minutes, alkalize to pH～10 and it be distributed between EtOAc and the 1N NaOH with 8N NaOH.Extract water and use salt water washing extract, drying (Na with EtOAc
2SO
4) and concentrate.Resistates is dissolved in MeOH (30ml) and the resulting solution of 1N HCl (3ml) stirred 1 hour down and stirred 5 hours down, this system is cooled to room temperature and concentrates at 75 ℃ at 50 ℃.Make resistates be distributed in CH
2Cl
2And between the 1N NaOH, use CH
2Cl
2Extract water and drying and concentrated extract.Resistates is used 10: 1 hexanes: EtOAc-100%EtOAc, used 98: 1.9 subsequently: 0.1-95: 9.5: 0.5 CH
2Cl
2: MeOH: NH
4OH alumina chromatography and obtain the 400mg product (according to
1It is 80% that H NMR measures purity), be yellow oil, with its not purified use:
1H?NMRδ1.19-1.90(m，9H)，2.11(m，1H)，2.28(m，1H)，2.44-2.59(m，3H)，2.80(m，1H)，3.05(m，1H)，3.22(m，1H)，7.06(m，2H)，7.23(m，2H)；MS?m/z?279.2(M+H)
+。
The preparation 6:(±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-ring butylamine preparation
With being dissolved in the resulting 1M BH of THF
3THF mixture (8.6ml, 8.6mmol) dropwise be in (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl of Ar environment]-(438mg 1.43mmol) is dissolved in the resulting solution of THF (13ml) and this system was at room temperature stirred 3 hours and stirred 20 hours down at 75 ℃ to cyclobutanone O-methyl-oxime.This reaction system is cooled to 0 ℃ also uses 6N HCl (1ml) exercise due diligence to pH～2.Evaporation THF also is dissolved in EtOH (9ml) and the resulting solution of 6N HCl (1ml) 75 ℃ of stirrings 1 hour down with resistates.Then this system is cooled to room temperature, alkalizes to pH～10, use H with 8N NaOH (4ml)
2O (5ml) dilution is with dissolving gained white precipitate and concentrated.Make resistates be distributed in CH
2Cl
2And between the 1N NaOH, use CH
2Cl
2Extract water and drying and concentrated extract.Resistates was used 90: 9.5: 0.5-60: 38: 2 CH
2Cl
2: MeOH: NH
4The chromatography of OH obtains according to elution order: the required product of 70mg (according to
1It is 80% that H NMR measures purity), be colorless oil; The required product of 48mg (12%) is colorless oil; With the required product of 125mg, steric isomer (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-mixture of ring butylamine and unidentified impurity.Product:
1H NMR δ 1.19-1.70 (m, 8H), 1.89-2.05 (m, 3H), 2.50 (d, J=6.9Hz, 2H), 2.56 (m, 1H), 2.78 (m, 2H), 3.44 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H);
13C NMR δ 24.39,25.56,31.63,31.76,38.01,42.61,49.17,49.63,51.74,62.51,128.25,130.42,131.50,139.16; MS m/z 279.2 (M+1)
+
The preparation of preparation 7:4-(4-benzyl chloride base) piperidines
The preparation of steps A: 4-(4-chloro-benzylidene)-piperidines-1-t-butyl formate
salt (phosphorium salt) (10g) is dissolved in THF and place ice bath.Slowly add KHMDS (42ml), remove ice bath ice this reaction system was at room temperature stirred 45 minutes.Then this reaction soln is cooled to-78 ℃ and the slow ketone (4.2g) that adds.This reaction system was stirred 30 minutes, remove cooling bath ice and this reaction system at room temperature stirred and spend the night.With the saturated NH of this reaction soln impouring
4Cl (100ml) solution separates each layer, with the water layer washed twice, merges organic layer, drying (MgSO with EtOAc
4) and be concentrated into～40ml.Diluting this solution with hexane also filters to remove most of Ph
3PO.Crude product is used 20: 1-10: the chromatography of 1 hexane: EtOAc and obtain product is colorless oil (4.7g).
The preparation of step B:4-(4-chloro-benzyl)-piperidines-1-t-butyl formate
The piperidines (10g) of protection is dissolved in EtOAc (100ml), adds PtO
2And with this mixture at H
2Stirred 3 hours fast in the environment.This mixture is filtered and concentrates by C salt.Crude product is dissolved in hot hexane, filters and makes it crystallization.Make the product recrystallization and obtain pure products (8.0g) with hot hexane.Separated product from mother liquor again.
The preparation of step C:4-(4-chloro-benzyl)-piperidines
Methyl alcohol (400ml) is placed ice bath and adds AcCl (60ml).After interpolation is finished, this solution was at room temperature stirred 1 hour.The piperidines (62.8g) that adds protection also at room temperature stirs this solution and spends the night.This reaction soln is concentrated into～70ml (this moment, product began to be precipitated out first), collects product (44.9g) with ether (500ml) dilution and by filtering.From mother liquor, collect the 3.1g product again.
Embodiment 1:(±)-preparation of anti-form-1-{ 2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-3-(3,4, the 5-trimethoxyphenyl) urea
According to general method C, at room temperature make (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(56mg, 0.18mmol) with 5-isocyanide acyl group-1,2, (76mg is 0.36mmol) at CH for the 3-trimethoxy-benzene for hexahydroaniline
2Cl
2(1ml) and coupling 1.5 hours among the DMF (1ml).Using H
2The extract that the O washing merges, drying were used 95: 4.75: 0.25CH after also concentrating
2Cl
2: MeOH: NH
4OH, it is 90: 9.5 then: 0.5CH
2Cl
2: MeOH: NH
4OH is prepared type TLC and used subsequently 93: 6.65: 0.35CH
2Cl
2: MeOH: NH
4OH is prepared type TLC, thereby obtains product (52mg, 55%), is gray solid: mp 196.9-200.0 ℃; IR 1670,1606,1545,1505cm
-1 1H NMR[(CD
3)
2SO, 87 ℃] δ 1.00-1.25 (m, δ H), 1.38-1.63 (m, 4H), 1.70 (m, 1H), 1.78 (m, 1H), 2.06 (m, 1H), 2.13-2.27 (m, 2H), 2.43 (d, J=6.8Hz, 2H), 2.44 (m, 1H), 2.59 (m, 1H), 2.74 (m, 1H), 3.39 (m, 1H), 3.63 (s, 3H), 3.73 (s, 6H), 5.69 (d, J=5.3Hz, 1H), 6.75 (s, 2H), 7.12 (m, 2H), 7.24 (m, 2H), 8.28 (s, 1H); MS m/z516 (M+H)
+
Embodiment 2:(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-preparation of 4-methylsulfonyl-benzamide
According to general method E; at room temperature use HOBt (8mg, 0.06mmol) and DEC (86mg 0.45mmol) makes (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-hexahydroaniline (92mg; 0.30mmol) and 4-methylsulfonyl-phenylformic acid (72mg is 0.36mmol) at CH
2Cl
2Coupling is 16 hours (2ml).By using 93: 6.65: 0.35CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying crude product of OH and obtain product (105mg, 72%) is the tawny solid:
Mp 184.5-186.7 ℃; IR 1637cm
-1 1H NMR δ 0.94 (ddd, J=3.9,11.7,23.9Hz, 1H), 1.09-1.93 (m, 12H), 2.05 (dt, J=2.4,11.5Hz, 1H), 2.35-2.74 (m, 6H), 3.10 (m, 3H), 3.55-3.66 (m, 1H), 7.04 (m, 2H), 7.16 (m, 1H), 7.23 (m, 2H), 7.95 (m, 2H), 8.04 (m, 2H); MS m/z 489 (M+H)
+. analyze. (C
26H
33ClN
2O
3S) H, N; C: theory, 63.85; Actual measurement, 60.83.HPLC purity: 99.4%.
Embodiment 3:(±)-preparation of anti-form-1-{ 2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-3-(3-methylsulfonyl-phenyl) urea hydrochloride
With 3-methylsulfonyl-aniline (120mg, 0.7mmol) and Et
3(125 μ l 0.90mmol) are dissolved in CH to N
2Cl
2(3ml) (60mg 0.2mmol) is dissolved in CH to resulting solution-treated triphosgene
2Cl
2(3ml) resulting solution, this system is descended stirring 1.5 hours at 4 ℃, makes it be cooled to room temperature and was divided two portions to join (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl in 30 minutes this system]-(88mg 0.29mmol) is dissolved in CH to hexahydroaniline
2Cl
2(1ml) in the resulting solution.This reaction system was stirred 1 hour and make it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 95: 4.75: 0.25CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali (140mg 0.28mmol), is milk oil sample solid.Et with 1N HCl
2(0.5ml 0.5mmol) is dissolved in CH with this free alkali of EtOAc solution-treated to O
2Cl
2Resulting solution, make this system at room temperature keep stablizing 3 days, down stablely spend the night and stablely down spend the night and filter and obtain product (80mg, 50%) at 0 ℃ at-20 ℃, be white solid: mp150.2-151.6 ℃; MS m/z 504 (M+H)
+
Embodiment 4:(±)-preparation of anti-form-1-{ 2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method D, at room temperature make (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(250mg, 0.85mmol) with 5-isocyanide acyl group-1,2, (355mg is 1.70mmol) at CH for the 3-trimethoxy-benzene for cyclopentamine
2Cl
2Coupling is 1 hour (5ml).At dry (MgSO
4) and the extract that concentrate to merge after, resistates was used 95: 4.75: 0.25CH
2Cl
2: MeOH: NH
4The chromatography of OH and using subsequently 98: 1.9: 0.1CH
2Cl
2: MeOH: Et
3The chromatography of N and obtain free alkali (248mg 0.494mmol), is white foam.Et with 1N HCl
2(0.5ml, 0.5mmol) (100mg 0.2mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution also is concentrated into and obtains product (104mg, 56%), is tawny powder: mp136.1-138.0 ℃; IR 1690,1607,1555,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.40-2.15 (m, 11H), 2.53 (m, 1.6H), 2.70 (m, 0.4H), 2.80-2.95 (m, 2H), 3.33-3.60 (m, 3H), 3.59 (s, 3H), 3.71 (s, 6H), 4.24-4.38 (m, 1H), 6.74 (s, 1.6H), 6.77 (s, 0.4H), 6.85 (d, J=8.2Hz, 0.8H), 6.91 (m, 0.2H), 7.21 (m, 2H), 7.33 (m, 2H), 8.77 (s, 0.8H), 8.86 (s, 0.2H), 10.10-10.23 (m, 0.8H), 10.45 (m, 0.2H);
13C NMR[(CD
3)
2SO] δ 21.82,26.88,29.06,32.57,34.82,40.68,50.73,51.01,51.82,56.02,60.52,71.47,96.26,128.51,131.07,131.27,132.61,136.25,138.62,153.10,155.10; MS m/z 502 (M+H)
+
Embodiment 5:(±)-preparation of anti-form-1-{ 4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetrahydrochysene-furans-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method D, under 0 ℃, make (±)-trans-4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetrahydrofuran (THF)-(3.03g, 10.3mmol) with 5-isocyanide acyl group-1,2, (2.37g is 11.3mmol) at CH for the 3-trimethoxy-benzene for 3-base amine
2Cl
2Coupling is 1 hour (60ml).Crude product is used 1: 1 hexane: EtOAc-100%EtOAc, used 50: 0.9 subsequently: 0.05-10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain free alkali (4.62g 9.2mmol), is white foam.Et with 1N HCl
2(10ml, 10mmol) (3.62g 7.2mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution also is concentrated into and obtains product (3.61g, 83%), is white solid:
mp?229.2-230.9℃；IR?3273(br)，2937，1690，1606，1554，1507cm
-1；
1H?NMR[(CD
3)
2SO]δ1.54-1.74(m，7H)，2.52(m，2H)，2.97(m，2H)，3.49-3.71(m，11H)，4.06(m，3H)，4.59(m，1H)，6.74(s，2H)，7.00(d，J＝7.6Hz，1H)，7.22(m，2H)，7.35(m，2H)，8.85(s，1H)，10.8(br?s，1H)；MS?m/z?504(M+H)
+。
Steps A: (±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-preparation of tetrahydrochysene-furan-3-ol
According to general method A, with 3,6-two oxa-s-two encircle [3.1.0] hexane (24.7g, 288mol) (Barili, P.L. under 90-95 ℃ and among the EtOH (75ml); Berti, G.; Mastroilli, E.; " tetrahedron " (Tetrahedron) 1993,49,6263) (10.1g, 48mmol) alkylation is 45 hours to make 4-(4-benzyl chloride base)-piperidines.Crude product is used CH
2Cl
2, used 90: 0.95 subsequently: 0.05-95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (10.7g, 76%) is white solid:
1H NMR δ 1.21 (m, 2H), 1.51 (m, 1H), 1.62 (m, 2H), 2.03 (tt, J=2.5,11.6Hz, 2H), 2.19 (br, 1H), 2.50 (d, J=6.9Hz, 2H), 2.73 (m, 2H), 3.08 (m, 1H), 3.61 (dd, J=6.9,9.3Hz, 1H), 3.70 (dd, J=3.1,10.0Hz, 1H), 3.93 (dd, J=5.7,10.0Hz, 1H), 4.05 (dd, J=7.0,9.3Hz, 1H), 4.33 (dt, J=3.0,5.7Hz, 1H), 7.05 (m, 2H), 7.24 (m, 2H); MS m/z 296.2 (M+H)
+
Step B:(±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-preparation of tetrahydrochysene-furans-3-base amine
Press general method B, use Et
3N (10.2ml, 72mmol) and MeSOCl
2(5.53ml 72mmol) will be dissolved in CH
2Cl
2(±) (150ml)-trans-4-[4-(4-benzyl chloride base) piperidines-1-yl]-(10.65g 36mmol) handled 1.25 hours and with products therefrom Zai diox (205ml) and NH tetrahydrofuran (THF)-3-alcohol
4Heating is 4 hours among the OH (83ml).Crude product was used 100: 1.9: 0.1-100: 19: 1CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (9.58g, 90%) is yellow oil:
1H?NMRδ1.21-1.68(m，7H)，2.01(m，2H)，2.50(d，J＝6.9Hz，2H)，2.58(dt，J＝3.4，6.8Hz，2H)，2.72(m，1H)，3.06(m，1H)，3.50(m，2H)，3.64(dd，J＝6.5，9.3Hz，1H)，3.99(m，2H)，7.05(m，2H)，7.25(m，2H)；MS?m/z?295.2(M+H)
+。
Embodiment 6:(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxyl-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea
At room temperature with (±)-1-{ (1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxyl-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) (605mg 0.96mmol) is dissolved in the resulting solution stirring of 1%HCl/EtOH (80ml) and spends the night urea.Evaporation EtOH also makes resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and use salt water washing extract, drying (MgSO
4) and concentrate.Resistates was used 95: 4.75: 0.25-90: 0.5: 0.5CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (440mg, 89%) is yellow solid:
mp?98.7-102.0℃；MS?m/z?518(M+H)
+。
Steps A: (±)-(1R, 2R, 4R)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentanol
According to general method A, 90-95 ℃ down and among the EtOH (5ml) with cis-tertiary butyl-dimethyl-(6-oxa--two ring [3.1.0] own-the basic oxygen base of 3-)-silane (1.51g, 7.06mmol) (Asami, M.; " Japanese chemical association journal " (Bull.Chem.Soc.Jpn.) 1990,63,1402) (741mg, 3.53mmol) alkylation is 82 hours to make 4-(4-benzyl chloride base)-piperidines.Crude product is used CH
2Cl
2, used 90: 0.95 subsequently: 0.05-95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (1.16g, 78%) is yellow foam:
1H NMR δ 0.00 (s, 6H), 0.81 (s, 9H), 1.19-1.99 (m, 12H), 2.44 (m, 2H), 2.80 (m, 2H), 3.13 (m, 1H), 4.07 (m, 1H), 4.28 (m, 1H), 6.99 (m, 2H), 7.17 (m, 2H);
13C NMR δ-4.55 ,-4.50,18.3,26.1,32.1,32.2,38.1,39.8,42.3,44.0,52.1,53.0,74.0,75.7,75.8,128.7,130.8,131.9,139.2; MS m/z 424.2 (M+H)
+.HPLC purity 98.5%.
Step B:(±)-1-(1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Press general method B, use Et
3N (740 μ l, 72mmol) and MeSOCl
2(410 μ l 5.36mmol) will be dissolved in CH
2Cl
2(±) (10ml)-1-{ (1R, 2R, 4R)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(1.14g 2.68mmol) handled 2 hours and with products therefrom Zai diox (15.6ml) and NH cyclopentanol
4Heating is 6 hours among the OH (6.2ml).Crude product was used 98: 1.9: 0.1-80: 19: 1CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (620mg, 55%) is colorless oil:
1H NMR δ 0.00 (s, 6H), 0.83 (s, 9H), 1.15-1.32 (m, 2H), 1.40-2.11 (m, 11H), 2.45 (m, 2H), 2.60 (m, 1H), 2.80 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 4.20 (m, 1H), 7.02 (m, 2H), 7.19 (m, 2H);
13CNMR δ-4.85 ,-4.87,17.9,25.8,32.0,32.1,37.8,39.2,42.4,44.8,51.0,52.8,54.8,72.8,75.8,128.2,130.4,131.5,139.0; MS m/z 423.2 (M+H)
+.HPLC purity 99.2%.
Step C:(±)-1-{ (1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea
According to general method C, under 0 ℃, make (±)-1-(1R, 2R; 4S)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(610mg is 1.44mmol) with 5-isocyanide acyl group-1,2 for cyclopentamine; (603mg is 2.88mmol) at CH for the 3-trimethoxy-benzene
2Cl
2Coupling is 1 hour (8.5ml).Crude product is used the chromatography of 1: 1 hexane: EtOAc-100%EtOAc and obtains product (665mg, 73%), be yellow solid: mp 81.0-84.0 ℃; IR 3379 (br), 2929,1653,1608,1555,1507cm
-1 1H NMR[(CD
3)
2SO] and δ 0.03 (d, 6H), 0. δ 6 (s, 9H), 1.12-1.69 (m, 8H), 1.95 (m, 2H), 2.18 (m, 1H), 2.46 (m, 2H), 2.79 (m, 3H), 3.58 (s, 3H), 3.71 (s, 6H), 3.93 (m, 1H), 4.16 (m, 1H), 5.94 (d, J=7.9Hz, 1H), 6.70 (s, 2H), 7.16 (m, 2H), 7.30 (m, 2H), 8.43 (s, 1H); MS m/z 632 (M+H)
+
Embodiment 7:(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxycyclopent base }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
Et with 1N HCl
2O (0.5ml, 0.5mmol) solution-treated (±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxycyclopent base-(102mg 0.20mmol) is dissolved in CH to 3-(3,4, the 5-trimethoxyphenyl) urea
2Cl
2Resulting solution also is concentrated into and obtains product (110mg, 100%), is yellow solid: mp 137.0-143.0 ℃; IR 3405 (br), 2935,1685,1606,1554,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.48-2.12 (m, 11H), 2.54 (m, 2H), 2.90 (m, 2H), 3.45 (m, 1H), 3.58 (s, 3H), 3.71 (s, 6H), 4.22 (m, 1H), 4.48 (m, 1H), 5.16 (br s, 1H), 6.42 (d, J=9.4Hz, 1H), 6.70 (s, 2H), 7.21 (m, 2H), 7.34 (m, 2H), 10.19 (br s, 1H); MS m/z 518 (M+H)
+
Embodiment 8:(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-methylol-cyclopentyl }-preparation of 3-(3,4,5-trimethoxy-phenyl) urea hydrochloride
At room temperature with (±)-1-{ (1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen base)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxyl-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) (1.13g 1.75mmol) is dissolved in the resulting solution stirring of 1%HCl/EtOH (120ml) 1 hour to urea.Evaporation EtOH also makes resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and use salt water washing extract, drying (MgSO
4) and concentrate.Resistates was used 95: 4.75: 0.25-90: 0.5: 0.5CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain free alkali (±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-methylol-cyclopentyl-(690mg 1.30mmol), is yellow solid to 3-(3,4,5-trimethoxy-phenyl) urea.Et with 1N HCl
2(0.5ml, 0.5mmol) (105mg 0.20mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution also is concentrated into and obtains product (112mg, 74%), is yellow solid:
mp?138.0-143.0℃；IR?3417(br)，2936，1687，1606，1554，1507cm
-1；
1HNMR[(CD
3)
2SO]δ1.28-2.12(m，10H)，2.54(m，2H)，2.91(m，2H)，3.26-3.59(m，8H)，3.71(s，6H)，4.34(m，1H)，4.70(br?s，1H)，6.66(d，J＝8.3Hz，1H)，6.73(s，2H)，7.21(m，2H)，7.32(m，2H)，8.78(s，1H)，10.13(br?s，1H)；MS?m/z?532(M+H)
+。
Steps A: (±)-(1R, 2R, 4R)-4-(tertiary butyl-dimethylsilane oxygen ylmethyl)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentanol
According to general method A, 95 ℃ down and among the EtOH (4ml) with cis-tertiary butyl-dimethyl-(6-oxa--two encircles [3.1.0] own-3-ylmethoxy)-silane (1.13g, 4.96mmol) (Asami, M.Takahashi, J.; Inoue, S. " asymmetric tetrahedron " (Tetrahedron Asymmetry) 1994,5,1649) (946mg, 4.50mmol) alkylation is 4.5 days to make 4-(4-benzyl chloride base)-piperidines.Crude product is used CH
2Cl
2, be 90: 0.95 subsequently: 0.05-95: 4.75: 0.25 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (1.38g, 74%) is brown oil:
1H?NMRδ0.00(s，6H)，0.84(s，9H)，1.34-1.86(m，8H)，2.08-2.31(m，5H)，2.48(m，2H)，2.80(m，1H)，3.13(m，1H)，3.28(m，1H)，3.48(m，2H)，4.28(m，1H)，7.00(m，2H)，7.19(m，2H)；MS?m/z?438.2(M+H)
+。
Step B:(±)-1-(1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen ylmethyl)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of cyclopentamine
Press general method B, use Et
3N (0.83ml, 6.0mmol) and MeSOCl
2(0.46ml 6.0mmol) will be dissolved in CH
2Cl
2(±) (15ml)-1-{ (1R, 2R, 4R)-4-(tertiary butyl-dimethylsilane oxygen ylmethyl)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(1.36g 3.0mmol) handled 1 hour and with products therefrom Zai diox (17.2ml) and NH cyclopentanol
4Heating is 2.5 hours among the OH (6.9ml).Crude product was used 98: 1.9: 0.1-90: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (780mg, 57%) is yellow oil:
1H NMR δ 0.00 (s, 6H), 0.85 (s, 9H), 0.92-1.70 (m, 11H), 1.96-2.21 (m, 3H), 2.44 (m, 3H), 2.83 (m, 2H), 3.12 (m, 1H), 3.43 (d, J=5.8Hz, 2H), 7.02 (m, 2H), 7.19 (m, 2H); MSm/z438.2 (M+H)
+.HPLC purity: 96.4%
Step C:(±)-1-{ (1R, 2R, 4S)-4-(tertiary butyl-dimethylsilane oxygen ylmethyl)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea
According to general method C, under 0 ℃, make (±)-1-(1R, 2R; 4S)-4-(tertiary butyl-dimethylsilane oxygen ylmethyl)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(770mg is 1.76mmol) with 5-isocyanide acyl group-1,2 for cyclopentamine; (442mg is 2.11mmol) at CH for the 3-trimethoxy-benzene
2Cl
2Coupling 30 minutes (10ml) and obtain the 1.19g product is yellow solid, it is directly used in next step: MS m/z646.2 (M+H)
+
Embodiment 9:(±)-preparation of anti-form-1-{ 4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea dihydrochloride
At room temperature with (±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-(410mg 0.68mmol) is dissolved in the resulting solution stirring of 2%HCl/MeOH (70ml) and spends the night tetramethyleneimine-1-t-butyl formate.Evaporation MeOH also makes resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and use salt water washing extract, drying (MgSO
4) and concentrate.Resistates is used CH
2Cl
2, be 50: 0.95 subsequently: 0.05-5.0: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The alumina chromatography of OH and obtain that free alkali (±)-anti-form-1-{ 4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetramethyleneimine-3-yl }-(225mg 0.45mmol), is white solid to 3-(3,4,5-trimethoxy-phenyl) urea.Et with 1N HCl
2(0.15ml, 0.15mmol) (25mg 0.05mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution also is concentrated into and obtains product (27mg, 68%), is yellow solid:
mp157.0-170.0℃；IR?3416(br)，2935，1686，1606，1554，1507cm
-1；
1H?NMR[(CD
3)
2SO]δ1.50-1.81(m，5H)，2.60(d，J＝6.6Hz，2H)，3.00-3.99(m，20H)，4.68(m，1H)，6.76(s，2H)，7.21(m，2H)，7.32(m，2H)；MS?m/z?504(M+H)
+。
Steps A: (±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of 4-hydroxyl-tetramethyleneimine-1-t-butyl formate
According to general method A, 95 ℃ down and among the EtOH (5.5ml) with 6-oxa--two encircle [3.1.0] own-the 3-ylmethoxy)-hexane-3-t-butyl formate (1.82g, 9.82mmol) (Okada, T.; Sao, H.; Tsuji, T.; Tsushima, T.; Nakai, H.; Yoshida, T.; Matsuura, S. " Japanese chemicals bulletin " (Chem.Pharm.Bull.Jpn.) 1993,41,132) (1.72g, 8.19mmol) alkylation is 60 hours to make 4-(4-benzyl chloride base)-piperidines.Crude product is used CH
2Cl
2, be 100: 0.95 subsequently: 0.05-30: 0.95: 0.05 CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain product (1.85g, 54%) is yellow solid:
mp?61.9-64.5℃；IR?3421(br)cm
-1；
1H?NMRδ1.26-1.69(m，14H)，1.94(br?s，1H)，2.19(m，2H)，2.53(d，J＝6.9Hz，2H)，2.89(m，2H)，3.05-3.33(m，3H)，3.60-3.79(m，2H)，4.33(m，1H)，7.08(m，2H)，7.28(m，2H)；MS?m/z?395.2(M+H)
+。
Step B:(±)-trans-3-amino-4-[4-(4-benzyl chloride base) piperidines-1-yl]-preparation of tetramethyleneimine-1-t-butyl formate
Press general method B, use Et
3N (1.26ml, 9.12mmol) and MeSOCl
2(0.70ml 9.12mmol) will be dissolved in CH
2Cl
2(±) (20ml)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-(1.80g 4.56mmol) handled 1 hour and with products therefrom Zai diox (26.0ml) and NH 4-hydroxyl-tetramethyleneimine-1-t-butyl formate
4Heating 6 hours and obtain 1.91g product (measuring purity by HPLC is 91%) among the OH (10.5ml) is yellow oil, and it is directly used in next step:
1H?NMRδ1.21-1.65(m，17H)，2.17(m，2H)，2.49(d，J＝7.0Hz，2H)，2.73-3.43(m，7H)，7.05(m，2H)，7.25(m，2H)；MS?m/z394.2(M+H)
+。
Step C:(±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl) urea groups]-preparation of tetramethyleneimine-1-t-butyl formate
According to general method C, under 0 ℃, make (±)-trans-3-amino-4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetramethyleneimine-1-t-butyl formate (394mg ,～0.9mmol) and 5-isocyanide acyl group-1,2, (250mg is 1.2mmol) at CH for the 3-trimethoxy-benzene
2Cl
2Coupling is 1 hour (6.0ml).Crude product used the chromatography of 1: 1 hexane: EtOAc-100%EtOAc and obtain product (445mg is 77%, by (±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-4-hydroxyl-tetramethyleneimine-1-t-butyl formate make), be white solid:
mp?99.0-102.5℃；IR?3371(br)，2932，1655，1607，1552，1507cm
-1；
1H?NMRδ1.17-1.80(m，14H)，2.18(m，2H)，2.48(d，J＝7.0Hz，2H)，2.95-3.51(m，8H)，3.81(m，9H)，4.32(br，1H)，5.30(br，1H)，6.61(s，2H)，7.02(m，2H)，7.20(m，2H)；MS?m/z?603.2(M+H)
+.
Embodiment 10:(±)-cis-1-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method D, with 5-isocyanide acyl group-1,2, the 3-trimethoxy-benzene (98mg 0.47mmol) handles (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl under 0 ℃]-(110mg 0.38mmol) is dissolved in CH to cyclopentamine
2Cl
2(2ml) resulting solution stirs this system 1 hour and makes it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.Resistates is used EtOAc, is 90: 9.5 subsequently: 0.5CH
2Cl
2: MeOH: NH
4The chromatography of OH and use 1: 3 hexane: EtOAc-100%EtOAc then, be 95: 4.74 subsequently: 0.25CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain free alkali (190mg 0.38mmol), is colorless oil.Et with 1N HCl
2(1ml, 1mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2(2ml) resulting solution and be concentrated into and obtain product (193mg, 96%) is white solid:
Mp 117.5-122.5 ℃; IR 1692,1606,1557,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.33-2.15 (m, 11H), 2.51 (m, 2H), 2.64 (br d, J=7.8Hz, 0.5H), 2.80-2.95 (m, 1.5H), 3.15-3.90 (m, 12H), 4.41 (m, 1H), 6.74 (s, 2H), 7.08-7.24 (m, 3H), 7.34 (m, 2H), 9.01 (br s, 0.7H), 9.06 (br s, 0.3H), 9.25-9.47 (m, 1H); The theoretical C of HRMS (FAB)
27H
37ClN
3O
4502.2473 (M+H)
+, actual measurement 502.2471.
Embodiment 11:(±)-cis-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-preparation of 4-methylsulfonyl-benzamide hydrochloride salt
According to general method E; 0 ℃ use down HOBt (10mg, 0.07mmol) and DEC (138mg 0.719mmol) makes (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentamine (105mg; 0.358mmol) and 4-methylsulfonyl-phenylformic acid (86mg is 0.43mmol) at CH
2Cl
2Coupling is 2.5 hours (2ml).Resistates is used CH
2Cl
2, be 98: 1.9 subsequently: 0.1CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain free alkali (176mg 0.36mmol), is colorless oil.Et with 1N HCl
2(0.8ml, 0.8mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (183mg, 100%), is milk oil sample foam: mp125.3-131.9 ℃; IR 1660cm
-1 1H NMR δ 1.63-2.23 (m, 11H), 2.56 (d, J=6.4Hz, 2H), 2.56-2.85 (m, 2H), 3.05 (s, 0.3H), 3.06 (s, 2.7H), 3.20-3.34 (m, 1H), 3.60 (br d, J=11.7Hz, 1H), 3.78 (br d, J=10.8Hz, 1H), 4.93 (m, 1H), 7.00-7.11 (m, 2H), 7.25 (m, 2H), 8.03 (m, 2H), 8.50 (m, 2H), 8.95 (m, 0.1H), 9.06 (br d, J=8.3Hz, 1H), 11.65-11.90 (m, 1H);
13CNMR δ 21.06,26.85,29.18,29.38, and 33.31,36.77,41.57,44.76,50.69,53.67,54.39,68.88,127.87,129.08,129.85,130.64,132.72,137.61,138.20,143.57,166.50; The theoretical C of HRMS (FAB)
25H
31ClN
2O
3S 475.1822 (M+H)
+, measure 475.1823.
Embodiment 12:(±)-preparation of anti-form-1-{ 1-ethanoyl-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
With acetic anhydride (15 μ l, 0.16mmol) dropwise handle (±)-anti-form-1 under 0 ℃-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea (80mg, 0.16mmol) and Et
3(26 μ l 0.19mmol) are dissolved in CH to N
2Cl
2(1ml) resulting solution descended this system stirring 10 minutes and made it be distributed in CH at 0 ℃
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is white solid.Et with 1N HCl
2(0.2ml, 0.2mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (84mg, 91%), is the tawny solid: mp 155.0-161.0 ℃; IR 3415 (br), 2936,1691,1608,1554,1508cm
-1 1H NMR[(CD
3)
2SO] δ 1.56-1.97 (m, 8H), 2.50-3.94 (m, 20H), 4.70 (m, 1H), 6.76 (s, 2H), 6.98 (m, 1H), 7.21 (m, 2H), 7.32 (m, 2H), 8.81 (s, 1H), 10.72 (s, 1H); MSm/z 545 (M+H)
+
Embodiment 13:(±)-cis-1-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method D, under 0 ℃, make (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(53mg, 0.17mmol) with 5-isocyanide acyl group-1,2, (40mg is 0.19mmol) at CH for the 3-trimethoxy-benzene for hexahydroaniline
2Cl
2Coupling is 1 hour (1ml).By using 93: 6.65: 0.35CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying crude product of OH and obtain free alkali (100mg 0.2mmol), is the tawny foam.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (83mg, 85%), is the tawny foam:
Mp 120.1-137.3 ℃; IR 1691,1607,1558,1507cm
-1 1H NMR (CD
3OD) δ 1.35-2.15 (m, 13H), 2.58 (d, J=6.4Hz, 1.8H), 2.72 (m, 0.2H), 2.87-2.98 (m, 2H), 3.22 (m, 1H), 3.59 (m, 1H), 3.70 (s, 0.3H), 3.73 (s, 2.7H), 3.78 (s, 0.6H), 3.82 (s, 5.4H), 3.92 (m, 1H), 4.55 (m, 1H), 6.76 (s, 1.8H), 6.77 (s, 0.2H), 7.17 (m, 2H), 7.27 (m, 2H); MS m/z 516 (M+H)
+. analyze. (C
28H
39Cl
2N
3O
41.15H
2O) C, H, N.
Embodiment 14:(±)-cis-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-preparation of 4-methylsulfonyl-benzamide hydrochloride salt
According to general method F; 0 ℃ use down HOBt (3mg, 0.02mmol) and DEC (30mg 0.16mmol) makes (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-hexahydroaniline (30mg; 0.10mmol) and 4-methylsulfonyl-phenylformic acid (24mg is 0.12mmol) at CH
2Cl
2Coupling 2 hours and coupling at room temperature are 2 hours (1ml).By using 90: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying crude product of OH and obtain free alkali (46mg 0.09mmol), is white solid.Et with 1N HCl
2(0.2ml, 0.2mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (47mg, 88%), is milk oil sample solid:
Mp 123.7-149.4 ℃; IR 1659cm
-1 1H NMR (CD
3OD) δ 1.28-2.20 (m, 13H), 2.59 (d, J=6.2Hz, 2H), 2.90-3.03 (m, 1H), 3.17 (s, 3H), 3.35 (m, 1H), 3.61 (m, 1H), 3.89 (m, 1H), 4.47-4.91 (m, 2H), 7.17 (d, J=8.3Hz, 2H), 7.28 (m, 2H), 8.10 (m, 4H); MS m/z 489 (M+H)
+. analyze. (C
26H
34Cl
2N
2O
3S); Theoretical: C, 59.42; H, 6.52; N, 5.33; Actual measurement: C, 55.39; H, 5.94; N, 4.88.HPLC purity: 98.6%.
Embodiment 15:(±)-preparation of anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1-methylsulfonyl-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
Use MeSOCl
2(12 μ l, 6.0mmol) dropwise handle (±)-anti-form-1 under 0 ℃-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea (78mg, 0.15mmol) and pyridine (13 μ l 0.15mmol) are dissolved in CH
2Cl
2(2.5ml) resulting solution and make this system be slowly to warm to room temperature.This reaction system was stirred 1 hour, in this process, add again pyridine (3 μ l, 0.04mmol) and MeSOCl
2(3 μ l, 0.04mmol) and make this system be distributed in CH
2Cl
2And between the 10%NaOH aqueous solution.Use CH
2Cl
2Extract water and use salt water washing extract, drying also to concentrate.By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and free alkali are yellow semi-solid.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (87mg, 91%), is the tawny solid:
Mp 148.0-158.0 ℃; IR 3405 (br), 2933,1691,1608,1554,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.51-1.78 (m, 5H), 2.50 (m, 2H), 3.05-3.71 (m, 21H), 4.66 (m, 1H), 6.74 (s, 2H), 6.91 (br d, 1H), 7.21 (m, 2H), 7.34 (m, 2H), 8.84 (s, 1H), 10.75 (s, 1H); MS m/z 581 (M+H)
+. analyze. (C
27H
38Cl
2N
4O
6S1.35H
2O) C, H, N.
Embodiment 16:(±)-trans-3-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-preparation of tetramethyleneimine-1-sulfonic acid diformamide hydrochloride
(21 μ l 0.20mmol) handle (±)-anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) ureas (80mg 0.16mmol) and Et with the dimethylamino SULPHURYL CHLORIDE
3(33 μ l 0.24mmol) are dissolved in CH to N
2Cl
2(2ml) resulting solution at room temperature stirred this system 20 hours and makes it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is white solid.Et with 1N HCl
2(0.35ml, 0.35mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (93mg, 93%), is white solid: mp 141.0-143.0 ℃; IR 3378 (br), 2937,1691,1607,1555,1508cm
-1 1H NMR ([(CD
3)
2SO], D
2O added, 87 ℃) δ 1.53 (m, 2H), 1.86 (m, 3H), 2.58 (d, J=6.7Hz, 2H), 2.84 (s, 6H), 3.07-3.86 (m, 18H), 4.60 (m, 1H), 6.74 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H); MS m/z 610 (M+H)
+. analyze. (C
28H
41Cl
2N
5O
6S1H
2O) C, H, N.
Embodiment 17:(±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-preparation of tetramethyleneimine-1-formic acid diformamide hydrochloride
(20 μ l 0.22mmol) handle (±)-anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) ureas (90mg 0.18mmol) and Et with dimethylcarbamyl chloride
3(37 μ l 0.27mmol) are dissolved in CH to N
2Cl
2(2ml) resulting solution is slowly to warm to this system room temperature, stirred 75 minutes and makes it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 6: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is white solid.Et with 1N HCl
2(0.2ml, 0.2mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (70mg, 69%), is yellow solid: mp 142.0-144.5 ℃; IR 3272 (br), 2936,1685,1608,1555,1507cm
-1 1H NMR ([(CD
3)
2SO], D
2O adds, 87 ℃) δ 1.54 (m, 2H), 1.84 (m, 3H), 2.54 (m, 2H), 2.82 (s, 6H), 3.05-3.76 (m, 18H), 4.55 (m, 1H), 6.76 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H); MS m/z 574 (M+H)
+. analyze. (C
29H
41Cl
2N
5O
51.1H
2O) C, H, N.
Embodiment 18:(±)-trans-3-[4-(4-benzyl chloride base) piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-preparation of tetramethyleneimine-1-benzoic acid amides hydrochloride
(36 μ l, (36mg 0.55mmol) is dissolved in CH 0.48mmol) to handle (±)-anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) ureas (120mg 0.24mmol) and NaOCN with trifluoroacetic acid
3The resulting solution of CN (2ml).This reaction mixture was at room temperature stirred 20 hours and concentrated.Make resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between, use CH
2Cl
2Extract water and drying and concentrated extract.By using 5.0: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is white solid.Et with 1N HCl
2(0.2ml, 0.2mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (70mg, 54%), is yellow solid: mp158.0-162.0 ℃; IR 3390 (br), 2935,1654,1605,1554,1508cm
-1 1H NMR ([(CD
3)
2SO], D
2O adds, 87 ℃) δ 1.53-1.86 (m, 5H), 2.59 (d, J=6.8Hz, 2H), 3.07-3.86 (m, 18H), 4.60 (m, 1H), 6.74 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H); MS m/z 546 (M+H)
+. analyze. (C
27H
37Cl
2N
5O
51.1H
2O) C, H, N
Embodiment 19:(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-4-methoxymethyl-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl)-urea hydrochloride
Diazomethane with new system is dissolved in Et
2O (60ml, (±)-1-{ under 30mmol) resulting 0.5N solution is slowly handled 0 ℃ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-methylol-cyclopentyl }-3-(3,4,5-trimethoxyphenyl)-urea (160mg 0.30mmol) and silica gel (1.5g) is dissolved in CH
2Cl
2(3ml) resulting mixture also filtered this mixture temperature to room temperature, stirring in 4 hours.With methanol wash silica gel and concentrated filtrate.By using 100: 19: 1CH
2Cl
2: MeOH: NH
4The preparation type TLC of OH, it is 100: 9.5 subsequently: 0.5CH
2Cl
2: MeOH: NH
4The another kind preparation type TLC purifying resistates of OH and obtain free alkali (48mg 0.09mmol), is white foam.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (48mg, 30%), is white solid: mp 109.0-112.0 ℃; IR3420 (br), 2934,1686,1606,1554,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.32-2.28 (m, 10H), 2.54 (m, 2H), 2.91 (m, 2H), 3.26-3.50 (m, 8H), 3.59 (s, 3H), 3.71 (s, 6H), 4.33 (m, 1H), 6.62 (d, J=8.3Hz, 1H), 6.77 (s, 2H), 7.20 (m, 2H), 7.34 (m, 2H), 8.75 (s, 1H), 10.14 (br s, 1H); MS m/z 546 (M+H)
+. analyze. (C
29H
41Cl
2N
3O
50.9H
2O) C, H, N.
Embodiment 20:(±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-methoxyl group-cyclopentyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl)-urea hydrochloride
Diazomethane with new system is dissolved in Et
2O (45ml, 22.5mmol) resulting 0.5N solution slowly handle 0 ℃ under (±)-1-{ (1R, 2R, 4S)-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-hydroxyl-cyclopentyl-3-(3,4,5-trimethoxyphenyl)-urea (105mg 0.20mmol) and silica gel (1.0g) is dissolved in CH
2Cl
2(3ml) resulting mixture is slowly to warm to this mixture room temperature, stirred 4 hours and filters.With methanol wash silica gel and concentrated filtrate.By using 100: 19: 1CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali (43mg 0.08mmol), is yellow solid.Et with 1NHCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (46mg, 40%), is the tawny solid:
Mp 112.5-119.5 ℃; IR3390 (br), 2935,1686,1607,1555,1506cm
-1 1H NMR[(CD
3)
2SO] δ 1.46-1.98 (m, 7H), 2.22 (m, 2H), 2.54 (m, 2H), 2.90 (m, 2H), 3.24 (s, 3H), 3.42 (m, 2H), 3.58-3.85 (m, 11H), 4.50 (m, 1H), 6.36 (d, J=9.1Hz, 1H), 6.70 (s, 2H), 7.21 (m, 2H), 7.35 (m, 2H), 10.10 (s, 1H); MS m/z 532 (M+H)
+. analyze. (C
28H
39Cl
2N
3O
50.7H
2O) C, H, N.
Embodiment 21:(±)-trans-2-{3-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-tetramethyleneimine-1-yl }-preparation of ethanamide dihydrochloride
Use i-Pr
2NEt (47 μ l, 0.27mmol) and 2-iodo-acid amide (40mg, 0.22mmol) handle (±)-anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3 successively, 4, the 5-trimethoxyphenyl)-urea (90mg 0.18mmol) is dissolved in the resulting solution of dry DMF (2.5ml), with this solution stirring at room 24 hours and make it be distributed in CH
2Cl
2With saturated NaHCO
3Between and use CH
2Cl
2Extract water and use H
2O and salt water washing extract, dry and concentrated.By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is yellow solid.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (54mg, 50%), is tawny solid: mp160.0-165.0 ℃; IR 3414 (br), 2933,1691,1607,1557,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.55-1.77 (m, 5H), 2.49 (m, 2H), 3.00-3.71 (m, 20H), 4.72 (br s, 1H), 6.76 (s, 2H), 7.01 (brd, 1H), 7.21 (m, 2H), 7.34 (m, 2H), 7.58 (br s, 1H), 7.83 (br s, 1H), 9.12 (br s, 1H); MS m/z560 (M+H)
+. analyze. (C
28H
40Cl
3N
5O
51.3H
2O) C, H, N.
Embodiment 22:(±)-preparation of anti-form-1-{ 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-methoxyl group-naphthalene-2-yl) urea
With (±)-trans-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-(140mg, 0.48mmol) and N, (180 μ l 1.0mmol) are dissolved in CH to the N-diisopropylethylamine to cyclopentamine
2Cl
2(1ml) resulting solution is dropwise handled triphosgene (47mg 0.16mmol) is dissolved in CH
2Cl
2(2ml) resulting solution and this system is joined 4-methoxyl group-naphthalene-2-base amine (83mg, 0.48mmol) and N, (180 μ l 1.0mmol) are dissolved in CH to the N-diisopropylethylamine
2Cl
2(1ml) in the resulting solution.With this reaction system stir 4 hours, use 1N KHSO
4, saturated NaHCO
3With salt water washing, dry and concentrated.By using 100: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain product (100mg, 43%) is yellow solid: mp 175-190 ℃;
MS?m/z?492(M+H)
+。
Embodiment 23:(±)-preparation of anti-form-1-{ 4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1-(2-methylsulfonyl-ethyl)-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea dihydrochloride
With methyl ethylene sulfone (18 μ l, 0.21mmol) processing (±)-anti-form-1-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) (100mg 0.20mmol) is dissolved in the resulting solution of MeOH (1ml) to urea.This mixture at room temperature stirred spend the night and concentrate.By using 7: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is white solid.Et with 1N HCl
2(0.5ml, 0.5mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (110mg, 83%), is white solid:
Mp 210.2-211.8 ℃; IR3422 (br), 2930,1686,1607,1556,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.54-1.77 (m, 5H), 2.51 (m, 2H), 3.05-3.71 (m, 25H), 4.71 (br s, 1H), 6.75 (s, 2H), 6.92 (br d, 1H), 7.21 (m, 2H), 7.34 (m, 2H), 9.01 (s, 1H); MS m/z 609 (M+H)
+. analyze. (C
29H
43Cl
3N
4O
6S1.15H
2O) C, H, N.
Embodiment 24:(±)-anti-form-1-{ 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-[2-(3,4, the 5-trimethoxyphenyl)-ethyl] preparation of urea hydrochloride
With (±)-trans-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-(140mg, 0.48mmol) and N, (180 μ l 1.0mmol) are dissolved in CH to the N-diisopropylethylamine to cyclopentamine
2Cl
2(1ml) resulting solution is dropwise handled triphosgene (47mg 0.16mmol) is dissolved in CH
2Cl
2(2ml) resulting solution and this system is joined 2-(3,4, the 5-trimethoxyphenyl)-ethamine (101mg, 0.48mmol) and N, (180 μ l 1.0mmol) are dissolved in CH to the N-diisopropylethylamine
2Cl
2(1ml) in the resulting solution.This reaction system stirred spend the night and use saturated NaHCO
3Washing.Use CH
2Cl
2Extract water and use salt water washing extract, drying also to concentrate.By using 10: 1CH
2Cl
2: the preparation type TLC purifying resistates of MeOH and obtain free alkali (83mg 0.16mmol), is yellow oil.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (86mg, 32%), is yellow solid:
mp?90.3-95℃；MS?m/z?530(M+H)
+。
Embodiment 25:(±)-trans-3-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-preparation of tetramethyleneimine-1-sulfonamide hydrochloride
(21 μ l, (23 μ l 0.26mmol) are dissolved in CH 0.22mmol) to handle isocyanic acid chlorine sulfonyl ester with t-BuOH
2Cl
2(1ml) resulting solution and with (±)-trans-{ 4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4, the 5-trimethoxyphenyl) urea (110mg, 0.22mmol) and pyridine (19 μ l 0.24mmol) are dissolved in CH
2Cl
2(1ml) resulting solution-treated.This reaction system was at room temperature stirred 2 days, in this process, add again isocyanic acid chlorine sulfonyl ester (46 μ l, 0.52mmol) and t-BuOH (42 μ l, 0.44mmol) and make it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain the 55mg yellow solid.
This solid is dissolved in the resulting solution of 10%HCl/MeOH (20ml) at room temperature to be stirred and spends the night.Evaporation MeOH also makes resistates be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and dry (MgSO
4) and concentrated extract.By using 5: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali is yellow solid.Et with 1N HCl
2(0.1ml, 0.1mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (20mg, 48%), is the tawny solid:
Mp 155.7-160.0 ℃; IR 3404 (br), 1686,1607,1554,1507cm
-1 1H NMR[(CD
3)
2SO] δ 1.48-1.77 (m, 5H), 2.54 (m, 2H), 3.00-3.83 (m, 18H), 4.60 (m, 1H), 6.73 (s, 2H), 6.85 (m, 1H), 7.11 (br s, 2H), 7.21 (m, 2H), 7.35 (m, 2H), 8.76 (s, 1H), 10.41 (s, 1H); MS m/z 582 (M+H)
+. analyze. (C
26H
37Cl
2N
5O
6S1.1H
2O) C, H, N.
Embodiment 26:(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclobutyl }-preparation of 4-methylsulfonyl-benzamide hydrochloride salt
With I-hydroxybenzotriazole hydrate (HOBt) (13mg; 0.10mmol) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (DEC) (138mg; 0.719mmol) handle (±)-2-[4-under 0 ℃ (4-benzyl chloride base)-piperidines-1-yl successively]-ring butylamine (130mg; purity 80%;～0.38mmol) (115mg 0.575mmol) is dissolved in CH with 4-methylsulfonyl-phenylformic acid
2Cl
2(1ml) resulting solution is slowly to warm to this system room temperature, stirred 3 days and makes it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.By using 90: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain free alkali (118mg 0.26mmol), is white solid.Et with 1N HCl
2(0.5ml, 0.5mmol) (93mg 0.20mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution and being concentrated into obtains product (90mg is 21%, by (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclobutanone O-methyl-oxime preparation), is the tawny powder:
Mp 173.2-184.1 ℃; IR 1657cm
-1 1H NMR[(CD
3)
2SO] δ 1.45-2.20 (m, 9H), 2.52 (m, 2H), 2.65-2.80 (m, 2H), 3.20-3.45 (m, 5H), 3.68-3.79 (m, 1H), 4.79-4.92 (m, 1H), 7.21 (m, 2H), 7.34 (m, 2H), 8.00-8.19 (m, 4H), 9.38 (d, J=8.3Hz, 1H), and 11.04-11.30 (m, 1H);
13C NMR[(CD
3)
2SO] δ 17.86,21.23,28.00,34.70,40.50,43.21,46.54,48.69,49.15,64.74,126.90,128.07,128.34,130.60,130.78,138.20,138.35,143.08,164.24; MS m/z 461 (M+H)
+. analyze. (C
24H
30Cl
2N
2O
3S0.4CH
2Cl
2) C, H, N.
Embodiment 27:(±)-anti-form-1-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1.1-dioxo-tetrahydrochysene-1 λ
6-thiene-3-yl-}-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method C, under 0 ℃, make (±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1.1-dioxo-tetrahydrochysene-1 λ
6(60mg, 0.18mmol) with 5-isocyanide acyl group-1,2, (44mg is 0.21mmol) at CH for the 3-trimethoxy-benzene for-thiene-3-yl-amine
2Cl
2Coupling is 1 hour (1.5ml).By using 90: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC of OH and obtain free alkali by the preparation type TLC purifying crude product that uses EtOAc subsequently (55mg 0.10mmol), is yellow solid.Et with 1N HCl
2(0.3ml, 0.3mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (59mg, 57%), is yellow solid:
Mp 162.0-166.0 ℃; IR 3377 (br), 2935,1690,1606,1556,1506cm
-1 1H NMR[(CD
3)
2SO] δ 1.48 (m, 2H), 1.78 (m, 3H), 2.56 (d, J=6.5Hz, 2H), 2.89 (m, 2H), 3.21-3.60 (m, 6H), 3.64 (s, 3H), 3.74 (s, 6H), 3.99 (m, 1H), 4.78 (m, 1H), 6.74 (s, 2H), 7.19 (m, 2H), 7.31 (m, 2H); MS m/z 552 (M+H)
+. analyze. (C
27H
37Cl
2N
3O0.4H
2O) C, H, N.
Steps A: (±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1.1-dioxo-tetrahydrochysene-1 λ
6-thiene-3-yl-}-preparation of urethanum
With (4-chloro-1.1-dioxo-tetrahydrochysene-1 λ
6-thiene-3-yl-)-urethanum (500mg, 2.07mmol) (Ohba, K.; Mori, K.; Kitahara, T.; Kitamura, S.; Matsui, M.Agr.Biol.Chem.1974,38,1679) and 4-(4-benzyl chloride base)-piperidines (599mg 2.85mmol) is dissolved in the resulting solution of EtOH (5ml) and refluxed 22 hours, this system is cooled to room temperature and concentrates.Resistates was used 95: 4.75: 0.25CH
2Cl
2: MeOH: NH
4The silica gel chromatography of OH and use 10 subsequently: 1CH
2Cl
2: the preparation type TLC of MeOH and obtain product (171mg, 20%) is yellow solid:
1H NMR δ 1.16-1.33 (m, 5H), 1.45-1.68 (m, 3H), 2.03 (m, 1H), 2.26 (m, 1H), 2.50 (d, J=7.0Hz, 2H), 2.80 (m, 2H), 2.92-3.08 (m, 2H), 3.19-3.36 (m, 2H), 3.78 (m, 1H), 4.14 (q, J=7.1Hz, 2H), 4.25 (m, 1H), 5.24 (br, 1H), 7.04 (m, 2H), 7.21 (m, 2H); MS m/z 415.2 (M+H)
+
Step B:(±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1.1-dioxo-tetrahydrochysene-1 λ
6The preparation of-thiene-3-yl-amine
With (±)-trans-4-[4-(4-benzyl chloride base)-piperidines-1-yl]-1.1-dioxo-tetrahydrochysene-1 λ
6-thiene-3-yl-}-(170mg 0.41mmol) is dissolved in the resulting solution of the 48%HBr aqueous solution (3ml) and refluxed 16 hours urethanum, and this system is cooled to room temperature and impouring ice and Na
2CO
3The particulate mixture.This reaction mixture is neutralized fully and use CH
2Cl
2Extract and also concentrate with salt water washing extract, drying.By using 100: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain product (60mg, 43%) is yellow solid:
1H NMR δ 1.26 (m, 2H), 1.49 (m, 1H), 1.66 (m, 4H), 2.00 (m, 1H), 2.29 (m, 1H), 2.50 (d, J=7.0Hz, 2H), 2.77-2.91 (m, 3H), 3.00-3.22 (m, 3H), 3.44 (m, 1H), 3.65 (m, 1H), 7.05 (m, 2H), 7.26 (m, 2H); MS m/z 343.1 (M+H)
+
Embodiment 28:(±)-trans-3-{3-[4-(4-benzyl chloride base)-piperidines-1-yl]-4-[3-(3,4, the 5-trimethoxyphenyl)-urea groups]-tetramethyleneimine-1-yl }-preparation of 3-oxo-propionic acid
Use Et
3N (27 μ l, 0.20mmol) and methyl malonyl chloride (19 μ l 0.18mmol) handle (±) under 0 ℃-trans-{ 4-[4-(4-benzyl chloride base) piperidines-1-yl]-tetramethyleneimine-3-yl }-3-(3,4 successively, the 5-trimethoxyphenyl) (82mg 0.16mmol) is dissolved in CH to urea
2Cl
2(3ml) resulting solution and make this system be slowly to warm to room temperature.This reaction system was stirred 19 hours, in this process, add Et again
3N (27 μ l, 0.20mmol) and methyl malonyl chloride (19 μ l, 0.18mmol) and make it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract and obtain the 87mg ester, be yellow solid, it is directly used in next step:
1H?NMRδ1.08-1.61(m，5H)，2.03-2.48(m，4H)，2.74-3.93(m，21H)，4.50(m，1H)，5.82(m，1H)，6.70(s，2H)，7.02(m，2H)，7.25(m，2H)，7.49(br?s，1H)；MS?m/z?603.2(M+H)
+。
This ester is dissolved in the resulting solution of 5%KOH/MeOH (6ml) at room temperature to be stirred and spends the night.Evaporation MeOH, with 1N HCl with the resistates exercise due diligence to pH～7 and use CH
2Cl
2Extract water and drying and concentrated extract.By using 95: 5MeOH: NH
4The preparation type TLC of OH and using subsequently 4: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying resistates of OH and obtain product (40mg, 42%) is yellow solid:
mp?184.0-184.9℃；IR?3377，2924，1607，1554，1506cm
-1；
1H?NMR[(CD
3)
25O]δ1.15-1.49(m，5H)，2.15(m，2H)，2.50(m，2H)，3.00-3.71(m，18H)，4.62(m，1H)，6.80(s，2H)，7.13(m，3H)，7.25(m，2H)，8.87(m，1H)；MS?m/z?589(M+H)
+。
Embodiment 29:(±)-preparation of anti-form-1-{ 2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclobutyl }-3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
With 5-isocyanide acyl group-1,2, the 3-trimethoxy-benzene (110mg, 0.53mmol) handle 0 ℃ under (±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-the ring butylamine (130mg, purity 80% ,～0.38mmol) be dissolved in CH
2Cl
2(1ml) resulting solution.This reaction system was stirred 2 hours down at 0 ℃, in this process, add 5-isocyanide acyl group-1,2 again, and the 3-trimethoxy-benzene (25mg, 0.12mmol) and make it be distributed in CH
2Cl
2With saturated NaHCO
3Between.Use CH
2Cl
2Extract water and drying and concentrated extract.Resistates is used 1: 1 hexane: EtOAc, is 95: 4.75 subsequently: 0.25-50: 47.5: 2.5CH
2Cl
2: MeOH: NH
4The chromatography of OH and obtain free alkali (138mg 0.28mmol), is vitreous solid.Et with 1N HCl
2(0.5ml, 0.5mmol) (74mg 0.15mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution and being concentrated into obtains product (76mg is 25%, by (±)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclobutanone O-methyl-oxime preparation), is yellow powder:
Mp 127.4-128.2 ℃; IR 1691,1607,1555,1507cm
-1 1H NMR[(CD
3)
2SO, 77 ℃] δ 1.45-1.85 (m, 6H), 1.93-2.20 (m, 3H), 2.54 (d, J=6.7Hz, 2H), 2.65-2.80 (m, 2H), 3.07 (brs, 0.5H), 3.28 (m, 1H), 3.47-3.62 (m, 1.5H), 3.62 (s, 3H), 3.72 (s, 6H), 4.45-4.58 (m, 1H), 6.75 (m, 2H), 6.90-7.03 (m, 1H), 7.19 (m, 2H), 7.31 (m, 2H), 8.67 (br s, 0.8H), 8.76 (br s, 0.2H), 10.70-11.00 (m, 1H); MS m/z 488 (M+H)
+. analyze. (C
26H
34Cl
2N
3O
40.65H
2O) C, H, N.
Embodiment 30:(±)-cis-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclobutyl }-preparation of 4-methylsulfonyl-benzamide hydrochloride salt
According to general method F; use HOBt (25mg down at 0 ℃; 0.18mmol) and DEC (106mg; 0.55mmol) make (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-hexahydroaniline (100mg; purity 90%;～0.33mmol) (88mg is 0.44mmol) at CH with 4-methylsulfonyl-phenylformic acid
2Cl
2Coupling is 3.5 hours (3ml).By using 10: 0.95: 0.05CH
2Cl
2: MeOH: NH
4The preparation type TLC purifying crude product of OH and obtain free alkali (102mg 0.22mmol), is colorless oil.Et with 1N HCl
2(0.5ml, 0.5mmol) (82mg 0.18mmol) is dissolved in CH to this free alkali of solution-treated to O
2Cl
2Resulting solution also is concentrated into and obtains product (83mg, 64%), is white solid:
mp?130.0-132.5℃；IR?3438，2924，1662，1541cm
-1；MS?m/z?461(M+H)
+.Anal.(C
24H
30Cl
2N
2O
3S·0.35H
2O)C，H，N。
Embodiment 31:(±)-cis-1-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclobutyl }-preparation of 3-(3,4, the 5-trimethoxyphenyl) urea hydrochloride
According to general method D, under 0 ℃, make (±)-cis-2-[4-(4-benzyl chloride base) piperidines-1-yl]-(40mg, 0.15mmol) with 5-isocyanide acyl group-1,2, (37mg is 0.18mmol) at CH for the 3-trimethoxy-benzene for the ring butylamine
2Cl
2Coupling is 1 hour (1ml).By using 100: 9.5: 0.5CH
2Cl
2: MeOH: NH
4The preparation type TLC of OH and obtain free alkali by the preparation type TLC purifying crude product that uses EtOAc subsequently is yellow solid.Et with 1N HCl
2(0.1ml, 0.1mmol) this free alkali of solution-treated is dissolved in CH to O
2Cl
2Resulting solution also is concentrated into and obtains product (26mg, 34%), is the tawny solid:
mp?123.7-127.9℃；IR?3423，2925，1690，1607，1556，1507.Anal.(C
26H
35Cl
2N
3O
4·0.7H
2O)C，H，N。
Embodiment 32: use general method C and the amine and the isocyanic ester that suit to prepare following compounds.
(±)-anti-form-1-2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-(3,4, the 5-trimethoxyphenyl) urea.
Embodiment 33: use general method E and the amine and the carboxylic acid that suit to prepare following compounds.
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl] cyclohexyl }-2-[5-(3,4-dimethoxy-phenyl)-pyrimidine-2-base sulfane base] ethanamide; With
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl] cyclopentyl }-2-[5-(3,4-dimethoxy-phenyl)-pyrimidine-2-base sulfane base] ethanamide.
Embodiment 34: prepare following compounds according to general method F, suitable amine and the carboxylic acid of use.
(±)-cis-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2-[5-(3,4-dimethoxy-phenyl)-pyrimidine-2-base sulfane base] acetamide hydrochloride;
(±)-cis-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclohexyl }-2-[5-(3,4-dimethoxy-phenyl)-pyrimidine-2-base sulfane base] acetamide hydrochloride; With
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclobutyl }-2-[5-(3,4-dimethoxy-phenyl)-pyrimidine-2-base sulfane base] acetamide hydrochloride.
Embodiment 35: prepare following compounds according to general method G, suitable amine and the SULPHURYL CHLORIDE of use.
(±)-trans-4-chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-fluoro-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-ethyl-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-methoxyl group-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2,4-two fluoro-benzsulfamides;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-trifluoromethyl-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-methyl-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-fluoro-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2-fluoro-benzsulfamide;
(±)-trans-2-chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-4-ethanoyl-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-nitro-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-nitro-benzsulfamide;
(±)-trans-3-chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2-methyl-benzsulfamide;
(±)-trans-naphthalene-1-sulfonic acid 2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-acid amides;
(±)-trans-2-chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-fluoro-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3,4-dimethoxy-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2,5-dimethoxy-benzsulfamide;
(±)-trans-2,3-two chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-2,4-two chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-3,4-two chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-4-methylsulfonyl-benzsulfamide;
(±)-trans-4-bromo-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzsulfamide;
(±)-trans-4-chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-3-nitro-benzsulfamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2-nitro-benzsulfamide; With
(±)-trans-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-2-nitro-4-trifluoromethyl-benzsulfamide.
Embodiment 36: prepare following compounds according to general method H, suitable amine and the chloride of acid of use.
(±)-trans-4-chloro-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-fluoro-benzamide;
(±)-trans-2-chloro-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-3-chloro-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-methyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-methyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-methyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-methoxyl group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-trifluoromethyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-methoxyl group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-fluoro-benzamide;
(±)-trans-3-bromo-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-2,4-two chloro-N-{2-[4-(4-benzyl chloride base)-piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-trifluoromethyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-trifluoromethyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3,5-pair-trifluoromethyl-benzamide;
(±)-trans-4-tertiary butyl-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-oxyethyl group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-cyano group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-cyano group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-methoxyl group-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-nitro-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-nitro-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3,5-dimethoxy-benzamide;
(±)-trans-3,4-two chloro-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-4-bromo-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide; With
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-iodo-benzamide.
Embodiment 37: prepare following compounds according to general method I, suitable amine and the carboxylic acid of use.
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-sec.-propyl-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-the isophthalamic acid methyl esters;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-4-methylsulfonyl-benzamide;
(±)-trans-3-ethanoyl-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-o-tolyl-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl-2-between tolyl-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-p-methylphenyl-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(4-fluoro-phenyl)-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(3-methoxyl group-phenyl }-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(4-methoxyl group-phenyl)-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(3-chloro-phenyl)-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(4-chloro-phenyl)-ethanamide;
(±)-trans-5-Methyl-1H-indole-2-formic acid 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-acid amides;
(±)-trans-5-fluoro-1H-indole-2-carboxylic acid 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-acid amides;
(±)-trans-2-(3-bromo-phenyl)-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-ethanamide;
(±)-trans-N-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-2-(3,4, the 5-trimethoxyphenyl)-ethanamide;
(±)-anti-form-1 H-indole-2-carboxylic acid 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-acid amides;
(±)-trans-5-methoxyl group-1H-indole-2-carboxylic acid 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-acid amides; With
(±)-trans-5-chloro-1H-indole-2-carboxylic acid 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-acid amides.
Embodiment 38: prepare following compounds according to general method J, suitable amine and the isocyanic ester of use.
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-chloro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-fluoro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-o-tolyl-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-chloro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-chloro-phenyl) urea;
(±)-anti-form-1-(3-bromo-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-p-methylphenyl-urea;
Tolyl-urea between (±)-anti-form-1-{ 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-methoxyl group-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-methoxyl group-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-methoxyl group-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-cyclohexyl-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-trifluoromethyl-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-trifluoromethyl-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-oxyethyl group-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-sec.-propyl-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-cyano group-phenyl) urea;
(±)-anti-form-1-(3-ethanoyl-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-nitro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-nitro-phenyl) urea;
(±)-trans-2-(3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea groups)-methyl benzoate;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3,5-dimethoxy-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2,4-two chloro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3,5-two chloro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3,4-two chloro-phenyl) urea;
(±)-anti-form-1-(4-bromo-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-fluoro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-fluoro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2,4-two fluoro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2,3-two chloro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-ethyl-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-naphthalene-1-base-urea;
(±)-anti-form-1-(3,5-pair-trifluoromethyl-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-nitro-phenyl) urea; With
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-iodo-phenyl) urea.
Embodiment 39: prepare following compounds according to general method K, suitable amine and the isocyanic ester of use.
(±)-anti-form-1-(4-ethanoyl-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-phenyl-urea;
(±)-anti-form-1-benzyl-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-chloro-2-methyl-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-styroyl-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-styroyl-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2,5-dimethyl-phenyl) urea;
(±)-anti-form-1-(1R, 2R)-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-((S)-1-phenyl-ethyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3,4-dimethoxy-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-trifluoromethoxy-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-trifluoromethoxy-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-trifluoromethyl-phenyl) urea;
(±)-anti-form-1-(the 4-tertiary butyl-phenyl)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-thiophene-2-base-ethyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-methyl-benzyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-chloro-3-nitro-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-fluoro-benzyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-methyl-benzyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-methyl-benzyl) urea;
(±)-anti-form-1-(2-benzyl chloride base)-3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-methoxyl group-benzyl) urea; With
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3, the 4-dichloro benzyl) urea.
Embodiment 40: according to general method L, suitable aniline and the Phoxime resins following compounds of use.
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-oxyethyl group-phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-naphthalene-2-base-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-isoquinoline 99.9-3-base-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2-toluquinoline-6-yl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-methylamino--phenyl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-quinoline-3-base-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-quinoline-2-base-urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(5-hydroxyl-naphthalene-2-yl) urea;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(8-hydroxyl-quinoline-2-yl) urea; With
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(5,7-dimethyl-[1,8] naphthyridine-2-yl) urea.
Embodiment 41: prepare following compounds according to general method M, the suitable aniline of use.
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-quinoline-6-base-urea;
(±)-trans-N-[3-(3-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-urea groups)-phenyl]-ethanamide;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(2,3, the 4-trimethoxyphenyl) urea; With
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-methylsulfonyl-phenyl) urea.
Embodiment 42: prepare following compounds according to general method N, the suitable isothiocyanic acid ester of use.
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-o-tolyl-thiocarbamide;
Tolyl-thiocarbamide between (±)-anti-form-1-{ 2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-;
1-{2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(3-chloro-phenyl)-thiocarbamide;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-p-methylphenyl-thiocarbamide;
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-fluoro-phenyl)-thiocarbamide; With
(±)-anti-form-1-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-3-(4-methoxyl group-phenyl)-thiocarbamide.
Embodiment 43: prepare following compounds according to general method O, the suitable succinimide of use.
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 4-fluoro-benzyl ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 3-benzyl chloride ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 4-benzyl chloride ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 2-benzyl chloride ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 3-nitro-benzyl ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 3-trifluoromethyl-benzyl ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 3,4-benzyl dichloride ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 3,5-benzyl dichloride ester;
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-benzyl carbamate; With
(±)-trans-2-[4-(4-benzyl chloride base) piperidines-1-yl]-cyclopentyl }-carboxylamine 4-nitro-benzyl ester.
Embodiment 44: example of formulations
Be the representational pharmaceutical preparation that contains general formula (I) compound below.Tablet
Following component closely mixed and be pressed into single scored tablet.
Amounts of components/sheet, mg
Compound 400 of the present invention
W-Gum 50
Croscarmellose sodium 25
Lactose 120
Magnesium Stearate 5
Capsule
With the following component hard-shell capsule that closely mixes and pack into.
Amounts of components/capsules, mg
Compound 200 of the present invention
Spray-dired lactose 148
Magnesium Stearate 2
Suspensoid
Following component is mixed into the oral administration suspensoid.
Amounts of components
Compound 1.0g of the present invention
Fumaric acid 0.5g
Sodium-chlor 2.0g
Methyl p-hydroxybenzoate 0.15g
Propylparaben 0.05g
Granulated sugar 25.5g
Sorbyl alcohol (70% solution) 12.85g
Veegum?K(Vanderbit?Co.) 1.0g
Seasonings 0.035ml
Tinting material 0.5mg
The distilled water capacity is to 100ml
Injection
Following component is mixed into injection.
Amounts of components
Compound 0.2g of the present invention
Sodium acetate buffer solution 0.4M 2.0ml
HCl (1N) or NaOH (1N) capacity are to appropriate pH
Water (distillation, aseptic) capacity is to 20ml
Liposomal formulation
Following component is mixed into Liposomal formulation.
Amounts of components
Compound 10mg of the present invention
L-α-phosphatidylcholine 150mg
Trimethyl carbinol 4ml
Sample lyophilize and freeze-drying are spent the night.Salt brine solution with 1ml 0.9% dissolves sample again.Reduce liposome by sonication.
Embodiment 45:CCR-3 receptor binding assays-external
By suppressing
125The binding ability of I eotaxin and CCR-3L1.2 transfectant cell is determined the antagonistic activity (referring to Ponath, P.D. etc. " experiment medicine magazine " are the 183rd volume (J.Exp.Med.), 2437-2448 (1996)) of the CCR-3 of The compounds of this invention.
On the polypropylene round bottom flat board of Costar 96-hole, carry out this test.Test compounds is dissolved in DMSO and uses binding buffer liquid (50mM HEPES, 1mM CaCl.sub., 2.5mM MgCl then
2, 0.5% bovine serum albumin(BSA) (BSA), 0.02% sodiumazide, pH 7.24) dilution, make that final DMSO concentration is 2%.In each hole, add 25 μ l test solns or only contain the damping fluid (control sample) of DMSO, add 25 μ l subsequently
125(Boston is Mass.) with 1.5 * 10 of the binding buffer liquid that is dissolved in 25 μ l for NEX314, New England Nuclear for I-eotaxin (100pmol)
5Individual CCR-3 L1.2 transfectional cell.The end reaction volume is 75 μ l.
After at room temperature this reaction mixture being incubated 1 hour, (Packard, Chicago III) filter this reaction of termination to the Packard Unifilter GF/C filter plate through this reaction mixture is handled by polymine.Descended dry about 10 minutes with filter washing 4 times and at 65 ℃ with the ice-cold wash buffer that contains 10mm HEPES and 0.5M sodium-chlor (pH 7.2).Add 25 μ l/ hole Microscint-20
Scintillation solution (Packard) also passes through to use Packard TopCount
Measure the radioactivity that keeps on the filter.
Compound of the present invention has activity in this test.
| Compound sequence number from table 1 | ?IC50(μM) |
| 1 | 0.5574 |
| 2 | 0.0185 |
| 3 | 1.1438 |
| 4 | 0.8644 |
| 5 | 2.6906 |
| 6 | 1.8558 |
| 7 | 1.4841 |
| 8 | 6.0949 |
| 9 | 5.1191 |
| 10 | 0.5122 |
Embodiment 46: to the restraining effect-in vitro tests of the CCR-3L1.2 transfectant cell chemotaxis of eotaxin mediation
Can be by using to Ponath, P.D. wait at " Journal of Clinical Investigation " (J.Clin.Invest.) 97, the method that method is revised a little described in the 604-612 (1996) is measured the antagonistic activity of the chemotaxis of the CCR-3L1.2 transfectant cell of eotaxin mediation being determined the CCR-3 of The compounds of this invention.(Costar Corp., Cambridge carry out these tests in Mass) at 24-hole chemotactic flat board.CCR-3L1.2 transfectant cell is grown in contains RPMI 1640,10%Hyclone
In the substratum of foetal calf serum, 55mM 2 mercapto ethanol and Geneticin 418 (0.8mg/ml).Before this test is carried out 18-24 hour is 5mM/1 * 10 with final concentration
6The butanic acid of individual cell/ml is handled cells transfected, separation and with 1 * 10
7Individual cell/ml is suspended in RPMI 1640 that contains equal portions and the test medium of the substratum 199 (M199) that has 0.5% bovine serum albumin(BSA) again.
To join with the people eotaxin that 1mg/ml is suspended in phosphate-buffered saline in the bottom compartment to final concentration be 100nm.The Transwell that will have 3 microns hole sizes cultivates insert, and (Mass) inserting the indoor adding final volume in each Kong Bingxiang top is the L1.2 cell (1 * 10 of 100 μ l for Coatar Corp., Cambridge
6).The test compounds that will be dissolved in DMSO joins in upper chambers and the bottom compartment, makes that final DMSO volume is 0.5%.Two groups of reference substances carry out this tests.Positive control upper chambers contain cell and do not contain test compounds and only eotaxin be positioned at bottom compartment.Negative control upper chambers contain cell and do not contain test compounds and down the indoor eotaxin that neither contains or not test compounds yet.Be incubated this flat board down at 37 ℃.After 4 hours, from the chamber, take out insert (insert) also by 500 μ l cell suspensions being counted them 30 seconds and the cell that migrates into bottom compartment is counted from down indoor suction 1.2ml Cluster pipe (Costar) and with FACS with transfer pipet.
Embodiment 47: to the chemotactic restraining effect-in vitro tests of people's eosinophilic granulocyte of eotaxin mediation
Can use Carr, M.W. etc. " NAS's journal " (Proc.Natl.Acad.Sci.USA) method is revised a little described in the 91:3652-3656 (1994) method estimate the chemotactic ability of people's eosinophilic granulocyte that The compounds of this invention suppresses the eotaxin mediation.(Coatar Corp., Cambridge Mass) experimentizes to use 24 hole chemotactic flat boards.Use the step described in the PCT application publication number WO96/22371 from blood, to separate eosinophilic granulocyte.Used endotheliocyte be available from European animal cell culture preservation endothelial cell line ECV 304 (Porton Down, Salisbury, U.K.).On 6.5mm diameter Biocoat.RTM, cultivate endotheliocyte.(Costar Corp., Cambridge Mass) have 3.0 μ M hole sizes to Transwell tissue culture insert.ECV 304 cell culture mediums are made up of M199,10% foetal calf serum, L-glutaminate and microbiotic.Test medium is made up of the RPMI 1640 of equal portions and M199 and 0.5%BSA.In test preceding 24 hours, ECV304 cell flat board is fixed on the insert of 24-hole chemotactic flat board and 37 ℃ of insulations down.To join in the bottom compartment with the 20nM eotaxin of test medium dilution.Final volume in the bottom compartment is 600 μ l.The tissue culture insert of interior suitcase quilt is inserted each hole.10 of 100 μ l test damping fluid will be suspended in
6Individual eosinophilic granulocyte joins in the upper chambers.The test compounds that will be dissolved in DMSO joins in upper chambers and the bottom compartment, makes that the final DMSO volume in each hole is 0.5%.Two groups of reference substances carry out this tests.Positive control contains cell and is descending the indoor eotaxin of containing in upper chambers.Negative control contains cell and is descending the indoor test damping fluid that only contains in upper chambers.Should descend and 5%CO at 37 ℃ by flat board
2Insulation is 1-1.5 hour in/95% air.
Use flow cytometer to migrating to the cell counting in the bottom compartment.To put into test tube and obtain relative cell counting from 500 μ l cell suspensions in the bottom compartment by the result who obtains 30 seconds setting-up time time limits.
Embodiment 48:CCR-3 antagonist is to the restraining effect-in vivo test of the eosinophilic granulocyte of the Balb/c mouse lung of inflow ovalbumin sensitization
Can carry out determining that by eosinophilic granulocyte cumulative restraining effect in measuring the balb/c mouse bronchial bronchoalveolar lavage fluid (BAL) that enters ovalbumin (OA)-sensitization The compounds of this invention suppresses the ability that leukocyte infiltration is gone into lung after antigen is attacked with aerosol.Briefly, make the male balb/c mouse sensitization of heavy 20-25g with OA (the 0.2ml aluminium hydroxide solution of 10 μ g) through intraperitoneal the 1st day and the 14th day.After 1 week, mouse is divided into 10 groups.Through intraperitoneal, subcutaneous or orally give test compounds or carrier (control group) is only arranged or anti--eotaxin antibody (positive controls).After 1 hour, mouse put into the synthetic glass chamber and makes their contacts that (Va) the OA aerosol of Chan Shenging is 20 minutes for PARI, Richmond by the PARISTAR.TM. nebulizer.As the mouse that comprises sensitization not or attack in the negative control group.After 24 or 72 hours, anesthetized mice (the about 1g/kg intraperitoneal of urethane), insert trachea cannula (PE60 conduit) and with 0.3ml PBS with lung lavage 4 times.Change BAL liquid over to plastics tubing and remain on ice.With Coulter Counter.TM. (Coulter, Miami, Fla.) total leukocyte in the mensuration 20 μ l BAL liquid aliquots.By opticmicroscope, use standard type standard the painted Cytospin.TM. goods of Wright ' s dyestuff (DiffQuick.TM.) with modification are carried out Arneth's count.
More specifically described the invention described above by explanation and embodiment, purpose is to be aware and understand.Those skilled in the art obviously can implement to change and revise in the claim scope that awaits the reply.Therefore, be understandable that foregoing description is used for explaining and non-limiting.Scope of the present invention is not with reference to foregoing description thus, and should determine with reference to the following scope that is equal to fully with this class claim that awaits the reply claim and authorize.
The full content of introducing the application's all patents, patent application and public publication is incorporated herein by reference, and the degree of being introduced is identical with the degree that each patent, patent application or public publication are mentioned separately.
Claims (22)
1. racemize and the non-racemic mixture and the pharmaceutically acceptable salt thereof of the ester class of the hydroxy functional group on the compound of general formula (I) or general formula (I) compound or amino formate, each steric isomer, steric isomer:
Wherein:
R
1Be (C
1-C
2) alkylidene group;
R
2It is the optional phenyl that replaces;
R
3Be hydrogen, C
1-C
6Alkyl, acyl group, aryl or aryl C
1-C
6Alkyl;
Ring A is C
3-C
7Cycloalkyl, heterocyclic radical or the optional phenyl that replaces;
L is-C (=O)-,-C (=S)-,-SO
2-,-C (=O) N (R
a)-,-C (=S) N (R
a)-, SO
2N (R
a)-,-C (=O) O-,-C (=S) O-;
R wherein
aBe hydrogen, C
1-C
6Alkyl, acyl group, aryl, aryl C
1-C
6Alkyl, C
1-C
6Carbalkoxy or carbobenzoxy-(Cbz);
X do not exist, for-(CR ' R ") O-,-(CR ' R ") S-,-(CR ' R ") NR
b-or C
1-C
6Alkylidene group;
Wherein " independent is hydrogen or C for R ' and R
1-C
6Alkyl and R
bBe hydrogen or C
1-C
6Alkyl;
R
4Be aryl or heteroaryl; And
R
5Be hydrogen or C
1-C
6Alkyl;
Condition is to work as R
1Be-CH
2-, R
2Be phenyl, R
3Be hydrogen, R
5Be hydrogen, A be phenyl, L be-C (=when O) NH-and X do not exist, R then
4Not 2, the 5-difluorophenyl;
Wherein:
Term " the optional phenyl that replaces " refers to the optional phenyl that is replaced by one or more substituting groups, and described substituting group is selected from C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, assorted alkyl, acyl group, amido, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, C
1-C
6Alkyl sulphinyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Alkoxyl group, halo C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, formamyl, hydroxyl, halogen, nitro, methylene-dioxy or ethylenedioxy are formed;
Term " acyl group " refers to group-C (O) R, and wherein R is hydrogen, C
1-C
6Alkyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyl C
1-C
6Alkyl, phenyl or phenyl C
1-C
6Alkyl;
Term " aryl " refers to the monocycle or the di pah group of 6-10 annular atoms, and it is chosen wantonly and is replaced by one or more substituting groups, and described substituting group is selected from C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, assorted alkyl, acyl group, amido, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, C
1-C
6Alkyl sulphinyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Alkoxyl group, halo C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, formamyl, hydroxyl, halogen, nitro, methylene-dioxy or ethylenedioxy are formed;
Term " heteroaryl " refers to the monocycle that contains at least one aromatic ring or the bicyclic groups of 5-12 annular atoms, wherein said aromatic ring contains 1,2 or 3 ring hetero atoms that are selected from N, O or S, remaining annular atoms is C, the tie point that should understand described heteroaryl is positioned on the aromatic ring, and this hetero-aromatic ring is optional to be replaced by one or more substituting groups independently, and described substituting group is selected from C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, assorted alkyl, acyl group, amido, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, C
1-C
6Alkyl sulphinyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Alkoxyl group, halo C
1-C
6Alkoxyl group, C
1-C
6Carbalkoxy, formamyl, hydroxyl, halogen, methylene-dioxy, ethylenedioxy or the optional phenyl that replaces;
Term " assorted alkyl " refers to C
1-C
6Alkyl, wherein 1,2 or 3 hydrogen atoms are independently selected from-OR
a,-NR
bR
cWith-S (O)
nR
dThe substituting group of the group of forming replaces, and wherein n is the integer of 0-2, and the tie point that should understand described assorted alkyl is by carbon atom, wherein R
aBe hydrogen, acyl group, C
1-C
6Alkyl, C
3-C
7Cycloalkyl or C
3-C
7Cycloalkyl C
1-C
6Alkyl; R
bAnd R
cIndependently of one another is hydrogen, acyl group, C
1-C
6Alkyl, C
3-C
7Cycloalkyl or C
3-C
7Cycloalkyl C
1-C
6Alkyl; When n is 0, R
dBe hydrogen, C
1-C
6Alkyl, C
3-C
7Cycloalkyl or C
3-C
7Cycloalkyl C
1-C
6Alkyl; And when n is 1 or 2, R
dBe C
1-C
6Alkyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyl C
1-C
6Alkyl, amino, amido, a C
1-C
6Alkylamino or two C
1-C
6Alkylamino;
Term " heterocyclic radical " refers to the saturated or undersaturated non-aromatic ring shape group of 3-8 annular atoms, and one of them or two annular atomses are to be selected from NR
x, O or S (O)
nHeteroatoms, each R wherein
xIndependent is hydrogen, C
1-C
6Alkyl, acyl group, C
1-C
6Alkyl sulphonyl, amino-sulfonyl, (C
1-C
6Alkylamino) alkylsulfonyl, (two C
1-C
6Alkylamino) alkylsulfonyl, formamyl, (C
1-C
6Alkylamino) carbonyl, (two C
1-C
6Alkylamino) carbonyl, (formamyl) C
1-C
6Alkyl, (C
1-C
6Alkylamino) carbonyl C
1-C
6Alkyl or two C
1-C
6Alkyl amino-carbonyl C
1-C
6Alkyl, n are the integers of 0-2, and remaining annular atoms is that C and this heterocycle can be chosen wantonly independently by 1,2 or 3 substituting groups and replace, and described substituting group is selected from C
1-C
6Alkyl; Halo C
1-C
6Alkyl; Assorted alkyl; Halogen; Hydroxyl; C
1-C
6Alkoxyl group; Amino;-C
1-C
6Alkylamino; Two C
1-C
6Alkylamino; Aryl C
1-C
6Alkyl;-(X)
n-COR, wherein X is O or NR ', and n is 0 or 1, and R is hydrogen, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, amino, a C
1-C
6Alkylamino, two C
1-C
6Alkylamino or the optional phenyl that replaces, and R ' is hydrogen or C
1-C
6Alkyl;-C
1-C
6Alkylidene group-C (O) R, wherein R is hydrogen, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, amino ,-C
1-C
6Alkylamino, two C
1-C
6Alkylamino or the optional phenyl that replaces; Or-S (O)
nR
d, wherein n is the integer of 0-2, and R
dBe C
1-C
6Alkyl, halo C
1-C
6Alkyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyl C
1-C
6Alkyl, amino ,-C
1-C
6Alkylamino, two C
1-C
6Alkylamino, hydroxyl C
1-C
6Alkyl or hydrogen, condition are that n is 0.
2. the described compound of claim 1 is the compound of general formula (II):
R wherein
1-R
5, A, L and X as defined in claim 1.
3. the described compound of claim 1 is the compound of general formula (III):
R wherein
1-R
5, A, L and X as defined in claim 1.
4. any described compound, wherein a R among the claim 1-3
1It is methylene radical.
5. any described compound, wherein a R among the claim 1-3
2Be 4-chloro-phenyl-or 3, the 4-dichlorophenyl.
6. any described compound, wherein a R among the claim 1-3
3Be hydrogen.
7. any described compound among the claim 1-3, wherein L be-C (=O)-,-SO
2-,-C (=O) N (R
a)-,-C (=S) N (R
a)-or-C (=O) O-.
8. the described compound of claim 7, wherein L be-C (=O)-.
9. the described compound of claim 1 is the compound of general formula (IV):
R wherein
3, R
4, A, L and X as defined in claim 1.
10. the described compound of claim 1 is the compound of general formula (VI):
Wherein X and R
4As defined in claim 1.
11. the described compound of claim 7, wherein X does not exist, is methylene radical, 1,2-second two bases, 1,3-glyceryl or 1,4-fourth two bases.
12. the described compound of claim 11, wherein R
4Be 3; the 4-dichlorophenyl; 3; 4; the 5-trimethoxyphenyl; 4-methylsulfonyl phenyl; 3-methylsulfonyl phenyl; 4-methoxynaphthalene-2-base; 5-(3; the 4-Dimethoxyphenyl) pyrimidine-2-base; phenyl; the 3-fluorophenyl; the 4-ethylphenyl; the 3-p-methoxy-phenyl; 2; the 4-difluorophenyl; the 3-trifluoromethyl; the 4-aminomethyl phenyl; the 4-fluorophenyl; the 2-fluorophenyl; 4-formamyl phenyl; 3-formamyl phenyl; the 4-acetylphenyl; the 4-nitrophenyl; the 2-aminomethyl phenyl; 2-chloro-4-fluorophenyl; 3; the 4-Dimethoxyphenyl; 2; the 5-Dimethoxyphenyl; 2; the 3-dichlorophenyl; 2; the 4-dichlorophenyl; the 4-bromophenyl; 4-chloro-3-nitrophenyl; the 2-nitrophenyl; 2-nitro-4-trifluoromethyl; the 4-chloro-phenyl-; the 3-chloro-phenyl-; the 2-chloro-phenyl-; the 3-aminomethyl phenyl; the 2-trifluoromethyl; the 2-p-methoxy-phenyl; the 3-bromophenyl; the 4-trifluoromethyl; the 3-trifluoromethyl; 3; 5-pair-trifluoromethyl; the 4-tert-butyl-phenyl; the 4-ethoxyl phenenyl; the 3-cyano-phenyl; the 4-cyano-phenyl; the 4-p-methoxy-phenyl; the 3-nitrophenyl; 3; the 5-Dimethoxyphenyl; the 4-iodophenyl; the 4-isopropyl phenyl; 3-methoxycarbonyl phenyl; the 3-acetylphenyl; the 2-aminomethyl phenyl; indoles-2-base; 5-methoxyl group indoles-2-base; 5-chloro-indole-2-base; 2-methoxycarbonyl phenyl; 3; the 5-dichlorophenyl; the 1-naphthyl; 3-chloro-2-aminomethyl phenyl; 2; the 5-3,5-dimethylphenyl; the 2-thienyl; the 3-ethoxyl phenenyl; the 3-isoquinolyl; 2-toluquinoline-6-base; 3-methylamino-phenyl; the 3-quinolyl; the 2-quinolyl; 5-hydroxyl naphthalene-2-base; oxine-2-base; 5; 7-dimethyl-[1; 8] naphthyridine-2-base; the 6-quinolyl; 3-(kharophen) phenyl or 2; 3, the 4-trimethoxyphenyl.
13. the described compound of claim 12, wherein R
4Be 3,4,5-trimethoxyphenyl, 4-ethanoyl-phenyl, 3-formamyl phenyl, 4-formamyl phenyl, 3-methylsulfonyl phenyl or 4-methylsulfonyl phenyl.
14. described compound of claim 8 and salt thereof, wherein X is-CH
2S-and R
4Be 5-(3, the 4-Dimethoxyphenyl)-pyrimidine-2-base, 5-(3, the 4-methylenedioxyphenyl)-pyrimidine-2-base or 5-(4-p-methoxy-phenyl) pyrimidine-2-base.
15. the described compound of claim 1, wherein encircling A is C
3-C
7Cycloalkyl or heterocyclic radical or the phenyl that is replaced by following group: C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, assorted alkyl, acyl group, amido, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, C
1-C
6Alkyl sulphinyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Alkoxyl group, halo C
1-C
6Alkoxyl group, C
1-C
6Carbalkoxy, formamyl, hydroxyl, halogen, nitro, methylene-dioxy or ethylenedioxy.
16. the described compound of claim 15, wherein encircling A is C
3-C
7Cycloalkyl or heterocyclic radical.
17. the described compound of claim 1, wherein R
2The phenyl that is replaced by following group: C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, assorted alkyl, acyl group, amido, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, C
1-C
6Alkyl sulphinyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Alkoxyl group, halo C
1-C
6Alkoxyl group, C
1-C
6Carbalkoxy, formamyl, hydroxyl, halogen, nitro, methylene-dioxy or ethylenedioxy.
18. the method for general formula (I) compound of preparation claim 1, wherein L is-C (=O) NR
a-, R
aBe hydrogen; This method comprises the compound that makes general formula (Ia)
With general formula: R
4The isocyanate reaction of-N=C=O.
19. the method for general formula (I) compound of preparation claim 1, wherein L be-C (=O)-; This method comprises the compound that makes general formula (Ia)
With general formula: R
4-C (=O) the compound reaction of OH.
20. composition contains compound or its salt any among the claim 1-17 and vehicle.
21. the compound or its salt of any general formula (I) is used for the treatment of application in the medicine of disease of available CCR-3 receptor antagonist treatment in preparation among the claim 1-17.
22. the described application of claim 21, wherein said disease is an asthma.
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|---|---|---|---|
| US33465301P | 2001-11-30 | 2001-11-30 | |
| US60/334,653 | 2001-11-30 |
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| CN1286831C true CN1286831C (en) | 2006-11-29 |
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ID=23308166
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Country Status (12)
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|---|---|
| EP (1) | EP1453825A1 (en) |
| JP (1) | JP2005515193A (en) |
| KR (1) | KR100652450B1 (en) |
| CN (1) | CN1286831C (en) |
| AR (1) | AR037458A1 (en) |
| AU (1) | AU2002352123A1 (en) |
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| US7491737B2 (en) * | 2002-10-30 | 2009-02-17 | Merck & Co., Inc. | Heterarylpiperidine modulators of chemokine receptor activity |
| IN2006CH00378A (en) * | 2003-06-30 | 2007-05-11 | Sumitomo Chemical Co | Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst |
| WO2005058805A1 (en) * | 2003-12-17 | 2005-06-30 | Sumitomo Chemical Company, Limited | Process for producing optically active amine compound |
| US7635698B2 (en) | 2004-12-29 | 2009-12-22 | Millennium Pharmaceuticals, Inc. | Compounds useful as chemokine receptor antagonists |
| WO2006071875A1 (en) | 2004-12-29 | 2006-07-06 | Millennium Pharmaceuticals, Inc. | Compounds useful as chemokine receptor antagonists |
| EP2805985A1 (en) * | 2013-05-22 | 2014-11-26 | Sika Technology AG | Polymer containing hydroxysilane and silane groups |
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| US6444686B1 (en) * | 1998-12-18 | 2002-09-03 | Brsitol-Myers Squibb Pharma Company | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
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2002
- 2002-11-25 EP EP02787796A patent/EP1453825A1/en not_active Withdrawn
- 2002-11-25 CA CA002467874A patent/CA2467874A1/en not_active Abandoned
- 2002-11-25 JP JP2003547387A patent/JP2005515193A/en active Pending
- 2002-11-25 KR KR1020047008357A patent/KR100652450B1/en not_active IP Right Cessation
- 2002-11-25 AU AU2002352123A patent/AU2002352123A1/en not_active Abandoned
- 2002-11-25 BR BR0214613-4A patent/BR0214613A/en not_active IP Right Cessation
- 2002-11-25 WO PCT/EP2002/013218 patent/WO2003045937A1/en active Application Filing
- 2002-11-25 CN CNB028239784A patent/CN1286831C/en not_active Expired - Fee Related
- 2002-11-25 PL PL02370821A patent/PL370821A1/en not_active Application Discontinuation
- 2002-11-25 RU RU2004120064/04A patent/RU2004120064A/en not_active Application Discontinuation
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| KR100652450B1 (en) | 2007-02-28 |
| AU2002352123A1 (en) | 2003-06-10 |
| MXPA04005176A (en) | 2004-08-11 |
| BR0214613A (en) | 2004-09-14 |
| PL370821A1 (en) | 2005-05-30 |
| JP2005515193A (en) | 2005-05-26 |
| WO2003045937A1 (en) | 2003-06-05 |
| CA2467874A1 (en) | 2003-06-05 |
| CN1599733A (en) | 2005-03-23 |
| AR037458A1 (en) | 2004-11-10 |
| KR20040062665A (en) | 2004-07-07 |
| EP1453825A1 (en) | 2004-09-08 |
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