CN1058709C - Amide compounds for medical treatment - Google Patents

Amide compounds for medical treatment Download PDF

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CN1058709C
CN1058709C CN96108113A CN96108113A CN1058709C CN 1058709 C CN1058709 C CN 1058709C CN 96108113 A CN96108113 A CN 96108113A CN 96108113 A CN96108113 A CN 96108113A CN 1058709 C CN1058709 C CN 1058709C
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trifluoromethyl
xenyl
carboxylic acid
acid amides
acid
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CN1141918A (en
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乔治·常
彼得·H·多尔夫
乔治·J·奎里克
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Pfizer Inc
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Pfizer Inc
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Priority claimed from PCT/IB1995/000448 external-priority patent/WO1996040640A1/en
Priority claimed from CA002223574A external-priority patent/CA2223574C/en
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Abstract

The amides of general formula (I), wherein X, Y and Z have the meanings stated in the claims. These compounds are useful for reducing the secretion of apo B, hence they are suitable as medicaments for treatment of diseases such as atherosclerosis.

Description

Amide compounds for medical treatment
The present invention relates to a compounds, this compound is MC triglyceride transfer protein and/or apolipoproteins B (Apo B) secretion inhibitor, and therefore be used for prevention and treatment atherosclerosis and clinical sequela thereof, and prevention and treatment relative disease with blood lipid reducing.The invention still further relates to and contain such compound compositions and with this compounds for treating atherosclerosis, the method for fat and relative disease and/or slight illness.
The transfer of MC triglyceride transfer protein (MTP) catalyzing glycerol three esters, cholesteryl ester and phosphatide, it contains the set of Apo B lipoprotein, biomolecule as a kind of possible factor affecting, promote the formation of atherosclerotic lesions, referring to European Patent Publication No 0 643 057 A1 and 0 584 446 A2, and Wetterau et al., Science, 258,999-1001, (1992).Suppress MTP and/or suppress Apo B excretory compound natural energy to be used for the treatment of atherosclerosis.This compound is because inhibition MTP and/or Apo secretion can make serum ornitrol and triglyceride levels reduce thereby also be used for the treatment of other disease, and these diseases comprise hypercholesterolemia, hypertriglyceridemia, pancreatitis and obesity; And and pancreatitis, fat relevant hypercholesterolemia, hypertriglyceridemia and high blood ester with diabetes.
The invention provides acceptable salt on formula 1 compound and the pharmacology thereof:
Figure C9610811300151
Wherein:
X is CH 2, CO, CS or SO 2
Y is selected from:
Direct key (being covalent linkage),
How can be by hydroxyl, (C to aliphatics alkylene, this alkyl of 20 carbon atoms 1-C 10) alkoxyl group, (C 1-C 10) acyl group, (C 1-C 10) acyloxy or (C 6-C 10) replacement of aryl list,
NH and O, condition is if X is CH 2, then Y is direct key;
Z is selected from following group:
(1) H, halogen, cyano group,
(2) hydroxyl, (C 1-C 10) alkoxyl group, (C 1-C 10) alkylthio, (C 1-C 10) acyl group, thienyl carbonyl, (C 1-C 10) carbalkoxy,
(3) (C 1-C 10) alkylamino, two (C 1-C 10) alkylamino, (C 6-C 10) aryl (C 1-C 10) alkylamino, condition is that Y is not O or NH,
(4) unsubstituted vinyl, (C 6-C 10) aryl, (C 3-C 8) cycloalkyl and condensed benzo derivative thereof, (C 7-C 10) multi-ring alkyl, (C 4-C 8) cycloalkenyl group, (C 7-C 10) many cycloalkenyl groups,
(5) (C 6-C 10) aryloxy, (C 6-C 10) arylthio, (C 6-C 10) aryl (C 1-C 10) alkoxyl group, (C 6-C 10) aryl (C 1-C 10) alkylthio, (C 3-C 8) cycloalkyloxy, (C 4-C 8) cyclenes oxygen base,
(6) be selected from the heterocyclic radical of monocycle base and fused polycycle base, described group contains a total 5-14 annular atoms, contain the heteroatoms that adds up to 1-4 that is independently selected from oxygen, nitrogen and sulphur, each ring of described group can be respectively saturated, part is undersaturated or fragrant
Condition is if X is CH 2, then Z is H or is selected from (4) and the group of (6),
Wherein, when Z contained one or more ring, described each ring can have 0-4 independently and be independently selected from following substituting group: halogen, hydroxyl, cyano group, nitro, oxo (O=), sulfo-(S=), amino-sulfonyl, phenyl, phenoxy group, thiophenyl, halogeno-benzene sulfenyl, benzyl, benzyloxy, (C 1-C 10) alkyl, (C 1-C 10) alkoxyl group, (C 1-C 10) carbalkoxy, (C 1-C 10) alkylthio, (C 1-C 10) alkylamino, (C 1-C 10) alkyl amino-carbonyl, two (C 1-C 10) alkylamino, two (C 1-C 10) alkyl amino-carbonyl, two (C 1-C 10) alkylamino (C 1-C 10) alkoxyl group, (C 1-C 3) perfluoroalkyl, (C 1-C 3) perfluoro alkoxy, (C 1-C 10) acyl group, (C 1-C 10) acyloxy, (C 1-C 10) acyloxy (C 1-C 10) alkyl and pyrrolidyl.
Be meant that about Z containing at least one is independently selected from O as " heterocyclic radical ", any monocycle of the ring hetero atom of N and S or condense ring system, therefore, as long as this system also contains at least one condensed ring (this condensed ring contains at least one above-mentioned heteroatoms), contain one or more carbocyclic fused saturated, part is unsaturated or many rings of aromatic nucleus (normally benzo ring) condense ring system and just belong to the above-mentioned heterocyclic range of definition.As substituting group, these heterocycles can be connected on the residue of carbocyclic ring (for example benzo) or heterocycle molecule.
About containing the Z of " one or more ring ", be meant any (list or the condensed ring) loop section among the Z, this ring can be carbocyclic ring or heterocycle, saturated, part is undersaturated, and fragrance or non-fragrance.
About fused polycycle system or group, be meant that all rings in the system are condensed.
About " halogen " in this specification sheets, comprise fluorine, chlorine, bromine and iodine unless otherwise indicated in addition.
About " aryl " substituting group ((C for example 6-C 10) aryl), be meant that this ring or substituting group are carbocyclic rings, as mentioned above,, comprise containing one or more heteroatomic aromatic portions as the subclass of term " heterocyclic radical ".
About " acyl group " substituting group, be meant the aliphatic series or the cyclic hydrocarbon part that are connected with carbonyl, substituting group connects by ketonic linkage.
About " alkyl " and " alkoxyl group ", comprise straight chain and branched group, but be construed as for the individual groups as " propyl group " or " propoxy-" and only be meant straight chain (" normal chain ") group, branched chain isomer is highlighted as " sec.-propyl " or " isopropoxy ".
Center benzo one heterocyclic system of formula 1, promptly be connected to-condensed-bicyclic system on the XYZ by its monocycle fluorine atom, typically refer to " 1; 2,3, the 4-tetrahydroisoquinoline " herein when 1 of compound called after 2-replacement of the present invention, 2,3, during 4-tetrahydroisoquinoline-6-base acid amides, traditionally the most frequent use it.When naming as the substituting group in the compound, this center ring system is also referred to as " 3,4-dihydro-1H-isoquinoline 99.9-2-yl " part that 6-replaces, and this name is not often used.
A group of formula 1 compound comprises following compound and pharmacy acceptable salt thereof as defined above: wherein:
X is CH 2, CO or SO 2
Y is selected from:
Directly key, NH,
(C 1-C 10) alkylidene group and (C 2-C 10) alkenylene, any one in them all can be replaced by phenyl, and condition is if X is CH 2, then Y is direct key;
Z is selected from following group:
(1)H，
(2) (C 1-C 10) alkoxyl group, (C 1-C 10) alkylthio,
(3) (C 1-C 10) alkylamino, two (C 1-C 10) alkylamino, (C 6-C 10) aryl (C 1-C 10) alkylamino, condition is that Y is not NH,
(4) unsubstituted vinyl, (C 6-C 10) aryl, (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group,
(5) (C 6-C 10) aryloxy,
(6) be selected from saturated, part is undersaturated or fragrant five-and the heterocyclic radical of six-unit and condense benzo derivative, wherein said group can contain and adds up to 1-3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur,
Condition is if X is CH 2, then Z is selected from the group of (4) and (6),
Wherein, when Z contained one or more ring, described each ring can have 0-3 independently and be independently selected from following substituting group: halogen, hydroxyl, nitro, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, two (C 1-C 6) alkyl amino-carbonyl, (C 1-C 3) perfluoro alkoxy, (C 1-C 10) acyl group and (C 1-C 10) acyloxy.
A more specific group comprises some compounds and the pharmacy acceptable salt thereof in the above-mentioned group, and wherein X is a methylene radical, and Y is direct key, and Z is selected from (C 6-C 10) aryl, (C 3-C 8) cycloalkyl and (C 4-C 8) cycloalkenyl group, each in them can have in 0-3 the above-mentioned group for the pointed independent substituent of Z, unsubstituted vinyl.The specific meanings of each illustrates hereinafter.
Another more specific group comprises some compounds and the pharmacy acceptable salt thereof in the above-mentioned group, wherein X is methylene radical or CO, Y is direct key, and Z is selected from thienyl, pyrrolidyl, pyrryl, furyl, thiazolyl isoxazolyl, imidazolyl, 1,2, the 4-triazolyl, pyridyl, pyrimidyl, and condensed-bicyclic (ortho position) benzo derivative, comprise benzimidazolyl-, benzothiazolyl, indyl, pseudoindoyl, benzofuryl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl and quinazolyl, each in them can have in 0-3 the above-mentioned group independent substituent for Z.
Z comprises 2-and 3-thienyl as the specific meanings (this heterocyclic radical can have 0-3 the independent substituting group of pointing out for Z in the above-mentioned group) of heterocyclic radical; 2-and 3-benzo [b] thienyl; 1-, 2-and 4-imidazolyl; The 2-benzimidazolyl-; 2-, 4-and 5 thiazolyls; The 2-[4-morpholinodithio base; 3-, 4-and 5-isoxazolyl; The 2-quinoxalinyl; 1-, 2-and-the 3-pyrrolidyl; 2-, 3-and 4-pyridyl; 2-and 4-pyrimidyl; 2-, 3-and 4-quinolyl; 1-, 3-and 4-isoquinolyl; 1-, 2-and 3-indyl; 1-, 2-and 3-pseudoindoyl; 2-and 3-tetrahydrofuran base; 1-, 2-and 3-pyrryl; 2-and 3-furyl; 2-and 3-benzo [b] furyl; 1-, 3-and 4-pyrazolyl and 1,2,4-triazole-3-base.
Preferred one group of compound comprises following compound and pharmacy acceptable salt thereof, wherein:
X is CH 2Or CO,
Y is direct key,
Z is H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thienyl, 1,2,4-triazolyl, pyridyl and pyrimidyl.In them each can have 0-3 the independent substituting group of pointing out in the above-mentioned group.The specific meanings of Z in this preferred group (as heterocyclic radical) comprises the above-mentioned respective specific implication of pointing out.
A group in above-mentioned preferred group comprises that wherein X is those compounds of CO.
Another group in above-mentioned preferred group comprises that wherein X is CH 2Those compounds.
The present invention also provide be suitable for treating comprise atherosclerosis, pancreatitis, obesity, blood cholesterol is too high, blood triglyceride is too high, the pharmaceutical composition of hyperlipidemia and diabetes, said composition comprises formula 1 compound and the pharmaceutically acceptable carrier of above-mentioned definition.
The compounds of this invention may be by suppressing the secretion that MTP suppresses or reduce Apo B, although other mechanism is also possible.This compound is used for any Apo B, serum cholesterol and/or the too high disease of triglyceride levels.Therefore, the present invention also provides treatment atherosclerosis, pancreatitis, obesity, blood cholesterol is too high, blood triglyceride is too high, the method for hyperlipidemia and diabetes, this method comprises that the Mammals to this treatment of needs, particularly human administration are enough to reduce formula 1 compound of the above-mentioned definition of apoprotein matter B secretory volume.A group of above-mentioned disease comprises atherosclerosis, obesity, pancreatitis and diabetes, and more specific group is an atherosclerosis.
Terminology used here " treatment " comprises the treatment of extenuating of prevention and disease.
The present invention further provides in Mammals, particularly reduced Apo B excretory method among the mankind, this method comprises that above-mentioned administration reduces formula 1 compound of the above-mentioned definition of Apo B (secretion) amount.
Another aspect of the present invention also provides some intermediate:
4 '-trifluoromethyl-xenyl-2-carboxylic acid (1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides,
4 '-trifluoromethyl-xenyl-2-carboxylic acid [3-(2-hydroxyethyl)-4-methylol-phenyl]-acid amides,
It should be appreciated by those skilled in the art that some compound of formula 1 contains asymmetric alternate c atoms, therefore can exist also separated with optically active and racemic form.May there be polytropism in some compound.Be construed as the present invention includes any racemic, optically active, form polymorphism or stereomeric or its mixture, these forms all have the atherosclerosis of being used for the treatment of, the character of fat and above-mentioned other disease, (for example how to prepare the optical activity form, by with the recrystallization technology resolution of racemates, by the optical activity raw material synthesize, by chirality synthetic or by carrying out chromatographic separation with chiral stationary phase) and how to measure the effect for the treatment of above-mentioned disease with following standard test, be well known to a person skilled in the art.
The chemical work personnel of general technology should admit, the combination of some substituting group described in the present invention or some part has determined that some compound is unsettled (but for example containing the compound amine bonding or the acetal bonding) under physiological condition, these compounds are not preferred.
For " the aliphatic hydrocarbon subunit " of the object of the invention is meant the only divalence open chain organic group of carbon containing and hydrogen, this group is meant above-mentioned Y as linking group, this group can be straight chain or side chain, and/or it is saturated or contain (two keys or triple bond or its mixture) group up to three unsaturated link(age)s, two valence links can be on different carbon atoms or same carbon atom, therefore " alkylidene group " belongs in this range of definition, and this group generally is categorized as (C 1-C 20) alkylidene group, (C 2-C 20) alkenylene or (C 2-C 20) alkynylene.Although longer chain group also is feasible really, and also belongs to scope of the present invention, as described in embodiment, this group contains 1-10 carbon atom usually.
Alkylidene group includes 1-20, preferred 1-10 carbon atom remove those saturated hydrocarbyls that two hydrogen atoms obtain from saturated non-cyclic hydrocarbon accordingly, the concrete group that contains 1-10 carbon atom includes formula (CH 2) n, wherein n is the straight chain base of 1-10, as methylene radical, dimethylene, trimethylene, tetramethylene, pentamethylene, hexa-methylene, heptamethylene, eight methylene radical, nine methylene radical etc., also comprise the alkylidene group of ethylidene, propylidene, butylidene and sec.-butylidene etc., comprise that also branched chain isomer is as 1,1-dimethyl dimethylene, 1,1-dimethyl tetramethylene, 2,2-dimethyl trimethylene and 3,3-dimethyl pentamethylene.
Alkenylene includes 2-20, the non-cyclic hydrocarbon from containing accordingly two keys at least of preferred 2-10 carbon atom is removed the straight or branched group that two hydrogen atoms obtain, and has the concrete alkenylene of two keys to comprise vinylidene, propenylidene, 1-crotonylidene, 2-crotonylidene and different crotonylidene.The alkenylene (this area is called the inferior two rare bases of chain sometimes) that contains two two keys comprises 3-methyl-2, the inferior heptadiene base of 6-; 2-methyl-2, the inferior heptadiene base of 4-; 2, the inferior nonadiene base of 8-; 3-methyl-2, the inferior octadienyl and 2 of 6-, the inferior decadiene base of 6-, the concrete group that contains the alkenylene (the inferior trialkenyl of chain) of three two keys is 9,11, inferior 17 trialkenyl of 13-.
Alkynylene includes 2-20, preferably 2-10 carbon atom removes the straight or branched group that two hydrogen atoms obtain from containing a non-cyclic hydrocarbon of triple-linked at least accordingly, concrete alkynylene comprises ethynylene, inferior proyl, 1-butynelene, the inferior pentynyl of 1-, the inferior hexin base of 1-, 2-butynelene, the inferior pentynyl, 3 of 2-, 3-dimethyl-1-butynelene etc.
Below be other parts and other substituent concrete group of above-mentioned name, but not as limitation of the present invention.It should be noted that by specification sheets, if do not point out specific tie point by the connected ring of different rings nuclear power or many cyclic groups, no matter by carbon atom still be all tie point of trivalent nitrogen atom can.For example, (unsubstituted) " naphthyl " is meant naphthalene-1-base and naphthalene-2-base; " pyridyl " is meant 2-, 3-or 4-pyridyl; " indyl " is meant and connects by any position among 1-, 2-, 3-, 4-, 5-, 6-or the 7-.
(C 1-C 10) the concrete group of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, heptan oxygen base etc.
(C 1-C 10) the concrete group of alkylthio comprises corresponding to above-mentioned (C 1-C 10) sulfocompound of alkoxyl group, comprise methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, penta sulfenyl, own sulfenyl, heptan sulfenyl etc.
(C 1-C 10) the concrete group of acyl group comprises (C 1-C 10) alkanoyl, as formyl radical, ethanoyl, propionyl, butyryl radicals and isobutyryl, also comprise ring-type acyl group such as benzoyl that other is common.
(C 1-C 10) the concrete group of acyloxy comprises (C 1-C 10) alkanoyloxy, as methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy and isobutyl acyloxy, also comprise ring-type acyloxy such as benzoyloxy that other is common.
(C 1-C 10) the concrete group of carbalkoxy comprises methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl and isobutyl boc.
(C 1-C 10) the concrete group of alkylamino comprises methylamino-, ethylamino, third amino, isopropylamino, fourth amino and isobutyl amino.
Two-(C 1-C 10) the concrete group of alkylamino comprises dimethylamino, diethylin, dipropyl amino, dibutylamino and two isobutyl amino.
(C 6-C 10) aryl (C 1-C 10) the concrete group of alkylamino is amino and (2-styroyl) amino of benzylamino, (1-styroyl).
(C 6-C 10) the concrete group of aryl is phenyl and naphthyl.
(C 3-C 8) the concrete group of cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
(C 3-C 8) the concrete group of benzo deutero-that condenses of cycloalkyl comprises 1,2,3,4-tetralyl, 2,3-indanyl, fluorenyl.
The concrete group of multi-ring alkyl comprises adamantyl and 2-dicyclo [2.2.1] heptyl.
(C 4-C 8) the concrete group of cycloalkenyl group comprises cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl.
The concrete group of many cycloalkenyl groups comprises dicyclo [3.1.1.] hept-2-ene" base.
(C 6-C 10) the concrete group of aryloxy comprises phenoxy group and naphthyloxy.
(C 6-C 10) the concrete group of arylthio comprises thiophenyl and naphthalene sulfenyl.
(C 6-C 10) aryl (C 1-C 10) the concrete group of alkoxyl group comprises benzyloxy and benzene oxyethyl group.
(C 6-C 10) aryl (C 1-C 10) the concrete group of alkylthio comprises benzylthio-and benzene ethylmercapto group.
(C 3-C 8) the concrete group of cyclenes oxygen base comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and ring oxygen base in heptan.
(C 4-C 8) the concrete group of cyclenes oxygen base comprises cyclobutene oxygen base, cyclopentenes oxygen base, tetrahydrobenzene oxygen base and suberene oxygen base.
The concrete group of the heterocyclic substituent of five yuan of monocycle bases comprises furyl, thienyl, pyrryl, pyrrolidyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl and 1,3,4-thiatriazole base etc.
The concrete group of the heterocyclic substituent of single six-membered rings base comprises 2H-and 4H-pyranyl, pyridyl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, pyrazinyl, morpholinyl, sulfo-sign indicating number quinoline base, 1,3,5-triazines base etc.
The concrete group that quinary heterocyclic radical condenses the heterocyclic substituent of benzo derivative comprises indyl, pseudoindoyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzothiazolyl and carbazyl.
The concrete group that the hexa-member heterocycle base condenses the heterocyclic substituent of benzo derivative comprises quinolyl, isoquinolyl, and quinazolyl, 2,3-dichloro mix naphthyl, phenothiazine base, bifurcation pyridine base is with the Fen oxazinyl.
Except the above-mentioned benzo system of enumerating that condenses, the specific examples of the heterocyclic group of fused polycycle base comprises purine radicals and pteridine radicals.
(C 1-C 10) the concrete group of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, isobutyl-, butyl, the tertiary butyl, amyl group, hexyl etc.
(C 1-C 3) the concrete group of perfluoroalkyl comprises trifluoromethyl, pentafluoroethyl group and seven fluoropropyls.
(C 1-C 3) the concrete group of perfluoro alkoxy comprises trifluoromethoxy and five fluorine oxyethyl groups.
Compound of the present invention often can be according to by 1,2,3, the theheterocyclic nitrogen atom of 4-tetrahydroisoquinoline ring (seeing formula 1) and-linking group that group among the XYZ forms together classifies, above-mentioned group partly is connected to XYZ on the described theheterocyclic nitrogen atom.These classes comprise:
Figure C9610811300251
About above-mentioned linking group, for acid amides and thioamides (being respectively X=CO or CS), Y preferred directly key or alkylene.Y is in the compound of direct key therein, and bonding preferably is connected on aliphatic series (the being open chain) carbon atom among the Z by carbonyl or thiocarbonyl.Described aliphatic carbon atom can be a part that contains one or more heteroatomic chains.Bonding also can preferably be connected to ring carbon atom by carbonyl or thiocarbonyl." ring carbon atom " is meant the saturated or unsaturated carbon atom that is contained in (saturated, part is undersaturated or fragrant) carbocyclic ring or the heterocycle.For Y wherein is the compound of alkylene, and bonding is to be connected on the aliphatic carbon atom among the Y by carbonyl or thiocarbonyl.
For urea that wherein is respectively X=CO or CS and Y=NH or thiocarbamide, bonding is preferably to be connected on the ring carbon atom among the Z by (as shown right half) amino, for some urea and thiocarbamide (X=CO, the direct key of Y=), the amino nitrogen of (right half) is the part of Z.In the case, preferred bonding is that amino group by right half is connected on the aliphatic carbon atom in the Z lingering section.
For sulphonamide of the present invention, X=SO 2With the preferred alkylene of Y, or directly connect.For Y wherein is the sulphonamide of alkylene, is connected on the aliphatic carbon atom among the Y by alkylsulfonyl.For Y wherein is the sulphonamide of direct key, preferably is connected on the ring carbon atom among the Z by this alkylsulfonyl.For Y wherein is the sulphonamide of direct key, also can be connected to as on the NH of Z for a part, and in this case, be to be directly connected on the amino nitrogen atom among the Z by X.
N-alkyls (X=CH 2, the direct key of Y=), preferably be connected on the ring carbon atom among the Z by methylene radical.
For the carbamate of X=CO and Y=O wherein, preferably be connected on the ring carbon atom of Z lingering section by the oxo in the key (O) part.For X=CO wherein, the carbamate of the direct key of Y=, oxo chain are the parts of Z, and preferably are connected on the ring or aliphatic carbon atom in the Z lingering section, most preferably are connected on the aliphatic carbon atom in the Z lingering section.
For Y wherein is formula 1 compound of alkylene, and being connected with Z is aliphatic carbon atom by among the Y, preferably is connected with H or ring carbon atom or heteroatoms among the Z.
When following and when dividing compounds by group in an embodiment, refer to classification by said structure.
Preferred compound comprises following compound, and as possible, they are according at the classification of type of the linking group shown in the above-mentioned part-structure. Amides:4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenyl-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenoxy group-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-tetramethylene-carbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-butyryl radicals-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-oxyethyl group-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-fluoro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-fourth-3-enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-methoxyl group-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-ethylmercapto group-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-diethyl-formamyl-hexamethylene-3-alkene carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(ring penta-1-thiazolinyl-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-oneself-3-enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(tetrahydrofuran (THF)-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiene-3-yl--ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, with 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides; Ureas:6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid phenyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid hexyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid benzyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid [(R)-1-phenyl-ethyl]-acid amides, and 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-pyridinecarboxylic acid-2-base acid amides; Sulfonamides:4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(propane-2-alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-dimethylamino alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-base-acid amides, with 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-trifluoro methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides; Thiourea:4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-cyclopropyl thiocarbamoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides; The N-alkyls:4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 6,6-trimethyl-cyclohex-2-en ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 4-two chloro-benzyls)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-[2-(1 for trifluoromethyl-xenyl-2-carboxylic acid, 5a, 6,9,9a, 9b-six hydrogen-4H-diphenylene-oxide-4a ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiophene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-furans-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, acetate 5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-furans-2-ylmethyl ester, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiene-3-yl-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 5-dimethoxy-tetrahydrofuran (THF)-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-quinoline-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyrimidine-2-base methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-benzimidazolyl-2 radicals-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiazol-2-yl methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1,2,4] triazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides and 4 '-trifluoromethyl-xenyl-2-carboxylic acid [(2-allyl group)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides; Amino formate:6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tertiary butyl ester; particularly preferred compound comprises: 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1; 2,3,4-tetrahydroisoquinoline-6-yl]-acid amides; 6-[(4 '-trifluoromethyl-xenyl-2-carboxyl)-and amino]-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid (1-phenylethyl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-thiazol-2-yl methyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl]-acid amides and 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1,2; 4] triazole-3-ylmethyl)-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
General chemistry abbreviation of Cai Yonging and initial letter abbreviation have in the following discussion: Me (methyl); Et (ethyl); THF (tetrahydrofuran (THF)); BOC (tertbutyloxycarbonyl, protecting group); Ms (methylsulfonyl); TFA (trifluoroacetic acid); Ac (ethanoyl); RP (anti-phase); HPLC (high pressure liquid chromatography).
Formula I compound can enoughly comprise the chemical field known method preparation for preparing similar compound.These methods that prepare the formula I compound of above-mentioned definition provide another feature of the present invention, and use following process explanation.Wherein unless otherwise indicated beyond, the connotation of general group is as mentioned above.This method comprises with a kind of reagent (it has constituted the XYZ part on molecule the right) handles formula II compound, Formula II compound has constituted molecule left-hand component, (i.e. the part of being made up of the hydrogen of removing from the tetrahydroisoquinoline theheterocyclic nitrogen atom among the formula II).The reagent of formation molecule right-hand component can have been bought usually or can find in scientific literature.Formula II compound is 4 '-trifluoromethyl-biphenyl base-2-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-6-yl) acid amides, this paper is called for short for convenience and makes " Compound I I ".Constituting The compounds of this invention molecule left-hand component is 6-[(4 '-trifluoromethyl) biphenyl-2-base carbonylamino]-3,4-dihydro-1H-isoquinoline 99.9-2-base section.
This method generally can be carried out according to following step:
(a) being the formula I compound of carbonyl for X wherein, is to handle Compound I I by the carboxylic acid with formula Z-Y-COOH in the presence of coupling agent.Coupling agent is generally used carbodiimide, and preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide is abbreviated as EDC usually, can buy.As USP 5,416,193 is disclosed such, and EDC can combine with polymkeric substance is fine.This reaction at room temperature reaches in the inert solvent usually to be carried out, but can heat if desired.Reaction time is very wide, from several minutes to 48 hour, generally spends the night.
(b) be the formula I compound of carbonyl or thiocarbonyl for X wherein, the activated form with corresponding carboxylic acid or thiocarboxylic acid in the presence of alkali is handled Compound I I.Typical activated form is respectively formula Z-Y-COCl or the corresponding chloride of acid of Z-Y-CSCl.This alkali for example amine it can with the fine bonding of polymkeric substance, simplify purification step, the alkali of typical bonding polymkeric substance is the morpholino-methylated polystyrene of bonding.This reaction is carried out under room temperature usually, stirs simultaneously, vibrates or with for some time that other form stirs necessity, make to react to proceed to suitable degree, and this time was generally 2-48 hour, was typically and spent the night.
As above-mentioned (a) and (b) the formed structure type of compound of disclosed method preparation, aforementioned amides and the thioamide analog of being called.
(c) be that carbonyl or thiocarbonyl and Y are the formula I compounds of NH for X wherein, prepare by handling Compound I I with the isothiocyanic acid ester of the corresponding isocyanic ester of formula Z-N=C=O or formula Z-N=C=S respectively.The structure type of the compound that is produced is this compounds that the present invention is called urea or thiocarbamide.This reaction is generally at inert solvent, typically at halohydrocarbon as 1, carry out in the 2-ethylene dichloride, the typical reaction times is 2-48 hour, generally spends the night.
(d) be the formula I compound of alkylsulfonyl for X wherein, by using formula Z-Y-SO 2The corresponding SULPHURYL CHLORIDE of Cl is handled formula Compound I I and is prepared.This reaction in inert solvent such as halohydrocarbon (for example 1,2-ethylene dichloride), is carried out a few hours or longer time usually under room temperature, generally spend the night.
(e) be CH for X wherein 2And Y is the formula I compound of direct key, prepares by handle formula II compound with the aldehyde of formula Z-CHO in the presence of sodium triacetoxy borohydride.This comes down to reductive amination process, at Abdel-Magid et.al., and TetrahedronLett, 31 (39), 5595-5598 has report in (1990).Products therefrom is a N-alkyl structure type.This is reflected in appropriate solvent such as the halohydrocarbon and carries out, and vibrates simultaneously or stirs, and not so at room temperature needs several hours to several days, but if desired, can heat and accelerate speed of reaction.
(f) be CH for X wherein 2With Y be the formula I compound of direct key, by in the presence of methylsulfonyl chloride (being generally 2 equivalents) with corresponding formula Z-CH 2-NH 2The compound of compound treatment following formula prepares:
(g) be the formula I compound of thiocarbonyl for X wherein, by using thiophosphoric anhydride P 4S 10The respective compound of processing formula 1 (wherein X is CO) prepares.Stoichiometric P is used in this reaction usually 4S 10(if desired also can be excessive), and in inert solvent such as pyridine heats with corresponding amide in dimethylbenzene, benzene, chlorobenzene or the toluene and finishes.This reaction usually refluxes and finished to a few hours in several minutes.
Formula II compound can be used as method as described in the flow process 1, and the preparation of the method for explanation in embodiment 1.In flow process 1,2-(4-bromophenyl) ethylamine hydrobromide and ethyl formate react in the presence of alkali and generate N-[2-(4-bromophenyl) ethyl] methane amide, this methane amide is handled with Vanadium Pentoxide in FLAKES in Tripyrophosphoric acid and is carried out cyclisation, use hydrogen halide (for example HCl) to handle subsequently and form 7-bromo-3, the halogen acid salt of 4-dihydro-isoquinoline.This halogen acid salt obtains 7-bromo-1,2,3 through reduction, the 4-tetrahydroisoquinoline.Then reduzate is handled with saltpetre in the vitriol oil and carried out nitrated and carry out suitable substep and separate, obtain 7-bromo-6-nitro-1,2,3, the 4-tetrahydroisoquinoline.This nitration product exists down and the reaction of dimethyl dicarbonate butyl ester in alkali then, so that protection tetrahydroisoquinoline theheterocyclic nitrogen atom obtains 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tertiary butyl ester thus.This ester carries out hydrogenation under pd/ lime carbonate exists, obtain corresponding 6-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylicesters.This amine then with 4 '-trifluoromethyl-biphenyl base-2-carboxylic acid reaction; generate 6-[4 '-trifluoromethyl-biphenyl base-2-carbonylamino]-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tertiary butyl ester; this compound is obtained Compound I I with the ordinary method deprotection; 4 '-trifluoromethyl-biphenyl base-2-carboxylic acid (1; 2,3,4-tetrahydroisoquinoline-6-yl) acid amides.
Flow process 1
Figure C9610811300361
In addition, formula II compound can be by the 2nd path of preparing shown in the flow process 2.In flow process 2, nitrobenzoic acid (1) is handled in the presence of alkali with dimethyl malonate and is obtained compound (2).Compound (2) is hydrolyzed with pure alkali aqueous solution processing and decarboxylation obtains compound (3), and if desired, compound (3) obtains acid anhydrides (3a) with the diacetyl oxide processing in toluene or other varsol.Reducing compound (3) or (3a) obtain corresponding diol (4) handles obtaining two methanesulfonates again with methylsulfonyl chloride, obtain compound (5) with the ammonia cyclisation subsequently.Compound (5) carries out N-protected usually and produces compound (6), obtains corresponding amine (7) through reduction again.Amine (7) with 4 '-acyl chlorides (handling corresponding free acid preparation with thionyl chloride) of trifluoromethyl-biphenyl base-2-carboxylic acid handles, and obtains Compound I I corresponding amide analogue (8).Described in flow process 1, compound (8) obtains Compound I I by the ordinary method deprotection.
Flow process 2
Figure C9610811300381
The formula III compound can be from the glycol the flow process 2 (4) beginning, according to flow process 3 described method preparations.In flow process 3, glycol (4) prepares corresponding aminodiol (9) with hydrogen reducing in the presence of platinum/C catalyst, aminodiol (9) with 4 '-acyl chlorides of trifluoromethyl-biphenyl base-2-carboxylic acid handles and obtains compound III, as noted, compound III obtains Compound I I with the ammonia cyclisation then in the presence of catalyzer.
Flow process 3 points out that also compound III also can directly be used formula Z-CH in the presence of alkali and catalyzer 2-NH 2Corresponding amine Processing of Preparation formula I compound, i.e. the formula Ia of indication in the flow process 3, wherein X is CH 2And Y is direct key.
Flow process 3
Figure C9610811300391
The separation method of common purification well known to those skilled in the art can be used for separating compound of the present invention with technology, these technology comprise various types of chromatographic technique (HPLC, use the column chromatography and the book layer chromatography of common sorbent material such as silica gel), recrystallization and fractional extraction technology (as liquid-liquid extraction method).
The application's compound can form cationic salts such as acid salt, and be called " pharmacy acceptable salt ", these salt can be defined as, but are not limited to following salt: hydrochloride, hydrobromate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, acetate, succinate, Citrate trianion, mesylate and tosilate.For chemical compound lot, it is possible adding salify.
The acid salt of The compounds of this invention is easy to make with the compound reaction of corresponding bronsted lowry acids and bases bronsted lowry form.When this salt is monobasic hydrochlorate (for example hydrochloride, hydrobromate, tosilate, acetate), during the dihydric salt (for example dihydrogen phosphate, Citrate trianion) of monohydric salt of diprotic acid (for example hydrosulfate, succinate) or triprotic acid, at least use the acid of a molar equivalent, use the acid of molar excess usually.But when required salt is as vitriol, hemisuccinic acid salt when hydrophosphate or phosphoric acid salt, uses suitable usually and is the normal acid of precise chemical structure.Generally combination in cosolvent of free alkali and acid, required salt is from wherein being precipitated out.Perhaps be separated by concentrating and/or adding non-solvent.
The compounds of this invention can be used for oral administration, therefore combines with pharmaceutically acceptable carrier or thinner and uses to be suitable for oral formulation mode.Suitable pharmaceutically acceptable carrier comprises inert solid packing or thinner and aseptic water or organic solution.Active compound will provide with the form of pharmaceutical composition, and its quantity is for being enough to provide the required dosage of following ranges.Therefore, for oral administration, The compounds of this invention can and suitable solid or liquid vehicle or thinner in conjunction with formation capsule, tablet, pulvis, syrup, solution, suspension etc.If desired, pharmaceutical composition also can contain other composition such as seasonings, sweeting agent, vehicle etc.
Tablet, pill, capsule etc. also can contain tackiness agent such as tragacanth gum, Sudan Gum-arabic, W-Gum or gelatin; Vehicle such as Lin Suanergai; Disintegrating agent such as W-Gum, potato shallow lake are divided, alginic acid; Lubricant such as Magnesium Stearate; Sweeting agent such as sucrose, lactose or asccharin.When dosage unit form is capsule, except that the material of the above-mentioned type, also can contain liquid vehicle such as fatty oil.
Can also add the physical aspect of various other materials as dressing or improvement dose unit.For example, tablet can be used shellac, sugar or its both dressings.Syrup and elixir can contain sucrose as sweeting agent except that containing active constituent, methyl p-hydroxybenzoate and propyl ester be as sanitas, tinting material and seasonings such as cherry or oranges and tangerines.
These active compounds also can be used for parenterai administration.For parenterai administration.This compound can be made injection solution or suspension with aseptic water or organic medium combination.The solution of these active compounds or suspension can suitably mix and prepare with tensio-active agent such as hydroxypropylcellulose in water.Dispersion liquid also can be with sesame oil or peanut oil, ethanol, water, polyvalent alcohol (for example glycerine, propylene glycol, liquid polyoxyethylene glycol) and suitable mixture thereof, vegetables oil, the N-methylglucosamine, the aqueous solution of acceptable salt prepares on the water-soluble pharmacy of polyvinylpyrrolidone and mixture in oil and The compounds of this invention.Under common storage and working conditions, these preparations should contain sanitas so that do not make microorganism growth.Injection solution with method for preparing can be used for vein, intraperitoneal, subcutaneous or intramuscular administration.
The formulation that is suitable for injecting drug use comprises aseptic aqueous solution or dispersion liquid and the sterilized powder that is used for temporarily preparing aseptic injectable solution or dispersion liquid.In all cases, this formulation must be aseptic and must be easy mobile so that it can easily be packed into syringe.Under preparation and condition of storage, it must be stable, and must be the pollution of preventing microorganism such as bacterium and fungi.
The dosage of formula I compound changes according to principle well known in the art, and rule is severity and the route of administration of considering by the treatment disease.Generally speaking, when formula I compound was used for warm-blooded animal (as the mankind) administration, common day effective dose (single administration or branch administration for several times) was an acceptable in the scope of about 0.1-15mg/kg body weight for example, preferably about 1-5mg/kg body weight.Acceptable TDD generally is 1-1000mg, preferred 5-350mg.
The compounds of this invention also can and other medicines, comprise the medication combined use of other fat depressant.These medicines comprise the cholesterol biosynthesis inhibitor, particularly the synthetic acyl inhibitor of HMG CoA reductase inhibitor and squalene; Bile acid chelating agent; Fibrates; Inhibitors of cholesterol absorption and nicotinic acid.
If test compound is activated in following any screening, it just is considered to active so.
The activity of The compounds of this invention suppresses to assess to apo B excretory by measuring in the Hep G2 cell.
The HepG2 cell there is being 10% fetal bovine serum (growth medium; In the 96 hole culture dish of Dul-becco ' s Modified Eagles substratum Gibco), in the damp atmosphere that contains 5% carbonic acid gas, grow, merge (confluent) up to about 70%.Test compound is dissolved in the methyl-sulphoxide with 10-20 mM, is diluted to 1 μ M then in growth medium.A series of 1: 1 diluent of this storing solution of preparation in growth medium, every hole 100 μ l join in each hole of the 96 hole culture dish that contain the HepG2 cell, collect the substratum of growth after 24 hours, the concentration of apo B and apo A1 (in contrast) is measured by specific ELISA.The secretion of apo B is reduced and inhibitor is identified in the secretion that do not influence apo A1 with compound.As follows for the ELISA of apo B operation: the monoclonal antibody to people's apo B (Ch-emico) is diluted to 5 μ g/ml in phosphate buffered saline (PBS)/stacked oxide (PBS+0.02% sodiumazide), add 100 μ l in each hole of 96 hole culture dish (NVNC Maxisorb).Incubated at room temperature is spent the night, and shifts out antibody-solutions, and wash 3 times with the PBS/ trinitride in these holes.Non--privileged site on the plastics protects it by cultivating hole, cave 1-3 hour in 1% (W/V) bovine serum albumin (BSA prepares in the PBS/ trinitride) solution.Be inserted in each hole and cultivated 18 hours from the various diluents (in the PBS/ trinitride, in 0.004% polysorbas20/1%BSA, preparing) of 100 μ l growth mediums of Hep G2 cell or apo B standard.The hole is sucked and washs (0.1% polysorbas20 among the PBS) 3 times, adds 1/1000 diluent of 100 μ l second antibody [being the anti-people apo of goat B (Chemicon)] then.After 3 hours, aspirate this solution in incubated at room temperature, wash 3 times more as stated above in the hole.The rabbit that combines alkaline phosphate is anti--and 1: 1600 diluent of goat 1 gG, 100 μ l is (at PBS/1%BSA/2mM MgCl 2In) (Sigma) be added in each hole and in incubated at room temperature 1 hour, after the suction, the hole was with aforesaid method washing 4 times, with 100 μ l 25mM sodium bicarbonate/2mM MgCl 2In 1mg/ml p-nitrophenyl benzyl phosphoric acid ester (pNPP; Sigma) (pH9.5) add and enter in each hole and cultivated 20-30 minute, by adding 50 μ l 0.2N NaOH termination reactions.Read the absorption in each hole at the 405nm place, deduct the background at 650nm place.Apo B concentration is calculated from the typical curve that is made of the LDL standard of purifying, and this purification LDL standard is parallel in same test.Apo A1 measures with similar method, just replace the antibody of apo B with the antibody (Chemicon) of apo A1, and antigenic cultivation is at 37 ℃ rather than at room temperature carries out.
If test compound directly suppresses the activity of MTP, then its activity also can be identified.
Compound suppresses the MTP activity can be shifted quantitatively from steeping to the acceptor vesica to somatocyst by the inhibition of observing the radioactivity triglyceride level in the presence of soluble human MTP.The method for preparing MTP is according to the method for Wetterau and Zilversmit (Biochem, Biophys.Acta (1986) 875:610).Briefly, will thaw on ice, shred and wash for several times with ice-cold 0.25M sucrose in-80 ℃ of refrigerated people's liver piece.Thereafter all steps are all in operation on ice.Use Potter-Elvehjem tetrafluoroethylene pestle prepares 50% homogenate in the 0.25M sucrose.With 0.25 M sucrose homogenate is diluted to 1: 1, in 4 ℃, 10, under 000 * g centrifugal 20 minutes, bead is suspended in the sucrose once more also again in 10, under 000 * g centrifugal 20 minutes, merge supernatant liquor, by under 105,000 * g, making microsome become bead in centrifugal 75 minutes, abandoning supernatant, MC bead is suspended in the 0.25M sucrose of minimum volume, liver weight is divided into 12 parts with this suspension when being diluted to the every gram of 3ml/ and beginning with 0.15M Tris-HCl PH8.0, under 105,000 * g centrifugal 75 minutes.Abandoning supernatant, the microsome bead is arrived in-80 ℃ of refrigerated storage need the time spent.Before finishing above-mentioned test, be preparation MTP, the bead that will thaw is suspended among 12ml cold 50mM Tris-HCl, 50mMKCl, the 5mM MgCl (PH 7.4), slowly adds 1.2ml 0.54% deoxycholate salt (PH7.4) solution while mixing, so that divide MC film.After slowly mixing is cultivated 30 minutes on ice down, with suspension in 105, under 000 * g centrifugal 75 minutes, will contain supernatant liquor dialysis 2-3 days of solvable mtp protein, change test damping fluid (150mM Tris-HCl, 40mM NaCl, 1mM EDTA, 0.02%NaN 4 times 3, PH7.4) people liver MTP stores down in 4 ℃, and diluting with the test damping fluid before just will using is 1: 5.The preparation of MTP is not found significant transfer activity loss when being stored to 30 days.
The preparation of liposome is under nitrogen atmosphere, and room temperature is bathed sonication 400 μ M ovum Cholinphospholipides (PC), 75 μ M OX-heart fat and 0.82 μ M[14C] dispersion of triolein (110Ci/mol) in the test damping fluid.Lipid in the chloroform is added with suitable quantity, and before with the hydration of test damping fluid, in nitrogen gas stream, carry out drying.The preparation of acceptor plasmalogen is under nitrogen atmosphere, and room temperature is bathed sonication 1.2mM PC, 2.3 μ M trioleins and 30 PM[3H]-dispersion of PC (50 Ci/mol) in the test damping fluid.Should be to body and acceptor liposome under 7 ℃ of 160,000 * g centrifugal 2 hours.Carefully remove the supernatant liquor of the top 80% that contains a small amount of unilamellar liposome, in 4 ℃ of storages, up to testing as shifting.
Use and shift test determination MTP activity, this on-test, will mix with soluble MTP and test compound to body and acceptor vesica earlier.In the 5%BSA of 100 μ l 5%BSA (contrast) or test compound, add the mtp protein that 500 μ l test damping fluid, 100 μ l dilute for body liposome, 200 μ l acceptor liposomes and 100 μ l.After 45 minutes, stop the transfer of triglyceride level in 37 ℃ of cultivations by adding 500 μ l 50% (W/V) DEAE cellulose suspensions in the test damping fluid.Stirred 4 minutes.Being attached to the cellulosic body liposome of giving of DEAE is optionally precipitated by low-speed centrifugal.The a part of supernatant liquor that contains the acceptor liposome is counted, and with the percentage recovery of the numerical evaluation acceptor liposome of 3H and 14C and use first order kinetics to calculate the percentage triglyceride level and shift.The restraining effect that test compound shifts triglyceride level is that the 14C radioactivity during with itself and non-test compound control group comparison reduces and represents.
Test compound also can be measured by following test method in vivo as the activity of MTR inhibitor.
Male mice (20-30g, not of the same race), use the test compound administration (0.25ml/25g body weight) that is suspended in 0.5% methylated cellulose aqueous solution by oral gavage, put to death preceding 90 minutes single administrations with compound solution multiple dosing or mouse in several days, and collect blood and prepare serum, with commercial enzyme sample (triglyceride level G; Wako Fine Ch-emicals) triglyceride concentration of evaluation serum.By confirming the MTP inhibitor with its ability that reduces serum triglyceride of control group mice comparison with the vehicle administration.
The present invention illustrates by following examples, but should be appreciated that the present invention is not subjected to the restriction of the detail among these embodiment.
Embodiment 1
The preparation method of this embodiment formula II midbody compound N-[2-(4-bromo-phenyl)-ethyl]-methane amide
With 500g (1.78mol) 2-(4-bromo-phenyl)-ethylamine hydrobromide, 1 liter of (12.4mol) carbamoyl ethyl and 248ml (1.78mol) triethylamine merge, reflux 3 hours.With reactant deionized water and each 1 liter of processing of ethyl acetate.Organic layer is told, and with 1 premium on currency and 1 liter of salt water washing.With the organic layer anhydrous magnesium sulfate drying, filter and concentrate, obtain the 378g solid.
MS (Cl): 245 (M+NH 4 +) 7-bromo-3,4-dihydro-isoquinoline hydrochloride
In 12 liter of three neck round-bottomed flask, the 4kg Tripyrophosphoric acid is heated to 150 ℃ and stirring.In the Tripyrophosphoric acid that is stirring, add three parts of 530g (3.75mol) Vanadium Pentoxide in FLAKES with every part of about 176.7g.After the Vanadium Pentoxide in FLAKES dissolving, add 378g (1.66mol) N-[2-(4-bromo-phenyl)-ethyl]-methane amide.Then temperature of reaction is risen to 200 ℃ and kept two hours.At this moment, make temperature of reaction be cooled to 160 ℃ and be poured into 16 liters of ice.This mixture was stirred 0.5 hour, alkalize to PH12 with the 10N sodium hydroxide solution, and with 3 liters of dichloromethane extractions three times.The organic layer that merges is washed with 1 liter of saturated nacl aqueous solution, use anhydrous sodium sulfate drying, filter and be condensed into oily matter.This oily matter is dissolved in 2.5 liters of methyl alcohol and saturated with anhydrous HCl gas.Gained solution concentration to is risen volume and add 1 liter of ether.With the gained sedimentation and filtration,, obtain the 219g solid with ether washing and air-dry.
MS (Cl): 210 (M+H +) 7-bromo-1,2,3, the 4-tetrahydroisoquinoline
With 219g (0.89mol) 7-bromo-3,4-dihydro-isoquinoline hydrochloride and 1.5 premium on currency merge, and are heated to 50 ℃.Added 33.7g (0.89mol) sodium borohydride in 0.5 hour, this moment, temperature rose to 62 ℃ in batches.Then reactant is cooled to envrionment temperature and with 1 liter of dichloromethane extraction three times.The organic layer that merges is washed with 1 liter of saturated nacl aqueous solution,, obtain 173g oily matter with anhydrous sodium sulfate drying and concentrated.
MS (Cl): 212 (M+H +) 7-bromo-6-nitro-1,2,3, the 4-tetrahydroisoquinoline
In 5 liter of three neck round-bottomed flask, with 173g (0.813mol) 7-bromo-1,2,3, the 4-tetrahydroisoquinoline is dissolved in the 950ml concentrated hydrochloric acid carefully.Gained solution is cooled to-5 ℃ and drip the solution that 82.7g (0.186mol) saltpetre forms in 1 liter of vitriol oil.After adding, reactant was placed 15 minutes and poured in 3 liters of ice at-5 ℃.The gained mixture is alkalized to PH14 with 50% sodium hydroxide solution.With this alkaline solution with 1 liter of dichloromethane extraction three times.The organic layer that merges is washed with 1 premium on currency and 1 liter of saturated nacl aqueous solution.With the organic layer anhydrous sodium sulfate drying, filter and concentrate, obtain 201g oily matter.Load onto the silicagel column of 4kg with being adsorbed on oily matter on the silica gel in advance, with 1-5% ethanol/methylene gradient elution.The stream part that will contain product merges, and concentrates, and obtains the 115g solid.
1H?NMR(400MHz，CDCl 3)δ7.61(s，1H)；7.38(s，1H)；4.10(s，2H)；3.20(t，2H)；2.90(t，2H)。 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tert-butyl ester
With 115g (0.447mol) 7-bromo-6-nitro-1,2,3, the 4-tetrahydroisoquinoline, 45.2g (0.447mol) TEA, 97.5g (0.447mol) heavy carbonic di tert butyl carbonate, 3.2 Sheng dioxs and 0.5 premium on currency merge, and stir at ambient temperature 1.5 hours.Reactant concentrated remove diox, adds 1 liter of saturated sodium bicarbonate also with twice of 1 liter of dichloromethane extraction.Organic layer is extracted with salt solution, with dried over mgso and concentrated.With gained solid Virahol recrystallization, obtain the 118g solid.
1H?NMR(250MHz，DMSO)δ7.89(s，1H)；7.81(s，H)；4.58(s，2H)；3.56(t，2H)；2.81(t，2H)；1.42(s，9H)。 6-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tert-butyl ester
With 59g (0.16mol) 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tert-butyl ester, 5% of 10g palladium and be present in the hydrogenation 5 hours on Parr shaker of 1 liter of 49g ammonium acetate among the acetate on the lime carbonate.With the reactant diatomite filtration, concentrate, alkalize to PH12 with 4N sodium hydroxide, and use dichloromethane extraction.With organic layer water, salt water washing, use dried over mgso, concentrate, obtain 40g oily matter.
1H?NMR(300MHz，DMSO)δ4.87(s，2H)；4.27(s，2H)；3.44(t，2H)；2.57(t，2H)；1.39(s，9H)。 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H -isoquinoline 99.9-2-carboxylic acid tert-butyl ester
With 7.6g (29mmol) 4 '-trifluoromethyl-xenyl-2-carboxylic acid, 7.1g (29mmol) 6-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tert-butyl ester, 100mg DMAP and 6.1g (32mmol) EDCI mixed 12 hours in the 130ml methylene dichloride.With reactant with 2 * 150ml 1N HCl, 2 * 150ml 1N NaOH, 150ml water.The salt solution extraction concentrates, and obtains the cream-coloured foam of 14g.
MS(Cl)：519(M+Na +)
1H?NMR(250MHz，CDCl 3)δ4.49(s，2H)；3.60(t，2H)；2.77(t，2H)。 4 '-trifluoromethyl-xenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-6- Base)-acid amides
With 4g (8mmol) 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tert-butyl ester and 6ml (78mmol) TFA mixed 5 hours in the 60ml methylene dichloride.Add the 40ml methylene dichloride and organic phase is extracted with 3 * 50ml saturated sodium bicarbonate and salt solution.With the organic layer dried over sodium sulfate, concentrate, obtain the 3.10gm solid.
MS (Cl): 397 (M+H +) following compounds, be categorized as acid amides by foregoing criterion, synthetic by the described step of method A. Method A
In having the glass vial of screw cap, add 150Ml 0.020M acyl chlorides 1, the solution that forms in the 2-ethylene dichloride (3.0 μ mol), then add 83 μ l 0.030M4 '-trifluoromethyl-xenyl-2-carboxylic acids (1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides is 1, the solution that forms in the 2-ethylene dichloride (2.5 μ mol) then adds 25 mg by morpholino methylated polystyrene bonded polymkeric substance (@2.5 μ mol/gm=62 μ mol).20 ℃ shake 16 hours after, take out 10 μ l and be diluted to 100 μ l with methyl alcohol, carry out RPHPLC and MS and analyze.The filtering polymkeric substance, and the filtrate vacuum concentration is extremely dried. Embodiment 2
A according to the method described above by in the presence of by morpholine bonded polymkeric substance, makes the reaction of Compound I I and 3-cyclopentyl propionyl chloride; preparation 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-cyclopentyl-propionyl)-1; 2,3,4-tetrahydroisoquinoline-6-yl]-acid amides.
MS (Cl): 521 (M+H +) Embodiment 3-39
According to similar methods described in the embodiment 2, by Compound I I and suitable acyl chloride reaction, the preparation following compounds.
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenyl acetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：519(M+H +)
1H NMR (250MHz, CDCl 3) δ 4.68 and 4.53 (s, 2H); 3.80 and 3.61 (t, 2H); 2.76 and 2.59 (t, 2H).
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：501(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(furans-2-carboxyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：491(M+H +)
4-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-chloro-butyryl radicals)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：501(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzyloxy ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：545(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-heptyl-benzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：599(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(dicyclo [2.2.1] heptan-5-alkene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：517(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(5-methyl-3-phenyl-different azoles-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：582(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-tetradecanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：607(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3,3-dimethyl-butyryl radicals)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：495(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzene oxygen ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：531(M+H +)
Acetate 2-oxo-1-phenyl-2-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-ethyl ester
MS(Cl)：573(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：507(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,2,5,7-tetramethyl--1-oxo-1,2-indane-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：611(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-capryloyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：523(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-Linolenic Acid-enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：661(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(quinoxaline-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：553(M+H +)
4 '-oxo-4-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-methyl-butyrate
MS(Cl)：511(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [(2-(xenyl-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：577(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：481(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：467(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-decanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：551(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-octadecanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：663(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-caproyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：495(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：529(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-hexanaphthene carbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：507(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-tetramethylene carbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：479(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-ethyl-caproyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：523(M+H +)
3-oxo-3-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-methyl propionate
MS(Cl)：497(M+H +)
5-oxo-5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-methyl valerate
MS(Cl)：525(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-chloro-propionyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：487(M+H +)
5-oxo-5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-Valeric acid ethylester
MS(Cl)：539(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(3-methoxyl group-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：545(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：521(M+H +)
1H NMR (250MHz, CDCl 3) δ 4.68 and 4.60 (s, 2H); 3.97 (s, 2H); 3.80 and 3.69 (t, 2H); 2.71 (m, 2H).
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：467(M+H +)
4-oxo-4-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-yl }-methyl-butyrate
MS(Cl)：511(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-18 carbon-11 enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS (Cl): 661 (M+H +) Method B By EDC bonded polymkeric substance
1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloric acid (20gm, 0.104 mol) is distributed between 400ml methylene dichloride, 200ml water and the dense ammonium hydroxide of 100ml.With water layer with 2 * 100ml dichloromethane extraction.With organic layer 100ml 10% solution of ammonium hydroxide that merges, the 100ml water washing, use dried over mgso, filter different vacuum concentration, obtain water white oily matter, this oily matter is dissolved in 350ml DMF, add Merrifield resin (100gm, 2%dvb, 200-400 order, 1.0mmol/gm), and with this mixture 100 ℃ of heated and stirred 16 hours.After the cooling, with resin filter, with 2 * 100ml DMF, 2 * 300ml THF washing, and 50 ℃ of vacuum-dryings 20 hours.IR?2131cm -1。 Reaction
In having the glass vial of screw cap, add 50 μ l 0.050M acid 1, the solution that forms in the 2-ethylene dichloride (2.5 μ mol), then add 50 μ l, 0.050M Compound I I 1, solution in 2 ethylene dichloride (2.5 μ mol), connect and add 30 μ l, 0.017MDMAP 1, the solution that forms in the 2-ethylene dichloride (0.5 μ mol) then adds 25mg by 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide bonded polymkeric substance (@1.0 μ mol/gm=25 μ mol).20 ℃ shake 16 hours after, take out 10 μ l and be diluted to 100 μ l with methyl alcohol, carry out RPHRLC and MS and analyze.The filtering polymkeric substance, and the filtrate vacuum concentration is extremely dried.
Embodiment 40
B according to the method described above by in the presence of by EDC bonded polymkeric substance, makes Compound I I and naphthalene-2-guanidine-acetic acid reaction, preparation 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(naphthalene-2-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides.
MS(Cl)：565(M+H +)
Embodiment 41-97
According to similar methods described in the embodiment 40, by in the presence of by EDC bonded polymkeric substance, Compound I I and suitable corresponding carboxylic acid reaction, preparation following compounds.
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,2-dimethyl propylene acyl group)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：481(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,2-dimethyl-pentanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：509(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-hydroxyl-2-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：545(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-phenyl-butyryl radicals-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：543(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-4-oxo-pentanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：509(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-ethyl-butyryl radicals)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：495(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid-(2-ethoxy ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：483(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-fluoro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：533(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiophenyl ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：547(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzylthio-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：561(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-butyryl radicals-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：481(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-butyryl radicals-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：501(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid-(2-fourth-3-enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：465(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-acetyl-tetramethyleneimine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS?(Cl)：536(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-oxo-2-sulfo--thiazolidine-3-yl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：570(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(pyridine-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：502(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(quinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：552(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-phenyl-pentamethylene-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：569(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(a-methoxyl group-phenyl-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：545(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-2,2-dimethyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：515(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-cyano group ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：464(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-methoxy ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：469(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-chloro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：549(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-ethylmercapto group ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：499(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-phenyl-third-2-acyl group)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：525(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-hydroxyl-butyryl radicals)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：483(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid the 2-[(1H-indol-3-yl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：554(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-methyl-pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：516(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(pyridine-2-base-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：516(M+H +)
1H NMR (300MHz, CDCl 3) δ 4.67 (s, 2H), 399 (s, 2H); 3.77 (m, 2H); 2.76 and 2.65 (t, 2H).
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-nitro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：560(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-diethylamino formyl radical-hexamethylene-3-alkene carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：604(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(diamantane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：559(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(3-chloro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：549(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenylbenzene ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：591(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(2,4-two chloro-phenyl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：583(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-phthalimido-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：584(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(biphenyl-4-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：591(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-O-tolyl ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：529(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-m-tolyl ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：529(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-phenyl-Ding-3-enoyl-)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：541(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(ring penta-1-thiazolinyl-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：505(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(3,4,5-trimethoxy-phenyl)-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：605(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(diamantane-1-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：573(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(9H-fluorenes-9-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：589(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(3-trifluoromethyl-phenyl)-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：583(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl-cyclohexyl alkyl carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：521(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[2-(1,3-dioxo-isoindole-2-yl)-propionyl] and-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：598(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-methyl-2-oxo-pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：509(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methoxyl group-ring-oneself-alkyl carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：537(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-oneself-3-enoyl--1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：493(M+H +)
2-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl }-tetramethyleneimine-1-t-butyl formate
MS(Cl)：594(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(tetrahydrochysene-furans-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：495(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(a-oxo-thiophene-2-base-ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：552(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiene-3-yl--ethanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：521(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(6-methoxyl group-3-oxo-2,3-indane-1-yl)-ethanoyl]-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：600(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-ethanoyl-tetramethyleneimine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：536(M+H +)
4 '-trifluoromethoxy-xenyl-2-carboxylic acid [2-(dicyclo [2.2.1] heptan-2-base-ethanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：533(M+H +)
Embodiment 98
With Compound I I (200mg, 0.50mmol), pyridine carboxylic acid (62mg, 0.60mmol) and EDCl (116mg 0.60mmol) mixed in methylene dichloride 14 hours.Reactant concentrated and through flash chromatography on silica gel method purifying (eluent: 70-100%EtOAc/HeX).Product is 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides, productive rate 98%.
MS(Cl)：502(M+H +)
1H NMR (250MHz, CDCl 3) δ 4.81 and 4.69 (s, 2H); 3.92 and 3.73 (t, 2H); 2,83 (m, 2H). Method C
In having the glass vial of screw cap, add 150 μ l 0.020M isocyanic ester 1, the solution that forms in the 2-ethylene dichloride (3.0 μ mol), then add 83 μ l 0.030M 4 '-trifluoromethyl-xenyl-2-carboxylic acids (1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides (Compound I I) is 1, the solution that forms in the 2-ethylene dichloride (2.5 μ mol).20 ℃ shake 16 hours after, take out 10 μ l and be diluted to 100 μ l with methyl alcohol, carry out RPHPLC and MS and analyze.The reactant vacuum concentration is extremely done.
Embodiment 99
C is described according to method, by making the reaction of Compound I I and phenylcarbimide, preparation 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid phenyl acid amides.
MS(Cl)：516(M+H +)
1H?NMR(250?MHz，DMSO)δ?4.56(s，2H)；3.66(t，2H)；2.77(t，2H)。 Embodiment 100-103
According to similar methods described in the embodiment 99, by making Compound I I and suitable different chlorate's reaction, preparation following compounds.
6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid hexyl acyl
MS(Cl)：524(M+H +)
(6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid }-amino)-ethyl acetate
MS(Cl)：526(M+H +)
6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid benzyl acid amides
MS(Cl)：530(M+H +)
6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid [(R)-1-phenyl-ethyl]-acid amides
Annotate: described by method C, use the product of Compound I I and (R)-(+)-isocyanic acid-α-Jia Jibianji ester preparation.
MS(Cl)：544(M+H +)
1H?NMR(250?MHz，CDCl 3)δ5.06(m，1H)；4.66(d，1H)；4.46(s，2H)；3.56(t，2H)；2.78(t，2H)；1.52(d，3H).
Embodiment 104
According to Ohsawa, A.; Arai, H.; Igeta, H.Chem.Pharm.Bull.1980, similar methods described in 28,3570, preparation 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-pyridinecarboxylic acid-2-base acid amides.Productive rate 23%.
MS(Cl)：517(M+H +)
1H NMR (300 MHz, CDCl 3) δ 4.60 (s, 2H); 3.69 (t, 2H); 2.86 (t, 2H). Method D
In having the glass vial of screw cap, add 150 μ l, 0.020 M SULPHURYL CHLORIDE 1, the solution that forms in the 2-ethylene dichloride (3.0 μ mol), then add 83 μ l, 0.030 M Compound I I 1, the solution that forms in the 2-ethylene dichloride (2.5 μ mol) then adds 25mg by morpholino methylated polystyrene bonded polymkeric substance (@2.5 μ mol/gm=62 μ mol).20 ℃ shake 16 hours after, take out 10 μ l and be diluted to 100 μ l with methyl alcohol, carry out RPHPLC and MS and analyze.The filtering polymkeric substance is also extremely dried with the filtrate vacuum concentration.
Embodiment 105
D is described according to method, makes Compound I I and naphthalene-1-SULPHURYL CHLORIDE reaction, preparation 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(naphthalene-1-alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides.
MS(Cl)：604(M+NH 4 +)
Embodiment 106-111
According to as the method D among the embodiment 105, make Compound I I and suitable SULPHURYL CHLORIDE reaction, the preparation following compounds.
2-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-alkylsulfonyl }-methyl benzoate
MS(Cl)：595(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(third-2-alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：520(M+NH 4 +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-third-1-alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：555(M+NH 4 +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(5-1-alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：534(M+NH 4 +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-dimethylamino alkylsulfonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：521(M+NH 4 +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-trifluoromethoxy benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：638(M+NH 4 +)
Embodiment 112
This embodiment explanation is the preparation of the compound of thiocarbamoyl at the group that on the XYZ XYZ is connected on the different pyridine quinoline of the tetrahydrochysene ring wherein.
In having the glass vial of screw cap, add 150 μ l 0.020M isothiocyanic acid esters (isothiocyanic acid ring propyl ester) 1, the solution that forms in the 2-ethylene dichloride (3.0 μ mol), then add 83 μ l, 83 μ l 0.030M 4 '-trifluoromethyl-xenyl-2-carboxylic acids (1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides is 1, the solution that forms in the 2-ethylene dichloride (2.5 μ mol).20 ℃ shake 16 hours after, take out 10 μ l and be diluted to 100 μ l with methyl alcohol, carry out RPHPLC and MS and analyze.With the reactant vacuum concentration to doing, obtain 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-cyclopropyl thiocarbamoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides.
MS (Cl): 496 (M+H +) Method F
Under the room temperature, with aldehyde (7.5 μ mol), Compound I I (5 μ mol), acetate (7.5 μ mol) and sodium triacetoxy borohydride (10 μ mol) are at 300 μ l 1, and the solution that forms in the 2-ethylene dichloride shook 60 hours.Take out 7.5 μ l samples and, carry out TLC and MS analysis with the dilution of 93 μ l methyl alcohol.Remaining sample vacuum-evaporation is extremely done.The crude product solid is dissolved in 500 μ l ethyl acetate also to be washed with 300 μ l, 5% sodium bicarbonate.The organic layer vacuum concentration is extremely done.
Embodiment 113
F is described according to method, makes compound and 2,6,6-3-methyl cyclohexanol-2-olefine aldehydr reaction, and preparation 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,6,6-trimethyl-cyclohex-2-en ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides.
MS(Cl)：533(M+H +)
Embodiment 114-162
According to embodiment 113, by method F, make Compound I I and suitable aldehyde reaction, the preparation following compounds.
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-hexamethylene-3-thiazolinyl methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：491(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：501(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-dimethylamino-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：530(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-methoxyl group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：517(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-fluoro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：505(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3,4-two chloro-benzyls)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：555(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-sec.-propyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：529(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-biphenyl-4-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：564(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-phenoxy group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：580(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-methoxyl group-naphthalene-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：568(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-naphthalene-1-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：538(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-methylthio group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：533(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(9-ethyl-9H-carbazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：605(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-tert-butyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：544(M+2)
3-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-the naphthenic acid ethyl ester
MS(Cl)：566(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(uncle 2--butylthio-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：576(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-cyclohexyl methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：494(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-fluoro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：505(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzo [1,3] dioxole-5-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：531(M+H +)
4 '-three oxygen methyl-xenyls-2-carboxylic acid (2-naphthalene-2-methyl first)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：538(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-methoxyl group-naphthalene-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：568(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-benzyloxy-3-methoxyl group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：624(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1,3,4-trimethylammonium-hexamethylene-3-thiazolinyl methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：533(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[2-(4-chloro-thiophenyl)-benzyl) and-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：629(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,4-two chloro-benzyls)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：555(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1,5a, 6,9,9a, 9b-six hydrogen-4H-diphenylene-oxide-4a-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：585(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid { 2-[4-(2-diethylin-oxyethyl group)-benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl }-acid amides
MS(Cl)：603(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：555(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6,6-dimethyl-dicyclo [3.1.1] heptan-2-base-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：531(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-benzyloxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：594(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-phenoxy group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：579(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-dimethylamino-naphthalene-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：580(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-tetramethyleneimine-1-base-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：557(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiophene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：493(M+H +)
1NMR(250MHz，DMSO)δ3.83(s，2H)；3.52(s，2H)；2.69(m，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2 (1H-indol-3-yl methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：526(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：476(M+H +)
1H?NMR(300MHz，DMSO)δ3.54(s，2H)；3.43(s，2H)；2.72(m，2H)；2.60(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-furans-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：477(M+H +)
1H?NMR(250MHz，DMSO)δ3.65(s，2H)；3.47(s，2H)；2.71(m，2H)；2.65(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 M-pyrazoles-4-ylmethyl]-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：598(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2,5-dimethyl-1-phenyl-1H-pyrroles-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：581(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：582(M+2)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-cumarone-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：527(M+H +)
Acetate 5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-furans-2-ylmethyl ester
MS(Cl)：549(M+H +)
1H?NMR(300MHz，CDCl 3)δ5.02(s，2H)；3.70(s，2H)；3.60(s，2H)；2.83(t，2H)；2.75(t，2H)；2.07(s，3H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-thiophene-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：507(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiene-3-yl-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：493(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-Methyl-1H-indole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-acid amides
MS(Cl)：540(M+H +)
2-methyl-5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-furans-3-ethyl formate
MS(Cl)：563(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2, the 5-dimethoxy)-tetrahydrofuran (THF)-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：541(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-Methyl-1H-indole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：557(M+NH 4 +)
2-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-the cyclopropane-carboxylic acid ethyl ester
MS(Cl)：523(M+H +)
Method G
According to being similar to Abdel-Magid, A.F.; Maryanoff, C.A.; Carson, K.G. be at Tetrahedron Lett.1990, and the step of describing in 31,5595 prepares following compounds through the reduction amination effect.Remove some and revise, normally outside the modification of the selection aspect of solvent and temperature of reaction, this method and method F are basic identical and used sodium triacetoxy borohydride, and all modifications are to each compound.In addition, unless otherwise noted, use the normal carbonyl compound of 1.5-2.This part prepared compound is separated with free alkali.In most of the cases, be used for the free alkali of field of biology,, be converted to single hydrochloride by ordinary method.
Embodiment 163
Use is similar to the method for above-mentioned Abdel-Magid etc., through following modification, by make Compound I I and phenyl aldehyde prepared in reaction 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: the DCE56% productive rate
MS(Cl)：487(M+H +)
1H?NMR(250MHz，DMSO)δ3.62(s，2H)；3.46(s，2H)；2.74(m，2H)；2.63(m，2H)。
Embodiment 164-193
Use is similar to the method for Abdel-Magid etc., through pointed suitable modification, makes Compound I I and suitable aldehyde reaction, the preparation following compounds.
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: the THF62% productive rate
MS(Cl)：488(M+H +)
1H?NMR(300MHz，CDCl 3)δ3.82(s，2H)；3.63(s，2H)；2.84(m，2H)；2.77(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridin-4-yl methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: THF
MS(Cl)：488(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-quinolyl-4 methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: THF
MS(Cl)：488(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-quinoline-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: the DCE66% productive rate
MS(Cl)：538(M+H +)
1H?NMR(250MHz，CDCl 3)δ3.99(s，2H)；3.67(s，2H)；2.82(m，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-methyl-pyridine-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE63% productive rate
MS(Cl)：502(M+H +)
1H?NMR(250MHz，CDCl 3)δ3.79(s，2H)；?3.63(s，2H)；2.81(s，2H)；2.76(s，2H)；2.55(s，3H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-bromo-pyridine-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-acid amides
MS(Cl)：568(M+H +)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-formyl radical-pyridine-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE; Use 10 normal aldehyde
MS(Cl)：516(M+H +)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-chloro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: DCE
MS(Cl)：521(M+H +)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE69% productive rate
MS(Cl)：521(M+H +)
1H?NMR(300MHz，DMSO)δ3.64(s，2H)；3.47(s，2H)；2.74(t，2H)；2.64(t，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(4-chloro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：521(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyrimidine-2-base methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: methylene dichloride; Use 6 normal aldehyde 61% productive rates
MS(Cl)：489(M+H +)
1H?NMR(250MHz，DMSO)δ3.87(s，2H)；3.60(s，2H)；2.77(m，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-nitro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE76% productive rate
MS(Cl)：532(M+H +)
1H?NMR(300MHz，CDCl 3)δ3.75(s，2H)；3.58(s，2H)；2.84(t，2H)；2.73(t，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methoxyl group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: DCE
MS(Cl)：517(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：555(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-cyano group-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：512(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-hydroxyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：503(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3,5-two chloro-benzyls)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：556(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3,5-di-trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: DCE
MS(Cl)：622(M+H +)
Acetate 3-[6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-phenylester solvent: DCE
MS(Cl)：545(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-sulphonamide-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: DCE
MS(Cl)：566(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: 7: 3 THF: DCE59% productive rate
MS(Cl)：477(M+H +)
1H?NMR(300MHz，CDCl 3)δ3.79(s，2H)；3.58(s，2H)；2.82(m，2H)；2.74(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl isophthalic acid H-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE57% productive rate
MS(Cl)：490(M+H +)
1H?NMR(250MHz，CDCl 3)δ3.64(s，3H)；3.57(s，2H)；3.51(s，2H)；2.77(t，2H)；2.65(t，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-benzimidazolyl-2 radicals-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE83% productive rate
MS(Cl)：527(M+H +)
1H?NMR(250MHz，DMSO)δ3.89(s，2H)；3.58(s，2H)；2.76(m，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazol-4 yl methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE66% productive rate
MS(Cl)：477(M+H +)
1H?NMR(250MHz，DMSO)δ3.56(s，2H)；3.46(s，2H)；2.72(m，2H)；2.63(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiazol-2-yl methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: the DCE38% productive rate
MS(Cl)：494(M+H +)
1H?NMR(250MHz，DMSO)δ3.99(s，2H)；3.64(s，2H)；2.76(s，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-benzo [b] thiophene-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: DCE
MS(Cl)：557(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl isophthalic acid H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide solvent: 7: 3 THF: DCE72% productive rate
MS(Cl)：491(M+H +)
1H?NMR(300MHz，DMSO)δ3.66(s，2H)；3.63(s，3H)；2.47(s，2H)；2.70(m，2H)；2.62(m，2H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-3H-imidazol-4 yl methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: THF
MS(Cl)：491(M+H +)
4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1,2,4] triazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: EtOH; Temperature: 70 ℃ of 42% productive rate
MS(Cl)：478(M+H +)
1H?NMR(250MHz，CDCl 3)δ3.87(s，2H)；3.63(s，2H)，2.79(s，4H)。
4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-6-yl]-amide solvent: THF; Use 3 normal aldehyde
MS(Cl)：411(M+H +)
Embodiment 194
The preparation of the formula II compound of this embodiment explanation shown in flow process 2.Digital consistent in number in each title compound parenthesis and the flow process 2. A.2-(carboxyl-5-nitro-phenyl) dimethyl malonate (2)
(75g, 372mmol) solution in dimethyl malonate (900mL) is used nitrogen jet 15 minutes with 2-chloro-4-nitrobenzoic acid.Once add sodium methylate (48.3g, 894mmol), reactant heat release to 48 ℃.After 15 minutes, with cupric bromide (I) (4.5g, 37mmol) once add and with reactant 70 ℃ of heating 24 hours.But detect principal reaction by nmr and finished 70%, after 5 hours, 2-chloro-4-nitrobenzoic acid exhausts fully in the reactant 85 ℃ of heating.In cooled reactant, add entry (900mL), then add hexane (900mL).Water layer is told, added methyl (900mL), use diatomite filtration, divide water-yielding stratum.Fresh toluene (1800mL) is added water layer, and with the 6N HCl aqueous solution (90mL) acidifying two-phase mixture.White precipitate generates, and reaction mixture was stirred 18 hours, product is leached and drying, obtains white solid (78.1g, 70%), mp=153 ℃.
1H?NMR(CD 3) 2)SO?δ8.37(d，J＝2Hz，1H)，8.30(d，J＝1Hz，2H)，5.82(s，1H)，3.83(s，6H)。
13C?NMR(CD 3) 2)SO?δ168.0，167.3，149.4，137.1，135.8，132.5，125.4，123.7，54.5，53.4。
C 11H 10NO 8Analytical calculation value: C, 48.49; H, 3.73; N, 4.71.Measured value: C, 48.27; H, 3.72; N, 4.76. B.2-carboxymethyl-4-nitro-phenylformic acid (3)
(5g, 125mmol) (25.0g is 84mmol) in the solution in methyl alcohol (200mL) for the adding of the solution in water (200mL) 2-(carboxyl-5-nitro-phenyl) dimethyl malonate with sodium hydroxide.After 3 hours, reaction is finished, and vacuum is removed methyl alcohol, and reactant is cooled to 0 ℃ also with dense HCl (37mL) acidifying.With water layer ethyl acetate (200mL is 100mL then) extracting twice, with the organic layer dried over mgso that merges, vacuum is removed most of solvent, adds methylene dichloride (30mL) then.White solid is leached and drying, obtain 19.3g white solid product, mp=180-83 ℃.IR(KBr)3080，3055，2983，1707，1611，1585，1516，1491，1424，1358，1298，1237cm -1。
13C?NMR(CD 3) 2)SO?δ172.3，167.5，149.2，138.8，137.3，132.1，127.2，122.4，39.8。C 9H 17NO 6Analytical calculation value: C, 48.01; H, 3.13; N, 6.22.Measured value: C, 47.67; H, 3.19; N, 6.31. C.2-(2-methylol-5-nitro-phenyl)-ethanol (4)
(53.3mL 53.3mmol) handles 2-carboxymethyl-4-nitro-phenylcarbinol (3.0g, THF 13.3mmol) (60mL) solution with borine-THF title complex in 0 ℃ and 15 minutes.Reactant was stirred 18.5 hours, and (1: 1,30mL) quencher added entry (20mL) and liquid layer is separated with THF/ water.Water layer is extracted with THF (30mL) again, with the organic phase salt water washing that merges, use dried over mgso, solvent removed in vacuo obtains mp=79-81 ℃ of white solid product (2.05g, 78%).
IR(KBr)3277，3192，2964，2932，1614，1525，1507，1170，1134，1089，1067cm -1。
13C?NMR(CD 3) 2SO?δ149.1，146.6，139.2，127.8，124.3，121.3，61.2，60.6，34.9。
C 9H 11NO 4Analytical calculation value: C, 54.82; H, 5.62; N, 7.10.Measured value: C, 54.54; H, 5.49; N, 7.07. C ' .2-(2-methylol-5-nitro-phenyl)-ethanol (4), the selectivity method for making
With 2-carboxymethyl-4-nitro-phenylformic acid (13g, 57.7mmol), diacetyl oxide (5.45mL, 57.7mmol) and the mixture heating up of toluene (130mL) refluxed 5 hours.Solvent removed in vacuo obtains yellow solid shape 6-nitro-isochroman-1,3-diketone (compound 3 (a) in the flow process 2) (10.51g, 88%).To 6-nitro-isochroman-1, (2g 9.66mmol) drips borine tetrahydrofuran (THF) title complex (35.6mL, 1M is in THF) to the 3-diketone in the solution in THF (40mL) in 0 ℃ and 40 minutes.Reactant was stirred 18 hours at 25 ℃, be cooled to 0 ℃,, and stirred 1 hour with methyl alcohol (30mL) quencher.Solvent removed in vacuo adds ethanol ethyl ester (30mL) and washs organic phase with 10% aqueous hydrochloric acid.Acid water layer is extracted with ethyl acetate (30mL) again, and with the organic layer dried over mgso that merges, and vacuum-evaporation is to only surplus 2mL ethyl acetate.This solution through filtered through silica gel, is washed with methylene dichloride (30mL), to remove impurity.Silica gel is washed with ethyl acetate, and solvent removed in vacuo obtains a solid, with its pulping in methylene dichloride, filters, and obtains the white solid glycol, 1.38g, 73%. D.6-nitro-1,2,3,4-tetrahydroisoquinoline (5)
(0.9mL, (1.0g, 5.07mmol), (1.8mL is 12.91mmol) in the solution in methylene dichloride (20mL) for triethylamine 11.63mmol) to splash into 2-(2-methylol-5-nitro-phenyl)-ethanol with methylsulfonyl chloride in 10 minutes.After 30 minutes, the TLC demonstration reacts completely. 1H?NMR(CD 3Cl)δ8.17-11(m，2H)，7.65(d，J＝9Hz，1H)，5.36(s，2H)，4.49(t，J＝6Hz，2H)，3.25(t，J＝6Hz，2H)，3.08(s，3H)，3.98(s，3H)。With the reaction mixture 10%HCl aqueous solution, saturated sodium bicarbonate aqueous solution and salt water washing.With the organic layer dried over mgso, vacuum removes methylene dichloride and (3 * 100mL) wash with THF.Product 1.9g need not to be further purified and is directly used in the next step.At-78 ℃ ammonia (50mL) is added two methanesulfonates (1.9g) in the solution of THF (30mL).With warm 60 hours of 24 ℃ of reactants, to steam and remove ammonia, solvent removed in vacuo obtains crude product (786mg, 82%).Add toluene and also this solution is filtered with sulfonic acid magnesium, solvent removed in vacuo obtains 721mg (75%) amber oil.
1H?NMR(CDCl 3)δ7.97(s，1H)，7.95(d，J＝9Hz，1H)，7.15(d，J＝9Hz，1H)，4.07(s，2H)，3.15(t，J＝6Hz，2H)，2.89(t，J＝6Hz，2H)，1.98(bs，1H)。 E.6-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (6)
(1.44mL 6.26mmol) adds 6-nitro-1,2,3, and (840mg, 4.71mmol) (0.72mL is in the solution in methylene dichloride 5.17mmol) (17mL) containing triethylamine for the 4-tetrahydroisoquinoline with the BOC-acid anhydride.After 5 hours, add saturated sodium bicarbonate aqueous solution, separate two-phase, with the organic layer dried over mgso, solvent removed in vacuo obtains pale solid shape product (1.2g, 92%).mp＝138-41℃。
IR(KBr)3056，3018，2982，2935，1734，1684，1612，1522，1399，1236cm -1。 1H?NMR(CDCl 3)δ8.04(t，J＝5Hz，1H)，8.01(s，1H)，7.26(t，J＝5Hz，1H)，4.65(s，2H)，3.68(t，J＝6Hz，2H)，2.93(t，J＝6Hz，2H)，1.49(s，9H)。 F.6-amino-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid uncle-butyl ester (7)
(50% water-wet, 10mg) with the 6-nitro-3 among the THF (2mL), (82mg, 0.29mmol) hydrogenation is 5 hours for 4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate with 50%Pt-C under 50psi.Leach catalyzer, solvent removed in vacuo by silica gel chromatography, is used the ethyl acetate/hexane wash-out, obtains 42mg (57%) product.
IR(KBr)3005，2975，2928，1685，1627，1509，1423，1365，1166cm -1。
1H?NMR(CDCl 3)δ6.90(d，J＝6?Hz，1H)，6.56(d，J＝6Hz，1H)，6.48(s，1H)，4.47(s，2H)，3.60(m，J＝6Hz，4H)，2.73(t，J＝6Hz，2H)，1.49(s，9H)。
The product that the foregoing description 194 makes can by embodiment 1 disclosed method and 4 '-trifluoromethyl-xenyl-2-carboxylic acid reaction, obtain the Compound I I of N-protected, deprotection obtains Compound I I then.
Embodiment 195
The preparation of the formula II compound of this embodiment explanation shown in flow process 3.Digital consistent in number in the parenthesis and the flow process 3. A.4 '-trifluoromethyl-xenyl-2-formyl chloride
With 4 '-(trifluoromethyl)-2-biphenyl acid (9.08g, 34mmol), the vlil of thionyl chloride (12mL) and dimethyl formamide (0.05mL) 2 hours.By the NMR detection reaction fully after, by steaming except that thionyl chloride with toluene (56mL) displacement.Solvent removed in vacuo obtains white solid acyl chlorides (9.46g, 97%).
1H?NMR(CDCl 3)δ8.12(dd，J＝1Hz，J＝8Hz，1H)，7.70-7.37(m，7H)。 13C?NMR?CD 3Clδ(CO)168。 B.4 '-trifluoromethyl-xenyl-2-carboxylic acid-[3-(2-hydroxyethyl)-4-hydroxyl first Base-phenyl]-acid amides (10)
With Pt-C (50% water-wet, 200mg) add 2-(2-methylol-5-nitrophenyl)-ethanol (1.0g, THF 5mmol) (40mL) solution, and under 50psi with reactant hydrogenation 2 hours.The NMR demonstration reacts completely, and has generated 2-(5-amino-2-hydroxymethyl phenyl)-ethanol (compound in the flow process 3 (9));
1H?NMR(CD 3Cl)δ7.08(d，J＝2Hz，1H)，6.54-6.50(m，2H)，4.51(s，2H)，3.82(t，J＝6Hz，2H)，3.80-2.95(bs，4H)，2.84(t，J＝6Hz，2H)。
Filtration catalizer, add triethylamine (1.4mL, 10mmol), then in 1 hour, drip 4 '-trifluoromethyl-xenyl-2-formyl chloride (1.44g, THF 5mmol) (10mL) solution.Reactant was stirred 24 hours, and solvent removed in vacuo adds ethyl acetate (40mL).(dried over mgso is used in 2 * 40mL) washings, and solvent removed in vacuo is with toluene (3 * 40mL) flushings with the organic phase water.Except that after desolvating, obtain the 2.11g white solid, it was placed methylene dichloride (21mL) 18 hours again, leach product, drying obtains white solid title product 1.71g (81%).
1H?NMR(CD 3) 2SOδ10.22(s，1H)，7.73(d，J＝8Hz，2H)，7.62-28(m，8H)，7.20(d，J＝8Hz，1H)，4.96(bs，1H)，4.96(bs，1H)，4.43(s，2H)，3.51(t，J＝7Hz，2H)，2.67(t，J＝7Hz，2H)。
IR(KBr)3264，3232，31278，3124，3106，2956，2928，1649，1613，1533，1328，1129cm -1。
13C NMR (CD 3) 2SO δ (acid amides CO) 167.7, aliphatic carbons 62.3,61.1,36.0.C 23F 3H 20NO 3Analytical calculation value: C, 66.50; H, 4.85; N, 3.37.Measured value: C, 66.29; H, 4.79; N, 3.27. C.4 '-trifluoromethyl-xenyl-2-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-6 -yl)-acid amides (Compound I I)
Under 0 ℃, methylsulfonyl chloride (0.085 mL) added 4 '-(2,4mg is 0.51mmol) and in the solution of triethylamine (0.18mL) in THF (8.5mL) for trifluoromethyl-xenyl-2-carboxylic acid-[3-(2-hydroxyethyl)-4-hydroxymethyl phenyl]-acid amides.After 30 minutes, TLC demonstration reaction is finished.Reactant is cooled to-78 ℃ and add ammonia, then reactant was stirred 18 hours at 25 ℃.Solvent removed in vacuo adds the methylene dichloride and the 1NHCl aqueous solution, and reactant was stirred 1 hour.After being separated water is alkalized to PH12 with aqueous sodium hydroxide solution.(4 * 10mL) extractions, solvent removed in vacuo obtains the 108mg white solid, and it by the silica gel chromatography purifying, is used the 5% ethanol/methylene wash-out that contains 0.5% ammonium hydroxide with methylene dichloride with organic phase.Obtain white solid product (40mg, 20%).
1H?NMR(CDCl 3)δ7.76-6.83(m，11H)，3.89(s，2H)，3.52(d，J＝7Hz，0.5H)，3.04(t，J＝6Hz，2H)，2.74(m，0.5H)，2.66(t，J＝7?Hz，2H)，2.27(s，1H)。
13C NMR CD 3Cl δ (only aliphatic carbons) 47.8,43.6,29.1.
The method for making of the The compounds of this invention of embodiment 196-197 explanation shown in flow process 3.
Embodiment 196
4 '-(2-benzyl-1,2,3, the 4-tetrahydrochysene is different for trifluoromethyl-xenyl-2-carboxylic acid Quinoline-6-yl]-acid amides
Under 0 ℃, methylsulfonyl chloride (0.041mL) added 4 '-(100mg is 0.24mmol) and in the solution of triethylamine (0.084mL) in THF (2mL) for trifluoromethyl-xenyl-2-carboxylic acid-[3-(2-hydroxyl-ethyl)-4-methylol-phenyl]-acid amides.After 30 minutes, the TLC demonstration reacts completely.Add benzyl amine (0.132mL), reactant was stirred 18 hours at 25 ℃, and stirred 60 hours at 50 ℃.Solvent removed in vacuo, the damping fluid that residue is dissolved in methylene dichloride (15mL) and PH9 washs, and is separated, with the organic phase dried over mgso.Solvent removed in vacuo obtains white solid crude product (204mg), and it is placed CDCl again 3In, to filter, drying obtains white solid with product (46mg, 39%).mp＝230-32℃。
1H?NMR(CD 3) 2SOδ7.73(d，J＝8Hz，2H)，7.60-23(m，12H)，7.17(d，J＝8Hz，1H)，6.87(d，J＝8Hz，1H)，3.60(s，2H)，3.43(s，2H)，2.71(m，2H)，2.62(m，2H)。
C 30F 3H 25N 2O analytical calculation value: C, 74.06; H, 5.18; N, 5.76.Measured value: C, 74.08; H, 5.38; N, 5.76.
Embodiment 197 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-allyl group-1,2,3,4-tetrahydrochysene Isoquinoline 99.9-6-yl]-acid amides
At-20 ℃, with methylsulfonyl chloride (0.041mL, 0.53mmol) splash into triethylamine (0.084mL, 0.60mmol) and 4 '-trifluoromethyl-xenyl-2-carboxylic acid [3-(2-hydroxyethyl)-4-methylol-phenyl]-acid amides (0.1g, THF 0.24mmol) (2mL) solution.Be added dropwise to complete back 15 minutes, (0.09mL 1.2mmol), stirs reactant 18 hours at 25 ℃, stirs 70 hours at 60 ℃ then to add allyl amine.Solvent removed in vacuo adds methylene dichloride (10mL), with water (10mL) the washing organic phase of PH 12.Vacuum is removed organic solvent, obtains the 281mg crude product.It by the silica gel chromatography purifying, with 10% ethanol/methylene wash-out, is obtained white solid product (91mg, 87%).
1H?NMR(CDCl 3)δ7.80(d，J＝8Hz，1H)，7.68(d，J＝8Hz，2H)-7.60-7.42(m，5H)，6.93-6.83(m，3H)，6.00-5.86(m，1H)，5.27-5.17(m，2H)，3.55(s，2H)，3.15(d，J＝7Hz，2H)，2.83(t，J＝6Hz，2H)，2.69(t，J＝6Hz，2H)，1.66(bs，1H)。
13C NMR CD 3Cl δ (only aliphatic carbons) 61.4,55.6,50.3,29.1.

Claims (33)

1, acceptable salt on formula I compound and the pharmacology thereof: Wherein:
X is CH 2, CO, CS or SO 2
Y is selected from:
Direct key,
How can be by hydroxyl, C to aliphatics alkylene, this alkyl of 20 carbon atoms 1-C 10Alkoxyl group, C 1-C 10Acyl group, C 1-C 10Acyloxy or C 6-C 10The aryl list replaces,
NH and O, condition is if X is CH 2, then Y is direct key;
Z is selected from following group:
(1) H, halogen, cyano group,
(2) hydroxyl, C 1-C 10Alkoxyl group, C 1-C 10Alkylthio, C 1-C 10Acyl group, thienyl carbonyl, C 1-C 10Carbalkoxy,
(3) C 1-C 10Alkylamino, two C 1-C 10Alkylamino, C 6-C 10Aryl C 1-C 10Alkylamino, condition are that Y is not O or NH,
(4) unsubstituted vinyl, C 6-C 10Aryl, C 3-C 8Cycloalkyl or its condensed benzo derivative, C 7-C 10Multi-ring alkyl, C 4-C 8Cycloalkenyl group, C 7-C 10Many cycloalkenyl groups,
(5) C 6-C 10Aryloxy, C 6-C 10Arylthio, C 6-C 10Aryl C 1-C 10Alkoxyl group, C 6-C 10Aryl C 1-C 10Alkylthio, C 3-C 8Cycloalkyloxy, C 4-C 8Cyclenes oxygen base,
(6) be selected from the heterocyclic radical of monocycle base and fused polycycle base, wherein said group contains a total 5-14 annular atoms, wherein the ring hetero atom that adds up to 1-4 that is independently selected from oxygen, nitrogen and sulphur is arranged, each ring of described group can be respectively saturated, fractional saturation or fragrant
Condition is if X is CH 2, then Z is H or is selected from (4) and the group of (6),
Wherein, when Z contained one or more ring, described each ring can have 0-4 independently and be independently selected from following substituting group: halogen, hydroxyl, cyano group, nitro, oxo, sulfo-, amino-sulfonyl, phenyl, phenoxy group, thiophenyl, halogeno-benzene sulfenyl, benzyl, benzyloxy, C 1-C 10Alkyl, C 1-C 10Alkoxyl group, C 1-C 10Carbalkoxy, C 1-C 10Alkylthio, C 1-C 10Alkylamino, C 1-C 10Alkyl amino-carbonyl, two C 1-C 10Alkylamino, two C 1-C 10Alkyl amino-carbonyl, two C 1-C 10Alkylamino C 1-C 10Alkoxyl group, C 1-C 3Perfluoroalkyl, C 1-C 3Perfluoro alkoxy, C 1-C 10Acyl group, C 1-C 10Acyloxy, C 1-C 10Acyloxy C 1-C 10Alkyl and pyrrolidyl.
2, wherein according to the compound of claim 1 and pharmacy acceptable salt thereof
X is CH 2, CO or SO 2
Y is selected from:
Direct key, NH,
C 1-C 10Alkylidene group and C 2-C 10Alkenylene, in them any one all can be replaced by phenyl, and condition is if X is CH 2, then Y is direct key;
Z is selected from following group:
(1)H，
(2) C 1-C 10Alkoxyl group, C 1-C 10Alkylthio,
(3) C 1-C 10Alkylamino, two C 1-C 10Alkylamino, C 6-C 10Aryl C 1-C 10Alkylamino, condition are that Y is not NH,
(4) unsubstituted vinyl, C 6-C 10Aryl, C 3-C 8Cycloalkyl, C 4-C 8Cycloalkenyl group,
(5) C 6-C 10Aryloxy,
(6) be selected from saturatedly, 5 and 6 yuan the heterocyclic radical that part is undersaturated or fragrant, and condense benzo derivative, wherein said group can contain and add up to 1-3 ring hetero atom that is independently selected from oxygen, nitrogen and sulphur,
Condition is if X is CH 2, then Z is selected from the group of (4) and (6),
Wherein, when Z contained one or more ring, described each ring can have 0-3 independently and be independently selected from following substituting group: halogen, hydroxyl, nitro, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkyl amino-carbonyl, C 1-C 3Perfluoro alkoxy, C 1-C 10Acyl group and C 1-C 10Acyloxy.
3, according to the compound and the pharmacy acceptable salt thereof of claim 2, wherein X is a methylene radical, and Y is direct key, and Z is selected from C 6-C 10Aryl, C 3-C 8Cycloalkyl, C 4-C 8Cycloalkenyl group, each in them can have 0-3 independent substituent as claimed in claim 2.
4, according to the compound and the pharmacy acceptable salt thereof of claim 2, wherein X is methylene radical or CO, Y is direct key, and Z is thienyl, pyrrolidyl, pyrryl, furyl, thiazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, pyridyl, pyrimidyl and condensed-bicyclic ortho position benzo derivative thereof, each in them can have 0-3 independent substituent as claimed in claim 2.
5, wherein according to the compound of claim 2 and pharmacy acceptable salt thereof
X is CH 2Or CO;
Y is direct key;
Z is H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thienyl, 1,2,4-triazolyl, pyridyl and pyrimidyl.
6, according to the compound of claim 5, wherein X is CO.
7, according to the compound of claim 5, wherein X is CH 2
8, according to the compound of claim 1, wherein by 1,2,3 in the formula 1, the theheterocyclic nitrogen atom of 4-tetrahydroisoquinoline and in-XYZ, this XYZ partly is connected to the linking group that the group on the described theheterocyclic nitrogen atom forms and is selected from:
Figure C9610811300061
9, according to the compound of claim 8, wherein linking group is an acid amides.
10; compound according to claim 9; be selected from: 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenyl-ethanoyl-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-phenoxy group-ethanoyl-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pentanoyl-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-tetramethylene-carbonyl-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-butyryl radicals-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-oxyethyl group-ethanoyl-1; 2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid 2-[(4-fluoro-phenyl)-ethanoyl]-1,2; 3; 4-tetrahydroisoquinoline-6-yl }-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-methyl-butyryl radicals)-1,2; 3; 4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-fourth-3-enoyl--1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-methoxyl group-ethanoyl-1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-ethylmercapto group-ethanoyl-1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(6-diethyl-formamyl-hexamethylene-3-alkene carbonyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(ring penta-1-thiazolinyl-ethanoyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl }-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-oneself-3-enoyl--1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(tetrahydrofuran (THF)-3-carbonyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiene-3-yl--ethanoyl)-1,2; 3; 4-tetrahydroisoquinoline-6-yl)-acid amides and 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2; 3,4-tetrahydroisoquinoline-6-yl]-acid amides.
11, according to the compound of claim 8, wherein said linking group is a urea.
12, compound according to claim 11, be selected from: 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid phenyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid hexyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid benzyl acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-carboxylic acid [(R)-1-phenyl-ethyl]-acid amides, and 6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1 H-isoquinoline 99.9-2-pyridinecarboxylic acid-2-base acid amides.
13, according to the compound of claim 8, wherein said linking group is a sulphonamide.
14, according to the compound of claim 13, be selected from: 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(propane-2-alkylsulfonyl)-1,2; 3; 4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-dimethylamino alkylsulfonyl)-1,2; 3; 4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides and 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(2-trifluoromethoxy benzaldehyde alkylsulfonyl)-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
15, according to the compound of claim 8, wherein said linking group is a thiocarbamide.
16, according to the compound of claim 15, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-cyclopropyl thiocarbamoyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
17, according to the compound of claim 8, wherein said linking group is the N-alkyl.
18, compound according to claim 17, be selected from: 4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 6,6-trimethyl-cyclohex-2-en ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 4-two chloro-benzyls)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-[2-(1 for trifluoromethyl-xenyl-2-carboxylic acid, 5a, 6,9,9a, 9b-six hydrogen-4H-diphenylene-oxide-4a ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiophene-2-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-furans-2-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, acetate 5-{6-[(4 '-trifluoromethyl-xenyl-2-carbonyl acid)-and amino]-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl }-furans-2-ylmethyl ester, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiene-3-yl-methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-[2-(2 for trifluoromethyl-xenyl-2-carboxylic acid, 5-dimethoxy-tetrahydrofuran (THF)-3-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-quinoline-2-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyrimidine-2-base methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(3-nitrobenzyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl-pyrroles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-benzimidazolyl-2 radicals-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiazol-2-yl methyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1-methyl-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1.2.4] triazole-3-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides, with 4 '-trifluoromethyl-xenyl-2-carboxylic acid [(2-allyl group)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
19, according to the compound of claim 8, wherein said linking group is a carbamate.
20,, be 6-[(4 '-trifluoromethyl-xenyl-2-carboxyl according to the compound of claim 19)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid tertiary butyl ester.
21, according to the compound of claim 8, wherein said linking group is a thioamides.
22; compound according to claim 8; be selected from 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1; 2; 3; 4-tetrahydrochysene-isoquinoline 99.9-6-yl] acid amides, 6-[(4 '-trifluoromethyl-xenyl-2-carboxyl)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid ([R]-1-phenylethyl)-acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl] acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl] acid amides; 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-thiazol-2-yl methyl)-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl] acid amides; with 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1; 2,4] triazole-3-ylmethyl)-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9-6-yl] acid amides.
23, according to the compound of claim 22, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(thiophene-2-base-ethanoyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
24,, be 6-[(4 '-trifluoromethyl-xenyl-2-carboxyl according to the compound of claim 22)-amino]-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid (1-phenyl-ethyl)-acid amides.
25, according to the compound of claim 22, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-pyridine-2-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides.
26, according to the compound of claim 22, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-imidazoles-2-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
27, according to the compound of claim 22, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid (2-thiazol-2-yl methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides.
28, according to the compound of claim 22, be 4 '-trifluoromethyl-xenyl-2-carboxylic acid [2-(1H-[1,2,4] triazole-3-ylmethyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl]-acid amides.
29, a kind of pharmaceutical composition, it comprises formula 1 compound and the pharmaceutically acceptable carrier of claim 1 definition.
30, the formula I compound of claim 1 is selected from following disease in preparation treatment: atherosclerosis, pancreatitis, obesity, blood cholesterol is too high, blood triglyceride is too high, the medicine of hyperlipidemia and diabetes or reduce application in the medicine of apolipoproteins B secretion quantity in preparation.
31, according to the application of claim 30, wherein said disease is selected from atherosclerosis, pancreatitis, obesity and diabetes.
32, according to the application of claim 31, wherein said disease is selected from atherosclerosis.
33, be selected from following compound:
4 '-trifluoromethyl-xenyl-2-carboxylic acid (1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-yl)-acid amides
4 '-trifluoromethyl-xenyl-2-carboxylic acid [3-(2-hydroxyethyl)-4-methylol-phenyl]-acid amides
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CA002223574A CA2223574C (en) 1995-06-07 1995-06-07 Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivatives, their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein b (apo b) secretion
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EP0106140A2 (en) * 1982-09-10 1984-04-25 The Wellcome Foundation Limited Benzoic acid derivatives
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