CN100490811C - Piperazine derivative used as CCRS antagonist - Google Patents

Piperazine derivative used as CCRS antagonist Download PDF

Info

Publication number
CN100490811C
CN100490811C CNB2004100858485A CN200410085848A CN100490811C CN 100490811 C CN100490811 C CN 100490811C CN B2004100858485 A CNB2004100858485 A CN B2004100858485A CN 200410085848 A CN200410085848 A CN 200410085848A CN 100490811 C CN100490811 C CN 100490811C
Authority
CN
China
Prior art keywords
alkyl
solution
product
pharmaceutical composition
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB2004100858485A
Other languages
Chinese (zh)
Other versions
CN1636567A (en
Inventor
B·M·布罗蒂
J·W·克拉德
H·B·约斯恩
S·W·麦坎比
B·A·麦基特里克
M·W·米勒
B·R·纽斯塔德特
A·帕拉尼
E·M·史密斯
R·斯特恩斯马
J·R·塔加特
S·F·维斯
M·A·劳林
E·吉尔博特
M·A·拉布罗利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Priority to CNB2004100858485A priority Critical patent/CN100490811C/en
Priority claimed from PCT/US2000/011632 external-priority patent/WO2000066558A1/en
Publication of CN1636567A publication Critical patent/CN1636567A/en
Application granted granted Critical
Publication of CN100490811C publication Critical patent/CN100490811C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses piperazine derivative as CCR5 agonist and its medicinal salt. The compound is used in treating HIV, organ graft rejection, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory enteritis, idiotypic dermatitis, etc. The present invention also discloses new compound and the medicinal composition containing the new compound. The CCR5 agonist of the present invention is applied together with the antiviral preparation for treating HIV and medicine for treating inflammatory diseases.

Description

Bridged piperazine derivatives as the CCR5 antagonist
Background technology
The present invention relates to the bridged piperazine derivatives as selectivity CCR5 antagonist, contain the pharmaceutical composition of this chemical compound and use the Therapeutic Method of this chemical compound.The present invention also relates to the purposes that CCR5 antagonist of the present invention and one or more antiviral agent or other are used for the treatment of the medication combined medication of HIV (human immunodeficiency virus) (HIV).The invention further relates to CCR5 antagonist of the present invention unites in the repulsion of treatment solid organ transplantation, graft versus host disease, arthritis separately or with other medicines, rheumatoid arthritis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, the purposes in allergy or the multiple sclerosis.
The global healthy crisis that is caused by the pathogen HIV of acquired immune deficiency syndrome (AIDS) (AIDS) is undoubted; though the latest developments in Drug therapy have successfully slowed down the development of AIDS; but still need to find safer; more effective, more inexpensive approach is controlled this virus.
There has been report CCR5 gene serving as the effect that antagonism HIV infects.HIV infects from virus by being connected on the target cell membrane with cell receptor CD4 and the interaction of molecules of secondary chemotactic factor accessory receptor, and is undertaken by duplicate and propagate infected cell in blood and other tissue.Knownly have a multiple chemokine receptors, but for macrophage-have a liking for tropism HIV (a kind of be considered to infect the crucial pathogenic strain that duplicates in vivo in early days), it is CCR5 that HIV enters the necessary important chemokine receptors of cell.Therefore, the interaction of viral interference receptor CCR 5 and HIV can stop HIV to enter cell.The present invention relates to micromolecular compound for the CCR5 antagonist.
It is reported that the CCR-5 receptor is in inflammation disease such as arthritis, rheumatoid arthritis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, mediated cell shifts in the allergy, and the inhibitor of this receptor is supposed to be used for these diseases and other inflammation disease or symptom, as inflammatory bowel, multiple sclerosis, the treatment of solid organ transplantation repulsion and graft versus host disease.
The relevant bridged piperazine derivatives that is used for cognitive illnesses such as treatment of alzheimer's disease as muscarine antagonist is disclosed in United States Patent (USP) 5,883,096; 6,037,352; 5,889,006.
A.M.Vandamme etc. exist Antiviral chemistry and chemotherapy( Antiviral Chemistry ﹠amp; Chemotherapy), disclose the clinical treatment method that present HIV-1 infects among the 9:187-203 (1998) and comprised at least three kinds of drug combinations or so-called high activity antiretroviral therapy (Highly Active antiretroviralTherapy) (" HAART ") in human body; HAART comprises multiple nucleoside reverse transcriptase inhibitor (" NRTI "), the drug combination of non-nucleoside reverse transcriptase inhibitors (" NNRTI ") and hiv protease inhibitor (" PI ").For the patient of first medication (drug-naive), HAART can reduce mortality rate and effectively by the development of HIV-1 to AIDS.But this multiple medicines thing therapy can not eliminate HIV-1 and long-term treatment can cause multidrug resistance usually.It is preferential all the time that exploitation can provide the new Drug therapy of better HIV-1 treatment.
Summary of the invention
The present invention relates to the treatment of HIV, comprise CCR5 antagonist or its pharmaceutical salts represented by structural formula I to the administration effective dose of this treatment of needs:
Figure C200410085848D00131
Wherein
R is R 8-phenyl, R 8-pyridine radicals, R 8-thienyl or R 8-naphthyl;
R 1Be hydrogen atom or C 1-C 6Alkyl;
R 2Be R 9, R 10, R 11-phenyl; R 9, R 10, R 11The 6-unit heteroaryl of-replacement; R 9, R 10, R 11The heteroaryl N-of the 6-unit oxide of-replacement; R 12, R 13The 5-unit heteroaryl of-replacement; Naphthyl; Fluorenyl; Diphenyl methyl
Figure C200410085848D00132
R 3Be hydrogen atom, C 1-C 6Alkyl, (C 1-C 6) alkoxyl (C 1-C 6) alkyl, C 3-C 10Cycloalkyl, C 3-C 10Cycloalkyl (C 1-C 6) alkyl, R 8-phenyl, R 8-phenyl (C 1-C 6) alkyl, R 8-naphthyl, R 8-naphthyl (C 1-C 6) alkyl, R 8-heteroaryl or R 8-heteroaryl (C 1-C 6) alkyl;
R 4, R 5, R 7And R 13Be selected from hydrogen atom and (C respectively 1-C 6)-alkyl;
R 6Be hydrogen atom, C 1-C 6Alkyl, C 2-C 6Alkenyl;
R 8Be 1 to 3 and be selected from following substituent group respectively: hydrogen atom, halogen, C 1-C 6Alkyl, C 1-C 6Alkoxyl ,-CF 3, CF 3O-, CH 3C (O)-,-CN; CH 3SO 2-, CF 3SO 2-, R 14-phenyl, R 14-benzyl,
CH 3C(＝NOCH 3)，CH 3C(＝NOCH 2CH 3)，
Figure C200410085848D00141
-NH 2，-NHCOCF 3，
-NHCONH (C 1-C 6Alkyl) ,-NHCO (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 6Alkyl), 5-unit heteroaryl and
Figure C200410085848D00142
Wherein X is-O-,-NH-or-N (CH 3)-;
R 9And R 10Be selected from (C respectively 1-C 6) alkyl, halogen ,-NR 17R 18,-OH ,-CF 3, OCH 3, O-acyl group ,-OCF 3With-Si (CH 3) 3
R 11Be R 9, hydrogen atom, phenyl ,-NO 2,-CN ,-CH 2F ,-CHF 2,-CHO ,-CH=NOR 17, pyridine radicals, pyridine radicals N-oxide, pyrimidine radicals, pyrazinyl ,-N (R 17)-CONR 18R 19,-NHCONH (chloro-(C 1-C 6) alkyl) ,-NHCONH ((C 3-C 1)) cycloalkyl (C 1-C 6) alkyl) ,-NHCO (C 1-C 6) alkyl ,-NHCO CF 3,-NHSO 2N ((C 1-C 6) alkyl) 2,-NHSO 2(C 1-C 6) alkyl) ,-N (SO 2CF 3) 2,-NHCO 2(C 1-C 6) alkyl), C 3-C 10Cycloalkyl ,-SR 20,-SOR 20,-SO 2R 20,-SO 2NH (C 1-C 6) alkyl) ,-OSO 2(C 1-C 6) alkyl) ,-OSO 2CF 3, hydroxyl (C 1-C 6) alkyl ,-CONR 17R 18, CON (CH 2CH 2-O-CH 3) 2,-OCONH (C 1-C 6) alkyl, CO 2R 17, Si (CH 3) 3Or-B (OC (CH 3) 2) 2
R 12Be (C 1-C 6) alkyl ,-NH 2Or R 14-phenyl;
R 14Be 1 to 3 and be selected from following substituent group respectively: hydrogen atom, (C 1-C 6) alkyl ,-CF 3,-CO 2R 17,-CN, (C 1-C 6) alkoxyl and halogen;
R 15And R 16Be selected from hydrogen atom and C respectively 1-C 6Alkyl, or R 15And R 16Be C together 2-C 5Alkylidene and form the volution that contains 3 to 6 carbon atoms with the carbon atom that links to each other with them;
R 17, R 18And R 19Be selected from H and C respectively 1-C 6Alkyl; And
R 20Be C1-C 6Alkyl or phenyl.
Preferred formula I chemical compound is that wherein R is R 8-phenyl or R 8-naphthyl, particularly R wherein 8Be single substituent group, and R wherein particularly 8Substituent group is in the 4-position.For R 8-phenyl, preferred R8 substituent group is-CF 3,-OCF 3, CH 3SO 2-, CH 3CO-, CH 3C (=NOCH 3)-, Br and I.For R 8-naphthyl, R 8Be preferably C 1-C 6Alkoxyl.R wherein 3Be hydrogen atom, (C 1-C 6) alkyl, R 8-phenyl, R 8-benzyl or R 8The formula I chemical compound of-pyridine radicals also is preferred; Preferred R 3Definition is a methyl, ethyl, phenyl, benzyl and pyridine radicals.R 1Be preferably hydrogen atom.For formula I chemical compound, R 6Be preferably hydrogen atom or methyl, particularly methyl.R 4Be preferably methyl; R 5And R 7Be preferably hydrogen atom respectively.
In formula I chemical compound, R 2R preferably 9, R 10, R 11-phenyl, R 9, R 10, R 11-pyridine radicals or its N-oxide, or R 9, R 10, R 11-pyrimidine radicals.Work as R 2When being pyridine radicals, be preferably 3-or 4-position pyridine radicals, and when for pyrimidine radicals, be preferably 5-position pyrimidine radicals.R 9And R 10Substituent group preferably be connected be connected this ring and molecule on the adjacent carbon atom of the carbon atom of other parts and R 11Substituent group can be connected on the remaining any unsubstituted ring carbon atom, for example descends shown in the array structure:
Figure C200410085848D00151
With
Figure C200410085848D00152
R 9And R 10Substituent group is preferably: (C 1-C 6) alkyl, particularly methyl; Halogen, particularly chlorine or bromine ,-OH and-NH 2Work as R 2When being phenyl, R 11Be preferably hydrogen atom or-OH; Work as R 2When being pyridine radicals, R 11Be preferably hydrogen atom; And work as R 2When being pyrimidine radicals, R 11Be preferably hydrogen atom, methyl or phenyl.Particularly preferred R 2Examples of groups is as follows:
Figure C200410085848D00161
Also required new CCR5 agonist compounds or its pharmaceutical salts shown in the structural formula II,
Figure C200410085848D00162
Wherein
(1) R aBe R 8a-phenyl, R 8b-pyridine radicals, R 8b-thienyl or R 8-naphthyl;
R 1Be hydrogen atom or C 1-C 6Alkyl;
R 2Be R 9, R 10, R 11-phenyl; R 9, R 10, R 11The 6-unit heteroaryl of-replacement; R 9, R 10, R 11The heteroaryl N-of the 6-unit oxide of-replacement; R 12, R 13The 5-unit heteroaryl of-replacement; Naphthyl; Fluorenyl; Diphenyl methyl,
Figure C200410085848D00163
R 3Be hydrogen atom, C 1-C 6Alkyl, (C 1-C 6) alkoxyl (C 1-C 6) alkyl, C 3-C 10Cycloalkyl, C 3-C 10Cycloalkyl (C 1-C 6) alkyl, R 8-phenyl, R 8-phenyl (C 1-C 6) alkyl, R 8-naphthyl, R 8-naphthyl (C 1-C 6) alkyl, R 8-heteroaryl or R 8-heteroaryl (C 1-C 6) alkyl;
R 4, R 5, R 7And R 13Be selected from hydrogen atom and (C respectively 1-C 6)-alkyl;
R 6Be hydrogen atom, C 1-C 6Alkyl or C 2-C 6Alkenyl;
R 8Be 1 to 3 and be selected from following substituent group respectively: hydrogen atom, halogen, C 1-C 6Alkyl, C 1-C 6Alkoxyl ,-CF 3, CF 3O-, CH 3C (O)-,-CN, CH 3SO 2-, CF 3SO 2-, R 14-phenyl, R 14-benzyl,
CH 3C(＝NOCH 3)，CH 3C(＝NOCH 2CH 3)，
Figure C200410085848D00171
-NH 2，-NHCOCF 3，
-NHCONH (C 1-C 6Alkyl) ,-NHCO (C 1-C 6Alkyl) ,-NHSO 2(C 1-C 6Alkyl), 5-unit heteroaryl and
Wherein X is-O-,-NH-or-N (CH 3)-;
R 8aBe 1 to 3 and be selected from following substituent group respectively: hydrogen atom, halogen ,-CF 3, CF 3O-,-CN, CF 3SO 2-, R 14-phenyl ,-NHCOCF 3, 5-unit heteroaryl and
Wherein the definition of X as above;
R 8bBe 1 to 3 and be selected from following substituent group respectively: hydrogen atom, halogen ,-CF 3, CF 3O-, CH 3C (O)-,-CN, CF 3SO 2-, R 14-benzyl, CH 3C (=NOCH 3), CH 3C (=NOCH 2CH 3),
Figure C200410085848D00181
-NHCOCF 3, 5-unit heteroaryl and
Figure C200410085848D00182
Wherein the definition of X as above;
R 9And R 10Be selected from (C respectively 1-C 6) alkyl, halogen ,-NR 17R 18,-OH ,-CF 3,-OCH 3, O-acyl group ,-OCF 3With-Si (CH 3) 3
R 11Be R 9, hydrogen atom, phenyl ,-NO 2,-CN ,-CH 2F ,-CHF 2,-CHO ,-CH=NOR 17, pyridine radicals, pyridine radicals N-oxide, pyrimidine radicals, pyrazinyl ,-N (R 17)-CONR 18R 19,-NHCONH (chloro-(C 1-C 6) alkyl) ,-NHCONH ((C 3-C 1)) cycloalkyl (C 1-C 6) alkyl) ,-NHCO (C 1-C 6) alkyl ,-NHCO CF 3,-NHSO 2N ((C 1-C 6) alkyl) 2,-NHSO 2(C 1-C 6) alkyl ,-N (SO 2CF 3) 2,-NHCO 2(C 1-C 6) alkyl), C 3-C 10Cycloalkyl ,-SR 20,-SOR 20,-SO 2R 20,-SO 2NH (C 1-C 6) alkyl) ,-OSO 2(C 1-C 6) alkyl) ,-OSO 2CF 3, hydroxyl (C 1-C 6) alkyl ,-CONR 17R 18,-CON (CH 2CH 2-O-CH 3) 2,-OCONH (C 1-C 6) alkyl ,-CO 2R 17,-Si (CH 3) 3Or-B (OC (CH 3) 2) 2
R 12Be (C 1-C 6) alkyl ,-NH 2Or R 14-phenyl;
R 14Be 1 to 3 and be selected from following substituent group respectively: hydrogen atom, (C 1-C 6) alkyl ,-CF 3,-CO 2R 17,-CN, (C 1-C 6) alkoxyl and halogen;
R 15And R 13Be selected from hydrogen atom and C respectively 1-C 6Alkyl, or R 15And R 16Be C together 2-C 5Alkylidene and form the volution that contains 3 to 6 carbon atoms with the carbon atom that links to each other with them;
R 17, R 18And R 19Be selected from H and C respectively 1-C 6Alkyl; And
R 20Be C 1-C 6Alkyl or phenyl; Or
(2) R aBe R 8-phenyl, R 8-pyridine radicals or R 8-thienyl;
R 2Be fluorenyl, diphenyl methyl,
Figure C200410085848D00191
And R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19And R 20As definition in (1).
Preferred formula II chemical compound is the chemical compound of definition in (1).
Preferred formula II (1) is R wherein aBe R 8a-phenyl or R 8-naphthyl, wherein R 8aBe-CF 3, CF 3O-or halogen and R 8Be C 1-C 6Alkoxyl.R 8aOr R 8Substituent group is preferably single substituent group; Particularly preferably be R 8aOr R 8Substituent group is in the 4-position.R wherein 3Be hydrogen atom, C 1-C 6Alkyl, R 8-phenyl, R 8-benzyl or R 8The formula II of-pyridine radicals (1) chemical compound also is preferred.R 3More preferred definition is a methyl, ethyl, phenyl, benzyl and pyridine radicals.R 1Be preferably hydrogen atom.For formula II (1) chemical compound, R 6Preferably hydrogen atom or methyl, particularly methyl.R 4Methyl preferably; R 5And R 7Be preferably hydrogen atom respectively.
R 2In formula II (1), be preferably the definition among the formula I, i.e. R 9, R 10, R 11-phenyl; R 9, R 10, R 11-pyridine radicals or its N-oxide, or R 9, R 10, R 11-pyrimidine radicals, wherein R 9, R 10, R 11Define in-replacement situation such as the preferred formula I chemical compound.
The present invention relates to the pharmaceutical composition for the treatment of HIV on the other hand, and said composition contains the formula II CCR5 antagonist and the pharmaceutical carrier of effective dose.The present invention also relates to the treatment solid organ transplantation on the other hand and repels, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, the pharmaceutical composition of allergy or multiple sclerosis, said composition contains CCR5 antagonist and the pharmaceutical carrier of effective dose formula II.
Another aspect of the present invention also relates to the method for the treatment of HIV, comprises that the people to this treatment of needs uses the formula II CCR5 antagonist of effective dose.Another aspect of the present invention relates to the treatment solid organ transplantation and repels, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, the method for allergy or multiple sclerosis, this method comprise that the people to this treatment of needs uses the formula I of effective dose or the CCR5 antagonist of formula II.
A further aspect of the present invention relates to the purposes of medication combined medication in treatment AIDS that is used for the treatment of the human immunodeficiency virus with the CCR5 antagonist of formula I of the present invention or formula II and one or more antiviral agent or other.The invention still further relates to and be used for the treatment of solid organ transplantation with the CCR5 antagonist of formula I of the present invention or formula II and one or more and repel graft versus host disease, inflammatory bowel, the purposes of the medication combined medication of rheumatoid arthritis or multiple sclerosis.CCR5 antagonist and antiviral agent or other active component in drug combination can be taken or separately take with single dose form; It also can be the medicine box that contains separate dose form active component.
Detailed description of the present invention
Following term used herein unless otherwise indicated is defined as follows.
Alkyl represent contains the straight or branched carbochain of 1 to 6 carbon atom.
The alkenyl representative contains the C of one or two unsaturated bond 2-C 6Carbochain, condition are that two unsaturated bonds are not adjacent to each other.
The phenyl that replaces be meant can be on phenyl ring the substituted phenyl in any possible position.
Acyl group be meant the carboxylic acid residues with following formula: alkyl-C (O)-, aryl-C (O)-, aralkyl-C (O)-, (C 3-C 7) cycloalkyl-C (O)-, (C 3-C 7) cycloalkyl-(C 1-C 6) alkyl-C (O)-, and heteroaryl-C (O)-, wherein alkyl and heteroaryl are as defined herein; Aryl is R 14-phenyl or R 14-naphthyl; And aralkyl is aryl-(C 1-C 6) alkyl, wherein the alkyl definition is as above.
The heteroaryl representative contains the ring-type aromatic group of 5 to 6 atoms or contains two cyclic groups of 11 or 12 atoms, and they contain 1 to 2 and are selected from O respectively, the hetero atom of S or N, described hetero atom inserts in the carbocyclic ring structure and has the delocalized of sufficient amount to make it have armaticity, and condition is not contain adjacent oxygen atom and/or sulphur atom in the ring.For 6-unit heteroaryl ring, carbon atom can be by R 9, R 10Or R 11Replace.Nitrogen-atoms can be the form of N-oxide.Comprise all regional isomers, as the 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.The first heteroaryl of typical 6-is a pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl and its N-oxide form.For 5-unit hetero-aromatic ring, carbon atom can be by R 12Or R 13Replace.The first heteroaryl ring of typical 5-is a furyl, thienyl, and pyrrole radicals, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl is with isoxazolyl.Having a first ring of heteroatomic 5-can connect by 2-position or 3-position; It is preferred by the connection of 4-position to have two first rings of heteroatomic 5-.Typical two cyclic groups are by the deutero-benzo-fused ring system of above-mentioned heteroaryl, quinolyl for example, 2 base, quinazolyl, benzofuranyl, benzothienyl and indyl.
R 2The position of substitution of the first heteroaryl ring of middle 6-preferably as mentioned above.Work as R 2When being 5-unit heteroaryl, R 12And R 13Substituent group preferably be connected with connecting ring and molecule on the adjacent carbon atom of the carbon atom of other parts.And R 12Be preferably alkyl; But, if when the carbon atom of other parts is adjacent in hetero atom and connecting ring and the molecule (promptly for example 2-pyrrole radicals), R 12Preferably be connected with connecting ring and molecule on the adjacent ring carbon atom of the carbon atom of other parts.
Halogen is represented fluorine, chlorine, bromine and iodine.
One or more, preferred a kind of or four kinds of antiviral agent that are used for the anti-HIV-1 treatment can be used for the drug combination with CCR5 antagonist of the present invention.The antiviral agent or the medicine that can be used for the medication of CCR5 antagonist combination can be single dose forms, or CCR5 antagonist and antiviral agent or medicine is taken simultaneously or with separate dosage forms administration successively.Can be used for comprising nucleoside and ucleotides reverse transcriptase inhibitors with the antiviral agent of The compounds of this invention drug combination, non-nucleoside class reverse transcriptase inhibitors, protease inhibitor and following listed other do not belong to the antiviral drugs of these kinds.Especially, known drug combination HAART (high activity antiretroviral therapy thing) also can be used for the drug combination with CCR5 antagonist of the present invention.
Term used herein " nucleoside and ucleotides reverse transcriptase inhibitors " (" NRTI " s) is meant to have nucleoside and nucleotide and the analog thereof that suppresses the HIV-1 reverse transcriptase activity, and this enzyme catalysis viral gene HIV-1RNA is to the conversion of provirus HIV-1DNA.
Typical suitable NRTIs comprises can be from Glaxo-Wellcome Inc.ResearchTriangle, the zidovudine (AZT) of the commodity that NC27709 is purchased RETROVIR by name; Can be from Bristol-Myers Squibb Co., the didanosine (ddi) of the commodity that Princeton, NJ08543 are purchased VIDEX by name; Can be from Roche PharmaceuticalsNutely, the zalcitabine (ddC) of the commodity that NJ07110 is purchased HIVID by name; Can be from Bristol-Myers Squibb Co., the stavudine (d4T) of the commodity that Princeton, NJ08543 are purchased ZERIT by name; Can be from Glaxo-Wellcome Inc.ResearchTriangle, the lamivudine (3TC) of the commodity that NC27709 is purchased EPIVIR by name; Be disclosed in WO96/30025 and can be, the abacavir (1592U89) of the commodity that NC27709 is purchased ZIAGEN by name from Glaxo-Wellcome Inc.Research Triangle; Can be from Gilead Sciences, two (the POM)-PMEA of the adefovir dipivoxil[of the commodity that Foster City, CA94404 are purchased PREVON by name]; Bristol-Myerg Squibb Co., Princeton, NJ08543 exploitation and be disclosed in nucleoside reverse transcriptase inhibitor lobucavir (BMS-180194) in European patent 0358154 and 0736533; By BiochemPharma, Laval, Quebec H7V, 4A7, the reverse transcriptase inhibitors BCH-10652 (the raceme mixture form of BCH-10618 and BCH-10619) of Canada's exploitation; By the Emory Univ. United States Patent (USP) 5,814,639 of Emory University permission and by Triangle Pharmaceuticals, Durham, the emitricitabine[(-of NC27707 exploitation) FTC]; Yale University permits the Pharmaceuticals in Vion, β-L-FD4 of NewHaven CT06511 (being also referred to as β-L-2 ', 3 '-dideoxy-5-fluoro-cytidene); Be disclosed in the European patent 0656778 and and permit the Pharmaceuticals in Triangle, Durham, the DAPD of NC27707 by Emory University and University of Georgia, be a kind of fast morpholine nucleoside, (-)-β-D-2,6 ,-diaminourea-purine dioxolanes.Disclosed and at NIH by u.S.Bioscience inc., WestConshohoken, the sour stable reverse transcriptase inhibitors lodensine (FddA) of PA19428 exploitation based on purine, 9-(2,3-dideoxy-2-fluoro-b-D-revive five furyl glycosyls) adenine.
Term used herein " non-nucleoside class reverse transcriptase inhibitors " (" NNRTIs ") is meant that having the HIV-1 reverse transcriptase suppresses active non-nucleoside class.
Typical NNRTIs comprises that the trade mark that can be purchased from Boehringer Ingelheim is the nevirapine (BI-RG-587) of VIRAMUNE, and the manufacturer is RoxaneLaboratories, Columbus, and OH 43216; Can be from Pharmacia﹠amp; Up john Co., the trade mark that Bridgewater NJ 08807 is purchased be RESCRIPTOR delaviradine (BHAP, U-90152); Be disclosed in WO94/03440 and can be from DuPont Pharmaceutical Co., the trade mark that Wi lmington, DE19880-0723 are purchased is the efavirenz (DMP-266) of SUSTIVA; By Pharmacia﹠amp; Up john Co., the fluorine pyridine-sulfur-pyrimidine PNU-142721 of Bridgewater NJ 08807 exploitation; AG-1549 (being Shionogi#S-1153 in the past); Be disclosed in WO96/10019 and by Agouron Pharmaceuticals, Inc., the 5-of LaJolla CA92037-1020 clinical development (3, the 5-Dichlorobenzene base)-sulfenyl-4-isopropyl-1-(4-pyridine radicals) methyl isophthalic acid H-imidazoles-2-ylmethyl carbonic ester; By Mitsubishi Chemical Co. discovery and by Triangle Pharmaceuticals, Durham, the MKC-442 of NC27707 exploitation (1-(ethyoxyl-methyl)-5-(1-Methylethyl)-6-(phenyl methyl)-(2,4-(1H, 3H)-hybar X); With NIN disclosed coumarin derivative in United States Patent (USP) 5489,697, by calanolide A (NSC-675451) and the B that Med Chem Research secures permission, the said firm and Vita-Invest develop (+) calanolide A jointly as Orally taken product.
Term used herein " protease inhibitor " (" PI ") is meant that HIV-1 protease inhibitor, this enzyme are the hydrolyzed protein of viral polyprotein precursor (for example viral GAG and GAG Pol polyprotein) is cracked into the independent function of finding in infected by HIV-1 the necessary enzymes of protein.The hiv protease inhibitor comprises having class peptide structure, and high molecular (7600 dalton) and the chemical compound that has the characteristic of peptide basically are as CRIXIVAN (can be purchased from Merck) and non-peptide protein inhibitor, as VIRACEPT (can be purchased from Agouron).
Typical suitable PIs comprises Saquinavir (Ro31-8959), and comprising can be from RochePharmaceuticals, and it is the soft capsule of FORTOUASE that Nutley, NJ07110-1199 are commercially available hard capsule and the trade mark that trade mark is INVIRASE; Can be from AbbottLaboratories, the trade mark that Abbott Park, IL60064 are commercially available is the ritonavir (ABT-538) of NORVIR; Can be from Merck﹠amp; Co., Inc., the trade mark that WestPoint, PA19486-0004 are commercially available are the indinavir (MK-639) of CRIXIVAN; Can be from Agouron Pharmaceuticals, Inc., the trade mark that Lajolla CA92037-1020 is commercially available are the nelfnavir (AG-1343) of VIRACEPT; By VertexPharmaceuticalsInc., Inc., Cambridge, MA02139-4211 develops and can be from Glaxo-Wellcome Research Triangle, and NC develops into non--peptide protease inhibitors amprenavir (141W94) that the trade mark that is commercially available after the project of oneself is AGENRASE; Can be from Bristol-Myers Squibb Co., the Iasinavir that Princeton, NJ08543 are commercially available (BMS-234475) (at first by Novaritis, Basel, Switzerland disclosed (CGP-61755)); DMP-450 is found and by the ring urea of Triangle Pharmaceuticals exploitation by Dupont; BMS-2322623, by Bristol-Myers Squibb Co., Princeton, the azepine peptide of NJ08543 exploitation is second filial generation HIV-1 PI; By Abbott, Abbott Park, the AB-378 of IL60064 exploitation; With find by Shionogi (Shionogi#S-1153) and by AgouronPharmaceuticals, Inc., the AG-1549 as Orally active imidazoles carbamate of Lajolla CA92037-1020 exploitation.
Other antiviral agent comprises hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum item number 11607.Hydroxyurea (Droxia) is a kind of ribonucleoside-triphosphate reductase inhibitor, and this enzyme can activate the T-cell, and is found in NCI and is developed by Bristol-Myers Squibb; The preclinical study demonstration has synergism to didanosine and studies with stavudine.IL-2 is disclosed in the European patent 0142268 of Ajinomoto, the European patent of Takeda-0176299, with the US Patent No s RE33653 of Chiron, 4530787,4569790,4604377, also can be in 4748234,4752585 and 4949314 from Chiron Corp., Emeryville, CA94608-2997 are with the lyophilized powder of trade mark PROLEUKIN (aldesleukin), rebuild and dilution is used for venoclysis or intramuscular injection by water; Dosage is about 2,000 ten thousand IU/ of about 1-days, preferred intramuscular injection; Dosage is about 1,500 ten thousand IU/ days, more preferably intramuscular injection.IL-12 is disclosed in WO96/25171 also can be from Roche Pharmaceuticals, Nutley, and NJ07110-1199 and American Home Products, Madison, NJ07940 is commercially available; The about 0.5 milligram/kg of dosage body weight/day is about 10 milligrams/kg body weight/day extremely, preferred intramuscular injection.(DP-178 T-20) for having 36 amino acid whose synthetic polypeptide, is disclosed in Dulce University and transfers the possession of United States Patent (USP) 5,464,933 in Trimens, and develop pentafuside cooperatively by Trimeris and Duke University Pentafuside; Pentafuside acts on the target film by the fusant that suppresses HIV-1.Pentafuside (3-100mg/ days) can successive muscle infusion or is injected male patients of HIV-1 to anti-three treatments with efavirenz and 2 PI ' s; Preferably use 100mg/ days.Yissum Project No.11607 is a kind of based on the proteic synthetic proteins of HIV-1Vif, and just by Yissum Research Development Co., Jerusalem 91042, and Israel carries out clinical preceding exploitation.Ribavirin, i.e. 1-β-D-ribose furyl glycosyl-1H-1,2,4-triazole-3-Methanamide can be from ICN Pharmaceuticals Inc., Costa Mesa, CA is commercially available; It is produced and preparation is seen United States Patent (USP) 4,211,771 description.
Term used herein " anti-HIV-1 therapeutant " is meant separately or as any anti-HIV-1 medicine that people HIV-1 infects that is used for the treatment of of a part in the multiple medicines therapeutic alliance thing (particularly HAART three and tetrad therapeutic alliance thing).Suitable known anti-HIV-1 therapeutant of typical case include, but are not limited to multiple medication combined therapeutant for example (i) be selected from two kinds of NRTIs PI, at least three kinds of anti-HIV-1 medicine of another kind of PI and a kind of NNRTI; (ii) at least two kinds of anti-HIV-1 medicines that are selected from NNRTIs and Pis.The suitable many kinds of medication combined treatments of HAART-of typical case comprise:
(a) three therapeutants are as two kinds of NRTIs and a kind of PI; Or (b) two kinds of NRTIs and a kind of NNRTI; (c) the tetrad therapeutant is as two kinds of NRTIs, a kind of PI and second kind of PI or a kind of NNRTI.For the patient of first medication, preferably begin the treatment of anti-HIV-1 with three therapeutants; Unless preferably it can not tolerate PI with two kinds of NRTIs and a kind of PI.The toleration of medicine is basic.Should every 3-6 month monitoring CD4 +With the HIV-1-RNA blood plasma level.If the viral load height can add the 4th kind of medicine, as a kind of PI or a kind of NNRTI.See the following form and wherein further described typical therapeutant:
Anti-HIV-medication combined the therapeutant of kind more than 1
A. three therapeutic alliance things:
1. two kinds of NRTIs 1+ a kind of PI 2
2. two kinds of NRTIs 1+ a kind of NNRTI 3
B. tetrad therapeutic alliance thing 4
Two kinds of NRTIs 1Second kind of PI of+a kind of PI+ or a kind of NNRTI
C. refill 5
Two kinds of NRTI1 1
A kind of NRTI 5+ a kind of PI 2
Two kinds of PIs 6± a kind of NRTI 7Or NNRTI 3
A kind of PI 2+ a kind of NRTI 7+ a kind of NNRTI 3
Last table footnote
One of 1. following: zidovudine+lamivudine; Zidovudine+didanosine; Stavudine+lamivudine; Stavudine+didanosine; Zidovudine+Zha Xitading
2.Indinavir, nelfinavir, ritonavir or Saquinavir soft capsule.
3. nevirapine or delavirdine.
4. see A-M Vandamne etc. Antiviral chemistry and chemotherapy(AntiviralChemistry﹠amp; Chemotherapy) 9:187 P193-197 and Fig. 1+2.
5. interchangeable scheme is to be used for because problem of resistance or toxicity and can not accept the patient of suggested design and for the patient's of suggested design failure or recurrence.Two kinds of nucleoside communitys make a lot of patients produce the HIV-drug resistance, and the result causes clinical failure.
6. most of data are from Saquinavir and ritonavir (respectively obeying 400mg)
7. zidovudine, stavudine or didanosine.
The treatment rheumatoid arthritis that can take with CCR5 antagonist combination of the present invention, graft versus host disease, the known drug of inflammatory bowel and multiple sclerosis is as follows:
Solid organ transplantation repels and graft versus host disease: immunosuppressant such as cyclosporin A and interleukin 10 (IL-10), fujimycin 506, antilymphocyte globulin, OKT-3 antibody and steroid;
Inflammatory bowel: IL-10 (seeing United States Patent (USP) 5,368,854), steroid and sulfasalazine;
Rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroid and Mycophenolate Mofetic;
Multiple sclerosis: beta-interferon, alpha-interferon and steroid.
There is (as enantiomer, diastereomer, atropisomer and rotamer) in some chemical compound of the present invention with different isomeric forms.The present invention includes all these pure isomer forms and its mixed form, comprise racemic mixture.
Some chemical compound itself is tart, as has the chemical compound of carboxyl and phenolic hydroxyl group.These chemical compounds can form pharmaceutical salts.The example of these salt can comprise sodium, potassium, calcium, aluminum, gold and silver salt.Also comprise and pharmaceutically acceptable amine such as ammonia alkylamine, hydroxy alkyl amine, the salt that N-methylglucosamine or the like forms.
Some alkali compounds also can form pharmaceutical salts, as acid-addition salts.For example, pyridine-nitrogen-atoms can form salt with strong acid, also can form salt with weak acid when chemical compound has alkali subtituent such as amino.The example of the suitable acid that salify is used is a hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and other mineral acid known in the art and carboxylic acid.Salt can contact free alkali by this area conventional method and form with the required acid of capacity.Can pass through salt suitable dilute alkaline aqueous solution such as rare NaOH, potassium carbonate, ammonia and sodium bicarbonate aqueous solution are handled and the regeneration free alkali form.Free alkali form is different on certain physical characteristics with its salt separately, and as the dissolubility in polar solvent, but bronsted lowry acids and bases bronsted lowry salt and its free alkali form separately are equal to again the object of the invention.
It is pharmaceutical salts and bronsted lowry acids and bases bronsted lowry salt that all these bronsted lowry acids and bases bronsted lowry salt need within the scope of the present invention and the chemical compound of corresponding free form is considered to be equal to for the object of the invention.
The compounds of this invention can be used methods known in the art production, for example uses the method described in the following reaction scheme, with the method described in the described method of the following example and WO96/26196 and the WO98/05292.
Following solvent and reagent can be represented with following abbreviation: oxolane (THF); Ethanol (EtOH); Methanol (MeOH); Acetic acid (HOAc or AcOH); Ethyl acetate (EtOAc); N, dinethylformamide (DMF); Trifluoroacetic acid (TFA); I-hydroxybenzotriazole (HOBT); Between-chlorine benzylhydroperoxide (MCPBA); Triethylamine (Et 3N); Ether (Et 3O); Dimethyl sulfoxine (DMSO); And 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (DEC).RT is that room temperature and TLC are thin layer chromatographys.Me is a methyl, and Et is an ethyl, and Pr is a propyl group, and Bu is a butyl, and Ph is that phenyl and Ac are acetyl group.
Scheme 1
Reagent and condition: a:R 4CH (OSO 2CF 3) CO 2CH 3, alkali is (as K 2CO 3); B:ClCH 2COCl; C:NH 3D:NaBH 4-BF 3The e:N-Boc-4-piperidones, NaBH (OAc) 3F:CF 3CO 2H; G: acetylation; The h:N-Boc-4-piperidones, Ti (Opr-i) 4, Et 2AlCN; I:CH 3MgBr.
In scheme 1, with benzylamine (1) wherein R and R 3Definition as above and R 1Be that hydrogen atom changes into diketo-piperazine (4), wherein R through (2) and (3) 4Definition as above is reduced to it piperazine (5) again.According to required R 6Substituent group has two kinds of methods to carry out.Reduction amination obtains (6), and deprotection obtains (7) and last acidylate obtains wherein R of formula IA chemical compound again 5And R 6Be H; Another kind method is, (5) are carried out improved Strecker reaction obtain amino nitrile (8), and then handle with methyl Ge Liya and to obtain (9), deprotection obtain (10) at last N-acidylate obtain formula IB chemical compound, wherein R 5Be H and R 6It is methyl.(7) and the acidylate of (10) under standard conditions, carry out, as use compound R 2COOH and reagent such as DEC and HOBT.At the chipal compounds of step a,, can obtain the formula IA and the IB chemical compound of chirality as (R)-methyl lactate triflate as benzylamine and the chirality lactate that (S)-methyl-4-replaces with formula 1.
Scheme 2
Figure C200410085848D00281
Reagent: j: oxa-bora pyrolle pyridine (oxaborazolidine), BH 3K:CH 3SO 2Cl, alkali; I:CF 3CO 2H.
In scheme 2, chemical compound is by preparing preformed bridged piperazine derivatives alkylation.For example; preferably has S; the stereochemical chemical compound of S can carry out chiral reduction with ketone (11) in this way and obtain alcohol (12); activation is methanesulfonates; by handling the displacement of reversing with suitable piperazine; described piperazine can be single protection; the first deprotection of final in this case procedure of processing needs, the step (e)-(g) of carrying out in the scheme 1 then obtain IC; or before displacement step, handle, last in such cases step be in the scheme 1 (f) and (g) (deprotection and acidylate) obtain ID.
Scheme 3
Figure C200410085848D00291
For R 3And R 1Be respectively the chemical compound of H, what can typically use is the alkylation approach of scheme 2 or the reduction amination method in the scheme 3.
Scheme 4
For wherein R and R 3Be respectively the biaryl compound of aryl, the typical alkylation in the preferred version 4.
Scheme 5
Figure C200410085848D00293
The piperazine of formula 14, particularly R wherein 3Be C 2-C 6The chemical compound of alkyl or benzyl can be by introducing as implied above
Figure C200410085848D00294
The part alkylation-decyanation step and obtain.Reaction can be CF by R wherein 3The O-phenyl, R 1Be hydrogen atom, R 3Be ethyl and R 4The chemical compound that is methyl illustrates, but with suitable initiation material, other formula 14 chemical compounds can prepare similarly.
Scheme 6
Figure C200410085848D00301
Reagent: m:BOC 2O, alkali; N:R 6MgBr; O:CCl 3CO 2H, NaBH 3CN; P:CF 3CO 2H; Q:NaBH 4, BF 3
Shown in scheme 6, on piperazine ring, also has an alkyl R in addition 5Chemical compound can prepare from the diketo-piperazine intermediate (4) the scheme 1.(4) be activated by changing into N (tert-butoxycarbonyl) chemical compound (17); The addition of Ge Liya reagent and follow-up reduction, the reduction of deprotection and lactams obtains (21), and this chemical compound can be with the method preparation I compound for preparing intermediate (5) in the scheme 1.
Scheme 7
Figure C200410085848D00302
R shown in the scheme 1 is R 8The piperazine of-phenyl (or its BOC derivant) can be from the intermediate of routine, wherein R 8Be that I obtains.A plurality of examples are shown in above-mentioned scheme, wherein with R 8Be converted into C1, CN ,-C (O) NH 2, H, Ph and p-ClC 6H 4CH 2-.Row embodiment is described as follows for the detailed process of this conversion.Gained piperazine or BOC-piperazine are handled with method shown in the scheme 1 then.
Scheme 8
Figure C200410085848D00311
Chemical compounds more of the present invention can obtain with the Mannich method, the instantiation shown in scheme 8.
The used chemical compound of the present invention illustrates with following preparation example, but should not be interpreted as disclosed restriction.Interchangeable mechanism pathway within the scope of the present invention and similar structures are conspicuous for art technology people unit.
Embodiment 1
Figure C200410085848D00312
Step 1: with the CH of R-methyl lactate (5.0g) 2Cl 2(40ml) solution stirs and adding trifluoromethanesulfanhydride anhydride (7.6ml) at-70 ℃, adds 2 then, 6-lutidines (7.8ml).Remove cooling bath, stirred 0.5 hour.Then organic solution is added (S)-methyl 4-bretylium tosylate (9.0g) and K with 2N HCl washing 2CO 3In water (11.2g) (60ml) solution.Stirring at room 20 hours is at K 2CO 3Go up dry organic facies, evaporation is also used Et on silica gel 2O-CH 2Cl 2Chromatogram purification obtains required product (7.50g), is thickness grease.
Step 2: with 1 of step 1 products obtained therefrom (7.5g), 2-dichloroethanes (40ml) and ClCH 2COCl (5.0ml) solution refluxed 5 hours.Evaporation also is directly used in the gained residue in the next step.
Step 3: with DMSO (80ml) solution of step 2 product, water (10ml) and NaI (8g) cooling and stirring in ice bath add dense NH 4OH solution (15ml) and stirring at room 20 hours.Drip water (200ml), collect solid, the water thorough washing also obtains diketo-piperazine in 70 ℃/5mm drying, is applicable to next step.
Step 4: at N 2Down, with step 3 products obtained therefrom (6.8g), 1,2-dimethoxy-ethane (60ml) and NaBH 4Mixture (3.4g) stirs, and drips BF 3OEt 2(6.8ml), then 100 ℃ of heating 10 hours.Cooling also drips CH 3OH (20ml) adds dense HCl (30ml) then.100 ℃ of heating 1 hour, cooling with excessive 2N naOH alkalization, extracted with EtOAc.Use K 2CO 3Dry and evaporation obtains piperazine (5.85g), is directly used in next step.
Step 5: under the room temperature with step 4 product (5.48g), N-Boc-4-piperidones (4.32g), HOAc (1.15ml), CH 2Cl 2(80ml) with triacetyl oxygen base-sodium borohydride (NaBH (OAc) 2) (8.3g) mixture stirred 20 hours.Slowly add excessive N a 2CO 3Aqueous solution stirred 0.5 hour, separated and the filtration organic facies with silicagel pad, used 10:1CH 2Cl 2-Et 2All products of O eluting.Evaporation also is dissolved in Et with residue 2Among the O (100ml).Stir and drip 1 of 4M HCl, 4-diox (10ml) solution.Collect solid, use Et 2The O washing is with CH 2Cl 2Together stir with excessive NaOH aqueous solution.Use K 2CO 3Dry organic facies and evaporation obtain required product (5.45g).
Step 6: the mixture with step 5 products obtained therefrom (1.5g) and TFA (4ml) under the room temperature stirred 2 hours.Evaporation is dissolved in CH with it 2Cl 2In and with excessive 1N NaOH solution washing.Use K 2CO 3Dry and evaporation obtains product (1.15g).
Chemical compound 1A: according to standard method, with step 6 product and 2, the CH of 6-dimethyl benzoyl chloride 2Cl 2Solution and NaOH reactant aqueous solution, and product is converted into hydrochlorate.Mp185-192 ℃ (decomposition).HRMS measured value: 498.2130; MH +Theoretical value: 498.2120.
Chemical compound 1B: according to standard method, with step 6 product and 2-amino-6-ar-Toluic acid HBOT and DEC and diisopropyl ethyl amine coupling in DMF, with preparing TLC purification amide and being translated into hydrochlorate.Mp188-196 ℃ (decomposition).HRMS measured value: 499.2069; MH +Theoretical value: 499.2072.
Chemical compound 1C: according to the method described above, with standard 6 products and 2-amino-6-chlorobenzoic acid coupling and behind purification, be converted into hydrochlorate.Mp192-200 ℃ (decomposition).HRMS measured value: 519.1530; MH +Theoretical value: 519.1526.
Embodiment 2
Figure C200410085848D00331
Step 1: with the product (1.00g) of embodiment 1 step 4, N-tert-butoxycarbonyl-4-piperidones (0.77g) and titanium isopropoxide (IV) (Ti (OiPr) 4) (1.00g) CH of mixture 2Cl 2(15ml) solution at room temperature stirred 20 hours, refluxed 3 hours and was cooled to room temperature.Add diethyl cyaniding aluminum (Et 2AlCN) (4.2ml1M toluene solution) and at dry N 2Following stirring at room 5 days.Use CH 2Cl 2-NaOH aqueous solution is handled, and drying is also evaporated organic facies also with silica gel chromatography purification CH 2Cl 2-CH 3OH (100:1) eluting obtains required product (0.72g).
Step 2: with dry THF (15ml) solution of step 1 product (0.70g) at N 2Descend and CH 3MgBr (4ml 3M Et 2O solution) at room temperature react 20 hours.Also use the filtered through silica gel organic facies with the EtOAc-water treatment, wash with EtOAc.Evaporation obtains required product (0.65g).
Step 3: according to the method for embodiment 1 step 6, with step 2 product TFA deprotection.
Chemical compound 2A: as described in embodiment 1, with the reaction of step 3 product and dimethyl benzoyl chloride and be translated into HCl salt.Mp180-187 ℃ (decomposition).HRMS measured value: 512.2272; MH +Theoretical value: 512.2276.
Chemical compound 2B: as described in embodiment 1, with step 3 product and 2-amino-6-chlorobenzoic acid reaction, with preparing TLC purification crude product and being translated into HCl salt.Mp195-200 ℃ (decomposition).HRMS measured value: 535.1662; MH +Theoretical value: 535.1652.
Chemical compound 2C: with embodiment 1 described method, with step 3 product and 2-hydroxyl-6-methyl benzoic acid, with preparing TLC purification crude product and being translated into HCl salt.Mp206-210 ℃ (decomposition).HRMS measured value: 514.2067; MH +Theoretical value: 514.2069.
Chemical compound 2D: use 1 described similar method, with step 3 product and 2-amino-6-methyl benzoic acid, with preparing TLC purification crude product and being translated into HCl salt with embodiment.Mp202-209 ℃ (decomposition).HRMS measured value: 513.2227; MH +Theoretical value: 513.2229.
Embodiment 3
Figure C200410085848D00341
Step 1: with S-methyl lactamine hydrochlorate (14g), anhydrous Na 2CO 3(60g), dry CH 3CN (125ml), the mixture of chloro diphenyl methane (22.3g) and NaI (5g) reflux and stirred 6 hours.Cooling adds frozen water and uses Et 2O (350ml is 50ml then) extraction.Merge Et 2The O extract also washs with the 1NHCl aqueous solution in batches: 200ml, 100ml, 4 x 10ml then.Merge the water soluble acid extract, stir and the excessive Na of small lot ground adding 2CO 3Until the mixture alkalize.Use Et 2The O extraction, MgSO 4Dry and evaporation obtains N-diphenylmethyl compounds (23.2g).
Step 2: with above-claimed cpd and ClCH 2The dichloroethane solution of COCl (10ml) refluxed 4 hours.Evaporation and with toluene (20ml) coevaporation.Residue is dissolved in CH 2Cl 2(200ml), stirred 0.5 hour, filter and evaporation with active carbon (10g).Residue is stirred in ice-cooled DMSO (200ml) and add dense NH gradually 3Aqueous solution (100ml) adds NaI (10g) then.Stirring at room 20 hours.Add frozen water (500ml), collect solid, the water thorough washing is used the 10:1 hexane-Et of small lot several times then 2The washing of O mixture obtains solid diketo-piperazine (15.5g) 50 ℃ of high vacuum dry.Use CH 2Cl 2-hexane recrystallization small amount of sample: mp186-188 ℃; [α] D 20=+272.6 °.
Step 3Dimethoxy-ethane (40ml) solution and NaBH with the product (4.0g) of step 2 4(1.6g) at N 2Following stirring also slowly adds BF 3-OEt 2(3.2ml).Refluxed 20 hours.Cooling also drips CH 3OH (10ml) adds dense HCl (15ml) then.Refluxed 2 hours, and handled and use CH with excessive 2NNaOH 2Cl 2Extraction.Use K 2CO 3Dry also evaporation.With silica gel chromatography purification CH 2Cl 2-CH 3OH mixture eluting is used 5:1:0.1v/v/v CH at last 2Cl 2-CH 3OH:NH 4The OH washing.Merging and evaporation product partly obtain required product (1.95g), are light yellow gluey thing.
Step 4: with the product (0.50g) of step 3, N-allyloxy carbonyl-4-piperidones (0.40g), CH 2Cl 2(5ml) and NaBH (OAc) 3(0.70g) stirred 20 hours under the room temperature.Use CH 2Cl 2Handle MgSO with excessive NaOH aqueous solution 4Dry.Evaporation is also passed through preparation TLC products of separated, uses 10%Et 2The CH of O 2Cl 2Eluant solution obtains required compound (0.8g), is grease, contains a small amount of starting ketone, but can be directly used in next step.
Step 5: with the product (0.80g) of step 4, CH 3CN (20ml), the mixture of water (5ml) and piperidines (1.5ml) stirs.Add three (4-sulfo group phenyl) phosphines (0.072g) and acid chloride (II) (0.02g) and at N 2Following stirring at room 2 hours.Handle with the NaOH aqueous solution, with 5:1v/v toluene-CH 2Cl 2K is used in extraction 2CO 3Dry and evaporation obtains yellow oil, is applicable to acylation reaction.
Chemical compound 3A: with step 5 products obtained therefrom (0.10g), N-(2,6-dimethoxy benzoyl)-4-diethyl piperidones (0.10g), CH 2Cl 2(2ml) and NaBH (OAc) 3Mixture (0.15g) stirred 2.5 hours, cooling, and use CH 2Cl 2Handle with the NaOH aqueous solution.The MgSO4 drying, 3:1v/v Et is used in evaporation and with preparation TLC separation major product 2O:CH 2Cl 2Eluting.The deposited salt acidulants obtains being the required compound of HCl salt (0.13g).Mp173-177 ℃ (decomposition).HRMS measured value: 482.3175; MH +Theoretical value: 482.3171.
Chemical compound 3B: product and the embodiment 1 described DEC-HOBT coupling of 2-amino-6-chlorobenzoic acid with step 5 obtain chemical compound 3B with PTLC products of separated and deposited salt hydrochlorate.Mp 188-195 ℃ (decomposition).HRMS measured value: 503.2567; MH +Theoretical value: 503.2578.
Chemical compound 3C: with the product and 2 of step 5,4-dimethyl nicotinic acid obtains chemical compound 3C with above-mentioned DEC-HOBT coupling with PTLC products of separated and deposited salt hydrochlorate.Mp180-188 ℃ (decomposition).HRMS measured value: 483.3114; MH +Theoretical value: 483.3124.
With preparing following compounds with above-mentioned similar methods:
Figure C200410085848D00351
3D:Mp.85-89 ℃; HRMS (MH+) measured value: 496.3343
Figure C200410085848D00361
Embodiment 4
Figure C200410085848D00362
Step 1: with 4-trifluoromethyl acetophenone (1.88g; Dry THF 10mmol) (10ml) solution cools off on ice bath and with freshly prepd solid (S)-2-methyl oxa-boron pentane (0.54g; 2mmol) handle.After 10 minutes, in 5 minutes, drip 2M borine-dimethyl sulphide complex (3ml; THF solution 6mmol).The TLC that carried out when finishing in 30 minutes shows that initiation material has changed into the bigger product of polarity.To react with about 5mlCH 3The careful cancellation of OH stops until effervescent; Vacuum is removed volatile matter.Residue is dissolved in CH 2Cl 2In and use 1N HCl, water, 10% NaHCO 3Solution and salt water washing.Vacuum concentration obtains the 2g yellow jelly.Obtain required chiral alcohol (1.6g with dodging the hexane solution eluting of formula silica gel chromatography (FSGC) purification with 10-20%EtOAc; 84%), is colorless oil.TLC R f=0.6 at 25% EtOAc: in the hexane.
Step 2: at refrigerative step 1 product of ice bath (1.55g; 8.16mmol) 10mlCH 2Cl 2Add Et in the solution 3N (2.3ml; 16.32mmol) and CH 3SO 2Cl (0.87ml; 10.6mmol) the muddy white solution of formation.To react the water cancellation and with organic products CH 2Cl 2Extraction, water, 1NHCl, 10%NaHCO 3Solution and salt water washing.Vacuum concentration obtains chirality methanesulfonates (2.1g; 96%), is light yellow oil.TLC R f=0.6 at 25% EtOAc: in the hexane.
Step 3: with step 2 product (2.1g; 7.8mmol), 2 (S)-methyl piperazine (1.56g of N-BOC protection; 7.8mmol-by 2 (S)-methyl piperazines that are purchased and the preparation of N-(tertiary butyloxycarbonyl oxygen base) phthalimide) and 2,2,6,6-tetramethyl piperidine (1.34ml; 14ml 8mmol) does CH 3The CN vlil shows methanesulfonates complete obiteration (16 hours) until TLC.Reactant mixture is cooled to room temperature, uses CH 2Cl 2(50ml) dilution and water (3x100ml) and salt water washing.With organic extract liquid MgSO 4Drying concentrates then and obtains the 2.8g yellow jelly.With FSGC (20%EtOAc is in hexane) separate required (S, S)-diastereomer (1.5g; 52%) and its benzyl epimer, (R, S)-diastereomer (0.5g; 17%) yield adds up to 69%.TLC R f=0.75 (S, S) and 0.56 (R is S) at 25% EtOAc: in the hexane.
Step 4: the 12mlCH that TFA (6ml) is added step 3 product 2Cl 2In the solution and with gained Huang-orange solution stirring at room 8 hours.To react by adding 1NNaOH solution and regulate pH to 10 and cancellation.Use CH 2Cl 2Extraction is handled and is obtained the yellow slurry of 1.1g.FSGC 10%CH 3The CH of OH 2Cl 2Solution is removed small amount of polar impurity and is used 1%Et 3The 10%CH of N 3OH:CH 2Cl 2Gradient elution obtains required unhindered amina (S, S) diastereomer.Yield=0.9g (75%), TLC R f=0.5 at 10%CH 3OH:CH 2Cl 2In.
Step 5: with the product of step 4 (0.90g, 3.3mmol), 4-piperidones (0.86g; 4.3mmol), NaB (OAc) 3H (1.05g; 4.95mmol) and ice AcOH (80 μ l) 8ml CH 2Cl 2Colourless solution stirring at room 1 day.TLC shows does not have initiation material.With reactant mixture 50ml CH 2Cl 2Dilution is with 1N NaOH solution, water (2x) and salt water washing.With CH 2Cl 2The anhydrous MgSO of extract 4Dry and the concentrated 1.7g yellow oil that obtains.Obtain pure product (1.3g, 86%) with FSGC (hexane solution of 25% acetone) separation, be white foam.TLC R f=0.6 in 25% acetone/hexane.
Step 6: TFA (5ml) is added step 5 product (1.3g, CH 2.87mmol) 2Cl 2(10ml) in the solution and with gained yellowish orange solution stirring at room 7 hours.To react with the cancellation of 1NNaOH solution and with pH and transfer to 10.Organic products is extracted into 50ml CH 2Cl 2In and water, use the salt water washing then, and use MgSO 4Dry.Concentrate and obtain unhindered amina (0.988; 98%), is yellow slurry.TLC R f=0.1 in 25% acetone/hexane.
Step 7: with step 6 product (0.78g; 2.21mmol), DEC (0.65g; 3.4mmol), HOBT (0.46g; 3.4mmol) and 2-amino-6-chlorobenzoic acid (0.51g; 2.9mmol) be dissolved in 8ml CH 2Cl 2In, add diisopropylethylamine (0.7ml) therein and with mixture stirring at room 16 hours.TLC analyze to show that the point that does not have initiation material and form two middle polarity that overlap each other (rotamer of the amide that is obstructed) is a principal product.With crude product (1.3g) usefulness extraction processing separation and by the CH of FSGC with 25% acetone 2Cl 2Eluant solution obtains title compound (0.88g; 80%), is light yellow foam.TLC R f=0.5 at 25% acetone: CH 2Cl 2In.
Et with hydrogen chloride 2O solution (1M; 3ml) be added to title compound free alkali (0.76g; 1.54mmol) CH 2Cl 2(5ml) obtain the white precipitate of moment in the solution.After the stirring at room 2 hours, rotary evaporation is removed volatile matter and is suspended in the dry toluene (3 x 10ml) white residue and azeotropic distillation.The gained white solid is suspended in the Et that contains 10%EtOAc 2Among the O, stirred 30 minutes, filter and use Et 2O (100ml) washing.The hydrochlorate high vacuum dry of title compound is obtained pale solid (0.88g; 95%).Mp：205-210℃。
As described in step 7, use suitable carboxylic acid that the product of step 6 is converted into other amide (4A-4E).The physical data of chemical compound 4-4E with following structural is as follows:
Figure C200410085848D00381
R wherein 8And R 2Be defined as follows table:
Embodiment 5
Figure C200410085848D00392
Will be from the freshly prepd raceme solution of corresponding methanol benzyl chloride 24 (1.26g, 5.62mmol), 2 (S)-methyl piperazine (1.12g, 5.62mmol) and 2,2,6, (1.9ml 11.2mmol) is dissolved in the dry DMF (2ml) and was heated to 100-110 ℃ (interior temperature) 10 hours 6-tetramethyl piperidine (TMP).TLC analyze to show does not have 24 and form two complete isolating products.Arrive Et with the mixture dilute with water and with organic substance extraction 2Among the O.With the saturated NH of organic extract liquid 4Cl and salt water washing and vacuum concentration obtain the 2g crude product.The silica gel flash chromatography separates uses 25%Et earlier 2The O-hexane obtains respectively～0.5 gram 25a and～0.5 gram 25b (total recovery～45%) with 25%EtOAc-hexane eluting then.TLC R f=0.6 (25a) and 0.4 (25b) are in the 25%EtOAc-hexane.
Pure 25a handles with preceding method and obtains having the final products 5 of following structural to 5F.
Figure C200410085848D00401
R wherein 2Be defined as follows table:
Figure C200410085848D00402
Figure C200410085848D00411
Embodiment 6
Figure C200410085848D00412
Step 1:
With aldehyde 26 (3.91,20.5mmol), 2 (S)-methyl-N-BOC-piperazine (4.1g, 20.5mmol) and Ti (OiPr) 4(6.1ml; 20.5mmol) at 40ml CH 2Cl 2In mixture stirring at room 24 hours.Import Et 2AlCN and restir 1 day.(the distinguishable diastereomer of TLCRf=0.4/0.5 is used 25%Et with the preceding method processing and with obtaining 4.71 gram (58%) cyano group amine 27 after the FSGC separation with reactant mixture 2The O-hexane is a solvent).
Step 2: with hexamethyldisilane ammonification sodium (1M; 3.1ml) be added in refrigerative 27 (1g on the dry ice/acetone batch; 2.5mmol) anhydrous THF solution in.With gained bright yellow solution CH 3CH 2I (7.5mmol; 0.6ml) handle.Remove the dry ice bath and with reactant liquor stirring at room 15 minutes.Mild heat (40 ℃) 30 minutes in hot water then.TLC shows two complete isolating points.Obtain two alkylated compound (total recoverys: 0.7g with the extraction processing of standard and with the FSGC purification; 70%).TLC R f=0.6 and 0.4 (25%EtOAc-hexane).
Step 3: with the product and the NaBH (OAc) of step 2 3(2x) and MgBr 2: OEt 2CH (1x) 3CN solution stirring 1 day.With the cancellation of reactant mixture water, with organic substance extraction in the EtOAc and handle and obtain 0.8 gram crude product.Respectively obtain～0.4 gram diastereomer (total recovery～100%) with FSGC (25% EtOAc-hexane) separation.TLC R f=0.55 (28a) and 0.45 (28b) (25%EtOAc-hexane).
Step 4: chemical compound 28a (S, S-diastereomer) is gone on foot synthetic embodiment 6 chemical compounds that react completely by 5 of routine, and chemical compound 6,6A and 6B have one's own department or unit (ipso)-methyl 6C and 6D does not then have one's own department or unit (ipso)-methyl:
Figure C200410085848D00421
Figure C200410085848D00422
Embodiment 7
Has alkyl or aryl sulfonyl R in para-position 8The synthetic 1-Phenylethanone. from corresponding para-position-replacement of the chemical compound of base begins with embodiment 4, and the method among the step 1-6 is handled, and obtains containing embodiment 7 sulphones with following formula structure:
Figure C200410085848D00431
R wherein 8With regard to R 2Be defined as follows table:
Figure C200410085848D00432
Embodiment 8
Figure C200410085848D00441
Step 1: (1.25g, 4.6mmol), (0.91g is 4.6mmol) with (Ti (OiPr) for the N-BOC-4-piperidones with embodiment 4 step 4 products 4) (1.4ml; 4.6mmol) 10mlCH 2Cl 2Solution stirring at room 24 hours.Then with reactant liquor Et 2AlCN (5.5ml; The 1M toluene solution) processing and continuation were stirred 20 hours.With reactant mixture with EtOAc dilution and with saturated NaHCO 3Solution stirs (10 minutes) layering as far as possible together.The organic layer (from unsegregated water layer) of muddiness is handled and filtered with excessive kieselguhr, filter cake is washed with EtOAc.With the filtrate layers separation and with organic layer water and salt water washing, anhydrous MgSO 4Dry and the concentrated amber jelly of 2.16g (98%) that obtains.
Step 2: the Strake amine 1 (2.16g) that step 1 is obtained is dissolved among the anhydrous THF, and the ice bath cooling is also used CH 3MgBr (the Et of 7.5ml3M 2O solution).After 1 hour, remove ice bath and with the non-homogeneous reactant mixture stirring at room of yellow 18 hours.To react and use saturated NH 4The cancellation of Cl solution, dilute with water is also used CH 2Cl 2Extraction.Concentrate and obtain the 2.2g yellow jelly, reuse FSGC purification is used 1:1CH 2Cl 2-EtOAc mixture eluting is removed the bigger impurity of polarity in the principal product.Separate obtaining one's own department or unit methyl mixture, be yellow jelly (1.85g; 88%).R f=0.5 Et at 1:1 2O: in the hexane).
Step 3: TFA (6ml) is added step 2 product (1.5g; 3.2mmol) 10mlCH 2Cl 2Stirred 2 hours in the solution and at 25 ℃. to make its pH be 9-10 and use CH will to react NaOH solution cancellation with 1N 2Cl 2Extraction obtains the 1.2g crude product.Use the FSGC purification, use 1:1CH 2Cl 2: EtOAc mixture eluting is removed used little polar impurity and is used 10%CH 3The CH of OH 2Cl 2Solution and last with 10% (about 7N-NH 3) CH 3OH/CH 2Cl 2The gradient elution separation piperidines that dissociates that obtains is yellow jelly (1.07g; 90%).TLC R f=0.2 at 10%CH 3The CH of OH 2Cl 2In.
Step 4: with step 3 product (1.03g; 2.8mmol), 2,4-dimethyl nicotinic acid (0.42g; 2.8mmol), DEC (0.8g; 4.2mmol), HOBT (0.57g; 4.2mmol) and diisopropylethylamine (1ml; 5.6mmol) CH 2Cl 2(15ml) solution stirred 24 hours for 25 ℃.With reactant mixture CH 2Cl 2Dilution (25ml), water, 10%NaHCO 3Solution and salt water washing concentrate and obtain 1.6g crude product grease.With its with FSGC with 10% acetone-CH 2Cl 2Then 2-5%CH 3The CH of OH 2Cl 2The solution gradient eluting obtains title compound (1.1g; 80%), is white foam.TLC R f=0.45 at 5%CH 3OH:CH 2Cl 2In.
Above-mentioned separation is obtained title compound free alkali (1g; 2mmol) be dissolved in the EtOAc:Et of 1:1 2Among the O (8ml) and to the Et that wherein adds freshly prepd hydrogen chloride 2O (6.1ml1M solution) solution is separated out white precipitate at once.25 ℃ were stirred after 1 hour, and vacuum is removed volatile matter.Product is suspended in Et 2Also filter among the O, filtrate is used Et 2The O washing.Hydrochlorate vacuum drying (1.1g with the title compound that obtains; Mp.213-215 ℃).HRMS(MH +)503.2997。
Get row 8A-8E amide from the product of step 3 with suitable processed with acid with similar methods, similarly prepare wherein R 8-substituent group is the chemical compound 8F-8H of right-methyl sulphonyl.
Figure C200410085848D00451
R wherein 8And R 2Be defined as follows table:
Figure C200410085848D00452
Figure C200410085848D00461
With the described method of following table, the chemical compound 8S-8EE of preparation following structural
R wherein 11Be defined as follows table:
8S: with embodiment 8, three-hydrochlorate (75mg of step 3 product; 0.16mmol), EDC (61mg; 0.32mmol), HOBT (49mg, 0.32mmol), iPr 2(0.16ml, 0.96mmol) and 2, (53mg 0.32mmol) is dissolved in CH to 6-dimethyl-4-hydroxy benzoic acid to NEt 2Cl 2In and stirred 20 hours at 25 ℃.Concentrated solution is with preparation TLC (EtOAc, SiO 2) to obtain title compound be yellow oil to purification.210-220 ℃ of m.p (2xHCl salt).C 29H 39O 2N 3F 3HRMS (MH +) theoretical value 518.2994; Measured value: 518.2997.
8T: with 8S (100mg; 0.19mmol), ethyl isocyanate (0.05ml, 0.58mmol), and Et 3(0.13ml 0.95mmol) is dissolved in CH to N 2Cl 2In and stirred 16 hours at 25 ℃.With solution CH 2Cl 2Dilution is also washed with 1NNaOH.With organic layer drying (sodium sulfate), filter and concentrate.With preparation TLC (2/1EtOAc/ hexane, SiO 2) to obtain title compound be yellow oil to purification.
8U: with 8S (250mg; 0.48mmol), the methanesulfonic acid acid anhydride (250mg, 1.44mmol) and NaH (38mg, 60% weight oil solution) is dissolved among the THF and stirred 20 hours at 25 ℃.With solution with EtOAc dilution and use saturated NaHCO 3Washing.With organic layer drying (sodium sulfate), filter and concentrate.With preparation TLC (1/1EtOAc/ hexane, SiO 2) to obtain title compound be yellow oil (280mg, 98%) to purification.
8V: with embodiment 8, three-hydrochlorate (50mg of step 3 product; 0.1mmol), EDC (38mg; 0.2mmol), HOBT (27mg, 0.2mmol), iPr 2Net (0.07ml, 0.4mmol) and 2,6-dimethyl-4-(4-pyridine radicals-N-oxide)-benzoic acid (73mg, 0.3mmol) (row preparation as follows) be dissolved in CH 2Cl 2In and stirred 19 hours at 25 ℃.Concentrated solution is with preparation TLC (2/1 acetone/hexane, SiO 2) to obtain 8V be yellow oil (23mg, 39%) to purification.
2,6-dimethyl-4-(4-pyridine radicals-N-oxide)-benzoic preparation
Figure C200410085848D00481
Steps A: with 4-benzyloxy-2,6 mesitylenic acid (8.7g, 34mmol; Thea, Journal of the American Chemical Society 1985,50,1867 such as S.), and MeI (3.2ml, 51mmol) and Cs 2CO 3(17g 51mmol) stirred 17 hours at 25 ℃ in DMF.With the solution filtration and at Et 2Distribute in O and the water.With water layer Et 2The O extraction.With the Et that merges 2O layer water and salt water washing.With organic layer drying (magnesium sulfate), filter and concentrate.By flash chromatography purification (10/1 hexane/Et 2O, SiO 2) obtain 8.6g (94%) and be the methyl ester of colorless oil.
Step B: with the phenol of benzyl protection (8.5g, 32mmol) and Pd/C (750mg 10wt%Pd) is dissolved in CH 3Among the OH.The hydrogen of logical 50psi in solution, and 25 ℃ of joltings 17 hours on the Pa Er instrument.Filtering solution (kieselguhr).Concentrate and to obtain 5.6g (98%) and be the phenol of white solid.
Step C: 0 ℃ with phenol (3.5g, 19.4mmol) and iPr 2(3.76g 29.1mmol) is dissolved in CH to Net 2Cl 2In.In this solution, drip trifluoromethanesulfanhydride anhydride (Tf at 0 ℃ 2O) (4.2ml, 25.2mmol).Solution is heated to 25 ℃ and stirred 4.5 hours in this temperature.With solution CH 2Cl 2Dilution is also used saturated NaHCO 3Washing.With water layer CH 2Cl 2Extraction.With the organic layer dried over sodium sulfate that merges, filter and the concentrated trifluoromethanesulfonic acid aryl ester crude product that obtains.By flash chromatography purification (10/1 hexane/Et 2O, SiO 2) obtain 5.4g (94%) and be the triflate of colorless oil.
Step D: with triflate (1g, 3.2mmol), 4-pyridine radicals boric acid (1.2g, 9.6mmol), Pd (PPh 3) 4(370mg, 0.32mmol), and Na 2CO 3(1g 9.6mmol) is dissolved in DME/H 2O (4/1,25ml). under nitrogen, solution is heated to 90 ℃ (oil baths) 18 hours.Solution distributed in EtOAc and water and use the EtOAc aqueous layer extracted.With the EtOAc layer drying (sodium sulfate) that merges, filter and the concentrated dark-brown grease that obtains.By flash chromatography purification (3/1 hexane/EtOAc, SiO 2) obtain 770mg (100%) and be the pyridine derivate of orange.
Step e: with pyridine derivate (390mg, 1.6mmol) and mCPBA (550mg 3.2mmol) is dissolved in CH 2Cl 2In.Solution was stirred 18 hours at 25 ℃.With solution CH 2Cl 2Dilution is also washed with 1NNaOH.With organic layer drying (sodium sulfate), filter and concentrate and obtain 400mg (97%) and be the N-oxide of orange.C 15H 16O 3HRMS (the MH of N +) theoretical value 258.1130; Measured value: 258.1131.
Step F: (400mg 1.6mmol) is dissolved among the NaOH and 2mlEtOH of 5ml3N with methyl ester.With vlil 20 hours.With solution concentration.Residue is handled with concentrated hydrochloric acid.With gained solid filtering and water and salt water washing.After the high vacuum dry, obtaining free acid (377mg, 100%) is the yellowish-brown solid.M.p.〉225 ℃ (decomposition).C 14H 14O 3HRMS (the MH of N +) theoretical value 244.0974; Measured value: 244.0981.
8W: with embodiment 8, three-hydrochlorate (1.34g of step 3 product; 2.8mmol), 2,6-dimethyl-4-formoxyl benzoic acid (500mg, 2.8mmol) (row preparation as follows), EDC (1.1g; 5.6mmol), HOBT (760mg, 5.6mmol), iPr 2NEt (2ml, 11mmol) coupling under standard conditions.By flash chromatography purification (2/1 hexane/EtOAc, SiO 2) to obtain 898mg (61%) be yellow foamy 8W.
2, the 6-dimethyl-benzoic preparation of 4-formoxyl
Figure C200410085848D00501
Steps A: with 4-hydroxyl-2, and 6-dimethyl-t-butyl perbenzoate (6.4g, 29mmol) and iPr 2(5.6g 43mmol) is dissolved in CH to NEt 2Cl 2In and be cooled to 0 ℃.In this solution, slowly add Tf at 0 ℃ 2O (5.8ml, 34mmol).Solution was stirred 3 hours at 0 ℃.With solution at saturated NaHCO 3And CH 2Cl 2Between distribute.With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges, filter and the concentrated brown oil that obtains.By flash chromatography purification (20/1 hexane/Et 2O, SiO 2) obtain 7.99g (82%) and be the triflate of yellow solid.
Step B: under nitrogen with triflate (5g, 15mmol), LiCl (1.25g, 30mmol), Pd (PPh 3) 4(340mg, 0.3mmol) (4.5ml 16mmol) is dissolved among the THF with the ethylene tributyl tin.With solution be heated to 70 ℃ 16 hours.Solution is distributed between EtOAc and saturated KF.Mixture is filtered.Separate organic layer, water layer is extracted with EtOAc.With the organic layer drying (magnesium sulfate) that merges, filter and the concentrated buff oily thing that obtains.By flash chromatography purification (20/1 hexane/Et 2O, SiO 2) obtain 1.96g (57%) and be the alkene of yellow oil.
Step C: (0.6g 2.6mmol) is dissolved in CH with alkene 2Cl 2/ MeOH (1/1).Solution is cooled to-78 ℃.Ozone is blown in the solution until being continuously navy blue.To react and use the methyl sulfide cancellation.Reactant liquor is concentrated the aldehyde that obtains to grease.
Step D: with the tert-butyl ester (650mg, 2.8mmol) and TFA (3ml) be dissolved in CH 2Cl 2In and stirred 19 hours at 25 ℃.With solution concentration is the acid of beige solid.
8X: with 8W (100mg, 0.19mmol), H 2(28mg, 0.34mmol), (32mg 0.46mmol) is dissolved among the MeOH NaOAc NOMe-HCl.Solution was stirred 17 hours at 25 ℃.Concentrated solution.With residue at CH 2Cl 2And distribute between the 1N NaOH.With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges, filter and the concentrated crude product that obtains.By preparation TLC (1/1 hexane/EtOAc, SiO 2) purification obtains 85mg (84%) 8X.
8Y: with embodiment 8, three-hydrochlorate (75mg of step 3 product; 0.16mmol) and 4-difluoromethyl-2,6-mesitylenic acid (32mg, O.16mmol) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By preparation TLC (2/1 hexane/EtOAc, SiO 2) purification obtains 64mg (73%) 8Y.
4-difluoromethyl-2, the preparation of 6-mesitylenic acid
Steps A: with aldehyde (400mg, 1.7mmol), [two (2-methoxy ethyl) amino]-sulfur trifluoride (640mg, 2.9mmol), and EtOH (0.02ml 0.34mmol1) is dissolved in 1, in the 2-dichloroethanes and 65 ℃ stirred 6 hours and 25 ℃ 19 hours.With the saturated NaHCO of solution 3Cancellation.With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges.Filter and concentrate and obtain crude product.By preparation TLC (10/1 hexane/Et 2O, SiO 2) purification obtains 210mg (50%) difluoro derivatives.
Step B: with the tert-butyl ester (210mg, 0.82mmol) and HCl (the 2.1ml4M dioxane solution 8.2mmol) is dissolved among the MeOH.Solution was stirred 20 hours at 45 ℃.Concentrated solution obtains the acid into white solid.
8Z: with embodiment 8, three-hydrochlorate (811mg of step 3 product; 1.7mmol) and the 4-[(ethylamino) carbonylamino]-2,6 mesitylenic acids (400mg, 1.7mmol) (preparation as follows) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By flash chromatography purification (1/1 hexane/acetone, SiO 2) to obtain 803mg (81%) be foamy 8Z.
The 4-[(ethylamino) carbonylamino] preparation of-2,6 mesitylenic acids
Figure C200410085848D00521
Steps A: with 3, (18.5ml 149mmo1) is dissolved in CH to the 5-dimethylaniline 2Cl 2In.Solution is cooled off in water-bath.In solution, slowly add trifluoroacetic anhydride (29.5ml, 209mmol).After adding, solution was stirred 15 minutes at 25 ℃.(7.3ml 142mmol) also remains in the water-bath of room temperature simultaneously slowly to add bromine in solution.Solution was stirred 3.5 hours at 25 ℃.With solution 10% Na 2S 2O 3Cancellation.With water layer CH 2Cl 2Extraction.Also filter with the organic layer drying (magnesium sulfate) of merging and with charcoal treatment.Concentrate and obtain orange solids.With recrystallization purifying (hexane/Et 2O) obtain two batches of products (being total to 34g, 77%), be the bromide derivant of white solid.
Step B: (17g 57mmol) is dissolved among the THF and is cooled to-78 ℃ with aromatic bromide under the nitrogen.In this solution, slowly add lithium methide/LiBr (54ml, the Et of 1.5M at-78 ℃ 2O solution, 80mmol).Stir after 5 minutes ,-78 ℃ in this reaction solution, slowly add sec-BuLi (62ml, the cyclohexane solution of 1.3M, 80mmo1).After 5 minutes, in this solution, add Bis(tert-butoxycarbonyl)oxide (22.5g, THF solution 103mmol) at-78 ℃.Solution is heated to 25 ℃.After 30 minutes, with reactant mixture at water and CH 2Cl 2Between distribute.With water layer CH 2Cl 2Extraction.With the organic layer drying (magnesium sulfate) that merges.Filter and concentrate and obtain yellow solid.(1/1 to 1/4 hexane/CH by the flash chromatography purification 2Cl 2, SiO 2) obtain 13.1g (72%) and be the tert-butyl ester of pale solid.
Step C: with three fluoro-acetamides (10g, 31mmol) and NaOH (2.5g 62mmol) is dissolved in MeOH/H 2Among the O and be heated to 60 ℃ 3 hours.With solution at CH 2Cl 2And distribute between the water.With water layer CH 2Cl 2Extraction.The organic layer that merges is washed with water and dry (sodium sulfate).Filter and concentrate and obtain 6.4g (93%) and be the aniline of orange solids.
Step D: 0 ℃ with aniline (1g, 4.5mmol), ethyl isocyanate (0.4ml, 5mmol), and CuCl (90mg 0.9mmol) is dissolved among the DMF.Solution is heated to 25 ℃ and stirred 2 hours under this temperature.Solution is distributed between EtOAc and 10%NH4OH.Water layer is extracted with EtOAc.With the organic layer that merges salt water washing and dry (magnesium sulfate).Filter and concentrate and obtain yellow solid.(3/1 to 1/1 hexane/EtOAc, SiO by the flash chromatography purification 2) obtain 904mg (69%) and be the urea of yellow solid.
Step e: with the tert-butyl ester (900mg, 3.1mmol) and 4MHCl De diox (3ml) be dissolved among the iPrOH and be heated to 45 ℃ 3.5 hours and 25 ℃ 16.5 hours.Solution decompression is concentrated.With residue at Et 2Distribute between O and the 1N NaOH.Water layer Et with alkalescence 2The O extraction.Water layer is cooled to 0 ℃ also with concentrated hydrochloric acid acidify (pH=1-2).Water layer is extracted with EtOAc.The EtOAc layer drying (sodium sulfate) that merges filtered and concentrate obtain 400mg (55%) and be the acid of white solid.
8AA: with embodiment 8, three-hydrochlorate (2g of step 3 product; 4.3mmol) and 4-amino-2,6-mesitylenic acid (710mg, 4.3mmol) (preparation as follows) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By flash chromatography purification (2/1 hexane/acetone, SiO 2) to obtain 1.16g (52%) be yellow foamy 8AA.
4-amino-2, the preparation of 6-mesitylenic acid
Figure C200410085848D00531
With the tert-butyl ester (950mg, 4.3mmol) and HCl (11ml4M De dioxane solution) be dissolved among the MeOH.In 45 ℃ of heating 20 hours.Solution concentration is quantitatively obtained acid (710mg).
8BB: with 8AA (100mg, 0.19mmol) and ethyl sulfonic chloride (0.02ml 0.21mmol) is dissolved in the pyridine and stirred 19 hours at 25 ℃.With solution concentration.With NaOH and the CH of residue at 1N 2Cl 2Between distribute.Water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges.Filter and concentrate and obtain brown oil.By preparation TLC (2/1 hexane/acetone, SiO 2) purification obtains 100mg (86%) and be the 8BB of colorless oil.
8CC: with embodiment 8, three-hydrochlorate (127mg of step 3 product; 0.27mmol) and 4-fluoro-2,6-mesitylenic acid (58mg, 0.35mmol) (preparation as follows) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By preparation TLC (2/1 hexane/EtOAc, SiO 2) purification obtains the 8CC (87mg, dihydrochloride, 54%) into colorless oil.
4-fluoro-2, the preparation of 6-mesitylenic acid
With 4-amino-2, and the 6-mesitylenic acid (200mg, 1.1mmol) and NOBF 4(196mg, 1.7mmol) 1, be heated in the 2-dichloro-benzenes 100 ℃ 30 minutes.Dilute with the solution cooling and with MeOH and water.Add several (2-3) KOH, with vlil 16 hours.With solution concentration.With residue at Et 2Distribute between the NaOH of O and 1N.With water layer Et 2The O extraction.Water layer is cooled to 0 ℃ also with concentrated hydrochloric acid acidify (pH=1-2).With water layer CH 2Cl 2Extraction.With organic layer drying (sodium sulfate).Filtration and the concentrated 58mg (31%) that obtains are the solid acid of yellowish-brown.
8DD: with embodiment 8, three-hydrochlorate (150mg of step 3 product; 0.31mmol) and 4-chloro-2,6-mesitylenic acid (76mg, 0.41mmol) (preparation as follows) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By preparation TLC (4/1 hexane/acetone, SiO 2) purification obtains the 8DD into colorless oil.
4-chloro-2, the preparation of 6-mesitylenic acid
Figure C200410085848D00542
0 ℃ with 4-amino-2, the 6-mesitylenic acid (172mg, 0.96mmol) and CuCl 2(155mg 1.15mmo1) is dissolved in CH 3Among the CN.In this solution, add nitrite tert-butyl (0.17ml.1.4mmol) at 0 ℃.With solution be heated to 25 ℃ then 65 ℃ 45 minutes.With solution at Et 2Distribute between O and the water.With water layer Et 2The O extraction.With the organic layer that merges salt water washing and dry (magnesium sulfate).Filter and concentrate and obtain methyl ester.With the method hydrolysis (KOH) of methyl ester with above-mentioned fluorine derivative.Extraction obtains the 4-chloro-2 into yellow solid, 6-mesitylenic acid (158mg, 89%) after handling.
8EE: with embodiment 8, three-hydrochlorate (180mg of step 3 product; 0.38mmol) and 4-bromo-2,6-mesitylenic acid (95mg, 0.41mmol) (preparation as follows) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By preparation TLC (4/1 hexane/acetone, SiO 2) purification obtains the 8EE (140mg, dihydrochloride, 56%) into colorless oil.
4-bromo-2, the preparation of 6-mesitylenic acid
Figure C200410085848D00551
Steps A: under nitrogen with triflate (500mg, 1.48mmol) hexa methyl ditin alkane (0.31ml, 1.48mmol), LiCl (377mg, 8.9mmol) and Pd (PPh 3) 4(171mg 0.15mmol) heated (70 ℃) 21 hours in THF.With solution at Et 2Buffer (the NH of O and pH=7 4OAc) distribute in.With water layer Et 2The O extraction.With the Et that merges 2O layer salt water washing and dry (sodium sulfate).Filter and concentrate and obtain being the semisolid aryl stannane of yellow crude product.
Step B: at 0 ℃ aryl stannane (0.74mmol) is dissolved in CH 2Cl 2In.In this solution, add bromine (0.7ml, 1MBr 2CH 2Cl 2Solution).Solution was stirred 30 minutes at 0 ℃.With solution CH 2Cl 2Dilution is also used 10%Na 2S 2O 3Washing.With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges.Solution is filtered, to wherein adding TFA (2ml) and stirring 17 hours at 25 ℃.With solution concentration.With residue at Et 2Distribute between O and the 1NNaOH.With water layer Et 2The O extraction.Water layer is cooled to 0 ℃ also with concentrated hydrochloric acid acidify (pH=1-2).With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges.Filter and concentrate and obtain 100mg (59%) and be the acid of white solid.
With the following chemical compound 8FF-8HH of the hereinafter described method composite structure of following table formula
Figure C200410085848D00552
R wherein 11As defining in the table:
Figure C200410085848D00561
8FF: with embodiment 8, three-hydrochlorate (100mg of step 3 product; 0.21mmol) and 2,6-two chloro-4-methoxyl group-benzoic acid (140mg, 0.63mmol) coupling (EDC/HOBT/iPr under standard conditions 2NEt).By preparation TLC (3/1 hexane/EtOAc, SiO 2) purification obtains the 8FF (27mg, 23%) into colorless oil.
8GG: with embodiment 8, three-hydrochlorate (330mg of step 3 product; 0.7mmol) and 2, (290mg 1.4mmol) (is listed as and prepares) coupling (EDC/HOBT/iPr according to conventional methods to 6-two chloro-4-hydroxy-benzoic acids as follows 2NEt).By preparation TLC (1/1 hexane/EtOAc, SiO 2) purification obtains the 8GG (75mg, 19%) into colorless oil.
2, the preparation of 6-two chloro-4-hydroxy-benzoic acids
Figure C200410085848D00562
-78 ℃ with 2, (500mg 2.3mmol) is dissolved in CH to 6-two chloro-4-methoxybenzoic acids 2Cl 2In, in this solution, add BBr at-78 ℃ 3(6.9ml 1M CH 2Cl 2Solution).Solution is heated to 25 ℃ and stirred 16 hours in this temperature.With solution 3NNaOH cancellation.With water layer CH 2Cl 2Extraction.Concentrated hydrochloric acid acidify (pH=1-2) is also used in water layer cooling (0 ℃).With water layer CH 2Cl 2Extraction.With the organic layer drying (sodium sulfate) that merges.Filter and concentrate and obtain crude phenol, do not need just to be further purified and to use.
8HH: with embodiment 8, three-hydrochlorate (96mg of step 3 product; 0.2mmol) and 2, (55mg 0.2mmol) (is listed as and prepares) coupling (EDC/HOBT/iPr according to conventional methods to 6-two chloro-4-(4-pyridine radicals-N-oxide)-benzoic acid as follows 2NEt).By preparation TLC (1/5 hexane/acetone, SiO 2) purification obtains the 8HH (54mg, 43%) into colorless oil.
2,6-two chloro-4-(4-pyridine radicals-N-oxide)-benzoic preparation
Figure C200410085848D00571
With 2,4, and the 6-trichlorobenzoic acid tert-butyl ester (500mg, 1.8mmol), 4-pyridine boric acid (270mg, 2.16mmol), Pd (PCy 3) 2Cl 2(130mg, 0.18mmol) and CsF (540mg 3.6mmol) is dissolved among the NMP and is heated to 100 ℃ (16 hours) under nitrogen.Solution is distributed between EtOAc and water.With organic layer water and salt water washing and dry (sodium sulfate) that merges.Filter and concentrate and obtain crude product.By preparation TLC (1/1 hexane/EtOAc, SiO 2) purification obtains 68mg (12%) pyridine ester.Processing method with aforementioned dimethyl derivant is converted into acid (a.mCPBA/b.TFA) with the tert-butyl ester.
With suitable raw material and the described method of embodiment 8S to 8HH, preparation has the chemical compound of following array structure:
R wherein 11As definition in the table
Figure C200410085848D00581
Figure C200410085848D00591
All fusing points all are that dihydrochloride is measured except that 8PP is free alkali.
Has the chemical compound 8AO-8AQ in the following table of following array structure by similarity method mentioned above preparation with the triflate midbody derivant described in the 8Z
R wherein 11As definition in the table
Ex. R 11 m.p.(℃)
8AO -CN 240-250
8AP -CONHEt 215-220
8AQ -N(CH 3)CONHEt 186-203
8AR -CONH 2 200-208
8AS -CONHCH 3 215-220
8AT -CON(CH 2CH 2OCH 3) 2 165-173
8AU -CON(Et) 2 170-180
8AV -N(CH 3)CONHCH 3 198-210
8AW -NHCH 3 190-200
8AX -N(CH 3)CONH 2， 190-220
8AO：
Figure C200410085848D00602
Step 1: with triflate intermediate (seeing 8W) (0.4g), Zn (CN) 2(0.2g), Pd (PPh 3) 4(0.3g) and DMF (1.5ml) be heated to 80 ℃ 17 hours.Reactant liquor is cooled to room temperature, with EtOAc and saturated NaHCO 3The aqueous solution dilution.Remove the EtOAc layer, wash with water, Use the saline dryingAnd evaporation obtains crude product grease, by preparation thin layer chromatography (2000 μ M silica gel plates; 8:1 hexane: the EtOAc eluting), obtain cyano intermediate (0.2g), yield 77% after separating suitable band.
Step Rapid 2: be dissolved in step 1 product (0.2g) among the MeOH (1.5ml) and add HCl (1 of 4M, the 4-dioxane solution, 2ml).Gained solution was stirred 3 hours and evaporation at 50 ℃.Should thick intermediate (0.038g) and embodiment 8, step 3 product (65mg, the tri hydrochloride form), according to embodiment 8, the method DMF (2ml) that step 4 is identical, HOBT (45mg), DEC (60mg) and diisopropylethylamine (0.1ml) are handled, obtain the 8AO of free alkali form after the separation and purification, be translated into hydrochlorate (45mg), yield 95%.
8AP：
Step 1: with 2,6-dimethyl-4-formoxyl benzoic acid (1.96g) (seeing 8W) is dissolved in the tert-butyl alcohol (94ml) and the 2-methyl-2-butene (24ml).With NaClO 2(6.89g), NaH 2PO 4The drips of solution of monohydrate (8.17g) and water is added in the above-mentioned solution.After adding pH regulator to 3 is obtained two layers of solution.Remove organic layer and the evaporation obtain intermediate acid (1.80g), be white crystalline solid.Purification is not directly used in next step.
Step 2: at the CH of step 1 product (0.62g) 2Cl 2(5ml) and add oxalyl chloride (0.31ml) among the DMF (1) and, during this period second batch of oxalyl chloride (0.3ml) added wherein reactant liquor was stirred 10 minutes, add toluene and also mixture is evaporated to dried gained solution stirring 10 minutes.Add CH 2Cl 2(10ml) and EtNH 2(1ml) and with reactant liquor stirred 2 days, just it is at saline and CH 2Cl 2Between distribute.With CH 2Cl 2Layer evaporation also adds HCl (4ml, 4Ml, 4-dioxane solution).With gained solution stirring 3 hours and evaporation, with gained solid Et 2O washing and collection obtain amide intermediate (0.13g), yield 24%.
Step 3: with embodiment 8, step 3 product (60mg; Three-hydrochlorate) and step 2 product (35mg) with embodiment 8, the method that step 4 is identical is handled, and obtains the 8AP into free alkali form behind post processing and purification, is translated into hydrochlorate (50mg), yield 62%.
8AQ：
Figure C200410085848D00612
Step 1: in amine intermediate (2g) (seeing 8Z) solution, add NaH (0.4g, 60% oil content loose thing).The gained suspension was stirred 15 minutes and add Me 2SO 4After the reflux 1.5 hours, reactant liquor is cooled to room temperature, is poured into saturated HN 4In the Cl aqueous solution and use Et 2The O extraction.After the evaporation, with crude product mixture silica gel chromatography purification, use the 4:1 hexane: the EtOAc eluting obtains methyl amine intermediate (0.8g), yield 38% behind the suitable fraction of evaporation.
Step 2: with step 1 product (0.12g), THF (5ml) and EtNCO (54mg) reflux 17 hours.Add EtNCO (54mg) and 1,4-diox (2ml) and with gained solution in sealed tube, be heated to 65 ℃ 17 hours.With solution cooling, evaporation and with preparing thin layer chromatography purification (silica gel; 25%EtOAc:CH 2Cl 2), obtain required product (0.1g), be crystalline solid, yield 64%.
Step 3: with step 2 product (0.1g) embodiment 8, the method that step 3 (D28) is identical is handled and is obtained required intermediate (0.08g), directly next step.
Step 4: with embodiment 8, step 3 product (75mg; Three-hydrochlorate) and step 3 product (0.04g) with embodiment 8, the method that step 4 is identical is handled, and obtains the 8AQ into free alkali form behind post processing and purification, is translated into hydrochlorate (65mg), yield 62%.
With said method and commercially available acid, preparation has the chemical compound 8AY-8BT of following array structure
Figure C200410085848D00621
R wherein 10And R 11Following table definition:
Figure C200410085848D00631
With synthesizing following compounds with the said method similar methods:
Figure C200410085848D00632
R wherein 8, R 3, R 6And R 2Following table definition:
Figure C200410085848D00641
Embodiment 9
Step 1: 4-N-BOC-2 (S)-methyl piperazine (1.5g; 7.5mmol), 4-methoxyl group-benzyl chloride (1.1ml; 8.1mmol) and the dry CH of diisopropylethylamine (1.5ml) 3CN vlil 5 hours.Reactant mixture is cooled to room temperature and vacuum is removed volatile matter.Residue is dissolved in CH 2Cl 2Also water and salt water washing (30ml).Concentrate and obtain crude product, obtain 2.1g (88%) with FSGC (10%EtOAc-hexane) purification and be the product of light yellow liquid.
TFA (6ml) is joined above-claimed cpd (2.1g, 12ml CH 6.56mmol) 2Cl 2Stirred 1.5 hours at 25 ℃ in the solution and with mixture.To react with the 1NNaOH cancellation and regulate pH to 10.Use CH 2Cl 2Extraction obtains required product (1 after handling.4g; 97%) is colourless jelly.
Step 2: with step 1 product (1.4g, 6.36mmol), N-BOC-4-piperidones (1.27g; 6.4mmol) and Ti (OiPr) 4(1.9ml; 6.4mmol) stirred 24 hours at 25 ℃.With 1MEt 2The toluene solution of AlCN (7.6ml) adds in this reactant mixture and with reactant mixture stirring at room 1 day.With gained Strake amine embodiment 8, the method for step 2 is handled and is separated (2.7g, 100%).TLCRf=0.3 is at 25%EtOAc-CH 2Cl 2In.
At 0 ℃ with Strake amine (2.7g; 6.3mmol) be dissolved in the 15ml dry THF and add CH 3MgBr (the Et of 3M 2O solution; 10.5ml).After 1 hour, remove ice bath, room temperature reaction 15 hours, this moment, the TLC of inhomogeneous reactant mixture analyzed the not variation of demonstration initiation material; With mixture heated to 60 ℃ 5 hours, TLC analyzed and does not also observe variation.Reactant mixture is extracted into CH with saturated NH4Cl cancellation and organic products 2Cl 2In.With FSGC purification crude product (2.7g), obtaining required one's own department or unit-methyl compound with 15% acetone-hexane eluting is colourless jelly (2.3g; 87%).
Step 3: with step 2 product (1.7g; 4.08mmol), ammonium formate (1.4g; 22mmol) be blended in 20mlCH with 10% palladium charcoal (0.4g) 3Among the OH and reflux 5 hours.With reactant mixture with diatomite filtration and remove volatile matter.Residue is dissolved in CH 2Cl 2In and use 10%NaOH solution, water and salt water washing.Vacuum concentration obtains the light yellow gluey thing of 1.1g (92%).
Step 4: with step 3 product (0.12g; 0.4mmol), right-trifluoromethyl benzyl bromine (0.1g; 0.4mmol) and the dry CH of diisopropylethylamine (0.1ml) 3CN solution mild heat (60-70 ℃) 16 hours.With the mixture cooling and by using CH 2Cl 2Extraction is handled and is separated organic products.With FSGC purification (10-30%Et 2O-CH 2Cl 2Rf=0.4) obtain major product (0.12g into colorless film; 68%).
With the said goods (at CH 2Cl 2In) obtained required compound (0.09g with the standard treatment methods alkalization then in 1 hour with TFA (1ml) processing; 96%), is colorless film.
Step 5: with step 4 product (0.045g; 0.13mmol) and 6-chloro-o-amino benzoic acid (0.022g; 0.13mmol) also use FSGC purification (5%CH with embodiment 1 described method coupling 3The CH of OH 2Cl 2Solution) separation obtains title compound, is colorless film (0.058g; 90%).
By free alkali and 1M HCl-ether are obtained light brown solid (0.066g) with conventional method reaction and precipitation.
Use similarity method, step 3 product transformed other chemical compound, at first with the nitrogen-atoms of piperazine with suitable halogenide alkylation, deprotection and piperidyl part and suitable sour coupling are formed the amide of following formula then:
Figure C200410085848D00661
Wherein R and R 2Following table definition:
Figure C200410085848D00671
Figure C200410085848D00681
Use following similar methods, synthetic wherein R is the chemical compound of 4-ethyoxyl naphthalene:
Step 1-3: see embodiment 9.
Step 4A: with 4-hydroxyl naphthaldehyde (0.86) and K 2CO 3The CH of (1.38g, 2 equivalents) 3CN (35ml) solution CH 3CH 2I (0.8ml, 2 equivalents) handled, with gained mixture stirring at room 20 hours.With the reactant mixture vacuum concentration, residue is handled filtering mixt with EtOAc.Filtrate is used H 2O distributes, and dry (magnesium sulfate) EtOAc layer and vacuum concentration obtain orange-brown residue (0.89g).With this residue place the preparation lamellae on (10,1000 μ) use CH 2Cl 2Eluting obtains title mixture (0.82g)
Step 4: under argon, with step 3 product (0.270g; 0.95mmol) and step 4A product (0.571g; 2.9mmol) CH 2Cl 2(25ml) the solution stirring at room is 30 minutes.Add Na (OAc) 3BH (0.506g; 3.4mmol).After 19 hours, with reactant mixture with rare NaOH cancellation.With water layer CH 2Cl 2Extraction (3x).With the CH that merges 2Cl 2Solution with water (3x) and salt water washing.Dry (magnesium sulfate) CH 2Cl 2Solution also is concentrated into-50ml.Add Amberlyst15 (4.5meq/g:2.4g; 11.025mmeq).After 19 hours, add Amberlyst 15 (2.3g) again.After 7 hours with resin CH 2Cl 2(5x), THF (5x), THF: water (5x), water (5X), CH 3OH (5X) and CH 2Cl 2(5x) washing.With the NH of resin with 2M 3CH 3OH (300ml) (5X) eluant solution then vacuum concentration obtain amber oily thing (0.215g).Crude product is placed on the preparation lamellae (4,1000 μ), use CH 2Cl 2: the NH of 2M 3CH 3OH (9:1) eluant solution obtains amber oily thing (0.125g, yield 36%).
Step 5: embodiment 9, synthesize following compounds with suitable carboxylic acid in the step 5:
Figure C200410085848D00691
LCMS measures M+H=531; HPLC* retention time 5.52 minutes.
Figure C200410085848D00692
LCMS measures M+H=516; HPLC* retention time 5.66 minutes.
*The HPLC:VYDAC218TP5405 post; Kept 2 minutes in gradient 5-95%B/10 minute; Solution A is water O.1%TFA/, and solution B O.1%TFA/CH 3CN is at 245nm.
Use similar methods, wherein initial piperazine does not have methyl substituents, the preparation following compounds
Figure C200410085848D00693
Embodiment 10
Figure C200410085848D00701
Step 1: with 4-N-BOC-2 (S)-methyl piperazine (0.4g; 2mmol), right-benzaldehyde iodine (0.46g; 2mmol) and NaBH (OAc) 3(0.65g; 6mlCH 3mmol) 2Cl 2The solution mild heat refluxed 14 hours.The cooling content is used 30ml CH 2Cl 2Dilution and with 1N NaOH solution, water and salt water washing, separation obtaining yellow oil (0.8g).Obtain required product (0.66g behind FSGC (25% ethyl acetate-hexane) purification; 79%) is colorless film.TLC Rf=0.6 is in 25% ethyl acetate-hexane.
With TFA (1ml) and CH 2Cl 2(2ml) handle that (0.66g removes in 1.58mmol), and standard is handled then, obtains monoalkylation piperazine (0.5g from product with the BOC protecting group; 100%) is colourless jelly.
Step 2: with NaBH (OAc) 3(0.63g; 3mmol) add step 1 product (0.5g with two acetic acid; 1.58mmol) and N-BOC-piperidones (0.6g; 5ml CH 3mmol) 2Cl 2In the solution.With gained solution stirring at room 16 hours.Handle and carry out the FSGC purification with conventional method, obtain required product (0.6g; 76%) is colorless oil.TLC Rf=0.4 is at 25% acetone-CH 2Cl 2In.
By using TFA (2ml) at CH 2Cl 2Handle the chemical compound (0.6g of N-BOC protection (5ml); 1.2mmol) the free piperidines (0.38g of preparation; 79%).
Chemical compound 10A: with 6-chloro-o-amino benzoic acid (0.065g; 0.38mmol) and step 2 product (0.127g; 0.32mmol) at DEC (0.092g; 0.48mmol), HOBT (0.065g; 0.48mmol) and diisopropylethylamine (0.1ml) existence coupling down, press the preceding method products of separated then.Obtain chemical compound 10A (0.13g; 73%) is colorless film.TLC Rf=0.5/0.45, a pair of rotamer is at 10% methanol-CH 2Cl 2In.
The hydrochlorate for preparing title compound with conventional method.Mp：198-202℃；HRMS(MH +)＝553.1231。
Chemical compound 10B: step 2 product and the coupling of 6-methyl ortho-aminobenzoic acid are obtained chemical compound 10B (hydrochlorate), yield 73%.Mp：197-200℃；HRMS(MH +)＝533.1774。
Chemical compound 10C: with 2, the 6-mesitylenic acid is coupled to and obtains amide 10C (hydrochlorate), yield 50% on step 2 product.Mp：202-205℃；HRMS(MH +)＝532.1826。
Embodiment 11
Figure C200410085848D00711
Step 1: in 15 minutes, (S)-methyl-benzyl amine (27ml, CH 0.2mol) 2Cl 2(50ml) drips of solution is added to the CH of ice-cooled trifluoroacetic anhydride (40ml) 2Cl 2(200ml) in the solution.With mixture stirring at room 1 hour.In ice-water bath, cool off then.Add iodine (27g, 0.106mol), add then [two (trifluoroacetyl oxygen base) iodine]-benzene (25g, 0.058mol).Stirred overnight at room temperature in the dark, (24g is 0.056mol) and again with mixture stirring at room 1 day to add [two (trifluoroacetyl oxygen base) iodine]-benzene once more.With mixture CH 2Cl 2(500ml) dilution and with ice-cooled Na 2SO 3(10% aqueous solution, 500ml) and stirred 0.5 hour.Separate organic layer and use NaHCO 3CH is filtered and used to washing by short silicagel column 2Cl 2(500ml) washing.Evaporation CH 2Cl 2After, add ether (125ml) and mixture was stirred 10 minutes.Gradually hexane (600ml) is added in the diethyl ether solution and with mixture and stir half an hour.Collecting precipitation is also used hexane wash.The white solid drying at room temperature is obtained iodide (TLC Rf=0.7 is at ethyl acetate/hexane 1:3 for 36.5g, yield 53%).
Step 2: with step 1 product (11.2g; 0.033mol) be dissolved in the methanol (200ml), and drip NaOH (15g; 0.375mol) water (100ml) solution.With mixture stirring at room 2.5 hours.Behind the evaporation methanol, water layer with ether (3 x 100ml) extraction and with the organic moiety water and the salt water washing that merge, is used dried over sodium sulfate, obtain unhindered amina after filtering and concentrating.
Under blanket of nitrogen with R-methyl lactate (4.08g; 0.093mol) be dissolved in CH 2Cl 2(40ml), mixture is stirred and under blanket of nitrogen, in acetone-carbon dioxide bath, be cooled to-78 ℃.Add trifluoromethanesulfanhydride anhydride (10.2g; 0.036mmol) adding 2 then, (6.27g 0.059mol), stirs mixture 5 minutes at-78 ℃ the 6-lutidines.With mixture heated to room temperature and stirred 30 minutes.In mixture, add CH once more 2Cl 2Then solution is washed with 2N HCl.Add above-mentioned freshly prepd amine in the trifluoromethanesulfonic acid ester solution and then adding potassium carbonate (18g; 0.132mol) water (20ml) solution.With the mixture stirred overnight at room temperature.Use CH 2Cl 2Extraction is handled, and carries out silica gel chromatography then and obtains secondary amine (8.27g; 75% Rf=0.65 is in hexane/ethyl acetate, among the 3:1), be yellow slurry.
Step 3: (17.3g 0.052mol) is dissolved in dichloroethanes (100ml) and ClCH with the amine of step 2 2COCl (117.2g, 82ml, 1.04mmol) in.The mixture backflow was stirred 3 hours.Solvent removed in vacuo and ClCH 2COCl.0 ℃ be dissolved in the yellow slurry of gained among the DMSO (40ml) and add NaI (5.2g, 0.035mol) and NH 4OH (56ml, 1.04mol).Reactant mixture was stirred 30 minutes at 0 ℃.Be heated to room temperature and stir and spend the night.In mixture, add entry (100ml) and filtering-depositing, wash with water.The gained white solid is obtained diketo-piperazine (14.3g, yield 77% Rf=0.56 is in hexane/ethyl acetate, among the 3:1) at air drying.
Step 4: (14.3g 0.04mol) is dissolved in the dimethoxy-ethane (200ml) and in this solution and adds NaBH with the diketo-piperazine of step 3 4(15.1g, 0.4mol) and BF 3.OEt 2(34g, 29.5ml, 0.24mol).Mixture backflow stirring was cooled to 0 ℃ in 3 hours then in ice bath.In mixture, slowly add methanol (500ml) and concentrated hydrochloric acid (300ml) then.The solution stirring at room was refluxed 45 minutes in 20 minutes then.Mixture concentrated and add NaOH surpass 10 until pH.Obtaining required piperazine with the ethyl acetate extraction processing is yellow slurry (12.9g, yield 98%).
Step 5: with step 4 product (1.9g, 5.79mmol), the N-BOC-4-piperidones (5.73g, 28.8mmol), NaBH (OAc) 3(6.1g, 28.8mmol) (5.76ml 11.52mmol) is incorporated in CH with 2M AcOH 2Cl 2Stir (150ml) and with mixture and spend the night.Remove and desolvate, adding NaOH (3N) and obtaining the pure product of Piperazino piperidones (2.21g, yield 75%, Rf=0.18 are in hexane/ethyl acetate, among the 1:1) with the silica gel chromatography purification then with the ethyl acetate extraction processing is slurry.
Step 6: (1.9g 3.7mmol) is dissolved in CH with step 5 product 2Cl 2(10ml) and add TFA (10ml).With mixture stirring at room 2 hours.Behind removal of solvent under reduced pressure and the TFA, adding sodium hydroxide solution (3N) and obtain Piperazino piperidines (1.3g, yield 85%) with the ethyl acetate extraction processing in this serosity is yellow slurry.At free Piperazino piperidines (200mg, CH 0.484mmol) 2Cl 2(2ml) add 2 in the solution, the 6-mesitylenic acid (150mg, 0.99mmol), DEC (191mg, 0.99mmol) and HOBT (135mg, 0.99mmol).With mixture stirred overnight at room temperature removal of solvent under reduced pressure then.In the gained serosity, add sodium hydroxide solution (3N) and handle and obtain title compound with the column chromatography purification then (Rf=0.37 is at CH for 210mg, 80% yield with ethyl acetate extraction 2C1 2/ methanol is among the 20:1).C 27H 37N 3OI (M+H +) the HRMS theoretical value: 546.1981, measured value: 546.1965.Mp:190 ℃ (decomposition).
Use similarity method, preparation following formula: compound, wherein R 9And R 10Following table definition:
Figure C200410085848D00731
Ex R 9 R 10 Mp(℃) HRMS
11A -CH 3 -NH 2 198(dec.) 547.1928
11B -Cl -NH 2 203(dec.) 567.1395
11C -OH -OH 200(d9c.) 550.1555
11D -OCH 3 -OCH 3 200(dec.) 578.1860
Embodiment 12
Figure C200410085848D00732
Step 1: at embodiment 11, (1.4g is 4.2mmol) with 1-tert-butoxycarbonyl-4-piperidones (0.93g, CH 4.67mmol) for step 4 product 2Cl 2Solution in add Ti (OiPr) 4(1.19g is 4.2mmol) and with the mixture stirred overnight at room temperature.Add 1MEt 2AlCN (5.04ml, 5.04mmol), with mixture stirred overnight at room temperature and evaporating solvent.Add saturated NaHCO at residue 3And handle with ethyl acetate extraction that to obtain Strake amine be yellow slurry.With this slurry dissolved at THF (40ml) and in this solution, add 3MCH 3MgBr (7ml, 21mmol).With the mixture stirred overnight at room temperature, be cooled to 0 ℃ and add saturated NH then 4Cl and water.Carry out the silica gel chromatography purification then with the ethyl acetate extraction processing and obtain Piperazino piperidine product (1.78g, 81% yield, Rf=0.52 are in hexane/ethyl acetate, among the 2:1).
Step 2: with embodiment 11, the product of the method treatment step 1 of step 6 obtains title compound.Mp:190 ℃ (decomposition); HRMS (hydrochlorate): measured value: 560.2145.
Prepare following formula: compound with similarity method
Figure C200410085848D00741
R wherein 2As defining in the following table:
Embodiment 13
Figure C200410085848D00751
Step 1: at embodiment 11, the N-BOC of step 4 protected product (250mg, in DMF 0.581mmol) (2.5ml) solution, add CuCl (1g, 10.1mmol).Suspension was stirred 24 hours with 110 ℃ under nitrogen.After mixture is cooled to room temperature, add NH 4OH, solution gradate and are sapphirine.Obtain the piperazine of chloro-replacement and the mixture of its BOC derivant with the ethyl acetate extraction processing.With the CH of mixture with TFA (5ml) 2Cl 2(5ml) solution-treated is after 2 hours, and evaporation is except that desolvating and adding NaOH (3N).With obtaining pure piperazine (110mg, 79%) after the ethyl acetate extraction processing is yellow slurry.
Step 2: with step 1 product embodiment 11, step 5 and 6 similar methods are handled, and obtain title compound.Mp:180 ℃ (decomposition); HRMS (hydrochlorate): measured value: 452.2617.
Use similarity method, the preparation following formula: compound
Figure C200410085848D00752
R wherein 9And R 10Following table definition:
Ex R 9 R 10 Mp(℃) HRMS
13A -CH 3 -NH 2 200(dec.) 455.2577
13B -Cl -NH 2 200(dec.) 475.2023
13C -Cl -Cl 187(dec.) 494.1536
Use the preparation of product following formula: compound of step 1 according to the method for embodiment 12:
Figure C200410085848D00761
R wherein 2Following table definition:
Figure C200410085848D00762
Embodiment 14
Figure C200410085848D00763
Step 1: at embodiment 11, the N-BOC of step 4 protected product (5g, add in DMF 0.012mol) (20ml) solution CuCN (20.8g, 0.23mol).This suspension was stirred 22 hours at 110 ℃ under nitrogen.After mixture is cooled to room temperature, add NH 4OH, solution gradate and are sapphirine.Obtain cyano derivative (2.29g, 60% yield, R with the ethyl acetate extraction processing and by silica gel chromatography f=0.5 in hexane/ethyl acetate, among the 4:1), carboxamides derivatives (0.95g, 23.6% yield, R f=0.2 at CH 2Cl 2/ methanol is among the 10:1) and unsubstituted derivant (85mg, 2.4% yield, R f=0.75 in hexane/ethyl acetate, among the 2:1).
Step 2: at first the BOC base on step 1 cyano compound is removed under acid condition then gained amine with embodiment 11, step 5 and 6 method are converted into title compound.HRMS (hydrochlorate): measured value: 445.4970.
Embodiment 15
Figure C200410085848D00771
Step 1: 0 ℃ at embodiment 11, the N-BOC of step 4 protected product (1.4g, 3.26mmol) and CuCl (1.61g slowly adds NaBH in methanol solution 16.3mmol) 4(3.69g, 97.6mmol).Form black precipitate.Mixture heated to room temperature and stirring spent the night.With diatomite filtration remove the precipitation and vacuum remove methanol.With obtaining desired mixt (1g, 100% yield, Rf=0.55 are in hexane/ethyl acetate, among the 5:1) after the ethyl acetate extraction processing is slurry.
Step 2: the BOC base on step 1 product removed under acid condition and with gained amine with embodiment 11, step 5 and 6 method are converted into title compound.Mp:195 ℃; HRMS (hydrochlorate): measured value: 420.3016.
Use similarity method, the preparation following formula: compound
Figure C200410085848D00772
HRMS (hydrochlorate): measured value: 441.2426.
Embodiment 16
Figure C200410085848D00781
Step 1: at embodiment 11, the product of N-BOC protection in the step 4 (2.5g, add in benzole soln 5.8mmol) phenylboric acid (1.68g, 13.8mmol), 2MNa 2CO 3(14ml) and tetrakis triphenylphosphine palladium (0.67g, 0.58mmol).Mixture backflow stirring is spent the night.Obtain phenyl derivatives (1.37g, 62% yield, R with the silica gel chromatography purification then with the ethyl acetate extraction processing f=0.55 in hexane/ethyl acetate, among the 5:1), be slurry.
Step 2: the BOC base on step 1 product removed under acid condition and with gained amine with embodiment 11, step 5 and 6 method are converted into title compound.Mp:190 ℃; HRMS (hydrochlorate): measured value: 496.3319.
Prepare following formula: compound with similarity method
R wherein 2As defining in the following table:
Figure C200410085848D00783
* free alkali
Embodiment 17
Figure C200410085848D00791
Step 1: with embodiment 11, (800mg 1.88mmol) is dissolved in the dry THF and with temperature and drops to-78 ℃ at nitrogen the product of N-BOC protection in the step 4.(2.5M solution, 0.832ml 2mmol) and with mixture stirred 10 minutes at-78 ℃ to add butyl lithium.(234mg is in THF solution 2.07mmol) at-78 ℃ this solution to be added right-chlorobenzaldehyde then.Mixture was stirred 30 minutes at-78 ℃, be heated to room temperature then gradually.In this mixture, add saturated NH 4Cl also handles with ethyl acetate extraction, obtains required alcohol (30mg, 3.6% yield, Rf=O.5 in hexane/ethyl acetate, 2: 1 in) with silica gel chromatography then, is yellow slurry.
Step 2: with the alcohol of step 1 (40mg, 0.09mmol), triethyl silicane (52mg, 0.45mmol) and the CH of TFA (5ml) 2Cl 2(5ml) solution refluxes and stirred 2 hours.CH is removed in decompression 2Cl 2, behind triethyl silicane and the TFA, in the slurry of remnants, add sodium hydroxide solution (3N).With obtaining benzyl chloride radical derivative (20mg, 68% yield) after the ethyl acetate extraction processing, be yellow slurry.
Step 3: with embodiment 11, step 5 and 6 method are converted into title compound with step 2 product.Mp:170 ℃ (decomposition); HRMS (hydrochlorate): measured value: 544.3101.
Embodiment 18
Figure C200410085848D00792
Step 1: at embodiment 14, the N-BOC of the cyano compound of step 1 is protected the 4-acyclic derivatives, and (510mg adds 3MCH with the mode that drips in ether 1.24mmol) (4ml) solution 3MgBr (4ml).Mixture backflow stirring is spent the night.Solution is cooled off on ice bath, add 12N HCl (4ml) and mixture was stirred on steam bath 2 hours.Solution is cooled to room temperature and adds the solid sodium hydroxide sheet and surpass 10 until pH.Obtain required methyl ketone (249mg, 61% yield) with ethyl acetate/methanol extraction (3:1), be slurry.
Step 2: according to embodiment 11, the method for step 6 obtains title compound with the DEC peptide coupling of standard with step 1 product.Mp:210 ℃; HRMS (hydrochlorate): measured value: 483.2522.
Prepare following compounds with similarity method:
Mp:210 ℃ (decomposition); HRMS (hydrochlorate): measured value: 463.3088.
Embodiment 19
Figure C200410085848D00802
Step 1: (140mg adds NH in methanol 0.29mmol) (10ml) and ethanol (1ml) solution at embodiment 22 products 2OCH 3HCl (738mg, 8.84mmol) and NaOAc (725mg, 8.84mmo1).Suspension is spent the night-40 ℃ of stirrings, and evaporating solvent also adds water in the residue.Handle with ethyl acetate extraction, (Rf=0.38 is at CH for 99mg, 68% yield to obtain title compound with silica gel chromatography then 2Cl 2/ CH 3OH is among the 20:1), C 31H 45N 4O 2(M+H +) HRMS (tartrate): theoretical value: 505.3534; Measured value: 505.3542.
Prepare following formula: compound with similarity method:
Figure C200410085848D00803
R wherein 8, R 6, R 2Following table definition:
Figure C200410085848D00811
Embodiment 20
Figure C200410085848D00812
With embodiment 11, (1.7g 3.3mmol) is dissolved in chloroform (30ml to the Piperazino piperidines of step 6;=material solution A).With 250 μ l material solution A (0.027mmol) add 0.15g (0.14mmol) in the resin-bonded carbodiimides serosity (and with the DMF solution of Argopore-Cl resin and 1-(3-dimethylaminopropyl) 3-ethyl carbodiimides 100 ℃ in DMF (1.5ml) in polyethylene SPE tube prepared in reaction).The DMF solution (0.075mmol) that in this mixture, adds 75 μ l 11M5-methyl-3-phenyl-isoxazole azoles-4-carboxylic acids, and HOBT (the 1MDMF solution of 24 μ l).With this mixture jolting 14 hours, filter and adding 0.1gAmberlyst-15 resin (0.47mmol) in filtrate.Jolting 1 to 2 hour is filtered and with each washed twice of following solvent: THF, CH 2Cl 2And methanol, use THF and CH then 2Cl 2Washing.Use 2MNH 3Methanol process resin (1 time 30 minutes and 1 time 5 minutes).Merging also, concentrating under reduced pressure filtrate obtains title compound.LCMS measured value MH +=599.1 (theoretical MW598); TLC Rf=0.74 is at CH 2Cl 2/ CH 3OH/NH 4Among the OH (95/5/0.5)).
Obtain following compounds with said method and suitable carboxylic acid
Figure C200410085848D00821
R wherein 2Following table definition:
Figure C200410085848D00822
Embodiment 21
Figure C200410085848D00832
Step 1: at first under acid condition with embodiment 14, the BOC group on the cyano compound of step 1 is removed, then with gained amine (1.59g, 6.96mmol), 1-tertbutyloxycarbonyl-4-piperidones (1.66g, 8.35mmol) and Ti (OiPr) 4(2.18g, CH 7.66mmol) 2Cl 2The solution stirred overnight at room temperature.Add Et 2(8.35ml is 8.35mmol) with mixture stirred overnight at room temperature and evaporating solvent for AlCN.In residue, add saturated NaHCO 3And handle with ethyl acetate extraction and to obtain Strake amine by the column chromatography purification then, be yellow slurry (Rf=0.70 is in hexane/ethyl acetate, among the 2:1 for 1.76g, 0.58 yield).
Step 2: (200mg 0.46mmol) is dissolved among the anhydrous THF (2ml) and drips the CH of 3M with the amine of step 1 3MgBr (0.76ml, 2.29mmol).The mixture stirred overnight at room temperature is cooled to 0 ℃ again.Add saturated NH 4Precipitation appears in Cl (10ml).Add entry (40ml) and precipitate disappearance then.Handle the back with ethyl acetate extraction and obtain required one's own department or unit-methyl-derivatives (169mg, 86% yield, R by the column chromatography purification f=0.53, in hexane/ethyl acetate, among the 2:1).
Step 3: with step 2 product embodiment 11, the method for step 6 is handled, and obtains title compound.198 ℃ (decomposition); HRMS (hydrochlorate): measured value: 460.3079.
Use similarity method, the preparation following compounds:
Figure C200410085848D00841
R wherein 2Following table definition:
Figure C200410085848D00842
Embodiment 22
Figure C200410085848D00843
Step 1: with embodiment 21, (380mg 0.87mmol) uses CH to the Strake amine of step 1 3(2.9ml, ether 8.7mmol) (5ml) solution-treated also refluxes to stir and spends the night MgBr.With mixture with ice-cooled and drip water (5ml).Add 12N HCl (6ml) and mixture was stirred in steam bath 2 hours.With after ice-cooled, adding sodium hydroxide is 10 until the pH of above-mentioned solution with mixture.Obtaining free alkali with the ethyl acetate extraction processing is slurry (307mg, 100% yield).
Step 2: with step 1 product embodiment 11, the method for step 6 and peptide coupling are converted into title compound.Mp:80-85 ℃; HRMS (hydrochlorate): measured value: 476.3271.
Use similar methods, the preparation following compounds:
Figure C200410085848D00851
R wherein 2Following table definition:
Embodiment 23
Figure C200410085848D00853
Step 1-3:
Figure C200410085848D00854
Step 1: with diacetyl ethyl acetate (93.4g), Cs 2CO 3(185g) and CH 3CN (550ml) mixes with overhead mechanical stirrer, adds CH 3CN (50ml) also is cooled to 0 ℃ with the gained mixture.Drip trifluoromethanesulfonic acid methyl ester (88.6g), remove cooling bath after adding.With mixture stirring at room 1 hour.Filter, and salt is washed with ether (2 x 50ml).Merge organic extract liquid and add ether (300ml).With the filtration of gained mixture, filter cake with ether (2 x 100ml) washing, is merged ether extraction liquid and also is evaporated to half volume, solution is washed once with the ice bath cooling and with cold 2N sodium hydroxide (pH=11) (0 ℃).With the ether layer dried over mgso, it is yellow liquid (64.7g) that filtration and evaporation obtain required product, and yield 65% is directly used in next step reaction with it.
Step 2: with step 1 product (64.2g), the alcoholic solution of the Sodium ethylate (solution that is purchased: 21 weight %; 113g), ethanol (587ml) and acetic acid carbonamidine ester (36.2g) mixed at room temperature are together.Reflux after 4 hours, mixture is cooled to room temperature, the gained sedimentation and filtration is removed then the ethanol vacuum is removed.Gained liquid distributed between water and dichloromethane and with water layer with dichloromethane (3 x 150ml) extraction.With dichloromethane extraction liquid dried over mgso, filtration and evaporation obtain dark-coloured liquid (50.7g), reuse silica gel chromatogram purification (980g, 4:1 hexane: eluent ethyl acetate).To suit to separate required product after the fraction evaporation, yield 46% is directly used in next step.
Step 3: with step 2 product (28.1g), sodium hydroxide (6.72g), water (65ml) and ethanol (130ml) mixed at room temperature are together and reflux 1 hour.Gained solution is cooled to room temperature and vacuum is removed volatile matter until obtaining heavy-gravity paste.Add entry (20ml), mixture is cooled to 0 ℃ also under agitation to wherein dripping concentrated hydrochloric acid (14.3ml).Filter and collect the gained white precipitate.With frozen water (2 x 10ml) washing and by air-dry 30 minutes of suction.With the gained white solid with O for toluene (2 x 20ml), at 50 ℃ of solvent removed in vacuo vacuum drying (1mmHg) 18 hours then.Required product (14.9g) separation is obtained white solid, yield 63%, C 7H 8N 2O 2Elementary analysis theoretical value: C55.26%, H5.30%, N18.41%; Measured value: C55.13%, H 5.44%, N18.18%.
Obtain second batch of product and add entry (20ml) therein by filtrate water solution (being obtained by above-mentioned) being evaporated to do to separate.With gained mixture stirring at room 15 minutes, the ice bath cooling was also collected the precipitation that forms by filtering.It is the off-white color solid that the gained solid is also obtained product (4.68g) with the said method drying with frozen water washing (2 x 5ml), merges yield 83%.
Step 4: with embodiment 4, step 6 product (tri hydrochloride form; 5.4g), DMF (11.3ml), HOBt (3.07g), diisopropylethylamine (12.3ml) and step 3 product (3.45g) mixed and added DEC (4.35g) in batches in 15 minutes.With gained mixture heated to 45 ℃ 18 hours, be cooled to room temperature, with ethyl acetate dilution (80ml) and with 2N sodium hydroxide (25ml) washing.Water layer with ethyl acetate (3 x 25ml) extraction, is merged organic extract liquid, use the salt water washing, dried over sodium sulfate is filtered and evaporation.(170g, 76:19:5 hexane: ethyl acetate: the triethylamine eluting), after suitable fraction evaporation, separation obtains the title compound (5.21g) of free alkali form, is light foam, yield 91% with the silica gel chromatography purification with gained grease crude product.
Step 5: in ethyl acetate (20ml) cooling solution (0 ℃) of step 4 free alkali (2.00g), add HCl (3.0ml, 1 of 4.0M, 4-dioxane solution).The gained mixture heated to room temperature, with ether dilution (20ml), is filtered, and with ether washing (2 x 20ml), aspirating 10 minutes air dryings, to obtain title mixture (2.3g) in 5 hours at 90 ℃ of vacuum dryings (1mmHg) then be white solid, yield 97%.Mp：159-162℃。C 27H 36N 5OF 32HCl.0.5H 2O elementary analysis theoretical value: C 55.38%, and H 6.71%, and N 11.96%, and Cl 12.11%; Measured value: C 55.19%, H 6.69%, and N 11.75%, and Cl 11.45%.
The pyrimidine derivatives for preparing other with similarity method:
Figure C200410085848D00871
Step 1-2:
Figure C200410085848D00872
Step 1: with embodiment 23, step 1 product is used and embodiment 23, step 2 similar methods, but replace the acetic acid carbonamidine with B amidine hydrochloric acid salt (2.03g).The consumption of reaction reagent is: embodiment 23, step 1 product (4.0g), and the alcoholic solution of ethanol (20ml) and Sodium ethylate (is purchased solution, 21 weight %; 8.03g).Behind said method extraction and purification, it is colourless oil liquid that separation obtains product (1.7g), and yield 41% is directly used in next step reaction.
Step 2: use and embodiment 23, the method that step 3 is identical is with ethanol (5ml), water (5ml) and sodium hydroxide (1.0g) treatment step 1 product (1.7g).Behind said method extraction and purification, separate the product (0.12g) that obtains to white solid, yield 8% is directly used in next step reaction.
Step 3: with embodiment 4, step 6 product (0.05g) and step 2 product (directly using the said goods) (0.028g) with embodiment 23, under the identical reaction condition of step 4, with HOBT (20ml), DEC (45mg) diisopropylethylamine (40mg), and DMF (1.5ml) reacts.Behind said method extraction and purification, with embodiment 23, the described method of step 5 is converted into hydrochlorate with product and obtains title compound (77mg), is white solid, the yield 97% in two steps.Mp：185-190℃。
Figure C200410085848D00881
HCl salt 23B
Step 1-2:
Figure C200410085848D00882
Step 1: with embodiment 23, step 1 product is used and embodiment 23, step 2 similar methods, but replace the acetic acid carbonamidine with Amidinobenzene hydrochloride (3.35g).The consumption of reaction reagent is: embodiment 23, step 1 product (4.0g), and the alcoholic solution of ethanol (20ml) and Sodium ethylate (is purchased solution, 21 weight %; 8.03g).Behind said method extraction and purification, it is liquid that separation obtains (4.5g) product, and yield 82% is directly used in next step reaction.
Step 2: use and embodiment 23, the method that step 3 is identical is with ethanol (10ml), water (10ml) and sodium hydroxide (2.0g) treatment step 1 product (4.5g).Behind said method extraction and purification, separate the product (3.0g) that obtains to white solid, yield 77% is directly used in next step reaction.
Step 3: with embodiment 4, step 6 product (75mg) and step 2 product (directly using the said goods) (39mg) with embodiment 23, under the identical reaction condition of step 4, with HOBT (35ml), DEC (53mg), diisopropylethylamine (100mg) and DMF (2ml) react.Behind said method extraction and purification, with embodiment 23, the described method of step 5 is converted into hydrochlorate with product and obtains title compound (98mg), is white solid, the yield 96% in two steps.Mp：250-253℃。
HCl salt 23C
Step 1-2:
Figure C200410085848D00892
Step 1: in room temperature with embodiment 23, between step 2 product (528mg) is dissolved in the dichloromethane (5.0ml) and adds in three batches-chlorine benzylhydroperoxide (mCPBA) (600mg).With gained mixture stirring at room 24 hours and add dichloromethane (2ml) and mCPBA (200mg).After 3 hours, mixture is poured on the silicagel column (40g) and uses the 1:1 hexane: ethyl acetate is the 10:1 dichloromethane then: methanol-eluted fractions.To suit after the fraction evaporation, products of separated (512g) is a wax shape white solid, and yield 89% is directly used in next step.
Step 2: be dissolved in step 1 product in the methanol (1.8ml) and add 1.0M sodium carbonate liquor (1.5ml).After the stirring at room 36 hours, the gained mixture is evaporated to dried, adds toluene (2ml) and also mixture is evaporated to dried.With the thick solid of gained (153mg) need not separate be directly used in next step the reaction in.
Step 3: with embodiment 4, step 6 product (94mg), with step 2 product (directly using the said goods) (76mg) at embodiment 23, under the identical reaction condition of step 4, with HOBT (92mg), DEC (130mg), diisopropylethylamine (0.14ml) and DMF (0.25ml) react, and the extraction back is with preparing thin layer chromatography (100 μ M silica gel plates; The 95:5 ethyl acetate: the triethylamine eluting), separating the title compound (52mg) that obtains free alkali form is foam, yield 40%.C 27H 37N 5O 2F 3HRMS:MH +: theoretical value: 520.2899; Measured value: 520.2908.
Step 4: with embodiment 23, under the identical reaction condition of step 5, with step 3 product (52mg) with ethyl acetate (1.0ml) and HCl (1 of 4.0M, 4-dioxane solution; 75 μ l) obtaining title compound (44.5mg) after the processing is white solid, yield 76%.Mp: be higher than 161 ℃ of decomposition.
Prepare following formula: compound with similarity method:
Figure C200410085848D00901
R wherein 8aAnd R 11Following table definition:
Figure C200410085848D00902
Embodiment 24
The aryl cyclopropyl amide
Method A:
Figure C200410085848D00911
Step 1: stannane (0.39g, add in DMF 0.95mmol) (10ml) solution 2-chloro-4-fluorine iodobenzene (0.73g, 2.86mmol), CuI (0.19g, 1.05mmol) and tetrakis triphenylphosphine palladium (0) (0.11g, 0.095mmol).With reactant liquor stirring at room 21 hours under nitrogen.Reactant mixture is added in the ether and should filter by bed of diatomaceous earth by inhomogeneous solution, wash with ethyl acetate.With filtrate water and salt water washing and dry (magnesium sulfate).The residue that filtrate vacuum evaporation is obtained is adsorbed on the silica gel in advance.Obtain aryl-acrylic acid esters (0.19g, 78%) by silica gel chromatography purification (4% ethyl acetate/hexane), be directly used in next step reaction.
Step 2: iodate trimethyl sulfoxonium (0.18g, add in DMSO 0.81mmol) (1.6ml) solution potassium tert-butoxide (0.09g, 0.81mmol).With reactant mixture stirring at room 1 hour, add aryl-acrylic acid esters (0.19g, DMSO 0.74mmol) (1.6ml) solution this moment.With reactant mixture stirring at room 5 hours and add entry.With the mixture ethyl acetate extraction.With organic layer water and salt water washing and dry (magnesium sulfate) that merges.Filtrate vacuum evaporation is obtained the aryl cyclopropyl ester, be dissolved in it in dichloromethane (3ml) and add TFA (0.5ml).With reactant mixture stirring at room 15 hours then vacuum concentration obtain aryl cyclopropyl carboxylic acid (0.14g, 91%-2 step).Need not be further purified, with this carboxylic acid and embodiment 8, the product coupling of step 4 obtains 24A, is hydrochlorate.HRMS:(M+H): measured value: 566.2561.
Method B:
Figure C200410085848D00921
2-fluorophenyl acetonitrile (0.80g, 5.92mmol), benzyltriethylammonium chloride (0.03g, 0.12mmol) and 1-bromo-2-ethyl chloride (1.7g adds 50% sodium hydrate aqueous solution (3.5ml) in 11.9mmol).Reactant liquor was stirred 21 hours and adds ethylene glycol (3ml) at 45 ℃.Reactant liquor is heated to 100 ℃ and stirred 7 hours.Be cooled to room temperature, wash with the reactant liquor dilute with water and with ethyl acetate.Water layer is acidified to pH2-3 with the 6N aqueous hydrochloric acid solution.With acidifying solution extracted with diethyl ether.With ether extraction liquid water and salt water washing and dry (magnesium sulfate) that merges.Filtering also, vacuum evaporating solvent obtains light yellow solid (1.06g, 99%).With aryl rings propanoic acid and embodiment 8, the product of step 3 embodiment 8, it is hydrochlorate that the method coupling of step 4 obtains 24B.HRMS:(M+H +): measured value: 532.2949.
Use similarity method, the preparation following formula: compound
Figure C200410085848D00922
Wherein
Figure C200410085848D00931
Following table definition:
Figure C200410085848D00932
Embodiment 25
Figure C200410085848D00941
Step 1:
Figure C200410085848D00942
With cyclopropyl formaldehyde (3.4ml), S-methyl N-BOC piperazine (8.28g), dichloromethane (82ml) and Ti (OiPr) 4(15.80ml) mix and stirring at room 23 hours, then gained solution is cooled to 0 ℃ and add Et 2AlCN (the toluene solution of 1.0M; 62.1ml).With solution stirring at room 5 hours.Add KF (20g) and kieselguhr (10g) mixture, carefully add ethyl acetate (120ml) and water (120ml) then.The gained serosity was stirred 15 minutes, filter, wash (3 x 35ml) and remove ethyl acetate layer with ethyl acetate, use the salt water washing, dried over sodium sulfate is filtered and evaporation obtains required intermediate (12.0g), is directly used in next step.
Step 2:
Figure C200410085848D00943
At 0 ℃, in the solution of 4-iodine benzotrifluoride (40g) and THF (52ml), add the isopropyl-magnesium chloride (diethyl ether solution of 2.0M; 74ml).Gained solution stirring at room was added in 10 minutes after 1 hour in 0 ℃ step 1 product (10.0g) and THF (26ml) solution.Reaction solution is heated to room temperature, and stirring is spent the night and is added ethyl acetate (50ml).Stir after 10 minutes, add 2N sodium hydroxide (50ml) and the gained mixture was stirred 30 minutes, filter and with salt with ethyl acetate (3 x 20ml) washing.With the acetic acid ethyl acetate extract salt water washing that merges, dried over sodium sulfate is filtered and evaporation obtains crude product (28g), is golden yellow grease, with silica gel chromatography purification (1kg), uses hexane: ethyl acetate (8:1) eluting.Two diastereomers are collected with single fraction form and are obtained (15.9g) and be further purified by above-mentioned column chromatography obtaining intermediate A (R f=0.47 at the 4:1 hexane: in the ethyl acetate; 5.34g), contain undetermined impurity.(also collect second diastereomer B (R f=0.29 at the 4:1 hexane: in the ethyl acetate; 5.34g).
Step 3:
Figure C200410085848D00951
In A of step 2 (3.96g) and dichloromethane (120ml) solution, add DOWEX50X2-100 ion exchange resin (15g) and with gained mixture room temperature jolting 2.5 hours.Remove by filter resin and use dichloromethane (2 x 40ml) washing.With resin 7N NH 3Methanol solution (30ml) handle, remove by filter resin and repeat twice of this process.Merge methanol extraction liquid and evaporation.With gained grease toluene: dichloromethane (1:1; 15ml) handle and evaporation to obtain piperazine intermediate (0.80g) be limpid grease.C 16H 21N 2F 3HRMS:MH +: theoretical value: 299.1735; Measured value: 299.1748.
Step 4:
Figure C200410085848D00952
According to embodiment 8, the method that step 1 is identical, with step 3 product (0.57g) with N-BOC4-piperidones (0.42g), dichloromethane (3.84ml), Ti (OiPr) 4(3.39ml), Et 2AlCN (2.88ml) and CH 3MgBr (the diethyl ether solution of 3.0M; 3.2ml) handle that to obtain required product (0.78g) be limpid grease, yield 83%.
Step 5: (0.12g) uses acetic acid with step 4 product: dichloromethane (3:1, v/v; 1.4ml) handle and use BF then 3Et 2O (0.14ml) handles.Stir after 1 hour, with gained solution with dichloromethane (10ml) dilution, be cooled to 0 ℃ and with sodium hydrate solid with pH regulator to 10.Add entry (2ml) and remove dichloromethane layer then.Further extract (2 x 10ml), organic layer water, salt water washing, dried over sodium sulfate with dichloromethane.Filter and evaporate and obtain free piperidines (80mg), yield 80%.
Step 6: according to embodiment 8, the method that step 4 is identical, with DMF (0.30ml), HBOt (41mg), DEC (57mg), diisopropylethylamine (0.08ml) and 4,6-dimethyl-5-pyrimidine carboxylic (43mg) treatment step 5 products (57mg); Reactant liquor was stirred 5 hours at 45 ℃.Crude product oil is carried out purification (silica gel adsorption by the preparation plate chromatography; 2000 μ M; 76:119:5 ethyl acetate: hexane: the triethylamine eluting), methanol) and concentrated solvent the suitable band of eluting (1:1 dichloromethane:, obtain title compound (70mg) and be clarification grease, yield 93%.With embodiment 8, the described method of step 4 prepares hydrochlorate (78mg), yield 100%, mp:147-149 ℃.
Use similar methods, the preparation following formula: compound
Figure C200410085848D00961
Embodiment 26
Figure C200410085848D00962
Step 1:
Figure C200410085848D00963
With with embodiment 25, step 1 similar methods replaces cyclopropyl formaldehyde with right-trifluoromethylated benzaldehyde (20g), after the processing to non-enantiomer mixture (22.7g), yield 59%.
Step 2:
Figure C200410085848D00971
At-70 ℃, (the THF solution of 1.0M 7.5ml) adds benzyl bromide a-bromotoluene (2ml) then, removes cooling bath and with gained solution stirring 45 minutes to add NaHMDS in the THF of step 1 product (1.9g) (15ml) solution.Add dense NH 4OH (10ml) also stirs reactant liquor 30 minutes.The gained mixture is distributed between water and dichloromethane, dichloromethane extraction liquid is removed and evaporated and obtain crude product oil, by column chromatography purification (silica gel; 2:1 hexane: dichloromethane; 10:1 to 7:1 hexane: eluent ethyl acetate), obtain intermediate mixture (1.92g) behind the suitable fraction of evaporation and be yellow foam.
Step 3:
Figure C200410085848D00972
With step 2 product (1.91g), CH 3CN (35ml), sodium triacetoxy borohydride (4.0g) and magnesium bromide ether compound (2.25g) mixing and stirring at room 70 hours.Add water (50ml) solution that entry (25ml) adds sodium carbonate (10g) then gradually.With ethyl acetate extraction (2 x 50ml), the dry organic layer that also evaporates, with gained grease by preparation plate chromatography purification after (5 x 200mM silica gel plates; The 6:1 hexane: eluent ethyl acetate), remove little polarity zone part, use the methanol of 1:1: dichloromethane is handled, and filters and also evaporates the intermediate A (0.84g) that obtains to white foam, C 25H 29O 2N 2F 3HRMS MH +: theoretical value: 449.2407; Measured value: 449.2416.
Step 4: according to embodiment 8, the method that step 3 is identical is handled step 3 product (0.81g) with TFA (5ml) and dichloromethane (10ml), obtain free piperazine (0.60g) after the post processing for clarifying jelly.C 20H 23N 2F 3HRMS MH +: theoretical value: 349.1892; Measured value: 349.1894.
Step 5: according to embodiment 8, the method that step 1 is identical, with step 4 product (0.39g) with N-BOC4-piperidones (O.25g), dichloromethane (8ml), Ti (OiPr) 4(0.40mg), Et 2AlCN (2ml) and CH 3MgBr (1.5ml) handle the piperidyl intermediate (0.44g) that obtains required BOC-protection and be clarification grease, yield 72% by the diethyl ether solution of 3.0M.C 31H 42O 2N 3F 3HRMS MH +: theoretical value: 546.3307; Measured value: 546.3315.
Step 6: according to embodiment 8, the method that step 3 is identical, with TFA (3ml), dichloromethane (2ml) and water (0.2ml) are handled with step 5 product (0.43g), after the post processing, obtain free piperidyl intermediate (0.37g), are to clarify grease.
Step 7: according to embodiment 8, the method that step 4 is identical, with step 6 product (50mg) with dichloromethane (3ml), HOBt (28mg), DEC (40mg), diisopropylethylamine (42mg) and 4,6-dimethyl 5-pyrimidine carboxylic (24mg) processing; With reactant liquor stirring at room 2 days.With embodiment 8, the described method of step 4, the hydrochlorate (59mg) of preparation title compound, yield 91% (in step 5 product).M.p：187-196℃。C 33H 40ON 5F 3HRMSMH +: theoretical value: 580.3263; Measured value: 580.3263.
Use similarity method, the preparation following formula: compound:
R wherein 8a, R 3And R 2Following table definition:
Figure C200410085848D00991
Figure C200410085848D01001
Embodiment 27
Figure C200410085848D01002
Step 1:
Figure C200410085848D01003
With 4 '-three reaction methyl) Propiophenone (2.02g, 0.01mol) and (S)-2-methyl-luxuriant alkane of CBS-oxygen azepine boron (oxazaborolidine) (the THF solution of 1M) (2.0ml, 0.002mol) THF (10ml) solution on the ice bath cooling and in this mixture, drip borine-dimethyl sulphide complex (the THF solution of 2M) (3ml, 0.006mol).Mixture was stirred 30 minutes and slowly added methanol until there not being bubble to produce at 0 ℃.Removal of solvent under reduced pressure also adds hydrochloric acid solution (1N) in mixture.Handle back reuse silica gel chromatogram purification with ethyl acetate extraction and obtain alcohol (1.47g), yield 72%.
Step 2: with step 1 product (4.32g, 0.021mol) and triethylamine (5.9ml, dichloromethane 0.042mol) (20ml) solution is cooled to 0 ℃ and to wherein dripping CH with ice bath 3SO 2Cl (2.13ml, 0.028mol).Mixture was stirred 1 hour and removes ice bath at 0 ℃.In mixture, add after the entry and quantitatively to obtain methanesulfonates (5.99g) after handling with dichloromethane extraction.
Step 3: (5.93g, 0.021mol) (4.2g 0.021mol) is dissolved in anhydrous CH with 1-tert-butoxy-carbonyl-3S-methyl piperazine with step 2 product 3Among the CN (20ml) to the potassium carbonate that wherein adds oven dry (4.35g, 0.032mol).The mixture backflow was stirred 2 days, then dilute with water.Carry out the silica gel chromatography purification after ethyl acetate extraction is handled and obtain required product (3.16g), yield 39%.
Step 4: TFA (10ml) is added step 3 product, and (1.15g is in dichloromethane 2.59mmol) (5ml) solution and with mixture stirring at room 2 hours.Concentrating under reduced pressure.In residue, add sodium hydroxide (3N) and, quantitatively obtain required amine with the ethyl acetate extraction processing.
Step 5: according to embodiment 8, step 1 similar methods is with step 4 product and 1-tert-butoxycarbonyl-4-piperidones (0.94g, 4.74mmol) usefulness Ti (OiPr) 4, Et 2AlCN and CH 3MgBr handles and obtains required product (1.09g), yield 87% (amine from step 4 begins meter).
Step 6: TFA (4ml) is added step 5 product, and (0.76mg is in dichloromethane 1.57mmol) (2ml) solution and with mixture stirring at room concentrating under reduced pressure after 2 hours.In residue, add sodium hydroxide (3N) and, quantitatively obtain required amine with the ethyl acetate extraction processing.
Step 7: with the amine and 4 of step 6, (0.36g, 2.35mmol), with embodiment 8, the described method coupling of step 4 obtains title compound (0.58g), yield 72% to 6-dimethyl pyrimidine 5-carboxylic acid.M.p160; HRMS (MH +): measured value: 518.3123.
Prepare following formula: compound with similarity method
Figure C200410085848D01021
Z wherein, R 3, R 6And R 2Following table definition:
Figure C200410085848D01022
Use similarity method, the preparation following formula: compound
Figure C200410085848D01041
Embodiment 28
Figure C200410085848D01042
Step 1-4:
Figure C200410085848D01043
Step 1: according to embodiment 6, the method for step 1 prepares cyano group amine with right-trifluoromethylated benzaldehyde and 2 (S)-methyl-4-(tertbutyloxycarbonyl) piperazine.
Step 2: with cyano group amine 2 (2.5g; 6.53mmol) 30ml dry THF solution place under the blanket of nitrogen and be cooled to-78 ℃.With the THF solution (1M of this solution with hexamethyldisilane ammonification sodium; 26ml) handle, use pure allyl bromide, bromoallylene (6ml) to handle then 5 minutes.After removing cooling bath reactant mixture is heated to room temperature (1 hour).Solution becomes dark brown red from yellow.To react and use saturated NH 4Cl solution cancellation and with the product ethyl acetate extraction, water, the salt water washing is also dry.Vacuum concentration obtains brown semisolid.It is amber jelly (TLC R that this product is obtained 2.5 gram (92%) required products with the FSGC purification with the hexane solution eluting of 25% ether f=0.65,0.6 two eclipsed points).
Step 3: the methanol solution of step 2 product (2.4g) is handled with 10%Pd/C (0.2g) and placed under the nitrogen.After the stirring at room 4 hours, remove catalyst, filtrate concentrating obtained amber jelly by diatomite filtration.
The above-mentioned α that obtains-propyl group nitrile is dissolved in CH 3Among the CN (12ml).Add magnesium bromide close ether (2.1g, 8.14mmol) and sodium triacetoxy borohydride (3.44g; 16.2mmol) and with the reactant mixture stirred overnight at room temperature.To react the water cancellation and alkalize with saturated sodium bicarbonate.Organic products is obtained～the 2g crude product with ethyl acetate extraction.Obtain two kinds of diastereomer products with FSGC (hexane solution of 10-25% ether) purifies and separates and (be total to 1.7g; Two steps 79%):
(S, S)-diastereomer (A): TLC R f=0.6 (25% ether-hexane).0.9g colourless jelly.
(R, S)-diastereomer (B): TLC R f=0.5 (25% ether-hexane).0.8g colourless jelly.
Step 4: intermediate A is removed the BOC-protecting group with the dichloromethane solution processing of TFA.With isolating free piperazine (0.68g; 2.3mmol), N-(tertbutyloxycarbonyl)-4-piperidones (0.45g; 2.3mmol) and Ti (OiPr) 4(0.7ml; 2.5mmol) be dissolved in also to stir in the 10ml dichloromethane and spend the night.In reactant mixture, add Et 2AlCN (the toluene solution of 1M; 2.7ml) then with gained solution stirring 1 day.Reactant liquor is diluted and the water cancellation with ethyl acetate.Add kieselguhr so that filter titanium and aluminum salt.With biphase filtrate water, the salt water washing is also dry.Vacuum concentration obtains 1.1g yellow jelly (TLC R f=0.55 in 25% ethyl acetate-hexane).
Be dissolved in gained one's own department or unit-cyano compound in the dry THF (8ml) and use CH 3MgBr (the diethyl ether solution of 3M; 6ml) solution-treated and stirred overnight at room temperature.Reaction flask is placed in the psychrolusia cooling and uses saturated NH 4The careful cancellation of Cl solution. with organic products with ethyl acetate extraction and water and salt water washing.The quick FSGC chromatogram purification of reuse (hexane solution of 10-25% ethyl acetate) obtains the boc piperidine based compound after concentrating crude product, is light yellow gluey thing (1.1g; 100%).TLC R f=0.6 in 25% ethyl acetate-hexane.
Step 5: handle by dichloromethane solution, the BOC-protecting group on the step 4 product piperidines nitrogen-atoms is removed with TFA.Obtain unprotected piperidines, yield 90% with the sodium hydroxide alkalization of 1M and with the dichloromethane processing.With this intermediate and aryl and heteroaryl carboxylic acid coupling (EDCl HOBt) obtains the listed amide of following table:
Figure C200410085848D01061
R wherein 2Following table definition:
Figure C200410085848D01071
Use similarity method, the preparation following compounds:
Figure C200410085848D01081
R wherein 8, R 3And R 2Following table definition:
With trifluoro-benzyl bromide or chloride alternate embodiment 28, the benzyl bromide a-bromotoluene among the step 1-4 (handling isomer B in the step 3) is used embodiment 1 then, and the method for step 5 is then carried out embodiment 26 again, the method for step 6-7, and preparation following compounds (HCl salt):
Figure C200410085848D01083
Embodiment 29
Figure C200410085848D01091
Step 1-3:
Figure C200410085848D01092
Step 1: solid m-CPBA is added right-trifluoromethyl styrene (3g; 17.4mmol) the 30ml dichloromethane solution in and stirring at room 20 hours.Added about 20ml saturated sodium bicarbonate and stirring at room 2 hours.Mixture is extracted in the dichloromethane layer with the dilution of 20ml dichloromethane and with organic products.To obtain crude product after the organic extract liquid processing.Obtain the required epoxide of 3g (90%) behind the FSGC purification, be colorless oil.TLC R f=0.8 (in 25% ethyl acetate-hexane).
Step 2: with freshly prepd Feldalat NM (0.6g; 10.6mmol) adding step 1 product (2g; 10.6mmol) the 20ml absolute methanol solution in.Stirring at room 1 day, vacuum is removed methanol.Be dissolved in the dichloromethane residue and water and salt water washing.Concentrate, carry out FSGC then, obtain 1.3g (55%) methanol, be colorless oil.(R f=0.3 in 50% ether-hexane).
Step 3: with the methanol (1.3g of step 2; 5.9mmol) be dissolved in the dichloromethane and with ice bath and cool off.Use Et3N (1.7ml successively; 12mmol) and CH 3SO 2Cl (0.6ml; 7.7mmol) handle and stir and formed methanesulfonates in 30 minutes.Product is handled (yield=100%) with the standard method extraction.
With methanesulfonates (1.76g; 5.9mmol) and 2 (S)-methyl-4-(tertbutyloxycarbonyl) piperazine (2.4g; 12mmol) be dissolved in 5ml CH 3Among the CN and reflux 19 hours.Reactant mixture is cooled to room temperature and directly dodges the formula silica gel chromatography.With 25% ether-hexane, 50% ether-hexane eluting separates diastereomer product A and B (total recovery 86%) then.
A:R f=0.5 (50% ether-hexane).Light yellow gluey thing (0.9g; 42%).
B:R f=0.4 (50% ether-hexane).Amber jelly (1.13g; 44%).
Step 4: will be by A (0.9g; 2.2mmol) according to embodiment 1, the method for step 4 is carried out reduction amination to deutero-free piperazine with the N-BOC-piperidin-4-one-with one's own department or unit-methyl, obtains the piperidinyl compounds (0.87g of BOC-protection; 92%).Rf=0.3 (50% ethyl acetate-hexane).
Step 5: handle by TFA, the BOC protecting group on the piperidines nitrogen-atoms is removed and with the gained chemical compound with acid with EDCI/HOBt according to embodiment 8, the method coupling of step 4 obtains chemical compound shown in the following table:
R wherein 2Following table definition:
Figure C200410085848D01102
Embodiment 30
Figure C200410085848D01111
Step 1:
Figure C200410085848D01112
With right-trifluoro-methoxybenzaldehyde (0.48ml, 3.36mmol), pyridine subbase-piperazine (1.00g, 3.36mmol) and benzotriazole (0.48g, dry toluene vlil 4.00mmol) 6 hours.Reactant mixture is cooled to room temperature and solvent removed in vacuo.Determine the formation of product then with NMR, product need not be further purified and be directly used in next step.
Step 2:
Figure C200410085848D01113
(1.16g, (the 2M diethyl ether solution is 1.1ml) and with mixture stirring at room 15 hours to add n-pro-pyl bromination magnesium in 20ml toluene solution 1.97mmol) at step 1 product.By pouring into ice and saturated NH 4Cl aqueous solution and cancellation reaction.With the water layer ethyl acetate extraction, use the 1M sodium hydroxide solution, water and salt water washing.Concentrate and obtain required product A with FSGC purification (20% ethyl acetate-hexane).Further with 30% ethyl acetate-hexane eluting obtain (R, S)-diastereomer B.
Step 3: amine A is removed the BOC-protecting group with the dichloromethane solution processing of TFA.Piperidines and acid are obtained chemical compound 30-30B in the following table with the EDCI/HOBt coupling; Prepare chemical compound 30C-1 with similar methods, they are non-enantiomer mixture.
Figure C200410085848D01122
Embodiment 31
Figure C200410085848D01131
With embodiment 12, and step 2 product (150mg, 0.27mmol), imidazoles (27.4mg, O.403mmol), 1, and the 10-phenanthroline (48mg, 0.27mmol), anti-, instead-and dibenzalacetone (6.28mg, 0.027mmol), copper trifluoromethanesulfcomposite (II) benzene complex (15mg, 0.027mmol) and Cs 2CO 3(96.1mg, dimethylbenzene 0.30mmol) (2ml) solution stirred 5 days at 110 ℃.Reactant mixture is cooled to room temperature and adds saturated sodium bicarbonate.Handle the back with ethyl acetate extraction and obtain title compound (70mg, yield 52%) with the silica gel chromatography purification.Decompose .215 ℃ (hydrochlorate).C 29H 39ClN 3HRMS (the M+H of OS +): theoretical value: 500.3389; Measured value: 500.3396.
Following test can be used for measuring the CCR5 antagonistic activity of The compounds of this invention.
The CCR5 film is in conjunction with determination experiment:
Utilize the CCR5 film to determine the bonded inhibitor of RANTES in conjunction with the high throughput screening method of test.This measures the membrane product that uses by the NIH3T3 cell preparation of expressing human CCR5 chemokine receptors, and they have and the bonded ability of RANTES (being the native ligand of receptor).Utilize the dull and stereotyped form in 96-hole, having or do not having in the presence of the chemical compound and use 125I-RANTES incubation membrane product 1 hour.Serial dilution chemical compound in 0.001 μ g/ml-1 μ g/ml wide region, and test in triplicate.Reactant mixture is gathered in the crops by glass fibre filter, and thorough washing.Obtain the meansigma methods of duplicate grand total, data are total to suppress 50% 125I-RANTES reports in conjunction with desired concn.Having strong active chemical compound in conjunction with test at film further uses HIV-1 based on cell to enter with replicated test to characterize.
HIV-1 enters test:
As Connor etc., Virology, 206(1995), p.935-944 described, by the plasmid of cotransfection coding HIV-1 NL4-3 strain (its sudden change by env gene and introduce luciferase reporting plasmid and modified) and the plasmid of one of several HIV-1 env genes of encoding, produce and duplicate deficient HIV-1 report virion.Gathered in the crops viral supernatant on the 3rd day after with two kinds of plasmids of calcium phosphate precipitation method transfection, and measurement function sexually transmitted disease (STD) poison titer.These original seeds are used to infect the U87 cell of stably express CD4 and chemokine receptor CCR 5 then, these cells with or do not use test compound precincubation.Infection was carried out under 37 ℃ 2 hours, washed cell then, and culture medium is replaced with the fresh culture that contains chemical compound.Incubation cell 3 days, cracking is also measured uciferase activity.The result is to suppress uciferase activity desired concn report in the 50% contrast culture group.
The HIV-1 replicated test
This test uses original peripheral blood mononuclear cell or stable U87-CCR5 cell line to measure the effect that anti--CCR5 chemical compound stops elementary HIV-1 strain to be infected.Purification derives from the lymphoblast of normal health donor, infects first three day with PHA and IL-2 stimulated in vitro.Utilize the dull and stereotyped lattice in 96-hole, 37 ℃ with medicine pretreatment cell 1 hour, has a liking for tropism HIV-1 (M-tropic HIV-1) separator with macrophage subsequently and infect.After the infection, washed cell is removed residual inoculum, cultivates 4 days in the presence of chemical compound.Collect culture supernatants, measure the virus replication situation by measuring viral p24 antigen concentration.
Calcium current goes out test
Add before chemical compound or the natural CCR5 part load calcium sensitive dye on the cell of expressing the HIV auxiliary receptor CCR 5.Chemical compound with agonist properties can induce calcium current to go out signal in cell, and the CCR5 antagonist then is considered to induce them itself to send signal but can stops native ligand RANTES to send the chemical compound of signal.
GTP γ S is in conjunction with test:
GTP γ S is used for measuring the receptor activation that the CCR5 part causes in conjunction with test.This experimental measurement suitable ligand causes that receptor activation produces 35S labelling-GTP combines with the G-G-protein linked receptor.In this test, the CCR5 part RANTES membrane product incubation of CCR5 express cell, and by analyzing knot 35S label mensuration combines with activated receptor.By inducing receptor activation, whether this test can demonstrate agonist properties by the quantitative assay chemical compound, and perhaps by measuring the bonded inhibition to RANTES with competition or non-competing mode, whether this test can demonstrate antagonist properties by the quantitative assay chemical compound.
The chemotactic test:
The chemotactic test is the functional trial that characterizes the agonist-antagonist properties of test compound.The non-adhesion mouse cell line (BaF-550) of this experimental measurement expressing human CCR5 replys test compound or native ligand (being RANTES, MIP-1 β) is striden the ability that film moves.Cell is crossed over permeable membrane to chemical compound one side shifting with agonist activity.Agonist compounds not only can not be induced chemotaxis, but also can suppress moving of the known CCR5 part of cell response.
Reported CC-chemokine receptor such as the effect of CCR-5 receptor in inflammation in the document, these documents as Immunology Letters, 57, (1997), 117-120 (arthritis); Clinical ﹠amp; Experimental Rheumatology, 17(4) (1999), p.419-425 (rheumatoid arthritis); Clinical ﹠amp; Experimental Immunology, 117(2) (1999), p.237-243 (atopic dermatitis); International Journal of Immunopharmacology, 20(11) (1998), p.661-7 (psoriasis); Journal of Allergy ﹠amp; Clinical Immunology, 100(6, Pt2) (1997), p.S52-5 (asthma); And Journal of Immunology, 159(6) (1997), p.2962-72 (allergy).
In measure suppressing the bonded test of RANTES, The compounds of this invention has the activity that Ki value is about 0.5-1500nM, and preferred compound has 0.5-750nM, more preferably 0.5-300nM, the activity of 0.5-60nM most preferably.Provided in the following table and measured the result who suppresses preferably to reach in the bonded test of RANTES representational formula I and II chemical compound." Ex.No. " representative " embodiment sequence number " in the table, and " nM " representative " nanomole ".
Ex.No. Ki (nM) is to the bonded inhibition of RANTES
3C 9.97
6C 30.0
6E 1.43
11 10.5
16 60
20A 1300
23 2.95
When using the CCR5 agonist compounds pharmaceutical compositions of the present invention's description, inertia pharmaceutically suitable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, dispersibility granule, capsule, cachet and suppository.Powder and tablet can contain the active component of about 5-about 95%.Suitable solid carrier is known in the art, for example magnesium carbonate, magnesium stearate, Talcum, sucrose or lactose.Tablet, powder, cachet and capsule all can be used as the solid dosage forms that is fit to oral administration.Pharmaceutically suitable carrier and the example for preparing various different components methods are found in Remington ' the s PharmaceuticalSciences that A.Gennaro edits, the 18th edition, (1990), Mack Publishing Co., Easton, Pennsvlvania.
Liquid form preparation comprises solution, suspension and emulsion.The example that can mention has water or the water-propylene glycol solution that is fit to non-intestinal injection, perhaps can add sweeting agent and opacifier for oral administration solution, suspension and emulsion.Liquid form preparation also comprises the solution that intranasal administration is used.
The aerosol that is fit to inhalation can comprise the solid of solution and powder type, and they can mix with pharmaceutically suitable carrier such as inertia Compressed Gas (for example nitrogen).
Equally also comprise and face the solid preparation of using liquid form preparation for oral or parenterai administration with before being converted into.This liquid form comprises solution, suspension and emulsion.
CCR5 agonist compounds of the present invention also can transdermal administration.Transdermal composition can be cream, lotion, and aerosol and/or Emulsion form, and they can be included in this area and usually are used in the matrix type or depot transdermal patch of this purpose.
Preferred CCR5 agonist compounds passes through oral administration.
Preferred described pharmaceutical preparation is unit dosage forms.In this type of dosage form, described preparation can be subdivided into the unit dose that contains the appropriate amount effective dose of required purpose (as reach) active component.
According to concrete application, the amount of the reactive compound in the unit dose formulations can approximately change between the 10mg-500mg and adjust, the about 300mg of 25mg-preferably approximately, the more preferably about about 250mg of 50mg-, and the about about 200mg of 55mg-most preferably.
The actual using dosage of CCR5 agonist compounds may change with patient's the needs and the order of severity of being treated disease.Art technology people unit can determine the optimal dose under the concrete condition.For convenience's sake, total daily dose can be segmented, and whole day is divided administration for several times as required.
The dosage of CCR5 agonist compounds of the present invention and/or its officinal salt and administration frequency are judged adjustment by clinical attending doctor according to following factors: such as patient's age, health and height and weight and the order of severity of treatment disease.The typical recommended of oral administration is about 100mg/ days-approximately 300mg/ days, preferred 150mg/ days-250mg/ days, and more preferably approximately 200mg/ days, and be divided into 2-4 divided dose and use.
The dosage of NRTIs, NNRTIs, PIs and other medicines and dosage by clinical attending doctor according to the approval dosage in the packing built-in description and dosage or as described in the therapeutic scheme, and the gradient of infection of consideration patient's age, health and height and weight and HIV-1 and deciding.
Although the present invention is illustrated in conjunction with above-mentioned specific embodiment,, all will be conspicuous to its various improvement, modification and change of carrying out to art technology people unit.And all these replacements, modification and improvement all drop within aim of the present invention and the scope.

Claims (21)

1. pharmaceutical composition, described pharmaceutical composition is a cream, described cream contains the compound or pharmaceutically acceptable salt thereof and the pharmaceutical carrier of following structural formula representative:
Figure C200410085848C00021
R wherein, R 3, R 6And R 2Following table definition:
Figure C200410085848C00031
Figure C200410085848C00041
Figure C200410085848C00051
2. the compositions of claim 1, chemical compound wherein has the following formula structure,
Figure C200410085848C00071
Wherein said R 2Has the following formula structure
Figure C200410085848C00072
3. the compositions of claim 1 is used for the treatment of purposes in human immunodeficiency virus's the medicine in preparation.
4. the compositions of claim 1 is used for the treatment of purposes in human immunodeficiency virus's the medicine of medication combined medication in preparation with one or more other.
5. pharmaceutical composition, described pharmaceutical composition contains the compound or pharmaceutically acceptable salt thereof that structural formula II is represented:
Figure C200410085848C00073
Wherein
(1) R aBe R 8a-phenyl, R 8b-pyridine radicals or R 8-naphthyl;
R 1It is hydrogen atom;
R 2Be R 9, R 10, R 11The phenyl of-replacement; R 9, R 10, R 11The pyridine radicals or the pyrimidine radicals of-replacement; R 9, R 10, R 11The pyridine radicals N-oxide or the pyrimidine radicals N-oxide of-replacement; R 12, R 13-replacement De oxazolyl; Naphthyl; Fluorenyl;
Figure C200410085848C00081
Thienyl
Or
Figure C200410085848C00082
Pyridine radicals;
R 3Be hydrogen atom, C 1-C 6Alkyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Cycloalkyl C 1-C 6Alkyl, R 8-phenyl, R 8-phenyl C 1-C 6Alkyl or R 8-thienyl C 1-C 6Alkyl;
R 4, R 5, R 7And R 13Be selected from hydrogen atom and C alone 1-C 6-alkyl;
R 6Be hydrogen atom or C 1-C 6Alkyl;
R 8Be 1 to 3 and be selected from following substituent group alone: hydrogen atom, halogen, C 1-C 6Alkoxyl and-CF 3
R 8aBe 1 to 3 and be selected from following substituent group alone: hydrogen atom, halogen ,-CF 3, CF 3O-,-CN, R 14-phenyl ,-NHCOCF 3And imidazole radicals;
R 8bBe 1 to 3 and independently be selected from following substituent group: hydrogen atom, halogen;
R 9And R 10Independently be selected from C 1-C 6Alkyl, halogen ,-NR 17R 18,-OH ,-CF 3With-OCH 3
R 11Be R 9, hydrogen atom, phenyl ,-NO 2,-CN ,-CH 2F ,-CHF 2,-CHO ,-CH=NOR 17, pyridine radicals, pyridine radicals N-oxide, pyrimidine radicals, pyrazinyl ,-NR 17-CONR 18R 19,-NHCONH chloro-C 1-C 6Alkyl ,-NHCONH C 3-C 10Cycloalkyl C 1-C 6Alkyl ,-NHCO C 1-C 6Alkyl ,-NHCOCF 3,-NHSO 2N (C 1-C 6Alkyl) 2,-NHSO 2C 1-C 6Alkyl ,-N (SO 2CF 3) 2,-NHCO 2C 1-C 6Alkyl, C 3-C 10Cycloalkyl ,-SR 20,-OSO 2C 1-C 6Alkyl ,-OSO 2CF 3, hydroxyl C 1-C 6Alkyl ,-CONR 17R 18,-CON (CH 2CH 2-O-CH 3) 2,-OCONHC 1-C 6Alkyl ,-Si (CH 3) 3Or-B (OC (CH 3) 2) 2
R 12Be C 1-C 6Alkyl or R 14-phenyl;
R 14Be 1 to 3 and independently be selected from following substituent group: hydrogen atom, C 1-C 6Alkyl ,-CF 3,-CO 2R 17,-CN, C 1-C 6Alkoxyl and halogen;
R 15And R 16Independently be selected from hydrogen atom and C 1-C 6Alkyl, or R 15And R 16Be C together 2-C 5Alkylidene and the carbon atom that links to each other with them form the volution that contains 3 to 6 carbon atoms;
R 17, R 18And R 19Independently be selected from H and C 1-C 6Alkyl; With
R 20Be C 1-C 6Alkyl,
Be used for the treatment of human immunodeficiency virus's medicine and pharmaceutical carrier with one or more antiviral agent or other.
6. the compositions of claim 5, wherein said one or more antiviral agent are selected from efabirenz, non-nucleoside reverse transcriptase inhibitor and protease inhibitor, and the wherein said medicine that other is used for the treatment of the human immunodeficiency virus is selected from hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.
7. the compositions of claim 6, wherein said efabirenz is selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, A Bokawei, Adefovir Dipivoxil, Lobucavir, BCH-10652, emtricitabine, β-L-FD4, DAPD, (-)-β-D-2,6-diaminourea-purine dioxolane and lodenosine; Described non-nucleoside reverse transcriptase inhibitor is selected from nevirapine, dilazep Wei Ding, Yi Feiweilun, PNU-142721, AG-1549,5-(3, the 5-Dichlorobenzene base)-sulfenyl-4-isopropyl-1-(4-pyridine radicals) methyl isophthalic acid H-imidazoles-2-ylmethyl carbonic ester, (1-(ethyoxyl-methyl)-5-(1-Methylethyl)-6-(phenyl methyl)-(2,4-(1H, 3H)-hybar X) and (+)-calanolide A and B; And described protease inhibitor is selected from Saquinavir, ritonavir, viracept see nelfinaivr, amprenavir, Iasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1549.
8. the compositions of claim 6, wherein said antiviral agent is selected from ritonavir, emtricitabine, Yi Feiweilun and BMS-2322623.
9. pharmaceutical composition, described pharmaceutical composition comprises the chemical compound with following formula
Figure C200410085848C00091
Be used for the treatment of human immunodeficiency virus's medicine and pharmaceutical carrier with one or more antiviral agent or other.
10. the compositions of claim 9, wherein said one or more antiviral agent are selected from efabirenz, non-nucleoside reverse transcriptase inhibitor and protease inhibitor, and the wherein said medicine that other is used for the treatment of the human immunodeficiency virus is selected from hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.
11. the compositions of claim 10, wherein said efabirenz is selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, A Bokawei, Adefovir Dipivoxil, Lobucavir, BCH-10652, emtricitabine, β-L-FD4, DAPD, (-)-β-D-2,6-diaminourea-purine dioxolane and lodenosine; Described non-nucleoside reverse transcriptase inhibitor is selected from nevirapine, dilazep Wei Ding, Yi Feiweilun, PNU-142721, AG-1549,5-(3, the 5-Dichlorobenzene base)-sulfenyl-4-isopropyl-1-(4-pyridine radicals) methyl isophthalic acid H-imidazoles-2-ylmethyl carbonic ester, (1-(ethyoxyl-methyl)-5-(1-Methylethyl)-6-(phenyl methyl)-(2,4-(1H, 3H)-hybar X) and (+)-calanolide A and B; And described protease inhibitor is selected from Saquinavir, ritonavir, viracept see nelfinaivr, amprenavir, Iasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1549.
12. the pharmaceutical composition of claim 11, wherein said antiviral agent is a ritonavir.
13. the pharmaceutical composition of claim 11, wherein said antiviral agent is emtricitabine.
14. the pharmaceutical composition of claim 11, wherein said antiviral agent is Yi Feiweilun.
15. the pharmaceutical composition of claim 11, wherein said antiviral agent is BMS-2322623.
16. a pharmaceutical composition, described pharmaceutical composition comprises the chemical compound with following formula
Figure C200410085848C00101
And pharmaceutical carrier.
17. have the chemical compound of following formula
Figure C200410085848C00102
Be used for the treatment of purposes in human immunodeficiency virus's the medicine in preparation.
18. the compositions of claim 5 is used for the treatment of purposes in human immunodeficiency virus's the medicine in preparation, wherein said one or more antiviral agent are selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, A Bokawei, Adefovir Dipivoxil, Lobucavir, BCH-10652, emtricitabine, β-L-FD4, DAPD, (-)-β-D-2,6-diaminourea-purine dioxolane, lodenosine, nevirapine, dilazep Wei Ding, Yi Feiweilun, PNU-142721, AG-1549,5-(3, the 5-Dichlorobenzene base)-sulfenyl-4-isopropyl-1-(4-pyridine radicals) methyl isophthalic acid H-imidazoles-2-ylmethyl carbonic ester, (1-(ethyoxyl-methyl)-5-(1-Methylethyl)-6-(phenyl methyl)-(2,4-(1H, 3H)-hybar X), (+)-calanolide A and B, Saquinavir, ritonavir, viracept see nelfinaivr, amprenavir, Iasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1549.
19. the purposes of claim 18, wherein said antiviral agent is selected from ritonavir, emtricitabine, Yi Feiweilun and BMS-2322623.
20. the purposes of claim 18 or 19, wherein the formula II chemical compound in the claim 5 has following structure
Figure C200410085848C00111
21. comprise the medicine box of the container of the isolating pharmaceutical composition that independent packaging is housed, wherein pharmaceutical composition is used for drug combination treatment human immunodeficiency virus, this medicine box comprises a container that the pharmaceutical composition of the formula II chemical compound described in the claim 1 in pharmaceutical carrier that contains effective dose is housed, with another container, one or more antiviral agent in pharmaceutical carrier or the pharmaceutical composition of other medicines that are used for the treatment of the human immunodeficiency virus that contain effective dose are housed.
CNB2004100858485A 2000-05-01 2000-05-01 Piperazine derivative used as CCRS antagonist Expired - Fee Related CN100490811C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB2004100858485A CN100490811C (en) 2000-05-01 2000-05-01 Piperazine derivative used as CCRS antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US2000/011632 WO2000066558A1 (en) 1999-05-04 2000-05-01 Piperazine derivatives useful as ccr5 antagonists
CNB2004100858485A CN100490811C (en) 2000-05-01 2000-05-01 Piperazine derivative used as CCRS antagonist

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CNB008071675A Division CN1182114C (en) 2000-05-01 2000-05-01 Piperazine derivatives used as CCR5 antagonists

Publications (2)

Publication Number Publication Date
CN1636567A CN1636567A (en) 2005-07-13
CN100490811C true CN100490811C (en) 2009-05-27

Family

ID=34847410

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2004100858485A Expired - Fee Related CN100490811C (en) 2000-05-01 2000-05-01 Piperazine derivative used as CCRS antagonist

Country Status (1)

Country Link
CN (1) CN100490811C (en)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
植物用抗病毒剂的研究. 陈洪等.厦门大学学报自然科学版，第38期. 1999

Also Published As

Publication number Publication date
CN1636567A (en) 2005-07-13

Similar Documents

Publication Publication Date Title
KR100439358B1 (en) Piperazine derivatives useful as CCR5 antagonists
US6391865B1 (en) Piperazine derivatives useful as CCR5 antagonists
US8114879B2 (en) Piperazine derivatives useful as CCR5 antagonists
EP1421075B1 (en) Piperidine derivatives useful as ccr5 antagonists for the treatment of hiv
AU2002255947A1 (en) CCR5 antagonists useful for treating AIDS
CN101326178A (en) Piperazine derivatives useful as CCR5 antagonists
CN100490811C (en) Piperazine derivative used as CCRS antagonist
AU2002329889A1 (en) Piperidine derivatives useful as CCR5 antagonists
MXPA01011185A (en) Piperazine derivatives useful as ccr5 antagonists

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20090527

Termination date: 20110501