CN1678591A - New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture - Google Patents

New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture Download PDF

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Publication number
CN1678591A
CN1678591A CNA038200767A CN03820076A CN1678591A CN 1678591 A CN1678591 A CN 1678591A CN A038200767 A CNA038200767 A CN A038200767A CN 03820076 A CN03820076 A CN 03820076A CN 1678591 A CN1678591 A CN 1678591A
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phenyl
alkyl
group
ethyl
ylmethyl
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Inventor
索尔斯坦·莱曼－林茨
德克·斯滕坎普
马丁·伦特
海克－安德烈·威兰
克劳斯·鲁道夫
斯蒂芬·G·米勒
拉尔夫·R·H·洛茨
柯尔斯滕·阿恩特
菲利普·勒斯滕伯格
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Publication of CN1678591A publication Critical patent/CN1678591A/en
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Abstract

The invention relates to carboxamide compounds of general formula (I), in which the groups and radicals A, B, W, X, Y, Z, R1, R2, R3, and k have the meanings indicated in claim 1. The invention also relates to methods for producing said carboxamide compounds and medicaments containing at least one inventive carboxamide. The inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, especially obesity, bulimia, anorexia, hyperphagia, and diabetes due to the MCH receptor-antagonistic activity thereof.

Description

Have the novel carboxamide compounds of MCH-antagonistic action, comprise pharmaceutical preparation of this compound and preparation method thereof
The invention relates to novel carboxamide compounds, the acceptable salt of its preparation and physiology thereof, with and as the purposes of MCH antagonist and be used for the purposes of useful in preparing drug formulations, this pharmaceutical preparation is applicable to that prevention and/or treatment are caused by MCH or with the symptom and/or the disease of other reasons and MCH dependency.The purposes that the present invention also is used to influence dietary behavior about The compounds of this invention and is used to reduce body weight and/or is used to prevent weight of mammal to increase simultaneously.The present invention is composition and the medicine about containing The compounds of this invention also, with and preparation method thereof.
Background of invention
For all biologies, the picked-up of food and conversion in vivo thereof play an important role in life.Therefore, the deviation of ingestion of food and conversion aspect generally all can cause disturbing, and causes disease.Nearly recent decades, the variation of human lives's form and daily life particularly in industrialized country, has caused fat increase.For patients, obesity directly causes the restriction of action and the reduction of quality of the life.Another problem is that then obesity can cause other diseases usually, such as, diabetes, hyperlipemia, hypertension, arteriosclerosis, and crown heart trouble.Simultaneously, high body weight itself promptly can be strengthened stress on support and motion structure, and it may cause chronic pain and disease, such as, sacroiliitis or osteoarthritis.Therefore, fat is a kind of serious health problem for society.
The term obesity means the too much of fatty tissue.Relevant at this point, the fat degree that increases that can cause health risk that is considered to be basically.And can't accurately distinguish normal individual and obese patient, but follow the fat health risk that produces to continue with the increase of obese degree to increase.For asking simplification, in the present invention, body-mass index (Body Mass Index, BMI) definition be the body weight measured with kilogram unit divided by height (is unit with rice) square, surpass 25 individuality, particularly surpass 30, promptly preferably being considered as is to suffer from the obese person.
Except the activity and the metatrophia of physical property, there is no the treatment possibility of convincing that other can effectively reduce body weight at present.Yet, because of obesity be development serious and even one of the life-threatening disease primary hazard factor, obtain that to can be used for preventing and/or treating fat pharmaceutically active substance be very important.One of method that is recently proposed is the therepic use (especially with reference to WO 01/21577, WO01/82925) of MCH antagonist.
Melanocyte concentrates hormone, and (Melanin-concentrating hormone MCH) is a kind of ring-type neuropeptide, is made of 19 Amino acids.It is mainly synthetic in hypothalamus in Mammals, and is passed to other zones of brain by the projection of hypothalamus neurons from this place.In human body, its biological activity is by from two kinds of different glycoprotein coupled receptors of the relevant GPCR group of Visual purple (glycoprotein-coupledreceptor GPCR) draws, that is, MCH-acceptor 1 and 2 (MCH-1R), MCH-2R).
Effect in the energy balance regulation and control provides good supporting to this peptide in the research of being carried out for the MCH function in animal model, that is, change metabolic activity and ingestion of food [1,2].For example, in the rat body, carry out the intravenously dispensing of MCH after, compared to the picked-up of control group food increase is arranged.In addition, control the transgenic rat that treated animal can produce more MCH, when accepting high fat diet, than not testing the body weight that variability MCH content animal is significantly increased.Can determine that the content of MCH mRNA has positive relationship in period that appetite increases and the rat hypothalamus.Yet, knock down the experiment that mouse carried out with MCH and with regard to the function that shows MCH, have importance especially.The forfeiture of this neuropeptide causes having the animal that becomes thin than the lower fat amount, and it is obviously less that it controls the treated animal pickuping food.
MCH to subtract that appetite acts in the muroid animal body be to pass through G α s-coupling MCH-1R causes [3-6].Be different from primate, ferret, reach dog, in the muroid animal body, find secondary acceptor so far.Behind forfeiture MCH-1R, defeat mouse and have lower fat quantity, higher Conversion of energy, and when the feeding high fat diet, compared to the control treated animal, it can't be put on weight.The MCH-MCH-1R system then is from the experiment [3] of using a kind of receptor antagonist (SNAP-7941) to be carried out for another index of the importance of energy balance regulation and control.In test of long duration, can reduce the body weight of significant quantity with the animal of this antagonist for treating.
Except it reduced the appetite effect, MCH-1R antagonist SNAP-7941 still can reach extra anxiety and anti-melancholy effect [3] in the behavior test of rat.Therefore, hint that clearly the MCH-MCH-1R system not only relates to the regulation and control of energy balance, also relates to emotion.
Document:
1.Qu, D., Deng the people, A role for melanin-concentrating hormone in the centralregulation of feeding behaviour (melanocyte concentrates the effect of hormone in the maincenter regulation and control of feeding behavior) .Nature, 1996.380 (6471): p.243-7.
2.Shimada M. waits the people, Mice lacking melanin-concentrating hormone arehypophagic and lean (lack melanocyte and concentrate the mouse of hormone for hanging down the appetite and the person of becoming thin) .Nature, 1998.396 (6712): p.670-4.
3.Borowsky, B., Deng the people, Antidepressant, anxiolytic and anorectic effects of amelanin-concentrating hormone-1 receptor antagonist (melanocyte concentrate hormone-1 receptor antagonist anti-melancholy, anxiety, and anoretic effect) .Nat Med, 2002.8 (8): p.825-30.
4.Chen, Y., Deng people Targeted disruption of the melanin-concentrating hormonereceptor-1 results in hyperphagia and resistance to diet-induced obesity (guidance quality that melanocyte concentrates hormone receptor-1 destroy to cause hyperingestion and for the resistance of bringing out property of diet obesity) .Endocrinology, 2002.143 (7): p.2469-77.
5.Marsh, D.J., Deng the people, Melanin-concentrating hormone 1 receptor-deficientmice are lean, hyperactive, and hyperphagic and have altered metabolism (mouse that melanocyte concentrates hormone 1 acceptor defect becomes thin, moving with excessivelying, reach and hang down appetite, and have the metabolism of variation) .ProcNatl Acad Sci USA, 2002.99 (5): p.3240-5.
6.Takekawa, S., Deng the people, T-226296:A novel, orally active and selectivemelanin-concentrating hormone receptor antagonist (a kind of Orally active of novelty and selective melanin concentrate hormone receptor antagonists).Eur?J?Pharmacol，2002.438(3)：p.129-35.
In patent documentation, certain amine compound has been proposed as the MCH antagonist.Therefore, WO01/21577 (Takeda) addresses the compound of following formula
Ar wherein 1In generation 8, shown cyclic group, and X represents spacer, and Y represents key or spacer, and Ar represents aromatic ring, and it can condense R with non-aromatic ring 1And R 2H or alkyl, the wherein R of representing independently of one another 1And R 2Can form jointly with the N atom of adjacency and to contain the N heterocycle, and R 2Also can form volution jointly with Ar, the N atom of R and adjacency and Y can form jointly and contain the N heterocycle, its as the MCH antagonist to be used for the treatment of obesity.
Simultaneously, in WO 01/82925 (Takeda), also address the compound of following formula
Figure A0382007600332
Ar wherein 1Represent cyclic group, X and Y represent spacer, the fused polycycle aromatic ring that on behalf of optional, Ar replace, R 1And R 2Represent H or alkyl independently of one another, wherein R 1And R 2Can form jointly with the N atom of adjacency and to contain the N heterocycle, and R 2Can form jointly with the N atom of adjacency and Y and to contain the N heterocycle, its as the MCH antagonist to be used for the treatment of obesity.
WO 02/057233 (Schering Corp.) proposes the amine compound that other have the MCH antagonistic activity.These compounds have general formula
Ar wherein 1, Ar 2, Ar 3Special representative's aryl or heteroaryl, X, O, S or N-CN, Y represent singly-bound or C 1-4Alkylidene group, and R 1And R 2Be as defined herein.
Equally, it is relevant with the piperidine derivative of following formula also to address the MCH antagonistic activity among the WO 02/051908 (Schering Corp.)
Figure A0382007600342
Wherein W represents the aminocarbonyl or the carbonyl amino of concrete definition, X representative-CHR 8,-CO ,-C (=NOR 9) or-CR 8=, Y represents CH, C (OH), C (C 1-4-alkoxyl group) or the two keys of C, R 2Aryl or heteroaryl that representative replaces, R 10Represent H, C 1-6-alkyl or aryl, and other groups are as defined herein.
WO 02/10146 (Smithkline Beecham) proposes can be used as the carboxylic acid amides of human 11CBy receptor antagonist.These compounds are representatives of following general structure
Wherein A represents H, alkyl, alkoxyl group, thiazolinyl, acyl group, halogen atom, OH, CN or CF 3, R 3Represent H, methyl or ethyl, R 4Aromatic carbocyclic that is substituted or heterocycle that representative is optional, Z represents O, S, NH, CH 2, or singly-bound, R 5Saturated or undersaturated carbocyclic ring of aromatics or heterocycle that representative randomly is substituted, Q represents group-X-Y-NR 1(R 2), simultaneously according to different situations, X can represent O, S or N, and Y can represent alkylidene group or ring alkylidene group (it also can be substituted), and R 1And R 2Can represent alkyl or phenyl-alkyl, simultaneously, R 1And R 2, R 1And Y or R 1And X also can interlink to form loop systems, as described in it.
Other compounds with MCH antagonistic properties are then in disclosing application case WO 03/035055, WO03/033480, WO 02/06245, WO 02/04433, WO 01/87834, WO 01/21169, reaching proposition among the JP 2001/226269.
The quinazolinones of following general formula
Figure A0382007600351
Be described in WO 01/23365 (Merck), wherein Z represents key or phenylene, and is described in WO01/23364 (Merck).Wherein Z represents cyclohexylene.In addition, Y represents key or C 2-4-thiazolinyl, and R 4Represent aryl, cycloalkyl, benzene alkyl or heterocyclic ring system.These compounds are described as the GPIbIX inhibitor, and particularly this acceptor has the Willebrand factor (vWF) ligand as inhibitor.
The aromatic substance that can contain lactam bridge and amino also proposes with regard to other symptoms in the literature.Therefore, (wherein Ar represents aromatics list or the bicyclic group that selectivity is substituted to compound by general formula Ar-A-E, A represents lactam bridge or ammonia bridge, and E is another phenyl, and it is replaced by the ammonia alkylidene group that is substituted by spacer B in contraposition) be described in WO 99/01127 (Smithkline Beecham Corp.).These compounds are as the CCR5 receptor ligand, especially with treatment asthma, dystopy disease, reach rheumatoid arthritis and propose.
WO 01/72712 (Cor Therapeutics Inc.) addresses the isoquinoline compound of following formula
Wherein A represents amino or the amidino groups that selectivity is substituted, and Z represents key or alkyl, cycloalkyl, thiazolinyl, alkynyl or aryl spacer, and m and n represent 0 to 3, and D represents key or specified bridge, and X represents NR 12Or CHR 12P represents 0 to 3, E except that specified ether, amino, amido, and carboxyl also represent key, J represent key, encircles alkylidene group, phenylene, naphthylidene or heteroaryl, G represents amido, imino-or amidino groups more specifically, and other groups are to define as preamble.These compounds are the inhibitor as separation factor Xa and blood coagulation, and therefore it propose as the reaching the antithrombotic acitivity material of anti-freezing.
The two substituted bicyclic heterocycles of warp of following formula are proposed in DE 197 18 181 A1 (Boehringer Ingelheim)
R a-A-Het-Ar-E
R wherein aBut amino or also alternative R that represents that more specifically defines 4-SO 2-NR 5Or R 4-SO 2(it has R to group 4And R 5Specified meaning), A represents phenylene-C 1-3-alkylidene group, just-C 2-6-alkylidene group or C 5-7-ring alkylidene group-C 1-3-alkylidene group, it can be as specified being substituted, benzoglyoxaline, indoles, tetrahydroquinolones or quinazoline ketone group that on behalf of selectivity, Het be substituted, phenylene, naphthylidene, inferior thienyl, inferior thiazolyl, pyridylidene, inferior pyrimidyl, inferior pyrazinyl or inferior pyridazinyl that on behalf of selectivity, Ar be substituted, and E represents cyano group or R bNH-C (=NH) group, wherein R bRepresent H, OH, C 1-3-alkyl or cracked group in vivo.These compounds are as zymoplasm inhibition and zymoplasm time delay active substance and propose.
Goal of the invention
The object of the present invention is to provide novel carboxamide compounds, particularly can be effectively as the MCH antagonist.The present invention also provides novel carboxamide compounds, and it can be used for influencing mammiferous food habits, and particularly Mammals is reached alleviating of body weight, and/or the increase of prevention body weight.Another task of the present invention provides novel pharmaceutical preparation, and it is applicable to that prevention and/or treatment cause because of MCH or has the symptom and/or the disease of other reasons dependency with MCH.Particularly, the purpose of this invention is to provide the pharmaceutical preparation that is used for the treatment of metabolic trouble, such as, obesity and/or diabetes and symptom and/or the disease relevant with obesity and/or diabetes.Another object of the present invention is the favourable purposes about the explanation The compounds of this invention.Same task of the present invention provides the method for preparing carbonyl amide compound of the present invention.By preamble and explanation hereinafter, skilled persons will can be understood other purposes of the present invention immediately.
Subject matter
First purpose of the present invention comprises the carboxamide compounds of general formula I
Figure A0382007600361
Wherein
R 1, R 2Represent H independently of one another, its selectivity is through radicals R 11The C that replaces 1-8-alkyl or C 3-7-cycloalkyl or selectivity are through radicals R 12Single or polysubstituted, and/or through the mono-substituted phenyl of nitro, or
R 1And R 2Form C 2-8-alkylidene bridge, wherein
-one or two-CH 2-group can be independently of one another and quilt-CH=N-or-CH=CH-replaces, and/or
-one or two-CH 2-group can be independently of one another and quilt-O-,-S-,-CO-,-C (CH 2)-or-NR 13-substitute, so that heteroatoms directly is not connected with each other,
Simultaneously, in defined alkylidene bridge above, one or more H atom can be by R 14Replace, and/or
Wherein defined alkylidene bridge can replace through one or more identical or different carbocyclic ring or heterocyclic group Cy, so that the key between this alkylidene bridge and this group Cy forms by following
-by single or two keys,
-by a shared C atom, form a volution system,
-by the C and/or the N atom of two shared, adjacency, form a condensed-bicyclic system, or
-by three or above C and/or N atom, form a bridged ring system,
R 3Represent H, C 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-4Alkyl-, C 3-7-cycloalkenyl group, C 3-7-cycloalkenyl group-C 1-4-alkyl-, phenyl, phenyl-C 1-4-alkyl-, C 1-3-alkoxy-C 2-6-alkyl-, amino-C 2-6-alkyl-, C 1-3-alkyl-amino-C 2-6-alkyl-or two-(C 1-3-alkyl)-amino-C 2-6-alkyl-,
X represents singly-bound or C 1-8-alkylidene bridge, wherein
-one or two-CH 2-group can be independently of one another and by-CH=CH-or-C ≡ C-substitutes, and/or
-one or two-CH 2-group can be independently of one another and by-O-,-S-,-(SO)-,-(SO 2)-,-CO-or-NR 4-substitute, so that two O, S under each situation or N atom or an O atom and a S atom directly be not connected with each other,
Wherein, one or two C atom independently of one another can be through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or under each situation through one or two identical or different C 1-6-alkyl replaces, and/or
Wherein alkylidene bridge can link R 1, link R so that it comprises 1And the N atom of X, form a heterocyclic radical,
Z represents C 1-4-alkylidene bridge, wherein the C atom of two adjacency and another C 1-4-alkylidene bridge can be connected to each other, simultaneously in group Z, and-CH 2-group can by-O-or-NR 5-substitute, and one or two C atom in this alkylidene bridge can be independently of one another through hydroxyl, ω-hydroxyl-C here 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-, C 1-3-alkoxyl group, amino-C 1-3-alkyl-, C 1-3-alkyl-amino-C 1-3-alkyl-or two-(C 1-3-alkyl)-amino-C 1-3-alkyl-replacement, and/or through one or two identical or different C 1-6-alkyl replaces, and/or
R 3Can link Z, link R so that it comprises 3The N atom, form a heterocyclic radical,
A, Y have one of specified meaning of Cy independently of one another,
Simultaneously, R 1Can link Y, so that it comprises radicals X and links R 1And the N atom of X, form a Y condensed heterocycle base, and/or
R 3Can link Y, so that it comprises group Z and links R 3And the N atom of Z, form a saturated or undersaturated heterocyclic radical of part of Y condensed, or
A and R 3Can be connected to each other, so that
The group of formula I
Figure A0382007600381
Represent the group of segment bounds II
And
Q represents a group that is selected from segment bounds IIIa to IIIg
-CR 6R 7-???????????IIIa
-CR 6＝CR 7-????????IIIb
-N＝CR 8-???????????IIIc
-N＝N-??????????????IIId
-CO-NR 9-???????????IIIe
-CR 8＝N-???????????IIIf
-CO-????????????????IIIg
L 1, L 2, L 3Independently of one another and have a R 20One of specified meaning,
B represents C 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more carbon atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, or
Have one of specified meaning of Cy, simultaneously, link group W or selectivity and directly be attached to group A it is by by this isocyclic part or this selected fused phenyl or the C atom on the pyridine ring, or form by the N or the C atom of this heterocyclic moiety,
Simultaneously, when k=0, group B and group A can be connected to each other by a shared C atom, form a volution system, or
The atom of, adjacency shared by two forms a condensed-bicyclic system,
W represent singly-bound ,-O-, C 1-4-alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N-(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-6-alkyl replaces, and/or
Have alkylidene group, oxyalkylene, and the W of alkylidene group oxyalkylene definition also can link B by two keys,
K represents 0 or 1,
Cy represents carbocylic radical or heterocyclic radical, and it is to be selected from one of following meaning
-saturated 3-to 7-member carbocylic radical,
-undersaturated 5-to 7-member carbocylic radical,
-phenyl,
-saturated 4-to 7-member or undersaturated 5-to 7-member have N, an O or S atom as heteroatomic heterocyclic radical,
-saturated or undersaturated 5-to 7-element heterocycle base, have two or more N atoms or have one or two N atom and O or S atom as heteroatomic heterocyclic radical,
The heterocycle 5-of-aromatics or 6-person's group, it has one or more identical or different N, O and/or S of being selected from,
Simultaneously, above-mentioned 4-, 5-, 6-or 7-person's group can link by C atom common by two, adjacency, condense with phenyl or pyridine ring, and
In above-mentioned 5-, 6-or 7-person's group, one or two non-adjacent-CH 2Group can by-CO-,-C (=CH 2)-,-(SO)-or-(SO 2)-group substitutes, and
Above-mentioned saturated 6-or 7-person's group also can with imino-, N-(C 1-4-alkyl)-imino-, methylene radical, C 1-4-alkyl-methylene radical-or two-(C 1-4-alkyl)-methylene bridge exists with the form of bridge joint loop systems jointly, and
Above-mentioned cyclic group can be at one or more C atom place by R 20Single or polysubstituted, and under the situation of phenyl, also can additionally replace through the nitro list,
And/or at one or more N atoms place through R 21Replace,
R 4, R 5Has R independently of one another 16One of specified meaning,
R 6, R 7, R 8, R 9H, the C of representing independently of one another 1-6-alkyl, ω-C 1-3-alkoxy-C 1-3-alkyl-or ω-hydroxyl-C 1-3-alkyl, and R 6, R 7, R 8Also represent halogen atom independently of one another,
R 11Represent R 15-O-, R 15-O-CO-, R 16R 17N-, R 18R 19N-CO-or Cy-,
R 12Has R 20Specified meaning,
R 13Has R 17Specified meaning,
R 14Represent halogen atom, C 1-6-alkyl, R 15-O-, R 15-O-CO-, R 16R 17N-, R 18R 19IN-CO-, R 15-O-C 1-3-alkyl-, R 15-O-CO-C 1-3-alkyl-, R 16R 17N-C 1-3-alkyl-, R 18R 19N-CO-C 1-3-alkyl-or Cy-C 1-3-alkyl-,
R 15Represent H, C 1-4-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, phenyl, phenyl-C 1-3-alkyl-or pyridyl,
R 16Represent H, C 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 4-7-cycloalkenyl group, C 4-7-cycloalkenyl group-C 1-3-alkyl-, ω-hydroxyl-C 2-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 2-3-alkyl-, amino-C 1-6-alkyl-, C 1-3-alkyl-amino-C 1-6-alkyl-or two-(C 1-3-alkyl)-amino-C 1-6-alkyl-,
R 17Has R 16Specified meaning, or represent phenyl, phenyl-C 1-3-alkyl-, pyridyl, dioxolane-2-base, C 1-3-alkyl-carbonyl, hydroxyl carbonyl-C 1-3-alkyl-, C 1-4-carbalkoxy, C 1-3-alkane carbonyl amino-C 2-3-alkyl-, C 1-3-alkyl sulphonyl-or C 1-3-alkyl sulfonyl amino-C 2-3-alkyl-,
R 18, R 19H or the C of representing independently of one another 1-6-alkyl,
R 20Represent halogen atom, hydroxyl, cyano group, C 1-4-alkyl, C 3-7-cycloalkyl, hydroxyl-C 1-3-alkyl, R 22-C 1-3-alkyl, or have R 22Specified meaning,
R 21Represent C 1-3-alkyl, ω-hydroxyl-C 2-3-alkyl, phenyl, phenyl-C 1-3-alkyl-, C 1-3-alkyl-carbonyl, carboxyl, C 1-4-alkoxyl group-carbonyl, C 1-3-alkyl sulphonyl, phenylcarbamoyl or phenyl-C 1-3-alkyl-carbonyl,
R 22Represent pyridyl, phenyl, phenyl-C 1-3-alkoxyl group-, C 1-3-alkoxyl group, C 1-3-alkylthio-, carboxyl, H-CO-, C 1-3-alkyl carbonyl, C 1-4-carbalkoxy, aminocarbonyl, C 1-3-alkylamino-carbonyl, two-(C 1-3-alkyl)-aminocarbonyl, C 1-3-alkyl-alkylsulfonyl, C 1-3-alkyl-sulfinyl, C 1-3-alkyl-sulfonamido-, amino, C 1-3-alkylamino-, two (C 1-3-alkyl)-amino-, phenyl-C 1-3-alkylamino-or N-(C 1-3-alkyl)-phenyl-C 1-3-alkyl-amino-, acetylaminohydroxyphenylarsonic acid, propionamido, phenylcarbamoyl, benzene carbonyl amino-, the phenylcarbamoyl methylamino--, hydroxyl-alkane aminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidyl) carbonyl, (piperidino) carbonyl, (six hydrogen-1-azepine _ yl) carbonyl, (4-methyl isophthalic acid-piperazinyl) carbonyl, methylene-dioxy, aminocarbonyl-amino-or alkylamino carbonyl amino-
Simultaneously, at group and part A, B, W, X, Y, Z, R 1To R 9, and R 11To R 22In, under each situation, one or more C atom can be single or polysubstituted through F, and/or, under each situation, one or two C atom can be independently of one another through Cl or the single replacement of Br, and/or under each situation, one or more phenyl ring can be independently of one another, have one, two or three substituting group in addition, this substituting group is selected from F, Cl, Br, I, C 1-4-alkyl, C 1-4-alkoxyl group, difluoromethyl, trifluoromethyl, hydroxyl, amino, C 1-3-alkylamino-, two-(C 1-3-alkyl)-amino-, acetylaminohydroxyphenylarsonic acid, aminocarbonyl, CN, difluoro-methoxy, trifluoromethoxy, amino-C 1-3-alkyl-, C 1-3-alkylamino-C 1-3-alkyl-, and two-(C 1-3-alkyl)-amino-C 1-3-alkyl-, and/or it can replace through the nitro list, and
Any H atom that is present in carboxyl, or link the H atom of N atom, under each situation, can by one in vivo the cracked group substituted,
Different my body of its tautomer, diastereomer, mapping, its mixture, with and salt.
Theme of the present invention also about with mixture, tautomeric forms and the free alkali of indivedual optically active isomer forms, indivedual enantiomer or racemoid or with these compounds of the formed relative acid additive salt of pharmaceutically acceptable acid form.Purpose of the present invention also comprises according to compound of the present invention, comprises its salt, and wherein one or more hydrogen atom is through deuterium exchange.
Another theme of the present invention is the method about a kind of preparation formula I carbonyl amide compound
Wherein A, B, W, X, Y, Z, R 1, R 2, R 3, and k have above specified meaning, wherein As A be one not with group A banded radicals R 3 :
A) represent by nitrogen-atoms and carbonyl amide group banded nitrogen-atoms heterocyclic radical with regard to A, it also can have the other heteroatomic situation that one or more is selected from N, O, reaches S except this nitrogen-atoms,
Can be in a solvent or solvent mixture, in the presence of at least a alkali, make the secondary amine compound reaction of the amine compound of at least a formula I-1 and CDT (1,1 '-carbonyl-two-(1,2, the 4-triazole)) and at least a formula I-2
R among the formula I-1 1, R 2, R 3, X, Y, and Z have the specified meaning of preamble,
A, B among the formula I-2, W, and k have above specified meaning, and group A has the secondary amine functional group, and
B) with regard to other situations,
Can be in a solvent or solvent mixture, in the presence of at least a alkali,
Make the amine compound reaction of carboxylic acid cpd and TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl--a tetrafluoro borate) and at least a formula I-1 of at least a formula I-3
Figure A0382007600423
A, B in the formula (I-3), W, and k have above specified meaning,
Figure A0382007600424
R in the formula (I-1) 1, R 2, R 3, X, Y, and Z have above specified meaning,
And
As B be and group A banded radicals R 3 :
A) has meaning-CR with regard to group Q 6R 7-(IIIa, wherein R 6And R 7Be situation as hereinbefore defined, can make the amine compound of formula Ia.1 and neighbour-brooethyl of formula Ia.2-benzoate derivatives reaction
R among the formula Ia.1 1, R 2, X, Y, and Z have specified meaning,
Figure A0382007600431
R among the formula Ia.2 6, R 7, W, B, and k have specified meaning,
B) has meaning-CR with regard to group Q 6=CR 7-(IIIb), R wherein 6And R 7Situation as hereinbefore defined can make the isoquinolinone derivatives of formula Ib.2 and the nucleophilie electronic compound reaction of formula Ib.3
Figure A0382007600432
R among the formula Ib.2 6, R 7, W, B, and k have specified meaning,
Y and Z have specified meaning among the formula Ib.3, and the suitable leaving group of OMs representative, and methanesulfonates preferably is to obtain the isoquinilone derivatives of formula Ib.4
Figure A0382007600434
R among the formula Ib.4 6, R 7, W, B, Y, Z, and k have specified meaning, and the isoquinilone derivatives of this formula Ib.4 can the further derivatize of currently known methods forming formula I compound,
C) has meaning-N=CR with regard to group Q 8-(IIIc), R wherein 8Above defined situation can make the 2 ketone derivatives of formula Ic.4 and the nucleophilie electronic compound reaction of formula Ic.5,
Figure A0382007600435
R among the formula Ib.4 8, W, B, and k have specified meaning,
The specified meaning of Y and Z tool among the formula Ib.5, and the suitable leaving group of OMs representative, methanesulfonates preferably is to obtain the 2 ketone derivatives of formula Ic.6
Figure A0382007600442
R wherein 8, W, B, Y, Z, and k have specified meaning, and the 2 ketone derivatives of the formula Ic.6 that so obtains can be with the further derivatize of known method to form wherein Q representative-N=CR 8-(IIIc) formula I compound,
D) with regard to the situation that group Q has meaning-N=N-(IIId), can make neighbour-amino-benzamide derivatives of formula Id.1
Figure A0382007600443
R wherein 1, R 2, W, B, X, Y, Z, and k have specified meaning, under the situation that suitable nitrite compound and acid exist, react, forming the wherein formula I compound of Q representative-N=N-,
E) has meaning-CO-NR with regard to group Q 9-(IIIe), R wherein 9Be situation as hereinbefore defined, can make neighbour-amino-benzamide derivatives of formula Ie.1
R wherein 1, R 2, R 9, W, B, X, Y, Z, and k have specified meaning, under CDI (carbonyl dimidazoles), react, to form wherein Q representative-CO-NR 9-formula I compound,
F) has meaning-CR with regard to group Q 8=N-(IIIf), wherein R 8Be situation as hereinbefore defined, can make neighbour-amino-benzamide derivatives of formula If.1
(R wherein 1, R 2, W, B, X, Y, Z, and k have specified meaning), with carboxylic acid R 8(it has the R that specifies meaning to COOH 8) and/or corresponding active carboxylic acid derivative's reaction, to produce wherein Q representative-CR 8The formula I Quinazol derivative of=N-,
G) with regard to the situation that group Q has meaning-CO-(IIIg), can make the amine reaction of isobenzofurandione derivative and the formula Ig.1 of formula Ig.2
Figure A0382007600452
W, B among the formula Ig.2, and k have specified meaning,
Figure A0382007600453
R among the formula Ig.1 1, R 2, X, Y, and Z have specified meaning, forming the wherein formula I compound of Q representative-CO-,
The present invention also comprises the physiological acceptable salt of the carboxamide compounds of the present invention that as above reaches hereinafter to be addressed.
The present invention also comprises composition, and it contains at least a carboxamide compounds of the present invention and/or salt of the present invention, optionally makes up the acceptable vehicle of one or more physiology.
The present invention also comprises pharmaceutical preparation, and it contains at least a carboxamide compounds of the present invention and/or salt of the present invention, and selectivity makes up one or more inert supports and/or thinner.
The present invention also about at least a carboxamide compounds of the present invention and/or salt of the present invention in the purposes that influences the mammalian diet behavior.
The present invention is also alleviating the purposes that mammiferous body weight and/or prevention weight of mammal increase about at least a carboxamide compounds of the present invention and/or salt of the present invention.
The present invention also has the purposes of the pharmaceutical preparation of MCH-acceptor-antagonistic activity about at least a carboxamide compounds of the present invention and/or salt of the present invention in preparation.
Simultaneously, a theme of the present invention be at least a carboxamide compounds of the present invention and/or salt of the present invention preparation be applicable to that prevention and/or treatment cause because of MCH or with the purposes of MCH with the pharmaceutical preparation of relevant symptom of other reasons and/or disease.
Another theme of the present invention be at least a carboxamide compounds of the present invention and/or salt of the present invention preparation be applicable to prevention and/or treatment by purposes, particularly obesity, voracity, bulimia nervosa, emaciation, apocleisis, the anorexia nervosa of the pharmaceutical preparation of metabolic disturbance and/or eating disorder, reach hyperingestion.
Theme of the present invention is at least a carboxamide compounds of the present invention and/or salt of the present invention are used to prevent and/or treat the pharmaceutical preparation of disease relevant with obesity and/or obstacle in preparation a purposes, diabetes particularly, type-II diabetes particularly, the syndromes of diabetes comprises diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathologic glucose tolerance, hematencephalon, heart inadequacy, cardiovascular disorder, particularly arteriosclerosis and hypertension, sacroiliitis, reaches gonitis.
Simultaneously, the present invention is applicable to the purposes of preventing and/or treating hyperlipidaemia, cellulitis, fat accumulation, pernicious urticaria pigmentosa, systemic urticaria pigmentosa, emotional handicap, affective disorder, melancholia, anxiety, somnopathy, dysgenesia, sexual dysfunction, dysmnesia, epilepsy, various dementia, reaching the pharmaceutical preparation of hormone obstacle about at least a carboxamide compounds of the present invention and/or salt of the present invention in preparation.
Another object of the present invention is at least a carboxylic acyl compound of the present invention and/or salt of the present invention are applicable to the pharmaceutical preparation of prevention and/or treatment dysuria in preparation a purposes; such as; for example, the urinary incontinence, bladder hyperactivity hyperkinesia, urgent urination, nycturia, and the enuresis.
Simultaneously, the invention relates to the method for preparing pharmaceutical preparation of the present invention, it is characterized in that at least a carbonyl amide compound of the present invention and/or salt of the present invention being added in one or more inert supports and/or the thinner with method non-chemically.
The present invention is also about pharmaceutical preparation, it contains first active substance that is selected from carboxamide compounds of the present invention and/or salt of the present invention, and one second active substance, it is selected from the active substance that can be used for treating diabetes, can be used for treating the active substance of diabetic syndrome, can be used for treating fat active substance (preferably not being the MCH antagonist), can be used for treating hypertensive active substance, can be used for treating the hyperlipidaemia active substance of (comprising arteriosclerosis), the active substance that can be used for treatment of arthritis, can be used for treating the active substance of anxiety state, and can be used for treating hypochondriacal active substance, one or more inert supports of selectivity common combination and/or thinner.
Detailed Description Of The Invention
Except as otherwise noted, group, partly, substituting group, and index, particularly A, B, W, X, Y, Z, R 1To R 9, and R 11To R 22, L 1, L 2, L 3, and k, have above or hereinafter specified meaning.
The present invention's one preferred embodiment comprises formula I compound,
Wherein
R 3Represent H, C 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-4-alkyl-, C 1-3-alkoxy-C 2-6-alkyl-, amino-C 2-6-alkyl-, C 1-3-alkyl-amino-C 2-6-alkyl-or two-(C 1-3-alkyl)-amino-C 2-6-alkyl-,
B has the specified meaning of Cy, and simultaneously, the key that binding group W or selectivity directly link group A is by the C atom on this isocyclic part or selected fused phenyl or the pyridine ring, or forms by the H or the C atom of this heterocyclic moiety,
Simultaneously, as k=0, group B and group A can be by shared C atoms and connected to each other, forming a volution system, or
The atom of, adjacency shared via two, form one condense, bicyclic system,
Cy represents carbocyclic ring or heterocyclic radical, and it is to be selected from one of following meaning
-saturated 3-to 7-member carbocylic radical,
-undersaturated 5-to 7-member carbocylic radical,
-phenyl,
-saturated 4-to 7-member or undersaturated 5-to 7-member have N, an O or S atom as heteroatomic heterocyclic radical,
-saturated or undersaturated 5-to 7-element heterocycle base, its have two or more N atoms or have one or two N atom and O or S atom as heteroatoms,
The heterocycle 5-of-aromatics or 6-person's group, it has one or more identical or different N, O and/or S heteroatoms of being selected from,
Simultaneously, above-mentioned 5-, 6-or 7-person's group can pass through two C atoms shared, adjacency, condense with phenyl or pyridine ring,
And in above-mentioned 5-, 6-or 7-person's group, one-CH 2Group can by-CO-,-C (=CH 2)-,-(SO)-or-(SO 2)-group substitutes,
And above-mentioned saturated 6-or 7-person's group also can with imino-, N-(C 1-3-alkyl)-imino-, methylene radical, C 1-3-alkyl-methylene radical-or two-(C 1-3-alkyl)-methylene bridge exists with the form of bridged ring system jointly, and
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl, also can additionally replace through the nitro list, and/or at one or more N atom place through R 21Replace,
R 15Represent H, C 1-4-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, phenyl or phenyl-C 1-3-alkyl-,
R 17Has R 16Specified meaning, or represent phenyl, phenyl-C 1-3-alkyl-, dioxolane-2-base, C 1-3-alkyl-carbonyl, hydroxyl carbonyl-C 1-3-alkyl-, C 1-3-alkane carbonyl amino-C 2-3-alkyl-, C 1-3-alkyl sulphonyl-or C 1-3-alkyl sulfonyl amino-C 2-3-alkyl-,
R 22Represent phenyl, phenyl-C 1-3-alkoxyl group-, C 1-3-alkoxyl group, C 1-3-alkylthio-, carboxyl, C 1-3-alkyl carbonyl, C 1-3-carbalkoxy, aminocarbonyl, C 1-3-alkylamino-carbonyl, two-(C 1-3-alkyl)-aminocarbonyl, C 1-3-alkyl-alkylsulfonyl, C 1-3-alkyl-sulfinyl, C 1-3-alkyl-sulfonamido-, amino, C 1-3-alkylamino-, two (C 1-3-alkyl)-amino-, phenyl-C 1-3-alkylamino-or N-(C 1-3-alkyl)-phenyl-C 1-3-alkyl-amino-, acetylaminohydroxyphenylarsonic acid, propionamido-, phenylcarbamoyl, benzene carbonyl amino-, the phenylcarbamoyl methylamino--, hydroxyl alkane aminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidyl) carbonyl, (piperidino) carbonyl, (six hydrogen-1-azepine _ yl) carbonyl, (4-methyl isophthalic acid-piperazinyl) carbonyl, methylene-dioxy, aminocarbonyl amino-or alkylamino carbonyl amino-
Simultaneously, at group and part A, B, W, X, Y, Z, R 1To R 9, and R 11To R 22In, under each situation, one or more C atom can be single or polysubstituted through F, and/or under each situation, one or two C atom can replace through Cl or Br list independently of one another, and
Any H atom that is present in carboxyl, or link the H atom of N atom, under each situation, can by one in vivo the cracked group substituted,
Its tautomer, diastereomer, enantiomer, its mixture, with and salt.
According to first group preferred embodiment, group A and radicals R 3Directly do not interlink.Therefore, group A has the specified meaning of Cy.
According to second group preferred embodiment, group A and radicals R 3Interlink, so that the group of formula I
Figure A0382007600491
Represent the group of segment bounds II
And
Q represents a group, and it is selected from segment bounds IIIa to IIIg
-CR 6R 7-????????????IIIa，
-CR 6＝CR 7-?????????IIIb，
-N＝CR 8-????????????IIIc，
-N＝N-??????????????IIId，
-CO-NR 9-????????????IIIe，
-CR 8＝N-????????????IIIf，
-CO-?????????????????IIIg。
The preferred meaning of group Q is to be selected from segment bounds IIIb, IIId, IIIe, IIIf, and IIIg, particularly IIId, IIIe, IIIf, and IIIg.
Substituent R 6, R 7, R 8, and R 9Preferred meaning be H independent of each other and C 1-4-alkyl, particularly H, methyl or ethyl.
Preferably, substituting group L 1, L 2, L 3Have one of following meaning H, F, Cl, Br, CH independently of one another 3, CHF 2, CF 3, C 2H 5, C 3H 7, CH (CH 3) 2, OCH 3, OCHF 2, OCF 3, OC 2H 5, OC 3H 7, and OCH (CH 3) 2
Preferably, get L 1, L 2, L 3In only have one not to be the meaning of H, specific is that one of above-mentioned meaning is preferred.Particularly preferred, all three substituting group L 1, L 2, L 3All represent H.
Preferably, radicals R 1, R 2H, the C of representing independently of one another 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkenyl group-C 1-3-alkyl-, ω-hydroxyl-C 2-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 2-3-alkyl-, C 1-4-alkoxyl group-carbonyl-C 1-3-alkyl-, amino-C 2-4-alkyl-, C 1-3-alkyl-amino-C 2-4-alkyl-or two-(C 1-3-alkyl)-amino-C 2-4-alkyl-, phenyl or phenyl-C 1-3Alkyl-,, simultaneously, in above-mentioned group and part, one or more C atoms or single or polysubstituted through F, and/or, one or two C atom can be independently of one another through Cl or Br is single replaces, and/or, phenyl can be through defined radicals R above 12Single or polysubstituted, and/or it can replace through the nitro list.
Preferred especially person, radicals R 1, R 2The C that represents independently of one another 1-4-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, ω-hydroxyl-C 2-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 2-3-alkyl-, C 1-4-alkoxyl group-carbonyl-C 1-3-alkyl-, simultaneously, radicals R 1, R 2In one of also can represent H.
Simultaneously, preferred, R 1And R 2Can form alkylidene bridge, so that R 1R 2The N-representative is selected from azetidine, tetramethyleneimine, piperidines, azepine cyclic group in heptan, 2,5-dihydro-1H-pyrroles, 1,2,3,6-tetrahydrochysene-pyridine, 2,3,4,7-tetrahydrochysene-1H-azepine _ base, 2,3,6,7-tetrahydrochysene-1H-azepine _, pyrazine (wherein should free imines functional group can be through R 13Replace), morpholine, and the group of thiomorpholine, simultaneously, according to R 1And R 2General definition, one or more H atom can be by R 14Substitute, and/or above-mentioned group can be according to R 1And R 2The specified method of general definition and replace through one or two identical or different carbocyclic ring or heterocyclic radical Cy.
Particularly preferred group
According to the definition one of in the following segment bounds
Figure A0382007600521
Wherein by radicals R 1R 2One or more H atom of the formed heterocyclic of N-can be by R 14Substitute, and itself and by radicals R 1R 2N-form heterocycle banded ring at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl ring, also can additionally replace through the nitro list.
Particularly preferably be most above-mentioned radicals R 1R 2N-, wherein R 1And R 2With radicals R 1R 2The N atom of N-forms tetramethyleneimine, piperidines or 2 jointly, 5-dihydro-1H-pyrrole ring, and it can be as specified replacement.
Radicals R 14Preferred meaning be C 1-4-alkyl, C 1-4-cycloalkyl, hydroxyl, C 1-4-alkoxyl group, C 1-4-alkoxy-C 1-3-alkyl-, hydroxyl C 1-3-alkyl, C 1-4-alkyl-carbonyl, C 1-4-alkoxyl group-carbonyl, C 1-4-alkoxyl group-carbonyl C 1-3-alkyl-, C 1-4-alkoxyl group-carbonyl amino-, C 1-4-alkoxyl group-carbonyl amino C 1-3-alkyl-, amino, (C 1-4Alkyl)-amino-, two-(C 1-4-alkyl)-amino-, phenyl, phenoxy group, pyridyl, and pyridyloxy.
Preferably the piperidyl that replaces through group Cy has structure
Figure A0382007600522
Wherein Cy preferably represents phenyl, and it can be as specified being substituted.
Preferably, alkylidene bridge X is not or have maximum one-NR 4-group.This NR 4The optimum seeking site of group in this alkylidene bridge X is through selecting, so that it links amino N R 1R 2Or another can't form aminal (aminal) functional group or two N atoms are adjacent to each other during in abutting connection with amino.Therefore, with regard to one-CH 2-group warp-NR 4The situation of-replacement, this alkylidene bridge is preferably represented C 2-7-alkylidene group-NR 4-C 0-5-alkylidene group, simultaneously, this bridge X has maximum 7 bridging C atoms except this N atom, and these C atoms can specified mode be substituted.
Preferably, X represents singly-bound or non-chain bridge, and it is selected from C 1-6-alkylidene group, C 2-6-alkenylene, C 2-6-alkynylene, C 1-6-alkylene oxide group, carbonyl, carbonyl-C 1-6-alkylidene group or C 1-6-alkylidene group-amino-, wherein should amino can be through R 4Replace, simultaneously one or two C atom can general definition by X in specified mode be substituted, and/or this alkylidene bridge can link R by specified mode 1
Particularly preferred, X represents singly-bound, carbonyl, alkylidene bridge, it is selected from methylene radical, ethylene, trimethylene, and tetramethylene, and wherein one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or, under each situation, through one or two identical or different C 1-4-alkyl replaces, and under each situation, one or more C atom can be single or polysubstituted through F, and/or under each situation, one or two C atom can be independently of one another through Cl or the single replacement of Br.
In radicals X, one or two C atom is through hydroxyl and/or C 1-3-alkoxyl group replaces, and the C atom that this is substituted preferably is not direct and amino, particularly-and NR 1R 2Or-NR 4-adjacency.
Best, bridge X be singly-bound ,-CH 2-or-CH (CH 3)-.
With regard to a CH among the bridge Z 2-group warp-NR 5The situation of-replacement, this NR 5The optimum seeking site of group in group Z will be selected so that its with amino-NR 3Or another is when amino links, and does not form the aminal functional group or two N atoms are adjacent to each other.
The preferred meaning of bridge Z is methylene radical, ethylene, trimethylene, and tetramethylene, inferior methoxyl group, 1,2-inferior ethoxyl, 1, and the inferior propoxy-of 3-, and 1, the inferior butoxy of 4-, wherein one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or, under each situation, can be through one or two identical or different C 1-4-alkyl replaces, and under each situation, one or more C atom can be single or polysubstituted through F, and/or under each situation, one or two C atom can replace through Cl or Br list independently of one another, and R 3Can link Z, link R so that it comprises 3The N atom, form a heterocyclic radical.
As in group Z, one or two C atom is through hydroxyl and/or C 1-3-alkoxyl group replaces, and the C atom that this is substituted is preferably not direct and amino, particularly-and NR 3-or-NR 5-adjacency.
Preferable especially, Z is selected from group-CH 2-,-CH 2-CH 2-,-CH 2-CH (CH 3)-,-CH 2-C (CH 3) 2-,-CH (CH 3)-CH 2-,-C (CH 3) 2-CH 2-, and-CH 2-O-, particularly-CH 2-CH 2-or-CH (CH 3)-CH 2-.
Simultaneously, according to a particularly preferred definition, Z and R 3Link, so that part
Figure A0382007600531
The group of formula has and is selected from 1,3-pyrrolidinylidene, 1,3-piperidylidene, 1,3-Asia-1,25,6-tetrahydropyridine-1,3-subunit, and 3-hydroxyl-1, the meaning of 3-piperidylidene.
Preferably, radicals R 3Be to be selected from methyl, ethyl, n-propyl, sec.-propyl, 2-hydroxyethyl, 3-hydroxyl-n-propyl or 2-hydroxyl-1-methyl-ethyl, simultaneously, in these specified groups, one, two or three H atom can be substituted by F, perhaps, and R 3Be to be selected from group H, amino-C 2-3-alkyl-, C 1-3-alkyl-amino-C 2-3-alkyl-or two-(C 1-3-alkyl)-amino-C 2-3-alkyl-.
Radicals R 3Particularly preferred meaning be H, methyl or ethyl, particularly H or methyl.
Radicals R 4And/or R 5Preferred meaning be H, C 1-4-alkyl, C 3-6-cycloalkyl, and C 3-6-cycloalkyl-C 1-3-alkyl-, particularly H and C 1-4-alkyl.
Radicals R 11Preferred especially meaning be C 1-6-cycloalkyl, hydroxyl, C 1-4-alkoxyl group, amino, C 1-4-alkyl-amino-, and two-(C 1-4-alkyl)-amino.
Radicals R 20Preferred especially meaning be halogen atom, hydroxyl, cyano group, C 1-4-alkyl, C 3-7-cycloalkyl, and hydroxyl-C 1-3-alkyl.Particularly preferred, R 20Represent F, Cl, Br, I, OH, cyano group, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, positive propoxy or isopropoxy.
Group Y is preferably selected from divalence cyclic group 1, inferior third cyclic group of 2-, 1, the inferior cyclobutyl of 3-, 1, the 3-cyclopentylidene, 1, the 3-cyclopentenylidene, 1,3-and 1, the 4-cyclohexylidene, 1, the 3-phenylene, 1, the 4-phenylene, 1,3-and 1, the 4-phenylidene, 1, the inferior suberyl of 4-, 1, the inferior cycloheptenyl of 4-, 1, the 3-pyrrolidinylidene, 1, the 3-pyrrolidinylidene, 1, the inferior pyrryl of 3-, 1, the 4-piperidylidene, 1, the inferior tetrahydro pyridyl of 4-, 1, the inferior dihydropyridine base of 4-, 2,4-and 2, the 5-pyridylidene, or 1, the inferior piperazinyl of 4-, simultaneously, above-mentioned 5-, 6-or 7-person's group can be shared by two, the C atom of adjacency links, and with phenyl or pyridine condensed, above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the situation of phenyl, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace, and with the mode of this general definition, R 1Can link Y and/or R 3Can link Y.
The most particularly preferred meaning of group Y is to be selected from following ring texture:
Figure A0382007600541
Wherein, these cyclic groups can be through R 20Single or two replacement, is preferably by halogen atom, CF preferred single the replacement 3, C 1-4-alkyl and/or C 1-4-alkoxyl group replaces.
In addition, group Y also can link radicals R 1, so that segment bounds
Group, have the meaning that is selected from following segment bounds
The preferred meaning of group A is to be selected from divalence cyclic group 1, inferior third cyclic group of 2-, 1, the inferior cyclobutyl of 3-, 1, the 3-cyclopentylidene, 1, the 3-cyclopentenylidene, 1,3-and 1, the 4-cyclohexylidene, 1,3-and 1,4-phenylene, 1,3-and 1, the 4-phenylidene, 1, the inferior suberyl of 4-, 1, the inferior cycloheptenyl of 4-, 1, the 3-pyrrolidinylidene, 1, the inferior pyrrolinyl of 3-, 1, the inferior pyrryl of 3-, 1, the 4-piperidylidene, 1, the inferior tetrahydro pyridyl of 4-, 1, the inferior dihydropyridine base of 4-, 2,4-and 2, the 5-pyridylidene, 1, the inferior piperazinyl of 4-, 7-aza-bicyclo [2.2.1] heptane-2,7-two bases, and 8-aza-bicyclo [3.2.1] octane-3,8-two bases, wherein, above-mentioned 5-, 6-, or 7-person's group can be shared via two, the C atom of adjacency condenses with phenyl or pyridine ring, and above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the situation of phenyl, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace.
The most particularly preferred meaning of group A is selected from following ring texture:
Figure A0382007600552
Wherein, these cyclic groups can be through R 20Single or two replacement, is preferably by halogen atom, CF preferred single the replacement 3, C 1-4-alkyl and/or C 1-4-alkoxyl group replaces.
The divalence cyclic group that Y and/or A are specified under each situation, comprises its enantiomerism form, that is, the form of exchanging with the binding of adjacency group (being the binding with X and Z with regard to Y, also is the binding with CO and W with regard to A) wherein.Therefore, for example, 1, the 4-phenylidene is represented simultaneously
Figure A0382007600553
And
Figure A0382007600554
Both.
Above the specified divalence cyclic group of Y and/or A comprises all possible isomer.Above-mentioned mentioning is that preferred part meaning will be in hereinafter explaining in more detail:
Define inferior tetrahydro pyridyl and comprise meaning 1,2,3,4-tetrahydropyridine-1,4-and-3, the 6-subunit-, 1,2,3,6-tetrahydropyridine-1,4-,-2,5-, and-3, the 6-subunit-, 2,3,4,5-tetrahydropyridine-2,5-and-3,6-subunit.Preferred meaning is 1,2,3,6-tetrahydropyridine-1,4-subunit.
Define inferior dihydropyridine base and comprise meaning 1,4-and 1,2-dihydropyridine 1,4-subunit, and-1,2-,-1,4-, 1,6-, 2,3-, 2,5-, 3,4-, 4,5-, and 5,6-dihydropyridine 2,5-subunit.Preferred meaning is 1,2-dihydropyridine-1,4-subunit.
Preferably, group A and/or B are unsubstituted or through R 20Single or two substituent, the best is to be unsubstituted or through R 20Single substituent.
According to first embodiment, the preferred meaning of group B is selected from group C 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more carbon atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, and
W represent singly-bound ,-O-, C 1-4Alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N-(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-4-alkyl replaces, and
K represents 0 or 1, and particularly 1, and
R 20Has one of above specified meaning.
In the preferred meaning of above-mentioned B, k preferably has numerical value 1, and W preferably represents singly-bound, imino-or N-(C 1-3-alkyl)-and imino--, singly-bound particularly.
Particularly preferred, group B is represented C 3-6-alkynyl, particularly C 3-6-alkynes-1-base, and/or group W is represented singly-bound, while k=1.
According to second embodiment, the preferred meaning of group B is to be selected from the cyclic group cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, the hexamethylene ketone group, cyclohexenyl, phenyl, suberyl, cycloheptenyl, the azepine propyl, azetidinyl, pyrrolidyl, pyrrolinyl, pyrryl, piperidyl, tetrahydro pyridyl, the dihydropyridine base, pyridyl, azepine cyclic group in heptan, piperazinyl, the 1H-pyrazolyl, imidazolyl, triazolyl, tetrazyl, morpholinyl, thio-morpholinyl, indyl, pseudoindoyl, quinolyl, benzimidazolyl-, isoquinolyl, furyl, and thienyl, simultaneously, the key that binding group W or selectivity directly link group A is by the C atom on isocyclic part or selected fused phenyl or the pyridine ring, or form by the N or the C atom of heterocyclic moiety, perhaps, B be to be selected from group cyclopentylidene-methyl jointly by two key banded group W, cyclohexylidene-methyl, and inferior pimelinketone-4-base-methyl, and above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the situation of phenyl, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace.
The most particularly preferred, group B is represented phenyl, and it is through R 20Single-, two-as or three to replace preferably single or two replacements.
Above the definition of B comprises all possible isomer of the group of touching upon.Therefore, particularly including following isomer: cyclopentenes-1-, 3-, and 4-base, pimelinketone-4-base, tetrahydrobenzene-1-, 3-and 4-base, suberene-1-, 3-, 4-, and 5-base, azepine propane-1-base, azetidine-1-base, tetramethyleneimine-1-base, pyrroline-1-base, pyrroles-1-base, piperidines-1-and 4-base, pyridine-2-,-3-, and-the 4-base, azepine ring-1-in heptan base, piperazine-1-base, 4-methyl-piperazine-1-base, morpholine-4-base, thiomorpholine-4-base, quinoline-2-, 3-, 4-, 5-, 6-, 7-, and 8-base, isoquinoline 99.9-1-, 3-, 4-, 5-, 6-, 7-, and 8-base, 1H-benzoglyoxaline-1-, 2-, 4-, 5-, 6-, and 7-base.
The pyrazoles definition comprises isomer 1H-, 3H-, reaches the 4H-pyrazoles.Preferably, pyrazolyl is represented the 1H-pyrazol-1-yl.
The imidazoles definition comprises isomer 1H-, 2H-, reaches the 4H-imidazoles.The preferred meaning of imidazolyl is 1H-imidazoles-1-base.
Tetrahydropyridine definition comprises isomer 1,2,3,4-, 1,2,3,6-, and 2,3,4,5-tetrahydropyridine.Preferably, tetrahydro pyridyl represents 1,2,3,4-and 1,2,3,6-tetrahydropyridine-1-base.
Dihydropyridine definition comprises isomer 1,2-, 1,4-, 2,3-, 2,5-, and 4,5-dihydropyridine.Preferably, the dihydropyridine base represents 1,2-and 1,4-dihydropyridine-1-base.
Triazole definition comprises isomer 1H, 3H-, and 4H-[1,2,4]-triazole, and 1H, 2H-, and 4H-[1,23]-triazole.Therefore triazolyl definition comprises 1H-[1,2,4]-triazole-1-, 3-, and 5-base, 3H-[1,2,4]-and triazole-3-and 5-base, 4H-[1,2,4]-triazole-3,4-, and 5-base, 1H-[1,2,3]-and triazole-1,4-, and 5-base, 2H-[1,2,3]-triazole-2,4-, and 5-base, and 4H-[1,1,3]-triazole-4-and 5-base.
The tetrazolium term comprises isomer 1H-, 2H-, reaches the 5H-tetrazolium.Therefore the tetrazyl definition comprises 1H-tetrazolium-1-and 5-base, 2H-tetrazolium-2-and 5-base and 5H-tetrazolium-5-base.
The indoles definition comprises isomer 1H-and 3H-indoles.1H-indoles-1-base preferably represented in the indyl term.
The isoindole definition comprises isomer 1H-and 2H-isoindole.2H-isoindole-2-base preferably represented in the pseudoindoyl term.
Generally speaking, with one of above-mentioned heterocyclic radical banded key, particularly, can pass through imido functional group's N atom formation by C atom or selectivity with pyrazolyl, imidazolyl, tetrahydro pyridyl, dihydropyridine base, triazolyl, tetrazyl, indyl or pseudoindoyl banded key.
Preferably, group B be unsubstituted, through R 20Single-, two-as or three to replace.Preferred especially, group B is through R 20Single or two replacement.With regard to B is to be substituted with regard to the situation of six membered ring, and preferred, it is linking group
The contraposition of key have a substituting group.
Index k can be numerical value 0 or 1.K=1 in the preferred case, bridge W has specified meaning, preferably singly-bound ,-CH 2-or-meaning of CH=.The preferred meaning of segment bounds-A-W-B is selected from the structure described in the following table,
Wherein V represents C or N atom, is preferably the C atom, and this described cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl or phenylene, it also can replace through the nitro list in addition:
Figure A0382007600582
Figure A0382007600591
Best is formula I compound, and wherein k=1 and W represent singly-bound.
Index k also can be numerical value 0.According to the variant first time, group A links group B by a shared C atom, form a volution system, simultaneously, group A represents saturated 5-to a 7-member carbocyclic ring or a heterocyclic radical, and group B is to represent saturated 4-to a 7-member carbocyclic ring or a heterocyclic radical, and under each situation, this heterocyclic radical has N, an O or S atom, and by the C atom of two adjacency phenyl or pyridine ring can be condensed on 5-to a 7-member group B, and above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of condensed phenyl ring, it also can replace through the nitro list in addition, and/or can be at one or more N atom place through R 21Replace.
According to second variant, the preferred meaning of segment bounds-A-W-B is to be selected from structure listed in the following table, and wherein, this listed cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl ring, it also can replace through the nitro list in addition:
Figure A0382007600592
Figure A0382007600601
According to second variant (wherein k=0), group B is that C atom shared by two, adjacency links group A, formation one condenses, 8-to the 12-member loop systems of saturated, the unsaturated or aromatics of dicyclo, it can contain one or more identical or different heteroatoms that is selected from N, O and/or S, and this bicyclic system can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of condensed phenyl ring, it also can replace through the nitro list in addition, and/or can be at one or more N atom place through R 21Replace.
According to this variant for the first time, the preferred meaning of segment bounds-A-W-B is to be selected from structure listed in the following table, and wherein, this listed cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl ring, it also can replace through nitro in addition:
Preferred The compounds of this invention be wherein one or more group, partly, substituting group and/or mark be one of above-mentioned preferred meaning.
Substituent R 20Preferable meaning be to be selected from fluorine, chlorine, bromine, CF 3, C 1-4-alkyl, and C 1-4-alkoxyl group.
Particularly preferred The compounds of this invention wherein
A, Y are independently of one another and be selected from divalence cyclic group 1,4-phenylene, 1,4-cyclohexylidene, 1,4-phenylidene, 1,4-piperidylidene ,-1,2,3,6-tetrahydropyridine-1,4-subunit, 2,5-pyridylidene, and 1, the inferior piperazinyl of 4-, simultaneously, A also can link R according to claim 3 3, and above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the situation of phenyl, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace,
B represents phenyl or cyclohexyl, and simultaneously, above-mentioned group can be through R 20Single or polysubstituted, and/or this phenyl ring can be in addition replaces through the nitro list, simultaneously, R 20Have the specified meaning of claim 1, and
K is a value 1,
W be singly-bound ,-CH 2-or-CH=, and
Z representative-CH 2-CH 2-,-CH 2-CH (CH 3)-,-CH 2-C (CH 3) 2-,-CH (CH 3)-CH 2-,-C (CH 3) 2-CH 2-or-CH 2-O-, perhaps, with R 3Link, so that the group of formula I segment bounds
Figure A0382007600611
Have and be selected from 1,3-pyrrolidinylidene and 1, the meaning of 3-piperidylidene.
Particularly preferred The compounds of this invention is to list in following formula I.1 extremely I.14:
Figure A0382007600631
Figure A0382007600641
Wherein
U, V represent C or N independently of one another,
R 23, R 24Represent H, F, methyl, trifluoromethyl, ethyl, sec.-propyl or n-propyl independently of one another, simultaneously, in formula I.1 in I.6, R 24Can with R 3Link, so that
Segment bounds Group have and be selected from 1, the inferior Pyrrolizidine base and 1 of 3-, the meaning of the inferior hexahydropyridine base of 3-, and
R 25、
R 26, R 27Has R independently of one another 20One of specified meaning, or under the situation of phenyl, also can represent nitro merely, simultaneously, radicals R for several times appears 25, R 26, R 27Can have identical or different meaning, and
J is 0,1,2,3 or 4, and
M, n represent 0,1 or 2 independently of one another.
The most special preferably be according to following formula I.1, I.2, I.8, I.10, and I.12 compound.Particular words it, the narration of formula that preferable especially compound can be following
Wherein group and substituting group are to reach hereinafter as mentioned to define.
According to the present invention, preferably has the compound of following segment bounds
Figure A0382007600662
Wherein
B is selected from C 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more C atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, and
W represent singly-bound ,-O-, C 1-4Alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N-(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-4-alkyl replaces, and
K represents 0 or 1.
Simultaneously, according to this embodiment, preferred compound is that wherein group B is represented C 1-6-alkyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more C atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, and/or
W represent singly-bound ,-O-, imino-or N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another and through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-4-alkyl replaces, and k=1.
According to this embodiment, the preferred especially meaning of group-W-B is to be selected from C 1-8-alkyl ,-C ≡ C-C 1-6-alkyl ,-CH=CH-C 1-6-alkyl ,-O-C 1-6-alkyl ,-NH (C 1-6-alkyl), reach-N (C 1-6-alkyl) (C 1-3-alkyl), be selected from C especially 3-8-alkyl ,-C ≡ C-C 3-6-alkyl ,-CH=CH-C 3-6-alkyl ,-O-C 3-6-alkyl ,-NH (C 3-6-alkyl), reach-N (C 3-6-alkyl) (C 1-3-alkyl).
In aforementioned preferred The compounds of this invention, particularly have segment bounds I.1 to person I.15, particularly preferably be wherein radicals R 1, R 2, R 3, L 1, L 2, L 3, and/or radicals X have the above-mentioned preferred meaning under each situation that is.
Especially, particularly preferred The compounds of this invention is that wherein X is selected from-CH 2-,-CH (CH 3)-or-C (CH 3) 2-compound.
Also particularly preferably be and have segment bounds I.1 to I.15 these compounds, wherein
A) on behalf of N atom and group V, group U represent the C atom, or
B) on behalf of C atom and group V, group U represent the N atom, or
A) two group U and V respectively represent the C atom.
In particularly preferred The compounds of this invention, substituent R 25, R 26, R 27Independently of one another and have the F of being selected from, Cl, Br, I, OH, cyano group, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, positive propoxy or an isopropoxy, and, under the situation that phenyl replaces, also can singly replace for nitro, simultaneously, radicals R for several times appears 25, R 26, R 27Can have identical or different meaning, and j is 0,1 or 2.And m, n represent 0 or 1 independently of one another.
Stated to the present invention in the preferred compound radicals R 6, R 7, R 8, and/or R 9Preferred meaning be independently of one another and be H, methyl, trifluoromethyl, ethyl, sec.-propyl or n-propyl and at R 6And R 7Situation under also can be F.
Preferable especially individual compound is to be selected from
(1) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(2) 3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
(3) 3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazoline-4-one
(4) 7-(4-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(5) 7-(3,4-two chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(6) 7-(4-fluoro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(7) 7-(4-ethyl-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(8) 2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazoline-4-one
(9) 2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
(10) 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(11) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-1H-quinazoline-2, the 4-diketone
(12) 7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(13) 7-(4-chloro-phenyl)-3-[2-(4-dimethylamino methyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(14) 7-(4-chloro-phenyl)-3-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(15) 7-(4-chloro-phenyl)-3-[2-(4-morpholine-4-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(16) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-3H-benzo [d] [1,2,3] triazine-4-ketone
(17) 5-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-isoindole-1, the 3-diketone
(18) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(19) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
(20) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
(21) 4 '-methoxyl group-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
(22) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-methyl-acid amides
(23) 4-(4-chloro-phenyl)-hexahydrobenzoic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(24) 4-aminomethyl phenyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(25) 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(26) 4-(4-chloro-phenyl)-piperidines-1-carboxyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(27) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
(28) 4 '-chloro-xenyl-4-carboxylic acid-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-acid amides
(29) 4-cyclohexyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(30) 4 '-chloro-xenyl-4-carboxylic acid-[2-(3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(31) 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-the 3H-quinazoline-4-one
(32) 4 '-chloro-xenyl-4-carboxylic acid-and 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl] ethyl }-acid amides
(33) 7-(3-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(34) 4-(4-oxo-cyclohexyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(35) 4-cyclohexyl-1-cyclohexane carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(36) 4-benzyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(37) 4-cyclohexyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(38) 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(39) 4-(4-fluoro-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(40) 4-(4-methoxyl group-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(41) 4-phenyl-Piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(42) (4 '-chloro-xenyl-4-yl)-[3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines-1-yl]-ketone
(43) 4 '-chloro-xenyl-4-carboxylic acid-[2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
(44) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethyl]-acid amides
(45) 4-benzyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(46) 4-(4-oxo-cyclohexylidene methyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(47) 4 '-chloro-xenyl-4-carboxylic acid-[2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(48) 5-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone
(49) 4-piperidines-1-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(50) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
(51) 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(52) 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
(53) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(54) 7-(4-chloro-phenyl)-3-(2-4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl-ethyl)-the 3H-quinazoline-4-one
(55) 6-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2H-isoquinoline 99.9-1-ketone
(56) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(57) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(58) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-ethyl-piperidines-2-yl)-phenyl]-ethyl }-acid amides
(59) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(4-ethanoyl-piperazine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(60) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aza-bicyclo [2.2.1] heptan-5-alkene-2-ylmethyl)-phenyl]-ethyl }-acid amides
(61) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1,3-dihydro-isoindole-2-ylmethyl)-phenyl]-ethyl }-acid amides
(62) 4 '-chloro-xenyl-4-carboxylic acid (2-{4-[(diisopropylaminoethyl)-methyl]-phenyl }-ethyl)-acid amides
(63) 4 '-chloro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(64) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-dimethylamino methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(65) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-dimethylamino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(66) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(67) 4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(68) 4 '-chloro-xenyl-4-carboxylic acid [2-(6-tetramethyleneimine-1-ylmethyl-pyridin-3-yl)-ethyl]-acid amides
(69) 4 '-chloro-xenyl-4-carboxylic acid [2-(1-tetramethyleneimine-1-base-indane-5-yl)-ethyl]-acid amides
(70) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-nitro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(71) 2 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(72) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-amino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(73) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aminomethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(74) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-2,6-diaza-spiro [3.4] suffering-6-ylmethyl)-phenyl]-ethyl }-acid amides
(75) 4 '-chloro-xenyl-4-carboxylic acid [2-(5-tetramethyleneimine-1-ylmethyl-pyridine-2-yl)-ethyl]-acid amides
(76) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(77) 4 '-bromo-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(78) 4-(5-chloro-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(79) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(80) 4 '-bromo-3-fluoro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(81) 4 '-chloro-2-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(82) 4 '-ethyl-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(83) [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-ylmethyl]-the carboxylamine tertiary butyl ester
(84) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
(85) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(86) 4 '-chloro-xenyl-4-carboxylic acid (2-4-[(cyclopropyl methyl-amino)-methyl]-phenyl }-ethyl)-acid amides
(87) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl)-phenyl]-ethyl }-acid amides
(88) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-{[(2-hydroxyl-ethyl)-methyl-amino]-methyl }-phenyl)-ethyl]-acid amides
(89) [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-3-yl]-the carboxylamine tertiary butyl ester
(90) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,6-dimethyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
(91) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-azetidine-1-ylmethyl-phenyl)-ethyl]-acid amides
(92) 3,4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(93) 4 '-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(94) 4 '-chloro-3-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(95) 2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(96) 5-(4-chloro-phenyl)-pyridine-2-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(97) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(98) 4 '-bromo-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(99) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-acid amides
The best is the above-mentioned individual compound with formula (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (47) and (50) to (99).
The part be used for preamble and hereinafter with the narration The compounds of this invention term will be in this more complete definition.
The representative of term halogen atom is selected from F, Cl, Br, reaches the atom of I.
Term C 1-n-alkyl (wherein n has 3 to 8 value) representative has saturated, the side chain of 1 to n C atom or the alkyl of non-side chain.These examples of groups comprise methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl etc.
Term C 1-nAlkylidene group (wherein n can have 1 to 8 value) representative has saturated, the side chain of 1 to n C atom or the hydrocarbon bridge of non-side chain.These examples of groups comprise methylene radical (CH 2-), ethylidene (CH 2-CH 2-), 1-methyl-ethylidene (CH (CH 3)-CH 2-), 1,1-dimethyl-ethylidene (C (CH 3) 2-CH 2-), positive the third-1,3-subunit (CH 2-CH 2-CH 2-), 1-methyl-the third-1,3-subunit (CH (CH 3)-CH 2-CH 2-), 2-methyl-the third-1,3-subunit (CH 2-CH (CH 3)-CH 2-) etc., and corresponding enantiomer.
Term C 2-nThiazolinyl (wherein n has 3 to 6 value) representative has 2 to n C atoms and the side chain of the two keys of at least one C=C-or the alkyl of non-side chain.These examples of groups comprise vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1,3-butadienyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl isophthalic acid-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butene base, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl etc.
Term C 1-n-alkoxyl group representative-O-C 1-n-alkyl, wherein C 1-n-alkyl as defined above.These examples of groups comprise methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy, positive hexyloxy, different hexyloxy etc.
Term C 1-n-alkylthio representative-S-C 1-n-alkyl, wherein C 1-n-alkyl as defined above, these examples of groups comprise methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, positive penta sulfenyl, isoamyl sulfenyl, new penta sulfenyl, uncle's penta sulfenyl, just own sulfenyl, dissident's sulfenyl etc.
Term C 1-n-alkyl carbonyl representative-C (=O)-C 1-n-alkyl, wherein C 1-n-alkyl as defined above, these examples of groups comprise first carbonyl, B carbonyl, positive third carbonyl, isopropyl carbonyl, positive fourth carbonyl, isobutyl carbonyl, Zhong Ding carbonyl, uncle's fourth carbonyl, positive penta carbonyl, isoamyl carbonyl, new penta carbonyl, uncle's penta carbonyl, just own carbonyl, dissident's oxygen carbonyl etc.
Term C 3-n-cycloalkyl representative have the saturated list of 3 to n C atoms-, two-, three-or spiral shell carbocylic radical.These examples of groups comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, dicyclo [3.2.1] octyl group, spiral shell [4.5] decyl, norpinanyl, norborneol alkyl, norcarane alkyl, adamantyl etc.
Term C 3-n-carbonyl naphthene representative-C (=O)-C 3-n-cycloalkyl, wherein C 3-n-cycloalkyl as defined above.
Term aryl is represented the aromatic ring system of carbocyclic ring, such as, for example, phenyl, xenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalene base, Azulene base, biphenylene etc.
In the application's case, used term heteroaryl is represented the aromatic ring system of heterocycle, and it still comprises the heteroatoms that one or more is selected from N, O and/or S except at least one C atom.These examples of groups comprise furyl, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl isoxazolyl, isothiazolyl, 1,2, the 3-triazolyl, 1,3, the 5-triazolyl, the piperazine base of muttering, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2, the 3-triazinyl, 1,2, the 4-triazinyl, 1,3, the 5-triazinyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, tetrazyl, the thiadiazine base, indyl, pseudoindoyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, purine radicals, quinazolyl, quinolizinyl (chinozillinyl), quinolyl, isoquinolyl, quinoxalinyl, the naphthyridine base, pteridine radicals, carbazyl, azepine _ base, diaza _ base, acridyl etc.The term heteroaryl also comprises partially hydrogenated heterocycle aromatic ring system, enumerates more than particularly.The example of these partial hydrogenation loop systems comprises 2, and 3-dihydro benzo furyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxa-azepine heptan is because of base etc.
Term is such as aryl-C 1-n-alkyl, heteroaryl-C 1-n-alkyl etc. are the C through aryl or heteroaryl replacement 1-n-alkyl (it is as hereinbefore defined).Many above-mentioned terms can be reused in the definition of a chemical formula or group, and have one of above specified meaning independently of one another under each situation.
Term " unsaturated carbon cyclic group " or " unsaturated heterocycle base ", as be used in particular for except that complete undersaturated group, also comprising the undersaturated group of only part of its correspondence in the definition of group Cy particularly single and two unsaturated groups.
In the application's case, term " selectivity is substituted " is meant that indicated group like this is to be unsubstituted or through specified substituting group list or polysubstituted.As this related group is through polysubstituted person, and its substituting group can be identical or different.
Above-mentioned group and substituting group can be in this way through fluorine lists or polysubstituted.Preferred fluorinated alkyl is methyl fluoride, difluoromethyl, and trifluoromethyl.Preferably fluoridize alkoxyl group and be fluorine methoxyl group, difluoro-methoxy, and trifluoromethoxy.Preferred alkyl fluoride sulfinyl and alkane alkylsulfonyl are trifluoromethyl sulphinyl base and trifluoromethyl sulfonyl.
Compound of Formula I of the present invention can have acidic-group (mainly being carboxyl) and/or basic group (such as, as, ammonia functional group).The compound of general formula I therefore can be used as inner salt, with medical operability mineral acid (such as, hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid) or organic acid (such as, for example, toxilic acid, fumaric acid, citric acid, tartrate or acetic acid) formed salt or with medical operability alkali (such as, basic metal or alkaline earth metal hydroxides or carbonate, the oxyhydroxide of zinc or ammonium or organic amine (such as, for example, diethylamine, triethylamine, trolamine)) form of formed salt exists.
Compound of the present invention can use known synthetic method to obtain in principle.Preferably, these compounds are to obtain by mentioned earlier and in the preparation method of hereinafter more complete explanation.
In order to obtain first group of preferred embodiment (that is, wherein group A and radicals R 3Not direct each other banded compound) preparation method of the present invention can divide into two kinds of situations basically.
First kind of situation comprises formula I compound, and wherein group A representative is by nitrogen-atoms and carboxamide groups banded nitrogen-atoms heterocyclic radical, and it also can comprise another heteroatoms that one or more is selected from N, O, reaches S except that this nitrogen-atoms.Reaction between formula I-1 amine compound and formula I-2 secondary amine compound is shown in the following general reaction process:
Reaction process 1:
Preferably, it is at first in a solvent or solvent mixture, make amine compound and the CDT (1 of formula I-1,1 '-carbonyl-two-(1,2, the 4-triazole)) reaction, then make again this reaction mixture further with the reaction of the amine compound of formula I-2, simultaneously, before the reaction of carrying out this amine compound and CDT and/or after, in this reaction mixture, add at least a alkali.Advantageously, it is under-20 ℃ to 20 ℃ temperature range, make amine compound and the CDT reaction of formula I-1, then again under 40 ℃ to 100 ℃ temperature range, make the amine compound reaction of this reaction mixture and formula I-2, its Chinese style I-1 amine compound: formula I-2 amine compound: CDT: the molar concentration rate of alkali is 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 3 ± 1.5.
Preferably, it is to use nitrogen base as alkali, tertiary amine particularly, such as, triethylamine.
The amine compound of formula I-2 can be saturated N-heterogeneous ring compound, such as, for example, according to the bridged piperazine derivatives of following reaction process 2.
Reaction process 2
Figure A0382007600751
These preparation methods' second situation comprises that other are not included in the formula I compound in the situation 1, and wherein group A does not directly link R 3Formula I-3 carboxylic acid cpd and TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-_ a tetrafluoro borate) and the reaction of formula I-1 amine compound in a solvent or solvent mixture, in the presence of at least a alkali are shown in the reaction process 3.
Reaction process 3
Figure A0382007600752
Preferably, it is in a solvent or solvent mixture, make carboxylic acid cpd and the TBTU reaction of formula I-3, then make again this reaction mixture further with the reaction of the amine compound of formula I-1, simultaneously, before the reaction of carrying out this carboxylic acid cpd and TBTU and/or after, in this reaction mixture, add at least a alkali.Except that carboxylic acid, also may use corresponding active carboxylic acid derivative, such as, for example, ester, former ester, carboxylic acid chloride or acid anhydride.Preferably, this used alkali is nitrogen base, tertiary amine particularly, such as, triethylamine.Preferably, it makes carboxylic acid cpd and the TBTU reaction of formula I-3, then again under 0 ℃ to 60 ℃ temperature range, make the amine compound reaction of this reaction mixture and formula I-1, its Chinese style I-3 carboxylic acid cpd: formula I-1 amine compound: TBTU: the mol ratio of alkali is 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 1 to 4.
The initial compounds of this formula I-3 can be obtained by the known method of those skilled in the art.Therefore, aryl-linking compound is to use the Suzuki coupling process to obtain, and is for example initial from right-bromine arylcarboxylic acid derivative and aryl boric acid derivative, and Pd[0 is being arranged] catalyzer in the presence of obtain.
In order to obtain second group of preferred embodiment (that is, wherein group A and radicals R 3These compounds that interlink) preparation method of the present invention can divide into seven kinds of situations, decides according to the meaning IIIa to IIIg of group Q.
According to this first kind of situation, wherein Q representative-CR 6R 7-(IIIa), it makes the amine compound of formula Ia.1 and neighbour-brooethyl of formula Ia.2-benzoate derivatives reaction, shown in following reaction process 4, the substituting group L on phenyl ring is described clearly wherein 1, L 2, L 3Leave out.
Reaction process 4:
Preferably, it is in a solvent or solvent mixture, makes the amine compound reaction of neighbour-brooethyl-benzoate derivatives and the formula Ia.1 of formula Ia.2, adds at least a alkali simultaneously.Except that neighbour-brooethyl-benzoate derivatives of formula Ia.2, also can use corresponding neighbour-benzyl-benzoate derivatives (replacing bromine) with iodine or methanesulfonates.Preferably, its be with salt of wormwood or cesium carbonate as alkali, but tertiary amine base, such as, triethylamine also is the dust head.Advantageously under 40-80 ℃ temperature range, in acetonitrile, neighbour-brooethyl-the benzoate derivatives of use formula Ia.2 and the amine compound of formula Ia.1, and use salt of wormwood to carry out its Chinese style Ia.2 neighbour-brooethyl-benzoate derivatives as alkali: formula Ia.1 amine compound: the mol ratio of salt of wormwood is 1 ± 0.25: 1 ± 0.25: 3 ± 0.50.
According to second kind of situation, wherein Q representative-CR 6=CR 7-(IIIb), it makes the isoquinolinone derivatives of formula Ib.3 and the nucleophilie electronic compound reaction of formula Ib.4, and to form the isoquinilone derivatives of formula Ib.5, it is again with the further derivation of known method, to obtain formula I compound.The isoquinolinone derivatives of formula Ib.3 can be from the cinnamic acid derivative of formula Ib.1, by with (EtO) 2P (O) N 3Reaction and obtain.The synthetic of this basic substance is set forth in Bioorganic ﹠amp by people such as M.Becker; Medicinal Chemistry Letters 9 (1999) is among the 2753-2758.This reaction is shown in the following reaction process 5, wherein clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Leave out.
Reaction process 5:
Figure A0382007600771
Preferably, the compound of formula Ib.2 is to be obtained by hereinafter described reaction sequence.Its at first effect by chlorizating agent (such as; thionyl chloride, phosphorus pentachloride or oxalyl chloride) do not have or optionally inert solvent (such as; methylene dichloride) under the situation in, the temperature chien shih acrylic acid derivative Ib.1 reaction at 0 ℃ to 80 ℃ obtains this chloride of acid.In a solvent or solvent mixture,, make this material transform into the vinylformic acid azide derivatives again by the effect of sodiumazide.Used solvent can be, for example ， diox, tetrahydrofuran (THF) or water.Preferably, the isocyanate derivates of this formula Ib.2 is between 0 ℃ to 150 ℃ temperature, in solvent, in the presence of alkali, synthesizes for the effect of acrylic acid derivative Ib.1 by the diphenyl phosphate trinitride.Appropriate solvent comprises, for example, and toluene Huo diox.Can use tertiary amine, for example, triethylamine is as alkali.Above-mentioned reaction has the reaction times between 1 to 12 hour.Favourable, this acrylic acid derivative Ib.1 and diphenyl phosphate trinitride and triethylamine are with 1 ± 0.25: the reaction that 1 ± 0.25: 1 ± 0.25 mol ratio is carried out is to carry out in solvent toluene.In solvent, optionally have alkali in the presence of (such as, Tributylamine), the isocyanate derivates of heating-type Ib.2, and form the isoquinolinone derivatives of formula Ib.3.Preferably, this reaction is in phenyl ether, carries out in boiling spread.The available thermal source comprises oil bath, metal bath or microwave.
The reaction that the mesylate derivatives of the isoquinolinone derivatives of formula Ib.3 and formula Ib.4 forms the isoquinolinone derivatives of formula Ib.5 is in solvent, under the existence that alkali is arranged, carries out between 0 ℃ to 150 ℃ temperature.Preferably, the mesylate derivatives of this isoquinolinone derivatives Ib.3 and formula Ib.4 and sodium hydride are with 1 ± 0.25: the reaction that 1 ± 0.25: 1 ± 0.25 mol ratio is carried out is to carry out in solvent DMF.The isoquinolinone derivatives of formula Ib.5 at first is in solvent, in that reaction in the presence of the acid is arranged, this acetal is transformed into corresponding aldehyde.Its again have hydride ion transforming agent, amine, and acid in the presence of, in solvent, transform into the compound of formula Ib.Example as the hydride ion transforming agent comprises, sodium triacetoxy borohydride, sodium borohydride, and SODIUM CYANO BOROHYDRIDE.Preferably, this aldehyde (Ib.5 disengages from isoquinolinone derivatives) and amine and SODIUM CYANO BOROHYDRIDE are with 1 ± 0.25: the reaction that 1 ± 0.25: 0.8 ± 0.25 mol ratio is carried out is methyl alcohol and acetic acid, carries out under about 20 ℃ temperature.
Formula Ib isoquinoline 99.9 synthetic comprises that its initial compounds and follow-up derivatization, will be by the synthesis flow explanations of a following particular compound to form this amine, simultaneously, the synthetic of educt 1 can be undertaken by following schema 6, with preparation 2 ketone (schema 8).
Reaction process 6:
Figure A0382007600791
According to the third situation, Q representative-N=CR wherein 8-(IIIc), it makes the 2 ketone derivatives of formula Ic.4 and the nucleophilie electronic compound reaction of formula Ic.5, and to form the 2 ketone derivatives of formula Ic.6, it forms the compound of formula Ic again with the further derivatize of known method.The 2 ketone derivatives of formula Ic.4 is R wherein 8=hydrogen atom can by acylation, form neighbour's-oxazolyls-benzaldehyde derivative of formula Ic.2 from the Ben of formula Ic.1 oxazole derivatives, by follow-up cyclic action, form 3-hydroxyl-3H-isobenzofuran-1-ketone derivatives of formula Ic.3.This basic substance synthetic by people such as M.Napoletano at Bioorganic ﹠amp; Medicinal Chemistry Letters 12 (2002) narrates among the 5-8.The reaction that forms general formula I c compound is shown in following reaction process 7, wherein clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Omit.
Reaction process 7:
Above-mentioned reaction sequence will be described in further detail later: use proper metal organic reagent Dui oxazole derivative I c.1 to metallize, again between-70 ℃ to 20 ℃ temperature, preferably between-20 ℃ to 0 ℃ temperature, (for example react with formaldehyde equivalent thing, the former ester of dimethyl formamide or formic acid), to form the compound of formula Ic.2.As solvent can be, for example ， diox, tetrahydrofuran (THF) or diethyl ether.In solvent (such as, ethanol) under temperature, in 1 to 24 hour time,, can obtain general formula I compound c.3 by the effect of aqueous sulfuric acid near this solvent or solvent mixture boiling point.The 2 ketone derivatives of formula Ic.4 can be by at acetic acid and optionally in solvent, between between 20 and 120 ℃ temperature, makes the compound of formula Ic.3 and hydrazine reaction and obtain.The synthetic of the 2 ketone derivatives of formula Ic is to carry out with the synthetic described reaction of similar general formula I b compound.
2 of formula Ic, synthesizing of 3-phthalazinone derivatives, particularly its initial compounds and follow-up derivatization, can describe with reference to the synthesis flow 8 of particular compound, wherein, abbreviation has following meaning: LAH and represents lithium aluminum hydride, BuLi represents n-Butyl Lithium, DMF represents dimethyl formamide, and MeOH is a methyl alcohol, and Ms-Cl is a methylsulfonyl chloride.
Reaction process 8
According to the 4th situation, Q representative-N=N-(IIId) wherein, it makes neighbour-amino-benzamide derivatives of formula Id.1, in the presence of suitable nitrite compound and acid, carry out derivation by the reaction of diazonium intermediate compound, form the phentriazine ketone derivatives of formula Id.This reaction is shown in following reaction process 9, wherein is clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Omit.
Reaction process 9:
Figure A0382007600831
Preferably, general formula I compound d.1 is in solvent (such as, methyl alcohol), exists down at the salt that mineral acid (for example, hydrochloric acid) is arranged and contain nitrite ion, reacts between-10 ℃ to 30 ℃ temperature.Advantageously, amine compound Id.1 and Sodium Nitrite are with 1 ± 0.25: the reaction that 1.5 ± 0.25 mol ratio is carried out is to carry out in solvent methanol and in the presence of hydrochloric acid.
According to the 5th situation, Q representative-CO-NR wherein 9-(IIIe), make neighbour-amino-benzamide derivatives of formula Ie.1, have CDI in the presence of react, to form the quinazolinedione derivatives of Ie.CDI is to add with the mol ratio more than or equal to 1 to the benzamide derivatives of Ie.1, and this to react to small part be to carry out 35 ℃ to 100 ℃ temperature range, preferably near the boiling point of this reaction mixture, carry out.This reaction is shown in following reaction process 10, wherein is clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Omit.
Reaction process 10:
Figure A0382007600841
According to the 6th situation, Q representative-CR wherein 8=N-(IIIf) makes neighbour-amino-benzamide derivatives of formula If.1, with carboxylic acid R 8COOH and/or corresponding activated carboxylic acid derivatives's reaction are to form the Quinazol derivative of formula .If.Suitable activated carboxylic acid derivatives comprises, for example, and ester, former ester, carboxylic acid chloride and acid anhydride.This optionally activated carboxylic acid is that the carboxamide derivative of If.1 is added with the mol ratio more than or equal to 1, and this to react to small part be to carry out 35 ℃ to 100 ℃ temperature range, preferably near the boiling point of this reaction mixture, carry out.This reaction is shown in following reaction process 11, wherein is clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Omit.
Reaction process 11:
Synthesizing of the Quinazol derivative of formula If, its initial compounds particularly, describe with reference to the synthesis flow 12 of particular compound, wherein use following abbreviation: CDI represents carbonyl dimidazoles, TBTU represents 2-(1H-benzotriazole-1-yl)-1,1,3, the 3-tetramethyl-_-a tetrafluoro borate, and NEt 3Represent triethylamine.At first, it illustrates the synthesis flow of two initial compounds 1 and 2.
Reaction process 12:
Figure A0382007600851
Initial compounds 1 and 2 is to use TBTU to link by acid amides and interlinks.At PtO 2Existence under, make the adjacent nitroreduction that is positioned at the gained amido linkage, to form amine.For the cyclic action that forms quinazolinone uses carboxylic acid (being formic acid in this case) to carry out.
According to seven human emotions shape, wherein Q representative-CO-(IIIg) makes the amine compound reaction of isobenzofurandione derivative and the formula Ig.1 of formula Ig.2, to form the isoindoledione of formula Ig.This reaction is shown in following reaction process 13, wherein is clearly explanation, the substituting group L on the phenyl ring 1, L 2, L 3Omit.
Reaction process 13:
G.2, the isobenzofurandione derivative I is in solvent (such as, acetic acid), with general formula I amine compound g.1, with 1 ± 0.25: 1.5 ± 0.25 molar ratio reaction.Temperature in the reaction process is the boiling point of this solvent preferably.
Yet the isoindoledione derivative of formula Ig also can be obtained according to following synthesis flow 14.This area professional can with shown in the synthesis of selective of individual compound modify and be applied to the compound of other formulas Ig easily.At first, obtain the isoindoledione functional group by the isobenzofurandione derivative linking under the amine, again by means of Pd[0 is being arranged] catalyzer in the presence of, add another aryl with the Suzuki coupling process.
Reaction process 14:
At wanting the individual compound of synthetic, the possible method of the synthetic The compounds of this invention of above-mentioned explanation can be used the principle of known at least method by those skilled in the art, for example, be set forth in Houben-Weyl, among the Methoden der organischen Chemie, modify easily and/or replenish.
In above-mentioned reaction; any reactive group of Cun Zaiing wherein; such as; hydroxyl, carboxyl, amino or imino-; all can be in the process of reaction; with known method in the document, protect the cracking more afterwards of this group by common protecting group: particularly, can use protecting group general in chemistry of peptides.Be found in about in this respect information, for example, WO 98/11128.
In principle, the Stereoisomeric compounds of formula (I) can be separated by prior art method.Diastereomer can separate according to its different physics-chem characteristic, as, by from appropriate solvent, carrying out fractional crystallization, pass through high pressure liquid chromatography or post chromatography, use chirality or more preferably being achiral stationary phase.
As do not mention the person, the compound of formula (I) can be converted into its salt, transforms into its physiology and pharmacologically acceptable salts in particular for medicinal use.This salt can exist with formula (I) compound and formed physiology of inorganic or organic acid and the acceptable acid salt form of pharmacy on the one hand.On the other hand, with regard to acid banded hydrogen atom, the compound of formula (I) also can transform into by the reaction with mineral alkali with basic metal or alkaline-earth metal ions medicine or the acceptable salt of pharmacy as counter ion.Acid salt can use, for example, and hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, acetic acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid and be prepared.Simultaneously, can use the mixture of above-mentioned acid.Basic metal or alkaline earth salt for preparation formula (I) compound and acid binding hydrogen atom, preferred oxyhydroxide and the hydride that uses basic metal or alkaline-earth metal, wherein, alkali-metal oxyhydroxide and hydride are preferred, particularly sodium and potassium, and sodium hydroxide and potassium are best.
According to compound of the present invention, comprise physiologically acceptable salt, can be effectively as the antagonist, particularly MCH-1 acceptor of MCH acceptor, and it links in the test at the MCH acceptor and has good avidity.Be set forth in hereinafter the experimental section for the pharmacy test system of MCH antagonistic properties.
As the antagonist of MCH acceptor, compound of the present invention is particularly conducive to and is suitable as the medicinal activity material, is caused by MCH or has the symptom and/or the disease of other reasons dependency with MCH with prevention and/or treatment.Generally speaking, compound of the present invention has hypotoxicity, and it can carry out good absorption by oral, and has transhipment property between brain, particularly brain negotiability (Hiringanglgkeit).
Therefore, the MCH antagonist that contains at least a The compounds of this invention is specially adapted to Mammals, such as, rat, mouse, guinea pig, rabbit, dog, cat, sheep, horse, pig, ox, monkey and the mankind are to be used to prevent and/or to treat by MCH and caused or have the symptom and/or the disease of other reasons dependency with MCH.
By MCH caused or with MCH have the symptom of other dependencys and/or disease particularly including metabolic disturbance (such as, obesity) and eating disorder (such as, voracity comprises bulimia nervosa).The symptom obesity comprises exogenous obesity, hyperinsulinemia obesity, the too much property of endochylema obesity, the too much property of vim and vigour obesity, endochylema deficiency obesity, hypothyroid obesity, hypothalamic obesity, symptom obesity, child's obesity, upper body obesity, alimentary obesity, hypogonad obesity, maincenter obesity.The scope of these symptom also comprises emaciation, apocleisis, reaches hyperingestion.Compound of the present invention is specially adapted to reduce hunger sensation, depress appetite, control feed behavior and/or brings out satiety.
In addition, caused by MCH or having the symptom of other reasons dependency and/or disease with MCH also comprises hyperlipidaemia, cellulitis, fat accumulation, pernicious urticaria pigmentosa, systemic urticaria pigmentosa, emotional handicap, affective disorder, melancholia, anxiety state, dysgenesia, dysmnesia, various dementia, and hormone obstacle.
Compound of the present invention also is suitable as active substance, with treatment and/or prevention other diseases and/or obstacle, particularly follow fat, such as, the complication (comprising diabetic retinopathy, diabetic neuropathy, diabetic nephropathy etc.) of diabetes, diabetes cheek inflammation (the particularly second type diabetes), hyperglycemia (particularly chronic hyperglycemia), diabetes, insulin resistance, pathologic glucose tolerance, cardiovascular disorder (particularly arteriosclerosis and hypertension), and gonitis.
Help in conjunction with sitotherapy (such as, the treating diabetes of diet) and use and take exercise according to MCH antagonist of the present invention and preparation.
Another symptom scope that The compounds of this invention preferably is suitable for is prevention and/or treatment dysuria, such as, the urinary incontinence, bladder hyperactivity hyperkinesia, nycturia, the enuresis, wherein the bladder hyperactivity hyperkinesia and the urinary incontinence may be relevant with benign prostate propagation or irrelevant.
To be generally through intravenously or subcutaneous route administration be 0.001 to 30 milligram/kg body weight in order to reach the required dosage of effect, 0.01 to 5 milligram/kg body weight preferably, and oral administration or nasal route or be 0.01 to 50 milligram/kg body weight by inhalation, 0.1 to 30 milligram/kg body weight preferably is every day 1 to 3 time under each situation.
At this point, formula I compound prepared in accordance with the present invention, other active substances as previously described of selective binding, in conjunction with the acceptable vehicle of one or more physiology, the carrier that inertia is known, and/or thinner, as, Semen Maydis powder, lactose, sucrose, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, the hexadecyl Stearyl alcohol, carboxymethyl cellulose, or fatty substance (such as, stearic), or its suitable mixture, be prepared into known Galenic formula, such as, conventional tablet or coated tablet, capsule, pulvis, granula, liquor, emulsion, syrup, inhalant aerosol, ointment, or suppository.
Except that pharmaceutical preparation, the present invention also comprises composition, and it contains except at least a carboxamide compounds of the present invention and/or salt of the present invention, the acceptable vehicle of one or more physiology of selective binding.These compositions also can be, for example, food, it can be solid or liquid, wherein includes compound of the present invention in.
With regard to above-mentioned composition, it can use another kind of active substance, particularly, for example, can strengthen the therapeutic efficiency person of MCH antagonist of the present invention with regard to one of above-mentioned symptom, and/or can reduce the dosage of MCH antagonist of the present invention.Preferably, this one or more other active substance is to be selected from:
-can be used for treating the active substance of diabetes,
-can be used for treating the active substance of diabetic complication.
-can be used for treating fat active substance, preferably not the MCH antagonist,
-can be used for treating hypertensive active substance,
-can be used for treating the hyperlipidaemia active substance of (comprising arteriosclerosis),
-can be used for the active substance of treatment of arthritis,
-can be used for treating the active substance of anxiety state,
-can be used for treating hypochondriacal active substance.
Above-mentioned active substance will be described in detail with by way of example below.
The active substance example that can be used for treating diabetes comprises insulin sensitizing agent element, insulin secretion accelerating element, biguanides, Regular Insulin, alpha-glucosidase inhibitor, β 3Adrenoceptor agonists.
The insulin sensitizing agent element comprises pioglitazone (pioglitazone) and salt (preferably hydrochloride), troglitazone (troglitazone), rosiglitazone (rosiglitazone) and salt (being preferably its maleate) thereof, JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929.
The insulin secretion accelerating element comprises sulfonylurea, such as, tolbutamide (tolbutamide), P-607 (chloropropamide), trazamide, acetohexamide (acetohexamide), glydlopyramide and ammonium salt thereof, Glyburide (glibenclamide), gliclazide (gliclazide), glimepiride (glimepiride).Other examples of insulin secretion accelerating element comprise repaglinide (repaglinide), nateglinide (nateglinide), mitiglinide (KAD-1229), reach JTT-608.
Biguanides comprises N1,N1-Dimethylbiguanide (metformin), butyl biguanides (buformin), reaches phenformin (phenformin).
Regular Insulin comprises the Regular Insulin of taking from animal (particularly cat or pig), narrow become second nature human insulin's (it is to carry out enzyme by the Regular Insulin of taking from animal to urge synthetic person), take from engineered human insulin (as, obtain from intestinal bacteria or yeast).In addition, also comprise Regular Insulin-zinc (zinc that contains 0.45 to 0.9 weight percent) and protamine-Regular Insulin-zinc (take from zinc chloride, Protamine sulfates, reach Regular Insulin) as Regular Insulin.Also can take from the Regular Insulin of insulin fragment or derivative (for example, INS-1 etc.).
Regular Insulin also can comprise different types, as, with regard to the time of origin and the effect with regard to the phase (" super instant effect type ", " instant effect type ", " two facies patterns ", " osculant ", " long term type " etc.) of effect, it can be selected according to patient's pathologic condition.
Alpha-glucosidase inhibitor comprises acarbose (acarbose), voglibose (voglibose), miglitol (miglitol), emiglitate (emiglitate).
β 3Adrenoceptor agonists comprises AJ-9677, BMS-196085, SB-226552, AZ40140.
The active substance that can be used for except above-mentioned points treated diabetes comprises bromocriptine quick releasing formulation (ergoset), tripro-amylin (pramlintide), leptin (leptin), BAY-27-9955, and glycogen phosphorylase inhibitors, SODH inhibitor, albumen Tyrosine phosphoesterase IB inhibitor, two peptide protease inhibitors, glipazide, Glyburide (glyburide).
The active substance that can be used for treating diabetic complication comprises aldose reductase inhibitor, saccharification inhibitor, and inhibitors of protein kinase C.
Aldose reductase inhibitor is, for example, and this naphthalene of Toure (tolrestat), beneficial Pa Ruisite (epalrestat), imirestat, folding Na Site (zenarestat), SNK-860, azoles pool department special (zopolrestat), ARI-50i, AS-3201.
The saccharification inhibitor is pimagedine (pimagedine).
Inhibitors of protein kinase C is, for example, and NGF, LY-333531.
The active substance that can be used for except that above-mentioned treated diabetic complication comprises Prostaglandin E1 (alprostadil), thiapride hydrochloride, Cilostazole (cilostazol), Mexiletine (mexiletinehydrochloride), 20 archidonic acid ethyl esters (ethyl eicosapentate), Memantine hydrochloride (memantine), pimagedine (pimagedine) (ALT-711).
Can be used for treating fat active substance (preferred right and wrong MCH antagonist) and comprise lipase inhibitor and anoretics.
The lipase inhibitor preferred embodiment is orlistat (orlistat).
The preferred embodiment of anoretics is PHENTERMINE (phentermine), Mazindol (mazindol), Isomeride (dexfenfluramine), fluoxetine (fluoxetine), sibutramin (sibutramine), baiamine, (S)-sibutramin ((S)-sibutramine), SR-141716, NGD-95-1.
Other can be used for treating fat active substance and comprises Li Busita fourth (lipstatin).
In addition, be used for the application's purpose, also comprise anoretics in the active substance type of anti-obesity activity material, wherein should emphasize β 3Agonist thyroxine simulation active substance, and NPY antagonist.The scope of preferred here anti-obesity/subtract appetite active substance can be pointed out by following other table, for example: Phenylpropanolamine, ephedrine, pseudo-ephedrine, PHENTERMINE (phentermine), cholecystokinin-A (hereinafter being called CCK-A) agonist, monoamine reuptake inhibitors (such as, sibutramin (sibutramine)), sympathetic nerve simulation active substance, serotonine enteramine energy active substance (such as, Phenfluoramine (dexfenfluramine) or Phenfluoramine (fenfluramine) are selected in the right side), dopamine antagonist (such as, bromocriptine (bromocriptine)), melanotropin receptor stimulant or stand-in, the melanotropin receptor analogs, class cannabinoid receptor antagonist, the MCH antagonist, OB albumen (hereinafter being called leptin (leptin)), the leptin analogue, the leptin receptor agonist, galanin (galanine) antagonist, GI lipase inhibitor or subtract is imitated agent (such as, orlistat (orlistat)).Other anoretics frog skin peptide agonists, 17-Hormoforin or its analogue, glucocorticoid receptor stimulant and antagonist, orexin (orexin) receptor antagonist, the conjugated protein antagonist of urine cortex (urocortin), like the agonist of glucagon-like peptide-1 acceptor (such as, and ciliary neurotrophic factor (such as, A Suosu (axokines)) exendin).
Can be used for treating hypertensive active substance comprises angiotensin converting enzyme inhibitor, calcium antagonist, potassium channel openers, reaches angiotension II antagonists.
Angiotensin converting enzyme inhibitor comprises captopril (captopril), Enalapril (enalapril), alacepril (alacepril), delapril (delapril) (hydrochloride), lisinopril (lisinopril), Imidapril (imidapril), benazepril (benazepril), Yipingshu (cilazapril), temocapril (temocapril), Trolapril (trandolapril), Manidipine (manidipine) (hydrochloride).
The example of calcium antagonist comprises nifedipine (nifedipine), amlodipine (amlodipine), efonidipine (efonidipine), nicardipine (nicardipine).
Potassium channel openers comprises levcromakalim (levcromakalim), L-27152, AL0671, NIP-121.
Angiotension II antagonists comprises telmisartan (telmisartan), losartan (losartan), CARDESARTAN cilexetil (candesartan cilexetil), valsartan (valsartan), Irb (irbeartan), CS-866, E4177.
The active substance that can be used for treating hyperlipidaemia (comprising arteriosclerosis) comprises HMG-CoA reductase inhibitor, benzene oxygen aromatic acid (fibrate) compound.
The HMG-CoA reductase inhibitor comprise Pravastatin (pravastantin), Simvastatin (simvastantin), lovastatin (lovastantin), holder cut down his spit of fland (atorvastantin), fluvastatin (fluvastatin), Benprofibratum (lipantil), simvastatin (cerivastatin), according to cutting down his spit of fland (itavastatin), ZD-4522 and salt thereof.
Benzene oxygen aromatic acid (fibrate) compound comprises bezafibrate (bezafibrate), S-8527 (clinofibrate), chlorine Bei Te (clofibrate), reaches simfibrate (simfibrate).
The active substance that can be used for treatment of arthritis comprises Ibuprofen BP/EP (ibuprofen).
The active substance that can be used for treating anxiety state comprises chlorine nitrogen _ (chlordiazepozide), diazepam (diazepam), oxazole logical sequence (oxozolam), medazepam (medazepam), cloxazolam (cloxazolam), Bromazepam (bromazepam), lorazepam (lorazepam), alprazolam (alprazolam), fludiazepam (fludiazepam).
Can be used for treating hypochondriacal active substance and comprise fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), imipramine (imipramine), handkerchief Roxette (paroxetine), Shan Telalin (sertraline).
The dosage of these active substances be from normal suggestion lowest dose level 1/5 to 1/1 of normal recommended doses.
In another embodiment, the present invention also is used to influence the purposes of Mammals feeding behavior about at least a carboxamide compounds of the present invention and/or salt of the present invention.This purposes especially based on compound of the present invention applicable to reducing hunger sensation, depress appetite, control feed behavior and/or bringing out the fact of satiety.The feed behavior advantageously reduces the picked-up of food through influence.Therefore, preferably can be used for reducing body weight according to compound of the present invention.Another purposes of the present invention is the increase of prevention body weight, for example, is used for the body weight that has before obtained loss of weight and had a mind to keep its reduction.According to this embodiment, the purposes of non-therapeutic preferably.The purposes of this kind non-therapeutic can be a kind of cosmetic use, for example, and with the change outward appearance, or a kind of purposes that is used to improve the general health situation.Compound of the present invention preferably is used for Mammals with non-therapeutic modality, particularly human, its do not suffer from any after diagnosing eating disorder, do not have obesity, voracity, diabetes after diagnosing and/or do not have after diagnosing dysuria, the particularly urinary incontinence.Preferably, compound of the present invention is adapted at carrying out in the human body non-therapeutic purposes, its human BMI (body-mass index) (its definition be the body weight measured with kilogram unit divided by height (is unit with rice) square) be lower than 30, preferably be lower than 25.
The following example is in order to explanation the present invention:
Preamble:
As a rule, to prepared compound provide fusing point, 1H-NMR and/or mass-spectrometric data.Except as otherwise noted, R fValue is to use the silica gel 60TLC dish F of ready-made preparation 254(E.Merck, Darmstadt, Itemno.1.05714) (saturated) and measure without post.Obtained R under mark Alox fValue is to use the aluminum oxide 60TLC dish F of ready-made preparation 254(E.Merck, Darmstadt, Item no.1.05713) (saturated) and measure without post.
Given HPLC data are to measure under following parameter condition: Zorbax post (AgilentTechnologies), SB (stable keys (Stable Bond))-C 183.5 μ m; 4.6 * 75mm; Column temperature: 30 ℃; Flow velocity: 0.8 ml/min; Volume injected: 5 microlitres; Detect at 254nm.
Method A: in 9 minutes, water: acetonitrile: formic acid is 9: 1: 0.01 to 1: 9: 0.01.
Method B: in 4 minutes, water: acetonitrile: formic acid is 9: 1: 0.01 to 1: 9: 0.01,6 minutes 1: 9: 0.01 of continuing again.
Configuration is not provided detailed data
Not relevant for the specific information of configuration, it promptly is not know whether it is pure enantiomer as it, or wherein whether carries out part or even racemization completely.
Following abbreviation is used for above reaching hereinafter:
BOC-acid anhydride tertbutyloxycarbonyl acid anhydride
The CDI carbonyl dimidazoles
CDT 1,1 '-carbonyl-two-(1,2, the 4-triazole)
The DMF dimethyl formamide
Acetic ester/EtOAc ethyl acetate
The ether ether
HOBt I-hydroxybenzotriazole-hydrate
Hunig alkali N, N-di-isopropyl-ethamine
Conc. dense
The Me methyl
MeOH methyl alcohol
RT room temperature (about 20 ℃)
TBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3 ,-tetramethyl-_ a tetrafluoro borate
The THF tetrahydrofuran (THF)
Eq. equivalent
Calc. calculated value
Fnd. experimental value
General methodology I (TBTU coupling):
Triethylamine (1.5eq.) and TBTU (1.0eq.) are added in the solution of carboxylic acid (1.0eq.) in THF or DMF successively.According to this carboxylic acid, between room temperature and 40 ℃, stirred this mixture 10 minutes to 12 hours, add amine (1.0eq.) again.Between room temperature and 40 ℃, stir this mixture 30 minutes to 2 hours, add half saturated NaHCO again 3Solution.After with appropriate solvent (as, ethyl acetate) aqueous phase extracted, this organic phase is dewatered with sal epsom.Using rotatory evaporator to remove desolvates; Further purifying is to carry out with post chromatograph or HPLC.Reaction also can be carried out in the Chemspeed automated synthesizer.
General methodology II (CDT coupling):
Under 0 ℃, CDT (1eq.) is added in the solution of primary amine (1.0eq.) in DMF (1 mmole/milliliter), and in this mixture of 0 ℃ of following restir 30 minutes.This reaction is heated at 25 ℃, and adds triethylamine (3eq.).Then add the secondary amine (1.0eq.) among the DMF (0.25 mmole/milliliter), heated this reaction soln 30 minutes to 3 hours down at 60 to 80 ℃ again.Under vacuum, remove DMF, again this resistates is dissolved in methylene dichloride and 5%-Na 2CO 3Solution in, or in water-soluble and the t-butyl methyl ether.Extract this organic phase with water, after selectively dewatering again, use rotatory evaporator to remove and desolvate with sal epsom; Further purifying is to carry out with post chromatograph or crystallization process.Reaction also can be carried out in the Chemspeed automated synthesizer.
Embodiment 1.1:
7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007600951
1.1.a.4-bromo-2-nitro-phenylformic acid
By the 4-bromo-2-nitro-methyl of 82 grams (0.397 mole) in the reaction mixture that 700 milliliters of pyridines and 500 ml waters constitute, in 8 hours time, add the potassium permanganate of 174.5 grams (1.104 moles) in batches.Stirred this mixture 12 hours down at 60 ℃.Then add successively other 20 the gram (0.092 mole) 4-bromo-2-nitro-toluene, 50 milliliters pyridine, and 30 the gram (0.189 mole) potassium permanganate.Down stirred these mixtures 12 hours at 60 ℃, mix, refluxed again 30 minutes with 200 milliliters ethanol.Follow this reaction mixture filtered while hot, and on rotatory evaporator, evaporate this filtrate.Surplus resistates is stayed in sodium hydroxide solution alkalization with 10%, and extracts with ether.Water phase separated, and carry out acidifying with dilute hydrochloric acid.Leach formed crystal, clean, carry out azeotropic drying with tetrahydrofuran (THF), and stir jointly with diisopropyl ether with water.
Productive rate: 37 grams (theoretical value 32.8%)
C 7H 4BrNO 4(M＝246.018)
Calculated value: mole peak (M+Na) +: 268/270 experimental value: mole peak (M+Na) +: 268/270
R fValue: 0.46 (silica gel, methylene chloride/acetic acid 8: 2: 0.1)
1.1.b.4 '-chloro-3-nitro-xenyl-4-carboxylic acid
Four-(triphenylphosphine)-palladium of 0.288 gram (0.25 mmole), 1.25 gram (7.99 mmole) 4-chloro-phenyl-boric acid in 30 ml methanol, 2.31 gram (21.7 mmole) yellow soda ash that reach in 14 ml waters are added in the solution of 4-bromo-2-nitro-phenylformic acid in 30 milliliters of dioxs of 1.92 grams (7.81 mmole) successively.In microwave oven, with 300 watts, with this reaction mixture be heated to 110 ℃ 1 hour.Then this filtrate of evaporation on rotatory evaporator is soluble in water with resistates, and is adjusted to pH3 with 1M hydrochloric acid.With this aqueous solution of ethyl acetate extraction.With sodium sulfate this organic phase is dewatered, use to distill on the rotatory evaporator and desolvate, and this resistates and diisopropyl ether are stirred jointly to remove.
Productive rate: 2.04 grams (theoretical value 93.9%)
C 13H 8ClNO 4(M＝277.666)
Calculated value: mole peak (M-H) -: 276 experimental values: mole peak (M-H) -: 276
R fValue: 0.5 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.1.c.4-cyanogen methyl-ethyl benzoate
In the solution of potassium cyanide in 250 milliliters of hot water of 147.5 grams (2.263 moles), dropwise add the solution of 4-brooethyl-ethyl benzoate in 1000 milliliters of ethanol of 500 grams (2.057 moles).This reaction mixture was refluxed 1 hour, at room temperature stirred again 12 hours.Add other 73.7 gram (0.5 mole) potassium cyanide, and this mixture was refluxed 2 hours.Leach the solid in this reaction mixture, and the mixture of this filtrate by silica gel and activated carbon filtered.The filtrate that evaporation obtains, and resistates poured in 1000 milliliters the water.Extract this aqueous solution with t-butyl methyl ether, extract this organic phase three times with water again.Then this organic phase is dewatered, and use the rotatory evaporator distillation to remove and desolvate with sal epsom.On silica gel, carry out purifying (petrol ether/ethyl acetate 8: 2) with the post chromatograph.
Productive rate: 64.46 grams (theoretical value 42.2%)
C 11H 11NO 2(M＝189.216)
Calculated value: mole peak (M+H) +: 190 experimental values: mole peak (M+H) +: 190
R fValue: 0.3 (silica gel, petrol ether/ethyl acetate 8: 2)
1.1.d:4-cyanogen methyl-phenylformic acid
Make the vlil of 1M sodium hydroxide solution in 100 milliliters of ethanol 1 hour of the 10 gram 4-cyanogen methyl-ethyl benzoates of (53 mmole) and 2.02 milliliters, then evaporate this reaction soln, and this resistates is mixed with frozen water.In this reaction soln, dropwise add concentrated hydrochloric acid, till no longer forming throw out.Leach this throw out, clean twice with water, and carry out drying.
Productive rate: 4.7 grams (theoretical value 55%)
C 9H 7NO 2(M＝161.162)
Calculated value: mole peak (M-H) -: 160 experimental values: mole peak (M-H) -: 160
(1.1.e 4-methylol-phenyl)-acetonitrile
The CDI of 5.17 grams (32 mmole) is added in the solution of 4-cyanogen methyl-phenylformic acid in 250 milliliters of tetrahydrofuran (THF)s of 4.7 grams (29 mmole), and stir, till gas generates end.This reaction mixture is dropwise added in the solution of sodium borohydride in 200 ml waters of 3.29 grams (87 mmole), make temperature be no more than 30 ℃.Stirred 2 hours, and this reaction mixture is adjusted to pH3-4 with potassium hydrogen sulfate solution.Then it is extracted, this organic phase is dewatered, and use the rotatory evaporator distillation to remove and desolvate with sal epsom with ethyl acetate.
Productive rate: 2.6 grams (theoretical value 60.9%)
C 9H 9NO(M＝147.178)
Calculated value: mole peak (M-H) -: 146 experimental values: mole peak (M-H) -: 146
(1.1.f. 4-brooethyl-phenyl)-acetonitrile
Under 0 ℃, the phosphorus tribromide of 0.86 milliliter (9 mmole) is dropwise added in the solution of (4-methylol-phenyl)-acetonitrile in 25 milliliters of t-butyl methyl ether of 2.6 grams (17.66 mmole).Reaction at room temperature makes this reaction mixture mix with water after finishing, and separates organic phase, and extracts in proper order with sodium hydrogen carbonate solution and water.With sal epsom this organic phase is dewatered, and use the rotatory evaporator distillation to remove and desolvate.
Productive rate: 2.9 grams (theoretical value 78.1%)
C 9H 8BrN(M＝210.075)
Calculated value: mole peak (M+H) +: 209/211 experimental value: mole peak (M+H) +: 209/211
(1.1.g. 4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile
The salt of wormwood of the tetramethyleneimine of 0.446 milliliter (5.44 mmole) and 1.366 grams (9.882 mmole) added in 20 milliliters the dimethyl formamide.Under agitation, add (4-brooethyl-phenyl)-acetonitrile of 1.038 grams (4.941 mmole), and at room temperature stirred this mixture 12 hours.This reaction mixture of evaporation extracts this resistates with ethyl acetate and water again in rotatory evaporator.With sal epsom this organic phase is dewatered, and use rotatory evaporator to remove and desolvate.
Productive rate: 0.732 gram (theoretical value 74%)
C 13H 16N 2(M＝200.286)
Calculated value: mole peak (M+H) +: 201 experimental values: mole peak (M+H) +: 201
R fValue: 0.5 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
(1.1.h.2-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
50 ℃ and 3 the crust hydrogen under, to 0.73 the gram (3.66 mmole) (4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile and 0.1 the gram the reaction mixture of Raney nickel in the ammonia soln of 25 ml methanolization carried out hydrogenation 9 hours.
Productive rate: 0.72 gram (theoretical value 96.4%)
C 13H 20N 2(M＝204.31)
Calculated value: mole peak (M+H) +: 205 experimental values: mole peak (M+H) +: 205
R fValue: 0.23 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.1.i.4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
At room temperature, stir 4 of 0.4 gram (1.44 mmole) '-HOBT of 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of chloro-3-nitro-xenyl-4-carboxylic acid, 0.29 gram (1.44 mmole), the TBTU of 0.46 gram (1.44 mmole), 0.19 gram (1.44 mmole), and the solution of triethylamine in 30 milliliters of tetrahydrofuran (THF)s of 0.42 milliliter (3 mmole) 14 hours.This reaction mixture of evaporation with water and ethyl acetate extraction, dewaters with sal epsom again in rotatory evaporator.On silica gel, carry out purifying (elutriant: methylene chloride/ammonia=90: 10: 1) with the post chromatography.
Productive rate: 0.47 gram (theoretical value 70.3%)
C 26H 26ClN 3O 3(M＝463.96)
Calculated value: mole peak (M+H) +: 464/466 experimental value: mole peak (M+H) +: 464/466
R fValue: 0.36 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.1.j.4 '-chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
20 ℃ and 3 the crust hydrogen under, to 0.47 the gram (1.01 mmole) 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides and 0.1 the gram the reaction mixture of Raney nickel in the ammonia soln of 50 ml methanolization carried out hydrogenation 24 hours.This raw product is not purified can further to react.
Productive rate: 0.46 gram raw product
C 26H 28ClN 3O(M＝433.98)
Calculated value: mole peak (M+H) +: 434/436 experimental value: mole peak (M+H) +: 434/436
R fValue: 0.34 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
(1.1.k.7-4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
At room temperature, stir 4 of 0.46 gram (1.06 mmole) '-formic acid of chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides and 5 milliliters 3 hours, stirred 2 hours down at 100 ℃ again.This reaction mixture is mixed, with the alkalization of 6N sodium hydroxide solution, suction filtration throw out with water.This throw out is dissolved in the methylene dichloride, and dewaters with sal epsom.Use the rotatory evaporator distillation to remove and desolvate, develop with diisopropyl ether again.
Productive rate: 0.3 gram (theoretical value 64.6%)
Fusing point: 178-179 ℃
C 27H 26ClN 3O(M＝443.98)
Calculated value: mole peak (M+H) +: 444 experimental values: mole peak (M+H) +: 444
R fValue: 0.35 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.2:3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
Figure A0382007600991
1.2.a.4 '-methyl-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 1.1.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 4-methyl-phenyl-boric acid.
Productive rate: 1.48 grams (theoretical value 70.8%)
C 14H 11NO 4(M＝257.24)
Calculated value: mole peak (M-H) -: 256 experimental values: mole peak (M-H) -: 256
R fValue: 0.54 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.2.b.4 '-methyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-methyl-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.51 gram (theoretical value 78.3%)
C 27H 29H 3O 3(M＝443.55)
Calculated value: mole peak (M+H) +: 444 experimental values: mole peak (M+H) +: 444
R fValue: 0.35 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.2.c.4 '-methyl-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.j, by 4 '-methyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.2 gram (theoretical value 69.2%)
C 28H 31N 3O(M＝413.56)
Calculated value: mole peak (M+H): 414 experimental values: mole peak (M+H) +: 414
R fValue: 0.36 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.3:3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazoline-4-one
1.3.a.4 '-trifluoromethyl-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 1.1.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 4-trifluoromethyl-phenyl-boric acid.
Productive rate: 1.24 grams (theoretical value 49%)
C 14H 8F 3NO 4(M＝311.21)
Calculated value: mole peak (M-H) -: 310 experimental values: mole peak (M-H) -: 310
R fValue: 0.3 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.3.b.4 '-trifluoromethyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-trifluoromethyl-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.36 gram (theoretical value 49.3%)
C 27H 26F 3N 3O 3(M＝497.52)
Calculated value: mole peak (M+H) +: 498 experimental values: mole peak (M+H) +: 498
R fValue: 0.3 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.3.c 4 '-trifluoromethyl-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
20 ℃ and 3 the crust under, to 0.1 the gram (0.2 mmole) 4 '-trifluoromethyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides and 0.08 the gram the reaction mixture of platinum oxide in 50 milliliters of ethyl acetate carried out hydrogenation 2.5 hours.Filtration catalizer.On silica gel, carry out purifying (elutriant: methylene chloride/ammonia=90: 10: 1) with the post chromatography.
Productive rate: 0.06 gram (theoretical value 63.8%)
C 27H 28F 3N 3O(M＝467.53)
Calculated value: mole peak (M+H) +: 468 experimental values: mole peak (M+H) +: 468
R fValue: 0.46 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.4:7-(4-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
1.4.a.4 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 1.1.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 4-methoxyl group-phenyl-boric acid:
Productive rate: 0.38 gram (theoretical value 48.9%)
C 14H 11NO 5(M＝273.24)
Calculated value: mole peak (M-H) -: 272 experimental values: mole peak (M-H) -: 272
R fValue: 0.39 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.4.b.4 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.j, by 4 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.23 gram (theoretical value 57%)
C 27H 29N 3O 4(M＝459.55)
Calculated value: mole peak (M+H) +: 460 experimental values: mole peak (M+H) +: 460
R fValue: 0.48 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.4.c.4 '-methoxyl group-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3.c, by 4 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.09 gram (theoretical value 42%)
C 27H 31N 3O 2(M＝429.56)
Calculated value: mole peak (M+H) +: 430 experimental values: mole peak (M+H) +: 430
R fValue: 0.44 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.5:
7-(3,4-two chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007601021
1.5.a.3 ', 4 '-two chloro-3-nitro-xenyl-4-carboxylic acids
Be similar to embodiment 1.1.b, by 4-bromo-2-nitro-phenylformic acid and 3,4-two chloro-phenyl-boric acid are prepared.
Productive rate: 0.72 gram (theoretical value 28.4%)
C 13H 7Cl 2NO 4(M＝312.11)
Calculated value: mole peak (M-H) -: 310/312/314 experimental value: mole peak (M-H) -: 310/312/314
R fValue: 0.39 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.5.b 3 ', 4 '-two chloro-3-nitro-xenyl-4-carboxylic acids-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 3 ', 4 '-two chloro-3-nitro-xenyl-4-carboxylic acids and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.47 gram (theoretical value 64.2%)
C 26H 25Cl 2N 3O 3(M＝-498.41)
Calculated value: mole peak (M+H) +: 498/500/502 experimental value: mole peak (M+H) +: 498/500/502
R fValue: 0.24 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.5.c.3 ', 4 '-two chloro-3-amino-xenyl-4-carboxylic acids-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3, c, by 3 ', 4 '-two chloro-3-nitro-xenyl-4-carboxylic acids-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.11 gram (theoretical value 25%)
C 26H 27Cl 2N 3O(M＝468.43)
Calculated value: mole peak (M+H) +: 468/470/472 experimental value: mole peak (M+H) +: 468/470/472
R fValue: 0.46 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.6:
7-(3-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
1.6.a.3 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 1.1.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 3-methoxyl group-phenyl-boric acid.
Productive rate: 0.39 gram (theoretical value 73.6%)
C 14H 11NO 5(M＝273.24)
Calculated value: mole peak (M+H) +: 274 experimental values: mole peak (M+H) +: 274
R fValue: 0.35 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.6.b.3 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 3 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.39 gram (theoretical value 57%)
C 27H 29N 3O 4(M＝459.55)
Calculated value: mole peak (M+H) +: 460 experimental values: mole peak (M+H) +: 460
R fValue: 0.23 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.6.c.3 '-methoxyl group-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.j, by 3 '-methoxyl group-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.11 gram (theoretical value 30.6%)
C 27H 31N 3O 2(M＝429.56)
Calculated value: mole peak (M+H) +: 430 experimental values: mole peak (M+H) +: 430
R fValue: 0.36 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.7:
7-(4-fluoro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007601041
1.7.a 4 '-fluoro-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 11.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 4-fluoro-phenyl-boric acid.
Productive rate: 1.3 grams (theoretical value 61.2%)
C 13H 8FNO 4(M＝261.21)
Calculated value: mole peak (M-H) -: 260 experimental values: mole peak (M-H) -: 260
R fValue: 0.34 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.7.b.4 '-fluoro-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-fluoro-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.38 gram (theoretical value 57.8%)
C 26H 26FN 3O 3(M＝447.51)
Calculated value: mole peak (M+H) +: 448 experimental values: mole peak (M+H) +: 448
R fValue: 0.24 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.7.c.4 '-fluoro-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3.c, by 4 '-fluoro-3-nitro-xenyl-4-carboxylic acid-[2-(4-Pyrrolizidine-1-ylmethyl-phenyl)-ethyl]-acid amides and being prepared.
Productive rate: 0.06 gram (theoretical value 32%)
C 26H 28FN 3O(M＝417.53)
Calculated value: mole peak (M+H) +: 418 experimental values: mole peak (M+H) +: 418
R fValue: 0.63 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.8:
7-(4-ethyl-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
1.8.a 4 '-vinyl-3-nitro-xenyl-4-carboxylic acid
Be similar to embodiment 1.1.b, be prepared by 4-bromo-2-nitro-phenylformic acid and 4-vinyl-phenyl-boric acid.
Productive rate: 0.58 gram (theoretical value 53%)
C 15H 11NO 4(M＝269.25)
Calculated value: mole peak (M-H) -: 268 experimental values: mole peak (M-H) -: 268
R fValue: 0.39 (silica gel, methylene chloride/acetic acid 9: 1: 0.1)
1.8.b.4 '-vinyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-vinyl-3-nitro-xenyl-4-carboxylic acid and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.38 gram (theoretical value 56.8%)
C 28H 29N 3O 3(M＝455.56)
Calculated value: mole peak (M+H) +: 456 experimental values: mole peak (M+H) +: 456
R fValue: 0.21 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.8.c.4 '-ethyl-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3, c, by 4 '-vinyl-3-nitro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.15 gram (theoretical value 63.9%)
C 28H 33N 3O(M＝427.56)
Calculated value: mole peak (M+H) +: 428 experimental values: mole peak (M+H) +: 428
R fValue: 0.47 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Following compound is to be similar to embodiment 1.1.k and to be prepared:
Figure A0382007601061
Embodiment ??R 20 Educt Total chemical formula Mass spectrum Fusing point [℃] ??R fValue
????1.1 4-chloro-phenyl ????1.1.k ??C 27H 26ClN 3O ??444[M+H] + ??178-179 ??0.35(A)
????1.2 4-methyl-phenyl ????1.2.c ??C 28H 29N 3O ??424[M+H] + ??157-158 ??0.36(A)
????1.3 4-trifluoromethyl-phenyl ????1.3.c ??C 28H 26F 3N 3O ??478[M+H] + ??179-181 ??0.4(A)
????1.4 4-methoxyl group-phenyl ????1.4.c ??C 28H 29N 3O 2 ??440[M+H] + ??143-144 ??0.37(A)
????1.5 3,4-two chloro-phenyl ????1.5.c ??C 27H 25Cl 2N 3O ??478/80/82[M+H] + ??148-149 ??0.36(A)
????1.6 3-methoxyl group-phenyl ????1.6.c ??C 28H 28N 3O 2 ??440[M+H] + The wax shape ??0.14(A)
????1.7 4-fluoro-phenyl ????1.7.c ??C 27H 26FN 3O ??428[M+H] + ??160-161 ??0.45(A)
????1.8 4-ethyl-phenyl ????1.8.c ??C 29H 31N 3O ??438[M+H] + ??165-166 ??0.37(A)
R fValue: A=(silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.9:
1.9.a 7-(4-trifluoromethyl-phenyl)-2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Make 4 of 0.07 gram (0.15 mmole) '-vlil of trifluoromethyl-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides (with reference to embodiment 1.3.c) in 4 milliliters of acetate and 0.028 milliliter of (0.3 mmole) diacetyl oxide 12 hours.Dilute this reaction soln with water, be adjusted to pH8, extract with methylene dichloride again with diluted sodium hydroxide solution.With sal epsom this organic phase is dewatered.On silica gel, carry out purifying (elutriant: methylene chloride/ammonia 90: 10: 1) with the post chromatograph.
Productive rate: 0.008 gram (theoretical value 11%)
C 29H 28F 3N 3O(M＝491.56)
Calculated value: mole peak (M+H) +: 492 experimental values: mole peak (M+H) +: 492
R fValue: 0.36 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Following compounds is similar to embodiment 1.9a and is prepared:
Figure A0382007601071
Example ??R 20 Educt Total chemical formula Mass spectrum Fusing point [℃] ????R fValue
1.9 4-trifluoromethyl-phenyl ??1.3.c ????C 29H 28F 3N 3O ????492[M+H] - The wax shape ????0.36(A)
1.10 4-methyl-phenyl ??1.2.c ????C 29H 3lN 3O ????437[M+H] + The wax shape ????0.66(A)
1.11 4-chloro-phenyl ??1.1.j ????C 28H 28CIN 3O ????458/60[M+H] + ????160-163 ????0.40(A)
R fValue: A=(silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.10:2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
Embodiment 1.11:7-(4-chloro-phenyl)-2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Embodiment 1.12:
Figure A0382007601072
1.12a 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-1H-quinazoline-2, the 4-diketone
Make 0.3 gram (0.69 mmole) 4 '-vlil of CDI in 50 milliliters of tetrahydrofuran (THF)s 24 hours of chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides (with reference to embodiment 1.1.j) and 0.1 gram (0.65 mmole).Then add the CDI of other 0.1 gram, and this reaction mixture reheat was refluxed 24 hours.This reaction mixture of evaporation on rotatory evaporator.On silica gel, carry out purifying (elutriant: methylene chloride/ammonia 60: 1: 0.1) with the post chromatography.
Productive rate: 0.2 gram (theoretical value 62.9%)
Fusing point: 274-276 ℃
C 27H 26ClN 3O 2(M＝459.98)
Calculated value: mole peak (M+H) +: 460/462 experimental value: mole peak (M+H) +: 460/462
R fValue: 0.1 (silica gel, methylene chloride/ammonia 50: 1: 0.1)
Embodiment 1.13:
7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(1.13.a[4-2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-acetonitrile
Be similar to embodiment 1.1.g, by 2-(S)-methoxymethyl-tetramethyleneimine and (4-brooethyl-phenyl)-acetonitrile and be prepared.
Productive rate: 0.9 gram (theoretical value 51.6%)
C 15H 20N 2O 5(M＝244.33)
Calculated value: mole peak (M+H) +: 245 experimental values: mole peak (M+H) +: 245
R fValue: 0.3 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.13.b 2-[4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethamine
Be similar to embodiment 1.1, h is prepared by [4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-acetonitrile.
Productive rate: 0.5 gram (theoretical value 54.7%)
C 15H 24N 2O(M＝248.37)
Calculated value: mole peak (M+H) +: 249 experimental values: mole peak (M+H) +: 249
R fValue: 0.3 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.13.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethamine is prepared.
Productive rate: 0.5 gram (theoretical value 54.7%)
C 28H 30CIN 3O 4(M＝508.02)
Calculated value: mole peak (M+H) +: 508/510 experimental value: mole peak (M+H) +: 508/510
R fValue: 0.6 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.13d.4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[4-(2-(S)-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.24 gram (theoretical value 51%)
C 28H 32CIN 3O 2(M＝478.03)
Calculated value: mole peak (M+H) +: 478/480 experimental value: mole peak (M+H) +: 478/480
R fValue: 0.2 (silica gel, methylene chloride/ammonia 10: 1: 0.1)
Embodiment 1.14:
7-(4-chloro-phenyl)-3-[2-(4-dimethylamino methyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007601091
(1.14.a 4-dimethylamino methyl-phenyl)-acetonitrile
Be similar to embodiment 1.1.g, be prepared by dimethylamine and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 1.0 grams (theoretical value 30%)
C 11H 14N 2(M＝174.24)
Calculated value: mole peak (M+H) +: 175 experimental values: mole peak (M+H) +: 175
R fValue: 0.2 (silica gel, hexanaphthene/acetate acetate 1: 1)
(1.14.b2-4-dimethylamino methyl-phenyl)-ethamine
Be similar to embodiment 1.1.h, be prepared by (4-dimethylamino methyl-phenyl)-acetonitrile.
Productive rate: 1.0 gram raw products
C 11H 18N 2(M＝178.28)
Calculated value: mole peak (M+H) +: 179 experimental values: mole peak (M+H) +: 179
R fValue: 0.2 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.14c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-dimethylamino methyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-(4-dimethylamino methyl-phenyl)-ethamine is prepared.
Productive rate: 0.5 gram (theoretical value 63.4%)
C 24H 24ClN 3O 3(M＝437.93)
Calculated value: mole peak (M+H) +: 438/440 experimental value: mole peak (M+H) +: 438/440
R fValue: 0.35 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.14.d.4 '-chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-dimethylamino methyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-dimethylamino methyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.2 gram (theoretical value 43%)
C 24H 26ClN 3O(M＝407.94)
Calculated value: mole peak (M+H) +: 408/410 experimental value: mole peak (M+H) +: 408/410
R fValue: 0.2 (silica gel, methylene chloride/ammonia 20: 1: 0.1)
Embodiment 1.15:
7-(4-chloro-phenyl)-3-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007601101
(1.15a 4-piperidines-1-ylmethyl-phenyl)-acetonitrile
Be similar to embodiment 1.1g, be prepared by piperidines and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 1.6 grams (theoretical value 39%)
C 14H 18N 2(M＝214.31)
Calculated value: mole peak (M+H) +: 215 experimental values: mole peak (M+H) +: 215
R fValue: 0.4 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.15.b 2-(4-piperidines-1-ylmethyl-phenyl)-ethamine
Be similar to embodiment 1.1h, be prepared by (4-piperidines-1-ylmethyl-phenyl)-acetonitrile.
Productive rate: 1.4 grams (theoretical value 85.9%)
C 14H 22N 2(M＝218.34)
Calculated value: mole peak (M+H) +: 219 experimental values: mole peak (M+H) +: 219
R fValue: 0.2 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.15.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-(4-piperidines-1-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.07 gram (theoretical value 40.7%)
C 27H 28ClN 3O 3(M＝477.99)
Calculated value: mole peak (M+H) +: 478/480 experimental value: mole peak (M+H) +: 478/480
R fValue: 0.5 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
1.15.d.4 '-chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3, c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.05 gram (theoretical value 76.4%)
C 27H 30ClN 3O(M＝448.01)
Embodiment 1.16:
7-(4-chloro-phenyl)-3-[2-(4-morpholine-4-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
Figure A0382007601111
(1.16.a 4-morpholine-4-ylmethyl-phenyl)-acetonitrile
Be similar to embodiment 1.1.g, be prepared by morpholine and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 1.63 grams (theoretical value 98.9%)
C 13H 16N 2O(M＝216.28)
Calculated value: mole peak (M+H) +: 217 experimental values: mole peak (M+H) +: 217
R fValue: 0.33 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.16.b 2-(4-morpholine-4-ylmethyl-phenyl)-ethamine
Be similar to embodiment 1.1.h, be prepared by (4-morpholine-4-ylmethyl-phenyl)-acetonitrile.
Productive rate: 1.65 grams (theoretical value 99.4%)
C 13H 20N 2O(M＝220.31)
Calculated value: mole peak (M+H) +: 221 experimental values: mole peak (M+H) +: 221
R fValue: 0.54 (silica gel, methylene dichloride/ethanol/ammonia 9: 1: 0.1)
1.16.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-morpholine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-(4-morpholine-4-ylmethyl-phenyl)-ethamine is prepared.
Productive rate: 0.53 gram (theoretical value 76.6%)
C 26H 26ClN 3O 4(M＝479.97)
Calculated value: mole peak (M+H) +: 480/482 experimental value: mole peak (M+H) +: 480/482
R fValue: 0.5 (silica gel, methylene dichloride/ethanol/ammonia 90: 1: 0.1)
1.16.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-morpholine-4-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-[2-(4-morpholine-4-ylmethyl-phenyl)-ethyl]-acid amides is prepared.
Productive rate: 0.45 gram (theoretical value 90.6%)
C 26H 28ClN 3O 2(M＝449.98)
Calculated value: mole peak (M+H) +: 450/452 experimental value: mole peak (M+H) +: 450/452
R fValue: 0.67 (silica gel, methylene dichloride/ethanol/ammonia 90: 1: 0.1)
Following compounds is to be similar to embodiment 1.1k to be prepared:
Figure A0382007601121
R fValue: A=(silica gel, methylene chloride/ammonia 9: 1: 0.1)
C=(silica gel, methylene chloride/ammonia 10: 1: 0.1)
D=(silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
Embodiment 1.17 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-the 3H-quinazoline-4-one
(1.17a 6-chloro-pyridin-3-yl)-acetonitrile
The 2-chloro-5-chloromethyl-pyridines of 7.5 grams (41.66 mmole) are dissolved in sodium cyanides that 100 milliliters of solution in the ethanol dropwise add the potassiumiodide of 6.91 grams (41.66 mmole) and 2.24 grams (49.01 mmole) to be dissolved in the solution in 400 milliliters the ethanol/water mixture (9: 1).Then, this reaction mixture is heated to 85 ℃ 5 hours.Under vacuum, fully distill to remove and desolvate, again with water and this resistates of ethyl acetate extraction.Clean this organic phase three times with water, dewater with sodium sulfate again.On silica gel, carry out purifying (elutriant: methylene dichloride/ethanol) with the post chromatography.
Productive rate: 2.9 grams (theoretical value 45.6%)
C 7H 5ClN 2(M＝152.58)
Calculated value: mole peak (M+H) +: 151/153 experimental value: mole peak (M+H) +: 151/153
(1.17.b[6-4-methyl-piperazine-1-yl)-pyridin-3-yl]-acetonitrile
In microwave oven, with the triethylamine of (6-chloro-pyridin-3-yl)-acetonitrile, 5.27 milliliters (38 mmoles) of 2.9 grams (19 mmole), and the N methyl piperazine of 2.1 milliliters (19 mmoles) be dissolved in 50 milliliters of solution in the propyl carbinol 180 ℃ of heating 2 hours.Distillation removes and desolvates under vacuum, and resistates is suspended in water, and extracts with ethyl acetate again.The organic phase that merges with water extraction three times is dewatered with sodium sulfate again.On Alox, carry out purifying (elutriant: petrol ether/ethyl acetate 1: 1) with the post chromatography.
Productive rate: 1 gram (theoretical value 24.6%)
Fusing point: 58-59 ℃
C 12H 16N 4(M＝126.28)
Calculated value: mole peak (M+H) +: 217 experimental values: mole peak (M+H) +: 217
R fValue: 0.35 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.17.c 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethamine
Be similar to embodiment 1.1.i, be prepared by [6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-acetonitrile.
Productive rate: 0.94 gram (theoretical value 96%)
C 12H 20N 4(M＝220.32)
Calculated value: mole peak (M+H) +: 221 experimental values: mole peak (M+H) +: 221
1.17.d 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-acid amides
Be similar to embodiment 1.1.j, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethamine is prepared.
Productive rate: 0.48 gram (theoretical value 36.7%)
Fusing point: 158-159 ℃
C 25H 26ClN 5O 3(M＝479.97)
Calculated value: mole peak (M+H) +: 480/482 experimental value: mole peak (M+H) +: 480/482
1.17.e 4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-acid amides is prepared.
Productive rate: 0.12 gram (theoretical value 64%)
Fusing point: 198-199 ℃
C 25H 28ClN 5O(M＝449.98)
Calculated value: mole peak (M+H) +: 450/452 experimental value: mole peak (M+H) +: 450/452
1.17.f 7-(4-chloro-phenyl)-3-2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-the 3H-quinazoline-4-one
Be similar to embodiment 1.1.1, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-acid amides is prepared.
Productive rate: 0.06 gram (theoretical value 53.5%)
Fusing point: 263-264 ℃
C 26H 26ClN 5O(459.98)
Calculated value: mole peak (M+H) +: 460/462 experimental value: mole peak (M+H) +: 460/462
Embodiment 1.18 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-3H-benzo [d] [1,2,3] triazine-4-ketone
Figure A0382007601151
1.18.a 7-(4-chloro-phenyl)-3-{2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Under the temperature between 0 ℃ and 5 ℃, with the Sodium Nitrite of 0.09 gram (0.93 mmole) be dissolved in solution in 2 ml waters dropwise add 4 of 0.27 gram (0.62 mmole) '-chloro-3-amino-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides (with reference to embodiment 1.1.j) is dissolved in the solution in 10 ml methanol and the 1N hydrochloric acid.Then, at room temperature stirred this reaction mixture 3 hours, alkalize again with the dilution of 30 milliliters water, and with ammonia soln.With this aqueous solution of ethyl acetate extraction.Clean the organic phase three times of this merging with water, dewater, it is filtered by activated carbon with sodium sulfate.Remove and desolvate, again with diisopropyl ether erase residual thing.
Productive rate: 0.09 gram (theoretical value 32.5%)
Fusing point: 151-152 ℃
C 26H 25ClN 4O(M＝444.96)
Calculated value: mole peak (M+H) +: 445/447 experimental value: mole peak (M+H) +: 445/447
R fValue: 0.35 (silica gel, methylene dichloride/ethanol 10: 1)
Embodiment 1.19 7-(4-chloro-phenyl)-3-(4-tetramethyleneimine-1-ylmethyl-benzyl)-3H-benzo [d] [1,2,3] triazine-4-ketone
1.19a 4-(1-tetramethyleneimine-1-base-ethyl)-benzonitrile
Be similar to embodiment 1.1g, be prepared by piperidines and 4-brooethyl-benzonitrile.
Productive rate: 2.4 grams (theoretical value 85.9%)
C 12H 14N 2(M＝186.25)
Calculated value: mole peak (M+H) +: 187 experimental values: mole peak (M+H) +: 187
R fValue: 0.63 (silica gel, methylene chloride/ammonia=8: 2: 1)
1.19.b 4-(1-tetramethyleneimine-1-base-ethyl)-benzylamine
Be similar to embodiment 1.1.h, be prepared by 4-(1-tetramethyleneimine-1-base-ethyl)-benzonitrile.
Productive rate: 2.42 grams (theoretical value 98.7%)
C 12H 18N 2(M＝190.29)
Calculated value: mole peak (M+H) +: 191 experimental values: mole peak (M+H) +: 191
R fValue: 0.26 (silica gel, methylene chloride/ammonia 90: 10: 1)
1.19c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-4-(1-tetramethyleneimine-1-base-ethyl)-benzyl acid amides
Be similar to embodiment 1.1.i, by 4 '-(4-4-(1-tetramethyleneimine-1-base-ethyl)-benzylamine is prepared for chloro-3-nitro-xenyl-4-carboxylic acid and 2-.
Productive rate: 0.28 gram (theoretical value 28.8%)
C 25H 24ClN 3O 3(M＝449.94)
Calculated value: mole peak (M+H) +: 450/452 experimental value: mole peak (M+H) +: 450/452
1.19.d.3-amino-4 '-chloro-xenyl-4-carboxylic acid-4-(1-tetramethyleneimine-1-base-ethyl)-benzyl acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-4-(1-tetramethyleneimine-1-base-ethyl)-benzyl acid amides is prepared.
Productive rate: 0.19 gram (theoretical value 72.7%)
C 25H 25ClN 3O(M＝419.95)
Calculated value: mole peak (M+H) +: 420/422 experimental value: mole peak (M+H) +: 420/422
1.19.e 7-(4-chloro-phenyl)-3-[4-(1-tetramethyleneimine-1-base ethyl)-benzyl]-3H-benzo [d] [1,2,3] triazine-4-ketone
Be similar to embodiment 1.18a, by 3-amino-4 '-chloro-xenyl-4-carboxylic acid-4-(1-tetramethyleneimine-1-base-ethyl)-benzyl acid amides is prepared.
Productive rate: 0.045 gram (theoretical value 31.4%)
Fusing point: 147-148 ℃,
C 25H 23ClN 4O(M＝430.94)
Calculated value: mole peak (M+H) +: 431/433 experimental value: mole peak (M+H) +: 431/433
R fValue: 0.3 (silica gel, methylene dichloride/ethanol=10: 1)
Embodiment 1.20 5-(4-fluoro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-isoindole-1, the 3-diketone
1.20.a 5-bromo-2-{2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-isoindole-1, the 3-diketone
With the 5-bromo-isobenzofuran-1 of 0.8 gram (3.52 mmole), 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (with reference to embodiment 1.1.h) of 3-diketone and 0.72 gram (3.52 mmole) is dissolved in 10 milliliters of solution in the acetic acid and heated 4 hours down at 100 ℃.Then this reaction mixture is poured in the water,, leached throw out again, clean this throw out for several times, carry out drying again with water with the alkalization of 2N sodium hydroxide solution.
Productive rate: 0.5 gram (theoretical value 34.3%)
C 21H 21BrN 2O 2(M＝413.31)
Calculated value: mole peak (M+H) +: 413/415 experimental value: mole peak (M+H) +: 413/415
1.20.b 5-(4-fluoro-phenyl)-2-{2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-isoindole-1, the 3-diketone
Be similar to embodiment 1.1.b, by 5-bromo-2-{2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-isoindole-1,3-diketone and 4-fluoro-phenyl-boron dihydroxide are prepared.
Productive rate: 0.01 gram (theoretical value 4.8%)
C 27H 25FN 2O 2(M＝428.51)
Calculated value: mole peak (M+H) +: 429 experimental values: mole peak (M+H) +: 429
Embodiment 1.21
7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
Figure A0382007601172
(1.21.a[4-4-phenyl-piperidines-1-ylmethyl)-phenyl] acetonitrile
Be similar to embodiment 1.1.g, be prepared by 4-phenyl-piperidines and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 3.8 grams (theoretical value 98%)
C 20H 22N 2(M＝290.41)
Calculated value: mole peak (M+H) +: 291 experimental values: mole peak (M+H) +: 291
R fValue: 0.5 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.21.b 2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethamine
Be similar to embodiment 1.1.h, be prepared by [4-(4-phenyl-piperidines-1-ylmethyl)-phenyl] acetonitrile.
Productive rate: 3.6 gram raw products
C 20H 26N 2(M＝294.44)
Calculated value: mole peak (M+H) +: 295 experimental values: mole peak (M+H) +: 295
R fValue: 0.49 (silica gel, methylene dichloride/ethanol 20: 1)
1.21.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethamine is prepared.
Productive rate: 1.33 grams (theoretical value 70.7%)
C 33H 32ClN 3O 3(M＝554.09)
Calculated value: mole peak (M+H) +: 554/556 experimental value: mole peak (M+H) +: 554/556
R fValue: 0.58 (silica gel, methylene dichloride/ethanol/ammonia 10: 1: 0.1)
1.21.d.4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.82 gram (theoretical value 65.2%)
C 33H 34ClN 3O 3(M＝524.11)
Calculated value: mole peak (M+H) +: 524/526/528 experimental value: mole peak (M+H) +: 524/526/528
R fValue: 0.65 (silica gel, methylene chloride 10: 1)
Embodiment 1.22:
7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
Figure A0382007601191
(1.22.a[4-4-phenyl-Piperazine-1-ylmethyl)-phenyl] acetonitrile
Be similar to embodiment 1.1.g, be prepared by 4-phenylpiperazine and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 3.7 grams (theoretical value 97%)
C 19H 21N 3(M＝291.39)
Calculated value: mole peak (M+H) +: 292 experimental values: mole peak (M+H) +: 292
R fValue: 0.6 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.22.b 2-[4-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-ethamine
Be similar to embodiment 1.1.h, be prepared by [4-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-acetonitrile
Productive rate: 1.1 grams (theoretical value 28.6%)
C 19H 25N 3(M＝295.43)
Calculated value: mole peak (M+H) +: 296 experimental values: mole peak (M+H) +: 296
1.22.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[4-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[4-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-ethyl }-amine is prepared.
Productive rate: 0.32 gram (theoretical value 18.2%)
C 32H 31ClN 4O 3(M＝555.08)
Calculated value: mole peak (M+H) +: 555/557 experimental value: mole peak (M+H) +: 555/557
1.22.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[4-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 1.11 grams (theoretical value 38.8%)
C 32H 33ClN 4O(M＝525.09)
Calculated value: mole peak (M+H) +: 525/527 experimental value: mole peak (M+H) +: 525/527
Embodiment 1.23:
7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(1.23.a[4-4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-acetonitrile
Be similar to embodiment 1.1.g, be prepared by 4-hydroxy-4-phenyl-piperidines and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 3.8 grams (theoretical value 98%)
C 20H 22N 2O(M＝306.41)
Calculated value: mole peak (M+H) +: 307 experimental values: mole peak (M+H) +: 307
R fValue: 0.1 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.23.b 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethamine
Be similar to embodiment 1.1.h, be prepared by [4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-acetonitrile
Productive rate: 3.36 grams (theoretical value 92.1%)
C 20H 26N 2O(M＝310.44)
Calculated value: mole peak (M+H) +: 311 experimental values: mole peak (M+H) +: 311
R fValue: 0.1 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.23.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethamine is prepared.
Productive rate: 1.2 grams (theoretical value 65.3%)
C 33H 32ClN 3O 4(M＝570.09)
Calculated value: mole peak (M+H) +: 570/572 experimental value: mole peak (M+H) +: 570/572
R fValue: 0.35 (silica gel, methylene chloride/ammonia 10: 1: 0.1)
1.23.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 1.04 grams (theoretical value 91.5%)
C 33H 34ClN 3O 2(M＝540.11)
Fusing point: 175-180 ℃
Calculated value: mole peak (M+H) +: 540/542/544 experimental value: mole peak (M+H) +: 540/542/544
R fValue: 0.34 (silica gel, methylene chloride/ammonia 10: 1: 0.1)
1.23.e 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
Be similar to embodiment 1.1.k, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.025 gram (theoretical value 8.2%)
Fusing point: 204-205 ℃
C 34H 32ClN 3O 2(M＝550.10)
Calculated value: mole peak (M+H) +: 550/552 experimental value: mole peak (M+H) +: 550/552
R fValue: 0.46 (silica gel, methylene dichloride/ethanol/ammonia 10: 1: 0.1)
Embodiment 1.24:
7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
1.24.a 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
Be similar to embodiment 1.1.k, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared, the by product of 123.e as an example.
Productive rate: 0.08 gram (theoretical value 27.1%)
Fusing point: 166-167 ℃
C 34H 30ClN 3O(M＝532.09)
Calculated value: mole peak (M+H) +: 532/534 experimental value: mole peak (M+H) +: 532/534
R fValue: 0.57 (silica gel, methylene dichloride/ethanol/ammonia 10: 1: 0.1)
Embodiment 1.25:
7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
Figure A0382007601221
(1.25.a[4-3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl] acetonitrile
Be similar to embodiment 1.1.g, be prepared by 3-azepine-spiral shell [5.5] undecane and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 3.38 grams (theoretical value 98%)
C 19H 26N 2(M＝282.43)
Calculated value: mole peak (M+H) +: 283 experimental values: mole peak (M+H) +: 283
R fValue: 0.56 (silica gel, cyclohexane/ethyl acetate 1: 1)
1.25.b 2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethamine
Be similar to embodiment 1.1.h, be prepared by [4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-acetonitrile
Productive rate: 3.33 grams (theoretical value 96.6%)
C 19H 30N 2(M＝286.46)
Calculated value: mole peak (M+H) +: 287 experimental values: mole peak (M+H) +: 287
R fValue: 0.18 (silica gel, methylene chloride 20: 1)
1.25.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethamine is prepared.
Productive rate: 1 gram (theoretical value 52.5%)
C 32H 36ClN 3O 3(M＝546.11)
Calculated value: mole peak (M+H) +: 546/548 experimental value: mole peak (M+H) +: 546/548
R fValue: 0.3 (silica gel, methylene dichloride/ethanol 20: 1)
1.25.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-{ 2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-acid amides and being prepared.
Productive rate: 0.8 gram (theoretical value 84.7%)
C 32H 38ClN 3O(M＝516.13)
Calculated value: mole peak (M+H) +: 516/518 experimental value: mole peak (M+H) +: 516/518
R fValue: 0.38 (silica gel, methylene chloride/10: 1)
Embodiment 1.26:
7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethyl)-the 3H-quinazoline-4-one
Figure A0382007601231
(1.26.a{4-[4-pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-acetonitrile
Be similar to embodiment 1.1.g, be prepared by 2-(piperidin-4-yl oxygen base)-pyridine and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 0.91 gram (theoretical value 49.8%)
C 19H 21N 3O(M＝307.39)
Calculated value: mole peak (M+H) +: 308 experimental values: mole peak (M+H) +: 308
R fValue: 0.49 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.26.b 2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethamine
Be similar to embodiment 1.1.h, be prepared by { 4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-acetonitrile
Productive rate: 0.92 gram (theoretical value 99.8%)
C 19H 25N 3O(M＝311.43)
Calculated value: mole peak (M+H) +: 312 experimental values: mole peak (M+H) +: 312
R fValue: 0.16 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.26.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethamine is prepared.
Productive rate: 0.8 gram (theoretical value 97.2%)
C 32H 31ClN 4O 4(M＝571.08)
Calculated value: mole peak (M+H) +: 571/573 experimental value: mole peak (M+H) +: 571/573
R fValue: 0.52 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.26.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides is prepared.
Productive rate: 0.38 gram (theoretical value 50%)
C 32H 33ClN 4O 2(M＝541.09)
Calculated value: mole peak (M+H) +: 541/543 experimental value: mole peak (M+H) +: 541/543
R fValue: 0.5 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 1.27:
7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethyl)-the 3H-quinazoline-4-one
(1.27.a{4-[4-pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-acetonitrile
Be similar to embodiment 1.1.g, be prepared by 2-(piperidin-4-yl amino)-pyridine and (4-brooethyl-phenyl)-acetonitrile.
Productive rate: 1.57 (theoretical values 86.1%)
C 19H 22N 4(M＝306.41)
Calculated value: mole peak (M+H) +: 307 experimental values: mole peak (M+H) +: 307
R fValue: 0.43 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.27.b 2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethamine
Be similar to embodiment 1.1.h, be prepared by { 4-[4-(pyridine-2-base amino)-piperidines-1-ylmethyl]-phenyl }-acetonitrile
Productive rate: 1.62 grams (theoretical value 99.8%)
C 19H 26N 4(M＝310.44)
Calculated value: mole peak (M+H) +: 311 experimental values: mole peak (M+H) +: 311
R fValue: 0.1 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.27.c 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides
Be similar to embodiment 1.1.i, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid and 2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethamine is prepared.
Productive rate: 0.36 gram (theoretical value 43.8%)
C 32H 32ClN 5O 3(M＝570.09)
Calculated value: mole peak (M+H) +: 570/572 experimental value: mole peak (M+H) +: 570/572
R fValue: 0.28 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
1.27.d 4 '-chloro-3-amino-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides
Be similar to embodiment 1.3.c, by 4 '-chloro-3-nitro-xenyl-4-carboxylic acid-(2-{4-[4-(pyridine-2-base is amino)-piperidines-1-ylmethyl]-phenyl }-ethyl)-acid amides is prepared.
Productive rate: 0.29 gram (theoretical value 85.7%)
C 32H 34ClN 5O(M＝540.11)
Calculated value: mole peak (M+H) +: 540/542 experimental value: mole peak (M+H) +: 540/542
R fValue: 0.27 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Following compounds is to be similar to embodiment 1.1.k and to be prepared:
Figure A0382007601261
R fValue: A=(silica gel, methylene chloride/ammonia 9: 1: 0.1)
E=(silica gel, methylene dichloride/ethanol 10: 1)
F=(silica gel, methylene dichloride/ethanol/ammonia 10: 1: 0.1)
Embodiment 1.28
7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Figure A0382007601262
1.28.a 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Be similar to embodiment 1.18.a, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[4-(4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.13 gram (theoretical value 50.9%)
Alkane point: 183-184 ℃
C 33H 31ClN 4O(M＝535.09)
Calculated value: mole peak (M+H) +: 535/537 experimental value: mole peak (M+H) +: 535/537
R fValue: 0.66 (silica gel, methylene dichloride/ethanol=10: 1)
Embodiment 1.29 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Figure A0382007601271
1.29.a 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Be similar to embodiment 1.18.a, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.21 gram (theoretical value 68.7%)
Alkane point: 265-266 ℃
C 33H 31ClN 4O 2(M＝551.09)
Calculated value: mole peak (M+H) +: 551/553 experimental value: mole peak (M+H) +: 551/553
R fValue: 0.53 (silica gel, methylene dichloride/ethanol=10: 1)
Embodiment 1.30 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Figure A0382007601281
1.30.a 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
Be similar to embodiment 1.18.a, by 4 '-chloro-3-amino-xenyl-4-carboxylic acid-{ 2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-acid amides is prepared.
Productive rate: 0.14 gram (theoretical value 54.9%)
Alkane point: 165-166 ℃
C 33H 35ClN 4O(M＝527.11)
Calculated value: mole peak (M+H) +: 527 experimental values: mole peak (M+H) +: 527
R fValue: 0.56 (silica gel, methylene dichloride/ethanol=10: 1)
Embodiment 1.31 6-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2H-isoquinoline 99.9-1-ketone
1.31.a 2-[2-(4-bromo-phenyl)-oxyethyl group]-tetrahydrochysene-pyrans
Under 0 ℃, 2-(4-bromo-phenyl)-ethanol that the right-toluenesulphonic acids and the dihydropyrane of 2.575 milliliters (28.22 Bo moles) of 0.025 gram added 4.83 grams (24.02 mmole) successively are dissolved in 12 milliliters of solution in the methylene dichloride.Then at room temperature stirred this reaction mixture 3 hours.Extract this reaction mixture with sodium hydrogen carbonate solution, with sodium sulfate this organic phase is dewatered again.On Alox, carry out purifying (elutriant: cyclohexane/ethyl acetate=8: 2) with the post chromatograph.
Productive rate: 37 grams (theoretical value 32.8%)
C 13H 17BrO 2(M＝285.18)
Calculated value: mole peak (M+H) +: 284/286 experimental value: mole peak (M+H) +: 284/286
1.31.b 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl]-phenyl aldehyde
Under-70 ℃, 2-[2-(4-bromo-the phenyl)-oxyethyl group that the 1.6M n-butyllithium solution of 11.5 milliliters (18.41 mmoles) is dropwise added 5 grams (17.53 mmole)]-tetrahydrochysene-pyrans is dissolved in 80 milliliters of solution in the tetrahydrofuran (THF), and stirred 1 hour under this temperature.The dimethyl formamide that then dropwise adds 2.8 milliliters (36.46 mmoles), and this reaction mixture of-70 ℃ of following restir 2 hours.This reaction mixture is mixed with ammonium chloride solution, extract with ethyl acetate again.The organic phase that merges with the extraction of saturated sodium chloride solution three times is dewatered with sodium sulfate again.On silica gel, carry out purifying (elutriant: cyclohexane/ethyl acetate=6: 4) with the post chromatograph.
Productive rate: 2.8 grams (theoretical value 68.2%)
C 14H 18O 3(M＝234.29)
Calculated value: mole peak (M+H) +: 235 experimental values: mole peak (M+H) +: 235
R fValue: 0.57 (silica gel, petrol ether/ethyl acetate 3: 1)
1.31.c 4-(2-hydroxyl-ethyl)-phenyl aldehyde
Under 5 ℃, stir 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl of 2.8 grams (11.95 mmole)]-solution of phenyl aldehyde in the mixture of 40 milliliters of 1M hydrochloric acid and 60 milliliters of acetone 5 hours.This reaction mixture is mixed with 140 milliliters saturated sodium bicarbonate solution, extract with ethyl acetate again.The organic phase that merges with water extraction three times is dewatered with sodium sulfate again.On silica gel, carry out purifying (elutriant: cyclohexane/ethyl acetate=6: 4) with the post chromatograph.
Productive rate: 1.3 grams (theoretical value 72.4%)
C 9H 10O 2(M＝150.17)
Calculated value: mole peak (M+H) +: 151 experimental values: mole peak (M+H) +: 151
R fValue: 0.52 (silica gel, petrol ether/ethyl acetate=1: 1)
1.31.d 2-(4-[1.3] diox-2-base-phenyl)-ethanol
Make 9.4 gram (62.59 mmole) 4-(2-hydroxyl-ethyl)-phenyl aldehydes, 15.83 milliliters of (219.07 mmoles) 1, ammediol, the right-toluenesulphonic acids of 0.3 gram, and the suspension reflux of 150 milliliters of toluene 3 hours.Extract this reaction mixture three times with saturated sodium hydrogen carbonate solution, with sodium sulfate this organic layer is dewatered again.
Productive rate: 8 grams (theoretical value 61.4%)
C 12H 16O 3(M＝208.26)
Calculated value: mole peak (M+H) +: 209 experimental values: mole peak (M+H) +: 209
1.31.e methylsulfonic acid-2-(4-[1.3] diox-2-base-phenyl)-ethyl ester
2-(4-[1.3] diox-2-base-phenyl)-ethanol of 8 grams (38.41 mmole) and the triethylamine of 10.65 milliliters (42.25 mmoles) are dissolved in 300 milliliters of methylene dichloride, and 3.27 milliliters of methylsulfonyl chlorides following at 0 ℃ and that be dissolved in 50 milliliters of methylene dichloride mix.At room temperature stirred this reaction mixture 1 hour, and, with sodium sulfate this organic phase was dewatered again with water extraction three times.On silica gel, carry out purifying (elutriant: petrol ether/ethyl acetate 1: 1) with the post chromatograph.
Productive rate: 7.7 grams (theoretical value 70%)
C 13H 18O 5S(M＝286.34)
Calculated value: mole peak (M+H) +: 287 experimental values: mole peak (M+H) +: 287
R fValue: 0.49 (silica gel, petrol ether/ethyl acetate=1: 1)
1.31.f (E)-3-(3-bromo-phenyl)-acryl trinitride
Under 0 ℃, in the solution of 800 milliliters of acetone, dropwise add the Vinyl chloroformate of 11.5 milliliters (121.11 mmoles) at the triethylamine of 25 gram (E)-3-(3-bromo-the phenyl)-vinylformic acid of (111.1 mmole) and 15.26 milliliters (110.10 mmoles).After 1 hour, also under 0 ℃, dropwise adding is dissolved in the gram of 11.45 in 88 ml distilled waters (176.16 mmole) sodiumazide.This reaction mixture is risen again to room temperature, be poured into again in 1.3 liters the frozen water.Leach formed throw out, clean, in circulation ventilation moisture eliminator, under 30 ℃, carry out drying again with water.
Productive rate: 21.1 grams (theoretical value 76.1%)
C 9H 6BrN 3O(M＝252.07)
Calculated value: mole peak (M+H) +: 256/258 experimental value: mole peak (M+H) +: 256/258
R fValue: 0.85 (silica gel, petrol ether/ethyl acetate=1: 1)
1.31.g 6-bromo-2H-isoquinoline 99.9-1-ketone
The phenyl ether of 150 grams and the Tributylamine of 7.08 milliliters (29.75 mmoles) are heated down at 100 ℃.Under this temperature, add (E)-3-(3-bromo-phenyl) acryl trinitride of 5 grams (19.83 mmole), heated 2 hours down at 195-205 ℃ again.Then make this reaction mixture cooling, again refrigerant is poured in the normal hexane.Leach throw out, the mixture with refrigerative normal hexane and ether cleans again.Then in circulation ventilation moisture eliminator, in 50 ℃ of down dry these solids.The mixture of this solid and diisopropyl ether and ethyl acetate is stirred jointly, repeat this drying process again.
Productive rate: 0.6 gram (theoretical value 13.5%)
C 9H 6BrN 3O(M＝224.05)
Calculated value: mole peak (M+H) +: 224/226 experimental value: mole peak (M+H) +: 224/226
1.31.h 6-(4-chloro-phenyl)-2H-isoquinoline 99.9-1-ketone
In microwave oven, 0.57 gram (2.54 mmole) 6-bromo-2H-isoquinoline 99.9-1-ketone, 0.398 gram (254 mmole) 4-chlorophenylboronic acid, 2.6 milliliters of 2M sodium hydrogen carbonate solutions are dissolved in the reaction mixture of 20 milliliters of dioxs and 5 ml methanol 110 ℃ of following heating 2 hours.Then this reaction mixture is poured in the water, leached throw out, in circulation ventilation moisture eliminator, under 40 ℃, carry out drying again.
Productive rate: 0.42 gram (theoretical value 64.6%)
C 15H 10ClNO(M＝255.70)
Calculated value: mole peak (M+H) +: 256/258 experimental value: mole peak (M+H) +: 256/258
R fValue: 0.6 (silica gel, methylene dichloride/ethanol=10: 1)
1.31.i 2-[2-(4-formyl radical-phenyl)-ethyl]-6-(4-chloro-phenyl)-2H-isoquinoline 99.9-1-ketone
Make 6-(4-chloro-the phenyl)-2H-isoquinoline 99.9-1-ketone of 0.41 gram (1.6 mmole) be dissolved in 10 milliliters of solution in the dimethyl formamide, mix with the potassium tert.-butoxide of 0.18 gram (1.6 mmole), and stirred 30 minutes down at 50 ℃.Methylsulfonic acid-2-(4-[1.3] diox-2-base-phenyl)-ethyl ester that then adds 0.46 gram (1.6 mmole).In microwave oven,, then be poured into again in 10% the citric acid solution in 180 ℃ of heating this reaction mixtures 5 hours.Extract with ethyl acetate.Extract this organic phase three times with water, dewater with sodium sulfate again.On silica gel, carry out purifying (elutriant: petrol ether/ethyl acetate=3: 1 to 1: 1) with the post chromatograph
Productive rate: 0.15 gram (theoretical value 24.1%)
C 24H 18ClNO 2(M＝387.87)
Calculated value: mole peak (M+H) +: 388/390 experimental value: mole peak (M+H) +: 388/390
R fValue: 0.7 (silica gel, petrol ether/ethyl acetate=1: 1)
1.31.j 6-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2H-isoquinoline 99.9-1-ketone
2-[2-(4-formyl radical-phenyl)-ethyl with 0.14 gram (0.36 mmole)]-tetramethyleneimine of 6-(4-chloro-phenyl)-2H-isoquinoline 99.9-1-ketone and 0.03 milliliter (0.36 mmole) is dissolved in 40 milliliters of methylene dichloride.With Glacial acetic acid pH is adjusted to 3.Then add the sodium triacetoxy borohydride of 0.076 gram (0.36 mmole), and at room temperature stirred this mixture 48 hours.Then the sodium carbonate solution with 2M extracts this reaction mixture, dewaters with sodium sulfate again.On the silica gel, carry out purifying (elutriant: methylene dichloride/ethanol 10: 1 to 1: 1) with the post look.
Productive rate: 0.04 gram (theoretical value 25%)
Fusing point: 136-137 ℃
C 28H 27ClN 2O(M＝442.99)
Calculated value: mole peak (M+H) +: 443 experimental values: mole peak (M+H) +: 443
R fValue: 0.5 (silica gel, methylene chloride=10: 1)
Following compound is to be similar to embodiment 1.1 to 1.31 to be prepared:
Figure A0382007601321
Embodiment 2.1:
4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.1.a 4 '-chloro-xenyl-4-carboxylic acid
The 4-bromo-phenylformic acid of 5.83 grams (29.0 mmole) are dissolved in the sodium carbonate solution of 50 milliliters of De dioxs and 29 milliliters.Add the 4-chlorophenylboronic acid of 4.5 grams (29.0 mmole) and four-(triphenylphosphine)-palladium of 1.68 grams (1.45 mmole) successively, make this reaction reflux 6 hours again.Make this thermal response solution carry out suction filtration by glass fibre filter.With this filtrate of ethyl acetate extraction.With citric acid this water is carried out acidifying, stirred 1 hour down at 0 ℃ again.Leach the throw out of formation, clean, under vacuum, carry out drying again with water.
Productive rate: 5.1 grams (theoretical value 75.6%)
C 13H 9ClO 2(M＝232.668)
Calculated value: mole peak (M-H) -: 231/233 experimental value: mole peak (M-H) -: 231/233
2.1.b 4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
At room temperature, with the TBTU of 471 milligrams (1.47 mmoles) and the Hunig alkali of 0.26 milliliter (1.47 mmole), join 251 milligrams (1.08 mmoles) 4 '-the suspension solution of chloro-xenyl-4-carboxylic acid in 5 milliliters of THF in.Stir this reaction mixture 10 minutes, and added 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (with reference to example 1.1.h) of 200 milligrams (0.98 mmoles) again.Stir this mixture overnight.Make this reaction soln and saturated HaHCO 3Solution mixture with the ethyl acetate extraction water, dewaters to this organic phase with sal epsom again.Use rotatory evaporator to remove and desolvate, this resistates and t-butyl methyl ether are stirred under heating.Leach the solid of formation, clean with a small amount of t-butyl methyl ether, again at air drying.
Productive rate: 210 milligrams (theoretical value 51.2%)
C 26H 27ClN 2O(M＝418.971)
Calculated value: mole peak (M+H) +: 419/421 experimental value: mole peak (M+H) +: 419/421
R fValue: 0.57 (silica gel, methylene chloride/ammonia 9: 1: 0.1)
Embodiment 2.2:
4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
(2.2.a 4-diethylin methyl-phenyl)-acetonitrile
The diethylamine of 0.88 milliliter (8.38 mmole) is dissolved in 30 milliliters the acetone, adds the salt of wormwood of 2.1 grams (15.2 mmole) and (4-brooethyl-phenyl)-acetonitrile (with reference to 1.1.f) of 1.6 grams (7.62 mmole) more successively.At room temperature stirred this reaction mixture 2 hours, and filtered, clean with ethyl acetate again by frit.This filtrate of evaporation extracts with water and ethyl acetate on rotatory evaporator.With sal epsom this organic phase is dewatered, re-use rotatory evaporator except that desolvating.On silica gel, carry out further purifying (elutriant: methylene dichloride/ethanol 9: 1) with the post chromatograph.
Productive rate: 900 milligrams (theoretical value 58.4%)
C 13H 18N 2(M＝202.30)
Calculated value: mole peak (M+H) +: 203 experimental values: mole peak (M+H) +: 203
R fValue: 0.65 (silica gel, methylene chloride 9: 1)
2.2.b 2-(4-diethylin methyl-phenyl)-ethamine
The solution that (4-diethylin methyl-phenyl)-acetonitrile of 900 milligrams (4.45 mmoles) is dissolved in the ammonia solution of 20 ml methanolization mixes with 100 milligrams of Raney nickel, and in autoclave, shakes under 50 ℃ and 5 crust.After suction filtration is removed catalyzer, use rotatory evaporator to remove and desolvate.
Productive rate: 900 milligrams (theoretical value 98.0%)
C 13H 22N 2(M＝206.334)
Calculated value: mole peak (M+H) +: 207 experimental values: mole peak (M+H) +: 207
R fValue: 0.12 (silica gel, methylene chloride/NH 39: 1: 0.1)
2.2.c 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.1.b, by 4 '-chloro-xenyl-4-carboxylic acid (248 milligrams, 1.07 mmoles) and 2-(4-diethylin methyl-phenyl)-ethamine (200 milligrams, 0.97 mmole) is prepared.
Productive rate: 280 milligrams (theoretical value 68.6%)
C 26H 29ClN 2O(M＝420.987)
Calculated value: mole peak (M+H) +: 421/423 experimental value: mole peak (M+H) +: 421/423
R fValue: 0.49 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.3:4 '-chloro-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601371
2.3.a 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.1.b, by 4 '-chloro-xenyl-4-carboxylic acid (234 milligrams, 1.01 mmoles) and 2-(4-piperidines-1-ylmethyl-phenyl)-ethamine (with reference to 1.15.b, 200 milligrams, 0.92 mmole) be prepared.
Productive rate: 260 milligrams (theoretical value 65.6%)
C 27H 29ClN 2O(M＝432.98)
Calculated value: mole peak (M+H) +: 433/435 experimental value: mole peak (M+H) +: 433/435
R fValue: 0.57 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.4:
4 '-methoxyl group-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
2.4a 1-(4 '-methoxyl group-biphenyl-4-yl)-ethyl ketone
The aluminum chloride that 4-methoxyl group-biphenyl is added 11.3 grams (85.0 mmole) is dissolved in 100 milliliters of solution in the dithiocarbonic anhydride.With this mixture heating up to 40 ℃, add the Acetyl Chloride 98Min. of 6.07 milliliters (81.4 mmoles) more very slowly.Make this reactant reflux 1 hour.After cooling, this reaction soln is added in the concentrated hydrochloric acid of the ice of 100 grams and 25 milliliters.After extracting, this organic phase is dewatered with sal epsom with methylene dichloride.Use rotatory evaporator to remove and desolvate, make this resistates again by carrying out recrystallize in the Virahol.
Productive rate: 8.8 grams (theoretical value 48.0%)
C 15H 14O 2(M＝226.278)
Calculated value: mole peak (M+H) +: 227 experimental values: mole peak (M+H) +: 227
2.4b 4 '-methoxyl group-xenyl-4-carboxylic acid
Under 0 ℃, the NaOH that the bromine of 6.0 milliliters (117 mmoles) is slowly dropwise added 15.6 grams (390.9 mmole) are dissolved in the solution in 70 ml waters.The 1-of 8.8 grams (39.1 mmole) in 50 milliliters of dioxs of then slow adding (4 '-methoxyl group-biphenyl-4-yl)-ethyl ketone.After 3 hours, leach formed solid, it is dissolved in the methylene dichloride, and filters once more.The use rotatory evaporator is removed the solvent in this filtrate.
Productive rate: 9.0 grams (theoretical value 100.0%)
C 15H 14O 2(M＝228.250)
Calculated value: mole peak (M-H) -: 227 experimental values: mole peak (M-H) -: 227
2.4.c 4 '-methoxyl group-xenyl-4-carboxyl acyl chloride
Under 50 ℃, stir 4 of 3.0 grams (0.013 mole) '-methoxyl group-xenyl-4-carboxylic acid is dissolved in 47.4 milliliters of solution in (0.65 mole) thionyl chloride 3 hours.After using rotatory evaporator to remove thionyl chloride, obtain being the product of little yellow solid, be stored in the refrigerator.
Productive rate: 3.2 grams (theoretical value 99.8%)
C 15H 14O 2(M＝246.696)
Calculated value: mole peak (M+H) +Pay attention to disastrously and 46/248 experimental value: mole peak (M+H) +: 246/248
2.4.d 4 '-methoxyl group-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
Under 0 ℃, the chloride of acid of 287 milligrams (1.16 mmoles) is added 2-(4-diethylin methyl-phenyl)-ethamine of 200 milligrams (0.97 mmoles) and the Hunig alkali of 0.25 milliliter (1.45 mmole) is dissolved in 5 milliliters of solution in the methylene dichloride.Stir this reactant and spend the night, then make itself and half saturated NaHCO 3Solution mixes.Clean this water with methylene dichloride, with sal epsom having mutually of this merging dewatered again.After using rotatory evaporator to remove to desolvate, develop this resistates with t-butyl methyl ether, again to the filtration of bleeding of formed solid.
Productive rate: 90 milligrams (theoretical value 22.3%)
C 27H 32N 2O 2(M＝416.568)
Calculated value: mole peak (M+H) +: 417 experimental values: mole peak (M+H) +: 417
R fValue: 0.46 (silica gel, ethyl acetate/methanol/NH 39: 0: 0.1)
Embodiment 2.5:
4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-methyl-acid amides
(2.5.a[2-4-diethylin methyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
2-(4-diethylin methyl-phenyl)-ethamine that the BOC acid anhydride of 815 milligrams (3.73 mmoles) is added 700 milligrams (3.93 mmoles) is dissolved in the solution in 5.0 milliliters of methylene dichloride and 0.52 milliliter of (3.73 mmole) triethylamine, and at room temperature stirs and spend the night.Make this mixture and saturated NaHCO 3Solution mixes.Clean this water with methylene dichloride, with sal epsom the organic phase of this merging is dewatered again.Using rotatory evaporator except that after desolvating, on silica gel, with this resistates of post chromatograph purifying (elutriant: methylene chloride/NH 3=9: 1: 0.1).
Productive rate: 600 milligrams (theoretical value 57.7%)
C 18H 30N 2O 2(M＝306.452)
Calculated value: mole peak (M+H) +: 307 experimental values: mole peak (M+H) +: 307
(2.5.b[2-4-diethylin methyl-phenyl)-ethyl]-methyl-amine
600 milligrams among the THF (1.96 mmoles) [2-(4-diethylin methyl-phenyl)-ethyl]-carboxylamine tertiary butyl ester is slowly dropwise added in the suspension of lithium aluminum hydride in 10 milliliters of tetrahydrofuran (THF)s of 250 milligrams (6.59 mmoles).Stir this reactant and spend the night, and heated 1 hour down at 50 ℃.Add 0.25 milliliter water, 0.25 milliliter 15%NaOH solution, and 0.75 milliliter water and operating successively.After filtering, with sal epsom this organic phase is dewatered, and use rotatory evaporator to remove and desolvate.
Productive rate: 350 milligrams (theoretical value 81.1%)
C 14H 24N 2(M＝220.361)
Calculated value: mole peak (M+H) +: 221 experimental values: mole peak (M+H) +: 221
2.5.c 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-diethylin methyl-phenyl)-ethyl]-methyl-acid amides
Be similar to embodiment 2.1.b, by 4 '-chloro-xenyl-4-carboxylic acid (222 milligrams, 0.95 mmole) and
[2-(4-diethylin methyl-phenyl)-ethyl]-methyl-amine (175 milligrams, 0.79 mmole) and being prepared.
Productive rate: 60 milligrams (theoretical value 17.4%)
C 27H 31ClN 2O(M＝435.014)
Calculated value: mole peak (M+H) +: 435/437 experimental value: mole peak (M+H) +: 435/437
R fValue: 0.39 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.6:
2.6.a 4-(4-chloro-phenyl)-hexahydrobenzoic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4-(4-chloro-phenyl)-hexahydrobenzoic acid (239 milligrams, 1.0 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.0 mmoles) and be prepared.
Productive rate: 65 milligrams (theoretical value 15.3%)
C 26H 33ClN 2O(M＝425.019)
Calculated value: mole peak (M+H) +: 425/427 experimental value: mole peak (M+H) +: 425/427
R fValue: 0.3 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.7:
4-piperidines-1-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007601411
2.7.a 4-piperidines-1-base-ethyl benzoate
0.41 milliliter piperidines is added in the suspension of salt of wormwood in 20 milliliters of DMSO of the 4-fluoro-ethyl benzoate of 0.5 milliliter (4.13 mmole) and 571 milligrams (4.13 mmoles).Stir this reaction mixture that spends the night down at 70 ℃, add the piperidines of other 1 milliliter (2.44 mmole), continue to stir 6 hours down at 70 ℃ again.After filtration, add entry, with this mixture of ethyl acetate extraction, separate this organic phase, re-use rotatory evaporator except that desolvating.This product is not purified promptly further to react.
Productive rate: 706 milligrams (theoretical value 73.2%)
C 14H 19NO 2(M＝233.313)
Calculated value: mole peak (M+H) +: 234 experimental values: mole peak (M+H) +: 234
HPLC dead time: 6.2 minutes (method A)
2.7.b 4-piperidines-1-base-phenylformic acid
4-piperidines-1-base-the ethyl benzoate that the 2N NaOH of 0.78 milliliter (0.74 mmole) is added 350 milligrams (1.50 mmoles) is dissolved in 10 milliliters of solution in the ethanol.Stir this reaction soln 2 hours down at 60 ℃, with 1N HCl pH is adjusted to 6-7 again.Under high vacuum, carrying out the formed throw out of dried overnight after the filtration.
Productive rate: 158 milligrams (theoretical value 51.3%)
C 12H 15NO 2(M＝205.259)
Calculated value: mole peak (M+H) +: 206 experimental values: mole peak (M+H) +: 206
HPLC dead time: 6.2 minutes (method A)
2.7.c 4-piperidines-1-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl (ethamine (157 milligrams, 0.77 mmole) and 4-piperidines-1-base-phenylformic acid (158 milligrams, 0.77 mmole) and be prepared.
Productive rate: 102 milligrams (theoretical value 33.8%)
C 25H 33N 3O(M＝391.561)
Calculated value: mole peak (M+H) +: 392 experimental values: mole peak (M+H) +: 392
HPLC dead time: 4.4 minutes (method A)
Embodiment 2.8:
2.8.a 4-benzyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I mentioned above, by xenyl methane-4-carboxylic acid (104 milligrams, 0.49 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (100 milligrams, 0.49 mmole) and be prepared.
Productive rate: 66 milligrams (theoretical value 33.9%)
C 27H 30N 2O(M＝398.553)
Calculated value: mole peak (M+H) +: 399 experimental values: mole peak (M+H) +: 399
R fValue: 0.46 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.9:
4-(4-oxo-cyclohexylidene methyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
2.9.a 4-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-ylidenylmethyl)-ethyl benzoate
Under-20 ℃, the Diisopropylamine that the n-BuLi solution of 350 milliliters (0.56 moles, 1.6M is in hexane) is dropwise added 90.0 milliliters (0.63 moles) is dissolved in 100 milliliters of solution among the THF, stirs these reaction solns 30 minutes down at-20 ℃ again.Slowly be added dropwise to 4-(diethoxy-phosphoryl methyl)-ethyl benzoate of the grams of 112 among 100 milliliters of THF (0.37 mole).Down stirred these reaction solns 1 hour at-20 ℃, be added dropwise to 1 of the grams of 58 among 200 milliliters of THF (0.37 mole) again, 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-ketone.Down stirred these reaction solns 30 minutes at-12 ℃,, add entry, with ether, ethyl acetate, and this water of dichloromethane extraction in 2 hours time of room temperature heating.This organic phase is filtered by silica gel.Using rotatory evaporator except that after desolvating, with this resistates of chromatography purifying (silica gel, petrol ether/ethyl acetate 9: 1)
Productive rate: 80 grams (theoretical value 72.0%)
2.9.b 4-(1,4-Er Evil-spiral shell [4.5] last of the ten Heavenly stems-8-ylidenylmethyl)-phenylformic acid
4-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-the ylidenylmethyl)-ethyl benzoate that in 130 ml waters 20 grams NaOH is added 35 grams (0.12 mole) is dissolved in 150 milliliters of solution in the ethanol, and this mixture heating up was refluxed 2 hours.This reaction soln is added in the concentrated hydrochloric acid of the ice of 400 grams and 60 milliliters,, re-use rotatory evaporator and remove and desolvate with this water of ethyl acetate extraction.
Productive rate: 32 grams (theoretical value 91.4%)
Fusing point: 164-165 ℃
2.9.c 4-(4-oxo-cyclohexylidene methyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, by 4-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-ylidenylmethyl)-phenylformic acid (134 milligrams, 0.49 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (100 milligrams, 0.49 mmole) and be prepared.
Productive rate: 57 milligrams (theoretical value 28.0%)
C 27H 32N 2O 2(M＝416.568)
Calculated value: mole peak (M+H) +: 417 experimental values: mole peak (M+H) +: 417
R fValue: 0.36 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.10
2.10.a 4-(4-oxo-cyclohexyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, by 4-(4-oxo-cyclohexyl)-phenylformic acid (128 milligrams, 0.49 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (100 milligrams, 0.49 mmole) and be prepared.
Productive rate: 26 milligrams (theoretical value 13.1%)
C 26H 32N 2O 2(M＝404.557)
Calculated value: mole peak (M+H) +: 405 experimental values: mole peak (M+H) +: 405
R fValue: 0.31 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.11:
4-cyclohexyl-1-cyclohexane carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.11.a 4-cyclohexyl-1-cyclohexane carboxylic acid
4-(4-chloro-phenyl-)-hexahydrobenzoic acid that 0.44 milliliter of concentrated hydrochloric acid and 100 milligrams of platinum oxides are added 500 milligrams (2.10 mmoles) is dissolved in the solution in 10 ml methanol.Under 50 ℃ and 5 crust hydrogen, stirred this reaction mixture 3 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate.
Productive rate: 440 milligrams (theoretical value 99.9%)
C 13H 22O 2(M＝210.319)
Calculated value: mole peak (M-H) -: 209 experimental values: mole peak (M-H) -: 209
2.11.b 4-cyclohexyl-1-cyclohexane carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by dicyclohexyl-4-carboxylic acid (103 milligrams, 0.49 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (100 milligrams, 0.49 mmole) and be prepared.
Productive rate: 2.0 milligrams (theoretical value 1.0%)
C 26H 40N 2O 2(M＝396.622)
Calculated value: mole peak (M+H) +: 397 experimental values: mole peak (M+H) +: 397
R fValue: 0.46 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 1.12:
Figure A0382007601451
2.12.a 4-aminomethyl phenyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to previously described general methodology II, by 4-aminomethyl phenyl-piperidines (175 milligrams, 1.0 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.0 mmoles) and be prepared.
Productive rate: 90.0 milligrams (theoretical value 22.2%)
C 26H 35N 3O(M＝405.558)
Calculated value: mole peak (M+H) +: 406 experimental values: mole peak (M+H) +: 406
R fValue: 0.30 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.13:
4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601452
2.13.a 4-(4-chloro-phenyl)-1,2,3,6-tetrahydrochysene-pyridine
Under 60 ℃, the formalin solution (37% is soluble in water) and 32.1 that 4-chloro-vinyl toluene is dropwise added 100 milliliters (1.2 moles) restrains in the ammonium chloride of (0.6 mole).Stir this reaction mixture 3 hours down at 60 ℃, be cooled to room temperature again.Add 100 ml methanol, and stir this mixture overnight.After using the rotatory evaporator evaporating solvent, this resistates is mixed with 150 milliliters concentrated hydrochloric acid, and 100 ℃ times stirrings 4 hours.After being cooled to room temperature, adding ice, and alkalize with the NaOH sheet.After repeatedly extracting, this organic phase is dewatered with sodium sulfate with ether.Using rotatory evaporator except that after desolvating, on silica gel, with this resistates of post chromatograph purifying (elutriant: ethyl acetate: methyl alcohol: NH 39: 1: 0.1).
Productive rate: 17.0 milligrams (theoretical value 29.3%)
C 11H 12ClN(M＝193.678)
Calculated value: mole peak (M+H) +: 194 experimental values: mole peak (M+H) +: 194
R fValue: 0.26 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.13.b 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-chloro-phenyl)-1,2,3,6-tetrahydrochysene-pyridine (193 milligrams, 1.0 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.0 mmoles) and being prepared.
Productive rate: 40.0 milligrams (theoretical value 9.4%)
C 25H 30ClN 3O(M＝423.990)
Calculated value: mole peak (M+H) +: 424/426 experimental value: mole peak (M+H) +: 424/426
R fValue: 0.30 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.14:
2.14.a 3,4,5,6-tetrahydrochysene-2H-[4.4 '] bipyridyl-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 1,2,3,4,5,6-six hydrogen-[4.4 '] dipyridyl (81 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and being prepared.
Productive rate: 43.8 milligrams (theoretical value 22.3%)
C 24H 32N 4O(M＝392.549)
Calculated value: mole peak (M+H) +: 393 experimental values: mole peak (M+H) +: 393
R fValue: 0.14 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.15:
2.15.a 4-benzyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-benzyl-piperidines (87.7 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 33.5 milligrams (theoretical value 16.5%)
C 26H 35N 3O(M＝405.6)
Calculated value: mole peak (M+H) +: 406 experimental values: mole peak (M+H) +: 406
R fValue: 0.36 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.16:
Figure A0382007601471
2.16.a 4-(1H-indol-3-yl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 3-piperidin-4-yl-1H-indoles (100 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 56.5 milligrams (theoretical value 26.2%)
C 27H 34N 4O(M＝430.6)
Calculated value: mole peak (M+H) +: 431 experimental values: mole peak (M+H) +: 431
R fValue: 0.36 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.17:
Figure A0382007601472
2.17.a 1 '-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethylamino formyl radical]-[4.4 '] connection piperidyl-1-carboxylic acid tertiary butyl ester
According to general methodology II, be prepared by the tertiary butyl [4.4 '] connection piperidyl-1-carboxylicesters (134 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole).
Productive rate: 51.0 milligrams (theoretical value 20.5%)
C 29H 46N 4O 3(M＝498.7)
Calculated value: mole peak (M+H) +: 499 experimental values: mole peak (M+H) +: 499
R fValue: 0.40 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.18:
4-cyclohexyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.18.a 4-cyclohexyl-piperidines
4-phenylpyridines at 1.0 grams (6.4 mmole) are dissolved in the solution in 20 ml methanol, add 1.35 milliliters of concentrated hydrochloric acids and 200 milligrams of platinum oxides.Under 50 ℃ and 3 crust hydrogen, stirred this reaction mixture 2.5 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate, and this product is with the form precipitation of hydrochloride.
Productive rate: 1.2 grams (theoretical value 91.4%)
C 11H 21N*HCl(M＝203.758)
Calculated value: mole peak (M+H) +: 168 experimental values: mole peak (M+H) +: 168
2.18.b 4-cyclohexyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-cyclohexyl-piperidines (83.7 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 38.0 milligrams (theoretical value 19.1%)
C 25H 39N 3O(M＝397.6)
Calculated value: mole peak (M+H) +: 398 experimental values: mole peak (M+H) +: 398
R fValue: 0.54 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.19
4-(4-chloro-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl-ethyl]-acid amides
Figure A0382007601482
2.19.a 4-(4-chloro-phenyl)-piperidines
4-(4-chloro-phenyl)-1,2,3 at 5.0 grams (21.7 mmole) in the solution of 6-tetrahydrochysene-pyridine (with reference to 2.13.a) in 20 ml methanol, adds 500 milligrams Pd/C.Under room temperature and 10psi hydrogen, stirred this reaction mixture 7 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate.On silica gel, carry out further purifying (elutriant: methylene chloride/ammonia=5: 4.9: 0.1) with the post chromatograph.
Productive rate: 3.2 grams (theoretical value 75.3%)
C 11H 14ClN(M＝195.694)
Calculated value: mole peak (M+H) +: 196/198 experimental value: mole peak (M+H) +: 196/198
R fValue: 0.37 (silica gel, methylene chloride/NH 35: 4.9: 0.1)
2.19.b 4-(4-chloro-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-chloro-phenyl)-piperidines (97.9 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 9.0 milligrams (theoretical value 4.2%)
C 25H 32ClN 3O(M＝426.0)
Calculated value: mole peak (M+H) +: 426/428 experimental value: mole peak (M+H) +: 426/428
R fValue: 0.49 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.20:
Figure A0382007601491
2.20.a 4-hydroxyl-4-(4-trifluoromethyl-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-hydroxyl-4-(4-trifluoromethyl-phenyl)-piperidines (123 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 35.0 milligrams (theoretical value 14.7%)
C 26H 32F 3N 3O 2(M＝475.6)
Calculated value: mole peak (M+H) +: 476 experimental values: mole peak (M+H) +: 476
R fValue: 0.45 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.21
2.21.a 3-phenyl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 3-phenyl-8-aza-bicyclo [3.2.1] octane (93.7 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 26.0 milligrams (theoretical value 12.5%)
C 27H 35N 3O(M＝417.6)
Calculated value: mole peak (M+H) +: 418 experimental values: mole peak (M+H) +: 418
R fValue: 0.51 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.22:
Figure A0382007601501
2.22.a 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-chloro-phenyl)-piperazine (117 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 13.0 milligrams (theoretical value 6.1%)
C 24H 31ClN 4O(M＝427.0)
Calculated value: mole peak (M+H) +: 427/429 experimental value: mole peak (M+H) +: 427/429
R fValue: 0.42 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.23:
Figure A0382007601502
2.23.a 4-cyano group-4-phenyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-cyano group-4-phenyl-piperidines (111 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 27.0 milligrams (theoretical value 13.0%)
C 26H 32N 4O(M＝416.6)
Calculated value: mole peak (M+H) +: 417 experimental values: mole peak (M+H) +: 417
R fValue: 0.46 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.24:
2.24.a 3-azepine-spiral shell [5.5] undecane-3-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 3-azepine-spiral shell [5.5] undecane (76.7 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 24.0 milligrams (theoretical value 12.5%)
C 24H 37N 3O(M＝383.6)
Calculated value: mole peak (M+H) +: 384 experimental values: mole peak (M+H) +: 384
R fValue: 0.49 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.25:
2.25.a 4-(4-fluoro-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-fluoro-phenyl)-piperidines (108 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 32.0 milligrams (theoretical value 15.6%)
C 25H 32FN 3O(M＝409.6)
Calculated value: mole peak (M+H) +: 410 experimental values: mole peak (M+H) +: 410
R fValue: 0.50 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.26:
Figure A0382007601521
2.26.a 1,2-dihydro-1-(methyl sulphonyl)-spiral shell [3H-indoles-3,4 '-piperidines]-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 1,2-dihydro-1-(methyl sulphonyl)-spiral shell [3H-indoles-3,4 '-piperidines] (133.2 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and being prepared.
Productive rate: 28.0 milligrams (theoretical value 11.3%)
C 27H 36N 4O 3S(M＝496.7)
Calculated value: mole peak (M+H) +: 497 experimental values: mole peak (M+H) +: 497
R fValue: 0.42 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.27:
2.27.a 4-(4-chloro-phenyl) 4-hydroxy-piperdine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-chloro-phenyl) 4-hydroxy-piperdine (106 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 32.0 milligrams (theoretical value 14.5%)
C 25H 32ClN 3O 2(M＝442.0)
Calculated value: mole peak (M+H) +: 442/444 experimental value: mole peak (M+H) +: 442/444
R fValue: 0.44 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.28:
Figure A0382007601523
2.28.a 4-(4-methoxyl group-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-methoxyl group-phenyl)-piperazine (133 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 35.0 milligrams (theoretical value 16.6%)
C 25H 34N 4O 2(M＝422.6)
Calculated value: mole peak (M+H) +: 423 experimental values: mole peak (M+H) +: 423
R fValue: 0.47 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.29:
Figure A0382007601531
2.29.a 4-(2-methoxyl group-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(2-methoxyl group-phenyl)-piperidines (114 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 20.0 milligrams (theoretical value 9.5%)
C 26H 35N 3O 2(M＝421.6)
Calculated value: mole peak (M+H) +: 422 experimental values: mole peak (M+H) +: 422
R fValue: 0.55 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.30:
2.30.a 1,3-dihydro-isoindole-2-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 1,3-dihydro-isoindole (77.8 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and being prepared.
Productive rate: 13.0 milligrams (theoretical value 7.4%)
C 22H 27N 3O(M＝349.48)
Calculated value: mole peak (M+H) +: 350 experimental values: mole peak (M+H) +: 350
R fValue: 0.30 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.31:
Figure A0382007601541
2.31.a 1,2,4,5-tetrahydrochysene-benzo [d] azepine _-3-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl] acid amides
According to general methodology II, by 1,2,4,5-tetrahydrochysene-benzo [d] azepine _ (73.6 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and being prepared.
Productive rate: 12.0 milligrams (theoretical value 6.4%)
C 24H 31N 3O(M＝377.543)
Calculated value: mole peak (M+H) +: 378 experimental values: mole peak (M+H) +: 378
R fValue: 0.33 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.32:
Figure A0382007601542
2.32.a 4-phenyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-phenyl-piperidines (80.6 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 24.0 milligrams (theoretical value 12.3%)
C 25H 33N 3O(M＝391.561)
Calculated value: mole peak (M+H) +: 392 experimental values: mole peak (M+H) +: 392
R fValue: 0.35 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.33:
4-(4-dimethylamino methyl-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.33.a 4-(4-dimethylamino methyl-phenyl)-4-hydroxy-piperdine-1-carboxylic acid tertiary butyl ester
Under-65 ℃,,, dropwise add in the solution of 4-bromine dimethyl benzylamine in 450 milliliters of THF of 81 grams (0.38 mole) with 35 minutes time with the n-BuL of 236 milliliters (0.38 moles, 1.6M is in hexane).With 60 minutes time, dropwise add the 4-oxo-4-piperidines-solution of 1-carboxylic acid tertiary butyl ester in 150 milliliters of THF of 75 grams (0.38 mole), so that temperature is no more than-60 ℃.Stirred this reaction soln 2 hours down at-65 ℃, at room temperature stirred again 17 hours.This reaction mixture is mixed with 300 milliliters of ether, be cooled to 5 ℃, more formed throw out is carried out suction filtration.Make this throw out mix restir 10 minutes with 200 ml waters and 700 milliliters of ether.With sal epsom this organic phase is dewatered, re-use rotatory evaporator except that desolvating.The product of dry gained under vacuum.
Productive rate: 45 grams (theoretical value 35.7%)
2.33.b dimethyl-[4-(1,2,3,6-tetrahydrochysene-pyridin-4-yl)-benzyl]-amine
Under-10 ℃, 70 milliliters of trifluoroacetic acids are dropwise added in 4-(4-dimethylamino methyl-phenyl)-4-hydroxy-piperdine-solution of 1-carboxylic acid tertiary butyl ester in 140 milliliters of methylene dichloride of 45 grams (0.14 mole).At room temperature stir this solution 1.5 hours, and be cooled to-10 ℃, add 30 milliliters of vitriol oils again.1.5 after hour, add 10 milliliters of sulfuric acid again.After 1 hour, use rotatory evaporator to remove and desolvate, add 300 gram ice again.With 6N NaOH pH is adjusted to 14.With saturated this water of salt of wormwood, again with twice of extracted with diethyl ether.Using rotatory evaporator should merge organic phase is concentrated into dried.
Productive rate: 25.2 grams (theoretical value 86.9%)
2.33.c dimethyl-(4-piperidin-4-yl-benzyl)-amine
Pd/BaSO with 6 grams 4Add in dimethyl-[4-(1,2,3,6-tetrahydrochysene-pyridin-4-yl)-the benzyl]-solution of amine in 200 ml methanol of 16 grams (74 mmole).Under hydrogen atmosphere,, re-use rotatory evaporator and remove and desolvate in this solution of stirring at room 1 hour, filtration catalizer.This resistates is dissolved in the methyl alcohol, adds methanolizing hydrochloric acid, again with the ether development, till this mixture becomes muddiness.Be stored in-20 ℃ down after, the hydrochloride of gained is carried out suction filtration.
Productive rate: 16 grams (theoretical value 84.9%)
2.33.d 4-(4-dimethylamino methyl-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-(4-dimethylamino methyl-phenyl)-piperidines (127 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 37.0 milligrams (theoretical value 16.5%)
C 28H 40N 4O(M＝448.657)
Calculated value: mole peak (M+H) +: 449 experimental values: mole peak (M+H) +: 449
R fValue: 0.37 (silica gel, methylene chloride/NH 39: 1: 0.1)
Embodiment 2.34:
(4 '-chloro-xenyl-4-yl)-[3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines-1-yl]-ketone
Figure A0382007601561
2.34.a 1-(4-bromo-benzyl)-tetramethyleneimine
Among the THF 20.0 gram (0.080 mole) 4-bromobenzyl bromination thing is dropwise added lentamente in the solution of the tetramethyleneimine of 13.1 milliliters (0.16 mmoles) and 200 milliliters of tetrahydrofuran (THF)s, make temperature be no more than 20 ℃.Stir this reaction soln and spend the night, after mixing ice, carry out acidifying again with concentrated hydrochloric acid.After extracting with ether again,, carry out saturated with salt of wormwood again with sodium hydroxide solution this water that alkalizes.After extracting with ether, this organic phase is dewatered, use rotatory evaporator to remove and desolvate with sal epsom.
Productive rate: 18.1 grams (theoretical value 94.2%)
C 11H 14BrN(M＝240.145)
Calculated value: mole peak (M+H) +: 240/242 experimental value: mole peak (M+H) +: 240/242
R fValue: 0.19 (silica gel, petrol ether/ethyl acetate 8: 2)
2.34.b 3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-pyridine
1-(4-bromo-the benzyl)-tetramethyleneimine of 1.11 grams (4.64 mmole) are dissolved in the 2M sodium carbonate solution of 10 milliliters of De dioxs and 5 milliliters.Add four-(triphenylphosphine)-palladium of 570 milligrams of (4.64 mmole) pyridine-3-boric acid and 270 milligrams (0.23 mmoles) successively, make this reaction reflux 6 hours again.Make this reaction soln carry out suction filtration by glass fibre filter.With this filtrate of ethyl acetate extraction repeatedly.With sal epsom this organic phase is dewatered, re-use rotatory evaporator except that desolvating.On silica gel, carry out further purifying (elutriant: ethyl acetate/methanol/NH with the post chromatograph 38: 2: 0.1).
Productive rate: 500 milligrams (theoretical value 45.2%)
C 16H 18N 2(M＝238.335)
Calculated value: mole peak (M+H) +: 239 experimental values: mole peak (M+H) +: 239
2.34.c 3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines
With the platinum oxide of 4 milliliters 1M hydrochloric acid and 200 milligrams add 500 milligrams (2.10 mmoles)-solution of (4-tetramethyleneimine-1-ylmethyl-phenyl)-pyridine in 10 milliliters of ethanol in.Under room temperature and 3 crust hydrogen, stirred this reaction mixture 4.5 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate, and this product is with the form precipitation of hydrochloride.
Productive rate: 600 milligrams (theoretical value 100%)
C 16H 24N 2*HCl(M＝280.844)
Calculated value: mole peak (M+H) +: 245 experimental values: mole peak (M+H) +: 245
2.34.d (4 '-chloro-xenyl-4-yl)-[3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines-1-yl]-ketone
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (183 milligrams, 0.78 mmole) and 3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines (200 milligrams, 0.71 mmole) and be prepared.
Productive rate: 20.0 milligrams (theoretical value 6.1%)
C 29H 31ClN 2O(M＝459.036)
Calculated value: mole peak (M+H) +: 459/461 experimental value: mole peak (M+H) +: 459/461
R fValue: 0.58 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.35:
4 '-chloro-xenyl-4-carboxylic acid-[2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
2.35.a 2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propionitrile
At room temperature, the potassium tert.-butoxide with 3.4 grams (30 mmole) adds in the solution of (4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile (with reference to 1.1.g) in 50 milliliters of tetrahydrofuran (THF)s of 2.0 grams (10 mmole).This reaction soln of of short duration stirring mixes its methyl-iodide with 1.9 milliliters (30 mmoles), and at room temperature restir is 2 hours, re-uses rotatory evaporator and is evaporated to dried.This resistates is distributed between water and ethyl acetate, clean this organic phase, dewater with sal epsom again with water.Use rotatory evaporator to remove and desolvate, this raw product is not purified promptly further to react.
Productive rate: 1.4 grams (theoretical value 61.3%)
C 15H 20N 2(M＝228.340)
Calculated value: mole peak (M+H) +: 229 experimental values: mole peak (M+H) +: 229
R fValue: 0.40 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.35.b 2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propylamine
150 milligrams Raney nickel are added 2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propionitrile of 1.4 grams (6.13 mmole) in the solution of 20 ml methanol ammonia solutions.At 50 ℃, stir this reaction mixture down in 5 crust hydrogen atmospheres and spend the night.Behind filtration catalizer, use rotatory evaporator to remove and desolvate.
Productive rate: 1.4 grams (theoretical value 98.3%)
C 15H 24N 2(M＝232.372)
Calculated value: mole peak (M+H) +: 233 experimental values: mole peak (M+H) +: 233
R fValue: 0.30 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.35.c 4 '-chloro-xenyl-4-carboxylic acid-[2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (233 milligrams, 1.0 mmoles) and 2-methyl 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propylamine (232 milligrams, 1.0 mmoles) and be prepared.
Productive rate: 400 milligrams (theoretical value 89.5%)
C 28H 31ClN 2O(M＝447.025)
Calculated value: mole peak (M+H) +: 447/449 experimental value: mole peak (M+H) +: 447/449
R fValue: 0.35 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.36:
4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
Figure A0382007601591
2.36.a 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propionitrile
At room temperature, the potassium tert.-butoxide with 1.12 grams (10 mmole) adds in the solution of (4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile (with reference to 1.1.g) in 50 milliliters of tetrahydrofuran (THF)s of 2.0 grams (10 mmole).Stirred this reaction soln 30 minutes, and made it again in conjunction with mixing with the methyl-iodide of 0.63 milliliter (10 mmole).Stir this reaction 1 hour down at 50 ℃, re-use rotatory evaporator and be evaporated to dried.This resistates is distributed between water and ethyl acetate, clean this organic phase twice, dewater with sal epsom again with water.Use rotatory evaporator to remove and desolvate, not purified can further reaction of this raw product (it contains 20% this dimethylated compound of having an appointment).
Productive rate: 0.5 gram (theoretical value 23.3%)
C 14H 18N 2(M＝214.314)
Calculated value: mole peak (M+H) +: 215 experimental values: mole peak (M+H) +: 215
R fValue: 0.40 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.36.b 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propylamine
2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propionitrile that 100 milligrams Raney nickel are added 400 milligrams (1.87 mmoles) is in the solution of 20 ml methanol ammonia solutions.Cling under the nitrogen atmosphere at 50 ℃ and 5, stir this reaction mixture and spend the night.Behind filtration catalizer, use rotatory evaporator to remove solution.Amine (it contains 20% the dimethylated compound of having an appointment) can further react without any further purifying.
Productive rate: 0.4 gram (theoretical value 98.6%)
C 15H 22N 2(M＝218.345)
Calculated value: mole peak (M+H) +: 219 experimental values: mole peak (M+H) +: 219
R fValue: 0.30 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.36.c 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (233 milligrams, 1.0 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propylamine (218 milligrams, 1.0 mmoles) and be prepared.
Productive rate: 10 milligrams (theoretical value 2.3%)
C 28H 31ClN 2O(M＝447.025)
Calculated value: mole peak (M+H) +: 447/449 experimental value: mole peak (M+H) +: 447/449
R fValue: 0.35 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.37
4 '-chloro-xenyl-4-carboxylic acid-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-acid amides
Figure A0382007601601
2.37.a 2-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-isoindole-1, the 3-diketone
At room temperature, mixture with gram (50 mmole) N-hydroxyl-phthalimide of 8.2 in 125 milliliters of acetonitriles and 8.7 milliliters of (50 mmole) Hunig alkali, the α that adds 13.2 grams (50 mmole), α '-bromo-is right-solution of dimethylbenzene in 125 milliliters of acetonitriles in.Stirred this reaction soln 10 minutes, and added the tetramethyleneimine of 4.1 milliliters (50 mmoles) again, and continue to stir 1 hour.After filtration, use rotatory evaporator that this mother liquid evaporation is extremely done.On silica gel, with this resistates of chromatography purifying (elutriant: ethyl acetate/methanol/ammonia).This material further reacts behind purifying at once.
Productive rate: 1.0 grams (theoretical value 5.9%)
R fValue: 0.60 (Alox, ethyl acetate/petroleum ether 1: 1)
2.37.b O-(4-tetramethyleneimine-1-ylmethyl-benzyl)-azanol
2-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-isoindole-1 with 50 milliliters of 40% methylamine solutions adding, 1.0 grams (2.97 mmole) in water in the solution of 3-diketone in 50 milliliters of toluene, and at room temperature stirred this mixture 2.5 days.After separating organic phase, extract this water twice with t-butyl methyl ether.Clean the organic phase of this merging with water, dewater with sal epsom again.Use rotatory evaporator to remove and desolvate, the product of gained is not purified can further to react.
Productive rate: 260 milligrams (theoretical value 42.4%)
C 12H 18N 2O(M＝206.290)
Calculated value: mole peak (M+H) +: 207 experimental values: mole peak (M+H) +: 207
2.37.c 4 '-chloro-xenyl-4-carboxylic acid-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (116 milligrams, 0.5 mmole) and O-(4-tetramethyleneimine-1-ylmethyl-benzyl)-azanol (103 milligrams, 0.5 mmole) and be prepared.
Productive rate: 10.0 milligrams (theoretical value 4.8%)
C 20H 25ClN 2O 2(M＝420.943)
Calculated value: mole peak (M+H) +: 421/423 experimental value: mole peak (M+H) +: 421/423
R fValue: 0.38 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.38:
4 '-chloro-xenyl-4-carboxylic acid-[1,1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601611
(2.38.a 4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl acetate
(4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitriles (with reference to 1.1.g) of 3.0 grams (15 mmole) are dissolved in the hydrochloric acid (saturated) of dealing with alcohol, and reflux 4 hours.Use rotatory evaporator to remove and desolvate, again this resistates is dissolved in rare NaHCO 3In solution and the t-butyl methyl ether.With sodium sulfate this organic phase is dewatered, make it carry out suction filtration, re-use rotatory evaporator except that desolvating by activated carbon.
Productive rate: 3.4 grams (theoretical value 91.6%)
C 15H 21NO 2(M＝247.340)
Calculated value: mole peak (M+H) +: 248 experimental values: mole peak (M+H) +: 248
R fValue: 0.25 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.28.b 2-methyl isophthalic acid-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propan-2-ol
At room temperature, 3.4 (4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl acetate that restrain (13.8 mmole) in 20 milliliters of tetrahydrofuran (THF)s dropwise are added in the 3.0M methyl chloride magnesium solution of 13.3 milliliters (40 mmoles) in the tetrahydrofuran (THF).Temperature is increased to 40 ℃.Stirred this reaction mixture 1 hour, and be poured in 100 milliliters of ammonium chloride solutions.With this water of dichloromethane extraction repeatedly.Clean the organic layer that merges with saturated brine solution, dewater with sal epsom again.Use rotatory evaporator to remove and desolvate, again on Alox, with this resistates of post chromatograph purifying (elutriant: hexanaphthene: ethyl acetate 4: 1).
Productive rate: 800 milligrams (theoretical value 24.9%)
C 15H 23NO(M＝233.357)
Calculated value: mole peak (M+H) +: 234 experimental values: mole peak (M+H) +: 234
R fValue: 0.50 (Alox, petrol ether/ethyl acetate 6: 4)
2.38.c N-[1,1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-methane amide
The sodium cyanide that the mixture of 2 milliliters of sulfuric acid and 1 milliliter of Glacial acetic acid is dropwise added 250 milligrams (5.0 mmoles) is dissolved in 2 milliliters of solution in the Glacial acetic acid, so that temperature is no more than 20 ℃.Then dropwise be added in 800 milligrams of (3.43 mmole) 2-methyl isophthalic acids-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propan-2-ol in 2 milliliters of Glacial acetic acid.Make temperature maintenance below 20 ℃.At room temperature stirred this reaction soln 1 hour, again with it on ice, and neutralize with sodium carbonate solution.With this water of extracted with diethyl ether, with sal epsom this organic phase is dewatered again.Use rotatory evaporator to remove and desolvate, this product is not purified can further to react.
Productive rate: 520 milligrams (theoretical value 58.2%)
C 16H 24N 2O(M＝260.382)
Calculated value: mole peak (M+H) +: 261 experimental values: mole peak (M+H) +: 261
2.38.d 1,1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
25 milliliters of concentrated hydrochloric acids are added the N-[1 of 520 milligrams (2 mmoles), 1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-solution of methane amide in 10 milliliters of ethanol in, and this mixture heating up is refluxed spend the night.After cooling, this reaction soln that alkalizes of the aqueous sodium hydroxide solution with 25% extracts this water repeatedly with t-butyl methyl ether again.Clean the organic phase of this merging with water, dewater, it is filtered by activated carbon with sal epsom.Using rotatory evaporator to remove desolvates.
Productive rate: 380 milligrams (theoretical value 81.8%)
C 15H 24CN 2(M＝232.372)
Calculated value: mole peak (M+H) +: 233 experimental values: mole peak (M+H) +: 233
R fValue: 0.10 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
2.38.e 4 '-chloro-xenyl-4-carboxylic acid-[1,1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (116 milligrams, 0.5 mmole) and 1,1-dimethyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (116 milligrams, 0.5 mmole) and being prepared.
Productive rate: 73.0 milligrams (theoretical value 32.7%)
C 28H 31ClN 2O 2(M＝447.025)
Calculated value: mole peak (M+H) +: 447/449 experimental value: mole peak (M+H) +: 447/449
R fValue: 0.48 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.39:
4 '-chloro-xenyl-4-carboxylic acid-4-(2-tetramethyleneimine-1-base-ethyl)-benzyl acid amides
2.39.a 4-(2-tetramethyleneimine-1-base-ethyl)-benzonitrile
With the salt of wormwood of the potassiumiodide of 91 milligrams (0.56 mmoles), 453 milligrams (3.28 mmoles), and 0.33 milliliter (2.74 mmole) 1, the 4-dibromobutane adds in 4-(2-the amino-ethyl)-solution of benzonitrile in 50 milliliters of acetonitriles of 500 milligrams (2.74 mmoles) successively.Stir this reaction 6 hours down at 78 ℃.Add other 0.08 milliliter (0.66 mmole) 1, the 4-dibromobutane stirs down these reactants at 78 ℃ again and spends the night.After the filtration, be evaporated to this filtrate dried.On silica gel, carry out further purifying (methylene chloride 8: 2) with the post chromatograph
Productive rate: 183.0 milligrams (theoretical value 33.4%)
C 13H 16N 2(M＝200.286)
Calculated value: mole peak (M+H) +: 201 experimental values: mole peak (M+H) +: 201
2.39.b 4-(2-tetramethyleneimine-1-base-ethyl)-benzylamine
75 milligrams Raney nickel are added in 4-(2-tetramethyleneimine-1-base-ethyl)-solution of benzonitrile in the ammonia solution of 20 ml methanolization of 183 milligrams (0.91 mmoles).Stirring this reaction mixture under 50 ℃ and 3 crust hydrogen spends the night.Add other 75 milligrams Raney nickel again, and under 50 ℃ and 3 crust hydrogen this mixture of restir 6 hours.The elimination catalyzer also removes on rotatory evaporator and desolvates.Crude product can further use without repurity.
Productive rate: 114.0 milligrams (theoretical value 61.0%)
C 13H 20N 2(M＝204.318)
Calculated value: mole peak (M+H) +: 205 experimental values: mole peak (M+H) +: 205
2.39.c 4 '-chloro-xenyl-4-carboxylic acid-4-(2-tetramethyleneimine-1-base-ethyl)-benzyl acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (130 milligrams, 0.56 mmole) and 4-(2-tetramethyleneimine-1-base-ethyl)-benzylamine (114 milligrams, 0.56 mmole) and be prepared.
Productive rate: 75.0 milligrams (theoretical value 32.1%)
C 26H 27ClN 2O(M＝418.971)
Calculated value: mole peak (M+H) +: 419/421 experimental value: mole peak (M+H) +: 419/421
R fValue: 0.38 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.40:
2.40.a[1,4 ']-Lian piperidyl-1 '-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, by 4-piperidinyl piperidine (84.1 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 3.0 milligrams (theoretical value 1.5%)
C 24H 38N 4O(M＝398.597)
Calculated value: mole peak (0.5M+H) +: 200 experimental values: mole peak (0.5M+H) +: 200
The HPLC residence time: 1.59 minutes (method A)
Embodiment 2.41:
2.41.a 4-cyclohexyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, by 4-phenylcyclohexane formic acid (102 milligrams, 0.50 mmole) and 4-(2-tetramethyleneimine-1-base-ethyl)-benzylamine (102 milligrams, 0.50 mmole) and be prepared.
Productive rate: 2.0 milligrams (theoretical value 1.0%)
C 26H 34N 2O(M＝390.574)
Calculated value: mole peak (M+H) +: 391 experimental values: mole peak (M+H) +: 391
R fValue: 0.38 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.42:
4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethyl]-acid amides
Figure A0382007601652
2.42.a 2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethamine
The platinum oxide of 1.52 milliliters of concentrated hydrochloric acids and 300 milligrams is added in 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-solution of ethamine (referring to embodiment 1.1.h) in 10 ml methanol of 500 milligrams (2.45 mmoles).Under 50 ℃ and 5 crust hydrogen, stirred this reaction mixture 50 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate.On silica gel, carry out further purifying (methylene chloride/ammonia 8: 2: 0.2) with the post chromatograph.
Productive rate: 130 milligrams (theoretical value 25.3%)
C 13H 26N 2(M＝210.366)
Calculated value: mole peak (M+H) +: 211 experimental values: mole peak (M+H) +: 211
R fValue: 0.14 (silica gel, ethyl acetate/methanol/NH 38: 2: 0.2)
2.42.b 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethyl]-acid amides
According to general methodology I, by 4 '-chloro-xenyl-4-carboxylic acid (116 milligrams, 0.50 mmole) and 2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethamine (105 milligrams, 0.50 mmole) and be prepared.
Productive rate: 53.0 milligrams (theoretical value 24.9%)
C 26H 33ClN 2O(M＝425.019)
Calculated value: mole peak (M+H) +: 425/427 experimental value: mole peak (M+H) +: 425/427
R fValue: 0.16 (silica gel, ethyl acetate/methanol/NH 39: 1: 0.1)
Embodiment 2.43:4 '-chloro-xenyl-4-carboxylic acid-[2-(3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601661
2.43.a.4-cyanogen methyl-2-methoxyl group-phenylformic acid
Be similar to embodiment 1.1.d, be prepared by 4-cyanogen methyl-methyl benzoate.
Productive rate: 6.5 grams (theoretical value 69.8%)
C 10H 9NO 3(M＝191.18)
Calculated value: mole peak (M+H) +: 192 experimental values: mole peak (M+H) +: 192
R fValue: 0.64 (silica gel, methylene dichloride/ethanol 10: 1)
(2.43.b. 4-methylol-3-methoxyl group-phenyl)-acetonitrile
Be similar to embodiment 1.1.e, be prepared by 4-cyanogen methyl 2-methoxyl group-phenylformic acid.
Productive rate: 4.81 grams (theoretical value 81%)
C 10H 11NO 2(M＝177.20)
Calculated value: mole peak (M+H) +: 177 experimental values: mole peak (M+H) +: 177
(2.43.c 4-brooethyl-3-methoxyl group-phenyl)-acetonitrile
Be similar to embodiment 1.1.f, be prepared by (4-methylol-3-methoxyl group-phenyl)-acetonitrile.
Productive rate: 4.2 grams (theoretical value 64.6%)
C 10H 10BrNO(M＝240.10)
Calculated value: mole peak (M) +: 239/241 experimental value: mole peak (M) +: 239/241
R fValue: 0.84 (silica gel, methylene dichloride/ethanol 50: 1)
(2.43.d. 3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile
Be similar to embodiment 1.1.g, be prepared by (4-brooethyl-3-methoxyl group-phenyl)-acetonitrile and piperidines.
Productive rate: 0.95 gram (theoretical value 24.2%)
C 14H 18N 2O(M＝230.31)
Calculated value: mole peak (M+H) +: 231 experimental values: mole peak (M+H) +: 231
(2.43.e 3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
Be similar to embodiment 1.1.h, be prepared by (3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile.This raw product is not purified can further to react at once.
2.43.f.4 '-chloro-xenyl-4-carboxylic acid-[2-(3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 2-(3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 0.5 gram (theoretical value 86.2%)
Fusing point: 162-163 ℃
C 27H 29ClN 2O 2(M＝448.99)
Calculated value: mole peak (M+H) +: 449/451 experimental value: mole peak (M+H) +: 449/451
R fValue: 0.85 (silica gel, methylene dichloride/ethanol/ammonia 5: 1: 0.1)
Embodiment 2.44:
4 '-chloro-xenyl-4-carboxylic acid-[2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601671
2.44.a. (E)-3-(4-cyano group-2-fluoro-phenyl)-vinylformic acid
The palladium of 2.75 grams (10 mmole) and the three-neighbour-tolyl-phosphoric acid ester of 7.0 grams (25 mmole) are added in the solution of 4-bromo-3-fluoro-benzonitrile in 200 milliliters of DMF of 20.0 grams (100 mmole).The ethyl propenoate that then adds 50 milliliters of triethylamines and 30 milliliters (30 mmoles).Stirred this reaction mixture 3 hours down at 100 ℃, after the cooling,, clean twice with water again with 400 milliliters methylene dichloride dilution.Use rotatory evaporator to remove and desolvate, again this resistates is dissolved in 250 ml methanol under heating.Carry out suction filtration to remove insoluble composition by diatomite, again rotation change vaporizer at last this filtrate be evaporated to 1/2nd volumes.After filtering once more, make its with 150 milliliters of THF, 100 milliliters of MeOH, and 43 milliliters of 2N NaOH mix, and at room temperature stirred 2 hours.Use rotatory evaporator to remove and desolvate, this resistates is mixed with 100 ml waters.After extracting, this water is carried out acidifying with concentrated hydrochloric acid with ether.With sedimentary crystal be dissolved in 300 milliliters the warm ethyl acetate, separate again and remove water.Ethyl acetate is removed in distillation, and the crystal with gained is suspended in the ether again, and carries out suction filtration.
Productive rate: 11.5 grams (theoretical value 60.2%)
Fusing point: 214-218 ℃
(2.44.b.3-4-cyano group-2-fluoro-phenyl)-propionic acid
(E)-3-(4-cyano group-2-fluoro-the phenyl)-solution of vinylformic acid in 200 ml waters of 11.5 grams (60 mmole) is mixed with 4.0 gram 5%Pd/C and 24.4 gram salt of wormwood.In autoclave, shook this mixture 6 hours down in room temperature and normal hydrogen air pressure.Behind the suction filtration catalyzer, this mother liquor is carried out acidifying with concentrated hydrochloric acid.With sedimentary crystal be dissolved in 250 milliliters the warm ethyl acetate, dewater, ethyl acetate is removed in redistillation.The crystal and the ether/hexane of gained are stirred jointly, carry out suction filtration again.
Productive rate: 900 milligrams (theoretical value 98.0%)
Fusing point: 102-106 ℃
(2.44.c[2-4-cyano group-2-fluoro-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
The diphenylphosphine acylazide thing of 1.25 milliliters of triethylamines and 0.61 milliliter (2.8 mmole) is added in 3-(4-cyano group-2-fluoro-the phenyl)-solution of propionic acid in 5 milliliters of trimethyl carbinols of 500 milligrams (2.6 mmoles).This reaction mixture reflux is spent the night, re-use rotatory evaporator except that desolvating.On silica gel, carry out purifying (methylene chloride 9: 1) with the post chromatograph.
Productive rate: 138 milligrams (theoretical value 20.2%)
C 14H 17FN 2O 2(M＝264.302)
Calculated value: mole peak (M+H) +: 265 experimental values: mole peak (M+H) +: 265
(2.44.d[2-4-aminomethyl-2-fluoro-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
138 milligrams (0.52 mmoles) [2-(4-cyano group-2-fluoro-phenyl)-ethyl]-carboxylamine tertiary butyl ester solution in 15 milliliters of dealing with alcohol ammonia solutions is mixed with 75 milligrams Raney nickel, and in autoclave, in 50 ℃ and 3 the crust hydrogen under, shake this mixture overnight.Behind the suction filtration catalyzer, use rotatory evaporator to remove and desolvate.
Productive rate: 137 milligrams (theoretical value 97.8%)
C 14H 21FN 2O 2(M＝268.334)
Calculated value: mole peak (M+H) +: 269 experimental values: mole peak (M+H) +: 269
(2.44.e[2-2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
In 300 milligrams (1.12 mmoles) [2-(4-aminomethyl-2-fluoro-phenyl)-the ethyl]-solution of carboxylamine tertiary butyl ester in 15 milliliters of acetonitriles, add 42 milligrams of (0.25 mmole) potassiumiodides, 180 milligrams of (1.30 mmole) salt of wormwood, and 0.13 milliliter of (1.11 mmole) 1 successively, the 4-dibromobutane.Stir this reaction 6 hours down at 78 ℃.Add other 0.08 milliliter (0.66 mmole) 1, the 4-dibromobutane stirs this reactant down at 78 ℃ again and spends the night.Use rotatory evaporator to remove and desolvate, this product is not purified can further to react.
Productive rate: 320 milligrams (theoretical value 88.8%)
C 18H 27FN 2O 2(M＝322.426)
Calculated value: mole peak (M+H) +: 323 experimental values: mole peak (M+H) +: 323
2.44.f 2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
In [2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-the ethyl]-solution of carboxylamine tertiary butyl ester in 5 milliliters of methylene dichloride of 232 milligrams (0.72 mmoles), add 1.5 milliliters trifluoroacetic acid.At room temperature stirred this reaction mixture 2 hours.Use rotatory evaporator to remove and desolvate, this raw product is not purified can further to react.
Productive rate: 160 milligrams (theoretical value 100%)
C 13H 19FN 2(M＝222.308)
Calculated value: mole peak (M+H +: 223 experimental values: mole peak (M+H) +: 223
2.44.g 4 '-chloro-xenyl-4-carboxylic acid-[2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (160 milligrams, 0.72 mmole) and 4 '-chloro-xenyl-4-carboxylic acid (168 milligrams, 0.72 mmole) is prepared.
Productive rate: 49 milligrams (theoretical value 15.6%)
C 26H 26ClN 2O(M＝436.961)
Calculated value: mole peak (M+H) +: 437/439 experimental value: mole peak (M+H) +: 437/439
The HPLC residence time: 6.6 minutes (method A)
Embodiment 2.45:
4-pyridin-4-yl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzylamine
Figure A0382007601701
2.45.a 4-pyridin-4-yl-methyl benzoate
The 4-bromo-pyridines of 3.0 grams (15 mmole) are dissolved in the 2M sodium carbonate solution of 50 milliliters of De dioxs and 15 milliliters.Add the 4-methoxycarbonyl phenyl-boric acid of 2.7 grams (15 mmole) and four-(triphenylphosphine)-palladium of 1.73 grams (2 mmole) successively, make this reaction reflux 6 hours again.Make this thermal response solution carry out suction filtration by glass fibre filter.Use rotatory evaporator to remove and desolvate, on silica gel, carry out purifying (methylene chloride 9: 1) again with the post chromatograph.
Productive rate: 845 milligrams (theoretical value 26.4%)
C 13H 11NO 2(M＝213.238)
Calculated value: mole peak (M+H) +: 214 experimental values: mole peak (M+H) +: 214
The HPLC residence time: 4.1 minutes (method A)
2.45.b 4-pyridin-4-yl-phenylformic acid
The 2N NaOH of 0.37 milliliter (0.74 mmole) is added in the solution of 150 milligrams of (0.70 mmole) 4-pyridin-4-yl-methyl benzoate in 10 milliliters of ethanol.Stir this reaction soln 2 hours down at 60 ℃, with 1N HCl pH is adjusted to 6-7 again.After filtration, dry formed throw out spends the night under high vacuum.
Productive rate: 84 milligrams (theoretical value 60.0%)
C 12H 9NO 2(M＝199.211)
Calculated value: mole peak (M+H) +: 200 experimental values: mole peak (M+H) +: 200
The HPLC residence time: 2.5 minutes (method A)
2.45.c 4-pyridin-4-yl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzylamine
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (86 milligrams, 0.42 mmole) and 4-pyridin-4-yl-phenylformic acid (84 milligrams, 0.42 mmole).
Productive rate: 65 milligrams (theoretical value 40.0%)
C 25H 27N 3O(M＝385.513)
Calculated value: mole peak (M+H) +: 386 experimental values: mole peak (M+H) +: 386
The HPLC residence time: (stablized bond C in 4.7 minutes 183.5 μ m; Water: acetonitrile: formic acid 91: 9: 0.01)
Embodiment 2.46:
5-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone
Figure A0382007601711
2.46.a 4-bromo-2-methyl-ethyl benzoate
The solution of 5.0 gram (23.3 mmole) 4-bromo-2-methyl-phenylformic acid in 50 milliliters dealing with alcohol hydrochloric acid was stirred 8 hours down at 45 ℃.Make reaction soln be cooled to ambient temperature overnight, re-use rotatory evaporator except that desolvating.This resistates is dissolved in the ether, filters, re-use rotatory evaporator except that desolvating.This product is not purified can further to react.
R fValue: 0.88 (silica gel, methylene dichloride/alcohol 95: 5)
2.46.b 4 '-chloro-3-methyl-xenyl-4-carboxylic acid, ethyl ester
1.66 gram (6.83 mmole) 4-bromo-2-methyl-ethyl benzoates are dissolved in 70 milliliters of De dioxs and the 7 milliliters of 2M sodium carbonate solutions.Add the 4-chloro-phenyl-boric acid of 1.07 grams (6.83 mmole) and four-(triphenylphosphine)-palladium of 0.40 gram (0.34 mmole) successively, make this reaction reflux 6 hours again, and restir 60 hours at room temperature.Make this thermal response solution carry out suction filtration by glass fibre filter.Using rotatory evaporator to remove desolvates.This resistates is mixed, again with this water of ethyl acetate extraction with water.With sal epsom this organic phase is dewatered, re-use rotatory evaporator except that desolvating.On silica gel, carry out purifying (petrol ether/ethyl acetate 8: 2) with the post chromatograph.
Productive rate: 1.3 grams (theoretical value 69.3%)
C 16H 15ClO 2(M＝274.750)
Calculated value: mole peak (M+H) +: 275/277 experimental value: mole peak (M+H) +: 275/277
R fValue: 0.67 (silica gel, petrol ether/ethyl acetate 8: 2)
2.46.c 3-brooethyl-4 '-chloro-xenyl-4-carboxylic acid, ethyl ester
With 78 milligrams (0.47 mmoles) 2,2 '-azo two (isopropyl cyanides) add 4 of 1.3 grams (4.73 mmole) '-solution of N-bromine succinimide in 10 milliliters of tetracol phenixin of chloro-3-methyl-xenyl-4-carboxylic acid, ethyl ester and 0.84 gram (4.73 mmole) in.This reaction mixture reflux is spent the night.After filtration, evaporating solvent in rotatory evaporator.On silica gel, carry out purifying (petrol ether/ethyl acetate 8: 2) with the post chromatograph.
Productive rate: 1.6 grams (theoretical value 62.1%)
C 16H 14BrClO 2(M＝353.646)
Calculated value: mole peak (M+H) +: 353/355/357 experimental value: mole peak (M+H) +: 353/355/357
R fValue: 0.57 (silica gel, petrol ether/ethyl acetate 8: 2)
2.46.d 5-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone
At room temperature, 375 milligrams of (1.47 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine is dropwise added lentamente the 3-brooethyl-4 of 800 milligrams (1.47 mmoles) '-suspension of salt of wormwood in 7.5 milliliters of acetonitriles of chloro-xenyl-4-carboxylic acid, ethyl ester and 508 milligrams (3.68 mmoles) in.Make this reaction mixture reflux 5 hours.After using rotatory evaporator to remove to desolvate, with this resistates in the water-soluble and ethyl acetate.With this water of ethyl acetate extraction, with sal epsom the organic phase of this merging is dewatered again.Using rotatory evaporator, this resistates is dissolved among the DMF, and carries out purifying with the HPLC chromatograph and (stablize bond C except that after desolvating 183.5 μ m; Water: acetonitrile: formic acid in 9 minutes 9: 1: 0.01 to 1: 9: 0.01).
Productive rate: 82 milligrams (theoretical value 12.9%)
C 27H 27ClN 2O 2(M＝430.982)
Calculated value: mole peak (M+H) +: 431/433 experimental value: mole peak (M+H) +: 431/433
The HPLC residence time: 6.13 minutes (method A)
Embodiment 2.47:
4-piperidines-1-ylmethyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601721
2.47.a 4-piperidines-1-ylmethyl-pyridine
242 milliliters piperidines (2.44 moles) are dropwise added in the solution of 4-chloromethyl-pyridine in 600 milliliters of anhydrous methanols of 100 grams (0.61 mole), stirred this reaction mixture 1 hour down at 50 ℃ again.Using rotatory evaporator to remove desolvates.This resistates is alkalized with 40% sodium hydroxide solution, again with this water of extracted with diethyl ether.With sal epsom this organic phase is dewatered, organic phase is used rotatory evaporator to remove and is desolvated by behind the active carbon filtration.This raw product is not purified can to carry out next step reaction.
Productive rate: 106 grams (theoretical value 98%)
2.47.b 4-piperidines-1-ylmethyl-piperidines
The solution of 4-piperidines-1-ylmethyl-pyridine in 1.0 liters of Glacial acetic acid of 106 grams (0.6 mole) is mixed with 7 gram platinum dioxides, and in autoclave, under room temperature and 3 crust hydrogen, shake.After suction filtration falls catalyzer, use rotatory evaporator to remove and desolvate.This raw product is not purified can to carry out next step reaction.
Productive rate: 48 grams (theoretical value 43.9%)
2.47.c 4-piperidines-1-ylmethyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, be prepared by 4-piperidines-1-ylmethyl-piperidines (182 milligrams, 1.00 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.00 mmoles).
Productive rate: 160.0 milligrams (theoretical value 38.8%)
C 25H 40N 4O(M＝412.624)
Calculated value: mole peak (M+H) +: 413 experimental values: mole peak (M+H) +: 413
The HPLC residence time: 1.75 minutes (stable keys C 183.5 μ m; Water: acetonitrile: formic acid in 8 minutes from 9: 1: 0.01 to 4: 6: 0.01)
Embodiment 2.48:
2.48.a 4-(the 1H-benzimidazolyl-2 radicals-yl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology II, be prepared by 2-piperidin-4-yl-1H-benzoglyoxaline (164 milligrams, 1.00 mmoles) and 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.00 mmoles).
Productive rate: 80.0 milligrams (theoretical value 18.5%)
C 26H 33N 5O(M＝431.586)
Calculated value: mole peak (M+H) +: 432 trial values: mole peak (M+H) +: 432
The HPLC residence time: 2.80 minutes (stable keys C 183.5 μ m; Water: acetonitrile: formic acid in 8 minutes from 9: 1: 0.01 to 4: 6: 0.01)
Embodiment 2.49:
4-(1-methyl-piperidin-4-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
2.49.a 4-piperidin-4-yl-methyl benzoate
The platinum oxide of 4.0 milliliters of 1M hydrochloric acid and 200 milligrams is added in the solution of 4-pyridin-4-yl-methyl benzoate (referring to example 2.45.a) in 10 milliliters of ethanol of 695 milligrams (3.26 mmoles).Under room temperature and 3 crust hydrogen, stirred this reaction mixture 2 hours.After adding other 300 milligrams platinum oxide and 6.0 milliliters of 1M hydrochloric acid again, under room temperature and 3 crust hydrogen, this reaction mixture of restir 16 hours.Behind separating catalyst, use rotatory evaporator to remove and desolvate.This raw product is not purified can to carry out next step reaction.
Productive rate: 589 milligrams (theoretical value 82.4%)
C 13H 17NO 2(M＝219.286)
Calculated value: mole peak (M+H) +: 220 trial values: mole peak (M+H) +: 220
The HPLC residence time: 3.5 minutes (method A)
2.49.b 4-(1-methyl-piperidin-4-yl)-methyl benzoate
At 0 ℃, under nitrogen atmosphere, the sodium hydride of 48 milligrams (2.00 mmoles) is added in the solution of 4-piperidin-4-yl-methyl benzoate in 10 milliliters of DMF of 429 milligrams (1.96 mmoles) in batches.At room temperature stirred this reaction mixture 1 hour.The methyl-iodide that dropwise adds 0.13 milliliter (2.10 mmole) at room temperature stirred this solution 2 hours again.This reaction soln is mixed with water, and with this water of ethyl acetate extraction, the organic phase of merging is dewatered with sal epsom, re-uses rotatory evaporator except that desolvating.On silica gel, carry out purifying (silica gel: methylene chloride 8: 2) with the post chromatograph
Productive rate: 70 milligrams (theoretical value 15.3%)
C 14H 19NO 2(M＝233.313)
Calculated value: mole peak (M+H) +: 234 trial values: mole peak (M+H) +: 234
The HPLC residence time: 2.7 minutes (method A)
2.49.c 4-(1-methyl-piperidin-4-yl)-phenylformic acid
The 2N NaOH of 0.37 milliliter (0.74 mmole) is added in 4-(1-methyl-piperidin-4-yl)-solution of methyl benzoate in 10 milliliters of ethanol of 70 milligrams (0.30 mmoles).Stir this reaction soln 2 hours down at 60 ℃, with 1N HCl pH is adjusted to 6-7 again.After the filtration, dry formed throw out spends the night under high vacuum.
Productive rate: 50 milligrams (theoretical value 76.0%)
C 13H 17NO 2(M＝219.286)
Calculated value: mole peak (M+H) +: 220 trial values: mole peak (M+H) +: 220
The HPLC residence time: 1.5 minutes (method A)
2.49.d 4-(1-methyl-piperidin-4-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (47 milligrams, 0.23 mmole) and 4-(1-methyl-piperidin-4-yl)-phenylformic acid (50 milligrams, 0.23 mmole).
Productive rate: 22 milligrams (theoretical value 23.8%)
C 26H 35N 3O(M＝405.588)
Calculated value: mole peak (M+H) +: 406 trial values: mole peak (M+H) +: 406
The HPLC residence time: 2.4 minutes (method A)
Embodiment 2.50:
1.21.a 4 '-chloro-xenyl-4-carboxylic acid-2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-acid amides
Similar example 1.1.i is by 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethamine and 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 0.94 milligram (theoretical value 96%)
Fusing point: 211-213 ℃
C 25H 27ClN 4O(M＝434.97)
Calculated value: mole peak (M+H) +: 435/437 trial value: mole peak (M+H) +: 435/437
Embodiment 2.51:
4 '-chloro-xenyl-4-carboxylic acid-2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl }-acid amides
Figure A0382007601761
(2.51.a[4-4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile
At room temperature, with 2 gram (12.41 mmole) 4-cyanogen methyl-phenylformic acid, 1.25 gram (12.5 mmole) N methyl piperazines, 4.01 gram (12.5 mmole) TBTU, and the solution stirring of triethylamine in 40 milliliter DMF of 3.48 milliliters (25 mmoles) 12 hours.Then this reaction mixture of evaporation in rotatory evaporator mixes with water again.With this mixture of ethyl acetate extraction, using the rotatory evaporator distillation except that desolvating.Water is evaporation simultaneously also, and this organic phase is mixed with this residue.On silica gel, carry out purifying (elutriant: methylene dichloride/ethanol/ammonia 30: 1: 0.1) with the post chromatograph.
Productive rate: 2.6 grams (theoretical value 86%)
C 14H 17N 3O(M＝243.31)
Calculated value: mole peak (M+H) +: 244 trial values: mole peak (M+H) +: 244
R fValue: 0.35 (silica gel, methylene dichloride/ethanol/ammonia 20: 1: 0.1)
(2.51.b[4-2-amino-ethyl)-phenyl]-(4-methyl-piperazine-1-yl)-ketone
Be similar to embodiment 1.1.i, be prepared by [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile.
Productive rate: 2.9 grams (theoretical value 90%)
C 14H 21N 3O×HCl(M＝283.80)
R fValue: 0.25 (silica gel, methylene dichloride/ethanol/ammonia 10: 1: 0.1)
2.51.c 4 '-chloro-xenyl-4-carboxylic acid-2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl }-acid amides
According to general methodology I, by [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazine-1-base (ketone and 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 0.18 gram (theoretical value 48.4%)
Fusing point: 217-218 ℃
C 27H 28ClN 3O 2(M＝461.99)
Calculated value: mole peak (M+H) +: 462/464 trial value: mole peak (M+H) +: 462/464
R fValue: 0.25 (silica gel, methylene chloride/ammonia 10: 1: 0.1)
Embodiment 2.52:
4 '-bromo-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.52.a 4 '-bromo-xenyl-4-carboxylate methyl ester
0.54 gram (2.5 mmole) 4-bromo-methyl benzoate is dissolved in the 2M sodium carbonate solution of 10 milliliters of De dioxs and 2.5 milliliters.Add the 4-bromophenyl-boric acid of 0.6 gram (3 mmole) and four-(triphenylphosphine)-palladium of 0.12 gram (0.1 mmole) successively, make this reaction reflux 5 hours again.This reaction mixture is mixed with water and EtOAc, filter, and phase-splitting.Extract this water with EtOAc, again with MgSO 4The organic phase that is combined is dewatered.After removing siccative and solvent, develop this resistates with acetonitrile, carry out suction filtration, in air, carry out drying again.
Productive rate: 100 milligrams (theoretical value 13.7%)
C 14H 11BrO 2(M＝291.15)
Calculated value: mole peak (M+H) +: 291/293 trial value: mole peak (M+H) +: 291/293
R fValue: 0.68 (silica gel, sherwood oil/EtOAc 8: 2)
2.52.b 4 '-bromo-xenyl-4-carboxylic acid
Make 100 milligrams (0.34 mmoles) 4 '-solution of bromo-xenyl-4-carboxylate methyl ester in 3 milliliters of THF mixes with 3 milliliters of 1M NaOH solution in water, and reflux 3 hours.This reaction mixture of vaporising under vacuum with this water-based resistates of 1M HCl acidifying, leaches sedimentary product, carries out drying again in air.
Productive rate: 60 milligrams (theoretical value 63.1%)
C 13H 9BrO 2(M＝277.19)
Calculated value: mole peak (M-H) -: 275/277 trial value: mole peak (M-H) -: 275/277
The HPLC residence time: 8.48 minutes (method A)
2.52.c 4 '-bromo-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of 45 milligrams (0.22 mmoles) and 60 milligrams (0.22 mmoles) '-bromo-xenyl-4-carboxylic acid is prepared.
Productive rate: 28 milligrams (theoretical value 27.5%)
C 26H 27BrN 2O(M＝463.42)
Calculated value: mole peak (M+H) +: 463/465 trial value: mole peak (M+H) +: 463/465
The HPLC residence time: 6.46 minutes (method A)
Embodiment 2.53:4 '-ethyl-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601781
According to general methodology I, from 4 of 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of 102 milligrams (0.5 mmoles) and 113 milligrams (0.5 mmoles) '-ethyl-xenyl-4-carboxylic acid (Lancaster) is prepared.
Productive rate: 65 milligrams (theoretical value 31.5%)
C 28H 32N 2O(M＝412.58)
Calculated value: mole peak (M+H) +: 463 trial values: mole peak (M+H) +: 463
The HPLC residence time: 6.64 minutes (method A)
Embodiment 2.54:
Xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, be prepared from 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of 102 milligrams (0.5 mmoles) and the xenyl-4-carboxylic acid of 99 milligrams (0.5 mmoles).
Productive rate: 46 milligrams (theoretical value 23.9%)
C 26H 28N 2O(M＝384.53)
Calculated value: mole peak (M+H) +: 385 trial values: mole peak (M+H) +: 385
The HPLC residence time: 5.70 minutes (method A)
Embodiment 2.55:
4 '-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.55a.4 '-fluoro-xenyl-4-carboxylic acid
The 4-bromo-phenylformic acid of 14.27 grams (71 mmole) is dissolved in 120 milliliters of dioxs and 70 milliliters of 2MNa 2CO 3Solution in.Add the 4-fluorophenyl-boric acid of 10 grams (71 mmole) and four-(triphenylphosphine)-palladium of 4.1 grams (4 Bo mole) successively, make this reaction reflux 6 hours again.The suction filtration catalyzer cleans with hot water again.This reaction mixture is mixed with EtOAc, separate phase, again with citric acid acidifying water.The formed throw out of suction filtration cleans with water, under vacuum, carries out drying in 45 ℃ again.
Productive rate: 4.9 milligrams (theoretical value 31.9%)
C 13H 9FO 2(M＝216.21)
Calculated value: mole peak (M-H) -: 215 trial values: mole peak (M-H) -: 215
2.55b.4 '-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 108 milligrams of (0.5 mmoles) 4 '-fluoro-xenyl-4-carboxylic acid is prepared.
Productive rate: 12 milligrams (theoretical value 6.0%)
C 26H 27FN 2O(M＝402.52)
Calculated value: mole peak (M+H) +: 403 trial values: mole peak (M+H) +: 403
The HPLC residence time: 5.83 minutes (method A)
Embodiment 2.56:
4 '-hydroxyl-3 '-nitro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601792
According to general methodology I, by 4 of 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of 102 milligrams (0.5 mmoles) and 130 milligrams (0.5 mmoles) '-fluoro-3 '-nitro-xenyl-4-carboxylic acid is prepared.
Productive rate: 9 milligrams (theoretical value 4.0%)
C 26H 27N 3O 4(M＝445.52)
Calculated value: mole peak (M+H) +: 446 trial values: mole peak (M+H) +: 446
The HPLC residence time: 5.83 minutes (method A)
Embodiment 2.57:
3 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601801
2.57a.3 '-chloro-xenyl-4-carboxylic acid
Be similar to embodiment 2.55a, be prepared by 9.64 4-bromo-phenylformic acid and 7.5 gram (47.96 mmole) 3-chloro-phenyl--boric acid that restrain (47.96 mmole).
Productive rate: 6.2 grams (theoretical value 55.6%)
C 13H 9ClO 2(M＝232.67)
Calculated value: mole peak (M-H -: 231/233 trial value: mole peak (M-H) -: 231/233
2.57b.3 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 116 milligrams of (0.5 mmoles) 3 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 63 milligrams (theoretical value 30.1%)
C 26H 27ClN 2O(M＝418.97)
Calculated value: mole peak (M+H) +: 419/421 trial value: mole peak (M+H) +: 419/421
The HPLC residence time: 6.20 minutes (method A)
Embodiment 2.58:
3 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.58a.3 ', 4 '-two chloro-xenyl-4-carboxylic acids
Be similar to embodiment 2.55a, by 5.27 the gram (26.20 mmole) 4-bromo-phenylformic acid and 5.0 the gram (26.20 mmoles) 3 ', 4 '-two chloro-phenyl-boron dihydroxides are prepared.
Productive rate: 4.05 grams (theoretical value 57.9%)
C 13H 8Cl 2O 2(M＝267.11)
Calculated value: mole peak (M-H) -: 265/267/269 trial value: mole peak (M-H) -: 265/267/269
2.58b.3 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 134 milligrams of (0.5 mmoles) 3 ', 4 '-two chloro-xenyl-4-carboxylic acids are prepared.
Productive rate: 45 milligrams (theoretical value 19.8%)
C 26H 26Cl 2N 2O(M＝453.42)
Calculated value: mole peak (M+H) +: 453/455/457 trial value: mole peak (M+H) +: 453/455/457
The HPLC residence time: 6.45 minutes (method A)
Embodiment 2.59:
2 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.59a.2 ', 4 '-two chloro-xenyl-4-carboxylic acids
Be similar to embodiment 2.55a, be prepared by 5.23 grams (26.0 millis rub) 4-bromo-phenylformic acid and 10.0 gram (52.0 mmole) 2,4 dichloro benzene ylboronic acids, wherein the reaction mixture reflux is 48 hours.
Productive rate: 1.5 grams (theoretical value 21.6%)
C 13H 8Cl 2O 2(M＝267.11)
Calculated value: mole peak (M-H) -: 265/267/269 trial value: mole peak (M-H) -: 265/267/269
2.59b.2 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 134 milligrams of (0.5 mmoles) 2 ', 4 '-two chloro-xenyl-4-carboxylic acids are prepared.
Productive rate: 72 milligrams (theoretical value 31.8%)
C 26H 26Cl 2N 2O(M＝453.42)
Calculated value: mole peak (M+H) +: 453/455/457 trial value: mole peak (M+H) +: 453/455/457
The HPLC residence time: 6.84 minutes (method A)
Embodiment 2.60:
2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601821
2.60a.2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid
Be similar to embodiment 2.55a, be prepared by 0.52 gram (2.5 mmole) 1-bromo-4-chloro-2-fluorobenzene and the 0.5 4-carboxyphenyl-boric acid that restrains (3.0 mmole).
Productive rate: 0.5 gram (theoretical value 79.8%)
C 13H 8ClFO 2(M＝250.66)
Calculated value: mole peak (M-H) +: 249/251 trial value: mole peak (M-H) -: 249/251
The HPLC residence time: 8.39 minutes (method A)
2.60b.2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 125 milligrams of (0.5 mmoles) 2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 36 milligrams (theoretical value 16.5%)
C 26H 26ClFN 2O(M＝436.96)
Calculated value: mole peak (M+H) +: 437/439 trial value: mole peak (M+H) +: 437/439
The HPLC residence time: 6.32 minutes (method A)
Embodiment 2.61:
3,4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601822
2.61a.3,4 '-two chloro-xenyl-4-carboxylic acids
Be similar to embodiment 2.55a, be prepared by 0.59 gram (2.5 mmole) 4-bromo-2-chloro-phenylformic acid and 0.47 gram (3.0 mmole) 4-chloro-phenyl--boric acid.
Productive rate: 0.55 gram (theoretical value 82.4%)
C 13H 8Cl 2O 2(M＝267.11)
Calculated value: mole peak (M-H) -: 265/267/269 trial value: mole peak (M-H) -: 265/267/269
The HPLC residence time: 8.83 minutes (method A)
2.61b.3,4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 134 milligrams of (0.5 mmoles) 3 ', 4 '-two chloro-xenyl-4-carboxylic acids are prepared.
Productive rate: 24 milligrams (theoretical value 10.6%)
C 26H 26Cl 2N 2O(M＝453.42)
Calculated value: mole peak (M+H) +: 453/455/457 trial value: mole peak (M+H) +: 453/455/457
The HPLC residence time: 6.41 minutes (method A)
Embodiment 2.62:
4 '-chloro-3-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601831
2.62a.4 '-chloro-3-fluoro-xenyl-4-carboxylic acid
Be similar to embodiment 2.55a, be prepared by 0.55 gram (2.5 mmole) 4-bromo-2-fluoro-phenylformic acid and 0.47 gram (3.0 mmole) 4-chloro-phenyl--boric acid.
Productive rate: 0.60 gram (theoretical value 95.7%)
C 13H 8ClFO 2(M＝250.66)
Calculated value: mole peak (M-H) -: 249/251 trial value: mole peak (M-H) -: 249/251
The HPLC residence time: 8.22 minutes (method A)
2.62b.4 '-chloro-3-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 125 milligrams of (0.5 mmoles) 4 '-chloro-3-fluoro-xenyl-4-carboxylic acid is prepared.
Productive rate: 37 milligrams (theoretical value 16.9%)
C 26H 26ClFN 2O(M＝436.96)
Calculated value: mole peak (M+H) +: 437/439 trial value: mole peak (M+H) +: 437/439
The HPLC residence time: 6.45 minutes (method A)
Embodiment 2.63:
4 '-chloro-2-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.63a.4 '-chloro-2-fluoro-xenyl-4-carboxylic acid
Be similar to embodiment 2.55a, be prepared by 0.66 gram (3.0 mmole) 4-bromo-3-fluoro-phenylformic acid and 0.47 gram (3.0 mmole) 4-chloro-phenyl--boric acid.
Productive rate: 0.60 gram (theoretical value 79.8%)
C 13H 8ClFO 2(M＝250.66)
Calculated value: mole peak (M-H) -: 249/251 trial value: mole peak (M-H) -: 249/251
The HPLC residence time: 8.50 minutes (method A)
2.63b.4 '-chloro-2-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 163 milligrams of (0.8 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 201 milligrams of (0.8 mmoles) 4 '-chloro-2-fluoro-xenyl-4-carboxylic acid is prepared.
Productive rate: 74 milligrams (theoretical value 21.2%)
C 26H 26ClFN 2O(M＝436?96)
Calculated value: mole peak (M+H) +: 437/439 trial value: mole peak (M+H) +: 437/439
The HPLC residence time: 6.61 minutes (method A)
Embodiment 2.64:
3-nitro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.64a.3-nitro-xenyl-4-carboxylic acid
150 milligrams of (0.13 mmoles) four-(triphenylphosphine)-palladium is added in the solution of 1.0 gram (4.07 mmole) 4-bromo-2-nitro-phenylformic acid in 20 milliliters of toluene, at room temperature stirred 10 minutes.Then add solution and the 1.0 gram Nas of 0.5 gram (4.10 mmole) phenyl-boron dihydroxide in 10 milliliters of MeOH 2CO 3Solution in 20 ml waters.Make this reaction mixture reflux 5 hours, at room temperature stir a week again.Under vacuum, remove and desolvate, this resistates is mixed with water, carry out acidifying, with the EtOAc extraction, with Na with dense HCl 2SO 4This organic phase is dewatered, and remove and desolvate.
Productive rate: 0.87 gram (theoretical value 87.5%)
R fValue: 0.40 (silica gel, methylene dichloride/ethanol 3: 1)
2.64b.3-nitro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, be prepared by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 122 milligrams of (0.5 mmole) 3-nitro-xenyl-4-carboxylic acids.
Productive rate: 100 milligrams (theoretical value 46.6%)
C 26H 27N 3O 3(M＝429.52)
Calculated value: mole peak (M+H) +: 430 trial values: mole peak (M+H) +: 430
The HPLC residence time: 5.83 minutes (method A)
Embodiment 2.65:
5-(4-chloro-phenyl)-pyridine-2-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(2.65a.5-4-chloro-phenyl)-pyridine-2-carboxylic acids
Be similar to embodiment 2.55a, be prepared by 0.51 gram (2.5 mmole) 5-bromo-pyridine-2-carboxylic acids and 0.47 gram (3.0 mmole) 4-chloro-phenyl--boric acid.
Productive rate: 0.23 gram (theoretical value 39.4%)
C 12H 8ClNO 2(M＝233.66)
Calculated value: mole peak (M-H) -: 232/234 trial value: mole peak (M-H) -: 232/234
The HPLC residence time: 5.89 minutes (method A)
(2.65b.5-4-chloro-phenyl)-pyridine-2-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 116 milligrams of (0.5 mmole) 5-(4-chloro-the phenyl)-pyridine-2-carboxylic acids of 102 milligrams (0.5 mmoles).
Productive rate: 7 milligrams (theoretical value 3.3%)
C 25H 26ClN 3O(M＝419.96)
Calculated value: mole peak (M+H) +: 420/422 trial value: mole peak (M+H) +: 420/422
The HPLC residence time: 6.40 minutes (method A)
Embodiment 2.66:
N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-thiene-3-yl--benzamide
Figure A0382007601861
2.66a.4-thiene-3-yl--ethyl benzoate
Be similar to embodiment 2.46b, be prepared by 414 milligrams of (1.5 mmole) 4-iodo-ethyl benzoates and 230 milligrams of (1.8 mmole) thiophene-3-boric acid.
Productive rate: 348 grams (theoretical value 100%)
C 13H 12O 2S(M＝232.30)
Calculated value: mole peak (M+H) +: 233 trial values: mole peak (M+H) +: 233
The HPLC residence time: 6.20 minutes (method A)
2.66b.4-thiene-3-yl--phenylformic acid
Be similar to embodiment 2.7b, be prepared by 280 milligrams of (1.5 mmole) 4-thiene-3-yl--ethyl benzoates.
Productive rate: 146 milligrams (theoretical value 59.3%)
C 11H 8O 2S(M＝204.25)
Calculated value: mole peak (M-H) -: 203 trial values: mole peak (M-H) -: 203
The HPLC residence time: 7.60 minutes (method A)
(2.66c.N-[2-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-thiene-3-yl--benzamide
According to general methodology I, be prepared by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 102 milligrams of (0.5 mmole) 4-thiene-3-yl--phenylformic acid.
Productive rate: 103 milligrams (theoretical value 53.0%)
C 24H 26N 2OS(M＝390.55)
Calculated value: mole peak (M+H) +: 391 trial values: mole peak (M+H) +: 391
The HPLC residence time: 6.10 minutes (method A)
Embodiment 2.67:
N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-thiophene-2-base-benzamide
Figure A0382007601871
2.67a.4-thiophene-2-base-ethyl benzoate
Be similar to embodiment 2.46b, be prepared by 414 milligrams of (1.5 mmole) 4-iodo-ethyl benzoates and 230 milligrams of (1.8 millis rub) thiophene-2-boric acid.
Productive rate: 348 grams (theoretical value 100%)
C 13H 12O 2S(M＝232.30)
Calculated value: mole peak (M+H) +: 233 trial values: mole peak (M+H) +: 233
The HPLC residence time: 6.29 minutes (method B)
2.67b.4-thiophene-2-base-phenylformic acid
Be similar to embodiment 2.7b, be prepared by 280 milligrams of (1.5 mmole) 4-thiophene-2-base-ethyl benzoates.
Productive rate: 126 milligrams (theoretical value 51.2%)
C 11H 8O 2S(M＝204.25)
Calculated value: mole peak (M-H) -: 203 trial values: mole peak (M-H) -: 203
The HPLC residence time: 7.60 minutes (method A)
(2.66c.N-[2-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-thiophene-2-base-benzamide
According to general methodology I, by 102 milligrams (0.5 mmoles) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 102 milligrams of (0.5 mmole) 4-thiophene-2-base-phenylformic acid are prepared.
Productive rate: 112 milligrams (theoretical value 57.5%)
C 24H 26N 2OS(M＝390.55)
Calculated value: mole peak (M+H) +: 391 trial values: mole peak (M+H) +: 391
The HPLC residence time: 6.05 minutes (method A)
Embodiment 2.68:
4-(5-chloro-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(2.68a.4-5-chloro-thiophene-2-yl)-phenylformic acid
Be similar to embodiment 2.55a,, use KHSO by 300 milligrams of (1.52 mmole) 2-bromo-5-chloro-thiophene and 277 milligrams of (1.67 mmole) 4-carboxyphenyl-boric acid 4Solution carries out acidifying to this reaction mixture that carries out and is prepared.
Productive rate: 76 milligrams (theoretical value 21.0%)
C 11H 7ClO 2S(M＝238.69)
Calculated value: mole peak (M-H) -: 237/239 trial value: mole peak (M-H) -: 237/239
The HPLC residence time: 8.75 minutes (method A)
(2.68b.4-5-chloro-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 61 milligrams of (0.3 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 71 milligrams of (0.3 mmole) 4-(5-chloro-thiophene-2-yl)-phenylformic acid.
Productive rate: 29 milligrams (theoretical value 22.9%)
C 24H 25ClN 2OS(M＝425.0)
Calculated value: mole peak (M+H) +: 425/427 trial value: mole peak (M+H) +: 425/427
The HPLC residence time: 6.65 minutes (method A)
Embodiment 2.69:
4-furans-2-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007601881
2.69a.4-furans-2-base-phenylformic acid
Be similar to embodiment 2.68a, be prepared by 302 milligrams of (1.5 mmole) 4-bromo-phenylformic acid and 201 milligrams of (1.8 mmole) FURAN-2-BORONIC ACID.
Productive rate: 166 milligrams (theoretical value 58.8%)
C 11H 8O 3(M＝188.19)
Calculated value: mole peak (M-H) -: 187 trial values: mole peak (M-H) -: 187
The HPLC residence time: 6.82 minutes (method A)
2.69b.4-furans-2-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 94 milligrams of (0.5 mmole) 4-furans-2-base-phenylformic acid.
Productive rate: 91 milligrams (theoretical value 48.4%)
C 24H 26ClN 2O 2(M＝374.49)
Calculated value: mole peak (M+H) +: 375 trial values: mole peak (M+H) +: 375
The HPLC residence time: 6.48 minutes (method A)
Embodiment 2.70:
4-(5-methyl-pyridine-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(2.70a.4-5-methyl-pyridine-2-yl)-phenylformic acid
Be similar to embodiment 2.55a, be prepared by 430 milligrams of (2.5 mmole) 2-bromo-5-methyl-pyridines and 498 milligrams of (3.00 mmole) 4-carboxyphenyl-boric acid.
Productive rate: 300 milligrams (theoretical value 56.3%)
C 13H 11NO 2(M＝213.24)
Calculated value: mole peak (M+H) +: 214 trial values: mole peak (M+H) +: 214
The HPLC residence time: 4.55 minutes (method A)
(2.70b.4-5-methyl-pyridine-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 107 milligrams of (0.5 mmole) 4-(5-methyl-pyridine-2-yl)-phenylformic acid.
Productive rate: 53 milligrams (theoretical value 26.5%)
C 26H 29N 3O(M＝399.54)
Calculated value: mole peak (M+H) +: 400 trial values: mole peak (M+H) +: 400
The HPLC residence time: 3.98 minutes (method A)
Embodiment 2.71:
4-(6-methyl-pyridin-3-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(2.71a.4-6-methyl-pyridin-3-yl)-phenylformic acid
Be similar to embodiment 2.55a, be prepared by 430 milligrams of (2.50 mmole) 5-bromo-2-methyl-pyridines and 498 milligrams of (3.00 mmole) 4-carboxyphenyl-boric acid.
Productive rate: 300 milligrams (theoretical value 56.3%)
C 13H 11NO 2(M＝213.24)
Calculated value: mole peak (M+H) +: 214 trial values: mole peak (M+H) +: 214
The HPLC residence time: 2.66 minutes (method A)
(2.71b.4-6-methyl-pyridin-3-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 102 milligrams of (0.5 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 107 milligrams of (0.5 mmole) 4-(6-methyl-pyridin-3-yl)-phenylformic acid.
Productive rate: 48 milligrams (theoretical value 24.6%)
C 26H 29N 3O(M＝399.54)
Calculated value: mole peak (M+H) +: 400 trial values: mole peak (M+H) +: 400
The HPLC residence time: 3.06 minutes (method A)
Embodiment 2.72:
4-(4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007601902
(2.72a.4-4-chloro-phenyl)-thiophene-2-carboxylic acid methyl esters
420 milligrams of (1.25 mmole) 4-bromo-thiophene-2-carboxylic acid methyl esters are dissolved in the 2M Na of 10 milliliters of De dioxs and 5 milliliters 2CO 3In the solution.Add the 4-fluoro-phenyl-boric acid of 196 milligrams (0.06 mmoles) and four-(the triphenylphosphine)-palladium of 72 milligrams (0.06 mmoles) successively, make this reaction reflux 6 hours, again restir 60 hours at room temperature.After the heating, make this thermal response solution carry out suction filtration by glass fibre filter once more, the Yi diox cleans, with semi-saturation NaHCO 3Solution mixes, and extracts with EtOAc again.With MgSO 4Organic phase to this merging is dewatered.After removing dewatering agent and solvent, on silica gel, with this resistates of post chromatograph purifying (petrol ether/ethyl acetate 9: 1).
Productive rate: 150 milligrams (theoretical value 47.3%)
C 12H 9ClO 2S(M＝252.72)
Calculated value: mole peak (M+H) +: 253/255 trial value: mole peak (M+H) +: 253/255
The HPLC residence time: 6.21 minutes (method B)
(2.72b.4-4-chloro-phenyl)-thiophene-2-carboxylic acid
In 4-(4-chloro-the phenyl)-solution of thiophene-2-carboxylic acid methyl esters in 10 milliliters of EtOH with 150 milligrams of 2 milliliters 1M NaOH solution addings, and at room temperature stir one week of this reaction soln.This reaction mixture of vaporising under vacuum makes this resistates and 2 milliliters of 1N mixed in hydrochloric acid, is cooled to 0 ℃ again.Sedimentary product is carried out suction filtration, clean, under 50 ℃, carry out drying again with water.
Productive rate: 140 milligrams (theoretical value 98.7%)
C 11H 7ClO 2S(M＝238.69)
Calculated value: mole peak (M+H) +: 239/241 trial value: mole peak (M+H) +: 239/241
The HPLC residence time: 8.31 minutes (method A)
(2.72c.4-4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, be prepared by 144 milligrams of (0.70 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 140 milligrams of (0.59 mmole) 4-(4-chloro-phenyl)-thiophene-2-carboxylic acid.
Productive rate: 78 milligrams (theoretical value 31.3%)
C 26H 29N 3O(M＝425.00)
Calculated value: mole peak (M+H) +: 425/427 trial value: mole peak (M+H) +: 425/427
The HPLC residence time: 3.90 minutes (method A)
Embodiment 2.73:
4-(5-ethanoyl-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007601911
2.73a.4-iodo-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2.04 gram (10.0 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 2.48 milligrams of (10.0 mmole) 4-iodo-phenylformic acid.
Productive rate: 1.91 grams (theoretical value 44.0%)
C 20H 23IN 2O(M＝434.32)
Calculated value: mole peak (M+H) +: 435 trial values: mole peak (M+H) +: 435
The HPLC residence time: 5.40 minutes (method A)
(2.73b.4-5-ethanoyl-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Be similar to embodiment 2.46b; by 250 milligrams of (0.58 mmole) 4-iodo-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 5-ethanoyl-2-thiophene-boric acid of benzamide and 118 milligrams (0.69 mmoles), make this reaction mixture reflux 15 hours and be prepared.
Productive rate: 50 milligrams (theoretical value 20.2%)
C 26H 28N 2O 2S(M＝432.59)
Calculated value: mole peak (M+H) +: 433 trial values: mole peak (M+H) +: 433
The HPLC residence time: 3.91 minutes (method B)
Embodiment 2.74:
4-(5-formyl radical-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Be similar to embodiment 2.46b; by 250 milligrams of (0.58 mmole) 4-iodo-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 5-formyl radical-2-thiophene-boric acid of benzamide and 107 milligrams (0.69 mmoles), make this reaction mixture reflux 15 hours and be prepared.
Productive rate: 22 milligrams (theoretical value 9.1%)
C 25H 26N 2O 2S(M＝418.56)
Calculated value: mole peak (M+H) +: 419 trial values: mole peak (M+H) +: 419
The HPLC residence time: 3.82 minutes (method B)
Embodiment 2.75:
4 '-chloro-xenyl-4-carboxylic acid [2-(4-aminomethyl-phenyl)-ethyl]-acid amides
2.75a.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-ethyl benzoate
With 20 milliliters of thionyl chloride and 1 milliliter of DMF dropwise add 4 of 9.31 grams (40 mmole) '-chloro-xenyl-4-carboxylic acid in.This reaction mixture was heated 2 hours down at 60 ℃.Then, under vacuum, remove excessive thionyl chloride, and resistates is dissolved in 200 milliliters CH at 50 ℃ 2Cl 2In.This solution is dropwise added 100 milliliters of 10%NaCO 3In 4-(2-the amino-ethyl)-ethyl benzoate of the gram of 9.19 in the aqueous solution (40 mmole) (using), at room temperature stirred this reaction mixture again 1 hour with hydrochloride form.Adding entry and CH 2Cl 2After, separate organic phase, with CH 2Cl 2Extract this water, with half saturated NaHCO 3Solution and water clean the organic phase of this merging, again with MgSO 4Dewater.After removing siccative, this solution is filtered by activated carbon, under vacuum, evaporate, make this resistates from t-butyl methyl ether, carry out crystallization again.
Productive rate: 11.93 grams (theoretical value 73.1%)
C 24H 22ClNO 3(M＝407.90)
Calculated value: mole peak (M+H) +: 408 trial values: mole peak (M+H) +: 408
The HPLC residence time: 9.8 minutes (method A)
2.75b.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-phenylformic acid
4-{2-[(4 '-chloro-xenyl-4-the carbonyl that 50 milliliters of 2M NaOH solution is added 11.93 grams (29.25 mmole))-amino]-ethyl-solution of ethyl benzoate in 150 milliliters of EtOH in, and at room temperature stirred 2 hours.With 1N HCl this reaction soln is adjusted to pH6-7, leaches sedimentary product, and in vacuum drying oven, carry out drying.
Productive rate: 10.74 grams (theoretical value 96.7%)
C 22H 18ClNO 3(M＝379.85)
Calculated value: mole peak (M+H) +: 380/382 trial value: mole peak (M+H) +: 380/382
The HPLC residence time: 8.0 minutes (method A)
2.75c.4 '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-phenyl)-ethyl]-acid amides
4-{2-[(4 '-chloro-xenyl-4-the carbonyl that the CDI of 4.82 grams (29.69 mmole) is added 10.74 grams (28.28 mmole))-amino]-ethyl-solution of phenylformic acid in 150 milliliters of anhydrous THF in, and with this reaction mixture 50 ℃ of heating 2 hours down.The NaBH that this solution is added 2.14 grams (56.56 mmole) 4In the suspension in 5 ml waters, and vigorous stirring 1 hour at room temperature.Use 1N HCl that the pH of this solution is adjusted to 6, it is mixed with EtOAc, and filter.With half saturated NaHCO 3Solution and water clean this filtrate, again with MgSO 4Dewater.After removing siccative and solvent, still contain unreacted 4-{2-[(4 '-chloro-xenyl-4-carbonyl in this resistates)-amino]-ethyl }-phenylformic acid, therefore repeat above-mentioned reduction step.The product of dry gained under 40 ℃.
Productive rate: 9.3 grams (theoretical value 89.9%)
C 22H 20ClNO 2(M＝365.86)
Calculated value: mole peak (M+H) +: 366/368 trial value: mole peak (M+H) +: 366/368
The HPLC residence time: 8.11 minutes (method A)
2.75d.4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides
PBr with 1.22 milliliters 3Dropwise add 4 of 7.9 grams (21.59 mmole) '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-phenyl)-ethyl]-acid amides is at 300 milliliters of CH 2Cl 2In solution in.At room temperature stirring this reaction mixture spends the night.The formed throw out of suction filtration, revaporization filtrate.With a spot of acetonitrile and CH 2Cl 2Develop this resistates, carry out suction filtration, merge, in air, carry out drying again with the throw out of at first obtaining.
Productive rate: 8.6 grams (theoretical value 92.9%)
C 22H 19BrClNO(M＝428.76)
Calculated value: mole peak (M+H) +: 428/430/432 trial value: mole peak (M+H) +: 428/430/432
R fValue: 0.4 (silica gel, CH 2Cl 2)
2.75e.4 '-chloro-xenyl-4-carboxylic acid [2-(4-aminomethyl-phenyl)-ethyl]-acid amides
With the 0.5M NH in 3 milliliters of Zai dioxs 3Solution add 150 milligrams (0.35 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-the ethyl]-solution of acid amides in 10 milliliters of acetonitriles in, and at room temperature stirred 3 days.Evaporate this reaction mixture, and with this resistates of post chromatograph purifying (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1).
Productive rate: 8 milligrams (theoretical value 6.3%)
C 22H 21ClN 2O(M＝364.88)
Calculated value: mole peak (M+H) +: 365/367 trial value: mole peak (M+H) +: 365/367
The HPLC residence time: 5.97 minutes (method A)
Embodiment 2.76:
4 '-chloro-xenyl-4-carboxylic acid (2-{4-[(diisopropylaminoethyl)-methyl]-phenyl }-ethyl)-acid amides
With the Diisopropylamine of 47 microlitres (0.33 mmole) add 129 milligrams (0.3 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 55 milligrams of (0.4 mmole) K 2CO 3In the suspension in 20 milliliters of acetonitriles, and at room temperature stir this reaction mixture and spend the night.With it with CH 2Cl 2Dilution is filtered to remove insoluble inorganic salt, this filtrate of revaporization.Develop this resistates with acetonitrile, carry out suction filtration, in air, carry out drying again.
Productive rate: 75 milligrams (theoretical value 55.7%)
C 28H 33ClN 2O(M＝449.04)
Calculated value: mole peak (M+H) +: 449/451 trial value: mole peak (M+H) +: 449/451
R fValue: 0.35 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.77:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-oxo-piperazine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.76, by 129 milligrams of (0.3 mmoles) 4 '-piperazine-2-ketone of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 33 milligrams (0.33 mmoles) is prepared.
Productive rate: 23 milligrams (theoretical value 17.1%)
C 26H 26ClN 3O 2(M＝447.97)
Calculated value: mole peak (M+H) +: 448/450 trial value: mole peak (M+H) +: 448/450
R fValue: 0.10 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.78:
[(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-methyl-amino]-ethyl acetate
Be similar to embodiment 2.76, by 257 milligrams of (0.6 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 193 milligrams K 2CO 3, and 101 milligrams of (0.66 mmole) methylamino--ethyl acetate be prepared.
Productive rate: 152 milligrams (theoretical value 54.5%)
C 27H 29ClN 2O 3(M＝465.0)
Calculated value: mole peak (M+H) +: 465/467 trial value: mole peak (M+H) +: 465/467
R fValue: 0.40 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.79:
[(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-methyl-amino]-acetate
0.3 milliliter 1M NaOH solution is added 80 milligrams of (0.17 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-benzyl)-methyl-amino]-solution of ethyl acetate in 3 milliliters of EtOH in, and reflux 1 hour.The vaporising under vacuum solvent, and the 1M HCl of resistates and water and 0.3 milliliter is mixed.The suction filtration throw out, and under 40 ℃, carry out drying.
Productive rate: 76 milligrams (theoretical value 100%)
C 25H 25ClN 2O 3(M＝436.94)
Calculated value: mole peak (M+H) +: 437/439 trial value: mole peak (M+H) +: 437/439
The HPLC residence time: 6.35 minutes (method A)
Embodiment 2.80:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(4-ethanoyl-piperazine-1-ylmethyl)-phenyl]-ethyl } acid amides
Be similar to embodiment 2.76, by 129 milligrams of (0.3 mmoles) 4 '-the 1-piperazine-1-base-ethyl ketone of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 42 milligrams (0.33 mmoles) is prepared.
Productive rate: 60 milligrams (theoretical value 42.0%)
C 28H 30ClN 3O 2(M＝476.02)
Calculated value: mole peak (M+H) +: 476/478 trial value: mole peak (M+H) +: 476/478
R fValue: 0.15 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.81:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aza-bicyclo [2.2.1] heptan-5-alkene-2-ylmethyl)-phenyl]-ethyl } acid amides
Figure A0382007601972
Be similar to embodiment 2.76, by 129 milligrams of (0.3 mmoles) 4 '-the 2-aza-bicyclo [2.2.1] of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 31 milligrams (0.33 mmoles) heptan-5-alkene and being prepared.
Productive rate: 100 milligrams (theoretical value 75.2%)
C 28H 27ClN 2O(M＝442.99)
Calculated value: mole peak (M+H) +: 443/445 trial value: mole peak (M+H) +: 443/445
R fValue: 0.08 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.82:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1,3-dihydro-isoindole-2-ylmethyl)-phenyl]-ethyl } acid amides
Figure A0382007601973
Be similar to embodiment 2.76, by 129 milligrams of (0.3 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 97 milligrams K 2CO 3, and 51 milligrams (0.33 mmoles) 2,3-dihydro-1H-isoindole (using with hydrochloride form) is prepared.
Productive rate: 80 milligrams (theoretical value 57.1%)
C 30H 27ClN 2O(M＝467.02)
Calculated value: mole peak (M+H) +: 467/469 trial value: mole peak (M+H) +: 467/469
R fValue: 0.40 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.83:
4 '-chloro-xenyl-4-carboxylic acid-2-[4-(7-methyl-2,7-diaza-spiro [4.4] ninth of the ten Heavenly Stems-2-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.76, by 129 milligrams of (0.3 mmoles) 4 '-the 2-methyl-2 of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 46 milligrams (0.33 mmoles), 7-diaza-spiro [4.4] nonane is prepared.
Productive rate: 42 milligrams (theoretical value 28.7%)
CxH 34ClN 3O(M＝488.08)
Calculated value: mole peak (M+H) +: 488/490 trial value: mole peak (M+H) +: 488/490
R fValue: 0.05 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.84:
4 '-chloro-xenyl-4-carboxylic acid-2-[4-(3-diethylin-azetidine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.76, by 129 milligrams (0.3 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 138 milligrams K 2CO 3, and the azetidine-3-base-diethyl-amine of 66 milligrams (0.33 mmoles) be prepared.
Productive rate: 15 grams (theoretical value 10.5%)
C 29H 34ClN 3O(M＝476.07)
Calculated value: mole peak (M+H) +: 476/478 trial value: mole peak (M+H) +: 476/478
R fValue: 0.10 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.85:
(S)-1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-pyridine alkane-2-carboxylic acid, ethyl ester
Figure A0382007601991
Be similar to embodiment 2.76, by 257 milligrams of (0.6 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 193 milligrams K 2CO 3, and 119 milligrams (0.66 mmole) (S)-tetramethyleneimine-2-carboxylic acid, ethyl ester (using) and being prepared with hydrochloride form; With this product of post chromatograph purifying.
Productive rate: 160 milligrams (theoretical value 54.3%)
C 26H 31ClN 2O 3(M＝491.04)
Calculated value: mole peak (M+H) +: 491/493 trial value: mole peak (M+H) +: 491/493
R fValue: 0.60 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.86:
(S)-1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-pyridine alkane-2-carboxylic acid
Figure A0382007601992
Be similar to embodiment 2.79, by (the S)-1-of 130 milligrams (0.27 mmoles) (4{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-carboxylic acid, ethyl ester is prepared.
Productive rate: 120 milligrams (theoretical value 97.8%)
C 27H 27ClN 2O 3(M＝462.98)
Calculated value: mole peak (M+H) +: 463/465 trial value: mole peak (M+H) +: 463/465
The HPLC residence time: 6.20 minutes (method A)
Embodiment 2.87:
[1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-3-yl]-the carboxylamine tertiary butyl ester
Be similar to embodiment 2.76, by 429 milligrams (1.0 mmoles) 4 '-tetramethyleneimine-3-yl of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 205 milligrams (1.10 mmoles)]-the carboxylamine tertiary butyl ester is prepared.
Productive rate: 500 milligrams (theoretical value 93.6%)
C 31H 36ClN 3O 3(M＝534.10)
Calculated value: mole peak (M+H) +: 534/536 trial value: mole peak (M+H) +: 534/536
R fValue: 0.33 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.88:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-amino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602002
1 milliliter of trichoroacetic acid(TCA) is added 500 milligrams (0.94 mmoles) [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-3-yl]-the carboxylamine tertiary butyl ester is at 15 milliliters of CH 2Cl 2In solution in, and stir this reaction mixture and spend the night.Then it is evaporated, this resistates is dissolved in a spot of CH 2Cl 2In, make itself and half saturated NaHCO again 3Solution mixes.The sedimentary product of suction filtration with the acetonitrile development, and carries out drying under 40 ℃.
Productive rate: 240 milligrams (theoretical value 59.1%)
C 26H 28ClN 3O(M＝433.99)
Calculated value: mole peak (M+H) +: 434/436 trial value: mole peak (M+H) +: 434/436
R fValue: 0.22 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.89:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-dimethylamino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
NaBH with 0.12 milliliter 37% formalin, 28 milligrams (0.45 mmoles) 3CN, and Glacial acetic acid, add 60 milligrams (0.14 mmoles) 4 '-chloro-xenyl-4-carboxylic acid { 2-[4-(3-amino-tetramethyleneimine-1-ylmethyl)-phenyl]-the ethyl }-solution of acid amides in 5 milliliters of acetonitriles in.At room temperature stir this reaction mixture and spend the night, make it mix dilute NaOH solution and EtOAc again.Separate phase, with MgSO 4This organic phase is dewatered, then remove siccative and solvent.Analyse this resistates of purifying with the post chromatograph.
Productive rate: 10 milligrams (theoretical value 15.7%)
C 28H 32ClN 3O(M＝462.04)
Calculated value: mole peak (M+H) +: 462/464 trial value: mole peak (M+H) +: 462/464
The HPLC residence time: 5.16 minutes (method A)
Embodiment 2.90:
[1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-ylmethyl]-the carboxylamine tertiary butyl ester
Figure A0382007602012
Be similar to embodiment 2.76, by 230 milligrams of (0.54 mmoles) 4 '-tetramethyleneimine-2-ylmethyl of chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides and 116 milligrams (1.10 mmoles)]-the carboxylamine tertiary butyl ester is prepared.
Productive rate: 230 milligrams (theoretical value 78.3%)
C 32H 38ClN 3O 3(M＝548.13)
Calculated value: mole peak (M+H) +: 548/550 trial value: mole peak (M+H) +: 548/550
R fValue: 0.35 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
Embodiment 2.91:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aminomethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602021
Be similar to embodiment 2.88, by [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-the amino]-ethyl of 230 milligrams (0.42 mmoles) }-benzyl)-tetramethyleneimine-2-ylmethyl]-the carboxylamine tertiary butyl ester is prepared.
Productive rate: 188 milligrams (theoretical value 100%)
C 27H 30ClN 3O(M＝448.01)
Calculated value: mole peak (M+H) +: 448/450 trial value: mole peak (M+H) +: 448/450
R fValue: 0.35 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.92:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-dimethylamino methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602022
Be similar to embodiment 2.89, by 40 milligrams of (0.09 mmoles) 4 '-chloro-xenyl-4-carboxylic acid { 2-[4-(2-aminomethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides, 0.08 milliliter of 37% formalin, and the NaBH of 19 milligrams (0.30 mmoles) 3CN is prepared.
Productive rate: 10 milligrams (theoretical value 23.6%)
C 29H 34ClN 3O(M＝476.07)
Calculated value: mole peak (M+H) +: 476/478 trial value: mole peak (M+H) +: 476/478
R fValue: 0.12 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.93:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-2,6-diaza-spiro [3.4] suffering-6-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602031
Be similar to embodiment 2.76, by 250 milligrams of (0.58 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 97 milligrams of K 2CO 3, and the 2-methyl-2 of 81 milligrams (0.64 mmoles), 6-diaza-spiro [3.4] octane is prepared.
Productive rate: 20 milligrams (theoretical value 7.2%)
C 29H 32ClN 3O(M＝474.05)
Calculated value: mole peak (M+H) +: 474/476 trial value: mole peak (M+H) +: 474/476
R fValue: 0.20 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.94:
3-[(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-ethyl-amino]-propionic acid
Figure A0382007602032
At room temperature, with 257 milligrams of (0.6 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-brooethyl-phenyl)-ethyl]-acid amides, 166 milligrams of (1.2 mmole) K 2CO 3, and the suspension of 138 milligrams of 3-ethylamino-propionic acid (0.9 mmole uses with hydrochloride form) in 20 milliliters of acetonitriles stirred 3 days.Add 5 milliliters of DMF, and this mixture was heated 3 hours down at 50 ℃.Filter this reaction mixture, evaporated filtrate is again with this resistates of HPLC purifying.
Productive rate: 50 milligrams (theoretical value 17.9%)
C 27H 29ClN 2O 3(M＝465.0)
Calculated value: mole peak (M+H) +: 465/467 trial value: mole peak (M+H) +: 465/467
The HPLC residence time: 5.85 minutes (method A)
Embodiment 2.95:
(S)-1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-carboxylate methyl ester
Figure A0382007602041
2.95a.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-ethyl benzoate
According to general methodology I, by 10.0 the gram (42.98 mmoles) 4 '-chloro-xenyl-4-carboxylic acid and 9.87 the gram (42.98 mmole) 4-(2-amino-ethyl)-ethyl benzoates be prepared.
Productive rate: 10.64 grams (theoretical value 60.7%)
C 24H 22ClNO 3(M＝407.90)
Calculated value: mole peak (M+H) +: 408/410 trial value: mole peak (M+H) +: 408/410
R fValue: 0.87 (silica gel, CH 2Cl 2/ MeOH 95: 5)
2.95b.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-phenylformic acid
14 milliliters of 2M NaOH solution are added 10.64 gram (26.08 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-solution of ethyl benzoate in 100 milliliters of EtOH in, and with reaction mixture 60 ℃ of following heated overnight, then add other 30 milliliters NaOH solution, and make this mixture maintain this temperature more following 3 hours.With 1M-HCl solution this reaction soln is adjusted to pH6-7, leaches sedimentary product, and under vacuum, carry out drying.
Productive rate: 7.65 grams (theoretical value 77.2%)
C 22H 18ClNO 3(M＝379.85)
Calculated value: mole peak (M+H) +: 380/382 trial value: mole peak (M+H) +: 380/382
The HPLC residence time: 8.1 minutes (method A)
2.95c.4 '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-phenyl)-ethyl]-acid amides
4-{2-[(4 '-chloro-xenyl-4-the carbonyl that 3.24 gram (20 mmole) CDI is added 7.2 grams (18.97 mmole))-amino]-ethyl-solution of phenylformic acid in 150 milliliters of anhydrous THF in, and with this reaction mixture 50 ℃ of heating 2 hours down.The NaBH that this solution is added 1.44 grams (38 mmole) 4In the suspension in 5 ml waters, and restir 1 hour.Use 1M HCl solution that this reaction mixture is adjusted to pH6-7, thoroughly extract with EtOAc again.With NaHCO 3Solution and water clean organic phase, again with MgSO 4Dewater.After removing siccative and solvent, with this resistates of chromatograph purifying (silica gel, CH 2Cl 2/ MeOH 9: 1).Because of in this product, still having educt, repeat above-mentioned flow process with 50% of agents useful for same.
Productive rate: 2.85 grams (theoretical value 41.0%)
C 22H 20ClNO 2(M＝365.86)
Calculated value: mole peak (M+H) +: 366/368 trial value: mole peak (M+H) +: 366/368
The HPLC residence time: 8.0 minutes (method A)
2.95.d methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl ester
With 1.25 milliliters of (9 mmole) triethylamines add 1.0 gram (2.73 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-phenyl)-the ethyl]-solution of acid amides in 100 milliliters of anhydrous THF in, and make this mixture-20 ℃ of coolings down.The methylsulfonyl chloride that then dropwise adds 0.64 milliliter (8.2 mmole), and under this temperature this mixture of restir 2 hours.The NaHCO of adding 5% 3Solution thoroughly extracts with EtOAc again.With Na 2SO 4This organic phase is dewatered, remove siccative and solvent, under vacuum, carry out drying again in 30 ℃.
Productive rate: 1.21 grams (theoretical value 99.7%)
C 23H 22ClNO 4S(M＝443.95)
Calculated value: mole peak (M+H) +: 444/446 trial value: mole peak (M+H) +: 444/446
The HPLC residence time: 8.8 minutes (method A)
2.95e. (S)-1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-carboxylate methyl ester
At N 2Under the atmosphere, in 50 milligrams of stirring at room (0.3 mmole) (2S)-tetramethyleneimine-2-carboxylate methyl ester (using) and the solution of 0.7 milliliter of (0.5 mmole) triethylamine in 4 milliliters of DMF 20 minutes with hydrochloride form.The methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyl that then adds 111 milligrams (0.25 mmoles))-amino]-ethyl-benzyl ester, and with this mixture 60 ℃ of down heating 2 hours.This reaction mixture of vaporising under vacuum, and with this resistates of HPLC purifying.
Productive rate: 4 milligrams (theoretical value 3.4%)
C 28H 29ClN 2O 3(M＝477.01)
Calculated value: mole peak (M+H) +: 477/479 trial value: mole peak (M+H) +: 477/479
The HPLC residence time: 6.51 minutes (method A)
Embodiment 2.96:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-pipecoline of benzyl ester and 35 microlitres (0.3 mmole), do not use triethylamine and be prepared.
Productive rate: 7 milligrams (theoretical value 6.3%)
C 28H 31ClN 2O(M＝447.03)
Calculated value: mole peak (M+H) +: 447/449 trial value: mole peak (M+H) +: 447/449
The HPLC residence time: 6.4 minutes (method A)
Embodiment 2.97:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602062
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-benzyl ester and 32 microlitres (0.3 mmole) 2-methyl-tetramethyleneimine does not use triethylamine and is prepared.
Productive rate: 2 milligrams (theoretical value 1.8%)
C 27H 29ClN 2O(M＝433.0)
Calculated value: mole peak (M+H) +: 433/435 trial value: mole peak (M+H) +: 433/435
The HPLC residence time: 6.3 minutes (method A)
Embodiment 2.98:
4 '-chloro-xenyl-4-carboxylic acid (2-{4-[(cyclopropyl methyl-amino)-methyl]-phenyl }-ethyl)-acid amides
Figure A0382007602071
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-cyclopropyl-methylamine of benzyl ester and 26 microlitres (0.3 mmole), do not use triethylamine and be prepared.
Productive rate: 4 milligrams (theoretical value 3.8%)
C 26H 27ClN 2O(M＝418.97)
Calculated value: mole peak (M+H) +: 418/420 trial value: mole peak (M+H) +: 418/420
The HPLC residence time: 6.4 minutes (method A)
Embodiment 2.99:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-benzyl ester and 40 milligrams of (0.3 mmoles) 1,2,3, the 4-tetrahydroisoquinoline does not use triethylamine and is prepared.
Productive rate: 21 milligrams (theoretical value 17.5%)
C 26H 27ClN 2O(M＝481.04)
Calculated value: mole peak (M+H) +: 481/483 trial value: mole peak (M+H) +: 481/483
The HPLC residence time: 6.8 minutes (method A)
Embodiment 2.100:
4 '-chloro-xenyl-4-carboxylic acid [2-(4-{[(2-hydroxyl-ethyl)-methyl-amino]-methyl }-phenyl)-ethyl]-acid amides
Figure A0382007602081
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-benzyl ester and 24 microlitres (0.3 mmole) 2-methylamino--ethanol, do not use triethylamine and be prepared.
Productive rate: 13 milligrams (theoretical value 12.3%)
C 25H 27ClN 2O 2(M＝422.96)
Calculated value: mole peak (M+H) +: 423/425 trial value: mole peak (M+H) +: 423/425
The HPLC residence time: 5.8 minutes (method A)
Embodiment 2.101:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,6-dimethyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-benzyl ester and 41 microlitres (0.3 mmole) 2,6-dimethyl-piperidines does not use triethylamine and is prepared.
Productive rate: 8 milligrams (theoretical value 6.9%)
C 29H 33ClN 2O(M＝461.05)
Calculated value: mole peak (M+H) +: 461/463 trial value: mole peak (M+H) +: 461/463
The HPLC residence time: 6.6 minutes (method A)
Embodiment 2.102:
4 '-chloro-xenyl-4-carboxylic acid [2-(4-azetidine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.95e, by 111 milligrams of (0.42 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-benzyl ester and 20 microlitres (0.3 mmole) azetidine, do not use triethylamine and be prepared.
Productive rate: 3 milligrams (theoretical value 3.0%)
C 25H 25ClN 2O(M＝404.94)
Calculated value: mole peak (M+H) +: 405/407 trial value: mole peak (M+H) +: 405/407
The HPLC residence time: 5.9 minutes (method A)
Embodiment 2.103:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
Be similar to embodiment 2.95e, by 50 milligrams of (0.11 mmole) methylsulfonic acid 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-benzyl ester and 11 microlitres (0.14 mmole) 2,5-dihydro-1H-pyrroles does not use triethylamine and is prepared.
Productive rate: 18 milligrams (theoretical value 38.2%)
C 26H 25ClN 2O(M＝416.95)
Calculated value: mole peak (M+H) +: 417/419 trial value: mole peak (M+H) +: 417/419
The HPLC residence time: 6.2 minutes (method A)
Embodiment 2.104:
4 '-bromo-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
Figure A0382007602093
2.104a.4 '-bromo-xenyl-4-carboxylic acid, ethyl ester
Be similar to embodiment 2.46b, by 1.22 milliliters of (7.47 mmole) 4-bromo-ethyl benzoates and 1.8 gram (8.96 mmole) 4-bromophenyl-boric acid, reflux 72 hours and being prepared.Make the crystallization in acetonitrile of this product.
Productive rate: 293 milligrams (theoretical value 12.8%)
C 15H 13BrO 2(M＝305.17)
Calculated value: mole peak (M+H) +: 304/306 trial value: mole peak (M+H) +: 304/306
R fValue: 0.9 (silica gel, sherwood oil/EtOAc 6: 4)
2.104b.4 '-bromo-xenyl-4-carboxylic acid
With 1.24 milliliters of 2M NaOH solution add 270 milligrams of (0.89 mmoles) 4 '-solution of bromo-xenyl-4-carboxylic acid, ethyl ester in 10 milliliters of EtOH in, and at room temperature stirred this reaction mixture 2 hours.With 1M HCl pH is adjusted to 6-7, leaches sedimentary product, and carry out drying.
Productive rate: 205 milligrams (theoretical value 83.6%)
C 13H 9BrO 2(M＝277.12)
Calculated value: mole peak (M-H) -: 275/277 trial value: mole peak (M-H) -: 275/277
The HPLC residence time: 8.5 minutes (method A)
(2.104c.[4-2-amino-ethyl)-phenyl]-methyl alcohol
580 milligrams of Raney nickel are added the NH of 5.8 gram (39.41 mmole) (4-methylol-phenyl)-acetonitriles (referring to example 1.1e.) in 116 ml methanolization 3In the solution in the solution, under 50psi hydrogen, this reaction mixture is carried out hydrogenation again.When reaction finishes, leach catalyzer, remove and desolvate, again with this resistates of chromatograph purifying (silica gel, EtOAc/MeOH/NH 37: 3: 0.3).
Productive rate: 3.9 grams (theoretical value 65.4%)
C 9H 13NO(M＝151.21)
Calculated value: mole peak (M+H) +: 152 trial values: mole peak (M+H) +: 152
R fValue: 0.18 (silica gel, EtOAc/MeOH/NH 38: 2: 0.2)
(2.104d.[2-4-methylol-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
At room temperature, with 17.36 milliliters at CH 2Cl 2In the 1MBOC acid anhydride add [4-(2-amino-ethyl)-the phenyl]-methyl alcohol of 2.5 grams (16.53 mmole) at 50 milliliters of CH 2Cl 2In solution in, and at room temperature stir this reaction mixture and spend the night.Add 100 milliliters of KHSO 4Solution separates organic phase, with rare NaHCO 3Solution and water clean, again with MgSO 4Dewater.After removing siccative and solvent, obtain desired product.
Productive rate: 4.06 grams (theoretical value 97.7%)
C 14H 21NO 3(M＝251.33)
Calculated value: mole peak (M+H) +: 252 trial values: mole peak (M+H) +: 252
The HPLC residence time: 6.4 minutes (method A)
(2.104e.[2-4-chloromethyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
1 milliliter of pyridine is added [2-(4-methylol-phenyl)-the ethyl]-carboxylamine tertiary butyl ester of 2.6 grams (10.35 mmole) at 50 milliliters of CH 2Cl 2In solution in, be cooled to 0 ℃, add the thionyl chloride of 1.03 milliliters (12.41 mmoles) again.Make this mixture maintain 0 ℃ 1 hour, it is risen again to room temperature.With water, rare KHSO 4Solution, clean this reaction mixture with water again, with MgSO 4Dehydration is filtered by activated carbon again.Except that after desolvating, obtain being the product of oil body, it can react without being further purified.
Productive rate: 1.8 grams (theoretical value 64.5%)
C 14H 20ClNO 2(M＝269.77)
Calculated value: mole peak (M-H) -: 268/270 trial value: mole peak (M-H) -: 268/270
R fValue: 0.62 (silica gel, sherwood oil/EtOAc 7: 3)
(2.104f.{2-[4-2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-the carboxylamine tertiary butyl ester
With 2.37 gram (17.13 mmole) K 2CO 3And 0.8 milliliter (10.38 mmole) 2,5-dihydro-1H-pyrroles adds in [2-(4-chloromethyl-phenyl)-the ethyl]-solution of carboxylamine tertiary butyl ester in 50 milliliters of acetonitriles of 1.4 grams (5.19 mmole), and at room temperature stirs this mixture overnight.With CH 2Cl 2Dilute this reaction mixture, clean with water, again with MgSO 4Dewater.After removing siccative and solvent, obtain desired product.
Productive rate: 1.46 grams (theoretical value 93.0%)
C 18H 26N 2O 2(M＝302.42)
Calculated value: mole peak (M+H) +: 303 trial values: mole peak (M+H) +: 303
R fValue: 0.15 (silica gel, sherwood oil/EtOAc 7: 3)
(2.104g.2-[4-2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethamine
5 milliliters of trifluoroacetic acids are added 1.21 grams (4 mmole) { 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-carboxylamine tertiary butyl ester at 50 milliliters of CH 2Cl 2In solution in, and at room temperature stirred 2 hours.This reaction mixture of vaporising under vacuum makes this resistates mixing water and CH 2Cl 2, again with K 2CO 3Solution alkalizes.Separate organic phase, clean with water, again with MgSO 4Dewater.After removing siccative and solvent, obtain desired product.
Productive rate: 0.35 gram (theoretical value 43.3%)
C 13H 18N 2(M＝202.30)
Calculated value: mole peak (M+H) +: 203 trial values: mole peak (M+H) +: 203
R fValue: 0.05 (silica gel, EtOAc/MeOH/NH 39: 1: 0.1)
2.104h.4 '-bromo-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
According to general methodology I, by 139 milligrams (0.50 mmoles) 4 '-2-[4-(2,5-dihydro-pyrroles-1-the ylmethyl)-phenyl of bromo-xenyl-4-carboxylic acid and 101 milligrams (0.50 mmoles)]-ethamine is prepared.
Productive rate: 21 milligrams (theoretical value 9.1%)
C 26H 25BrN 2O(M＝461.41)
Calculated value: mole peak (M+H) +: 461/463 trial value: mole peak (M+H) +: 461/463
The HPLC residence time: 6.46 minutes (method A)
Embodiment 2.105:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-ethyl-piperidines-2-yl)-phenyl]-ethyl }-acid amides
Figure A0382007602121
(2.105a. 4-pyridine-2-base-phenyl)-acetonitrile
Be similar to embodiment 2.46b, be prepared by 0.52 milliliter of (5.40 mmole) 2-bromo-pyridine and 1.0 gram (5.96 mmole) 4-cyanogen aminomethyl phenyl-boric acid.After removing siccative and solvent, develop this resistates with diisopropyl ether, and in air, carry out drying.
Productive rate: 0.76 milligram (theoretical value 72.5%)
C 13H 10N 2(M＝194.24)
Calculated value: mole peak (M+H) +: 195 trial values: mole peak (M+H) +: 195
The HPLC residence time: 3.56 minutes (method B)
(2.105b.2-4-cyanogen methyl-phenyl)-1-ethylpyridine iodine
0.38 milliliter of (4.7 mmole) iodoethane is added in the solution of (4-pyridine-2-base-phenyl)-acetonitrile in 5 milliliters of DMF of 760 milligrams (3.91 mmoles), and at room temperature stir and spend the night, for finishing reaction, in microwave oven, handled this solution 20 minutes in 120 ℃.The vaporising under vacuum solvent makes this resistates mixing water, extracts with EtOAc again.Evaporate this water,, again this suspension is cooled to 0 ℃ with THF development resistates.This product of suction filtration, and under 50 ℃, carry out drying.
Productive rate: 800 milligrams (theoretical value 58.4%)
C 15H 15IN 2(M＝350.21)
Calculated value: mole peak (M+)+: 223 trial values: mole peak (M)+: 223
The HPLC residence time: 1.76 minutes (method A)
(2.105c.2-[4-1-ethyl-piperidines-2-yl)-phenyl]-ethamine
100 milligrams of Raney nickel are added the NH of 800 milligrams of (2.28 mmole) 2-(4-cyanogen methyl-phenyl)-1-ethylpyridine iodine in 10 ml methanolization 3In the solution in the solution, in autoclave, under 20psi and room temperature, this reaction mixture was carried out hydrogenation 24 hours again.This catalyzer of suction filtration makes this reaction soln mix 100 milligrams PtO 2, under room temperature and 20psi, carry out hydrogenation 30 hours more once more.Obtain product (being hydrochloride form) after removing catalyzer, it is not purified can to carry out next step reaction.
Productive rate: 700 milligrams (theoretical value 85.1%)
C 15H 24IN 2(M＝360.28)
Calculated value: mole peak (M)+: 233 trial values: mole peak (M)+: 233
The HPLC residence time: the 0.93 minute (water of 8 minutes isocratic elution: acetonitrile: formic acid 95: 5: 0.01)
2.105d.4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-ethyl-piperidines-2-yl)-phenyl]-ethyl }-acid amides
According to general methodology I, by 480 milligrams of (1.33 mmole) 2-[4-(1-ethyl-piperidines-2-yl)-phenyl]-ethamine (using) and 310 milligrams of (1.33 mmoles) 4 with hydrochloride form '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 20 milligrams (theoretical value 3.4%)
C 28H 31ClN 2O(M＝447.03)
Calculated value: mole peak (M+H) +: 447/449 trial value: mole peak (M+H) +: 447/449
The HPLC residence time: 6.68 minutes (method A)
Embodiment 2.106
4 '-chloro-xenyl-4-carboxylic acid [2-(1-tetramethyleneimine-1-base-indane-5-yl)-ethyl]-acid amides
Figure A0382007602141
2.106a. (E)-3-(2-oxo-indane-5-yl)-ethyl propenoate
At N 2Down, with 5.96 milliliters of (55 mmole) ethyl propenoates, 275 milligrams of (1.21 mmole) Pd (OAc) 2, and 704 milligrams of (2.31 mmole) three-neighbours-tolylphosphine, add in the solution of 4.64 gram (21.99 mmole) 5-bromo-dihydro 1-Indanones in 110 milliliters of triethylamines, again with this reaction mixture 100 ℃ of heating 4 hours down.Distillation removes and desolvates, and makes this resistates mix 150 milliliters of EtOAc and 100 milliliters of frozen water, carries out acidifying with dense HCl, cleans this organic phase with 100 milliliters water, again with MgSO 4Dewater.After removing siccative and solvent, with this resistates of chromatograph purifying (silica gel, hexane/EtOAc 9: 1 to 8: 2).
Productive rate: 4.0 grams (theoretical value 79.0%)
Fusing point: 100-102 ℃
2.106.b. (E)-3-(1-oxo-indane-5-yl)-vinylformic acid
With 10 milliliters of 2N NaOH add 4.0 grams (17.0 mmole) (E)-3-(1-oxo-indane-5-the yl)-solution of ethyl propenoate in 50 milliliters of MeOH in, and make this reaction mixture reflux 30 minutes.Then make its 2N HCl solution that mixes 11 milliliters, distillation removes and desolvates, and the suction filtration crystal carries out drying again.
Productive rate: 3.0 grams (theoretical value 87.3%)
Fusing point: 240-244 ℃
(2.106c.3-1-oxo-indane-5-yl)-propionic acid
With 150 milligrams of 10%Pd/C add 1.6 grams (7.91 mmole) (E)-3-(1-oxo-indane-5-the yl)-solution of vinylformic acid in 50 milliliters of MeOH in, again in the Parr autoclave, in room temperature and 3 crust H 2Shake this reaction mixture, up to reaching H in theory down, 2Till the absorption.Add 10 milliliters of 1NNaOH, remove again and desolvate.With rare this resistates of HCl acidifying, thoroughly extract with EtOAc, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, develop this resistates with t-butyl methyl ether, this throw out of suction filtration, and carry out drying.
Productive rate: 500 milligrams (theoretical value 31.0%)
C 12H 12O 3(M＝204.23)
Calculated value: mole peak (M-H) -: 203 trial values: mole peak (M-H) -: 203
R fValue: 0.45 (silica gel, CH 2Cl 2/ MeOH 9: 1)
(2.106d.[2-1-oxo-indane-5-yl)-ethyl]-the carboxylamine tertiary butyl ester
Under argon gas atmosphere, 1.6 gram (7.83 mmole) 3-(1-oxo-indane-5-yl)-propionic acid are added in 25 milliliters of trimethyl carbinols and the 2.5 milliliters of triethylamines.In this solution, add 2.22 milliliters of (10.0 mmole) nitrine phosphoric acid diphenyl, heated 3 hours down at 80 ℃ again.This reaction mixture of vaporising under vacuum is again on silica gel, with this resistates of chromatograph purifying.
Productive rate: 750 milligrams (theoretical value 34.8%)
C 16H 21NO 3(M＝275.35)
Calculated value: mole peak (M)+: 275 trial values: mole peak (M)+: 275
R fValue: 0.65 (silica gel, CH 2Cl 2/ MeOH 95: 5)
(2.106e.[2-1-hydroxyl-indane-5-yl)-ethyl]-the carboxylamine tertiary butyl ester
NaBH with 700 milligrams (18.5 mmoles) 4Add in 700 milligrams (2.54 mmoles) [2-(1-oxo-indane-5-yl)-the ethyl]-solution of carboxylamine tertiary butyl ester in 70 milliliters of MeOH in batches, and at room temperature stir and spend the night.Make careful 10% the KHSO that mixes of this reaction soln 4Solution with the water dilution, thoroughly extracts with t-butyl methyl ether again.Clean this organic layer with water, again with MgSO 4Dehydration.After removing siccative and solvent, on silica gel, analyse this resistates of purifying with chromatograph.
Productive rate: 350 milligrams (theoretical value 49.7%)
C 16H 23NO 3(M＝277.37)
Calculated value: mole peak (M)+: 277 trial values: mole peak (M)+: 277
R fValue: 0.30 (silica gel, sherwood oil/EtOAc 6: 4)
(2.106f.[2-1-tetramethyleneimine-1-base-indane-5-yl)-ethyl]-the carboxylamine tertiary butyl ester
109 microlitres (1.5 mmole) thionyl chloride (is dissolved in a spot of CH 2Cl 2In) slowly dropwise add be cooled to 0 ℃ 350 milligrams (1.26 mmoles) [2-(1-hydroxyl-indane-5-yl)-ethyl]-carboxylamine tertiary butyl ester at 7.5 milliliters of CH 2Cl 2In solution in.Continue to stir 30 minutes at 10 ℃, make this reaction soln mix ice-cold NaHCO 3Solution separates organic phase, cleans with frozen water, again with MgSO 4Dewater.After removing siccative and solvent, this filtrate is cooled to 0 ℃, dropwise add the tetramethyleneimine of 417 microlitres (5.0 mmole), at room temperature stir this reaction mixture again and spend the night.Evaporate this reaction mixture, again on silica gel, with this resistates of chromatograph purifying.
Productive rate: 120 milligrams (theoretical value 28.8%)
C 20H 30N 2O 2(M＝330.47)
Calculated value: mole peak (M+H) +: 331 trial values: mole peak (M+H) +: 331
The HPLC residence time: 5.6 minutes (method A)
(2.106g.2-1-tetramethyleneimine-1-base-indane-5-yl)-ethamine
[2-(1-tetramethyleneimine-1-base-indane-5-yl)-the ethyl]-carboxylamine tertiary butyl ester that 100 microlitre trifluoroacetic acids is added 100 milligrams (0.3 mmoles) under cooling off slightly is at 10 milliliters of CH 2Cl 2In solution in, at room temperature stirred again 1 hour.For finishing reaction, under cooling, add other 500 microlitre trifluoroacetic acids, at room temperature stirred again 2 hours.This reaction mixture of vaporising under vacuum, this product (being two-trifluoroacetic acid salt form) is not purified can to carry out next step reaction.
Productive rate: 100 milligrams (theoretical value 72.7%)
C 19H 24F6N 2O 4(M＝458.51)
Calculated value: mole peak (M+H) +: 231 trial values: mole peak (M+H) +: 231
R fValue: 0.3 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
2.106h.4 '-chloro-xenyl-4-carboxylic acid [2-(1-tetramethyleneimine-1-base-indane-5-yl)-ethyl]-acid amides
According to general methodology I, by 100 milligrams of (0.29 mmole) 2-(1-tetramethyleneimine-1-base-indane-5-yl)-ethamine (using) and 70 milligrams of (0.3 mmoles) 4 with two trifluoroacetic acid salt forms '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 40 milligrams (theoretical value 30.0%)
C 28H 29ClN 2O(M＝445.01)
Calculated value: mole peak (M+H) +: 445/447 trial value: mole peak (M+H) +: 445/447
The HPLC residence time: 6.65 minutes (method A)
Embodiment 2.107:
4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602161
2.107a.2-bromo-4-cyanogen methyl-methyl benzoate
With the solution of 98.55 gram (0.32 mole) 2-bromine 4-brooethyl-methyl benzoate in 60 milliliters of EtOH, add in the solution of 24.51 gram (0.5 mole) NaCN in 40 ml waters, and make this reaction mixture reflux 5 hours.Add 1 liter of t-butyl methyl ether and 500 ml waters, separate organic phase, clean for several times with water, again with MgSO 4Dewater.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (sherwood oil/EtOAc 8: 2).
Productive rate: 15.0 milligrams (theoretical value 16.6%)
C 10H 8BrNO 2(M＝254.09)
Calculated value: mole peak (M-H) -: 252/254 trial value: mole peak (M-H) -: 252/254
2.107b.2-bromo-4-cyanogen methyl-phenylformic acid
35 milliliters of 1M NaOH solution are added in the solution of 7.9 gram (31.0 mmole) 2-bromo-4-cyanogen methyl-methyl benzoate in 100 milliliters of EtOH, make this reaction mixture reflux 1 hour, at room temperature stir again and spend the night.Add frozen water, again with rare KHSO 4This mixture of solution acidifying.This throw out of suction filtration cleans with water, carries out drying again under 50 ℃.
Productive rate: 6.2 grams (theoretical value 83.3%)
C 9H 6BrNO 2(M＝240.06)
Calculated value: mole peak (M-H) -: 238/240 trial value: mole peak (M-H) -: 238/240
The HPLC residence time: 3.99 minutes (method B)
(2.107c. 3-bromo-4-methylol-phenyl)-acetonitrile
1.78 gram (11 mmole) CDI are added in the solution of 2.4 gram (10 mmole) 2-bromo-4-cyanogen methyl-phenylformic acid in 50 milliliters of THF, in water-bath, heat, up to gas send out become to stop till.The NaBH that then it is added 0.76 gram (20 mmole) 4In the solution in 50 ml waters, simultaneous temperature should be no more than 30 ℃.At room temperature continue again to stir 2 hours, with rare KHSO 4This reaction mixture of the careful acidifying of solution thoroughly extracts with t-butyl methyl ether, cleans this organic phase with water, again with MgSO 4Dewater.It is filtered by activated carbon, under vacuum, remove again and desolvate.
Productive rate: 2.2 milligrams (theoretical value 97.3%)
C 9H 8BrNO(M＝226.07)
Calculated value: mole peak (M-H) -: 224/226 trial value: mole peak (M-H) -: 224/226
R fValue: 0.6 (silica gel, CH 2Cl 2/ MeOH 9: 1)
(2.107d. 3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile
1.25 milliliters of (9 mmole) triethylamines are added 1.9 gram (8.4 mmole) (3-bromo-4-methylol-phenyl)-acetonitriles at 50 milliliters of CH 2Cl 2In solution in, be cooled to 0 ℃, and the methylsulfonyl chloride that dropwise adds 0.66 milliliter (8.5 mmole) is at 10 milliliters of CH 2Cl 2In solution.Down stirred this mixture 1 hour at 0 ℃, then at the ice-cooled tetramethyleneimine that dropwise adds 1.4 milliliters (17 mmoles) down at 10 milliliters of CH 2Cl 2In solution.This reaction mixture is risen again to ambient temperature overnight, and mixing water separates organic phase, cleans twice with water, makes it pass through active carbon filtration, evaporates under vacuum again.Make this resistates and toluene carry out coevaporation twice, the not purified reaction of promptly carrying out next step of the product of gained.
Productive rate: 2.25 grams (theoretical value 95.9%)
C 13H 15BrN 2(M＝279.18)
Calculated value: mole peak (M+H) +: 279/281 trial value: mole peak (M+H) +: 279/281
R fValue: 0.5 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
(2.107e.2-3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
20 milligrams of Raney nickel are added the NH of 225 milligrams of (0.81 mmole) (3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitriles in 5 ml methanolization 3Reach in the solution among 5 milliliters of EtOAc, again in the Parr autoclave, in room temperature and 5psi H 2Under shook 1 hour.Filtration catalizer, vaporising under vacuum solvent, the not purified reaction that can carry out next time of this product.
Productive rate: 225 milligrams (theoretical value 98.1%)
C 13H 19BrN 2(M＝283.21)
Calculated value: mole peak (M+H) +: 283/285 trial value: mole peak (M+H) +: 283/285
R fValue: 0.08 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
2.107f.4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 220 milligrams of (0.78 mmole) 2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 186 milligrams of (0.8 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.After removing siccative and solvent, this resistates is dissolved in the isopropanol/tert-butyl methyl ether, make it mix the HCl of etherization, under vacuum, evaporate again.This resistates is dissolved in once more in 20 milliliters the Virahol, develops, suction filtration cleans with a small amount of Virahol, carries out drying again under 50 ℃.
Productive rate: 165 milligrams (theoretical value 39.6%)
C 26H 27BrCl 2N 2O(M＝534.33)
Calculated value: mole peak (M+H) +: 497/499/501 trial value: mole peak (M+H) +: 497/499/501
R fValue: 0.35 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.108:
4 '-chloro-xenyl-4-carboxylic acid [2-(3-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
With 17.3 milligrams of (0.28 mmole) methyl-boron-dihydroxides, 2.5 milliliters of 2M Na 2CO 3Solution, and 32 milligrams of (0.03. mmole) four-(triphenylphosphine)-palladiums, add 150 milligrams (0.28 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-the ethyl]-solution of amide salt acidulants in 5 milliliters of dioxs in, make this reaction reflux 5 hours again.Make this hot aaerosol solution carry out suction filtration, make this filtrate mix half saturated NaHCO by glass fibre filter 3Solution thoroughly extracts with EtOAc, again with MgSO 4Dewater.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (CH 2Cl 2/ MeOH 8: 2).
Productive rate: 20 milligrams (theoretical value 16.4%)
C 27H 29ClN 2O(M＝433.0)
Calculated value: mole peak (M+H) +: 433/435 trial value: mole peak (M+H) +: 433/435
The HPLC residence time: 6.47 minutes (method A)
Embodiment 2.109:
4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(2.109a.4-2-amino-ethyl)-3-nitro-ethyl benzoate
With 5.78 gram (57 mmole) KNO 3Add in batches be cooled to-5 ℃ 12.0 gram (52 mmole) 4-(2-amino-ethyl)-ethyl benzoates at 80 milliliters of dense H 2SO 4In solution in, and under this temperature, stirred 1 hour again.This reaction soln is slowly dropwise added in the ice (this temperature should be no more than 0 ℃) restir 1 hour.The suction filtration throw out after the water cleaning, carries out drying under 50 ℃.
Productive rate: 8.2 grams (theoretical value 66.2%)
C 11H 14N 2O 4(M＝238.25)
Calculated value: mole peak (M+H) +: 239 trial values: mole peak (M+H) +: 239
The HPLC residence time: 3.64 minutes (method A)
2.109b.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-the 3-ethyl nitrobenzoate
According to general methodology I, by 8.2 gram (34 mmole) 4-(2-amino-ethyl)-3-nitro-ethyl benzoates and 7.91 gram (34 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 7.7 grams (theoretical value 50.0%)
C 24H 21ClN 2O 5(M＝452.90)
Calculated value: mole peak (M+H) +: 452/454 trial value: mole peak (M+H) +: 452/454
The HPLC residence time: 6.14 minutes (method B)
2.109c.3-amino-4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-ethyl benzoate
0.5 gram Raney nickel is added 7.7 gram (17 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-solution of 3-ethyl nitrobenzoate in 200 milliliters of EtOAc in, again in autoclave, in room temperature and 10psi H 2Under shake this reaction mixture and spend the night.For finishing reaction, add 50 milliliters of THF and shake 2 hours suction filtration catalyzer again, after thoroughly cleaning with THF, the vaporising under vacuum solvent is developed this resistates with EtOAc, carries out drying again in air.
Productive rate: 5.0 grams (theoretical value 69.5%)
C 24H 23ClN 2O 3(M＝422.92)
Calculated value: mole peak (M+H) +: 423/425 trial value: mole peak (M+H) +: 423/425
The HPLC residence time: 5.71 minutes (method B)
2.109d.3-bromo-4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl } ethyl benzoate
20 milliliters of 48%HBr are added 5.0 gram (7.69 mmole) 3-amino-4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-solution of ethyl benzoate in 20 ml waters in, and be cooled to 0 ℃.Then dropwise add 0.9 gram (13 mmole) NaNO 2Solution in 5.2 ml waters makes temperature be no more than 5 ℃, again in this mixture of 0 ℃ of following restir 10 minutes.Then under this temperature, dropwise add the solution of 1.87 gram (13 mmole) CuBr in 6.65 milliliters of 48%HBr.Then this reaction mixture was heated 1 hour down at 60 ℃.Add entry, thoroughly extract this mixture with EtOAc again.Clean this organic phase with water, again with MgSO 4Dewater.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (sherwood oil/EtOAc 6: 4).
Productive rate: 1.3 grams (theoretical value 34.7%)
C 24H 21BrClNO 3(M＝486.80)
Calculated value: mole peak (M+H) +: 486/488/490 experimental value: mole peak (M+H) +: 486/488/490
R fValue: 0.55 (silica gel, sherwood oil/EtOAc 6: 4)
2.109e.3-bromo-4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-phenylformic acid
6 milliliters of 1N NaOH solution are added 1.3 gram (2.67 mmole) 3-bromo-4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-suspension of ethyl benzoate in 20 milliliters of EtOH and 5 milliliters of THF in, and at room temperature stir this reaction mixture and spend the night.Under vacuum, evaporate, make the resistates mixing water, neutralize with 1N HCl again, thereby be settled out product.Ice-cooled down restir 1 hour, this mixture of suction filtration cleaned with water simultaneously, carries out drying again under 50 ℃.
Productive rate: 1.2 grams (theoretical value 97.9%)
C 22H 17BrClNO 3(M＝458.74)
Calculated value: mole peak (M+H) +: 456/458/460 experimental value: mole peak (M+H) +: 456/458/460
The HPLC residence time: 5.51 minutes (method B)
2.109f.4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-methylol-phenyl)-ethyl]-acid amides
0.64 gram (3.92 mmole) CDI is added 1.2 gram (2.62 mmole) 3-bromo-4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl-solution of phenylformic acid in 10 milliliters of DMF in, again this mixture is heated down at 50 ℃, till gas stops.The NaBH that this reaction mixture is added 0.3 gram (7.85 mmole) 4In the solution in 10 ml waters, at room temperature stirred 1 hour, with rare KHSO 4Solution carries out acidifying, thoroughly extracts with EtOAc again.With half saturated NaHCO 3Solution cleans this organic phase, again with MgSO 4Dewater.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 0.87 gram (theoretical value 74.8%)
C 22H 19BrClNO 2(M＝444.76)
Calculated value: mole peak (M+H) +: 444/446/448 experimental value: mole peak (M+H) +: 444/446/448
The HPLC residence time: 8.07 minutes (method A)
2.109g.4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-acid amides
With the pyridine of 0.24 milliliter (2.93 mmole) add 4 of 0.87 gram (1.96 mmole) '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-methylol-phenyl)-ethyl]-acid amides is at 20 milliliters of CH 2Cl 2In solution in, and be cooled to 0 ℃.The thionyl chloride that adds 0.21 milliliter (2.93 mmole) stirred this mixture 1 hour under this temperature, it is risen again to room temperature.Add entry, this mixture is filtered, by diatomite with CH 2Cl 2Extract this water, again with MgSO 4The organic phase that is combined is dewatered.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 0.66 gram (theoretical value 72.8%)
C 22H 18BrCl 2NO(M＝463.21)
Calculated value: mole peak (M+H) +: 462/464/466 experimental value: mole peak (M+H) +: 462/464/466
The HPLC residence time: 6.37 minutes (method B)
2.109h.4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
With 0.59 gram (4.28 mmole) K 2CO 3And 0.24 milliliter of (2.85 mmole) tetramethyleneimine add 0.66 gram (1.43 mmole) 4 '-solution of chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-acid amides in 20 milliliters of acetonitriles and 6 milliliters of DMF in, and at room temperature stirred 5 hours.Add entry, thoroughly extract this mixture, clean this organic phase repeatedly, again with MgSO with water with EtOAc 4Dewater.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (CH 2Cl 2/ MeOH 9: 1).
Productive rate: 0.2 gram (theoretical value 28.2%)
C 26H 26BrClN 2O(M＝497.87)
Calculated value: mole peak (M+H) +: 497/499/501 experimental value: mole peak (M+H) +: 497/499/501
The HPLC residence time: 4.39 minutes (method B)
Embodiment 2.110:
4 '-chloro-xenyl-4-carboxylic acid [2-(2-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602221
Be similar to embodiment 2.108, by 200 milligrams of (0.40 mmoles) 4 '-methyl-boron-dihydroxide of chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides and 27.3 milligrams (0.44 mmoles), reflux only 2 hours, and be prepared with this product of HPLC purifying.
Productive rate: 62 milligrams (theoretical value 35.6%)
C 27H 29ClN 2O(M＝433.0)
Calculated value: mole peak (M+H) +: 433/435 experimental value: mole peak (M+H) +: 433/435
The HPLC residence time: 6.15 minutes (method A)
Embodiment 2.111:
4 '-chloro-xenyl-4-carboxylic acid [2-(2-nitro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.111a.4-{2-[(4 amino '-chloro-xenyl-4-carbonyl)]-ethyl }-3-nitro-phenylformic acid
2 milliliters of 1N NaOH solution are added 200 milligrams of (0.44 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino-ethyl-solution of 3-ethyl nitrobenzoate (embodiment 2.109b) in 10 milliliters of EtOH in, and at room temperature stirred this reaction mixture 1 hour.This mixture of vaporising under vacuum adds entry and 2 milliliters of 1N HCl solution in this resistates, stirred this suspension 30 minutes again in ice bath.The suction filtration product cleans with water, carries out drying again under 50 ℃.
Productive rate: 180 milligrams (theoretical value 95.9%)
C 22H 17ClN 2O 5(M＝424.84)
Calculated value: mole peak (M+H) +: 425/427 experimental value: mole peak (M+H) +: 425/427
R fValue: 0.07 (silica gel, EtOAc/MeOH/NH 39: 1: 0.1)
2.111b.4 '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-2-nitro-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.109f, by 180 milligrams of (0.42 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-3-nitro-phenylformic acid is prepared.
Productive rate: 110 milligrams (theoretical value 63.1%)
C 22H 19ClN 2O 4(M＝410.86)
Calculated value: mole peak (M+H) +: 411/413 experimental value: mole peak (M+H) +: 411/413
The HPLC residence time: 8.27 minutes (method A)
2.111c.4 '-chloro-xenyl-4-carboxylic acid [2-(2-nitro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
With 23 microlitre methylsulfonyl chlorides slowly dropwise add 110 milligrams of (0.27 mmoles) 4 being cooled to 5 ℃ '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-2-nitro-phenyl)-ethyl]-acid amides and 48 microlitre triethylamines are at 5 milliliters of CH 2Cl 2In solution in.This solution was heated 1 hour down at 40 ℃, add 5 milliliters of DMF and 115 microlitres (1.34 mmole) tetramethyleneimine, this mixture was heated 1 hour down at 80 ℃, in its process, evaporate CH 2Cl 2This reaction mixture of vaporising under vacuum makes this resistates mixing water, thoroughly extracts with EtOAc, and with MgSO 4This organic phase is dewatered.After removing siccative and solvent, with this resistates of HPLC purifying.
Productive rate: 11 milligrams (theoretical value 8.8%)
C 26H 26ClN 3O 3(M＝463.97)
Calculated value: mole peak (M+H) +: 464/466 experimental value: mole peak (M+H) +: 464/466
The HPLC residence time: 6.44 minutes (method A)
Embodiment 2.112:
4 '-chloro-xenyl-4-carboxylic acid [2-(2-methylsulfonyl amino-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.112a.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-3-methylsulfonyl amino-ethyl benzoate
44 microlitres (0 57 mmole) methylsulfonyl chloride is slowly dropwise added 200 milligrams of (0.47 mmole) 3-amino-4-{2-[(4 '-chloro-xenyl-4-carbonyls being cooled to 0 ℃)-amino]-ethyl-solution of ethyl benzoate (embodiment 2.109c) in 5 milliliters of pyridines in, at room temperature stirred this reaction mixture again 1 hour.Make it mix frozen water, thoroughly extract, clean this organic phase repeatedly with water with EtOAc, and with MgSO 4Dewater.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 230 milligrams (theoretical value 97.1%)
C 25H 25ClN 2O 5S(M＝501.01)
Calculated value: mole peak (M+H) +: 501/503 experimental value: mole peak (M+H) +: 501/503
The HPLC residence time: 5.66 minutes (method B)
2.112b.4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-3-methylsulfonyl amino-phenylformic acid
Be similar to embodiment 2.111a, by 230 milligrams of (0.46 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-3-methylsulfonyl amino-ethyl benzoate is prepared.
Productive rate: 180 milligrams (theoretical value 82.9%)
C 23H 21ClN 2O 5S(M＝472.95)
Calculated value: mole peak (M-H) -: 471/473 experimental value: mole peak (M-H) -: 471/473
The HPLC residence time: 7.67 minutes (method A)
2.112c.4 '-chloro-xenyl-4-carboxylic acid [2-(4-methylol-2-methylsulfonyl amino-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.109f, by 180 milligrams of (0.38 mmole) 4-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-3-methylsulfonyl amino-phenylformic acid is prepared.
Productive rate: 150 milligrams (theoretical value 85.8%)
C 23H 23ClN 2O 4S(M＝458.97)
Calculated value: mole peak (M+H) +: 459/461 experimental value: mole peak (M+H) +: 459/461
The HPLC residence time: 7.53 minutes (method A)
2.112d.4 '-chloro-xenyl-4-carboxylic acid [2-(2-methylsulfonyl amino-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.111c, by 150 milligrams of (0.33 mmoles) 4 '-tetramethyleneimine of chloro-xenyl-4-carboxylic acid [2-(4-methylol-2-methylsulfonyl amino-phenyl)-ethyl]-acid amides and 140 microlitres (1.64 mmole) is prepared.After carrying out purifying, make the product that is the formate form with HPLC.
Productive rate: 18 milligrams (theoretical value 9.9%)
C 27H 30ClN 3O 3S*CH 2O 2(M＝558.10)
Calculated value: mole peak (M+H) +: 512/514 experimental value: mole peak (M+H) +: 512/514
The HPLC residence time: 6.13 minutes (method A)
Embodiment 2.113:
4 '-chloro-xenyl-4-carboxylic acid [2-(3-pyridin-4-yl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Be similar to embodiment 2.108, by 200 milligrams of (0.40 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides and 74 milligrams of (0.60 mmole) pyridine-4-boric acid, be prepared with this product of HPLC purifying.
Productive rate: 13 milligrams (theoretical value 6.5%)
C 31H 30ClN 3O(M＝496.06)
Calculated value: mole peak (M+H) +: 496/498 experimental value: mole peak (M+H) +: 496/498
The HPLC residence time: 6.37 minutes (method A)
Embodiment 2.114:
5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-2-tetramethyleneimine-1-ylmethyl-methyl benzoate
2.114a.5-cyanogen methyl-2-tetramethyleneimine-1-ylmethyl-methyl benzoate
With 0.5 milliliter of triethylamine (3.58 mmole), 40 milligrams of (0.18 mmole) Pd (OAc) 2, and 99 milligrams of (0.18 mmoles) 1,1 '-the diphenylphosphino ferrocene, add in the solution of 500 milligrams (1.79 mmoles) (3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile (embodiment 2.107d) in 10 milliliters of MeOH and 10 milliliters of DMF.In autoclave, stirred this reaction mixture 15 hours down in 50 ℃ with 2 crust CO.For finishing reaction, add other 0.5 milliliter of triethylamine, 40 milligrams of Pd (OAc) 2, and 99 milligram 1,1 '-the diphenyl phosphine ferrocene, under 50 ℃ and 2 crust CO, stirred 10 hours again, then stir down and spend the night 4 crust CO and 70 ℃.The vaporising under vacuum solvent makes this resistates mixing EtOAc, again with the water extracting twice.With K 2CO 3Saturated this water thoroughly extracts with EtOAc, again with MgSO 4Dewater.After removing siccative and solvent, this product is residual with black oil bodily form formula, and it is not purified can to carry out next step reaction.
Productive rate: 380 milligrams (theoretical value 82.1%)
C 15H 18N 2O 2(M＝258.32)
Calculated value: mole peak (M+H) +: 259 experimental values: mole peak (M+H) +: 259
The HPLC residence time: 2.49 minutes (method B)
(2.114b.5-2-amino-ethyl)-2-tetramethyleneimine-1-ylmethyl-methyl benzoate
100 milligrams of Raney nickel are added the NH of 380 milligrams of (1.47 mmole) 5-cyanogen methyl-2-tetramethyleneimine-1-ylmethyl-methyl benzoate in 20 ml methanolization 3In solution in, again in room temperature, at 20psi H 2This reaction mixture was carried out hydrogenation 27 hours down.The suction filtration catalyzer removes and desolvates, and this resistates is not purified can to carry out next step reaction.
Productive rate: 330 milligrams (theoretical value 85.5%)
C 15H 22N 2O 2(M＝262.36)
Calculated value: mole peak (M+H) +: 263 experimental values: mole peak (M+H) +: 263
The HPLC residence time: 1.40 minutes (method A)
2.114c.5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-2-tetramethyleneimine-1-ylmethyl-methyl benzoate
According to general methodology I, by 330 milligrams of (1.26 mmole) 5-(2-amino-ethyl)-2-tetramethyleneimine-1-ylmethyl-methyl benzoate and 293 milligrams of (1.26 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 315 milligrams (theoretical value 52.5%)
C 28H 29ClN 2O 3(M＝477.01)
Calculated value: mole peak (M+H) +: 477/479 experimental value: mole peak (M+H) +: 477/479
The HPLC residence time: 6.82 minutes (method A)
Embodiment 2.115:
5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-2-tetramethyleneimine-1-ylmethyl-phenylformic acid
Figure A0382007602271
Be similar to embodiment 2.111a, by 310 milligrams of (0.65 mmole) 5-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-2-tetramethyleneimine-1-ylmethyl-methyl benzoate is prepared.
Productive rate: 85 milligrams (theoretical value 28.2%)
C 27H 27ClN 2O 3(M＝462.98)
Calculated value: mole peak (M+H) +: 463/465 experimental value: mole peak (M+H) +: 463/465
The HPLC residence time: 6.30 minutes (method A)
Embodiment 2.116:
(5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-2-tetramethyleneimine-1-ylmethyl-phenyl)-the carboxylamine tertiary butyl ester
(5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino that the triethylamine of 0.27 milliliter (1.92 mmole) and 0.41 milliliter of (1.92 mmole) nitrine phosphoric acid diphenyl is added 740 milligrams (1.6 mmoles)]-ethyl-2-tetramethyleneimine-1-ylmethyl-phenylformic acid in the solution of 10 milliliters of trimethyl carbinols, and make this reaction mixture reflux 5 hours.Under vacuum, evaporate, make resistates mixed C H 2Cl 2, extract with 1N NaOH solution, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying.
Productive rate: 85 milligrams (theoretical value 28.2%)
C 31H 36ClN 3O 3(M＝534.10)
Calculated value: mole peak (M+H) +: 534/536 experimental value: mole peak (M+H) +: 534/536
The HPLC residence time: 4.82 minutes (method B)
Embodiment 2.117
4 '-chloro-xenyl-4-carboxylic acid [2-(3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(2.117a. 4-tetramethyleneimine-1-ylmethyl-3-three silyl ethynyl-phenyl)-acetonitrile
In microwave oven (CEM), under 100 ℃ and 200Watt, stir 0.36 gram (1.29 mmole) (3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-acetonitrile (embodiment 2.107d), 0.36 milliliter of (2.58 mmole) three silyl acetylene, 0.36 milliliter of (2.58 mmole) triethylamine, 25 milligrams of (0.13 mmole) CuI, and the suspension of four-(triphenylphosphine)-palladium in 3 milliliters of DMF of 0.15 gram (0.13 mmole) 15 minutes.After cooling off this reaction mixture, add saturated NaCl solution, with EtOAc this mixture is thoroughly extracted, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (EtOAc).
Productive rate: 50 milligrams (theoretical value 13.1%)
C 18H 24N 2Si(M＝296.49)
Calculated value: mole peak (M+H) +: 297 experimental values: mole peak (M+H) +: 297
The HPLC residence time: 6.39 minutes (method A)
(2.117b.2-3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine
20 milligrams of Raney nickel are added the NH of 50 milligrams of (0.17 mmole) (4-tetramethyleneimine-1-ylmethyl-3-three silyl ethynyl-phenyl)-acetonitriles in 5 ml methanolization 3In solution in, and room temperature and 3 the crust H 2Shook this reaction mixture 22 hours down.The suction filtration catalyzer removes under vacuum and desolvates.This raw product is not purified can to carry out next step reaction.
Productive rate: 39 milligrams (theoretical value 100%)
C 15H 24N 2(M＝232.37)
Calculated value: mole peak (M+H) +: 233 experimental values: mole peak (M+H) +: 233
2.117c.4 '-chloro-xenyl-4-carboxylic acid [2-(3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 40 milligrams of (0.17 mmole) 2-(3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 48 milligrams of (0.21 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 2 milligrams (theoretical value 2.6%)
C 28H 31ClN 2O(M＝447.03)
Calculated value: mole peak (M+H) +: 447/449 experimental value: mole peak (M+H) +: 447/449
The HPLC residence time: 6.87 minutes (method A)
Embodiment 2.118:
4 '-chloro-xenyl-4-carboxylic acid [2-(6-tetramethyleneimine-1-ylmethyl-pyridin-3-yl)-ethyl]-acid amides
2.118a 6-two brooethyls-nicotinic acid methyl ester
53.4 gram (0.3 mole) NBS and 2 gram dibenzoyl superoxide, the 6-methyl-nicotinic acid methyl ester that adds 38.96 grams (0.25 mole) is dissolved in 1 liter of CCl 4Solution in, this reaction mixture reflux is spent the night.Then add other 26.7 gram (0.15 mole) NBS and 1 gram dibenzoyl superoxide, and this mixture reheat was refluxed 24 hours.After cooling off this reaction mixture, this throw out of suction filtration removes and desolvates, again with this resistates of chromatograph purifying.
Productive rate: 15.0 grams (theoretical value 19.4%)
C 8H 7Br 2NO 2(M＝308.96)
Calculated value: mole peak (M+H) +: 308/310/312 experimental value: mole peak (M+H) +: 308/310/312
R fValue: 0.6 (silica gel, sherwood oil/EtOAc 8: 2)
2.118b.6-dimethoxy-methyl-nicotinic acid methyl ester
13.9 milliliters among the 100 milliliters of MeOH NaOMe (30%, 75 mmole) in MeOH are heated to and boil.The solution of 6-two brooethyls-nicotinic acid methyl ester in 10 milliliters of MeOH of 11.0 grams (34.1 mmole) is dropwise added in this boiling solution, its reflux is spent the night.For finishing reaction, add other 1.5 milliliters (8.1 mmole) NaOMe solution, and this mixture reheat was refluxed 24 hours.This reaction mixture of vaporising under vacuum makes resistates mixing KHSO 4Solution is with rare NaHCO 3The solution neutralization thoroughly extracts with EtOAc, cleans this organic phase with water, again with MgSO 4Dewater.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 5.0 grams (theoretical value 69.5%)
C 10H 13NO 4(M＝211.22)
Calculated value: mole peak (M+H) +: 212 experimental values: mole peak (M+H) +: 212
R fValue: 0.44 (silica gel, sherwood oil/EtOAc 6: 4)
2.118c.6-dimethoxy methyl-nicotinic acid
15 milliliters 1N NaOH solution are added in the solution of 2.8 gram (13.26 mmole) 6-dimethoxy-methyl-nicotinic acid methyl esters in 50 milliliters of MeOH, and at room temperature stirred 24 hours.With 15 milliliters of 1NHCl this reaction mixture that neutralizes, vaporising under vacuum is developed this resistates with MeOH/THF, suction filtration throw out, revaporization filtrate.The product of gained is not purified can to carry out next step reaction.
Productive rate: 2.6 grams (theoretical value 99.4%)
C 9H 11NO 4(M＝197.19)
Calculated value: mole peak (M+H) +: 198 experimental values: mole peak (M+H) +: 198
The HPLC residence time: 3.65 minutes (method A)
(2.118d. 6-dimethoxy-methyl-pyridin-3-yl)-methyl alcohol
Be similar to embodiment 2.109f, by 2.7 gram (13.7 mmole) 6-dimethoxy-methyl-nicotinic acid, use THF, and the use t-butyl methyl ether extract and is prepared as solution.
Productive rate: 2.1 grams (theoretical value 83.7%)
C 9H 13NO 3(M＝183.21)
Calculated value: mole peak (M+H) +: 184 experimental values: mole peak (M+H) +: 184
The HPLC residence time: 2.85 minutes (method A)
2.118e.5-chloromethyl-2-dimethoxy-methyl-pyridine
0.3 milliliter of (4.14 mmole) thionyl chloride (is dissolved in a small amount of CH 2Cl 2In) slowly dropwise add be cooled to 0 ℃ 500 milligrams of (2.73 mmole) (6-dimethoxy-methyl-pyridin-3-yl)-methyl alcohol at 10 milliliters of CH 2Cl 2In solution in.Under this temperature, continue again to stir 30 minutes.With CH 2Cl 2Dilute this reaction mixture, with refrigerative NaHCO 3Solution cleans, again with MgSO 4Dewater.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 500 milligrams (theoretical value 90.8%)
C 9H 12ClNO 2(M＝201.65)
Calculated value: mole peak (M+H) +: 202/204 experimental value: mole peak (M+H) +: 202/204
R fValue: 0.3 (silica gel, sherwood oil/EtOAc 6: 4)
(2.118f. 6-dimethoxy-methyl-pyridin-3-yl)-acetonitrile
20 milliliters of DMSO are added in the solution of 5.21 gram (80 mmole) KCN in 5.2 ml waters, and under 80 ℃, slowly dropwise add the solution of 5-chloromethyl-2-dimethoxy-methyl-pyridine in 10 milliliters of DMSO of 500 milligrams (2.48 mmoles), this reaction mixture was kept 1 hour at 80 ℃.It is to 200 ml waters, saturated with NaCl, thoroughly extract with EtOAc, again with MgSO 4This organic phase is dewatered, and it is filtered by activated carbon.Evaporated filtrate, and on silica gel, with chromatograph purifying resistates (CH 2Cl 2/ MeOH 9: 1).
Productive rate: 330 milligrams (theoretical value 69.2%)
C 10H 12N 2O 2(M＝192.22)
Calculated value: mole peak (M+H) +: 193 experimental values: mole peak (M+H) +: 193
R fValue: 0.48 (silica gel, CH 2Cl 2/ MeOH 9: 1)
(2.118g.2-6-dimethoxy-methyl-pyridin-3-yl)-ethamine
50 milligrams of Raney nickel are added the NH of 330 milligrams of (1.72 mmole) (6-dimethoxy-methyl-pyridin-3-yl)-acetonitriles in 10 ml methanolization 3In solution in, again 3 the crust H 2In the Parr autoclave,, this reaction mixture was carried out hydrogenation 15 hours at 30 ℃ down.Filtration catalizer removes under vacuum and desolvates, and this raw product is not purified can to carry out next step reaction.
Productive rate: 340 milligrams (theoretical value 100%)
C 10H 16N 2O 2(M＝196.25)
Calculated value: mole peak (M+H) +: 197 experimental values: mole peak (M+H) +: 197
The HPLC residence time: 1.3 minutes (method A)
2.118h.4 '-chloro-xenyl-4-carboxylic acid [2-(6-dimethoxy-methyl-pyridin-3-yl)-ethyl]-acid amides
According to general methodology I, by 340 milligrams of (1.73 mmole) 2-(6-dimethoxy-methyl-pyridin-3-yl)-ethamine and 419 milligrams of (1.80 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 210 milligrams (theoretical value 28.4%)
C 23H 23ClN 2O 3(M＝410.90)
Calculated value: mole peak (M+H) +: 411/413 experimental value: mole peak (M+H) +: 411/413
R fValue: 0.4 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
2.118i.4 '-chloro-xenyl-4-carboxylic acid [2-(6-formyl radical-pyridin-3-yl)-ethyl]-acid amides
With 5 milliliters 12%HCl add 205 milligrams of (0.5 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(6-dimethoxy-methyl-pyridin-3-yl)-the ethyl]-solution of acid amides in 10 milliliters of MeOH in, and at room temperature stirred this reaction mixture 4 hours, 80 ℃ of following heated overnight.Add other 2.5 milliliters of 12%HCl, heated this mixture 8 hours down at 80 ℃ again, and 100 ℃ of following heated overnight.Make this reaction mixture 50 ml waters, with Na 2CO 3Solution is adjusted to pH8, with CH 2Cl 2Thoroughly extract, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 180 milligrams (theoretical value 98.7%)
C 21H 17ClN 2O 2(M＝364.84)
Calculated value: mole peak (M+H) +: 365/367 experimental value: mole peak (M+H) +: 365/367
The HPLC residence time: 5.25 minutes (method A)
2.118k.4 '-chloro-xenyl-4-carboxylic acid [2-(6-tetramethyleneimine-1-ylmethyl-pyridin-3-yl)-ethyl]-acid amides
With 50 microlitres (0.6 mmole) tetramethyleneimine, 37.7 milligrams of (0.6 mmole) NaBH 3CN, and 2 milliliters of MeOH; add 180 milligrams of (0.49 mmoles) 4 '-chloro-xenyl-4-carboxylic acid [2-(6-formyl radical-pyridin-3-yl)-the ethyl]-solution of acid amides in 5 milliliters of acetonitriles in; with Glacial acetic acid the pH value is adjusted to 5-6, at room temperature stirred this mixture again 5 hours.With 1M KHSO 4This reaction mixture of solution acidifying is with 2MNa 2CO 3The solution alkalization is with CH 2Cl 2Thoroughly extract, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, on silica gel, with this resistates of chromatograph purifying (CH 2Cl 2/ MeOH/NH 39: 1: 0.1).
Productive rate: 25 milligrams (theoretical value 12.1%)
C 25H 26ClN 3O(M＝419.96)
Calculated value: mole peak (M+H) +: 420/422 experimental value: mole peak (M+H) +: 420/422
R fValue: 0.2 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
Embodiment 2.119:
4 '-chloro-xenyl-4-carboxylic acid [2-(5-tetramethyleneimine-1-ylmethyl-pyridine-2-yl)-ethyl]-acid amides
Figure A0382007602331
2.119a.6-methylol-nicotinic acid methyl ester
Be similar to embodiment 2.109f, by 5.0 gram (27.6 mmole) pyridines-2,5-dicarboxylic acid 5-methyl ester uses THF as solvent, and the use t-butyl methyl ether extracts and is prepared.
Productive rate: 2.0 grams (theoretical value 43.3%)
C 8H 9NO 3(M＝167.17)
Calculated value: mole peak (M+H) +: 168 experimental values: mole peak (M+H) +: 168
R fValue: 0.2 (silica gel, CH 2Cl 2/ MeOH 95: 5)
2.119b.6-chloromethyl-nicotinic acid methyl ester
Be cooled to 0 ℃ 2.0 the gram (11.96 mmole) 6-methylol-nicotinic acid methyl esters at 100 milliliters of CH 2Cl 2In solution in, add 1.06 milliliters of (13 mmole) pyridines, and slowly dropwise add the thionyl chloride of 1.08 milliliters (13 mmoles).And under 0 ℃, stirred 1 hour, then slowly be heated to room temperature.For finishing reaction, add the thionyl chloride of other 1 milliliter (12 mmole), and at room temperature stirred this mixture 1 hour.In this reaction mixture, add entry, separate organic phase, with rare NaHCO 3Solution and water clean, again with MgSO 4Dewater.Make it pass through active carbon filtration, again vaporising under vacuum filtrate.The product of gained is not purified can to carry out next step reaction.
Productive rate: 1.7 grams (theoretical value 65.1%)
C 8H 8ClNO 2(M＝185.61)
Calculated value: mole peak (M+H) +: 186/188 experimental value: mole peak (M+H) +: 186/188
The HPLC residence time: 6.7 minutes (method A)
2.119c.6-cyanogen methyl-nicotinic acid methyl ester
Be similar to embodiment 2.118f, by 1.5 gram (8.08 mmole) 6-chloromethyl-nicotinic acid methyl esters and 5.2 gram (80 mmole) KCN, the hexanaphthene/EtOAc that uses 8: 2 is as elutriant, chromatograph purifying on silica gel and being prepared.
Productive rate: 220 milligrams (theoretical value 15.5%)
C 9H 8N 2O 2(M＝176.18)
Calculated value: mole peak (M+H) +: 177 experimental values: mole peak (M+H) +: 177
R fValue: 0.6 (silica gel, sherwood oil/EtOAc 1: 1)
(2.119d.6-2-amino-ethyl)-nicotinic acid methyl ester
20 milligrams Raney nickel are added the NH of 75 milligrams of (0.43 mmole) 6-cyanogen methyl-nicotinic acid methyl esters in 5 ml methanolization 3In solution in, again 3 the crust H 2In the Parr autoclave,, this reaction mixture was carried out hydrogenation 6 hours at 30 ℃ down.Filtration catalizer, the vaporising under vacuum solvent, this resistates is not purified can to carry out next step reaction.
Productive rate: 70 milligrams (theoretical value 90.3%)
C 9H 12N 2O 2(M＝180.21)
Calculated value: mole peak (M+H) +: 181 experimental values: mole peak (M+H) +: 181
The HPLC residence time: 2.5 minutes (method A)
2.119e.6-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-nicotinic acid methyl ester
According to general methodology I, by 70 milligrams of (0.39 mmole) 6-(2-amino-ethyl)-nicotinic acid methyl ester and 100 milligrams of (0.43 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 150 milligrams (theoretical value 88.3%)
C 22H 19ClN 2O 3(M＝394.86)
Calculated value: mole peak (M+H) +: 395/397 experimental value: mole peak (M+H) +: 395/397
The HPLC residence time: 8.6 minutes (method A)
2.119f.6-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-nicotinic acid
The 6-{2-[(4-chloro-xenyl-4-carbonyl that 0.8 milliliter of 1M NaOH solution is added 150 milligrams (0.38 mmoles))-amino]-ethyl-solution of nicotinic acid methyl ester in 25 milliliters of MeOH in, and made the reaction mixture reflux 1 hour.1N HCl with 0.8 milliliter neutralizes, and evaporates under vacuum, and this resistates and water are stirred jointly, goes out throw out with suction filtration again.It is dissolved among the THF, with MgSO 4This solution is dewatered, filter, under vacuum, evaporate again.This resistates is not purified can to carry out next step reaction.
Productive rate: 90 milligrams (theoretical value 62.2%)
C 21H 17ClN 2O 3(M＝380.83)
Calculated value: mole peak (M+H) +: 381/383 experimental value: mole peak (M+H) +: 381/383
The HPLC residence time: 6.9 minutes (method A)
2.119g.4 '-chloro-xenyl-4-carboxylic acid [2-(5-methylol-pyridine-2-yl)-ethyl]-acid amides
Be similar to embodiment 2.109f, by 90 milligrams of (0.24 mmole) 6-{2-[(4 '-chloro-xenyl-4-carbonyls)-amino]-ethyl }-nicotinic acid, use THF as solvent, and the use t-butyl methyl ether extract and is prepared.
Productive rate: 50 milligrams (theoretical value 56.8%)
C 21H 19ClN 2O 2(M＝366.85)
Calculated value: mole peak (M+H) +: 367/369 experimental value: mole peak (M+H) +: 367/369
R fValue: 0.5 (silica gel, CH 2Cl 2/ MeOH 9: 1)
2.119h.4 '-chloro-xenyl-4-carboxylic acid [2-(5-tetramethyleneimine-1-ylmethyl-pyridine-2-yl)-ethyl]-acid amides
22 microlitre thionyl chloride are added 50 milligrams (0.14 mmoles) being cooled to 0 ℃ 4 '-chloro-xenyl-4-carboxylic acid [2-(5-methylol-pyridine-2-yl)-ethyl]-acid amides is at 5 milliliters of CH 2Cl 2In solution in, and this reaction mixture is slowly risen again to room temperature.After at room temperature placing 1 hour, the thionyl chloride that dropwise adds other 22 microlitres to be finishing reaction, and continues to stir 1 hour.With 30 milliliters of CH 2Cl 2Diluted reaction mixture makes it mix frozen water, with NaHCO 3Solution alkalizes, and separates organic phase, cleans with water, again with MgSO 4Dewater.After removing siccative, the tetramethyleneimine of 50 microlitres (0.6 mmole) is added in this solution, and at room temperature stir this reaction mixture and spend the night.Under vacuum, evaporate, again with this resistates of HPLC chromatograph purifying.
Productive rate: 2.4 milligrams (theoretical value 4.1%)
C 25H 26ClN 3O(M＝419.96)
Calculated value: mole peak (M+H) +: 420/422 experimental value: mole peak (M+H) +: 420/422
R fValue: 0.3 (silica gel, CH 2Cl 2/ MeOH 9: 1)
The HPLC residence time: 6.0 minutes (method A)
Embodiment 2.120:
4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-acid amides
(2.120a.[2-4-ethanoyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
1-[4-(2-the amino-ethyl)-phenyl that 5.46 gram (25 mmole) BOC acid anhydrides is added 4.99 grams (25 mmole)]-ethyl ketone (using with hydrochloride form) is at 100 milliliters of CH 2Cl 2In solution in, and at room temperature, slowly dropwise add 25 milliliters 1N NaOH, add finish after, at room temperature stirred this mixture 2 hours.This reaction mixture is filtered by diatomite, clean twice with water, again with MgSO 4Dewater.It is filtered by activated carbon, evaporate under vacuum, this product is not purified can to carry out next step reaction.
Productive rate: 6.4 grams (theoretical value 97.2%)
C 15H 21NO 3(M＝263.34)
Calculated value: mole peak (M+H) +: 262 experimental values: mole peak (M+H) +: 262
R fValue: 0.88 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
(2.120b.{2-[4-1-hydroxyl-ethyl)-phenyl]-ethyl }-the carboxylamine tertiary butyl ester
At room temperature, with 4.72 the gram (125 mmole) NaBH 4Add in [2-(4-ethanoyl-phenyl)-the ethyl]-solution of carboxylamine tertiary butyl ester in 250 milliliters of MeOH of 6.58 grams (25 mmole) in batches, and at room temperature stir one week of this reaction mixture.With KHSO 4Solution carefully carries out acidifying, thoroughly extracts with t-butyl methyl ether, cleans organic phase with saturated NaCl solution, again with MgSO 4Dehydration.After removing siccative and solvent, the product that stays is faint yellow oil body, and it is leaving standstill post crystallization.
Productive rate: 5.4 grams (theoretical value 81.4%)
C 15H 23NO 3(M＝265.36)
Calculated value: mole peak (M)+: 266 experimental values: mole peak (M)+: 266
R fValue: 0.4 (silica gel, sherwood oil/EtOAc 6: 4)
(2.120c.{2-[4-1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-the carboxylamine tertiary butyl ester
The methylsulfonyl chloride of 0.66 milliliter (8.5 mmole) (is dissolved in 1 milliliter CH 2Cl 2In) dropwise add 2.89 grams (10.89 mmole) be cooled to 0 ℃ { 2-[4-(1-hydroxyl-ethyl)-phenyl]-ethyl }-carboxylamine tertiary butyl ester at 50 milliliters of CH 2Cl 2Reach in the solution in 1.25 milliliters of triethylamines.After stirring 1 hour under this temperature, the tetramethyleneimine that slowly dropwise adds 1.4 milliliters (17 mmoles) is at 10 milliliters of CH 2Cl 2In solution.At room temperature stir this reaction mixture and spend the night, make it mix rare KHSO 4Solution separates organic phase, with rare KHSO 4Solution cleans twice, with K 2CO 3The alkalize water of this merging of solution thoroughly extracts with t-butyl methyl ether again.Clean the organic phase several that merges with a spot of water, again with MgSO 4Dewater.After removing siccative and solvent, this product is not purified can to carry out next step reaction.
Productive rate: 0.3 gram (theoretical value 8.7%)
C 19H 30N 2O 2(M＝318.46)
Calculated value: mole peak (M+H) +: 319 experimental values: mole peak (M+H) +: 319
R fValue: 0.22 (silica gel, CH 2Cl 2/ MeOH/NH 39: 1: 0.1)
(2.120d.2-[4-1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethamine
{ 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-carboxylamine tertiary butyl ester that 0.72 milliliter trifluoroacetic acid is added 300 milligrams (0.94 mmoles) is at 20 milliliters of CH 2Cl 2In solution in, and at room temperature stirred 1 hour.For finishing reaction, add other 0.72 milliliter trifluoro ethyl ester, and this reaction mixture was at room temperature kept 1 hour.The vaporising under vacuum solvent, this resistates is soluble in water, alkalize with 2N NaOH, thoroughly extract with EtOAc, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, this product is not purified can to carry out next step reaction.
Productive rate: 150 milligrams (theoretical value 72.9%)
C 14H 22N 2(M＝218.35)
Calculated value: mole peak (M+H) +: 219 experimental values: mole peak (M+H) +: 219
R fValue: 0.15 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.120e.4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-acid amides
According to general methodology I, by 150 milligrams of (0.69 mmole) 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethamine and 176 milligrams of (0.76 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 150 milligrams (theoretical value 88.3%)
C 27H 29ClN 2O(M＝433.0)
Calculated value: mole peak (M+H) +: 433/435 experimental value: mole peak (M+H) +: 433/435
The HPLC residence time: 6.33 minutes (method A)
Embodiment 2.121:
4 '-chloro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(2.121a.[4-2-amino-ethyl)-2-bromo-phenyl]-methyl alcohol
100 milligrams of Raney nickel are added the NH of (3-bromo-4-methylol-phenyl)-acetonitrile (referring to embodiment 2.107c.) of 4 grams (17.68 mmole) in 100 milliliters of THF and 50 ml methanolization 3In solution in, again in the Parr autoclave, at room temperature and 5psi H 2Down, concussion reaction mixture.Leach catalyzer, remove and desolvate, this product is not purified can to carry out next step reaction.
Productive rate: 3.8 grams (theoretical value 93.4%)
C 9H 12BrNO(M＝230.11)
Calculated value: mole peak (M+H) +: 230/232 experimental value: mole peak (M+H) +: 230/232
The HPLC residence time: 1.85 minutes (method A)
(2.121b.[2-3-bromo-4-hydroxymethyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
With 17 milliliters at CH 2Cl 2In 1M BOC anhydride solution add [4-(2-amino-ethyl)-2-bromo-the phenyl]-methyl alcohol of 3.8 grams (16.51 mmole) at 50 milliliters of CH 2Cl 2In solution in, and at room temperature stir this reaction mixture and spend the night.Rare KHSO with 100 milliliters 4Solution dilution separates organic phase, with rare NaHCO 3Solution and water clean, again with MgSO 4Dewater.After removing siccative and solvent, on silica gel, with chromatograph purifying resistates.
Productive rate: 2.3 grams (theoretical value 42.2%)
C 14H 20BrNO 3(M＝330.22)
R fValue: 0.44 (silica gel, sherwood oil/EtOAc 6: 4)
(2.121c.[2-3-bromo-4-chloromethyl-phenyl)-ethyl]-the carboxylamine tertiary butyl ester
With the thionyl chloride of 0.54 milliliter (6.5 mmole) slowly dropwise add be cooled to 0 ℃ 1.98 gram (6.0 mmole) [2-(3-bromo-4-methylol-phenyl)-ethyl]-carboxylamine tertiary butyl ester at 50 milliliters of CH 2Cl 2Reach in the solution in 0.53 milliliter of pyridine, continue down to stir 1 hour at 0 ℃, reheat is to room temperature.Water is added in the reaction mixture, with rare KHSO 4Solution and water clean organic phase, again with MgSO 4Dewater.It is filtered by activated carbon and remove desolvate after, this product is not purified can to carry out next step reaction.
Productive rate: 2.0 grams (theoretical value 95.6%)
C 14H 19BrClNO 2(M＝348.67)
Calculated value: mole peak (M+H) +: 348/350/352 experimental value: mole peak (M+H) +: 348/350/352
R fValue: 0.6 (silica gel, sherwood oil/EtOAc 6: 4)
2.121d.{2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-the carboxylamine tertiary butyl ester
With 0.84 milliliter (11 mmole) 2,5-dihydro-1H-pyrroles add 1.9 the gram (5.45 mmole) [2-(3-bromo-4-chloromethyl-phenyl)-ethyl]-carboxylamine tertiary butyl ester and 2.5 the gram (18.1 mmole) K 2CO 3In the suspension in 50 milliliters of acetonitriles, and at room temperature stir this reaction mixture and spend the night.Filter this suspension, this filtrate of vaporising under vacuum is again on silica gel, with chromatograph purifying residue.
Productive rate: 0.5 gram (theoretical value 24.1%)
C 18H 25BrN 2O 2(M＝381.32)
Calculated value: mole peak (M+H) +: 381/383 experimental value: mole peak (M+H) +: 381/383
R fValue: 0.58 (silica gel, CH 2Cl 2/ MeOH 8: 2)
2.121e.2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethamine
{ 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-carboxylamine tertiary butyl ester that 5 milliliters trifluoroacetic acids are added 500 milligrams (1.31 mmoles) is at 50 milliliters of CH 2Cl 2In solution in, and at room temperature stirred 2 hours.This reaction mixture of vaporising under vacuum makes this residue mixing water and CH 2Cl 2, again with K 2CO 3Solution is adjusted to alkaline pH, separates organic phase, and cleans with water.Under vacuum, evaporate, on silica gel, with this product of chromatograph purifying.
Productive rate: 350 milligrams (theoretical value 95.0%)
C 13H 17BrN 2(M＝281.20)
Calculated value: mole peak (M+H) +: 281/283 experimental value: mole peak (M+H) +: 281/283
R fValue: 0.08 (silica gel, CH 2Cl 2/ MeOH/NH 395: 5: 0.5)
2.121f.4 '-chloro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
According to general methodology I, by 141 milligrams of (0.5 mmole) 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethamine and 116 milligrams of (0.5 mmoles) 4 '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 140 milligrams (theoretical value 56.5%)
C 26H 24BrClN 2O(M＝495.85)
Calculated value: mole peak (M+H) +: 495/497/499 experimental value: mole peak (M+H) +: 495/497/499
The HPLC residence time: 6.6 minutes (method A)
Embodiment 2.122:
4 '-bromo-3-fluoro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
2.122a.4 '-bromo-3-fluoro-xenyl-4-carboxylic acid
With 1.04 gram (5 mmole) 4-bromophenyl boric acid, 115 milligrams of (0.1 mmole) four-(triphenylphosphine)-palladiums, and 2 milliliters of 2M Na 2CO 3Solution adds in the solution of 4-bromo-2-fluoro-phenylformic acid in 5 milliliters of DMF and 5 milliliters of dioxs of 1.1 grams (5 mmole) successively, makes this reaction mixture reflux 2 hours again.For finishing reaction, the 4-bromophenyl boric acid of remix 250 milligrams (f1.25 mmoles) and reflux 2 hours.Make this reaction soln carry out heat filtering, clean with water, with rare KHSO by glass fibre filter 4Solution carries out acidifying, and the formed throw out of suction filtration cleans with water again.Develop this resistates with acetonitrile and a small amount of MeOH, filter, evaporate this filtrate, develop this residue, again this product is carried out suction filtration with MeOH to remove insoluble material.
Productive rate: 140 milligrams (theoretical value 9.5%)
C 13H 8BrFO 2(M＝295.11)
Calculated value: mole peak (M+H) +: 293/295 experimental value: mole peak (M+H) +: 293/295
R fValue: 0.5 (silica gel, CH 2Cl 2/ MeOH 9: 1)
2.122b.4 '-bromo-3-fluoro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
According to general methodology I, by 141 milligrams of (0.5 mmole) 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethamine and 140 milligrams of (0.47 mmoles) 4 '-bromo-3-fluoro-xenyl-4-carboxylic acid is prepared.
Productive rate: 10 milligrams (theoretical value 3.8%)
C 26H 23Br 2FN 2O(M＝558.29)
Calculated value: mole peak (M+H) +: 557/559/561 experimental value: mole peak (M+H) +: 557/559/561
The HPLC residence time: 7.0 minutes (method A)
Embodiment 2.123:
4 '-chloro-xenyl-4-carboxylic acid [2-(3-amino-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602401
(5-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino that 0.12 milliliter of trifluoroacetic acid is added 40 milligrams (0.08 mmoles)]-ethyl }-2-tetramethyleneimine-1-ylmethyl-phenyl)-carboxylamine tertiary butyl ester (referring to embodiment 2.116) is at 3 milliliters of CH 2Cl 2In solution in, and at room temperature stir one week of this reaction mixture.Under vacuum, evaporate, make it mix half saturated NaHCO 3Solution extracts with EtOAc, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, with this residue of HPLC purifying.
Productive rate: 3 milligrams (theoretical value 7.3%)
C 26H 28ClN 3O*C 2HF 3O 2(M＝548.01)
Calculated value: mole peak (M+H) +: 434/436 experimental value: mole peak (M+H) +: 434/436
The HPLC residence time: 5.35 minutes (stable keys C18; 3.5 μ M; Water: acetonitrile: formic acid 6: 4: 0.015)
Embodiment 2.124:
4 '-chloro-xenyl-4-carboxylic acid-ethyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.124a. ethyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
The solution of iodoethane in 5 milliliters of THF with 89 microlitres (1.1 mmole), add in 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and the solution of 0.17 milliliter of triethylamine in 5 milliliters of THF of 204 milligrams (1.0 mmoles), at room temperature stirred this reaction mixture again 24 hours.Make it mix saturated NaHCO 3Solution extracts with EtOAc, again with MgSO 4This organic phase is dewatered.After removing siccative and solvent, this residue is not purified can to carry out next step reaction.
Productive rate: 70 milligrams (theoretical value 30.1%)
2.124b.4 '-chloro-xenyl-4-carboxylic acid-ethyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of 70 milligrams of (0.3 mmole) ethyls-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine and 81 milligrams (0.35 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 20 milligrams (theoretical value 14.9%)
C 28H 31ClN 2O(M＝447.03)
Calculated value: mole peak (M+H) +: 447/449 experimental value: mole peak (M+H) +: 447/449
The HPLC residence time: 6.92 minutes (method A)
Embodiment 2.125:
4 '-chloro-xenyl-4-carboxylic acid-isobutyl--[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602412
2.125a. isobutyl--[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
With 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine of the slight acidifying of Glacial acetic acid 204 milligrams (1.0 mmoles) and the solution of isobutyric aldehyde in 20 milliliters of THF of 91 microlitres (1.0 mmole), make it mix the NaBH (OAc) of 253 milligrams (1.2 mmoles) 3, at room temperature stir again and spend the night.Make the half saturated NaHCO of this reaction mixture 3Solution thoroughly extracts with EtOAc; With K 2CO 3Saturated this water extracts with EtOAc again.With MgSO 4Organic phase to this merging is dewatered.After removing siccative and solvent, this residue is not purified can to carry out next step reaction.
Productive rate: 250 milligrams (theoretical value 96.0%)
C 17H 28N 2(M＝260.43)
Calculated value: mole peak (M+H) +: 261 experimental values: mole peak (M+H) +: 261
R fValue: 0.4 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.125b.4 '-chloro-xenyl-4-carboxylic acid-isobutyl--[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of isobutyl--[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-the ethyl]-amine of 250 milligrams (0.96 mmoles) and 244 milligrams (1.05 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 67 milligrams (theoretical value 14.7%)
C 30H 35ClN 2O(M＝475.08)
Calculated value: mole peak (M+H) +: 475/477 experimental value: mole peak (M+H) +: 475/477
The HPLC residence time: 7.67 minutes (method A)
Embodiment 2.126:
4 '-chloro-xenyl-4-carboxylic acid-hexamethylene-3-thiazolinyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602421
2.126a. hexamethylene-3-thiazolinyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
Be similar to embodiment 2.125a, by 204 milligrams of (1.0 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 114 microlitres (1.0 mmole) 1,2,3,6-tetrahydrochysene phenyl aldehyde is prepared.
Productive rate: 100 milligrams (theoretical value 33.5%)
C 20H 30N 2(M＝298.48)
R fValue: 0.2 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.126b.4 '-chloro-xenyl-4-carboxylic acid-hexamethylene-3-thiazolinyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of hexamethylene-3-thiazolinyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-the ethyl]-amine of 100 milligrams (0.34 mmoles) and 86 milligrams (0.37 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 46 milligrams (theoretical value 26.8%)
C 33H 37ClN 2O(M＝513.13)
Calculated value: mole peak (M+H) +: 513/515 experimental value: mole peak (M+H) +: 513/515
The HPLC residence time: 8.20 minutes (method A)
Embodiment 2.127:
4 '-chloro-xenyl-4-carboxylic acid-benzyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602431
2.127a. benzyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
Be similar to embodiment 2.125a, be prepared by 204 milligrams of (1.0 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 102 microlitres (1.0 mmole) phenyl aldehyde.
Productive rate: 160 milligrams (theoretical value 54.3%)
C 20H 26N 2(M＝294.44)
R fValue: 0.28 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.127b.4 '-chloro-xenyl-4-carboxylic acid-benzyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of 160 milligrams of (0.54 mmole) benzyls-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine and 140 milligrams (0.60 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 16 milligrams (theoretical value 5.8%)
C 33H 33ClN 2O(M＝509.10)
Calculated value: mole peak (M+H) +: 509/511 experimental value: mole peak (M+H) +: 509/511
The HPLC residence time: 7.51 minutes (method A)
Embodiment 2.128:
4 '-chloro-xenyl-4-carboxylic acid-cyclohexyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
2.128a. cyclohexyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
Be similar to embodiment 2.125a, be prepared by the hexanaphthene formaldehyde of 204 milligrams of (1.0 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 121 microlitres (1.0 mmole).
Productive rate: 100 milligrams (theoretical value 33.3%)
C 20H 32N 2(M＝300.49)
R fValue: 0.18 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.128b.4 '-chloro-xenyl-4-carboxylic acid-cyclohexyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of 100 milligrams of (0.33 mmole) cyclohexyl methyls-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine and 86 milligrams (0.37 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 70 milligrams (theoretical value 40.8%)
C 33H 33ClN 2O(M＝515.15)
Calculated value: mole peak (M+H) +: 515/517 experimental value: mole peak (M+H) +: 515/517
The HPLC residence time: 8.63 minutes (method A)
Embodiment 2.129:
4 '-chloro-xenyl-4-carboxylic acid-cyclopropyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
Figure A0382007602442
2.129a. cyclopropyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine
Be similar to embodiment 2.125a, be prepared by 204 milligrams of (1.0 mmole) 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine and 75 microlitres (1.0 mmole) cyclopanecarboxaldehyde.
Productive rate: 100 milligrams (theoretical value 38.7%)
C 17H 26N 2(M＝258.41)
R fValue: 0.30 (silica gel, CH 2Cl 2/ MeOH/NH 38: 2: 0.2)
2.129b.4 '-chloro-xenyl-4-carboxylic acid-cyclopropyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
According to general methodology I, by 4 of 100 milligrams of (0.39 mmole) cyclopropyl methyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-amine and 100 milligrams (0.43 mmoles) '-chloro-xenyl-4-carboxylic acid is prepared.
Productive rate: 23 milligrams (theoretical value 12.6%)
C 30H 33ClN 2O(M＝473.06)
Calculated value: mole peak (M+H) +: 473/475 experimental value: mole peak (M+H) +: 473/475
The HPLC residence time: 7.45 minutes (method A)
Embodiment 2.130:
4-amyl group-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602451
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and 4-amyl group-phenylformic acid (96 milligrams, 0.50 mmole).
Productive rate: 75 milligrams (theoretical value 39.6%)
C 25H 34N 2O(M＝378.56)
Calculated value: mole peak (M+H) +: 379 experimental values: mole peak (M+H) +: 379
The HPLC residence time: 6.5 minutes (method A)
Embodiment 2.131:
4-butyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602452
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and 4-butyl-phenylformic acid (89 milligrams, 0.50 mmole).
Productive rate: 60 milligrams (theoretical value 32.9%)
C 24H 32N 2O(M＝364.54)
Calculated value: mole peak (M+H) +: 365 experimental values: mole peak (M+H) +: 365
The HPLC residence time: 6.0 minutes (method A)
Embodiment 2.132:
4-fourth amino-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (204 milligrams, 1.0 mmoles) and 4-fourth amino-phenylformic acid (155 milligrams, 0.80 mmole).
Productive rate: 30 milligrams (theoretical value 9.9%)
C 24H 33N 3O(M＝379.55)
Calculated value: mole peak (M+H) +: 380 experimental values: mole peak (M+H) +: 380
The HPLC residence time: 6.0 minutes (method A)
Embodiment 2.133:
4-(1-methyl-butyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602462
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (82 milligrams, 0.40 mmole) and 4-(1-methyl-butyl)-phenylformic acid (75 milligrams, 0.39 mmole).
Productive rate: 40 milligrams (theoretical value 27.1%)
C 24H 32N 2O(M＝378.56)
Calculated value: mole peak (M+H) +: 379 experimental values: mole peak (M+H) +: 379
The HPLC residence time: 4.3 minutes (method B)
Embodiment 2.134:
N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-three fluoro-butoxy)-benzamide
Figure A0382007602471
(2.134a.4-4,4,4-three fluoro-butoxy)-methyl benzoate
With 608 milligrams of (4.4 mmole) K 2CO 3Add in the solution of 4-methyl hydroxybenzoate in 10 milliliters of DMF of 304 milligrams (2.0 mmoles), add the 1-bromo-4,4 of 382 milligrams (2.0 mmoles) again, 4-trifluoro butane.At room temperature stir the mixture and spend the night, mix 1-bromo-4,4 once more, 4-trifluoro butane at room temperature stirred 24 hours again.Dilute this reaction soln with water, again with the thorough extracting twice of EtOAc.With MgSO 4Organic phase to this merging is dewatered, and evaporates under vacuum again.This raw product promptly can be used in next reactions steps without further purifying.
Productive rate: 500 milligrams (theoretical value 95.3%)
C 12H 13F 3O 3(M＝262.23)
Calculated value: mole peak (M+H) +: 263 experimental values: mole peak (M+H) +: 263
R fValue: 0.9 (silica gel, sherwood oil/EtOAc 6: 4)
(2.134b.4-4,4,4-three fluoro-butoxy)-phenylformic acid
The 1M sodium hydroxide solution of 10.0 milliliters (10.0 mmoles) is added in 4-(4,4,4-three fluoro-the butoxy)-solution of methyl benzoate in 7 milliliters of THF of 500 milligrams (1.9 mmoles).Under refluxing, stirred this mixture 8 hours.Under vacuum, remove THF and go, with hydrochloric acid this residue is carried out acidifying again.After filtration, at the formed throw out of air drying.
Productive rate: 350 milligrams (theoretical value 73.9%)
C 11H 11F 3O 3(M＝248.20)
Calculated value: mole peak (M-H) -: 247 experimental values: mole peak (M-H) -: 247
The HPLC residence time: 7.5 minutes (method A)
(2.134c.N-[2-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-three fluoro-butoxy)-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and 4-(4,4,4-three fluoro-butoxy)-phenylformic acid (124 milligrams, 0.50 mmole).
Productive rate: 37 milligrams (theoretical value 17.0%)
C 24H 29F 3N 2O 2(M＝434.51)
Calculated value: mole peak (M+H) +: 435 experimental values: mole peak (M+H) +: 435
The HPLC residence time: 5.8 minutes (method A)
Embodiment 2.135:
3-methyl-4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602481
2.135a.3-methyl-4-penta-1-alkynyl-methyl benzoate
With 0.39 milliliter of (4.0 mmole) pentyne, 0.56 milliliter of (4.0 mmole) triethylamine, 70 milligrams (0.1 mmole) two-(triphenylphosphine)-palladium (II)-muriate, and the cupric iodide (I) of 19 milligrams (0.1 mmoles), add successively in the solution of 4-bromo-3-methyl-methyl benzoate in 3.0 milliliters of DMF of 458 milligrams (2.0 mmoles).In microwave oven, under 200Watt and 65 ℃, stirred this reaction soln 10 minutes.The pentyne that adds other 0.20 milliliter (2.0 mmole), again in microwave oven, under 200Watt and 70 ℃, this reaction soln of restir 20 minutes.Dilute this mixture with 30 milliliters of EtOAc, filter, clean this filtrate three times with 50 ml waters again by diatomite.With MgSO 4Organic phase to this merging is dewatered, and it is filtered by activated carbon, removes under vacuum and desolvates.On silica gel, carry out purifying (cyclohexane/ethyl acetate 9: 1 follow-up be hexanaphthene) with the post chromatograph.
Productive rate: 200 milligrams (theoretical value 46.2%)
C 14H 16O 2(M＝216.28)
Calculated value: mole peak (M+H) +: 217 experimental values: mole peak (M+H) +: 217
The HPLC residence time: 6.8 minutes (method B)
2.135b.3-methyl-4-penta-1-alkynyl-phenylformic acid
3.0 milliliters of (3.0 mmole) 1M sodium hydroxide solutions are added in the solution of 200 milligrams of (0.93 mmole) 3-methyl-4-penta-1-alkynyl-methyl benzoate in 3 ml methanol.This mixture heating up was refluxed 3 hours.With water diluting reaction solution, more once with 40 milliliters of EtOAc extractions.With MgSO 4The organic phase that is combined is dewatered.After removing siccative and solvent, this raw product promptly can be used for next reactions steps without further purifying.
Productive rate: 50 milligrams (theoretical value 26.7%)
C 13H 14O 2(M＝202.26)
Calculated value: mole peak (M-H) -: 201 experimental values: mole peak (M-H) -: 201
The HPLC residence time: 5.6 minutes (method B)
2.135c.3-methyl-4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (51 milligrams, 0.25 mmole) and 3-methyl-4-penta-1-alkynyl-phenylformic acid (50 milligrams, 0.25 mmole).
Productive rate: 22 milligrams (theoretical value 22.9%)
C 26H 32N 2O 2(M＝388.558)
Calculated value: mole peak (M+H) +: 389 experimental values: mole peak (M+H) +: 389
The HPLC residence time: 6.9 minutes (method A)
Embodiment 2.136:
4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602491
2.136a.4-penta-1-alkynyl-ethyl benzoate
With 0.39 milliliter of (4 mmole) 1-pentyne, 0.56 milliliter of triethylamine, 70 milligrams (0.1 mmole) two-(triphenylphosphine)-palladium (II)-muriate, and 19 milligrams of (0.1 mmole) CuI, add successively in the solution of 552 milligrams of (2.0 mmole) 4-iodo ethyl benzoates in 3 milliliters of DMF.Stirred this reaction soln 4 hours down at 80 ℃.Dilute this mixture with 30 milliliters EtOAc, (Celite) filters by diatomite, and each washs filtrate three times with 50 milliliters water cleaning.Again with MgSO 4Dewater.After it is filtered by activated carbon, under vacuum, remove and desolvate.On silica gel, carry out purifying (cyclohexane/ethyl acetate 9: 1 follow-up be hexanaphthene) with the post chromatograph.
Productive rate: 150 milligrams (theoretical value 34.7%)
C 14H 16O 2(M＝216.282)
Calculated value: mole peak (M+H) +: 217 experimental values: mole peak (M+H) +: 217
The HPLC residence time: 6.8 minutes (method B)
2.136b.4-penta-1-alkynyl-phenylformic acid
5.0 milliliters of (5.0 mmole) 1M sodium hydroxide solutions are added in the solution of 150 milligrams of (0.69 mmole) 4-penta-1-alkynyl-ethyl benzoates in 3 ml methanol.Under refluxing, stirred this mixture 3 hours.Dilute this reaction soln with water, once with 40 milliliters of EtOAc extractions.With 1M KHSO 4This water of solution acidifying.Again with 40 milliliters of EtOAc extraction secondaries.With MgSO 4The organic phase that is combined is dewatered.Under vacuum, remove again and desolvate.This raw product promptly can be used for next reactions steps without being further purified.
Productive rate: 150 milligrams (theoretical value 115%)
C 12H 12O 2(M＝188.23)
Calculated value: mole peak (M-H) -: 187 experimental values: mole peak (M-H) -: 187
R fValue: 0.2 (silica gel, sherwood oil/EtOAc 8: 2)
2.136c.4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (163 milligrams, 0.80 mmole) and 4-penta-1-alkynyl-phenylformic acid (150 milligrams, 0.80 mmole).
Productive rate: 122 milligrams (theoretical value 40.9%)
C 25H 30N 2O(M＝374.53)
Calculated value: mole peak (M+H) +: 375 experimental values: mole peak (M+H) +: 375
R fValue: 0.35 (silica gel, EtOAc/ methyl alcohol/NH 39: 1: 0.1)
Embodiment 2.137:
(4-penta-1-thiazolinyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
2.137a.4-penta-1-thiazolinyl-methyl benzoate
At 0 ℃, under argon atmospher, 246 milligrams of (2.2 mmole) potassium tert.-butoxides are added in 1.08 gram (2.2 mmole) (4-methoxycarbonyl-benzyl)-solution of triphenyl-phosphorus-bromide in 20 milliliters of THF.This orange solution of 0 ℃ of following restir 15 minutes, then make it mix the butyraldehyde of 0.18 milliliter (2.0 mmole).Make this reaction soln reflux 3 hours, then dilute with EtOAc.Clean this organic phase twice with water, dewater, again the vaporising under vacuum solvent with sal epsom.On silica gel, carry out further purifying (sherwood oil/EtOAc 6: 4) with the post chromatograph.Obtain being 4-penta-1-thiazolinyl-methyl benzoate of 2: 1 mixtures of E/Z isomer.
Productive rate: 350 milligrams (theoretical value 56.5%)
C 13H 16O 2(M＝204.27)
Calculated value: mole peak (M+H) +: 204 experimental values: mole peak (M+H) +: 204
R fValue: 0.90 (silica gel, sherwood oil/EtOAc 6: 4)
2.137b.4-penta-1-thiazolinyl-phenylformic acid
5.0 milliliters of (5.0 mmole) 1M sodium hydroxide solutions are added in the solution of 350 milligrams of (1.71 mmole) 4-penta-1-thiazolinyl-ethyl benzoates in 4 ml methanol.This mixture is refluxed to be stirred 2 hours down.Under vacuum, remove solvent, make this residue mixing 6M hydrochloric acid soln again.The formed throw out of suction filtration in the drying by circulating air device, carries out drying again under 35 ℃.Carry out further purifying (. sherwood oil/EtOAc 6: 4) by means of filtering by silicagel column.
Productive rate: 300 milligrams (theoretical value 92.1%)
C 12H 14O 2(M＝190.24)
Calculated value: mole peak (M-H) -: 189 experimental values: mole peak (M-H) -: 189
R fValue: 0.4 (silica gel, sherwood oil/EtOAc 6: 4)
(2.137c. 4-penta-1-thiazolinyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (306 milligrams, 1.50 mmoles) and 4-penta-1-thiazolinyl-phenylformic acid (300 milligrams, 1.56 mmoles) of being 2: 1 mixtures of E/Z isomer.
Productive rate: 130 milligrams (theoretical value 23.0%)
C 25H 32N 2O(M＝376.547)
Calculated value: mole peak (M+H) +: 377 experimental values: mole peak (M+H) +: 377
The HPLC residence time: 6.9 minutes (method A)
Embodiment 2.138:
3-chloro-4-cyclohexyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
Figure A0382007602511
According to general methodology I, be prepared by 2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethamine (102 milligrams, 0.50 mmole) and 3-chloro-4-cyclohexyl-phenylformic acid (119 milligrams, 0.50 mmole).
Productive rate: 46 milligrams (theoretical value 21.6%)
C 26H 33ClN 2O(M＝425.019)
Calculated value: mole peak (M+H) +: 425/427 experimental value: mole peak (M+H) +: 425/427
The HPLC residence time: 4.7 minutes (method B)
Below narration be can be used for measuring the test method of MCH receptor antagonist activity.Relevant this respect, the test method of also using other professionals to know, as, suppress the cAMP-product by suppressing the MCH acceptor, as people such as Hoogduijn M in " Melanin-concentrating hormone and its receptorare expressed and functional in human skin (melanocyte concentrate hormone and expression and the effect of acceptor in human skin) thereof ", described in Biochem.Biophys.Res Commun.296 (2002) 698-701, and in the presence of the antagonism material, resonate by cytogene, the measurement of the biosensor that the combination of MCH on the MCH acceptor is carried out, as Karlsson OP and Lofas S. at " Flow-MediatedOn-Surface Reconstitution of G-Protein Coupled Receptors for Applications inSurface Plasmon Resonance Biosensors (being used for circulating medium surface reconstruction) " at the protein-coupled property of the G acceptor of surperficial cytogene group resonance biological inductor block, Anal.Biochem.300 (2002) is described in the 132-138.Other testing method that are used for the MCH receptor antagonist activity are contained in document and the patent document that reaches mentioned above, and the narration of relevant these used test methods is listed in the application's case.
The MCH-1 receptor binding assays
The combination of method: MCH on the hMCH-1R transfectional cell
Species: the mankind
The test cell: stable transfection enters the hMCH-1R of CHO/Galpha16 cell
Result: IC50 value
The use syringe (pin 0.6 * 25mm), the film of the CHO/Galpha16 cell of human hMCH-1R stable transfection is taken from suspension again, and with test buffered soln (50mM HEPES, 10mM MgCl 2, 2mM EGTA (pH7.00); 0.1% bovine serum albumin (no proteolytic enzyme), 0.021% bacitracin, 1 mcg/ml aprotinin, 1 mcg/ml leupeptin, and 1 μ M phosphoramidon), be diluted to the concentration of 5 to 15 mcg/ml.At room temperature, make the I of this membrane portions of 200 microlitres (containing 1 to 3 microgram albumen) and 100pM 125-tyrosyl melanocyte concentrates hormone (I 125-MCH can be obtained with commercially available by NEN) and the test compound of cumulative concentration, in the final volume of 250 microlitres, carried out incubation 60 minutes.After carrying out incubation, use cell harvestor, the glass fibre filter (GF/B, Unifilter Packard) by handling through 0.5%PEI filters this reactant.After then adding scintillator material (Packard Microscint 20) again, in measuring apparatus (TopCount of Packard), measure the membrane-bound radioactive activity that is retained on the filter.
Non-narrow spectrum binding is to define with the banded radioactivity in the presence of 1 micromolar MCH in the incubation process.
The analysis of concentration binding curve is to carry out according to the hypothesis of a receptor binding site.
Standard substance:
Non-marking MCH with through mark I 125-MCH compete relevant receptors bind and have one in 0.06 and 0.15nM between the IC50 value.
The KD value of radioactivity ligand is 0.156nM.
The Ca of MCH-1 acceptor coupling 2+Nigration
Method: with the Ca that human MCH was carried out 2+Nigration (FLIPR 384)
Biological species: the mankind
Test cell: through the CHO/Galpha of hMCH-1R stable transfection 16 cells
Result: first observed value: (MCH 10 for the % reference substance -6M) stimulation
Second observed value: pKB value
Reagent: HBSS (10x) (GIBCO)
HEPES buffered soln (1M) (GIBCO)
Pluronic?F-127??????????????????????(Molecular?Probes)
Fluo-4??????????????????????????????(Molecular?Probes)
4-(dipropyl sulfamyl) phenylformic acid (Sigma)
MCH?????????????????????????????????(Bachem)
Bovine serum albumin (Serva)
(no proteolytic enzyme)
BMSO????????????????????????????????(Serva)
Ham′s?F12??????????????????????????(Bio?Whittaker)
FCS?????????????????????????????????(Bio?Whittaker)
L-glutamine (GIBCO)
Hygromycin B (GIBCO)
PENStrep????????????????????????????(Bio?Whittaker)
Zeocin??????????????????????????????(Invitrogen)
(contain the L-glutamine at the F12 of Ham cell culture medium; Bio Whittaker; Cat.No.:BE12-615F) in, cultivate pure lines CHO/Galpha 16hMCH-1R cell.This substratum in per 500 milliliters, contain 10%FCS, 1%PENStrep, 5 milliliters of L-glutamine (stock solution of 200mM), 3 milliliters of hygromycin B (50 mg/ml are in PBS), and 1.25 milliliters of Zeocin (stock solutions of 100 mcg/ml) in experiment the day before yesterday, (black wall on 384 hole droplet price fixings, the tool clear bottom, make by Costar), density with every hole 2500 cells, carry out flat board and cultivate, and in above-mentioned substratum, in 37 ℃, 5%CO 2, and 95% relative humidity under overnight incubation.Testing the same day, under 37 ℃, make these cells and wherein add the benzoic cell culture medium of 2mM Fluo-4 and 4.6mM4-(dipropyl sulfamyl) and carried out incubation 45 minutes.After adding the fluorescent stain, clean cell four times to mix the benzoic Hanks buffered soln of 0.07%4-(dipropyl sulfamyl) (1 * HBSS, 20mM HEPES).To mix the Hanks buffered soln dilution test material of 2.5%DMSO.(Molecular Devices in the FLIPR384 device; Excitation wavelength: 488nm; Emission wavelength: 510 to 570nm), in the end behind the cleaning step 5 minutes the time, in 384 hole droplet price fixings, have material in the presence of, measure the not background fluorescent value of activated cell.Be activated cell, to contain the Hanks buffered soln dilution MCH of 0.1%BSA, in the end behind the cleaning step 35 minutes time shift liquid to this 384 hole droplet price fixing, again at this FLIPR 384Measure MCH-excitability fluorescent in the device.
Data analysis:
First observed value: cell Ca 2+Mobile is to measure with the relative fluorescent peak of subtracting background value, and (MCH 10 with reference substance -6M) per-cent of peak signal is represented.This observed value can be in order to the possible agonism of identification substances.
Second observed value: cell Ca 2+Mobile is to measure with the relative fluorescent peak of subtracting background value, and (MCH 10 with reference substance -6M, signal standardization to 100%) per-cent of peak signal is represented.With GraphPadPrism 2.01 curve programs, the EC50 value that has and do not have the MCH dosage activity curve of substances (deciding concentration) is measured in mapping.The MCH antagonist can make this MCH stimulate curve to move to right and map.
Restraining effect is with the pKB value representation:
PKB=log (EC 50 (substances+MCH)/ EC 50 (MCH)-1)-log c (substances)
In above-mentioned test, compound of the present invention comprises its salt, all has the MCH-receptor antagonist activity.Use above-mentioned MCH-1 receptor binding assays, antagonistic activity be its about 10 -10To 10 -5In the dosage range of M, preferably 10 -9To 10 -6M.
Use above-mentioned MCH-1 receptor binding assays, record following IC50 value:
According to embodiment number of compound The IC50 value
????1.14 ??2.1nM
????2.4 ??3.5nM
????2.12 ??30.5nM
Hereinafter will describe the part examples of formulations, wherein notion " active substance " represents one or more according to compound of the present invention, comprises its salt.With regard to regard to one of composition of described one or more active substances, notion " active substance " also comprises the active substance that this is other.
Embodiment 3
The powder inhalation capsules that contains 1 milligram of active substance
Form:
1 powder inhalation capsules contains:
1.0 milligrams of active substances
20.0 milligrams of lactose
50.0 milligrams of hard gelatin capsules
70.0 milligram
The preparation method:
This active substance is ground to the required globule size of suction.Make active substance and lactose uniform mixing through grinding.This mixture is packed in the hard gelatine capsule.
Embodiment 4
The Respimat that contains 1 milligram of active substance _Use inhalable solution
Form:
Contain in 1 spraying:
1.0 milligrams of active substances
0.002 milligram of Zephiran chloride
0.0075 milligram of disodium salt disodium
Pure water is added to 15.0 microlitres
The preparation method:
Active substance and Zephiran chloride is soluble in water, and the Respimat that packs into _In the cartridge case.
Embodiment 5
The atomizer inhalable solution that contains 1 milligram of active substance
Form:
Contain in 1 bottle:
Active substance 1.0 grams
Sodium-chlor 0.18 gram
Zephiran chloride 0.002 gram
Pure water is added to 20.0 milliliters
The preparation method:
With active substance, sodium-chlor, soluble in water with Zephiran chloride.
Embodiment 6
The propelling gas dosing aerosols that contains 1 milligram of active substance
Form:
Contain in 1 spraying:
1.0 milligrams of active substances
Yelkin TTS 0.1%
Propelling gas is added to 50.0 microlitres
The preparation method:
Micronized active substance evenly is suspended in the mixture of Yelkin TTS and propelling gas.This suspension is moved in the pressurizing vessel with metering valve.
Embodiment 7
The nasal spray that contains 1 milligram of active substance
Form:
Active substance: 1.0 milligrams
0.9 milligram in sodium-chlor
0.025 milligram of Zephiran chloride
0.05 milligram of disodium ethylene diamine tetraacetate
Pure water is added to 0.1 milliliter
The preparation method:
Active substance and vehicle is soluble in water, move in the cell therefor again.
Embodiment 8
The syringeability solution that contains 5 milligrams of active substances in per 5 milliliters
Form:
Active substance: 5 milligrams
250 milligrams of glucose
10 milligrams of human serum albumin
250 milligrams in glucose furfural
Water for injection is added to 5 milliliters
The preparation method:
Glucose furfural and glucose are dissolved in the water for injection (WfI); Add human serum albumin; Heating is with the lytic activity material; Inject WfI to specified volume; Under nitrogen, move in the ampoule.
Embodiment 9
The syringeability solution that contains 100 milligrams of active substances in per 20 milliliters
Form:
100 milligrams of active substances
Potassium primary phosphate
=KH 2PO 412 milligrams
Sodium phosphate dibasic
=Na 2HPO 42H 22 milligrams of O
180 milligrams in sodium-chlor
50 milligrams of human serum albumin
80 20 milligrams of Polysorbate
Water for injection is added to 20 milliliters
The preparation method:
With Polysorbate 80, sodium-chlor, potassium primary phosphate, and Sodium phosphate dibasic be dissolved in the water for injection (WfI); Add human serum albumin; Heating is with the lytic activity material; Inject WfI to specified volume; Move in the ampoule.
Embodiment 10
The lyophilized products that contains 10 milligrams of active substances
Form:
10 milligrams of active substances
300 milligrams of mannitols
20 milligrams of human serum albumin
The preparation method:
Mannitol is dissolved in the water for injection (WfI); Add human serum albumin; Heating is with the lytic activity material; Inject WfI to specified volume; Move in the bottle: carry out freeze-drying.
The solvent that lyophilized products is used:
80 20 milligrams of Polysrbate 80=Tween
200 milligrams of mannitols
Water for injection is added to 10 milligrams
The preparation method:
Polysorbate 80 and mannitol are dissolved in the water for injection (WfI); Move in the ampoule.
Embodiment 11
The tablet that contains 20 milligrams of active substances
Form:
20 milligrams of active substances
120 milligrams of lactose
40 milligrams of W-Gums
2 milligrams of Magnesium Stearates
25 18 milligrams of Povidone K
The preparation method:
With active substance, lactose, and W-Gum uniform mixing; Aqueous solution granulation with Povidone K 25; Mix with Magnesium Stearate; In the film-making suppressor, carry out compressing tablet; 200 milligrams of tablet weight.
Embodiment 12
The capsule that contains 20 milligrams of active substances
Form:
20 milligrams of active substances
80 milligrams of W-Gums
5 milligrams in polymolecularity silica gel
2.5 milligrams of Magnesium Stearates
The preparation method:
With active substance, W-Gum, and silica gel uniform mixing; Mix with Magnesium Stearate; In the capsule packing machine, mixture is packed in the hard gelatine capsule of No. 3 sizes.
Embodiment 13
The suppository that contains 50 milligrams of active substances
Form:
50 milligrams of active substances
Stearic fat (Adeps sodius) is added to 1700 milligrams in right amount
The preparation method:
Melt stearic fat down at about 38 ℃; Active substance through grinding is dispersed in the stearic fat of thawing; After being cooled to about 35 ℃, be poured in advance in the refrigerative model.
Embodiment 14
The syringeability solution that contains 10 milligrams of active substances in per 1 milliliter
Form:
10 milligrams of active substances
50 milligrams of mannitols
10 milligrams of human serum albumin
Water for injection is added to 1 milliliter
The preparation method:
Mannitol is dissolved in the water for injection (WfI); Add human serum albumin; Heating is with the lytic activity material; Inject WfI to specified volume; Under nitrogen, inject ampoule.

Claims (44)

1. the carboxamide compounds of a general formula I
Wherein
R 1, R 2Represent H independently of one another, optionally through radicals R 11The C that replaces 1-8-alkyl or C 3-7-cycloalkyl, or selectivity is through radicals R 12Single or polysubstituted, and/or through the mono-substituted phenyl of nitro, or
R 1And R 2Form C 2-8-alkylidene bridge, wherein
-one or two-CH 2-group can be independently of one another and by-CH=N-or-CH=CH-replaces, and/or
-one or two-CH 2-group can be independently of one another and by-O-,-S-,-CO-,-C (CH 2)-or-NR 13-substitute, so that heteroatoms directly is not connected with each other,
Simultaneously, in defined alkylidene bridge above, one or more H atom can be by R 14Replace, and/or
Above defined alkylidene bridge can replace through one or more identical or different carbocyclic ring or heterocyclic group Cy, so that the chain between alkylidene bridge and group Cy is to be formed by following
-by single or two keys,
-by a shared C atom, forming a volution system,
-by the C and/or the N atom of two shared, adjacency, form a condensed-bicyclic system, or
-by C and/or N atom more than two or three, form the loop systems of a bridge joint,
R 3Represent H, C 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-4Alkyl-, C 3-7-cycloalkenyl group, C 3-7-cycloalkenyl group-C 1-4-alkyl-, phenyl, phenyl-C 1-4-alkyl-, C 1-3-alkoxy-C 2-6-alkyl-, amino-C 2-6-alkyl-, C 1-3-alkyl-amino-C 2-6-alkyl-or two-(C 1-3-alkyl)-amino-C 2-6-alkyl-,
X represents singly-bound or C 1-8-alkylidene bridge, wherein
-one or two-CH 2-group can be independently of one another and by-CH=CH-or-C=C-substitutes, and/or
-one or two-CH 2-group can be independently of one another and by-O-,-S-,-(SO)-,-(SO 2)-,-CO-or-NR 4-substitute, so that each situation following two O, S or N atom or an O atom and a S atom directly be not connected with each other,
Simultaneously, one or two C atom independently of one another can through hydroxyl-, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or under each situation through one or two identical or different C 1-6-alkyl replaces, and/or
This alkylidene bridge can link R 1, link R so that it comprises 1And the N atom of X, forming a heterocyclic radical,
Z represents C 1-4-alkylidene bridge, wherein the C atom of two adjacency and another C 1-4-alkylidene bridge can be connected to each other, simultaneously in group Z, and-CH 2-group can by-O-or-NR 5-substitute, and one or two C atom in this alkylidene bridge can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-, C 1-3-alkoxyl group, amino-C 1-3-alkyl-, C 1-3-alkyl-amino-C 1-3-alkyl-or two-(C 1-3-alkyl)-amino-C 1-3-alkyl-replacement, and/or through one or two identical or different C 1-6-alkyl replaces, and/or
R 3Can link Z, link R so that it comprises 3The N atom, forming a heterocyclic radical,
A, Y have one of specified meaning of Cy independently of one another,
Simultaneously, R 1Can link Y, so that it comprises radicals X and links R 1And the N atom of X, form a Y condensed heterocycle base, and/or
R 3Can link Y, so that it comprises group Z and links R 3And the N atom of Z, form a saturated or undersaturated heterocyclic radical of part of Y condensed, or
A and R 3Can be connected to each other, so that
The group of formula I
Represent the group of segment bounds II
Figure A038200760004C1
And
Q represents a group, and it is selected from segment bounds IIIa to IIIg
-CR 6R 7-????????IIIa
-CR 6＝CR 7-?????IIIb
-N＝CR 8-?????????IIIc
-N＝N-????????????IIId
-CO-NR 9-?????????IIIe
-CR 8＝N-?????????IIIf
-CO-??????????????IIIg
L 1, L 2, L 3Independently of one another and have a R 20One of specified meaning,
B represents C 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more carbon atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, or
Has one of specified meaning of Cy, simultaneously, link group W or optionally directly link group A and optionally condense C atom on banded phenyl or the pyridine ring by this isocyclic part or this, or form by the N or the C atom of this heterocyclic moiety, simultaneously, when k=0, group B and group A can be by shared C atoms, and form a volution system, or
The atom of, adjacency shared by two, forming a condensed-bicyclic system,
W represent singly-bound ,-O-, C 1-4-alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N=(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-6-alkyl replaces, and/or
Alkylidene group, oxyalkylene, and the definition of alkylidene group oxyalkylene in W also can link B by two keys,
K represents 0 or 1,
Cy represents carbocylic radical or heterocyclic radical, and it is to be selected from one of following meaning
-saturated 3-to 7-member carbocylic radical,
-undersaturated 5-to 7-member carbocylic radical,
-phenyl,
-saturated 4-to 7-member or undersaturated 5-to 7-element heterocycle base has N, an O or S atom as heteroatoms,
-saturated or undersaturated 5-to 7-element heterocycle base, have two or more N atoms or have one or two N atom and O or S atom as heteroatoms,
The heterocycle 5-of-aromatics or 6-person's group have one or more identical or different heteroatoms that is selected from N, O and/or S,
Simultaneously, above-mentioned 4-, 5-, 6-or 7-person's group can be shared by two, the C atom of adjacency links and condense with phenyl or pyridine ring, and
In above-mentioned 5-, 6-or 7-person's group, one or two non-adjacent-CH 2Group can by-CO-,-C (=CH 2)-,-(SO)-or-(SO 2)-group substitutes, and
Saturated or the 7-person's group of above-mentioned saturated 6-also can with imino-, N-(C 1-4-alkyl)-imino-, methylene radical, C 1-4-alkyl-methylene radical-or two-(C 1-4-alkyl)-methylene bridge exists with the form of bridged ring system jointly, and
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl, also can replace through the nitro list in addition, and/or at one or more N atoms place through R 21Replace,
R 4, R 5Has R independently of one another 16One of specified meaning,
R 6，R 7，
R 8, R 9H, the C of representing independently of one another 1-6-alkyl, ω-C 1-3-alkoxy-C 1-3-alkyl-or ω-hydroxyl-C 1-3-alkyl, and R 6, R 7, R 8Also represent halogen atom independently of one another,
R 11Represent R 15-O-, R 15-O-CO-, R 16R 17N-, R 18R 19N-CO-or Cy-,
R 12Has R 20Specified meaning,
R 13Has R 17Specified meaning,
R 14Represent halogen atom, C 1-6-alkyl, R 15-O-, R 15-O-CO-, R 16R 17N-, R 18R 19N-CO-, R 15-O-C 1-3-alkyl-, R 15-O-CO-C 1-3-alkyl-, R 16R 17N-C 1-3-alkyl-, R 18R 19N-CO-C 1-3-alkyl-or Cy-C 1-3-alkyl-,
R 15Represent H, C 1-4-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, phenyl, phenyl-C 1-3-alkyl-or pyridyl,
R 16Represent H, C 1-6-alkane is at, C 3-7-ring cycloalkanes, C 3-7-cycloalkyl-C 1-3-alkyl-, C 4-7-cycloalkenyl group, C 4-7-cycloalkenyl group-C 1-3-alkyl-, ω-hydroxyl-C 2-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 2-3-alkyl-, amino-C 1-6-alkyl-, C 1-3-alkyl-amino-C 1-6-alkyl-or two-(C 1-3-alkyl)-amino-C 1-6-alkyl-,
R 17Has R 16Specified meaning, or represent phenyl, phenyl-C 1-3-alkyl-, pyridyl, diox-2-base, C 1-3-alkyl-carbonyl, hydroxyl carbonyl-C 1-3-alkyl-, C 1-4-carbalkoxy, C 1-3-alkane carbonyl amino-C 2-3-alkyl-, C 1-3-alkyl sulphonyl-or C 1-3-alkyl sulfonyl amino-C 2-3-alkyl-,
R 18, R 19H or the C of representing independently of one another 1-6-alkyl,
R 20Represent halogen atom, hydroxyl, cyano group, C 1-4-alkyl, C 3-7-cycloalkyl, hydroxyl-C 1-3-alkyl, R 22-C 1-3-alkyl, or have R 22One of specified meaning,
R 21Represent C 1-3-alkyl, ω-hydroxyl-C 2-3-alkyl, phenyl, phenyl-C 1-3-alkyl-, C 1-3-alkyl-carbonyl, carboxyl, C 1-4-alkoxyl group-carbonyl, C 1-3-alkyl sulphonyl, phenylcarbamoyl or phenyl-C 1-3-alkyl-carbonyl,
R 22Represent pyridyl, phenyl, phenyl-C 1-3-alkoxyl group-, C 1-3-alkoxyl group, C 1-3-alkylthio-, carboxyl, H-CO-, C 1-3-alkyl carbonyl, C 1-4-carbalkoxy, aminocarbonyl, C 1-3-alkylamino-carbonyl, two-(C 1-3-alkyl)-aminocarbonyl, C 1-3-alkyl-alkylsulfonyl, C 1-3-alkyl-sulfinyl, C 1-3-alkyl-sulfonamido-, amino, C 1-3-alkylamino-, two (C 1-3-alkyl)-amino-, phenyl-C 1-3-alkylamino-or N-(C 1-3-alkyl)-phenyl-C 1-3-alkyl-amino-, acetylaminohydroxyphenylarsonic acid, propionamido, phenylcarbamoyl, benzene carbonyl amino-, the phenylcarbamoyl methylamino--, hydroxyl-alkane aminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidyl) carbonyl, (piperidino) carbonyl, (six hydrogen-1-azepine _ yl) carbonyl, (4-methyl isophthalic acid-piperazinyl) carbonyl, methylene-dioxy, aminocarbonyl-amino-or alkylamino carbonyl amino-
Simultaneously, at group and part A, B, W, X, Y, Z, R 1To R 9, and R 11To R 22In, under each situation, one or more C atom can be single or polysubstituted through F, and/or, under each situation, one or two C atom can be independently of one another through Cl or the single replacement of Br, and/or under each situation, one or more phenyl ring can be independently of one another, have one, two or three substituting group in addition, this substituting group is selected from F, Cl, Br, I, C 1-4-alkyl, C 1-4-alkoxyl group, difluoromethyl, trifluoromethyl, hydroxyl, amino, C 1-3-alkylamino-, two-(C 1-3-alkyl)-amino-, acetylaminohydroxyphenylarsonic acid, aminocarbonyl, CN, difluoro-methoxy, trifluoromethoxy, amino-C 1-3-alkyl-, C 1-3-alkylamino-C 1-3-alkyl-, and two-(C 1-3-alkyl)-amino-C 1-3-alkyl-, and/or it can replace through the nitro list, and
Any H atom that is present in carboxyl, or be attached at the H atom of N atom, under each situation, can by one in vivo the group of cleavable replace,
Its tautomer, diastereomer, enantiomer, its mixture, with and salt.
2. according to the carboxamide compounds of claim 1, it is characterized in that
R 3Represent H, C 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-4-alkyl-, C 1-3-alkoxy-C 2-6-alkyl-, amino-C 2-6-alkyl-, C 1-3-alkyl-amino-C 2-6-alkyl-or two-(C 1-3-alkyl)-amino-C 2-6-alkyl-,
B has the specified meaning of Cy, and simultaneously, it is by this isocyclic part or this selected fused phenyl or the C atom on the pyridine ring that binding group W or selectivity directly link group A, or forms by the N or the C atom of heterocyclic moiety,
Simultaneously, as k=0, then its B and group A can form a volution system by a shared C atom, or
The atom of, adjacency shared by two, form one condense, bicyclic system,
R 15Represent H, C 1-4-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkyl-C 1-3-alkyl-, phenyl or phenyl-C 1-3-alkyl-,
R 17Has R 16Specified meaning, or represent phenyl, phenyl-C 1-3-alkyl-, dioxolane-2-base, C 1-3-alkyl-carbonyl, hydroxyl carbonyl-C 1-3-alkyl-, C 1-3-alkane carbonyl amino-C 2-3-alkyl-, C 1-3-alkyl sulphonyl-or C 1-3-alkyl sulfonyl amino-C 2-3-alkyl-,
R 22Represent phenyl, phenyl-C 1-3-alkoxyl group-, C 1-3-alkoxyl group, C 1-3-alkylthio-, carboxyl, C 1-3-alkyl carbonyl, C 1-3-carbalkoxy, aminocarbonyl, C 1-3-alkylamino-carbonyl, two-(C 1-3-alkyl)-aminocarbonyl, C 1-3-alkyl-alkylsulfonyl, C 1-3-alkyl-sulfinyl, C 1-3-alkyl-sulfonamido-, amino, C 1-3-alkylamino-, two (C 1-3-alkyl)-amino-, phenyl-C 1-3-alkylamino-or N-(C 1-3-alkyl)-phenyl-C 1-3-alkyl-amino-, acetylaminohydroxyphenylarsonic acid, propionamido-, phenylcarbamoyl, benzene carbonyl amino-, the phenylcarbamoyl methylamino--, hydroxyl alkane aminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidyl) carbonyl, (piperidino) carbonyl, (six hydrogen-1-azepine _ yl) carbonyl, (4-methyl isophthalic acid-piperazinyl) carbonyl, methylene-dioxy, aminocarbonyl amino-or alkylamino carbonyl amino-
Simultaneously, at group A, B, W, X, Y, Z, R 1To R 9, and R 11To R 22In, under each situation, one or more C atom can be single or polysubstituted through F, and/or under each situation, one or two C atom can replace through Cl or Br list independently of one another, and
Group A, W, X, Y, Z, R 1, R 2, R 4To R 9, R 11To R 14, R 16, and R 18To R 21, and k have meaning according to claim 1, and
Any H atom that is present in carboxyl, or link the H atom of N atom, under each situation, can by one in vivo the cracked group replaced,
Its tautomer, diastereomer, enantiomer, its mixture, with and salt.
3. according to the carboxamide compounds of claim 1 or 2, it is characterized in that group A has in the claim 1 the specified meaning of Cy.
4. according to the one or more of carboxamide compounds in claim 1 or 3, it is characterized in that A and R 3Interlink, so that
The group of formula I
Represent the group of segment bounds II
And
Q represents a group that is selected from segment bounds IIIa to IIIg,
-CR 6R 7-??????????IIIa，
-CR 6＝CR 7-???????IIIb，
-N＝CR 8-??????????IIIc，
-N＝N-??????????????IIId，
-CO-NR 9-??????????IIIe，
-CR 8＝N-???????IIIf
-CO-????????????IIIg
L 1, L 2, L 3, R 6, R 7, R 8, and R 9Has meaning specified in the claim 1.
5. according to the one or more of carboxamide compounds in the claim 1 to 4, it is characterized in that R 1, R 2H, the C of representing independently of one another 1-6-alkyl, C 3-7-cycloalkyl, C 3-7-cycloalkenyl group-C 1-3-alkyl-, ω-hydroxyl-C 2-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 2-3-alkyl-, C 1-4-alkoxyl group-carbonyl-C 1-3-alkyl-, amino-C 2-4-alkyl-, C 1-3-alkyl-amino-C 2-4-alkyl-or two-(C 1-3-alkyl)-amino-C 2-4-alkyl-, phenyl or phenyl-C 1-3-alkyl-,
Simultaneously, in above-mentioned group and part, one or more C atom or single or polysubstituted through F, and/or one or two C atom can replace through Cl or Br list independently of one another, and
Phenyl can be in claim 1 defined radicals R 12Single or polysubstituted, and/or it can replace through the nitro list.
6. according to the one or more of carboxamide compounds in the claim 1～4, it is characterized in that R 1And R 2Can form the alkylidene bridge of claim 1, so that R 1R 2N-forms and is selected from azepine butane, tetramethyleneimine, piperidines, azepine cycloalkanes in heptan, 2,5-dihydro-1H-pyrroles, 1,2,3,6-tetrahydrochysene-pyridine, 2,3,4,7-tetrahydrochysene-1H-azepine _ base, 2,3,6,7-tetrahydrochysene-1H-azepine _, and piperazine (wherein free imido functional group can be through R 13Replace), the base of morpholine and thiomorpholine,
Simultaneously, can be according to the one or more H atoms of claim 1 by R 14Replace, and/or can replace through one or two identical or different carbocyclic ring or heterocyclic radical Cy, wherein R according to the specified method of claim 1 13, R 14, and Cy have meaning specified in claim 1 or 2.
7. according to the carboxamide compounds of claim 6, it is characterized in that
Group
It is the meaning that one of has in the following segment bounds
Figure A038200760009C2
Figure A038200760010C1
Figure A038200760011C1
Wherein by radicals R 1R 2One or more H atom of heterocyclic that N-forms can be by R 14Substitute, and with this by radicals R 1R 2N-forms heterocycle banded ring can be at one or more C atom place through R 20Single or polysubstituted, and under the situation of phenyl ring, also can replace through the nitro list in addition,
R wherein 13, R 14, R 20, R 21, and X have meaning specified in claim 1 or 2.
8. according to the one or more of carboxamide compounds in the claim 1～7, it is characterized in that X represents singly-bound or non-chain bridge, it is selected from C 1-6-alkylidene group, C 2-6-alkenylene, C 2-6-alkynylene, C 1-6-alkylene oxide group, carbonyl, carbonyl-C 1-6-alkylidene group or C 1-6-alkylidene group-amino-, wherein should amino can be through R 4Replace, simultaneously one or two C atom can claim 1 in specified mode replace, and/or this alkylidene bridge can claim 1 in specified mode link R 1
9. carboxamide compounds according to Claim 8 is characterized in that
X represents singly-bound, carbonyl, alkylidene bridge, it is selected from methylene radical, ethylene, trimethylene, and tetramethylene,
Wherein one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or under each situation, through one or two identical or different C 1-4-alkyl replaces, and
Under each situation, one or more C atoms can be single or polysubstituted through F, and/or under each situation, one or two C atom can be independently of one another through Cl or the single replacement of Br.
10. according to the one or more of carboxamide compounds in the claim 1～9, it is characterized in that Z represents methylene radical, ethylene, 1,3-propylidene, and tetramethylene, inferior methoxyl group, 1,2-inferior ethoxyl, 1, the inferior propoxy-of 3-, and 1, the inferior butoxy of 4-
Wherein one or two C atom can be independently of one another and through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or, under each situation, through one or two identical or different C 1-4-alkyl replaces, and
Under each situation, one or more C atom can be single or polysubstituted through F, and/or under each situation, one or two C atom can replace through Cl or Br list independently of one another, and
R 3Can link Z, link R so that it comprises 3The N atom, to form a heterocyclic radical.
11., it is characterized in that Z is selected from bridge-CH according to the carboxamide compounds of claim 10 2-,-CH 2-CH 2-,-CH 2-CH (CH 3)-,-CH 2-C (CH 3) 2-,-CH (CH 3)-CH 2-,-C (CH 3) 2-CH 2-, and-CH 2The group of-O-, perhaps, Z links R 3, so that segment bounds
Figure A038200760012C1
Group have and be selected from 1,3-pyrrolidinylidene, 1,3-piperidylidene ,-1,2,5,6-tetrahydropyridine 1,3-subunit, and 3-hydroxyl-1, the meaning of 3-piperidylidene.
12. the one or more of carboxamide compounds according in the aforesaid right requirement is characterized in that R 3Be to be selected from methyl, ethyl, n-propyl, sec.-propyl, 2-hydroxyethyl, 3-hydroxyl-n-propyl or 2-hydroxyl-1-methyl-ethyl, simultaneously, in above-mentioned group, one, two or three H atom can be replaced by F, perhaps, and R 3Be selected from group H, amino-C 2-3-alkyl-, C 1-3-alkyl-amino-C 2-3-alkyl-or two-(C 1-3-alkyl)-amino-C 2-3-alkyl-.
13. the one or more of carboxamide compounds according in the aforesaid right requirement is characterized in that Y is selected from divalence cyclic group 1, inferior third cyclic group of 2-, 1, the inferior cyclobutyl of 3-, 1, the 3-cyclopentylidene, 1, the 3-cyclopentenylidene, 1,3-and 1, the 4-cyclohexylidene, 1, the 3-phenylene, 1, the 4-phenylene, 1,3-and 1,4-phenylidene, 1, the inferior suberyl of 4-, 1, the inferior cycloheptenyl of 4-, 1, the 3-pyrrolidinylidene, 1, the inferior pyrrolinyl of 3-, 1, the inferior pyrryl of 3-, 1, the 4-piperidylidene, 1, the inferior tetrahydro pyridyl of 4-, 1, the inferior dihydropyridine base of 4-, 2,4-and 2, the 5-pyridylidene, or 1, the inferior piperazinyl of 4-
Simultaneously, above-mentioned 5-, 6-or 7-person's group can condense with phenyl or pyridine ring by the C atom of two shared, adjacency,
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the situation of phenyl, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace,
Simultaneously, as the specified mode of claim 1, R 1Can link Y and/or R 3Can link Y, and
R 1, R 3, R 20, and R 21Has meaning specified in claim 1 or 2.
14. the carboxylic acid amides compound as claim 13 is characterized in that R 1Be to link Y, so that segment bounds
Figure A038200760013C1
Group, have the meaning that is selected from following segment bounds.
15. according to claim 1,2, one or multinomial carboxamide compounds in 3 and 5～13 is characterized in that group A is selected from divalence cyclic group 1, inferior third cyclic group of 2-, 1, the inferior cyclobutyl of 3-, 1, the 3-cyclopentylidene, 1, the 3-cyclopentenylidene, 1,3-and 1, the 4-cyclohexylidene, 1,3-and 1,4-phenylene, 1,3-and 1, the 4-phenylidene, 1, the inferior suberyl of 4-, 1, the inferior cycloheptenyl of 4-, 1, the 3-pyrrolidinylidene, 1, the inferior pyrrolinyl of 3-, 1, the inferior pyrryl of 3-, 1, the 4-piperidylidene, 1, the inferior tetrahydro pyridyl of 4-, 1, the inferior dihydropyridine base of 4-, 2,4-and 2,5-pyridylidene, 1, the inferior piperazinyl of 4-, 7-aza-bicyclo [2.2.1] heptane-2,7-two bases, and 8-aza-bicyclo [3.2.1] octane-3,8-two bases
Simultaneously, above-mentioned 5-, 6-or 7-person's group can be shared by two, the C atom of adjacency and phenyl or pyridine ring condense binding, and
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the phenyl situation, it also can replace through the nitro list in addition, and/or it can be at one or more N atom place through R 21Replace, and
R 20, R 21, and Y have meaning specified in claim 1 or 2.
16. according to or multinomial carboxamide compounds in the aforesaid right requirement, it is characterized in that group B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, the hexamethylene ketone group, cyclohexenyl, phenyl, suberyl, cycloheptenyl, the ethylenimine base, azetidinyl, pyrrolidyl, pyrrolinyl, pyrryl, piperidyl, tetrahydro pyridyl, the dihydropyridine base, pyridyl, azepine cycloalkyl in heptan, piperazinyl, the 1H-pyrazolyl, imidazolyl, triazolyl, tetrazyl, morpholinyl, thio-morpholinyl, indyl, pseudoindoyl, quinolyl, benzimidazolyl-, isoquinolyl, furyl, and thienyl
Simultaneously, binding group W or selectivity directly link group A is undertaken by the C atom on this isocyclic part or this selected fused banded phenyl or the pyridine ring, or forms by the N or the C atom of this heterocyclic moiety,
Perhaps, B is with being to be selected from group cyclopentylidene-methyl, cyclohexylidene-methyl, and inferior pimelinketone-4-base-methyl by two key banded W, and
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the phenyl situation, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace, and
R 20And R 21Has meaning specified in claim 1 or 2.
17., it is characterized in that group B is selected from group C according to 1 in the claim 1～15 or multinomial carboxamide compounds 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more carbon atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, and
W represent singly-bound ,-O-, C 1-4Alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N-(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-4-alkyl replaces, and
K represents 0 or 1, and
R 20Has meaning specified in claim 1 or 2.
18. the carboxamide compounds according to claim 1 or 2 is characterized in that k=0, and group A links group B by a shared C atom, forming a volution system,
Simultaneously, group A represents saturated 5-to a 7-member carbocyclic ring or a heterocyclic radical, and group B is represented saturated 4-to a 7-member carbocyclic ring or a heterocyclic radical, and under each situation, this heterocyclic radical contains N, an O or S atom, and can condense by the C atom of two adjacency with 5-to a 7-member group B and to be connected a phenyl or pyridine ring, and
Above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, and condensing under the banded phenyl ring situation, it also can replace through the nitro list in addition, and/or can be at one or more N atom place through R 21Replace, simultaneously, R 20And R 21Has meaning specified in claim 1 or 2.
19. according to 1 in the claim 1～15 or multinomial carboxamide compounds, it is characterized in that k=0, and group B is that C atom shared by two, adjacency links group A, and formation one condenses, 8-to the 12-member carbocyclic ring or the heterocyclic ring system of saturated, the unsaturated or aromatics of dicyclo
Simultaneously, this heterocyclic ring system has one or more identical or different heteroatoms that is selected from N, O and/or S, and
This bicyclic system can be at one or more C atom place through R 20Single or polysubstituted, and condensing under the banded phenyl ring situation, it also can replace through the nitro list in addition, and/or can be at one or more N atom place through R 21Replace, simultaneously, R 20And R 21Has meaning specified in claim 1 or 2.
20. according to 1 in the claim 1～16 or multinomial carboxamide compounds, it is characterized in that W be singly-bound ,-CH 2-or-CH=.
21. 1 or multinomial sour amide compound according in the aforesaid right requirement is characterized in that
A, Y are independently from each other divalence cyclic group 1,4-phenylene, 1,4-cyclohexylidene, 1,4-phenylidene, 1,4-piperidylidene, 1,4 ,-Ya-1,2,3,6-tetrahydro pyridyl, 2,5-pyridylidene, and 1, the inferior piperazinyl of 4-, simultaneously, A also can link R according to claim 3 3, and above-mentioned cyclic group can be at one or more C atom place through R 20Single or polysubstituted, under the phenyl situation, it also can be in addition replaces through the nitro list, and/or at one or more N atom place through R 21Replace,
B represents phenyl or cyclohexyl, and simultaneously, above-mentioned group can be through R 20Single or polysubstituted, and/or phenyl ring can be in addition replaces through the nitro list, simultaneously, R 20Have claim 1 or 2 specified meanings, and
W be singly-bound ,-CH 2-or-CH=, and
Z representative-CH 2-CH 2-,-CH 2-CH (CH 3)-,-CH 2-C (CH 3) 2-,-CH (CH 3)-CH 2-,-C (CH 3) 2-CH 2-or-CH 2-O-, perhaps,
Link R 3, so that formula I segment bounds
Figure A038200760015C1
Group have and be selected from 1,3-pyrrolidinylidene and 1, the meaning of 3-piperidylidene, and R 3, R 20And R 21Has specified meaning in the claim 1,2 and/or 12.
22. according to 1 or multinomial carboxamide compounds in the aforesaid right requirement, I.1 extremely I.14 it be selected from formula
Figure A038200760016C1
Wherein
U, V represent C or N independently of one another,
R 23, R 24Represent H, F, methyl, trifluoromethyl, ethyl, sec.-propyl or n-propyl independently of one another, simultaneously, in formula I.1 in I.6, R 24Can link R 3, so that
Segment bounds
Figure A038200760019C1
Group have and be selected from 1, the inferior Pyrrolizidine base and 1 of 3-, the meaning of 3-piperidylidene, and
R 25、
R 26, R 27Have independently of one another claim 1 or 2 to R 20One of specified meaning, or under the phenyl situation, also can represent nitro merely, simultaneously, radicals R repeatedly appears 25, R 26, R 27Can have identical or different meaning, and
J is 0,1,2,3 or 4, and
M, n represent 0,1 or 2 independently of one another, and
L 1, L 2, L 3, R 1, R 2, R 3, R 6, R 7, R 8, R 9, R 20, and X have specified meaning in the claim 1,2,5 to 9 and/or 12.
23. 1 or multinomial carboxamide compounds according in the aforesaid right requirement is characterized in that formula I.15
Wherein
B is selected from C 1-6-alkyl, C 1-6-thiazolinyl, C 1-6-alkynyl, C 3-7-cycloalkyl-C 1-3-alkyl-, C 3-7-cycloalkenyl group-C 1-3-alkyl-, C 3-7-cycloalkyl-C 1-3-thiazolinyl-or C 3-7-cycloalkyl-C 1-3-alkynyl-, wherein one or more C atom can be through halogen atom list or polysubstituted and/or replace through hydroxyl or cyano group list, and/or cyclic group can be through R 20Single or polysubstituted, and
W represent singly-bound ,-O-, C 1-4Alkylidene group, C 2-4-alkenylene, C 2-4-alkynylene, C 1-4-alkylene oxide group, oxygen-C 1-4-alkylidene group, C 1-3-alkylidene group-oxygen-C 1-3-alkylidene group-, imino-, N-(C 1-3-alkyl)-imino--, imino--C 1-4-alkylidene group-, N-(C 1-3-alkyl)-imino--C 1-4-alkylidene group-, C 1-4-alkylidene group-imino--or C 1-4-alkylidene group-N-(C 1-3-alkyl)-and imino--, simultaneously, one or two C atom can be independently of one another through hydroxyl, ω-hydroxyl-C 1-3-alkyl-, ω-(C 1-3-alkoxyl group)-C 1-3-alkyl-and/or C 1-3-alkoxyl group replaces, and/or through one or two identical or different C 1-4-alkyl replaces, and
K represents 0 or 1, and
U, V, R 23, R 24, R 26, R 27, m, n, L 1, L 2, L 3, R 1, R 2, R 3, R 6, R 7, R 8, R 9, R 20, and X have meaning specified in the claim 22.
24. the carboxamide compounds according in claim 22 or 23 is characterized in that, under each situation, U and V represent the C atom.
25. the carboxamide compounds according in the claim 21,22,23 or 24 is characterized in that
R 1, R 2Have the meaning in claim 5 and/or 6 independently of one another, and
R 3Meaning with claim 12, and
X has the meaning in claim 8 or 9,
Simultaneously, radicals R 1R 2N-X-also can have according to the meaning in the claim 7.
26., it is characterized in that X is-CH according to 1 in the claim 21～25 or multinomial carboxamide compounds 2-,-CH (CH 3)-or-C (CH 3) 2-.
27., it is characterized in that according to 1 in the claim 21～26 or multinomial carboxamide compounds
R 25、
R 26, R 27F, Cl, Br, I, OH, cyano group, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, positive propoxy or the isopropoxy represented independently of one another, under the situation that phenyl replaces, can be merely nitro also, simultaneously, appearance radicals R repeatedly 25, R 26, R 27Can have identical or different meaning, and
J is 0,1 or 2, and
28. above-mentioned according to 1 in the claim or multinomial carboxamide compounds, it is characterized in that R 6, R 7, R 8, and/or R 9Represent H, methyl, trifluoromethyl, ethyl, sec.-propyl or n-propyl independently of one another, at R 6, R 7Situation under also represent F.
29. according to claim 1 or 2 s' carboxamide compounds, it is selected from
(1) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(2) 3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
(3) 3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazoline-4-one
(4) 7-(4-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(5) 7-(3,4-two chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(6) 7-(4-fluoro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(7) 7-(4-ethyl-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(8) 2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazoline-4-one
(9) 2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-7-is right-tolyl-3H-quinazoline-4-one
(10) 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(11) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-1H-quinazoline-2, the 4-diketone
(12) 7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(13) 7-(4-chloro-phenyl)-3-[2-(4-dimethylamino methyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(14) 7-(4-chloro-phenyl)-3-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(15) 7-(4-chloro-phenyl)-3-[2-(4-morpholine-4-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(16) 7-(4-chloro-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-3H-benzo [d] [1,2,3] triazine-4-ketone
(17) 5-(4-fluoro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-isoindole-1, the 3-diketone
(18) 4 '-chloro-xenyl-4-carboxyl [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(19) 4 '-chloro-xenyl-4-carboxyl-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
(20) 4 '-chloro-xenyl-4-carboxyl-[2-(4-piperidines-1-ylmethyl-phenyl)-ethyl]-acid amides
(21) 4 '-methoxyl group-xenyl-4-carboxyl-[2-(4-diethylin methyl-phenyl)-ethyl]-acid amides
(22) 4 '-chloro-xenyl-4-carboxyl-[2-(4-diethylin methyl-phenyl)-ethyl]-methyl-acid amides
(23) 4-(4-chloro-phenyl)-hexanaphthene carboxyl-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(24) 4-aminomethyl phenyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(25) 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(26) 4-(4-chloro-phenyl)-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(27) 4 '-chloro-xenyl-4-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
(28) 4 '-chloro-xenyl-4-carboxylic acid-(4-tetramethyleneimine-1-ylmethyl-benzyloxy)-acid amides
(29) 4-cyclohexyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(30) 4 '-chloro-xenyl-4-carboxylic acid-[2-(3-methoxyl group-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(31) 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl]-ethyl }-the 3H-quinazoline-4-one
(32) 4 '-chloro-xenyl-4-carboxylic acid-and 2-[6-(4-methyl-piperazine-1-yl)-pyridin-3-yl] ethyl }-acid amides
(33) 7-(3-methoxyl group-phenyl)-3-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-the 3H-quinazoline-4-one
(34) 4-(4-oxo-cyclohexyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(35) 4-cyclohexyl-1-cyclohexane carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(36) 4-benzyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(37) 4-cyclohexyl-piperidines-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(38) 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(39) 4-(4-fluoro-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(40) 4-(4-methoxyl group-phenyl)-piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(41) 4-phenyl-Piperazine-1-carboxylic acid-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(42) (4 '-chloro-xenyl-4-yl)-[3-(4-tetramethyleneimine-1-ylmethyl-phenyl)-piperidines-1-yl]-ketone
(43) 4 '-chloro-xenyl-4-carboxyl-[2-methyl-2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-propyl group]-acid amides
(44) 4 '-chloro-xenyl-4-carboxyl-[2-(4-tetramethyleneimine-1-ylmethyl-cyclohexyl)-ethyl]-acid amides
(45) 4-benzyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(46) 4-(4-oxo-cyclohexylidene methyl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(47) 4 '-chloro-xenyl-4-carboxylic acid-[2-(2-fluoro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(48) 5-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone
(49) 4-piperidines-1-base-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(50) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
(51) 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(52) 7-(4-chloro-phenyl)-3-{2-[4-(3-azepine-spiral shell [5.5] undecane-3-ylmethyl)-phenyl]-ethyl }-3H-benzo [d] [1,2,3] triazine-4-ketone
(53) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-the 3H-quinazoline-4-one
(54) 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridine-2-base oxygen base)-piperidines-1-ylmethyl]-phenyl-ethyl)-the 3H-quinazoline-4-one
(55) 6-(4-chloro-phenyl)-2-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-2H-isoquinoline 99.9-1-ketone
(56) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(57) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(58) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-ethyl-piperidines-2-yl)-phenyl]-ethyl }-acid amides
(59) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(4-ethanoyl-piperazine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(60) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aza-bicyclo [2.2.1] heptan-5-alkene-2-ylmethyl)-phenyl]-ethyl }-acid amides
(61) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1,3-dihydro-isoindole-2-ylmethyl)-phenyl]-ethyl }-acid amides
(62) 4 '-chloro-xenyl-4-carboxylic acid (2-{4-[(diisopropylaminoethyl)-methyl]-phenyl }-ethyl)-acid amides
(63) 4 '-chloro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(64) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-dimethylamino methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(65) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-dimethylamino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(66) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-bromo-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(67) 4-penta-1-alkynyl-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(68) 4 '-chloro-xenyl-4-carboxylic acid [2-(6-tetramethyleneimine-1-ylmethyl-pyridin-3-yl)-ethyl]-acid amides
(69) 4 '-chloro-xenyl-4-carboxylic acid [2-(1-tetramethyleneimine-1-base-indane-5-yl)-ethyl]-acid amides
(70) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-nitro-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(71) 2 ', 4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(72) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3-amino-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(73) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-aminomethyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(74) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-2,6-diaza-spiro [3.4] suffering-6-ylmethyl)-phenyl]-ethyl }-acid amides
(75) 4 '-chloro-xenyl-4-carboxylic acid [2-(5-tetramethyleneimine-1-ylmethyl-pyridine-2-yl)-ethyl]-acid amides
(76) 4 '-chloro-xenyl-4-carboxylic acid [2-(3-ethyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(77) 4 '-bromo-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(78) 4-(5-chloro-thiophene-2-yl)-N-[2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-benzamide
(79) 4 '-chloro-xenyl-4-carboxylic acid [2-(2-methyl-4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(80) 4 '-bromo-3-fluoro-xenyl-4-carboxylic acid 2-[3-bromo-4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(81) 4 '-chloro-2-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(82) 4 '-ethyl-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(83) [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-2-ylmethyl]-the carboxylamine tertiary butyl ester
(84) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
(85) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2-methyl-tetramethyleneimine-1-ylmethyl)-phenyl]-ethyl }-acid amides
(86) 4 '-chloro-xenyl-4-carboxylic acid (2-{44 (cyclopropyl methyl-amino)-methyl]-phenyl }-ethyl)-acid amides
(87) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl)-phenyl]-ethyl }-acid amides
(88) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-{[(2-hydroxyl-ethyl)-methyl-amino]-methyl }-phenyl)-ethyl]-acid amides
(89) [1-(4-{2-[(4 '-chloro-xenyl-4-carbonyl)-amino]-ethyl }-benzyl)-tetramethyleneimine-3-yl]-the carboxylamine tertiary butyl ester
(90) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,6-dimethyl-piperidines-1-ylmethyl)-phenyl]-ethyl }-acid amides
(91) 4 '-chloro-xenyl-4-carboxylic acid [2-(4-azetidine-1-ylmethyl-phenyl)-ethyl]-acid amides
(92) 3,4 '-two chloro-xenyl-4-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(93) 4 '-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(94) 4 '-chloro-3-fluoro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(95) 2 '-fluoro-4 '-chloro-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(96) 5-(4-chloro-phenyl)-pyridine-2-carboxylic acids [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(97) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(2,5-dihydro-pyrroles-1-ylmethyl)-phenyl]-ethyl }-acid amides
(98) 4 '-bromo-xenyl-4-carboxylic acid [2-(4-tetramethyleneimine-1-ylmethyl-phenyl)-ethyl]-acid amides
(99) 4 '-chloro-xenyl-4-carboxylic acid 2-[4-(1-tetramethyleneimine-1-base-ethyl)-phenyl]-ethyl }-acid amides
30. according to the carboxamide compounds of claim 29, it is selected from formula (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (47) and (50) to (99).
31. the method for a preparation formula I carboxamide compounds
Figure A038200760025C1
Wherein A, B, W, X, Y, Z, R 1, R 2, R 3, and k have one of claim 1 to 28 specified meaning, wherein
As A representative not with group A banded radicals R 3:
A) with regard to the nitrogen-atoms heterocyclic radical of A representative by nitrogen-atoms and this carbonyl amide group of binding, it also can have the heteroatomic situation that one or more is selected from N, O, reaches S except that this nitrogen-atoms,
Can in a solvent or solvent mixture, in the presence of at least a alkali, make the amine compound of at least a formula I-1
(R wherein 1, R 2, R 3, X, Y, and Z have the specified meaning of preamble)
Secondary amine compound reaction with CDT (1,1 '-carbonyl-two-(1,2, the 4-triazole)) and at least a formula I-2
Figure A038200760025C3
Wherein A, B, W, and k have the specified meaning of preamble, and group A has this secondary amine functional group, and
B) with regard to other situations,
Can be in a solvent or solvent mixture, in the presence of at least a alkali,
Make the carboxylic acid cpd of at least a formula I-3
(wherein A, B, W, and k have the specified meaning of preamble)
With TBTU (2-(1H-benzotriazole-1-yl) 1,1,3, the 3-tetramethyl-_-a tetrafluoro borate) and the amine compound of at least a formula I-1 reaction
Figure A038200760025C5
R wherein 1, R 2, R 3, X, Y, and Z have the specified meaning of preamble,
And
As B be and group A banded radicals R 3:
A) has meaning-CR with regard to group Q 6R 7-(IIIa), while R 6And R 7Be as the defined situation of preamble, can make the amine compound of formula Ia.1
(R wherein 1, R 2, X, Y, and Z have specified meaning) with neighbour-brooethyl of formula Ia.2-benzoate derivatives reaction
Figure A038200760026C2
R wherein 6, R 7, W, B, and k have specified meaning,
B) has meaning-CR with regard to group Q 6=CR 7(IIIb), R wherein 6And R 7Be as the defined situation of preamble, can make the isoquinolinone derivatives of formula Ib.2
Figure A038200760026C3
(R wherein 6, R 7, W, B, and k have specified meaning) with the nucleophilie electronic compound reaction of formula Ib.3
Wherein Y and Z have specified meaning, and the suitable leaving group of OMs representative, and methanesulfonates preferably is to make the isoquinilone derivatives of formula Ib.4
Figure A038200760027C1
(R wherein 6, R 7, W, B, Y, Z, and k have specified meaning), and the isoquinilone derivatives of this formula Ib.4 can form formula I compound with the further derivatize of currently known methods,
C) has meaning-N=CR with regard to group Q 8-(IIIc), R wherein 8Be as the defined situation of preamble, can make the 2 ketone derivatives of formula Ic.4
(R wherein 8, W, B, and k have specified meaning) with the nucleophilie electronic compound reaction of formula Ic.5
Wherein Y and Z have specified meaning, and the suitable leaving group of OMs representative, and methanesulfonates preferably makes the 2 ketone derivatives of formula Ic.6
Figure A038200760027C4
R wherein 8, W, B, Y, Z and k have specified meaning, and the 2 ketone derivatives of the formula Ic.6 that so obtains can be with the further derivatize of known method to form formula I compound, wherein Q representative-N=CR 8-(IIIc),
D) with regard to the situation that group Q has meaning-N=N-(IIId), can make neighbour-amino-benzamide derivatives of formula Id.1
Figure A038200760028C1
(R wherein 1, R 2, W, B, X, Y, Z, and k have specified meaning), under the situation that suitable nitrous compound and acid exist, react, to form formula I compound, Q representative-N=N-wherein,
E) has meaning-CO-NR with regard to group Q 9-(IIIe), R wherein 9Be as the defined situation of preamble, can make neighbour-amino-benzamide derivatives of formula Ie.1
(R wherein 1, R 2, R 9, W, B, X, Y, Z, and k have specified meaning), under CDI (carbonyl dimidazoles), react, to form formula I compound, Q representative-CO-NR wherein 9-,
F) has meaning-CR with regard to group Q 8=N-(IIIf), wherein R 8As the defined situation of preamble, can make neighbour-amino-benzamide derivatives of formula If.1
(R wherein 1, R 2, W, B, X, Y, Z, and k have specified meaning), with carboxylic acid R 8(it has the R that specifies meaning to COOH 8) and/or corresponding active carboxylic acid derivative reaction, with the Quinazol derivative of production I, Q representative-CR wherein 8=N-,
G) with regard to the situation that group Q has meaning-CO-(IIIg), can make the isobenzofurandione derivative of formula Ig.2
(wherein W, B, and k have specified meaning), with the reaction of the amine of formula Ig.1,
Figure A038200760029C2
R wherein 1, R 2, X, Y, and Z have specified meaning, to form formula I compound, wherein Q representative-CO-.
32. physiologically acceptable salt according to 1 in the claim 1～30 or multinomial carboxylic acyl compound.
33. a composition, it contains at least a according to outside 1 in the claim 1～30 or the multinomial carboxamide compounds and/or the salt according to claim 32, also optionally contains the acceptable vehicle of one or more physiology.
34. a pharmaceutical preparation, it contains outside the salt of at least a claim 1～30 1 or multinomial carboxamide compounds and/or claim 32, and also selectivity contains one or more inert support and/or thinner.
35. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt of claim 32, it is used to influence the Mammals feeding behavior.
36. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it is used to alleviate mammiferous body weight and/or the prevention weight of mammal increases.
37. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it is used to prepare the pharmaceutical preparation with MCH-acceptor-antagonistic activity.
38. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it be used to prepare be applicable to that prevention and/or treatment are caused by MCH or with the medical thing preparation of MCH with the symptom and/or the disease of other reasons dependency.
39. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it be used to prepare be applicable to prevention and/or treatment by the pharmaceutical preparation, particularly obesity of metabolic disturbance and/or eating disorder, voracity, bulimia nervosa, emaciation, apocleisis, anorexia nervosa, reach hyperingestion.
40. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it is used to prepare and is applicable to prevention and/or treatment and the relevant disease of obesity and/or the pharmaceutical preparation of obstacle, diabetes particularly, type-II diabetes particularly, the complication of diabetes comprises diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, the pathologic glucose tolerance, hematencephalon, heart inadequacy, cardiovascular disorder, particularly arteriosclerosis and hypertension, sacroiliitis, and piperazine sacroiliitis.
41. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it be used to prepare be applicable to that prevention and/or treatment hyperlipemia disease, cellulitis, fat accumulation, pernicious urticaria pigmentosa, systemic tint permanence nettle are examined, emotional handicap, affective disorder, melancholia, anxiety, somnopathy, dysgenesia, sexual dysfunction, dysmnesia, epilepsy, various dementia, and the pharmaceutical composition of hormone obstacle.
42. one kind according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the purposes of a kind of salt in the claim 32, it is used to prepare the pharmaceutical preparation that is applicable to prevention and/or treatment dysuria, such as, the urinary incontinence, bladder hyperactivity hyperkinesia, urgent urination, nycturia, and the enuresis.
43. a method for preparing according to the pharmaceutical preparation one of in the claim 33～38, it is characterized in that with method non-chemically with at least a according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to combined in the salt in the claim 32 and one or more inert support and/or the thinner.
44. pharmaceutical preparation, it contains first active substance, be selected from according to 1 in the claim 1～30 or multinomial at least a carboxamide compounds and/or according to the salt of claim 32, and second active substance, be selected from the active substance that can be used for treating diabetes, can be used for treating the active substance of diabetic complication, can be used for treating fat active substance (preferably's right and wrong MCH antagonist), can be used for treating hypertensive active substance, can be used for treating the hyperlipidaemia active substance of (comprising arteriosclerosis), the active substance that can be used for treatment of arthritis, can be used for treating the active substance of anxiety state, and can be used for treating hypochondriacal active substance, and selective binding one or more inert carrier and/or thinners.
CNA038200767A 2002-08-24 2003-08-16 New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture Pending CN1678591A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101412682B (en) * 2007-10-19 2012-06-27 上海药明康德新药开发有限公司 Process for synthesizing aryl anthranilic acid and derivatives thereof
TWI398440B (en) * 2006-06-29 2013-06-11 Kinex Pharmaceuticals Llc Biaryl compositions and methods for modulating a kinase cascade
CN104016980A (en) * 2008-04-23 2014-09-03 里格尔药品股份有限公司 Carboxamide compounds for treatment of metabolic disorders
CN110407824A (en) * 2019-08-08 2019-11-05 安徽医科大学 Aryl methanamide compounds and preparation method thereof, pharmaceutical composition and purposes

Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
WO2004072018A1 (en) 2003-02-12 2004-08-26 Takeda Pharmaceutical Company Limited Amine derivative
KR20060060047A (en) 2003-10-01 2006-06-02 더 프록터 앤드 갬블 캄파니 Melanin concentrating hormone antagonists
CA2541949A1 (en) * 2003-10-07 2005-05-26 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US7605176B2 (en) 2004-03-06 2009-10-20 Boehringer Ingelheim International Gmbh β-ketoamide compounds with MCH antagonistic activity
US7524862B2 (en) 2004-04-14 2009-04-28 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
DE102004017934A1 (en) 2004-04-14 2005-11-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New alkyne compounds having MCH antagonist activity and medicaments containing these compounds
WO2005115389A2 (en) * 2004-05-25 2005-12-08 Pfizer Products Inc. Specific ppar agonists for treating negative energy balance
TW200613272A (en) 2004-08-13 2006-05-01 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
DE102004039789A1 (en) 2004-08-16 2006-03-02 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, process for their preparation and their use as pharmaceuticals
PL1836169T3 (en) * 2004-12-28 2012-07-31 Kinex Pharmaceuticals Llc Compositions and methods of treating cell proliferation disorders
US7968574B2 (en) 2004-12-28 2011-06-28 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
WO2007021309A1 (en) * 2005-08-12 2007-02-22 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
US7807706B2 (en) 2005-08-12 2010-10-05 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
RU2008129679A (en) 2005-12-21 2010-01-27 Янссен Фармацевтика Н.В. (Be) NEW SUBSTITUTED PYRAZINONIC DERIVATIVES FOR USE IN SIT-1-MEDIATED DISEASES
TW200804347A (en) 2006-01-10 2008-01-16 Janssen Pharmaceutica Nv Urotensin II receptor antagonists
CA2636879A1 (en) * 2006-02-15 2007-08-23 Sanofi-Aventis Novel amino alcohol-substituted arylthienopyrimidinones, process for their preparation and their use as medicaments
BRPI0707836A2 (en) 2006-02-15 2011-05-10 Sanofi Aventis Substituted amino alcohol arylhydroisoquinolinines, process for their preparation and use as a medicament, medicament and process for their production
CN101384583A (en) * 2006-02-15 2009-03-11 塞诺菲-安万特股份有限公司 Azacyclyl-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments
BRPI0707869A2 (en) * 2006-02-15 2011-05-10 Sanofi Aventis azacyclyl substituted arylthienopyrimidinones, process for their preparation and their use as medicines
AU2007265373B2 (en) 2006-06-29 2013-02-21 Atnx Spv, Llc Biaryl compositions and methods for modulating a kinase cascade
WO2008016534A1 (en) 2006-07-31 2008-02-07 Janssen Pharmaceutica, N.V. Urotensin ii receptor antagonists
EP2383259A1 (en) 2006-08-25 2011-11-02 Boehringer Ingelheim International GmbH New pyridone derivatives with MCH antagonistic activity and medicaments comprising these compounds
CA2664112C (en) 2006-12-05 2015-02-17 Janssen Pharmaceutica N.V. Novel substituted diaza-spiro-pyridinone derivatives for use in mch-1 mediated diseases
CL2007003580A1 (en) 2006-12-11 2009-03-27 Boehringer Ingelheim Int Pyridazine derived compounds, mch antagonists; pharmaceutical composition comprising said compound; preparation procedure; and use of the compound in the treatment of metabolic disorders and / or eating disorders such as obesity, bulimia, anorexia, hyperphagia, diabetes.
US7935697B2 (en) 2006-12-28 2011-05-03 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
JP2010514837A (en) * 2007-01-03 2010-05-06 コーテックス ファーマシューティカルズ， インコーポレイテッド 3-Substituted- [1,2,3] benzotriazinone compounds for enhancing glutamatergic synaptic responses
DK2124562T3 (en) 2007-03-09 2016-08-01 Second Genome Inc BICYCLOHETEROARYLFORBINDELSER AS P2X7 modulators and uses thereof
TWI417100B (en) 2007-06-07 2013-12-01 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators-842
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
SA109300358B1 (en) 2008-06-06 2012-11-03 استرازينيكا ايه بي Isoindolone Metabotropic Glutamate receptor Potentiators
US9079896B2 (en) 2008-08-02 2015-07-14 Janssen Pharmaceutica Nv Urotensin II receptor antagonists
TW201040153A (en) 2009-02-13 2010-11-16 Sanofi Aventis Novel substituted tetrahydronaphthalenes, process for preparation thereof and use thereof as medicaments
AR075401A1 (en) 2009-02-13 2011-03-30 Sanofi Aventis SUBSTITUTED INDANS, PROCESSES FOR THEIR PREPARATION AND USE OF THE SAME AS A MEDICINAL PRODUCT
CA2796419C (en) 2010-04-16 2018-11-06 Kinex Pharmaceuticals, Llc Compositions and methods for the prevention and treatment of cancer
GB201009853D0 (en) 2010-06-11 2010-07-21 Chroma Therapeutics Ltd HSP90 inhibitors
ES2785475T3 (en) * 2011-05-10 2020-10-07 Gilead Sciences Inc Heterocyclic compounds fused as ion channel modulators
NO3175985T3 (en) 2011-07-01 2018-04-28
UY34171A (en) 2011-07-01 2013-01-31 Gilead Sciences Inc FUSIONED HETEROCYCLIC COMPOUNDS AS IONIC CHANNEL MODULATORS
UY34194A (en) * 2011-07-15 2013-02-28 Astrazeneca Ab ? (3- (4- (SPIROHETEROCYCLIC) METHYL) PHENOXI) AZETIDIN-1-IL) (5- (PHENYL) -1,3,4-OXADIAZOL-2-IL) METHANONE IN THE TREATMENT OF OBESITY?
US8933079B2 (en) * 2012-03-07 2015-01-13 Boehringer Ingelheim International Gmbh Pyridone and pyridazinone derivatives as anti-obesity agents
LT2890680T (en) 2012-08-30 2018-05-10 Athenex, Inc. N-(3-fluorobenzyl)-2-(5-(4-morpholinophenyl)pyridin-2-yl) acetamide as protein tyrosine kinase modulators
FR3000491B1 (en) * 2012-09-27 2015-08-28 Univ Lille Ii Droit & Sante COMPOUNDS FOR USE IN THE TREATMENT OF MYCOBACTERIAL INFECTIONS
JP2022549227A (en) * 2019-09-17 2022-11-24 バイアル－アールアンドディー インベストメンツ ソシエダッド アノニマ Substituted saturated and unsaturated N-heterocyclic carboxamides and related compounds for use in treating medical disorders

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1218336A2 (en) * 1999-09-20 2002-07-03 Takeda Chemical Industries, Ltd. Melanin concentrating hormone antagonist
WO2001087834A1 (en) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Melanin-concentrating hormone antagonist
EP1299362A4 (en) * 2000-07-05 2004-11-03 Synaptic Pharma Corp Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof
US20030022891A1 (en) * 2000-12-01 2003-01-30 Anandan Palani MCH antagonists and their use in the treatment of obesity
CA2431953A1 (en) * 2000-12-22 2002-07-04 Schering Corporation Piperidine mch antagonists and their use in the treatment of obesity
GB0124627D0 (en) * 2001-10-15 2001-12-05 Smithkline Beecham Plc Novel compounds
GB0124931D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI398440B (en) * 2006-06-29 2013-06-11 Kinex Pharmaceuticals Llc Biaryl compositions and methods for modulating a kinase cascade
CN101412682B (en) * 2007-10-19 2012-06-27 上海药明康德新药开发有限公司 Process for synthesizing aryl anthranilic acid and derivatives thereof
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CN104016980B (en) * 2008-04-23 2016-12-07 里格尔药品股份有限公司 For treating the benzamide compound of dysbolismus
CN112079769A (en) * 2008-04-23 2020-12-15 里格尔药品股份有限公司 Carboxamide compounds for the treatment of metabolic disorders
CN110407824A (en) * 2019-08-08 2019-11-05 安徽医科大学 Aryl methanamide compounds and preparation method thereof, pharmaceutical composition and purposes

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