CN1449380A - Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors - Google Patents

Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors Download PDF

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CN1449380A
CN1449380A CN01814846A CN01814846A CN1449380A CN 1449380 A CN1449380 A CN 1449380A CN 01814846 A CN01814846 A CN 01814846A CN 01814846 A CN01814846 A CN 01814846A CN 1449380 A CN1449380 A CN 1449380A
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compound
methyl
formula
solvate
acceptable salt
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M·D·亚当
M·D·安德鲁斯
M·L·埃里奥特
G·E·吉默
D·赫普沃斯
H·R·小霍华德
D·S·米德尔顿
A·斯托比
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SmithKline Beecham Ltd
Pfizer Ltd
Pfizer Inc
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SmithKline Beecham Ltd
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Priority claimed from GB0021593A external-priority patent/GB0021593D0/en
Priority claimed from GB0107116A external-priority patent/GB0107116D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1449380A publication Critical patent/CN1449380A/en
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Abstract

A compound of general formula (I) wherein R<1> and R<2> are H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0, 1, 2 or 3; or R<1> and R<2> together with the nitrogen to which they are attached from an azetidine ring; Z or Y is -SR<3> and the other Z or Y is halogen or -R<3>; wherein R<3> is C1-C4 alkyl optionally substituted with fluorine; except that R<3> is not CF3; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; R<4> and R<5>, which may be the same or different, are: A-X, wherein A = -CH=CH- or -(CH2)p- where p is 0, 1 or 2; X is hydrogen, F, CI, Br, I, CONR<6>R<7>, SO2NR<6>R<7>, SO2NHC(=O)R<6>, OH, C1-4alkoxy, NR<8>SO2R<9>, NO2, NR<6>R<11>, CN, CO2R<10>, CHO, SR<10>, S(O)R<9> or SO2R<10>; or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally substituted independently by one or more R<13>; wherein R<13> is hydroxy, C1-C4alkoxy, F, C1-C6alkyl, haloalkyl, haloalkoxy, -NH2, NH(C1-C6alkyl) or -N(C1-C6alkyl)2. The compounds of general formula (I) inhibit monoamine reuptake and in particular exhibit activity as selective serotonin reuptake inhibitors.

Description

Phenoxybenzylamine derivatives as selective serotonin reuptake inhibitor
The present invention relates to novel diphenyl ether compound, they suppress monoamine-reuptake.Definitely, the activity of compound performance selective serotonin reuptake inhibitor of the present invention (SSRIs) therefore has practicality in various treatments field.Compound particularly of the present invention can be used for treatment or prevents various obstacles, comprise those that wherein involve monoamine transporter function regulating effect, for example obstacle and sexual dysfunction (comprising premature ejaculation) due to depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material the invention still further relates to the pharmaceutical preparation that contains this compounds.
According to first aspect, the invention provides general formula (I) compound, its pharmacy acceptable salt, solvate or polymorphic form:
Wherein:
R 1And R 2Can be identical or different, be H, C 1-C 6Alkyl or (CH 2) d(C 3-C 6Cycloalkyl), d=0,1,2 or 3 wherein; Perhaps R 1And R 2Constitute the azetidine ring with the nitrogen that they connected;
Z or Y are-SR 3, another Z or Y be halogen or-R 3R wherein 3Be the optional C that is replaced by fluorine independently 1-C 4Alkyl; But R 3Not CF 3
Perhaps Z is to be connected like this with Y, atom with interconnection, Z and Y constitute condensed 5 to 7 yuan of carbocyclic rings or heterocycles, it can be saturated, undersaturated or aromatics, wherein when Z and Y formation heterocycle, except carbon atom, contain the heteroatoms that one or two independently is selected from oxygen, sulphur and nitrogen in the key; If its condition is R 5Be fluorine, R 2Be methyl, then fused rings is not 1, and 3-dioxolane, Z and Y do not constitute the condensed benzyl ring together;
R 4And R 5Can be identical or different, be:
A-X, wherein A=-CH=CH-or-(CH 2) p-, wherein p is 0,1 or 2; X is hydrogen, F, Cl, Br, I, CONR 6R 7, SO 2NR 6R 7, SO 2NHC (=O) R 6, OH, C 1-C 4Alkoxyl group, NR 8SO 2R 9, NO 2, NR 6R 11, CN, CO 2R 10, CHO, SR 10, S (O) R 9Or SO 2R 10R 6, R 7, R 8And R 10Can be identical or different, be that hydrogen or optional independence are by one or more R 12The C that replaces 1-6Alkyl; R 9Be that optional independence is by one or more R 12The C that replaces 1-6Alkyl; R 11Be that hydrogen, optional independence are by one or more R 12The C that replaces 1-6Alkyl, C (O) R 6, CO 2R 9, C (O) NHR 6Or SO 2NR 6R 7R 12Be F (preferably at the most 3), OH, CO 2H, C 3-6Cycloalkyl, NH 2, CONH 2, C 1-6Alkoxyl group, C 1-6Carbalkoxy or 5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O, and optional independence is by one or more R 13Replace; Perhaps R 6And R 7Constitute optional independence by one or more R with the nitrogen that they connected 134,5 or 6 yuan of heterocycles that replace; Perhaps
5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O, and optional independence is by one or more R 13Replace;
R wherein 13Be hydroxyl, C 1-4Alkoxyl group, F, C 1-6Alkyl, haloalkyl, halogenated alkoxy ,-NH 2,-NH (C 1-6Alkyl) or-N (C 1-6Alkyl) 2
Unless indication is arranged in addition, any alkyl can be a straight or branched, is 1 to 6 carbon atom, preferred 1 to 4,1 to 3 carbon atom particularly.
Unless indication is arranged in addition, any carbon ring group contains 3 to 8 annular atomses, can be saturated, undersaturated or aromatics.Preferred saturated carbon ring group is cyclopropyl, cyclopentyl or cyclohexyl.Preferred unsaturated carbon cyclic group contains 3 two keys at the most.Preferred aromatic carbocyclic group is a phenyl.The term carbocyclic ring should be done similar explanation.What in addition, the term carbocyclic ring comprised carbon ring group condenses combination, for example naphthyl, phenanthryl, dihydro indenyl and indenyl arbitrarily.
Unless indication is arranged in addition, any heterocyclic group contains 5 to 7 annular atomses, wherein at the most 4 can be heteroatoms, for example nitrogen, oxygen and sulphur can be saturated, undersaturated or aromatics.The example of heterocyclic group is a furyl, thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, dioxolanyl oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyranyl, pyridyl, piperidyl alkyl dioxin, the morpholino base, the dithiane base, thiomorpholine is for base, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, the tetramethylene sulfone base, tetrazyl, triazinyl, the azatropylidene base, oxygen azatropylidene base, sulphur azatropylidene base, diaza base and thiazolinyl.In addition, the term heterocycle comprises the condensed heterocycle group, for example benzimidazolyl-, benzoxazolyl, imidazopyridyl, benzoxazinyl, benzothiazine Ji, oxazole and pyridyl, benzofuryl, quinolyl, quinazolyl, quinoxalinyl, dihydroquinazoline base, benzothiazolyl, phthaloyl imino, benzofuryl, benzodiazepine base, indyl and pseudoindoyl.The term heterocycle should be done similar explanation.
Halogen is represented fluorine, chlorine, bromine or iodine.
Preferably, R 1And R 2Can be identical or different, be hydrogen or C 1-C 6Alkyl, more preferably hydrogen or methyl.
When Z or Y are-SR 3The time, R 3Be preferably methyl or ethyl.
When Z and Y formation condensed ring, this ring is preferably heterocycle.More preferably, contain one or two sulphur atom in the key.
Preferably, R 4And R 5Not all be hydrogen.
Preferably, R 4And R 5Can be identical or different, be
-(CH 2) p-X, wherein p is 0,1 or 2 (being preferably 0 or 1); X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7, NR 8SO 2R 9, SR 10, SOR 9Or SO 2R 10, R wherein 6, R 7, R 8, R 9And R 10Be defined, perhaps as first aspect
5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms (You Xuan Wei oxadiazole base, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl or pyrimidyl) that is selected from N, S and O.
More preferably, R 4And R 5Can be identical or different, be
-(CH 2) p-X, wherein p is 0 or 1; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7Or NR 8SO 2R 9R wherein 6And R 7Can be identical or different, be hydrogen or optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl; R 8Be hydrogen, hydroxyethyl or methyl; Or R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl; Perhaps
Triazolyl, imidazolyl or pyrazolyl.
And then more preferably, R 4Be hydrogen.
Preferably, R 6And R 7Can be identical or different, be hydrogen, optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl.More preferably, R 6And R 7Can be identical or different, be hydrogen or methyl, and then hydrogen more preferably.
When existing, R 12You selects Di Shi oxadiazole base, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl or pyrimidyl.More preferably triazolyl, imidazolyl or pyrazolyl.
At R 6And R 7Constitute under the heterocyclic situation with the nitrogen that they connected, preferred ring is tetramethyleneimine or piperidine ring, separately can be by OH or CONH 2Replace, or the morpholine ring, can be by CONH 2Replace.
Preferably, R 11Be hydrogen or C 1-6Alkyl.
Preferably, R 8Be hydrogen, hydroxyethyl or methyl, more preferably hydrogen.
Preferably, R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl, more preferably methyl or ethyl (being preferably methyl).
Preferably, R 10Be methyl or ethyl.
Preferably, p is 1 or 0, more preferably 0.
Preferably,
R 1And R 2Can be identical or different, be hydrogen or methyl;
When existing, R 3Be methyl or ethyl; Perhaps Z is to be connected like this with Y, atom with interconnection, Z and Y constitute condensed 5 to 7 yuan of carbocyclic rings or heterocycles, it can be saturated, undersaturated or aromatics, wherein when Z and Y formation heterocycle, except carbon atom, contain the heteroatoms that one or two independently is selected from oxygen, sulphur and nitrogen in the key; And
R 4And R 5Can be identical or different, be:
-(CH 2) p-X, wherein p is 0 or 1; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7, NR 8SO 2R 9, SR 10, SOR 9Or SO 2R 10R wherein 6And R 7Can be identical or different, be hydrogen, optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl; Perhaps R 6And R 7Can constitute morpholine, tetramethyleneimine or piperidine ring with the nitrogen that they connected, separately can be by OH or CONH 2Replace; R 8Be hydrogen, hydroxyethyl or methyl (being preferably hydrogen); R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl; R 10Be methyl or ethyl; Perhaps
Oxadiazole base, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl or pyrimidyl.
More preferably,
R 1And R 2Can be identical or different, be hydrogen or methyl;
When existing, R 3Be methyl or ethyl; Perhaps Z is to be connected like this with Y, and with the atom of interconnection, Z and Y constitute 5 to 7 yuan of heterocycles of condensed, contain 1 or 2 sulphur atom; And
R 4And R 5Can be identical or different, be:
-(CH 2) p-X, wherein p is 0 or 1; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7Or NR 8SO 2R 9R wherein 6And R 7Can be identical or different, be hydrogen, optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl; R 8Be hydrogen, hydroxyethyl or methyl; R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl; Perhaps
Triazolyl, imidazolyl or pyrazolyl.
And then more preferably,
R 1And R 2Can be identical or different, be hydrogen or methyl;
When existing, R 3Be methyl or ethyl; Perhaps Z is to be connected like this with Y, and with the atom of interconnection, Z and Y constitute saturated 5 to the 7 yuan of heterocycles of condensed, contain 1 or 2 sulphur atom;
R 4Be hydrogen; And
R 5Be:
-(CH 2) p-X, wherein p is 0 or 1; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7Or NR 8SO 2R 9R wherein 6And R 7Can be identical or different, be hydrogen, optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl; R 8Be hydrogen, hydroxyethyl or methyl; R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl; Perhaps
Triazolyl, imidazolyl or pyrazolyl.
And then more preferably, R 4And R 5Not all be hydrogen.
Preferred compound is:
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(methylamino-) methyl]-benzsulfamide (embodiment 2);
The 3-[(dimethylamino) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group]-benzsulfamide (embodiment 12);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(dimethylamino) methyl]-benzsulfamide (embodiment 16);
4-[3-chloro-4-(methylthio group) phenoxy group]-the 3-[(dimethylamino) methyl]-benzsulfamide (embodiment 17);
The 3-[(dimethylamino) methyl]-4-[3-fluoro-4-(methylthio group) phenoxy group]-benzsulfamide (embodiment 18);
N, N-dimethyl-N-[2-(6-quinoline oxy) benzyl] amine (embodiment 29);
The 3-[(methylamino-) methyl]-4-(6-quinoline oxy) benzsulfamide (embodiment 35);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(methylamino-) methyl] benzamide (embodiment 60);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-N-methyl-3-[(methylamino-) methyl]-benzamide (embodiment 62);
The N-{3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] benzyl } Toluidrin (embodiment 75);
The 3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] benzamide (embodiment 79);
4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen base)-3-[(dimethylamino) methyl] benzamide (embodiment 88);
The 3-[(dimethylamino) methyl]-4-[3-fluoro-4-(methylthio group) phenoxy group] phenyl]-methyl alcohol (embodiment 90);
The 3-[(dimethylamino) methyl]-4-(6-quinoline oxy) benzamide (embodiment 100);
The 3-[(methylamino-) methyl]-4-(6-quinoline oxy) benzamide (embodiment 102);
N-methyl-N-{3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] phenyl } Toluidrin (embodiment 116); With
N-{4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen base)-3-[(dimethylamino) methyl] phenyl }-Toluidrin (embodiment 124).
According to second aspect, the invention provides formula (I) or (XIX) compound and pharmacy acceptable salt or solvate:
Figure A0181484600171
(in this respect): R wherein 1And R 2Represent H, C independently 1-C 6Alkyl or (CH 2) d(C 3-C 6Cycloalkyl), d=0,1,2 or 3 wherein, perhaps NR wherein 1R 2As interval scale 4 yuan of rings, the wherein R of connecting together 1And R 2Represent C together 3Alkyl; Z and Y be representative-SR independently 3, wherein if Z=-SR 3, then the Y=halogen ,-OR a,-R aOr-SR aPerhaps if Y=-SR 3, then the Z=halogen ,-OR a,-R aOr-SR aR 3And R aRepresent C independently 1-C 4Alkyl (replaced by fluorine atom alternatively, for example-CF 3); Perhaps Z and Y can represent 5 to 7 yuan of rings of condensed of being set forth as general formula X IX when connecting together, wherein said 5 to 7 yuan of rings can be saturated, undersaturated or aromatics, wherein said 5 to 7 yuan of rings can contain one or more heteroatoms P and Q alternatively, wherein P and Q can be O, S or N independently, and wherein E, F or G represent CH or CH independently 2, wherein k and p can be 0,1,2 or 3 independently, m=1,2 or 3; And
Figure A0181484600172
R 4And R 5Represent A-X independently, wherein A=-(CH 2) n-, wherein n represents 0,1 or 2, and wherein X represents H, F, Cl, Br, I, CONR 6R 7Or SO 2NR 6R 7, OH, NR 8SO 2R 9, NO 2, NR 6R 11, CN, CO 2R 10, CHO, S (O) mR 10, wherein m=0,1 or 2, wherein R 6, R 7, R 8And R 10Represent H or C independently 1-6Alkyl, wherein R 9Represent C 1-8Alkyl, R 11Represent H, C 1-6Alkyl, C (O) R 6, CO 2R 9, C (O) NHR 6Or SO 2NR 6R 6, wherein said C 1-6Alkyl is replaced by one or more groups alternatively, and substituting group is selected from OH, CO 2H, C 3-6Cycloalkyl, NH 2, CONH 2, C 1-6Alkoxyl group, C 1-6Carbalkoxy and 5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O; Perhaps its condition is as if P=Q=oxygen, and then k and p not all are zero; Its condition is that Z and Y do not constitute the condensed benzyl ring together; R 4Or R 5Can represent 5 or 6 yuan of heterocycles, contain 1,2 or 3 heteroatoms that is selected from N, S and O; In addition, R 6And R 7Can represent with the N atom that they connected can optional substituted 5 or 6 yuan of heterocycles; And pharmacy acceptable salt or solvate, its condition is R 4And R 5Not all be H.
For fear of query, unless indication is arranged in addition, term " replacement " expression is replaced by one or more defined groups.Group therein can be selected under the situation of a large amount of alternative groups, and selected group can be identical or different.
For fear of query, term " independently " expression, when an above substituting group was selected from possible in a large number substituting group, these substituting groups can be identical or different.
According to the third aspect, the invention provides compound of Formula I and pharmacy acceptable salt thereof, wherein R 1, R 2, R 3, Z and Y be defined as first aspect; R 4And R 5Can be identical or different, be-(CH 2) p-A ', wherein p is 0,1 or 2, A ' is a polar group.In this respect, polar group can be defined as having negative π value those (referring to C Hahsch and A Leo, " Substituent Constants for Correlation Analysis inChemistry and Biology ", Wiley, New York, 1979).In this system, for example the π value of H is 0.00 ,-OCH 3The π value be-0.02 ,-SO 2NH 2The π value be-1.82 (referring to Table VI-I, " Well-Characterized AromaticSubstituents ", p 49, ibid).Preferred polar group has more negative π value; Thereby preferred group has the more negative π value in ratio-0.1, and is more preferably more negative than-0.5, most preferably more negative than-1.0.And then when the p in the above-mentioned definition was not zero, the definition of A ' was based on above-mentioned standard (is zero as p).
Unless indication is arranged in addition, the compound of first, second and the third aspect is hereinafter referred to as compound of the present invention.
The advantage of The compounds of this invention is that they are serotonin reuptake transporter selective depressant (SRIs) (therefore may reduce side effect), their rapid-action (they are suitable in the administration not long ago of needs drug effect), they have desirable effectiveness and relevant character.Selectivity suppresses serotonin but not the compound of the re-uptake of norepinephrine or Dopamine HCL is preferred.
We have found that the formula I compound with these character is at R 4/ R 5On have relative polarity group.
Contain basic center formula I compound pharmaceutically or the animal doctor go up the nontoxic acid salt that acceptable salt for example is and mineral acid, carboxylic acid or organic sulfonic acid generate, mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid for example.Example comprises HCl, HBr, HI, vitriol or hydrosulfate, nitrate, phosphoric acid salt or hydrophosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactic acid salt, Citrate trianion, tartrate, gluconate, camsilate, mesylate, esilate, benzene sulfonate, tosilate and pamoate.The compounds of this invention can also provide pharmaceutically with alkali or the animal doctor goes up acceptable metal-salt, definitely is nontoxic basic metal and alkaline earth salt.Example comprises sodium, potassium, aluminium, calcium, magnesium, zinc, glycol amine, hydramine, quadrol, Trometamol, choline (chloine), meglumine (megulamine) and diethanolamine salt.About the comment of the drug salts that is fit to, referring to Berge etc., J.Pharm.Sci., 66,1-19,1977; P L Gould, InternationalJournal of Pharmaceutics, 33 (1986), 201-217; Bighley etc., Encyclopedia of Pharmaceutical Technology, Marcel DekkerInc, New York 1996, Vol.13, p.453-497.
Below, all be called " compound of the present invention " at the defined compound of any aspect of the present invention, their pharmacy acceptable salt, their solvate and polymorphic form (except the midbody compound in the chemical process).
The pharmaceutically acceptable solvate of The compounds of this invention comprises its hydrate.
The compounds of this invention can have one or more chiral centres, therefore has a large amount of stereoisomeric forms in any ratio.All steric isomers and composition thereof all comprise within the scope of the invention.Utilize method known to those skilled in the art, racemic compound both can utilize preparation HPLC to be separated with the pillar with chiral stationary phase, also can split, and obtained one enantiomorph.In addition, the chiral intermediate compound can be used to prepare chipal compounds of the present invention by fractionation.
Under the situation that The compounds of this invention exists with E and Z isomer, the present invention includes one isomer and composition thereof.
Under the situation that The compounds of this invention exists with tautomer, the present invention includes one tautomer and composition thereof.
Under the situation that The compounds of this invention exists with optically active isomer, the present invention includes one isomer and composition thereof.
Under the situation that The compounds of this invention exists with diastereomer, the present invention includes one diastereomer and composition thereof.
Diastereomer or E can realize for example fractional crystallization, chromatogram or H.P.L.C. by common process with separating of Z isomer.The single enantiomorph of The compounds of this invention can prepare like this, from the pure intermediate of the optically-active of correspondence, perhaps utilize the chiral support that is fit to split, the H.P.L.C. of Dui Ying racemoid for example, the racemoid of perhaps fractional crystallization correspondence take the circumstances into consideration and the optically active acid that is fit to or the reaction gained diastereo-isomerism salt of alkali.
Can there be one or more change forms in The compounds of this invention.All tautomers and composition thereof all comprise within the scope of the invention.For example the claim of 2 hydroxy pyrimidine base also will cover its change form α-pyriconyl.
To be by what those skilled in the art figured out; some protected derivative of the The compounds of this invention that can prepare before final going protected itself may not have pharmacologically active; but can be generated the The compounds of this invention of pharmacologically active afterwards in vivo by metabolism by oral or administered parenterally in some cases.Therefore this analog derivative can be described to " prodrug ".And then some The compounds of this invention can serve as the prodrug of other The compounds of this invention.
Protected derivative of all of The compounds of this invention and prodrug all comprise within the scope of the invention.The case description of prodrug that is suitable for The compounds of this invention is at Drugs ofToday, Vol.19, No.9,1983, pp 499-538; Topics in Chemistry, Chapt.31, pp 306-316; " Design of Prodrugs ", H.Bundgaard, Elsevier, 1985, Chapt.1 (disclosure of these documents is quoted at this as a reference).
Further will be by what those skilled in the art figured out, some part is " precursor portions " well known by persons skilled in the art, for example H.Bundgaard is (disclosure of the document is quoted at this as a reference) described in " Design of Prodrugs ", they can be endowed suitable functionality, when this class functionality is present in the The compounds of this invention.
The prodrug of preferred The compounds of this invention comprises: ester, carbonic ether, half ester, phosphoric acid ester, nitro ester, sulfuric ester, sulfoxide, acid amides, carbamate, azo-compound, phosphamide, glycosides, ether, acetal and ketal.
The present invention also comprises all isotopic variations that are fit to of The compounds of this invention.It is identical but atomic mass is different from the displaced kind of atom of the common atomic mass of nature by atomicity that isotopic variations is defined as at least one atom.Can be combined in isotropic substance example in the The compounds of this invention and comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively for example 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl.Some isotopic variations of the present invention, for example combine radio isotope, for example 3H or 14Those of C can be used for medicine and/or the research of substrate tissue distribution.Tritiate, promptly 3H and carbon-14, promptly 14The C isotropic substance is particularly preferred, because they are easy to preparation and detect.And then, with deuterium, promptly 2Isotropic substances such as H replace, and the advantage in some treatment can be provided because of metabolic stability is higher, and for example therefore transformation period or minimizing dosage demand in the extension body may be preferred in some cases.The isotopic variations of The compounds of this invention generally can utilize the suitable isotopic variations that is fit to reagent to be prepared for example described method of the following example and preparation example or preparation by common process.
The compounds of this invention can be by various known way preparations.At following reaction process and hereinafter, unless otherwise prescribed, R 1To R 13, Z and Y be defined as first aspect.These methods constitute others of the present invention.
The general formula that spreads all over this specification sheets is with appointments such as Roman number I, II, III, IV.The subclass of these general formulas is defined as Ia, Ib, Ic etc.. IVa, IVb, IVc etc.
General formula (I) compound can prepare like this, from formula (II) compound, with general formula HNR 1R 2The amine reaction is perhaps with its salt form that is fit to reaction, and with hydride reducer reaction (referring to flow process 1) in the solvent that is fit to.Work as R 1Or R 2When being hydrogen, suitable solvent comprises protonic solvent, ethanol for example, and sodium borohydride is suitable reductive agent, for example this paper embodiment 36 is described.Work as R 1Or R 2When being not hydrogen, tetrahydrofuran (THF)/methylene dichloride is the solvent systems that is fit to, and sodium triacetoxy borohydride is the reductive agent that is fit to.In this class reaction, HNR 1R 2The use of salt form, for example hydrochloride is preferred, and can add complementary alkali alternatively, helps HNR 1R 2The dissolving of salt, for example triethylamine, and adding acetate, for example this paper embodiment 25 is described.
Flow process 1
Formula (II) compound can prepare then like this, coupling general formula (IV) compound and general formula (III) aldehyde cpd, wherein L is the leavings group that is fit to, for example halogen (F, Cl, Br or I) or sulphonate, for example triflate or methanesulfonates, preferably, L is that F or this class linked reaction of Cl. can utilize technology known in the art to finish, for example react with salt of wormwood, in the solvent that is fit to, dimethyl formamide for example is under appropriate reaction conditions, for example in temperature of Ti Gaoing and the inert atmosphere.
Thereby according to yet another aspect, the invention provides from the method for general formula (II) compound general formula (I) compound.
Select R as an alternative 4And/or R 5Can after the ether coupling, be introduced into (referring to flow process 2).General formula (I) compound can prepare like this, from general formula (Ia) compound, and R wherein just 4And R 5It is general formula (I) compound of hydrogen.General formula (Ia) compound can be from (IIa) preparation, and mode is similar to from (II) preparation (I) (referring to flow process 1), and general formula (IIa) compound can be from (IV) and (IIIa) preparation, and mode is similar to the preparation (referring to flow process 1) of (II).
Flow process 2
Thereby according to yet another aspect, the invention provides from the method for general formula (Ia) compound general formula (I) compound.
Introduce R to formula (Ia) compound 4And/or R 5Method comprise:
I) if R 4/ R 5Be halogen, (Ia) and the halogenating agent that is fit to are reacted in inert solvent, this solvent can influence reaction sharply.The halogenating agent that is fit to comprises trifluoromethanesulfonic acid and N-iodine succinimide, and suitable inert solvent comprises methylene dichloride.
Ii) if R 4/ R 5Be-NO 2, then making (Ia) and the nitrating agent that is fit to, the reaction of for example base metal nitrate, this solvent can influence reaction sharply, and temperature is a room temperature or following.The nitrating agent that is fit to comprises trifluoromethanesulfonic acid/saltpetre, and suitable solvent comprises trifluoroacetic acid.
Iii) if R 4/ R 5Be-SO 2NR 6R 7, then make intermediate sulfonyl chloride and essential formula HNR 6R 7Amine reacts in the solvent that is fit to.The solvent that is fit to comprises the mixture of water and methylene dichloride, and reacting generally is to carry out under room temperature or following temperature.Intermediate sulfonyl chloride can prepare like this, from formula (Ia) compound, react under cold condition with chlorsulfonic acid, existence can influence the solvent of reaction sharply, in solvent, handle or need not handle subsequently with chlorizating agent, for example phosphoryl chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, described solvent can influence reaction sharply.Be fit to comprise trifluoroacetic acid with the solvent of chlorsulfonic acid reaction, typical temperature of reaction is 0 ℃.Be fit to comprise acetonitrile that suitable condition is included in and refluxes down, as described in this paper embodiment 12 with the solvent of chlorination reaction.
For example, R wherein 5Be-SO 2NR 6R 7Formula (Iq) compound can prepare like this, via intermediate sulfonyl chloride (XVIII), from formula (Ia) compound, react with chlorsulfonic acid, handle or need not handle with chlorizating agent subsequently, for example phosphoryl chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride are then with HNR 6R 7Reaction (referring to flow process 2a).Reaction conditions comprises low temperature usually.Reaction can be carried out purely, does not just have the existence of solvent, and perhaps in the presence of inert solvent, inert solvent can influence reaction sharply.Can be with intermediate sulfonyl chloride (XVII) separation, purifying, then with HNR 6R 7Reaction selects it to generate on the spot as an alternative, need not separate, then with HNR 6R 7Reaction.
Flow process 2a
Figure A0181484600241
Thereby according to yet another aspect, the invention provides from the method for general formula (II) compound general formula (I) compound.In preferred embodiment, provide the method for preparation formula (Iq) compound: formula (Ia) compound is reacted with chlorsulfonic acid in the solvent that is fit to, handle or need not handle with chlorizating agent subsequently, for example phosphoryl chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, obtain formula (XVIII) compound, then with HNR 6R 7Reaction obtains formula (Iq) compound.Preferably, formula (XVIII) compound generates on the spot, need not separate to get final product and HNR 6R 7Reaction.
Select as an alternative, have specific R 4/ R 5Substituent general formula (I) compound can utilize already known processes to be converted into other formulas (I) compound.For example:
I) if R 4/ R 5Be halogen, for example chlorine, bromine or iodine, then it can be converted into cyano group via the reaction with cyanide salt, is reflected at Pd (O) or (II) under the existence of catalyzer, in high boiling solvent, at high temperature carries out.The Pd catalyzer that is fit to comprises four (triphenyl phosphine) palladium, and suitable cyanide salt comprises Zn (CN) 2, the high boiling solvent that is fit to can influence reaction sharply, comprises dimethyl formamide, and for example this paper embodiment 78 is described;
Ii) if R 4/ R 5Be halogen, for example chlorine, bromine or iodine, then it can be handled with carbon monoxide and be converted into corresponding ester-CO 2R, the reaction under high pressure, Pd (O) or (II) catalyzer in the presence of, (ROH, wherein R is C at alcoholic solvent 1-C 4Alkyl) in, in the presence of alkali, at high temperature carries out.For example, reaction can be carried out under the pressure of about 100p.s.i., and the Pd catalyzer that is fit to comprises two (triphenyl phosphine) palladiums (II) of dichloro, and the alkali that is fit to comprises triethylamine, and suitable alcoholic solvent comprises methyl alcohol, and for example this paper preparation example 50 is described;
Iii) if R 4/ R 5Be nitro, then it can be handled via reductive agent and is reduced to corresponding-NH 2Group is reflected in the protonic solvent, carries out under room temperature or above temperature.The reductive agent that is fit to comprises iron powder/calcium chloride, and suitable protonic solvent comprises aqueous ethanolic solution, and typical temperature of reaction is from about 70 ℃ to about 100 ℃, and preferred about 90 ℃, for example this paper embodiment 103 is described;
Iv) if R 4/ R 5Be-NH 2, then it can be by being converted into corresponding-NHSO with the reaction of sulfonyl agent 2R 9Group is reflected under the existence of alkali, can influence in the inert solvent of reaction sharply, carries out under room temperature or following temperature.The sulfonyl agent that is fit to comprises methylsulfonyl chloride, and suitable alkali comprises triethylamine, and suitable inert solvent comprises methylene dichloride, and for example this paper embodiment 128 is described;
V) if R 4/ R 5Be-NHSO 2R 9Group, then it can be converted into corresponding-NR via alkylating agent and alkaline purification 8SO 2R 9Group is reflected in the suitable inert solvent and carries out.The example of the alkylating agent that is fit to comprises methyl-iodide, and suitable alkali comprises salt of wormwood, and suitable inert solvent comprises acetonitrile, and for example this paper preparation example 88 is described;
Vi) if R 4/ R 5Be nitrile-CN, then it can be converted into corresponding-C (O) NH by the hydrolytic action under alkalescence, oxidisability or acidic conditions 2Group.Alkaline hydrolysis preferably utilizes hydroxide salt to carry out, and for example potassium hydroxide is reflected in the protonic solvent, and for example the trimethyl carbinol at high temperature carries out, and for example this paper embodiment 79 is described;
Vii) if R 4/ R 5Be ester-CO 2R, then it can be handled via hydride reducer and be converted into corresponding alcohol radical-CH 2OH, reductive agent is lithium aluminium hydride for example, and for example this paper preparation example 69 is described;
Viii) if R 4/ R 5Be ester-CO 2R, then it can be converted into corresponding acid-CO by handling with the hydroxide salt that is fit to 2H, be reflected at water and the existence of the solubility promoter that is fit under carry out.The hydroxide salt that is fit to comprises lithium hydroxide, and suitable solubility promoter comprises tetrahydrofuran (THF), and for example this paper preparation example 55 is described;
Ix) if R 4/ R 5Be acid-CO 2H, then it can be by using coupling agent, alkali and amine HNR 6R 7Processing is converted into corresponding acid amides-CONR 6R 7, being reflected in the suitable inert solvent and carrying out, solvent can influence reaction sharply.The coupling agent that is fit to is included in 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride under the existence of I-hydroxybenzotriazole, and suitable alkali comprises triethylamine, and suitable solvent comprises methylene dichloride, and for example this paper preparation example 59 is described;
X) if R 4/ R 5Be halogen, for example chlorine, bromine or iodine, then it can by with acrylamide, Pd (O) or (II) catalyzer and the alkaline purification that is fit to be converted into α, beta-unsaturated acyl amine, being reflected at can influence in the inert solvent of reaction sharply, at high temperature carries out.The Pd catalyzer that is fit to comprises the acid chloride (II) in the presence of three (o-tolyl) phosphine, and the alkali that is fit to comprises triethylamine, and suitable inert solvent comprises acetonitrile, and for example this paper embodiment 50 is described;
Xi) if R 4/ R 5Be α, beta-unsaturated acyl amine, then it can be converted into-CH by handling with the reductive agent that is fit to 2CH 2CO 2NH 2, be reflected under the suitable temperature, in the solvent that is fit to, carry out, this solvent can influence reaction sharply.The reductive agent that is fit to comprises the samarium diodide under the room temperature, and suitable solvent comprises the tetrahydrofuran (THF) that contains less water, and for example this paper embodiment 51 is described;
Xii) if R 4/ R 5Be-CH 2OH, then it can be converted into-CH by the Mitsunobu reaction 2NR 8SO 2R 9, be reflected under the suitable temperature, in the solvent that is fit to, carry out, this solvent can influence reaction sharply.The reagent that is fit to comprises diethylazodicarboxylate, triphenyl phosphine and methylsulfonyl t-butyl carbamate, and 0 ℃ is the temperature of reaction that is fit to, and tetrahydrofuran (THF) is the solvent that is fit to, and for example this paper preparation example 72 is described.
Select as an alternative, have specific NR 1R 2The general formula of group (I) compound can be converted into other and have different N R 1R 2The general formula of group (I) compound.For example:
I) R wherein 1Or R 2Be formula (Ib) compound of hydrogen can through type (Ib) compound and the reaction of aldehyde and hydride reducer be converted into wherein R 1And R 2It not formula (Ic) compound of hydrogen.The aldehyde that is fit to comprises formaldehyde, and suitable reductive agent comprises three (acetoxyl group) sodium borohydride, and reaction is preferably in can not the solvent of disturbance reponse, and methylene dichloride for example carries out under room temperature or following temperature, and for example this paper embodiment 12 is described.
Ii) R wherein 1Or R 2Formula (Ib) compound that is hydrogen can be converted into wherein R like this 1Or R 2Be formula (Ic) compound of methyl: formula (Ib) compound and formylating agent react in the solvent that is fit to, and then intermediate N formylation compound are reduced with hydride reducer, are reflected in the inert solvent, preferably at high temperature carry out.The formylating agent that is fit to comprises pentafluorophenyl group manthanoate (generating from formic acid, Pentafluorophenol and dicyclohexylcarbodiimide), is suitable for formylated solvent and comprises methylene dichloride.The reductive agent that is fit to comprises borine-tetrahydrofuran (THF) title complex, is suitable for the reductive inert solvent and comprises tetrahydrofuran (THF), and for example this paper embodiment 110 is described.
Select as an alternative, general formula (I) compound can be from formula V compound (referring to flow process 3), and wherein L is defined as flow process 1, and T can be converted into CH 2NR 1R 2Group.The substituent example of T that is fit to comprises-CO 2R 10,-CN and-C (O) NR 1R 2
Flow process 3
Conversion formula V compound to the method for formula (I) compound comprises:
I) as if T be-CO 2R 10, R 10=methyl or ethyl are then with general formula NHR 1R 2The amine reaction generates acid amides, and reduction obtains amine then.
Ii) if T=-CN then is reduced to its corresponding formula-CH 2NH 2Amine.
Iii) if T=-C (O) NR 1R 2, then reduction obtains amine.
Logical formula V compound can be prepared by coupling general formula (VI) compound and general formula (IV) compound then.The reagent of this class linked reaction and condition are with (III) the compound coupling is defined as front flow process 1 formula of (IV).
General formula (VI) compound then can be from general formula (VII) compound (referring to flow process 4).
Flow process 4
Formula (VI) compound can through type (VII) compound the aromatics electrophilic substitution prepared, directly obtain formula (VI) compound.Select as an alternative, formula (VI) compound can divide two or more step preparations; The aromatics electrophilic substitution of formula (VII) compound obtains midbody compound, and further reaction of experience then obtains formula (VI) compound.Midbody compound can be separated or be generated on the spot, need not separate.Preferred approach is shown in flow process 5.
Flow process 5
Formula (VII) compound and SULPHURYL CHLORIDE reaction obtain formula (VIII) compound, then with NHR 6R 7Reaction obtains formula (VIa) compound.
According to yet another aspect, the invention provides as defined above formula (II), (IIa) and (V) compound.
Formula (III), (IIIa), (IV), (VI) or (VII) compound be known, can obtain or utilize already known processes to make (referring to the following example) from commercial source from commercial available raw material.
To be that susceptibility functional group may protectedly between the synthesis phase of formula I compound protect with going by what those skilled in the art figured out.This can realize by common process, for example " Protective Groups in Organic Synthesis ", 3rd ed., T W Greeneand P G M Wuts, John Wiley and Sons Inc, 1999.Embodiment 35 is provided at an example of the blocking group strategy that is adopted in synthesizing of The compounds of this invention.
Skilled chemist will figure out, and diaryl ether can utilize a large amount of synthetic method preparations.About the comment of method, referring to J S Sawyer, Tetrahedron, 56 (2000) 5045-5065 quote at this as a reference.
Compound of the present invention is useful because they to Mammals, comprise that the people has pharmacologically active.More properly, they can be used for treating or preventing to involve the obstacle of monoamine transporter function regulating effect.The morbid state that can mention comprises hypertension, depressed (the depression among the cancer patients for example, depression among the Parkinsonian, the myocardial infarction retarded depression, subsyndromal symptomatic depression, depression among the infertile women, the paediatrics depression, the severe depression, single ictal depression, the recurrent depression, the depression that child abuse is brought out, postpartum depression and grumpy elderly men syndrome), generalized-anxiety disorder, terrified (for example agoraphobia, social phobia and simple phobia), nervous syndrome after the wound, shy with strangers property personality disorder, premature ejaculation, eating disorder (for example anorexia nervosa and bulimia nervosa), fat, chemical relies on (for example to alcohol, Cocaine, heroine, phenylethyl barbituric acid, nicotine and benzodiazepine habituation), bunch headache, migraine, pain, alzheimer's disease, obsession, Phobias, dysmnesia are (for example dull-witted, amnesia and the cognitive decline (ARCD) relevant) with aging, Parkinson's disease (the dementia in the Parkinson's disease for example, parkinson's syndrome that Antipsychotic drug is brought out and tardive dyskinesia), endocrine disorder (for example high prolactin hyperandrogenism), vasospasm (particularly in the brain vascular system), cerebellar ataxia, gastrointestinal tract disorder (involving the change in motility and the secretion), schizoid passive paresthesia, premenstrual tension syndrome, fibromyalgia syndrome, stress incontinence, tourette's syndrome, trichotillomania, the kleptomania, impotence, distractibility hyperkinetic syndrome (ADHD), chronic paroxysmal hemicrania, headache (relevant) with vascular disorder, emotional instability, pathologic is cried and is cried, somnopathy (dampinging off) and shock.
Relevant especially obstacle comprises obstacle and sexual dysfunction due to depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material, and (definitely) comprises premature ejaculation.Premature ejaculation can be defined in penis insert before the sex partner, in or soon persistence or recurrent ejaculation afterwards.It can also be defined as occurring in the ejaculation (referring to " The Merck Manual ", the 16th edition, p 1576, and Merck ResearchLaboratories publishes, 1992) before of individual wish.
Thereby, according to yet another aspect, the invention provides:
I) as the The compounds of this invention of medicine;
The ii) purposes of The compounds of this invention in medicine is made, this medicine is used for the treatment of or prevents to involve the obstacle of monoamine transporter function regulating effect, for example obstacle or sexual dysfunction due to depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material comprise premature ejaculation;
The iii) purposes of The compounds of this invention in medicine is made, this medicine are used for the treatment of or prevent premature ejaculation;
Iv) obstacle or sexual dysfunction due to treatment or prevention depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material, comprise the method for premature ejaculation, comprise will the treatment significant quantity The compounds of this invention to this class treatment of needs or patient's administration of preventing;
V) increase the method for ejaculation latency, comprise the male sex's administration that the The compounds of this invention of significant quantity is increased ejaculation latency to needs; And
Vi) be used for the treatment of or prevent to involve the The compounds of this invention of the obstacle of monoamine transporter function regulating effect, these obstacles are obstacle or sexual dysfunction due to depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material for example, comprises premature ejaculation;
The The compounds of this invention that vii) is used for the treatment of premature ejaculation.
Figure out be this paper all relate to the appellation for the treatment of and comprise healing, alleviate and preventative processing.
The compounds of this invention can be individually dosed or as the part of conjoint therapy.If give the combination of active medicine, so they can be simultaneously, separately or the order administration.Definitely, The compounds of this invention can be preferably and the medication combined administration of following treatment PE:
I) α-Zu Zhiji (embodiment 19 of phentolamine, Doxazosin, tamsulosin, terazosin, Prazosin and WO 9830560 for example.The possible principle of α-Zu Zhiji treatment premature ejaculation is as follows.By the release of norepinephrine, the muscle activity of ejaculation unstriated muscle (vas deferens, seminal vesicle and urethra) is subjected to the control of sympathetic nervous system.Norepinephrine acts on α 1 adrenergic receptor, and stimulated muscle is shunk, and causes seminal fluid emission and ejaculation subsequently.Block these acceptors and will therefore suppress ejaculation.
Ii) apomorphine can be referring to US-A-5945117 as the instruction of the purposes of medicine about apomorphine.
Iii) dopamine D 2 agonist (Premiprixal for example, Pharmacia Upjohn compound, numbering PNU95666).
Iv) Melanocortin receptor stimulant (for example Melanotan II).
V) PGE1 receptor stimulant (for example Prostaglandin E1).
Vi) the monoamine transporter inhibitor definitely is NRI (NRIs) (a for example Reboxetine), other serotonin reuptake inhibitors (SRIs) (for example paroxetine) or dopamine reuptake inhibitor (DRIs).
Vii) 5-HT3 antagonist (for example ondansetron and granisetron).The possible principle of 5-HT3 antagonist for treating premature ejaculation is as follows.Be present in the interior 5-HT3 acceptor of urethra rear chamber is subjected to the 5-HT in the seminal fluid during the seminal fluid emission stimulation, cause the sensitization of spinal reflex approach, cause ejaculation.Therefore, antagonist will prevent this sensibilized, thereby postpone ejaculation.
Viii) PDE inhibitor; PDE2 (the embodiment 100 of erythro-9-(2-hydroxyl-3-nonyl)-VITAMIN B4 and EP 0771799 for example for example; quote as a reference) at this; definite is PDE5 inhibitor (for example Virga, 1-{[3-(3; 4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5; 1-f]-as-triazine-2-yl)-the 4-ethoxyl phenenyl] alkylsulfonyl }-4-ethyl piperazidine, i.e. vardenafil/Bayer BA 38-9456 or IC351 (referring to following array structure, Icos Lilly)).The possible principle of PDE inhibitor for treating premature ejaculation is as follows.Therefore the muscle step of these ejaculation muscle of cAMP in the ejaculation unstriated muscle and CGMP horizontal adjustment postpones ejaculation.
Ix) potassium channel openers.
X) P2X purinergic receptor antagonists.
Xi) endothelin receptor antagonists.
About human, The compounds of this invention can be individually dosed, but in people's therapy, generally will with the drug excipient, diluent or carrier the mixings administration that are fit to, their selection is put into practice according to expection route of administration and standard pharmaceutical.
For example, The compounds of this invention can be oral, cheek with or sublingual administration, formulation is tablet, capsule (comprising the soft gel capsule agent), the agent of ovum shape body, elixir, solution or suspension, wherein can contain correctives or tinting material, be used for immediately, the application of delay, modification, lasting, dual, sustained release or pulse release.The compounds of this invention can also be via the intracavernous injection administration.The compounds of this invention can also be via quick dispersion or rapidly-soluble formulation administration.
This class tablet can contain vehicle, for example Microcrystalline Cellulose, lactose, Trisodium Citrate, lime carbonate, secondary calcium phosphate, glycine and starch (preferred corn, potato or tapioca (flour)), disintegrating agent, for example primojel, croscarmellose sodium and some composition silicate, and Granulating Bonding Agent, for example polyvinylpyrrolidone, Vltra tears (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and gum arabic.In addition, can comprise lubricant, for example Magnesium Stearate, stearic acid, Gan You docosoic ester and talcum.
The solids composition that can also adopt similar type is as the weighting agent in the gelatine capsule.Preferred in this respect vehicle comprises lactose, starch, Mierocrystalline cellulose, toffee or high molecular weight polyethylene glycol.About aqueous suspensions and/or elixir, can be with The compounds of this invention and pharmacy acceptable salt and various sweet taste or correctives, tinting material or stain, emulsification and/or suspension agent and thinner---for example water, ethanol, propylene glycol and glycerine---and combined hybrid is in the same place.
The formulation of modification release and pulse release can contain vehicle, for example about the formulation that discharges immediately described in detail those and serve as the vehicle of release rate modifier in addition, they coated and/or be included on the medical instrument body and/or within.Release rate modifier comprises but exclusively is not limited to Vltra tears, methylcellulose gum, Xylo-Mucine, ethyl cellulose, rhodia, polyoxyethylene, xanthan gum, carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin, rhodia phthalic ester, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and composition thereof.The formulation of modification release and pulse release can contain a kind of of rate of release modulability vehicle or combination.Rate of release modulability vehicle may reside in the formulation, just in the matrix, and/or on the formulation, just on surface or the dressing.
The dosage formulation that disperses or dissolves fast (FDDFs) can contain following ingredients: aspartame, Sunnett, citric acid, croscarmellose sodium, polyvinylpolypyrrolidone, two xitix, ethyl propenoate, ethyl cellulose, gelatin, Vltra tears, Magnesium Stearate, mannitol, methyl methacrylate, peppermint correctives, polyoxyethylene glycol, the silica of being fuming, silicon-dioxide, primojel, sodium stearyl fumarate, Sorbitol Powder, Xylitol.The term that this paper is used to describe FDDFs disperses or dissolves the solubleness that depends on used drug substance, that is to say,, then can prepare quick dispersive formulation if drug substance is insoluble, if drug substance is a solubility, then can prepare rapidly-soluble formulation.
The compounds of this invention can also be by administered parenterally, for example in intravenously, intra-arterial, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, encephalic, intramuscular or subcutaneous, perhaps they can pass through the infusion techniques administration.About this class administered parenterally, they preferably use the form of aseptic aqueous solution, wherein can contain other materials, and for example enough salt or glucose ooze solution and blood etc.If necessary, the aqueous solution should suitably be cushioned (preferably to pH 3 to 9).The preparation of parenteral administration under aseptic condition that is fit to realized by standard pharmaceutical technology well known to those skilled in the art easily.
Other dosage levels of following dosage level and this paper are about about 65 to 70kg the general population's of body weight.The technician will readily be able to determine that body weight exceeds the required dosage level of curee of this scope, for example children and old man.
About oral and administered parenterally to human patients, The compounds of this invention or its salt or solvate every day dosage level will be usually from 10 to 500mg the dosage of gradation (single or).
Thereby for example, the tablet of The compounds of this invention or capsule can contain 5mg to 250mg active compound, are used for taking the circumstances into consideration to be administered once or in certain time twice or repeatedly.In any case the doctor will determine actual dosage, it will be suitable for individual patient most, and will be different because of age, body weight and the reaction of particular patient.Above-mentioned dosage is the demonstration of average case.Certainly have individual instances, wherein higher or lower dosage range is worth, and these all belong to scope of the present invention.The technician also will figure out, and in the treatment of (comprising PE) of some disease, on the basis of " depending on the needs " (just as required or require), The compounds of this invention can be taked single dosage.
Tablet embodiment
Generally speaking, tablet can contain 0.01mg to the 500mg The compounds of this invention of having an appointment usually, can be from 50mg to 1000mg and sheet is heavy.Embodiment is as follows for the 10mg tablet:
Composition %w/w
The compounds of this invention 10.000 *
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium Stearate 1.500
*This quantity is adjusted according to pharmaceutical activity usually.
The compounds of this invention can also pass through in the nose or the suction administration, and suitable form with Foradil Aerolizer formoterol fumarate or aerosol discharges in pressurizing vessel, pump, atomizer or spraying gun, uses suitable propelling agent when discharging, for example Refrigerant 12, trichlorine methyl fuoride, dichloro tetrafluoro ethane, hydrofluoroalkane (for example 1,1,1, the 2-Tetrafluoroethane (HFA 134A[trade mark]) or 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227EA[trade mark])), carbonic acid gas or other gas that is fit to.Under the situation of pressurised aerosol, dose unit can be determined by the valve that discharges metering is provided.Pressurizing vessel, pump, atomizer or spraying gun can contain the solution or the suspension of active compound, and the mixture that for example uses ethanol and propelling agent can also contain lubricant, for example sorbitan trioleate in addition as solvent.Be used in the powdered mixture that interior capsule of sucker or insufflator and cartridge case (for example being made by gelatin) can be formulated into the powder matrix (for example lactose or starch) that contains The compounds of this invention and be fit to.
Aerosol or dry powder formulations are preferably arranged like this, so that the dosage of every measure unit or " every spray " contain 1 to the 50mg The compounds of this invention that is used to discharge to the patient.Aerosol total every day dosage will be in 1 to 50mg scope, can single administration, perhaps more generally administration several times in whole day.
The compounds of this invention can also be formulated into via spraying gun and discharge.The preparation that is used for spraying gun can contain following ingredients as solubilizing agent, emulsifying agent or suspension agent: water, ethanol, glycerine, propylene glycol, low molecular poly, sodium-chlor, fluorocarbon, polyglycol ether, sorbitan trioleate, oleic acid.
Select as an alternative, The compounds of this invention can be with the form administration of suppository or vaginal suppository, and perhaps they can be with the form local application of gelifying agent, hydrogel adhesive, lotion, solution, creme, ointment or spreading pulvis.The compounds of this invention can also for example utilize skin patch through skin or transdermal administration.They can also be by eye, lung or rectum administration.
About eye usefulness, The compounds of this invention can be formulated into the micronization suspension in isoosmotic, pH regulator, Sterile Saline, perhaps is preferably the solution in isoosmotic, pH regulator, Sterile Saline, alternatively with sanitas combination, for example benzalkonium chloride.Select as an alternative, they can be formulated in the ointment, for example vaseline.
About the local skin medication, The compounds of this invention can be mixed with suitable ointment, wherein contain and suspend or be dissolved in active compound in the mixture of following one or more reagent for example: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Select as an alternative, can be mixed with suitable lotion or creme, suspend or be dissolved in the mixture of following one or more reagent for example: mineral oil, Arlacel-60, polyoxyethylene glycol, whiteruss, polysorbate60, spermaceti alcohol ester, wax, cetostearyl alcohol (cetearyl alcohol), 2-Standamul G, phenylcarbinol and water.
The compounds of this invention can also be used in combination with cyclodextrin.Known cyclodextrin and drug molecule form the mixture of embedding and non-embedding.The formation of drug-cyclodextrin mixture can the modified medicaments molecule solubleness, solubility rate, bioavailability and/or stable character.The drug-cyclodextrin mixture generally can be used for most of formulations and route of administration.As direct and the alternative of medicine compound, cyclodextrin can also be used as supplementary additive, for example carrier, thinner or solubilizing agent.α-, β-and γ-Huan Hujing be the most frequently used, the case description that is fit to is in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
About oral or administered parenterally to human patients, The compounds of this invention every day dosage level will be from 0.01 to 30mg/kg the dosage of gradation (single or), preferred 0.01 to 5mg/kg.Thereby tablet will contain 1mg to 0.4g compound, be used for taking the circumstances into consideration to be administered once or in certain time twice or repeatedly.In any case the doctor will determine actual dosage, it will be suitable for individual patient most, and will be different because of age, body weight and the reaction of particular patient.Certainly, above-mentioned dosage only is the demonstration of average case, can have such situation, and wherein higher or lower dosage range is worth, and these all belong to scope of the present invention.
Oral administration is preferred.Preferably, administration was carried out before the needs result of treatment soon.
About veterinary purpose, put into practice The compounds of this invention as suitable acceptable preparation administration according to normal animal doctor, the animal doctor will determine to be suitable for most the administration system and the route of administration of particular animals.
Thereby according to yet another aspect, the invention provides pharmaceutical preparation, contain The compounds of this invention and pharmaceutically acceptable auxiliary agent, diluent or carrier.
Following non-limiting examples is set forth the present invention; Wherein use following abbreviation and definition: the bimodal Δ heating of Arbocel  filtering agent br broad peak Boc tertbutyloxycarbonyl CDI carbonyl dimidazoles δ chemical shift d DCCI dicyclohexylcarbodiimide DCM carrene DMF DMF DMSO dimethyl sulfoxide (DMSO) ES+The positive scanning of EFI ionization ES -The unimodal t triplet of EFI ionization negative scanning Ex embodiment h hour HOBt I-hydroxybenzotriazole HPLC high pressure liquid chromatography m/z mass spectra peak min minute MS mass spectrum NMR nuclear magnetic resonance Prec precursor Prep preparation example q quartet s Tf trifyl TFA trifluoroacetic acid THF oxolane TLC thin-layer chromatography TS+The positive scanning of heat spray ionization WSCDI hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimine
1H nucleus magnetic resonance (NMR) spectrum is all consistent with the imagination structure in all cases.Characterization displacement study (δ) moves down 1,000,000/umber from tetramethylsilane and provides, and use conventional abbreviation to represent main peak: for example s is unimodal, and d is bimodal, and t is a triplet, and q is a quartet, and m is a multiplet, and br is a broad peak.Following abbreviation is used to represent common solvent: CDCl 3, deuterochloroform; DMSO, dimethyl sulfoxide (DMSO).Abbreviation psi represents pound/square inch, and LRMS represents Low Resolution Mass Spectra.If when using thin-layer chromatography (TLC), silica gel 60 F are used in its expression 254The silica gel tlc of plate, R fBe that compound is divided a word with a hyphen at the end of a line apart from the distance of dividing a word with a hyphen at the end of a line divided by the solvent front on the TLC plate.Fusing point utilizes Perkin Elmer DSC7 to measure, and heating rate is 20 ℃/minute.
When expression like this, compound be as they hydrochloride in addition feature differentiate.Embodiment 12 has provided the technology that typically is used to generate hydrochloride.This technology can utilize other solvents to carry out, for example diethyl ether or DCM.
Commercial materials obtains from Aldrich Chemical Co, Lancaster Synthesis Ltd or Acros Organics.
Embodiment 1
3-[(first ammonia) methyl]-4-[3-methyl-4-methylthio group) phenoxy group]-benzsulfamide
(760mg 2.07mmol) is suspended among the THF (10ml), and the gained suspension is at room temperature used borine-tetrahydrofuran (THF) title complex, and (1M THF solution, 6.22ml 6.22mmol) handle with the acid amides of preparation example 8.With gained solution reflux 5 hours under dry nitrogen atmosphere.Reaction is cooled to room temperature, uses 6M HCl solution (6ml) to handle carefully.The gained mixture heating up was refluxed 30 minutes.After being cooled to room temperature,, carefully adding potash solid and alkalize mixture water (10ml) dilution.The waterbearing stratum produces precipitation with EtOAc (20ml) extraction in organic layer, the waterbearing stratum is further with DCM extraction (2 * 20ml).EtOAc partly uses 2M NaOH (20ml) washing, is separated into clarifying two-phase, and alkaline layer extracts (4 * 25ml) with DCM.Merge all organic moiety, with salt solution (20ml) washing, dry (MgSO 4), be evaporated to colourless oil.Through purification by flash chromatography [SiO 295: 5: 0.5 to 90: 10: 1 (EtOAc/MeOH/880NH 3)], obtain the white powder (646mg, 89%) of required amine.δ H(300MHz，d 6-DMSO)2.26(3H，d)，2.32(3H，d)，2.45(3H，d)，3.75(2H，d)，6.90(3H，m)，7.25(3H，br)，7.67(1H，t)7.98(1H，d)；MS?m/z(TS +)353(MH +).
According to the mode that is similar to embodiment 1, from specified precursor preparation formula Id compound, i.e. R wherein 1Be methyl, R 2Be hydrogen and R 5Be-SO 2NH 2Compound of Formula I, as shown in table 1.
Figure A0181484600381
Table 1
Embodiment 12 and 13
The 3-[(dimethylamino) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group]-benzsulfamide (embodiment 12) and 3-[(dimethylamino) methyl]-N-methyl-4-[3-methyl-4-(methylthio group) Phenoxy group]-benzsulfamide (embodiment 13)
Under room temperature and nitrogen, to embodiment 1 secondary amine (409mg, DCM 1.16mmol) (20ml) suspension add formaldehyde (37% aqueous solution, 282 μ l, 3.76mmol).The gained mixture was stirred 15 minutes, add then sodium triacetoxy borohydride (984mg, 4.64mmol).The gained reaction mixture was stirred 5 hours, use saturated NaHCO then 3Solution (10ml) alkalization is with DCM extraction (3 * 20ml).Organic layer is washed dry (MgSO with salt solution (10ml) 4), be evaporated to xanchromatic oil.Through HPLC purifying (Phenomonex Luna C 1875 * 4.6mm post, CH 3CN, H 2O, TFA).Evaporation contains the part of primary product, with the saturated NaHCO of resistates 3Solution (5ml) is handled, with DCM extraction (3 * 30ml).Merge organic moiety, with salt solution (30ml) washing, dry (MgSO 4), evaporation obtains the white foam (155mg, 36%) of embodiment 12;
δ H(300MHz，CDCl 3)2.30(6H，s)，2.35(3H，s)，2.48(3H，??s)，3.60(2H，s)，6.83(3H，m)，7.20(1H，m)，7.28(2H，s)，7.74(1H，d)，8.08(1H，s)；MS??m/z(TS+)367(MH +).
Also obtain secondary product behind the HPLC purifying.Evaporate relevant part, with the saturated NaHCO of resistates 3Solution (5ml) is handled, with DCM extraction (2 * 30ml).Merge organic moiety, with salt solution (30ml) washing, dry (MgSO 4), be evaporated to natural gum.It is dissolved in DCM (5ml), handles with 1M ether HCl (2ml), evaporation obtains the white powder (39mg, 9%) of embodiment 13; HCl salt:
δ H(CDCl 3，300MHz)2.30(6H，s)，2.35(3H，s)，2.48(3H，s)，3.60(2H，s)，??6.83(3H，m)，7.20(1H，m)，7.28(2H，s)，7.74(1H，d)，8.08(1H，s)；MS?m/z(TS +)381??(MH +).
In reaction repeated, embodiment 1 amine is used 1 equivalent formaldehyde, at column chromatography [SiO 295: 5: 0.5 to 90: 10: 1 (EtOAc/MeOH/880 NH 3)] after obtain embodiment 12, yield 78%.It is dissolved in EtOAc, adds 1M ether HCl and be converted into HCl salt.With the gained sedimentation and filtration, dry in a vacuum, obtain the HCl salt of embodiment 12; M.p.188 ℃.
Select as an alternative, can also generate embodiment 12 from embodiment 1 amine by the method for embodiment 110.
Embodiment 12 still is prepared as follows.
Slowly add trifluoroacetic acid (100ml) solution of embodiment 94 hydrochlorides (20g) to chlorsulfonic acid (72g) solution, maintain the temperature at simultaneously between 0 and 5 ℃.After 1 hour, under 0-20 ℃, the slow quencher of reaction mixture is arrived in the water (200ml).Mixture is used methylene dichloride (200ml) extraction then, separates.Methylene dichloride (60ml) extraction is used in the waterbearing stratum then, separates.Merge organic layer, water (200ml) washing.Separate each layer, remove methylene dichloride in a vacuum, obtain solid.Add acetonitrile (240ml), add phosphoryl chloride (28.8ml) to these slurries.Then vlil is spent the night.Reaction mixture is cooled to room temperature, and quencher maintains the temperature between 0 and 10 ℃ in the mixture of the ammonia that is stirring (90ml), methylene dichloride (240ml) and water (100ml) simultaneously.With ammonia adjust mixture (if necessary) to pH greater than 8.After 15 minutes, make reaction mixture be warmed to room temperature, separate each layer.Concentrate organic layer in a vacuum, obtain the oil of dense thick brown.It is dissolved in acetone (100ml), and (Norit SX plus 50%w/w), filters, and (Norit SX plus 50%w/w) handles with another part carbon to add carbon.Filtering mixt once more, concentrated solution, water (200ml) replaces.With the slurries granulation, to filter, vacuum-drying is spent the night, and obtains title product, is creamy white solid (40%).
Embodiment 14 and 15
4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen base)-3-[(dimethylamino) Methyl]-benzsulfamide and 4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen Base)-and the 3-[(dimethylamino) methyl]-the N-methyl benzenesulfonamide
Figure A0181484600421
According to the mode that is similar to embodiment 12 and 13,, generate these compounds from embodiment 5 secondary amine.
Embodiment 14, HCl salt:
δ H(CD 3OD，400MHz)2.97(6H，s)，3.18(2H，m)，4.42(2H，m)，4.52(2H，s)，6.68(2H，d)，6.99(1H，d)，7.14(1H，d)，7.94(1H，d)，8.07(1H，s)；MS?m/z(ES +)381(MH +).
Embodiment 15, HCl salt:
δ H(CD 3OD，400MHz)2.56(3H，s)，2.80(6H，s)，3.17(2H，m)，??4.35(2H，s)，4.41(2H，m)，6.68(2H，m)，6.98(1H，d)，7.13(1H，d)，7.81(1H，d)，8.00(1H，s)；MS?m/z?(ES +)395(MH +)
According to embodiment 12, from specified precursor preparation formula Ie compound, i.e. R wherein 1And R 2Be methyl and R 5Be-SO 2NH 2Compound of Formula I, as shown in table 2.In these reactions, do not separate the N-sulfonyloxy methyl amine that is similar to embodiment 13, do not need the HPLC purifying yet.
Table 2
Figure A0181484600431
Embodiment 24
The 3-[(dimethylamino) methyl]-4-[4-methyl-3-(methylthio group) phenoxy group]-benzsulfamide
Figure A0181484600441
By the method for embodiment 110, prepare title compound from embodiment 9 secondary amine;
δ H(CD 3OD，400MHz)2.27(3H，s)，2.41(3H，s)，2.61(6H，s)，4.19(2H，s)，6.76(1H，d)，6.88-6.93(2H，m)，7.20(1H，d)，7.82(1H，d)，8.03(1H，d)；MSm/z(TS +)367(MH +).
Embodiment 25
N-{5-methoxyl group-2-[3-methyl-4-(methylthio group) phenoxy group] benzyl }-N, N dimethylamine
To preparation example 24 aldehyde (1.00g, THF 3.47mmol) (15ml) and DCM (15ml) solution add Dimethylammonium chloride (424mg, 5.2mmol), Et 3N (725 μ l, 5.2mmol), AcOH (298 μ l, 5.2mmol) and sodium triacetoxy borohydride (1.10g 5.2mmol), at room temperature stirred mixture 16 hours.Except that after desolvating, resistates is dissolved in 2M HCl (20ml) in a vacuum, with ether washing (2 * 15ml).The waterbearing stratum with the alkalization of NaOH particle, is extracted (4 * 20ml) with DCM.Merge the DCM extraction liquid, use the salt water washing, dry (MgSO 4), evaporation.Resistates is dissolved in a small amount of DCM, and HCl handles with 1M ether, is settled out HCl salt.With its filtration, with the ether washing, drying obtains white solid (936mg), contains Triethylammonium chloride.It is dissolved in 1M NaOH (10ml), with EtOAc extraction (3 * 15ml).Organic extract liquid is washed dry (MgSO with salt solution (10ml) 4), evaporation, and then be dissolved in EtOAc, evaporation once more.Resistates is dissolved in DCM, and HCl handles with 1M ether, is settled out HCl salt, and with its filtration, with the ether washing, drying obtains white solid (635mg, 52%);
δ H(CDCl 3，300MHz)2.35(3H，s)，2.45(3H，s)，2.79(6H，s)，3.90(3H，s)，4.21(2H，s)，6.70(1H，d)，6.73(1H，s)，6.90(2H，m)，7.18(1H，d)，7.65(1H，s)，12.83(1H，brs)；MS?m/z(TS +)318(MH +).
According to embodiment 25, from specified precursor preparation formula If compound, i.e. R wherein 1And R 2Be the compound of Formula I of methyl, as shown in table 3.
Figure A0181484600451
Table 3
Figure A0181484600461
Embodiment 34
The 3-[(dimethylamino) methyl]-N-methyl-4-(6-quinoline oxy) benzsulfamide
Figure A0181484600471
(50mg, DCM 0.16mmol) (2ml) solution add chlorsulfonic acid, and (106 μ l 1.6mmol), at room temperature stirred mixture 3 hours to embodiment 29.Add entry (2ml), with the saturated NaHCO of mixture 3The aqueous solution is adjusted to pH 6, with DCM extraction (2 * 5ml).With organic extract liquid in dry (MgSO 4), filter, add the EtOH solution (0.3ml) of 8M methylamine.Place after 1 hour, remove in a vacuum and desolvate, resistates is through column chromatography purifying [SiO 295: 5: 0.5 (DCM/MeOH/880NH 3)].Product is dissolved in EtOAc, adds ether HCl and be converted into HCl salt.Obtain required product, be water absorbability solid (3mg, 5%);
δ H(CD 3OD，300MHz)2.60(3H，s)，2.99(6H，s)，4.60(2H，??s)，7.21(1H，d)，7.96(1H，d)，8.04(3H，m)，8.19(1H，s)，8.38(1H，d)，9.03(1H，d)，9.18??(1H，d)；MS?m/z(TS +)371(MH +).
Embodiment 35
The 3-[(methylamino-) methyl]-4-(6-quinoline oxy) benzsulfamide
Under 0 ℃, (900mg is 3.4mmol) with triethylamine (1.9ml, CH 13.6mmol) to embodiment 48 amine 2Cl 2(15ml) (0.96ml 6.8mmol), stirs mixture 5 minutes solution adding trifluoroacetic anhydride.Remove in a vacuum and desolvate, make resistates at CH 2Cl 2And distribute between the water.With organic layer salt water washing, dry (MgSO 4), evaporation obtains xanchromatic oil, need not during use to be further purified.Should be dissolved in CH by thick oil 2Cl 2(20ml), be cooled to 0 ℃, drip ClSO 3H (2.4ml, 36.1mmol).Make mixture be warmed to room temperature, stirred 4 hours, be poured in the frozen water then.Mixture CH 2Cl 2(50ml) extraction, the saturated NH of organic layer 3MeOH solution (10ml) handle.Stir after 4 hours, add 1M LiOH (20ml), continue to stir and spend the night.Analyze the demonstration reaction not exclusively, therefore add other 1MLiOH (50ml), mixture was stirred 2 hours.Mixture is acidified to pH 8 with 2M HCl, uses CH 2Cl 2Extraction (3 * 200ml).Merge organic extract liquid, dry (MgSO 4), evaporation, resistates is developed with ether, obtains title compound (500mg, 43%), is yellow solid;
δ H(CDCl 3，400MHz)??2.46(3H，s)，3.87(2H，s)，6.93(1H，d)，7.25(1H，s)，7.39(1H，t)，7.42(1H，d)，7.78(1H，??d)，8.00-8.08(2H，m)，8.12(1H，d)，8.86(1H，s)；MS?m/z(ES +)344(MH +).
Embodiment 36
N-[5-bromo-2-(2,3-dihydro-1-thionaphthene-5-base oxygen base) benzyl]-the N-methylamine
(1.10g, (4.1ml 32.8mmol), stirred 5 hours, went through then to add NaBH in 30 minutes in batches 3.28mmol) to be dissolved in the EtOH solution of 8M methylamine with preparation example 19 aldehyde 4(372mg, 9.83mmol).Add EtOH (100ml), will react and stir 16 hours, concentrate in a vacuum then.Resistates, filters and collects sedimentary HCl salt to pH 1 with 6M HCl quencher, and water (100ml) washing is dry in a vacuum, obtains crystalline solid (1.04g, 82%);
δ H(CDCl 3，400??MHz)2.62(3H，s)，3.26(2H，t)，3.41(2H，t)，4.18(2H，s)，6.66(1H，d)，6.90(1H，d)，7.03??(1H，s)，7.19(1H，d)，7.39(1H，d)，7.80(1H，s)；MS?m/z(ES +)350，352(MH +).
According to embodiment 36, from specified precursor preparation formula Ig compound, i.e. R wherein 1And R 4Be hydrogen and R 2Be the compound of Formula I of methyl, as shown in table 4.About being separated into those compounds of free alkali, remove reaction solvent in a vacuum after, reaction mixture is distributed between 2M HCl and ether.Then with the waterbearing stratum alkalization, with the DCM extraction, with DCM layer drying (MgSO 4), evaporation obtains required secondary amine.
Table 4
Figure A0181484600501
Figure A0181484600511
A: the MeOH solution (2 equivalent) and the Ti (O that use the 2M methylamine iPr) 4The EtOH solution of (2 equivalent) (～0.1M aldehyde solution) replaces the EtOH solution of methylamine.Behind the separated free alkali, be converted into maleate by standard method.
Embodiment 50
(2E)-3-{4-(2,3-dihydro-1-thionaphthene-6-base oxygen base)-3-[(dimethylamino) Methyl] phenyl }-the 2-acrylamide
With embodiment 32 bromide (400mg, 1.10mmol), acrylamide (156mg, 2.19mmol), triethylamine (0.38ml, 2.74mmol), acid chloride II (12.5mg, 0.06mmol) (33.4mg, 0.11mmol) mixture heating up in acetonitrile (15ml) refluxed 72 hours with three adjacent toluene phosphines.After being cooled to room temperature, removing in a vacuum and desolvate, resistates is distributed between EtOAc (50ml) and 2M HCl (50ml).Contain water with 2M NaOH alkalization, with EtOAc extraction (3 * 50ml).Merge alkaline extraction liquid, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 296: 4: 0.5 (DCM/MeOH/880NH 3) increase polarity to 90: 10: 1], obtain title compound (196mg, 50%), be cream-coloured foam;
δ H(CDCl 3，400MHz)2.28??(6H，s)，3.24(2H，t)，3.38(2H，t)，3.51(2H，s)，5.73(2H，br)，6.42(1H，d)，6.59(1H，dd)，??6.82(2H，m)，7.10(1H，d)，7.32(1H，d)，7.60(1H，d)，7.69(1H，s)；MS?m/z(ES +)355??(MH +).
Embodiment 51
3-{4-(2,3-dihydro-1-thionaphthene-6-base oxygen base)-3-[(dimethylamino) methyl] Phenyl } propionic acid amide
Figure A0181484600521
Under nitrogen, (194mg, THF 0.55mmol) (5ml) solution adds SmI to embodiment 50 alkene 2THF solution (0.1M, 21.9ml 2.19mmol), add entry (1ml) then.After at room temperature stirring 10 minutes, will react quencher, stir 30 minutes with 6M NaOH (10ml).Separate organic phase, contain water and extract (2 * 20ml) with EtOAc.Merge organic layer, dry (MgSO 4), be evaporated to oil, through column chromatography purifying [SiO 293: 7: 1 (DCM/MeOH/880 NH 3) increase polarity to 90: 10: 1], obtain title compound (90mg, 46%);
δ H(CDCl 3，400MHz)2.25(6H，s)，2.54(2H，t)，2.97(2H，t)，??3.22(2H，t)，3.36(2H，t)，3.42(2H，s)，5.20-5.46(2H，br)，6.54(1H，d)，6.73(1H，s)，6.81??(1H，d)，7.05(2H，m)，7.31(1H，s)；MS?m/z(TS +)357(MH +).
According to preparation example 50, from specified precursor preparation formula If compound, i.e. R wherein 1And R 2Be the compound of Formula I of methyl, as shown in table 5.
Figure A0181484600531
Table 5
According to preparation example 55, from specified precursor preparation formula If compound, i.e. R wherein 1And R 2Be the compound of Formula I of methyl, as shown in table 6.
Table 6
According to preparation example 59, from specified precursor preparation formula If compound, i.e. R wherein 1And R 2Be the compound of Formula I of methyl, as shown in table 7.
Table 7
According to preparation example 69, from specified precursor preparation formula If compound, i.e. R wherein 1And R 2Be the compound of Formula I of methyl, as shown in table 8.
Table 8
Figure A0181484600551
Preparation example 60
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(methylamino-) methyl] benzoyl Amine
Figure A0181484600552
Under 0 ℃, (317mg 0.76mmol) is dissolved in the DCM solution (25ml) of saturated HCl, places 1 hour, adds 10% K then with protected preparation example 59 amine 2CO 3The aqueous solution (25ml) neutralizes.Add entry (50ml), separate each layer.The waterbearing stratum merges organic layer with DCM (25ml) extraction, dry (MgSO 4), evaporation.Gained oil is dissolved in EtOAc (10ml), handles with 1M ether HCl (1ml).Filter and collect white precipitate, dry in a vacuum, obtain required product (211mg, 77%); δ H(CD 3OD, 400MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s), 6.79 (1H, d), 6.90 (1H, dd), 7.02 (1H, s), 7.21 (1H, d), 7.83 (1H, d), 8.00 (1H, s); MS m/z (TS +) 315 (MH +).
According to embodiment 60, from specified precursor preparation formula Ig compound, i.e. R wherein 1And R 4Be hydrogen and R 2Be the compound of Formula I of methyl, as shown in table 9.
Figure A0181484600561
Table 9
Figure A0181484600571
Figure A0181484600581
Embodiment 77
The N-{4-[(dimethylamino) methyl]-3-[3-methyl-4-(methylthio group) phenoxy group] benzyl } Toluidrin
Figure A0181484600591
By the method for embodiment 60, preparation example 74 sulphonamide of protecting from Boc prepare embodiment 77; HCl salt:
δ H(CD 3OD，400MHz)2.29(3H，s)，2.42(3H，s)，2.82??(3H，s)，2.89(6H，s)，4.17(2H，s)，4.39(2H，s)，6.39(3H，m)，7.19(1H，d)，7.24(1H，d)，??7.48(1H，d)；MS?m/z(TS +)395(MH +).
Embodiment 78
The 3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] benzonitrile
(3.0g, DMF 8.52mmol) (20ml) solution adds Zn (CN) to embodiment 44 bromides 2(700mg, 5.96mmol) and Pd (PPh 3) 4(1.97g 1.7mmol), heats mixture 17 hours down at 100 ℃.Reaction is cooled to room temperature, and water (100ml) dilution is with extracted with diethyl ether (2 * 100ml, then 3 * 50ml).Merge organic layer, wash with water (3 * 50ml), dry (MgSO 4), be evaporated to xanchromatic oil.Initial through column chromatography purifying [SiO 295: 5: 0.5 (DCM/MeOH/880NH 3)] be unsuccessful, therefore pass through chromatogram purification [SiO once more 295: 5: 0.5 (DCM/MeOH/880NH that contain 50% pentane 3) increase polarity to 0% pentane], obtain product (1.275g, 50%), be light yellow oil.Sample is dissolved in DCM (5ml), and HCl handles with 1M ether, obtains HCl salt, is white powder, the filtration collection;
δ H(CDCl 3，300MHz)2.35(3H，s)，2.47(6H，s)，3.88??(2H，s)，6.79(1H，d)，6.87(2H，m)，7.20(1H，d)，7.46(1H，d)，7.72(1H，s)；MS?m/z(TS +)??299(MH +).
Embodiment 79
The 3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] benzamide
(404mg, 1.35mmol) (304mg, 5.42mmol) mixture in the trimethyl carbinol (10ml) is at N with KOH with embodiment 78 nitriles 2Following reflux 1 hour.After being cooled to room temperature, removing in a vacuum and desolvate, resistates is distributed between water (10ml) and DCM (10ml).(4 * 20ml), the merging organic layer is used the salt water washing, dry (MgSO with the DCM extraction in the waterbearing stratum 4), evaporation.Resistates is through column chromatography purifying [SiO 293: 7: 1 (DCM/MeOH/880NH 3)], obtain required product (376mg, 88%), be white foam;
δ H(CDCl 3，??300MHz)2.35(3H，s)，2.47(3H，s)，2.49(3H，s)，3.88(2H，s)，5.90-6.30(2H，brs)，6.82??(3H，m)，7.19(1H，d)，7.70(1H，d)，7.90(1H，s)；MS?m/z(TS +)317(MH +).
According to embodiment 12, from specified precursor preparation formula Ih compound, i.e. R wherein 1And R 2Be methyl and R 4Be the compound of Formula I of hydrogen, as shown in table 10.
Table 10
Figure A0181484600611
Figure A0181484600631
Embodiment 94 still is prepared as follows.
Add preparation example 30 products (200g, DCM 0.78mol) (1.4L) solution to THF (1.4L).To this mixture add continuously Dimethylammonium chloride (69.5g, 0.85mol) and triethylamine (235g, 2.33mol).Temperature is adjusted to 20 ℃, and (246g 1.16mol) (after 20 hours, if reaction is finished, continues operation to add sodium triacetoxy borohydride after 3 hours; Otherwise note as follows).Add methylene dichloride (2L), go through 0.5 hour adding 8% sodium hydrogen carbonate solution (0.9L).Separate each layer, organic layer water (1L) washing.Separate each layer once more, concentrate organic layer.Add ethyl acetate (0.27L), remove and desolvate, replace with fresh ethyl acetate (800ml).Then solution is cooled to below 5 ℃, (0.117L 0.82mol), maintains the temperature at below 10 ℃ simultaneously to add 7.02M HCl/IPA.After stirring 1 hour below 5 ℃, filter slurries, with the ethyl acetate washing (3 * 0.2L), spend the night 50 ℃ of vacuum oven, obtain required product, be powdery solid (141.5g, 56%).[annotate: also do not finish if be reflected at 20 hours, add continuously another part Dimethylammonium chloride (13g, 0.16mol) and triethylamine (43.4g, 0.43mol).After at room temperature 2 hours, and the adding sodium triacetoxy borohydride (46g, 0.22mol).Placed 20 hours, then as above operation.]
According to embodiment 79, from specified precursor preparation formula Ii compound, i.e. R wherein 2Be methyl, R 4Be hydrogen and R 5Be-C (=O) NH 2Compound of Formula I, as shown in table 11.
Table 11
Embodiment 103
N-{5-amino-2-[3-methyl-4-(methylthio group) phenoxy group] benzyl }-N, N dimethylamine
Figure A0181484600651
With embodiment 27 nitro-compounds (2.0g, 6mmol), the Fe powder (2.51g, 44.9mmol) and CaCl 2(300mg, 2.7mmol) mixture heating up in EtOH (20ml) and water (4ml) refluxed 20 hours.After being cooled to room temperature, removing in a vacuum and desolvate, resistates is distributed between salt solution (100ml) and ether (100ml).Aqueous layer with diethyl ether (50ml) extraction merges organic layer, dry (MgSO 4), evaporation obtains product (1.47g, 81%), is orange oil;
δ H(CDCl 3，??300MHz)2.22(6H，s)，2.32(3H，s)，2.40(3H，s)，3.33(2H，s)，6.59(1H，dd)，6.60-6.75??(2H，m)，6.78(1H，dd)，6.94(1H，s)，7.10-7.20(3H，m)；MS?m/z(ES +)303(MH +).
Embodiment 104
N-[5-amino-2-(2,3-dihydro-1-thionaphthene-5-base oxygen base) benzyl]-N, N-two Methylamine
By the method for embodiment 103, prepare title compound from embodiment 28 nitro-compounds;
δ H(CDCl 3，400MHz)2.20(6H，s)，3.16(2H，t)，3.30(4H，m)，3.54(2H，br)，6.53(1H，dd)，6.60(1H，d)，6.71(2H，m)，6.79(1H，d)，7.01(1H，d)；MS?m/z(ES +)301(MH +).
Embodiment 105
N-[3-(amino methyl)-4-(2,3-two-hydrogen-1,4-benzo oxathiene-6-base oxygen Base) phenyl]-Toluidrin
(720mg 1.99mmol) is dissolved in 1M BH with preparation example 95 nitriles 3.THF (10ml's THF solution 10mmol), refluxes mixture heating up 3 hours.After being cooled to room temperature, carefully add MeOH (10ml) quencher reaction.Evaporating solvent is handled resistates reflux 1 hour with 6M HCl (10ml).After the cooling, mixture with 2M NaOH alkalization, is used saturated NH 4The Cl aqueous solution is adjusted pH to 7.Mixture with EtOAc (3 * 50ml) and DCM (2 * 50ml) extractions merge organic layer, drying (MgSO 4), evaporation obtains cream-coloured foam (685mg, 94%), need not during use to be further purified;
δ H(CDCl 3，400MHz)3.00(3H，s)，3.13(2H，m)，3.87(2H，s)，4.40(2H，m)，??6.62(1H，d)，6.67(1H，s)，6.79(2H，d)，7.08(1H，d)，7.25(1H，d)；MS?m/z(TS +)367??(MH +).
According to embodiment 105, from specified precursor preparation formula Ij compound, i.e. R wherein 1, R 2And R 4Be hydrogen and R 5Be-NR 8-SO 2The compound of Formula I of Me, as shown in table 12.
Figure A0181484600662
Table 12
Figure A0181484600671
Embodiment 110
N-{4-(2,3-dihydro-1,4-benzo oxathiene-6-base oxygen base)-3-[(first ammonia Base) methyl] phenyl }-Toluidrin
To Pentafluorophenol (413mg, ether 2.24mmol) (10ml) solution add dicyclohexylcarbodiimide (460mg, 2.23mmol), add then formic acid (95 μ l, 2.5mmol).Mixture was stirred 2 hours, filter then, resistates washs with ether.Concentrated filtrate adds embodiment 105 primary amine (411mg, DCM 1.1mmol) (10ml) solution to～5ml.Mixture was stirred 16 hours, be concentrated into the oiliness resistates then.Should be dissolved in BH by thick oil 3THF solution .THF (1M, 20ml, 20mmol), at N 2Following reflux 1.5 hours.After being cooled to room temperature, carefully add MeOH (10ml) quencher reaction, concentrate in a vacuum then.The oiliness resistates is handled reflux 30 minutes with 6M HCl.After being cooled to room temperature, with mixture K 2CO 3Aqueous solution alkalization is with DCM extraction (3 *).Merge organic extract liquid, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 290: 10: 1 (DCM/MeOH/880NH 3)], obtain colourless oil, it is dissolved in EtOAc (20ml), handle with 1M ether HCl (2ml).Stir after 1.5 hours, solid collected by filtration obtains title product (282mg, 60%);
δ H??(CD 3OD，400MHz)2.78(3H，s)，2.98(3H，s)，3.18(2H，m)，4.29(2H，s)，4.39(2H，m)，??6.74(1H，d)，6.80-6.90(3H，m)，7.22(1H，d)，7.44(1H，s)；MS?m/z(TS +)381(MH +).
According to embodiment 110, from specified precursor preparation formula Ik compound, i.e. R wherein 1And R 4Be hydrogen, R 2Be methyl and R 5Be-NHSO 2The compound of Formula I of Me, as shown in table 13.
Figure A0181484600681
Table 13
Figure A0181484600682
According to embodiment 110, from specified precursor preparation formula Im compound, i.e. R wherein 1And R 4Be hydrogen, R 2Be methyl and R 5Be-NR 8SO 2The compound of Formula I of Me, as shown in table 14.
Figure A0181484600691
Table 14
A: also the method by embodiment 110 prepares from embodiment 108.
According to embodiment 12, from specified precursor preparation formula In compound, i.e. R wherein 1And R 2Be methyl, R 4Be hydrogen and R 5Be-NR 8SO 2The compound of Formula I of Me, as shown in Table 15.
Table 15
Figure A0181484600711
Embodiment 128
The N-{3-[(dimethylamino) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] phenyl } Toluidrin
Under 0 ℃, to embodiment 103 aniline (725mg, 2.4mmol) and Et 3N (1ml, and DCM 7.17mmol) (10ml) solution adding methylsulfonyl chloride (371 μ l, 4.79mmol).After stirring 1 hour under 0 ℃, make reaction be warmed to room temperature, remove in a vacuum then and desolvate.Add 2M NaOH (10ml) to resistates, mixture is stirred spend the night.Add saturated NH to the gained settled solution 4The Cl aqueous solution neutralizes, with DCM extraction (2 * 30ml).Merge organic layer, dry (MgSO 4), evaporation obtains oil.It is dissolved in EtOAc (10ml).Add 1M ether HCl and be settled out HCl salt, filter and collect product (669mg, 67%);
δ H(d 6-DMSO，400MHz)2.23(3H，s)，2.42(3H，s)，2.75??(6H，s)，3.04(3H，s)，4.38(2H，s)，6.84(1H，d)，6.93(1H，d)，6.98(1H，s)，7.17-7.25(2H，??m)，7.50(1H，s)；MS?m/z(ES +)381(MH +).
According to embodiment 128, from specified precursor preparation formula Ip compound, i.e. R wherein 1And R 2Be methyl, R 4Be hydrogen and R 5Be-NHSO 2R 9Compound of Formula I, shown in table 16.
Table 16
Figure A0181484600731
Preparation example
Preparation example 1
5-(amino-sulfonyl)-2-fluoro-N-methyl-benzamide
Figure A0181484600732
Under room temperature and nitrogen, to 5-(amino-sulfonyl)-2-fluorobenzoic acid [according to Chem.Pharm.Bull.1995,43,582-7 preparation] (22.98g, THF 105mmol) (500ml) solution add carbonyl dimidazoles (17g, 105mmol).Stir after 2.25 hours, (2M, 70ml 140mmol), will react and stir 18 hours the THF solution of dropping methylamine.Concentrate crude product mixture to small volume, add EtOAc (150ml) to the dense thick oil of gained.Stir this mixture, have the particulate state precipitation to generate, the filtration collection.This crude product that will contain imidazoles is suspended among the DCM (300ml) reflux 5 hours.After being cooled to room temperature, filtering mixt obtains required product (19.8g, 81%), contains＜the 2%w/w imidazoles; 1H NMR δ H(300MHz, d 4-MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS +) 250 (MNH 4 +).
Preparation example 2
3-chloro-4-(methylthio group) phenol
Figure A0181484600733
(i) preparation of 2-chloro-1-(methylthio group)-4-oil of mirbane
At room temperature, ((10g 143mmol), will react and stir 6 hours to add sulfo-sodium methylate (NaSMe) then for 27g, DMF 156mmol) (150ml) solution adding 5-tertiary butyl-4-hydroxy-2-aminomethyl phenyl thioether (100mg) to 4-fluoro-3-chloronitrobenzene.Remove DMF in a vacuum, resistates is distributed between ether (1L) and water (1L).With ether layer water (1L) and salt solution (1L) washing, dry (MgSO 4), under reduced pressure remove and desolvate.Resistates is through column chromatography purifying (SiO 2DCM: pentane increases polarity to 3 at 1: 5: 7), obtain title compound (15.22g, 49%), be yellow solid; δ H(400MHz, CDCl 3) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).
The (ii) preparation of 3-chloro-4-(methylthio group) aniline
(14.08g, 69mmol) mixture in acetate (300ml) and water (60ml) adds the Fe powder (23g 412mmol), swirls reaction mixture and dissolves until whole raw materials to above-claimed cpd.Mixture was placed 1.5 hours, under reduced pressure removed acetate then.Resistates is dissolved in saturated NaHCO 3The aqueous solution (500ml) and EtOAc (500ml) filter by Arbocel .Separate each layer, contain water, merge organic layer, use the salt water washing, dry (MgSO with EtOAc (300ml) extraction 4), remove in a vacuum and desolvate, obtain title compound (11.52g, 96%), be beige solid; δ H(400MHz, CDCl 3)
2.38(3H，s)，3.66(2H，br)，6.53(1H，dd)，6.70(1H，d)，7.12(1H，d)；MS?m/z(ES +)174
(MH +).
The (iii) preparation of 3-chloro-4-(methylthio group) phenol
With above-mentioned aniline (11.5g, 66.2mmol) be dissolved in a small amount of THF (～15ml), under vigorous stirring, add entry (500ml), add dense H then 2SO 4(25ml).Cooling mixture in ice-water bath adds NaNO via volumetric pipette below the surface of reaction mixture 2(5.0g, frozen water 72.5mmol) (10ml) solution.To be reflected at 0 ℃ and stir 1.5 hours down, with gained yellow/brown solution from all the other solids decantation to containing ice (in～200g) the dropping funnel.At room temperature, this solution is gone through with steady rate joined the Cu (NO that vigorous stirring in 7 minutes 3) 2(230g, 0.99mol) and Cu 2(8.52g is 67.4mmol) in the mixture in water (1L) for O.After adding fully, mixture was stirred other 15 minutes, use ether (500ml) extraction then.Redness/the brown solid that remains in the reaction flask is dissolved in MeOH (100ml),, pours above-mentioned waterbearing stratum then into ether (300ml) dilution.Separate ether layer, merge organic layer, with 1M NaOH extraction (3 * 100ml).Aqueous extract with dense HCl acidifying, is used extracted with diethyl ether (2 * 150ml) then.Then ether layer is used the salt water washing, dry (MgSO 4), remove in a vacuum and desolvate, obtain phenol (5.465g, 47%), be the brown crystalline solid; δ H(400MHz, CDCl 3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES -) 173 (M-H +).
Preparation example 3
3-fluoro-4-(methylthio group) phenol
Utilize and above-mentioned preparation example 2 similar methods, from commercial available 3, the 4-difluoro nitrobenzene prepares this compound; δ H(CDCl 3, 300MHz) 2.40 (3H, s), 5.03 (1H, br), 6.60 (2H, m), 7.27 (1H, m obscured); MS m/z (ES -) 157 (M-H +).
Preparation example 4
2,3-dihydro-1,4-benzo oxathiene-6-alcohol
Figure A0181484600752
With glycol dibromide (2.3ml, 26.7mmol) and K 2CO 3(8.21g 59.4mmol) is suspended in the acetone (250ml), goes through to add 2-sulfenyl-1 in 4 hours 4-dihydroxy-benzene (according to J.Org.Chem.1990,55,2736 preparations) (4.22g, acetone 29.7mmol) (50ml) solution to the mixture that is stirring.In case add fully, continue to stir other 10 hours, remove in a vacuum then and desolvate.Resistates is distributed between water (50ml) and EtOAc (50ml), and the waterbearing stratum merges organic layer with EtOAc (50ml) extraction, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 29: 1 (pentane/EtOAc)], obtain title compound (2.48g, 55%), be light orange oil; δ H(CDCl 3, 400MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s), 6.66 (1H, d); MS m/z (ES -) 167 (M-H +).
Preparation example 5
2,3-dihydro-1,4-benzo oxathiene-7-alcohol
Figure A0181484600761
According to the similar mode of preparation example 4 compounds, from 4-sulfenyl-1,3-dihydroxy-benzene (according to J.Org.Chem.1979,26,4971-4973 preparation) preparation title compound;
δ H(CDCl 3，400MHz)3.05(2H，t)，4.37(2H，t)，6.32(1H，s)，6.35(1H，d)，6.84(1H，d)；MS?m/z(TS +)169(MH +).
Preparation example 6
1,3-dihydro-2-cumarone-5-alcohol
With 1,3-dihydro-2-cumarone-5-amine (according to US 4000286 preparations) (2.7g, 20mmol) water-soluble (300ml) and dense H 2SO 4Mixture (21ml) is cooled to 0 ℃, goes through to add NaNO in 15 minutes 2(1.43g, water 20.7mmol) (10ml) solution.After stirring 1 hour under 0 ℃, mixture was stirred 30 minutes down at 10 ℃, add urea, test negative until observing starch/KI test paper.Under 90 ℃, solution gone through then and poured water (180ml) and dense H in 2 minutes into 2SO 4In the mixture (12.6ml), under this temperature, stirred 1.5 hours.Filter the mixture of heat, be cooled to room temperature then.(2 * 100ml), the merging organic layer is in dry (MgSO with the EtOAc extraction for aqueous mixture 4), evaporation obtains title phenol (974mg, 36%), is the creamy solid; δ H(CDCl 3, 400MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).
Preparation example 7
2,3-dihydro-1-thionaphthene-6-alcohol
Figure A0181484600771
(i) 2,3-dihydro-1-thionaphthene-6-alcohol 1, the preparation of 1-dioxide
Heating 2,3-dihydro-1-thionaphthene-6-amine 1,1-dioxide (according to J.Am.Chem.Soc.1955,77,5939 preparations) (15.73g, water 85.8mmol) (500ml) and dense H 2SO 4(35ml) suspension is until forming solution.Mixture is cooled to 0 ℃, goes through 5 minutes adding NaNO then 2(6.22g, water 90mmol) (15ml) solution.To be reflected at 0 ℃ and stir 1 hour down, add urea then,, obtain negative findings until starch/KI test paper test to remove excessive nitrous acid ester.Make mixture be warmed to room temperature, under agitation join 90 ℃ dense H then 2SO 4(55ml) with the mixture of water (750ml) in.To react and be heated to 90 ℃ once more, under this temperature, stir 30 minutes.The reaction mixture of heat is filtered by Arbocel , at room temperature stir then and spend the night.Aqueous mixture is with ether (2.5L) extraction, then with EtOAc extraction (5 * 500ml), merge organic layer, dry (MgSO 4), evaporation obtains required phenol (12.7g, 80%), need not during use to be further purified;
δ H(CDCl 3，400MHz)3.30(2H，m)，3.50(2H，m)，7.05(1H，??m)，7.14(1H，s)，7.23(1H，m)；MS?m/z(ES -)183(M-H +).
(ii) 2, the preparation of 3-dihydro-1-thionaphthene-6-alcohol
(100mmol) (4.84g, toluene 26.3mmol) (100ml) and THF (70ml) solution reflux mixture heating up 16 hours adding stage (i) sulfone then for 1M, 100ml to the toluene solution of DIBAL.After being cooled to room temperature, carefully add EtOH (75ml), under agitation add entry (100ml) then.Add 6M HCl to the dense thick suspension of gained, separate organic layer.The waterbearing stratum with EtOAc extraction (3 * 150ml), merge organic layer, dry (MgSO 4), be evaporated to beige solid.Through column chromatography purifying [SiO 2DCM/MeOH/880NH 3(97: 3: 0.25) increase polarity to (95: 5: 0.5)], obtain required title phenol, be beige solid (1.85g, 53%);
δ H(CD 3OD，400MHz)3.13(2H，t)，??3.30(2H，m)，6.41(1H，d)，6.60(1H，s)，6.98(1H，d)；MS?m/z(ES -)151(M-H +).
Preparation example 8
5-(amino-sulfonyl)-2-[3-methyl-4-(methylthio group) phenoxy group]-the N-toluyl Amine
With preparation example 1 fultolanil (732mg, 3.15mmol) with 4-(methylthio group)-meta-cresol (commercial obtaining) (535mg, 3.47mmol) and salt of wormwood (457mg, DMF 3.31mmol) (10ml) solution-treated.Mixture was heated 5 hours down at 100 ℃.Vapourisation under reduced pressure removes and desolvates, and resistates is handled with 2M HCl (10ml).Gained suspension dichloromethane extraction several times.The combined dichloromethane layer contains suspension, is evaporated to solid residue.Resistates is with ether (5ml) development, all the other solids with ether washing (3 * 10ml), obtain pale solid (765mg, 66%); 66%). δ H(300MHz, d 6-DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1H, d), 7.02 (1H, d), 7.03 (1H, s), 7.30 (1H, d), 7.35 (2H, s), 7.79 (1H, d), 8.10 (1H, d), 8.30 (1H, m); MS m/z (TS +) 367 (MH +), 385 (MNH 4 +).
Preparation example 9-18
According to preparation example 8, use preparation example 1 sulphonamide and specified phenol preparation formula Va compound, promptly wherein T is-C (=O) NHMe, R 4Be hydrogen and R 5Be-SO 2NH 2General formula V compound, shown in table 17.
Figure A0181484600791
Table 17
Figure A0181484600801
Preparation example 19
5-bromo-2-(2,3-dihydro-1-thionaphthene-5-base oxygen base) phenyl aldehyde
With 5-bromo-2-fluorobenzaldehyde (1.08g, 5.32mmol), 5-hydroxyl-2,3-dihydrobenzo thiophene (as Synth.Commun.1991,21, the described preparation of 959-964) (808mg, 5.31mmol) and K 2CO 3(1.47g, 10.6mmol) mixture in DMF (5ml) heated 16 hours down at 90 ℃.After being cooled to room temperature, mixture is distributed between water (50ml) and ether (50ml), aqueous layer with diethyl ether (50ml) extraction.Merge organic extract liquid, water (50ml) washing, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 29: 1 (pentane/EtOAc)], with the ether development, obtain product (1.1g, 62%) then, be faint yellow solid;
δ H(CDCl 3，400MHz)3.28(2H，t)，3.41(2H，t)，6.78(1H，d)，6.84(1H，d)，6.92(1H，s)，7.20(1H，d)，7.58(1H，d)，8.00(1H，s)，10.43(1H，s).
According to preparation example 19, make the reaction of specified phenol and required 2-fluorobenzaldehyde, preparation general formula I I compound, shown in table 18.In most of the cases, the crude reaction product after the moisture operation is directly used in step subsequently, need not to be further purified.
Table 18
Figure A0181484600812
A:4-fluoro-3-formyl radical benzonitrile is according to Synth.Commun.1997,27 (7), 1199 and J.Org.Chem.1961, and 26,2522 synthetic.
Preparation example 30 products still are prepared as follows.
To DMF (2L) add continuously salt of wormwood (334.1g, 2.42mol) and 4-(methylthio group)-meta-cresol (273.4g, 1.77mol).Then to slurries add the 2-fluorobenzaldehyde (200g, 1.61mol), at 100-110 ℃ scope internal heating mixture.After 48 hours, make reaction mixture be cooled to room temperature, add entry (1.2L).Solution is cooled to below 10 ℃, adjusts pH to 5, maintain the temperature at simultaneously below 10 ℃ with dense HCl (0.37L).Add entry (0.15L) and methylene dichloride (0.9L), stir the mixture.Separate each layer, organic layer washes (4 * 0.75L) with water.Solvent distillation is with azeotropic removal of water.Add fresh methylene dichloride as required.Concentrate anhydrous methylene chloride solution then in a vacuum, obtain crude product, be oil (422g, 100%).
According to preparation example 19, use 2-chloro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile and specified phenol preparation formula IX compound, shown in table 19.About these reactions, the shorter reaction times (about 2-3 hour) is enough to realize good conversion usually.In most of the cases, the crude reaction product after the moisture operation is directly used in step subsequently, need not to be further purified.
Table 19
Preparation example 44
5-bromo-2-(2,3-dihydro-1-thionaphthene-5-base oxygen base) benzyl (methyl) carboxylamine The tert-butyl ester
Figure A0181484600861
(1.04g 2.7mmol) is suspended among the DCM (12ml), adds Et with embodiment 36 hydrochlorides 3N (750 μ l, 5.38mmol), add then tert-Butyl dicarbonate (766mg, 3.51mmol).After at room temperature stirring 20 minutes, add 0.2M HCl (20ml) quencher reaction.Separate the mixture that fully shook, the waterbearing stratum extracts with DCM (10ml).Merge organic layer, dry (MgSO 4), evaporation obtains product (supposing quantitative yield), is colourless oil, need not during use to be further purified;
δ H(CDCl 3，400MHz)1.56(9H，??s)，2.82-2.98(3H，brd)，3.23(2H，t)，3.40(2H，t)，4.44(2H，brd)，6.71(2H，d)，6.79(1H，??s)，7.12(1H，d)，7.29(1H，d)，7.39(1H，s).
According to preparation example 44, begin preparation formula X compound from specified precursor, shown in table 20.
Figure A0181484600862
Table 20
Figure A0181484600871
Preparation example 49
5-cyano group-2-[3-fluoro-4-(methylthio group) phenoxy group] benzyl-(methyl) t-butyl carbamate
Figure A0181484600872
By the method for embodiment 78, prepare title compound from preparation example 47 bromides;
；δ H(CDCl 3，300MHz)1.48(9H，brs)，2.50(3H，s)，2.93(3H，brs)，4.55(2H，brs)，6.79(2H，m)，6.88(1H，d)，7.35(1H，t)，7.53(1H，d)，7.59(1H，s)；MS?m/z(TS +)403(MH +).
Preparation example 50
The 3-{[(tertbutyloxycarbonyl) (methyl) amino] methyl }-4-(2,3-dihydro-1-thionaphthene -5-base oxygen base) methyl benzoate
With preparation example 44 bromides (1.22g, 2.7mmol), Et 3(1.13ml is 8.11mmol) with two (triphenyl phosphine) palladiums (II) of dichloro (190mg, the 0.27mmol) heating 18 hours under 80 ℃ and 100psi CO pressure of the mixture in MeOH (14ml) for N.Tlc analyze to show reaction not exclusively, therefore add another part catalyzer (190mg, 0.27mmol), with mixture heating 24 hours under 100 ℃ and 100psi CO pressure.Mixture with EtOAc (20ml) dilution, is filtered by silicagel pad, with excessive EtOAc wash-out.Remove in a vacuum and desolvate, make resistates at EtOAc (50ml) and water: 880NH 32: 1 mixtures (50ml) between distribute.The waterbearing stratum merges organic layer with EtOAc (25ml) extraction, dry (MgSO 4), evaporation.Through column chromatography purifying [SiO 24: 1 (pentane/EtOAc)], obtain product (970mg, 84%), be oil;
δ H(CDCl 3，400MHz)1.42??(9H，s)，2.90(3H，brs)，3.22(2H，t)，3.38(2H，t)，3.84(3H，s)，4.50(2H，brd)，6.74(2H，??d)，6.82(1H，s)，7.13(1H，d)，7.82(1H，d)，7.93(1H，brd)；MS?m/z(ES +)430(MH +).
According to preparation example 50, begin preparation formula XI compound from specified precursor, shown in table 21.
Figure A0181484600891
Table 21
Preparation example 55
The 3-{[tertbutyloxycarbonyl) (methyl) amino] methyl }-4-(2,3-dihydro-1-thionaphthene -5-base oxygen base) phenylformic acid
With preparation example 50 esters (970mg, THF 2.26mmol) (20ml) and 1M LiOH (20ml) vlil 16 hours.After being cooled to room temperature, remove THF in a vacuum, the saturated NH of resistates 4The neutralization of the Cl aqueous solution, mixture is used ether (100ml) extraction then with DCM (100ml) extraction.Merge organic layer, dry (MgSO 4), evaporation obtains white foam (960mg), need not during use to be further purified;
δ H(CDCl 3，400MHz)1.30(9H，s)，2.78(3H，brs)，3.20(2H，brs)，3.38(2H，t)，4.41(2H，m)，6.62(2H，m)，6.78(1H，m)，7.10(1H，m)，7.84(1H，m)，7.99(1H，m)；MS?m/z(ES -)414(M-H).
According to preparation example 55,, shown in table 22 from specified precursor preparation formula XII compound.
Table 22
Preparation example 59
5-(aminocarboxyl)-2-(2,3-dihydro-1-thionaphthene-5-base oxygen base) benzyl (methyl) T-butyl carbamate
(318mg, DCM 0.77mmol) (10ml) solution adds Et to preparation example 55 acid 3N (267 μ l, 1.92mmol), HOBt.H 2O (129mg, 0.84mmol) and WSCDI (191mg 1.0mmol), stirs mixture 1 hour, adds saturated NH then 3THF solution (2ml).After stirring other 16 hours, will react water (50ml), 0.2M HCl (20ml) and DCM (25ml) dilution.Separate organic layer, the waterbearing stratum extracts with DCM (25ml).Merge organic layer, dry (MgSO 4), evaporation obtains white foam (supposing quantitative yield), need not during use to be further purified;
δ H(CDCl 3，400MHz)1.44(9H，s)，2.91(3H，br)，3.27(2H，t)，3.40(2H，t)，4.54(2H，br)，6.75-6.88(3H，m)，7.18(1H，d)，7.68(1H，d)，7.74(1H，s).
According to preparation example 59,, shown in table 23 from specified precursor preparation formula XIII compound.
Figure A0181484600921
Table 23
Figure A0181484600922
Preparation example 69
2-[3-chloro-4-(methylthio group) phenoxy group]-5-(methylol) benzyl (methyl) carboxylamine The tert-butyl ester
At N 2Down, (452mg, THF 1mmol) (10ml) solution drips LiAlH to preparation example 52 esters 4THF solution (1M, 2ml, 2mmol).In case react completely by the tlc analysis and judgement, add ether (10ml), carefully add the excessive LiAlH of 2M NaOH quencher 4Separate organic layer, use the salt water washing, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 239: 1 (DCM/MeOH)], obtain required alcohol (200mg, 47%), be gluey white solid;
δ H(CDCl 3，400MHz)1.41(9H，brs)，1.80(1H，brs)，2.43(3H，s)，2.81(3H，brd)，4.42(2H，brd)，4.66(2H，s)，6.82(1H，d)，6.88(1H，d)，6.96(1H，s)，7.16(1H，d)，7.27(2H，obs)；MS?m/z(ES +)446(MNa +).
According to preparation example 69, begin preparation formula XIV compound from specified precursor, shown in table 24.
Figure A0181484600941
Table 24
Preparation example 72
The 3-{[(tertbutyloxycarbonyl) (methyl) amino] methyl }-4-[3-methyl-4-(methylthio group) benzene The oxygen base] benzyl (methylsulfonyl) t-butyl carbamate
Figure A0181484600951
Under 0 ℃; to the methylsulfonyl t-butyl carbamate (according to Tetrahedron Lett.1994; 35; 379-380 is synthetic) (655mg; 3.36mmol), preparation example 71 alcohol (1.226g; 3.04mmol) (880mg, THF 3.36mmol) (15ml) solution drips diethylazodicarboxylate (505 μ l, THF 3.21mmol) (5ml) solution with triphenyl phosphine.To be reflected at 0 ℃ and stir 2 hours down, use EtOAc (80ml) dilution then, use 10%K 2CO 3The aqueous solution (100ml) washing.With organic layer salt water washing, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 21: 4 EtOAc: pentane], obtain title compound (1.406g, 80%), be colourless oil; δ H(CDCl 3, 300MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.22 (3H, s), 4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18-7.29 (3H, obs); MS m/z (TS +) 481 (MH +-BOC).
Preparation example 73
The 3-{[(tertbutyloxycarbonyl) (methyl) amino] methyl }-4-[3-fluoro-4-(methylthio group) benzene oxygen Base] benzyl (methylsulfonyl) t-butyl carbamate
Figure A0181484600952
By the method for preparation example 72, from preparation example 70 alcohol preparation title compounds;
δ H(CDCl 3，300MHz)1.44(9H，s)，1.52(9H，s)，2.44(3H，s)，2.82(3H，s)，3.23(3H，s)，4.45(2H，s)，4.87(2H，s)，6.61-6.70(2H，m)，6.90(1H，d)，7.25-7.33(3H，m)；MS?m/z(ES +)607(MNa +).
Preparation example 74
The 4-[(dimethylamino) methyl]-3-[3-methyl-4-(methylthio group) phenoxy group] benzyl (first sulphur Acyl group) t-butyl carbamate
Figure A0181484600961
By the method for preparation example 72, from embodiment 59 alcohol preparation title compounds.Crude product is without the column chromatography purifying, but is directly used in next step; δ H(CDCl 3, 400MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, s), 2.38 (3H, s), 3.07 (3H, s), 3.42 (2H, s), 4.76 (2H, s), 6.72 (2H, m), 6.79 (1H, s), 7.07 (1H, d), 7.12 (1H, d), 7.40 (1H, obs).
Preparation example 75
Methyl [2-[3-methyl-4-(methylthio group) phenoxy group]-5-({ [(trifluoromethyl) alkylsulfonyl] Amino } methyl) benzyl] t-butyl carbamate
Use the fluoroform sulphonamide to replace the methylsulfonyl t-butyl carbamate, by the method for preparation example 72, from preparation example 71 alcohol preparation title compounds.Required product contains 5-({ { 3-{[(tertbutyloxycarbonyl) (methyl) amino] methyl }-4-[3-methyl-4-(methylthio group) phenoxy group] benzyl } [(trifluoromethyl) alkylsulfonyl] amino } methyl)-2-[3-methyl-4-(methylthio group) phenoxy group] benzyl (methyl) t-butyl carbamate, be regarded as mixture; MS m/z (ES -) 533 (M-H +).
According to preparation example 44, use specified precursor preparation formula XV compound, as shown in Table 25.
Table 25
Preparation example 79
Methyl 2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrobenzyl } carboxylamine uncle fourth Ester
Figure A0181484600981
N-methyl-N-{2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrobenzyl amine and 2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrophenyl } methyl alcohol
To preparation example 39 aldehyde (21.0g, EtOH 69.2mmol) (100ml) suspension add the 8M methylamine EtOH solution (86.5ml, 692mmol).Obtain solution, the short period of time is observed precipitation after stirring.Add THF (100ml) and dissolve once more, solution is cooled to 0 ℃, add NaBH then 4(7.85g, 208mmol).Make sluggish be warmed to room temperature, stirring is spent the night, and removes in a vacuum then and desolvates.With resistates water-soluble (150ml) and ether (150ml), carefully add 2M HCl until pH 1.Separate each layer, aqueous layer with diethyl ether washing (2 * 100ml).Merge organic extract liquid, drying, evaporation, obtain 2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrophenyl } methyl alcohol (18.9g, 89%), be yellow solid; δ H(CDCl 3, 400MHz) 2.35 (3H, s), 2.48 (3H, s), 4.90 (2H, s), 6.79 (1H, d), 6.89 (1H, s), 6.91 (1H, d), 7.22 (1H, d), 8.07 (1H, dd), 8.41 (1H, d).
Above-mentioned waterbearing stratum is poured on excessive solid K 2CO 3On neutralize.The alkaline solution extracted with diethyl ether (2 * 100ml), with these ether extraction liquid dryings (MgSO 4), evaporation obtains N-methyl-N-{2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrobenzyl } amine (1.65g, 7.5%), be orange oil; MS m/z (ES +) 319 (MH +).
Prepare the N-first from { 2-[3-methyl-4-(methylthio group) phenoxy group]-5-nitrophenyl } methyl alcohol Base-N-{2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrobenzyl } amine
To { 2-[3-methyl-4-(methylthio group) phenoxy group]-5-nitrophenyl } methyl alcohol (18.9g, 61.9mmol) and Et 3N (9.5ml, DCM 68.2mmol) (60ml) solution slowly add methylsulfonyl chloride (4.81ml, 61.9mmol).Mixture was at room temperature stirred 3 hours, pour into then in the water, with DCM extraction (3 times).Merge organic extract liquid, dry (MgSO 4), evaporation obtains the oil of dark viscosity.This oil is dissolved in DCM (50ml), and (200ml 1.6mol), adds Et to the EtOH solution of adding 8M methylamine then 3N (10ml, 71.7mmol).Stir after 18 hours, enriched mixture obtains thick amine in a vacuum, need not during use to be further purified.
Methyl 2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-nitrobenzyl } t-butyl carbamate
Under 0 ℃, above-mentioned thick amine is dissolved in DCM (100ml), add Et 3N (11.4ml, 81.8mmol), add then tert-Butyl dicarbonate (15.0g, 68.7mmol).Make reaction be warmed to room temperature, stirred 16 hours, concentrate in a vacuum then.Resistates is distributed between EtOAc and water, and the waterbearing stratum extracts (2 times) with EtOAc.Merge organic layer, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying (SiO 2The 1st post-the contain DCM of 3%MeOH; The 2nd post-EtOAc: pentane 1: 3), obtain title compound (14.2g, 54%), be xanchromatic oil;
δ H(CDCl 3，400MHz)1.44(9H，s)，2.32(3H，s)，2.44(3H，s)，2.95(3H，s)，4.56(2H，br)，6.75(1H，d)，6.84(2H，m)，7.17(1H，d)，8.00(1H，d)，8.18(1H，br)；MS?m/z(TS +)419(MH +).
According to embodiment 103,, shown in table 26 from specified precursor preparation formula XVI compound.
Figure A0181484600991
Table 26
Figure A0181484600992
Preparation example 84
Methyl 2-[3-methyl-4-(methylthio group) phenoxy group]-the 5-[(methylsulfonyl) amino] benzyl } T-butyl carbamate
Figure A0181484601001
Under 0 ℃, to preparation example 83 aniline (9.5g, 24.5mmol) and Et 3N (7.5ml, and DCM 53.8mmol) (50ml) solution dropping methylsulfonyl chloride (4.16ml, 53.7mmol).After stirring 30 minutes under 0 ℃, make reaction be warmed to room temperature, remove in a vacuum then and desolvate.Add 2M NaOH (50ml) to resistates, mixture was stirred 30 minutes.Mixture extracts with EtOAc, organic layer salt water washing, dry (MgSO 4), evaporation obtains oil.Through column chromatography purifying [SiO 297.5: 2.5: 0.25 (DCM/MeOH/880NH 3)], obtain product (9.0g, 79%), be the brown foam; δ H(CDCl 3, 300 MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s), 4.46 (2H, brs), 6.76 (2H, d+s), 6.83 (1H, d), 7.16 (1H, s), 7.20 (2H, brs); MS m/z (ES +) 467 (MH +).
According to preparation example 84,, shown in table 27 from specified precursor preparation formula XVII compound.
Table 27
Figure A0181484601011
Preparation example 88
Methyl 2-[3-methyl-4-(methylthio group) phenoxy group]-5-[methyl (methylsulfonyl) amino] Benzyl } t-butyl carbamate
Figure A0181484601012
At N 2Down, to preparation example 84 sulphonamide (2.0g, 4.3mmol) and K 2CO 3(592mg is 4.3mmol) at CH 3Mixture dropping MeI among the CN (10ml) (1.07ml, 17.2mmol).Mixture was stirred 16 hours, between EtOAc (50ml) and 2M NaOH (50ml), distribute then.With organic layer salt water washing, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 2590: 10: 1 (DCM/MeOH/880NH 3)], obtain product (1.23g, 60%), be xanchromatic oil;
δ H(CDCl 3，300??MHz)1.45(9H，s)，2.34(3H，s)，2.42(3H，s)，2.86(3H，s)，2.90(3H，s)，3.28(3H，s)，??4.49(2H，s)，6.80(3H，br)，7.18(3H，m)；MS?m/z(TS +)498(MNH 4 +).
Preparation example 89
The 5-[(2-hydroxyethyl) (methylsulfonyl) amino]-2-[3-methyl-4-(methylthio group) benzene oxygen Base] benzyl (methyl) t-butyl carbamate
Figure A0181484601021
At N 2Down, to preparation example 84 sulphonamide (2.0g, 4.3mmol) and K 2CO 3(2.605g is 18.8mmol) at CH 3Mixture adding ethylene bromohyrin among the CN (10ml) (1.34ml, 18.9mmol).Mixture heating up was refluxed 16 hours, and cooling distributes between EtOAc (50ml) and 2M NaOH (50ml) then.With organic layer salt water washing, dry (MgSO 4), evaporation.Resistates is through column chromatography purifying [SiO 2390: 10: 1 (DCM/MeOH/880NH 3)], obtain product (524mg, 24%), be pink foam; δ H(CDCl 3, 300MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H, s), 2.91 (3H, s), 2.98 (3H, s), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s), 6.81 (3H, m), 7.19 (3H, m); MS m/z (TS +) 528 (MNH 4 +).
Preparation example 90
5-amino-2-(2,3-dihydro-1,4-benzo oxathiene-6-base oxygen base) benzonitrile
Figure A0181484601022
(740mg, AcOH 2.38mmol) (5ml) adds the Fe powder with water (1ml) solution, and (930mg 16.7mmol), at room temperature stirred mixture 16 hours to preparation example 41 nitro-compounds.Remove in a vacuum and desolvate, resistates is dissolved in EtOAc (50ml) and 10%K 2CO 3The aqueous solution (50ml) filters by Arbocel .Separate organic layer, the waterbearing stratum extracts with EtOAc (50ml).Merge organic extract liquid, dry (MgSO 4), be evaporated to brown foam (670mg, 99%), need not during use to be further purified;
δ H(CDCl 3，400MHz)3.18??(2H，m)，4.36(2H，m)，6.60-6.70(2H，m)，6.70-6.80(3H，m)，6.85(1H，s)；MS?m/z(TS +)??302(MNH 4 +).
According to preparation example 90, from specified precursor preparation formula Vb compound, promptly wherein T is cyano group, R 4Be hydrogen and R 5Be amino formula V compound, shown in table 28.
Table 28
Figure A0181484601032
Preparation example 94
5-amino-2-[4-methyl-3-(methylthio group) phenoxy group] benzonitrile
Figure A0181484601041
By the method for embodiment 103, prepare title compound from preparation example 43 nitro-compounds;
δ H(CDCl 3，400MHz)2.27(3H，s)，2.41(3H，s)，3.66(2H，br)，??6.62(1H，d)，6.79(2H，s)，6.82(1H，s)，6.89(1H，s)，7.08(1H，d)；MS?m/z(ES +)293??(MNa +)，(ES -)269(M-H +).
According to preparation example 84, from specified precursor preparation formula Vc compound, promptly wherein T is cyano group, R 4Be hydrogen and R 5Be-NHSO 2The formula V compound of Me, shown in table 29.
Table 29
Figure A0181484601043
Preparation example 100
N-{3-cyano group-4-[3-methyl-4-(methylthio group) phenoxy group] phenyl }-N-methyl methylsulfonyl Amine
Figure A0181484601052
By the method for preparation example 88, prepare title compound from preparation example 98 sulphonamide;
δ H(CDCl 3，400MHz)2.31(3H，s)，2.44(3H，s)，2.83(3H，s)，3.27(3H，s)，6.79(1H，d)，6.88(2H，m)，7.17(1H，d)，7.44(1H，dd)，7.58(1H，d)；MS?m/z(ES +)385(MNa +).
Preparation example 101
1,3-dihydro-2-thionaphthene-5-alcohol
Figure A0181484601061
(i) preparation of [4-(allyloxy)-2-(methylol) phenyl] methyl alcohol
With 4-(allyloxy) dimethyl phthalate [according to Inouye, M.; Tsuchiya, K.; Kitao, T.Angew.Chem.1992,104, the 198-200 preparation (is seen Angew.Chem. in addition, Int.Ed.Engl., 1992,204-205)] (9.9g 38mmol) is dissolved in THF (40ml), be cooled to 0 ℃, go through then dripped in 10 minutes lithium aluminium hydride (1M THF solution, 77ml, 77mmol).Then mixture was at room temperature stirred 3 hours, carefully add entry (1.4ml) then, add 2M NaOH (1.4ml) again and carry out quencher.Add excessive MgSO then 4, add entry again, until generating particulate state precipitation (about 5ml).Filtering mixt then is evaporated to the oil (7.1g, about 95%) of brown. 1H NMR shows this material purity about 85%.Being directly used in next stage need not to be further purified;
δ H(CDCl 3，400MHz)2.63(1H，brs)，2.91(1H，brs)，4.52(2H，??m)，4.67(4H，m)，5.26(1H，dd)，5.38(1H，dd)，5.97-6.09(1H，m)，6.80(1H，dd)，6.92??(1H，d)，7.22(1H，d).
(ii) 5-(allyloxy)-1, the preparation of 3-dihydro-2-thionaphthene
(3.5g 18mmol) is dissolved in DCM (60ml), uses Et with thick glycol of stage (i) 3(10ml 72mmol) handles N, and solution is cooled to 0 ℃.(4.2ml 54mmol), with solution stirring 1 hour, makes it reach room temperature to drip methylsulfonyl chloride.Add entry then, add 2M HCl (50ml) quencher reaction again.Separating the DCM layer, strips with DCM (50ml) in the waterbearing stratum.Merge organic moiety, water (50ml) washing, dry (MgSO 4), be concentrated into the about 30ml of volume.Add benzyl triethylammonium chloride (1g), add sodium sulphite (5g, water 91mmol) (50ml) solution then.Mixture was stirred 15 hours rapidly under nitrogen atmosphere.Separating organic layer, strips with DCM (50ml) in the waterbearing stratum.Merge organic layer, dry (MgSO 4), be evaporated to xanchromatic oil.Flash chromatography obtains two portions; First part is pure products, and second part of product contains the material of dimerization.The development second section causes the dimerization substance crystallization, removes by filter it.The merging filtrate and first chromatographic fraction obtain required product (800mg, 23%);
δ H(CDCl 3，400MHz)4.16(2H，s)，4.19(2H，s)，4.48
(2H，m)，5.26(1H，d)，5.37(1H，d)，5.95-6.06(1H，m)，6.74(2H，m)，7.09(1H，d).
(iii) 1, the preparation of 3-dihydro-2-thionaphthene-5-alcohol
With the stage (ii) allyl ethers (800mg 4.16mmol) is dissolved in THF (10ml), and (481mg 0.42mmol) handles, and (944mg 25mmol) handles to use sodium borohydride then with four (triphenyl phosphine) palladium.With mixture heating up to 45 ℃, under this temperature, stirred 15 hours then.After being cooled to room temperature, evaporation THF distributes resistates between 2M NaOH solution (25ml) and diethyl ether (25ml).Separate the waterbearing stratum, organic layer is stripped with 2M NaOH solution (25ml).Merge the waterbearing stratum, be neutralized to pH 7-8, with EtOAc extraction (2 * 25ml) with concentrated hydrochloric acid.Merge organic extract liquid, dry (MgSO 4), be evaporated to clarifying oil, be title phenol, place after fixing (540mg, 85%);
4.14(2H，s)，4.17(2H，s)，6.63-??6.68(2H，m)，7.04(1H，d).
Biological activity
By suppressing the ability of people's serotonin transporter picked-up serotonin, the biological activity of testing a large amount of compounds is as follows.
(i) cell cultures
(cell is grown in 37 ℃ and 5%CO to utilize the standard cell lines culture technique to cultivate the human embryonic kidney cell (HEK-293) of personnel selection serotonin transporter (hSERT), norepinephrine transporter (hNET) or dopamine transporter (hDAT) stable transfection 2Down, DMEM substratum (being supplemented with 10% dialysis foetal calf serum (FCS), 2mM l-glutamine and 250 μ g/ml Geneticins)).Gather in the crops the cell that is used to measure, obtain the cell suspension of 750,000 cells/ml.
The (ii) mensuration of inhibitor effectiveness
Whole test compounds are dissolved in 100%DMSO, are diluted in and measure in the damping fluid, obtain suitable experimental concentration.Mensuration is filtered in the base plate in 96 holes and is carried out.Cell (7500 cells/mensuration hole) was cultivated in the standard test damping fluid 5 minutes in advance, wherein contained test compound, standard inhibitor or compound carrier (1%DMSO).Add 3The H-5-hydroxy-tryptamine, 3The H-norepinephrine or 3H-Dopamine HCL substrate begins reaction.Respond all at room temperature, in shaking cultivating container, carry out.About the cultivation time, it is 5 minutes that hSERT and hDAT measure, and it is 15 minutes that hNET measures.Reaction is such terminated, utilizes vacuum manifold to remove reaction mixture, washs rapidly with ice-cold mensuration damping fluid then.Quantize to be combined in intracellular then 3The amount of H-substrate.
Assay plate at the microwave oven inner drying, is added the flicker fluid, measure radioactivity.The effectiveness of test compound is quantified as IC 50Value (suppressing the concentration that 50% radiolabeled substrate is entered the required test compound of cell by the specificity picked-up).
(iii) the standard test damping fluid is formed:
Hydrochloric acid Trizma (26mM)
NaCl(124mM)
KCl(4.5mM)
KH 2PO 4(1.2mM)
MgCl 2.6H 2O(1.3mM)
Xitix (1.136mM)
Glucose (5.55mM)
pH?7.40
CaCl 2(2.8mM)
Pargyline (100 μ M)
Annotate: adding CaCl 2Before the pH of damping fluid is adjusted to 7.4O with 1M NaOH with Pargyline.
(iv) location parameter is summed up
HSERT measures HDAT measures HNET measures
The cell concn in every mensuration hole 75,000 75,000 75,000
Concentration of substrate 3H-5HT (50nM) 3H-Dopamine HCL (200nM) 3H-norepinephrine (200nM)
The cultivation time (minute) 5 5 15
Serotonin reuptake transporter suppresses (SRI) IC 50The compound that value is less than or equal to 100nM comprises the title compound of embodiment 1-6,8-23,25,26,29-32,34-36,43,45-49,51,56-102,109-130.
Serotonin reuptake transporter suppresses (SRI) IC 50Value is less than or equal to 100nM and serotonin reuptake transporter restraining effect and comprises embodiment 1-6,9-13,16-19,21,22,25,26,29-32,34-36,43,45,47-49,51,57-88,90-102,109-121,123,124,127,129 title compound than dopamine reuptake or the strong 10 times compound of norepinephrine reuptake restraining effect.
Serotonin reuptake transporter suppresses (SRI) IC 50Value is less than or equal to 100nM and serotonin reuptake transporter restraining effect and comprises embodiment 1,2,4,5,9,12,13,16-19,21,22,25,26,29-32,34-36,43,45,48,49,58-80,83-88,90,92-97,99-102,111-113,115-118,120,123,124,127 title compound than dopamine reuptake or the strong 100 times compound of norepinephrine reuptake restraining effect.
Serotonin reuptake transporter suppresses (SRI) IC 50Value is less than or equal to 50nM and serotonin reuptake transporter restraining effect and comprises embodiment 1,2,4,9,12,17,18,26,29,30,36,43,45,48,49,60-66,68-75,78,79,90,92-94,100,102,116,118,124 title compound than dopamine reuptake and the strong 100 times compound of norepinephrine reuptake restraining effect.
Definitely, the serotonin reuptake transporter of embodiment 16 title compounds suppresses (SRI) IC 50Value is 4.7nM; The serotonin reuptake transporter of embodiment 29 title compounds suppresses (SRI) IC 50Value is 2.0nM; The serotonin reuptake transporter of embodiment 62 title compounds suppresses (SRI) IC 50Value is 3.7nM.

Claims (32)

1, general formula (I) compound, its pharmacy acceptable salt, solvate or polymorphic form:
Figure A0181484600021
Wherein:
R 1And R 2Can be identical or different, be H, C 1-C 6Alkyl or (CH 2) d(C 3-C 6Cycloalkyl), d=0,1,2 or 3 wherein; Perhaps R 1And R 2Constitute the azetidine ring with the nitrogen that they connected;
Z or Y are-SR 3, another Z or Y be halogen or-R 3R wherein 3Be the optional C that is replaced by fluorine independently 1-C 4Alkyl; But R 3Not CF 3
Perhaps Z is to be connected like this with Y, atom with interconnection, Z and Y constitute condensed 5 to 7 yuan of carbocyclic rings or heterocycles, it can be saturated, undersaturated or aromatics, wherein when Z and Y formation heterocycle, except carbon atom, contain the heteroatoms that one or two independently is selected from oxygen, sulphur and nitrogen in the key; Its condition is, if R 5Be fluorine, R 2Be methyl, then fused rings is not 1, and 3-dioxolane, Z and Y do not constitute the condensed benzyl ring together;
R 4And R 5Can be identical or different, be:
A-X, wherein A=-CH=CH-or-(CH 2) p-, wherein p is 0,1 or 2; X is hydrogen, F, Cl, Br, I, CONR 6R 7, SO 2NR 6R 7, SO 2NHC (=O) R 6, OH, C 1-C 4Alkoxyl group, NR 8SO 2R 9, NO 2, NR 6R 11, CN, CO 2R 10, CHO, SR 10, S (O) R 9Or SO 2R 10R 6, R 7, R 8And R 10Can be identical or different, be that hydrogen or optional independence are by one or more R 12The C that replaces 1-6Alkyl; R 9Be that optional independence is by one or more R 12The C that replaces 1-6Alkyl; R 11Be that hydrogen, optional independence are by one or more R 12The C that replaces 1-6Alkyl, C (O) R 6, CO 2R 9, C (O) NHR 6Or SO 2NR 6R 7R 12Be F, OH, CO 2H, C 3-6Cycloalkyl, NH 2, CONH 2, C 1-6Alkoxyl group, C 1-6Carbalkoxy or 5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O, and optional independence is by one or more R 13Replace; Perhaps R 6And R 7Constitute optional independence by one or more R with the nitrogen that they connected 134,5 or 6 yuan of heterocycles that replace; Perhaps
5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O, and optional independence is by one or more R 13Replace;
R wherein 13Be hydroxyl, C 1-4Alkoxyl group, F, C 1-6Alkyl, haloalkyl, halogenated alkoxy ,-NH 2,-NH (C 1-6Alkyl) or-N (C 1-6Alkyl) 2
2, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of claim 1 1And R 2Can be identical or different, be hydrogen or C 1-C 6Alkyl.
3,, wherein as Z or Y be-SR according to compound, its pharmacy acceptable salt, solvate or the polymorphic form of claim 1 or 2 3The time, R 3Be methyl or ethyl.
4, according to compound, its pharmacy acceptable salt, solvate or the polymorphic form of claim 1 or 2, wherein when Z and Y connected and composed the condensed ring, this ring was a heterocycle.
5, according to compound, its pharmacy acceptable salt, solvate or the polymorphic form of claim 4, wherein except carbon atom, contain one or two sulphur atom in the key.
6, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 6And R 7Can be identical or different, be hydrogen, optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group replaces 1-C 3Alkyl.
7, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 8Be hydrogen, hydroxyethyl or methyl.
8, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl.
9, according to compound, its pharmacy acceptable salt, solvate or the polymorphic form of arbitrary claim formerly, wherein p is 1 or 0.
10, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 4And R 5Can be identical or different, be
-(CH 2) p-X, wherein p is 0,1 or 2; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7, NR 8SO 2R 9, SR 10, SOR 9Or SO 2R 10, R wherein 6, R 7, R 8, R 9And R 10Be defined, perhaps as claim 1
5 or 6 yuan of heterocycles contain 1,2 or 3 heteroatoms that is selected from N, S and O.
11, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 4And R 5Can be identical or different, be
-(CH 2) p-X, wherein p is 0 or 1; X is hydrogen, hydroxyl, CONR 6R 7, SO 2NR 6R 7Or NR 8SO 2R 9R wherein 6And R 7Can be identical or different, be hydrogen or optional by hydroxyl ,-CONH 2Or C 1-C 3The C that alkoxyl group (being preferably methoxyl group) replaces 1-C 3Alkyl; R 8Be hydrogen, hydroxyethyl or methyl; Or R 9Be methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl; Perhaps
Triazolyl, imidazolyl or pyrazolyl.
12, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 4And R 5Not all be hydrogen.
13, according to compound, its pharmacy acceptable salt, solvate or polymorphic form, the wherein R of arbitrary claim formerly 4Be hydrogen.
14, according to compound, its pharmacy acceptable salt, solvate or the polymorphic form of claim 1, be selected from:
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(methylamino-) methyl]-benzsulfamide (embodiment 2);
The 3-[(dimethylamino) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group]-benzsulfamide (embodiment 12);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(dimethylamino) methyl]-benzsulfamide (embodiment 16);
4-[3-chloro-4-(methylthio group) phenoxy group]-the 3-[(dimethylamino) methyl]-benzsulfamide (embodiment 17);
The 3-[(dimethylamino) methyl]-4-[3-fluoro-4-(methylthio group) phenoxy group]-benzsulfamide (embodiment 18);
N, N-dimethyl-N-[2-(6-quinoline oxy) benzyl] amine (embodiment 29);
The 3-[(methylamino-) methyl]-4-(6-quinoline oxy)-benzsulfamide (embodiment 35);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-3-[(methylamino-) methyl]-benzamide (embodiment 60);
4-(2,3-dihydro-1-thionaphthene-5-base oxygen base)-N-methyl-3-[(methylamino-) methyl]-benzamide (embodiment 62);
The N-{3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] benzyl } Toluidrin (embodiment 75);
The 3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group]-benzamide (embodiment 79);
4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen base)-3-[(dimethylamino) methyl]-benzamide (embodiment 88);
The 3-[(dimethylamino) methyl]-4-[3-fluoro-4-(methylthio group) phenoxy group] phenyl }-methyl alcohol (embodiment 90);
The 3-[(dimethylamino) methyl]-4-(6-quinoline oxy)-benzamide (embodiment 100);
The 3-[(methylamino-) methyl]-4-(6-quinoline oxy)-benzamide (embodiment 102);
N-methyl-N-{3-[(methylamino-) methyl]-4-[3-methyl-4-(methylthio group) phenoxy group] phenyl } Toluidrin (embodiment 116); With
N-{4-(2,3-dihydro-1,4-benzo oxathiene-7-base oxygen base)-3-[(dimethylamino) methyl] phenyl }-Toluidrin (embodiment 124).
15, as medicine, as the defined compound of arbitrary claim formerly, its pharmacy acceptable salt, solvate or polymorphic form.
16, pharmaceutical preparation contains just like any defined compound of claim 1 to 14 or its pharmacy acceptable salt, solvate or polymorphic form and pharmaceutically acceptable auxiliary agent, diluent or carrier.
17, as any defined compound of claim 1 to 14, its pharmacy acceptable salt, solvate or the polymorphic form purposes in medicine is made, this medicine is used for the treatment of or prevents to involve the obstacle of monoamine transporter function regulating effect.
18, according to the purposes of claim 17, wherein this obstacle is obstacle or a sexual dysfunction due to depression, distractibility hyperkinetic syndrome, obsession, post-traumatic stress disorder, the abuse mentation material.
19, according to the purposes of claim 18, wherein this obstacle is a premature ejaculation.
20, treatment or prevention involve the method for obstacle of monoamine transporter function regulating effect, comprise with significant quantity as the patient's administration of any defined compound of claim 1 to 14, its pharmacy acceptable salt, solvate or polymorphic form to this class treatment of needs or prevention.
21, the method for treatment or prevention premature ejaculation, comprise with significant quantity as the patient's administration of any defined compound of claim 1 to 14, its pharmacy acceptable salt, solvate or polymorphic form to treatment of this class of needs or prevention.
22, increase the method for ejaculation latency, comprise significant quantity increased male sex's administration of ejaculation latency as any defined compound of claim 1 to 14, its pharmacy acceptable salt, solvate or polymorphic form to needs.
23, the method for preparing general formula (I) compound:
Figure A0181484600061
R wherein 1, R 2, R 4, R 5, X and Z be as claim 1 to 14 any one defined, comprise making general formula I a compound
Figure A0181484600062
Under the reaction conditions that is fit to, react, production I compound, wherein the reaction conditions of Shi Heing is:
I) if R 4/ R 5Be halogen, (Ia) and the halogenating agent that is fit to are reacted in inert solvent, this solvent can influence reaction sharply;
Ii) if R 4/ R 5Be-NO 2, (Ia) and the nitrating agent that is fit to are reacted in inert solvent, this solvent can influence reaction sharply, and temperature is a room temperature or following; Perhaps
Ii) if R 4/ R 5Be-SO 2NR 6R 7, then make intermediate sulfonyl chloride and essential formula HNR 6R 7Amine reacts in the solvent that is fit to.
24,, be used for preparation formula (Iq) compound, i.e. R wherein according to the method for claim 23 5Be-SO 2NR 6R 7And R 4Be the formula I compound of hydrogen,
Figure A0181484600071
Comprise
A) alternatively in the solvent that is fit to, formula Ia compound and chlorsulfonic acid are reacted, obtain formula XVIII compound
Then
B) and HNR 6R 7Reaction obtains formula (Iq) compound.
25, according to the method for claim 24, its Chinese style XVIII compound generates on the spot, just need not to separate and HNR 6R 7Reaction.
26, the method any according to claim 23 to 25 further comprises the step of preparation formula (Ia) compound just making formula (IIa) compound
Figure A0181484600081
With formula HNR 1R 2Compound or its salt form that is fit to and hydride reducer react production (Ia) compound in the solvent that is fit to.
27, as defined formula of claim 23 to 26 (IIa) or (XVIII) midbody compound.
28, the method for preparation I compound:
Figure A0181484600082
R wherein 1, R 2, R 4, R 5, X and Z be as claim 1 to 14 any one defined,
Comprise and make formula II compound
Figure A0181484600091
With formula HNR 1R 2Compound or its salt form that is fit to and hydride reducer react in the solvent that is fit to.
29,, further be included in coupling formula III compound under the suitable reaction conditions according to the method for claim 28
Figure A0181484600092
Wherein L is the leavings group that is fit to, for example halogen or sulphonate, and for example triflate or methanesulfonates,
With formula IV compound,
Figure A0181484600093
Obtain formula II compound.
30, as the defined formula II midbody compound of claim 28.
31, general formula (I) compound or its pharmacy acceptable salt, solvate or polymorphic form, wherein R 1, R 2, Y and Z be defined as claim 1; R 4And R 5Can be identical or different, be-(CH 2) p-A ', wherein p is 0,1 or 2, A ' is a polar group.
32, according to the compound of claim 23, wherein this polar group has the more negative value in ratio-0.1.
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