CN101228139A - Substituted benzo[d]isoxazol-3-yl amine compounds as analgesics - Google Patents
Substituted benzo[d]isoxazol-3-yl amine compounds as analgesics Download PDFInfo
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- CN101228139A CN101228139A CNA2006800264751A CN200680026475A CN101228139A CN 101228139 A CN101228139 A CN 101228139A CN A2006800264751 A CNA2006800264751 A CN A2006800264751A CN 200680026475 A CN200680026475 A CN 200680026475A CN 101228139 A CN101228139 A CN 101228139A
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Abstract
Disclosed are substituted benzo[d]isoxazol-3-yl amine compounds of general formula (I), which are suitable for the treatment of pain while being provided with an excellent affinity to the KCNQ2/3 K<+> channel and thus being suitable for the treatment of disorders or diseases that are transmitted at least in part through KCNQ2/3 K<+> channels.
Description
Technical field
The different azoles of the benzo that the present invention relates to replace [d]-3-base-amine compound, its preparation method contains the medicine of these compounds and the purposes that these compounds are used to prepare medicine.
Background technology
Pain, particularly neuralgic treatment has significance in medical science.Worldwide all there is the effectively demand of treatment pain.Be suitable for the patient and treat this urgent requirement of chronic and non-chronic pain targetedly---and be interpreted as be a kind of concerning the patient fruitful and gratifying pain therapy---also in many science monographs to some extent the record, these monographs all relate to use the field of analgesic agent or pain fundamental research recently.
Characteristics on the physiopathology of chronic pain are neuronic overexcites.Neuronic excitement very crucially is subjected to K
+The influence of channel activity is because determined the Ruhemembranpotential of cell also therefore also to determine the threshold value of excitability on their certain degrees.The heterozygosis K of molecular isoform KCNQ2/3 (Kv7.2/7.3)
+In each regional neurone of the present maincenter of channel table (hippocampus, tonsilla) and peripheral (Hinterwurzelganglien) neural system and the excitability of regulating them.KCNQ2/3 K
+The activity of passage can make the cytolemma hyperpolarization also therefore attach the decline that causes these being excited property of neurone electricity.The neurone of the expressing K CNQ2/3 of Hinterwurzelganglien can participate in the process (people such as Passmore, 2003) of pain stimulation from the peripheral transfer to the spinal cord.Correspondingly, can authenticate under the pain pattern that preclinical neurodynia and inflammation cause for KCNQ2/3 agonist Retigabine and have a kind of analgesic effect (Blackburn-Munro andJensen, 2003; People such as Passmore, 2003; People such as Dost, 2004).KCNQ2/3 K
+Therefore passage is a suitable starting point of treatment pain; Particularly treatment is selected from the pain, particularly neurodynia of pain that chronic pain, neurodynia, inflammation cause and myalgia people such as (, 2004) Nielsen and the pain that inflammation causes.In addition, KCNQ2/3 K
+Passage is for treating many other diseases such as migraine (US2002/0128277), cognitive disorders (Gribkoff, 2003), anxiety disorder (Korsgaard etc., 2005), the epilepsy (Wickenden etc., 2004) and the urinary incontinence (Streng etc., 2004) also are suitable targets.
Summary of the invention
Therefore, task of the present invention is to provide and is particularly suitable as the new compound that pharmacologically active principles is used for medicine, preferably be used for the treatment of to small part be by KCNQ2/3 K
+In the disorder of passage mediation or the medicine of disease.
Now be surprised to find, the different azoles of benzo [the d]-3-base-amine compound with replacement of the following stated general formula I is suitable for treating pain and also has outstanding for KCNQ2/3 K
+The affinity of passage, therefore also just be suitable for treating to small part be by KCNQ2/3 K
+The disorder or the disease of passage mediation.
Therefore, theme of the present invention is to have the different azoles of benzo [the d]-3-base-amine compound of the replacement of general formula I,
Wherein,
R
1, R
2, R
3And R
4Expression respectively independently of each other
H；F，Cl，Br，I；-CN；-NO
2；-SF
5；-NR
7R
8；-OR
9；-SR
10；-C(＝O)OR
11；
-(C＝O)NR
12R
13；-S(＝O)
2R
14；-C(＝O)R
15；-NR
16-S(＝O)
2R
17；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Represent saturated or undersaturated, do not replace or monobasic at least and optional alicyclic (cycloaliphatischen) group with at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via alkylidene group, alkenylene or the alkynylene of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or be connected via alkylidene group, alkenylene or the alkynylene of straight or branched,
R
5Expression
-C(＝S)NR
21R
22；
Perhaps represent straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with alkylidene group via straight or branched with monocycle or polycyclic member ring systems and be connected,
R
7And R
8Expression respectively independently of each other
H ,-C (=O) R
15Or the expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group, perhaps
R
7And R
8Saturated or undersaturated with forming as their nitrogen-atoms of connection that becomes annular atoms, do not replace or monobasic at least and optional heterocycle aliphatic series (heterocycloaliphatischen) group with at least one other heteroatoms as ring members,
R
9, R
10, R
11And R
16Expression respectively independently of each other
H；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Represent saturated or undersaturated, do not replace or monobasic at least and optional alicyclic group with at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
12And R
13Expression respectively independently of each other
H or expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group, perhaps
R
12And R
13With their nitrogen-atoms of connection as ring members form saturated or undersaturated, do not replace or monobasic at least and optional heterocycle aliphatic group with at least one other heteroatoms as ring members,
R
14Expression
-NR
7R
8；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least and optionally have at least one heteroatoms as the alicyclic group that becomes annular atoms, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
15And R
17Expression respectively independently of each other
Straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least and optional alicyclic group with at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
21And R
22Represent H independently of each other respectively,
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least and optional alicyclic group with at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
And described compound is racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
Preferably aforementioned (mixing) alicyclic group can be chosen wantonly and be respectively 1,2,3,4 or 5 substituting group and replace, and described substituting group be selected from independently of each other oxo (=O), sulfo-(=S), F, Cl, Br, I ,-CN ,-CF
3,-SF
5,-OH ,-O-C
1-5-alkyl ,-NH
2,-NO
2,-O-CF
3,-S-CF
3,-SH ,-S-C
1-5-alkyl ,-C
1-5-alkyl ,-C (=O)-OH ,-C (=O)-O-C
1-5-alkyl ,-NH-C
1-5-alkyl ,-N (C
1-5-alkyl)
2,-O-phenyl ,-O-benzyl, phenyl and benzyl, wherein group-O-phenyl ,-loop section of O-benzyl, phenyl and benzyl can be respectively 1,2,3,4 or 5 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br ,-OH ,-CF
3,-SF
5,-CN ,-NO
2,-C
1-5-alkyl ,-O-C
1-5Alkyl ,-O-CF
3,-S-CF
3, phenyl and-the O-benzyl.If alicyclic group has one or more for example 1,2,3,4 or 5 heteroatoms as ring members, then they can be preferably selected from oxygen, nitrogen and sulphur independently of each other.
As (mixing) alicyclic group, the example that can mention has cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidyl, tetrahydrofuran base, tetrahydro-thienyl (Tetrahydrothiophenyl), pyrrolidyl, piperidyl, morpholinyl, piperazinyl, thio-morpholinyl, THP trtrahydropyranyl, azepan base (Azepanyl), Diazesuberane base and dithiolane base (Dithiolanyl).
So-called monocycle or polycyclic member ring systems, being interpreted as in category of the present invention is that list or polycyclic are saturated or unsaturated and can have the alkyl of optional 1,2,3,4 or 5 heteroatoms as ring members, and it is selected from oxygen, nitrogen and sulphur independently of each other.A kind of like this monocycle or polycyclic member ring systems can be for example and aryl or heteroaryl-condensed (Cheng Huan (anneliert)).
If there is the member ring systems of polycyclic member ring systems such as dicyclo, then different rings can have different saturation ratios respectively separately independently of each other, and is promptly saturated or undersaturated.The member ring systems of dicyclo preferably.
The example with monocyclic member ring systems or polycyclic member ring systems condensed aryl of being worth mentioning is (1,3)-benzo dioxolyl and (1,4)-benzo two alkyl.
The preferred above-mentioned monocycle or the ring of polycyclic member ring systems are 5,6 or 7 yuan of rings and can choose 1,2,3,4 or 5 heteroatoms that has as ring members separately wantonly that they are selected from oxygen, nitrogen and sulphur independently of each other respectively.
The ring of same preferred above-mentioned monocycle or polycyclic member ring systems can be chosen 1,2,3,4 or 5 substituting group of respectively doing for oneself wantonly and replace, and described substituting group be selected from independently of each other oxo (=O), sulfo-(=S), F, Cl, Br, I ,-CN ,-CF
3,-SF
5,-OH ,-O (C=O)-C
1-5-alkyl ,-O-C
1-5-alkyl ,-NH
2,-NO
2,-O-CF
3,-S-CF
3,-SH ,-S-C
1-5-alkyl ,-C
1-5-alkyl ,-C (=O)-OH ,-C (=O)-O-C
1-5-alkyl ,-NH-C
1-5-alkyl ,-N (C
1-5-alkyl)
2,-O-phenyl ,-O-benzyl, phenyl and benzyl, wherein group-O-phenyl ,-loop section of O-benzyl, phenyl and benzyl can be respectively 1,2,3,4 or 5 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br ,-OH ,-CF
3,-SF
5,-CN ,-NO
2,-C
1-5-alkyl ,-O-C
1-5-alkyl ,-O-CF
3,-S-CF
3, phenyl and-the O-benzyl.
Equally also preferred above-mentioned aryl or heteroaryl can randomly be respectively 1,2,3,4 or 5 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br, I ,-CN ,-CF
3,-SF
5,-OH ,-O-C
1-5-alkyl ,-NH
2,-NO
2,-O-CF
3,-S-CF
3,-SH ,-S-C
1-5-alkyl ,-C
1-5-alkyl ,-C (=O)-OH ,-C (=O)-O-C
1-5-alkyl ,-NH-C
1-5-alkyl ,-N (C
1-5-alkyl)
2,-NH-C (=O)-O-C
1-5-alkyl ,-C (=O)-H ,-O (C=O)-C
1-5-alkyl ,-C (=O)-C
1-5-alkyl ,-C (=O)-NH
2,-C (=O) NH-C
1-5-alkyl ,-C (=O)-N (C
1-5-alkyl)
2,-S (=O)
2NH
2-S (=O)
2N (H) (C
1-5-alkyl);-S (=O)
2N (C
1-5-alkyl) (C
1-5-alkyl);-S (=O)
2Phenyl;-S (=O)
2-C
1-5-alkyl; Cyclohexyl; Cyclopentyl;-O-phenyl ,-O-benzyl, phenyl and benzyl, wherein group-O-phenyl ,-O-benzyl, phenyl, cyclohexyl, cyclopentyl ,-S (=O)
2The loop section of phenyl and benzyl can be respectively 1,2,3,4 or 5 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br ,-OH ,-CF
3,-CN ,-NO
2,-C
1-5-alkyl ,-O-C
1-5-alkyl ,-O-CF
3,-S-CF
3, phenyl and-the O-benzyl.
Equally also preferred above-mentioned heteroaryl all has 1,2,3,4 or 5 heteroatoms of the oxygen, nitrogen and the sulphur that are selected from independently of each other as ring members.
As aryl, the example of being worth mentioning has phenyl and naphthyl (comprising 1-naphthyl and 2-naphthyl).
As heteroaryl, the example of being worth mentioning has thienyl (Thiophenyl), furyl, pyrryl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridyl, imidazolyl, indyl, pseudoindoyl, benzo [b] furyl, benzo [b] thienyl, thiazolyl, azoles base, different azoles base, pyridazinyl, pyrazinyl, pyrimidyl, indazolyl, quinoxalinyl, quinolyl and isoquinolyl.
Above-mentioned aliphatic group, also be alkyl, thiazolinyl and alkynyl, can in moieties, have preferred 1-10 or 2-10 carbon atom and preferably replace with optional 1,2,3,4,5,6,7,8 or 9 substituting group, and described substituting group be selected from independently of each other F, Cl, Br, I ,-CN ,-NO
2,-OH ,-NH
2,-SH ,-O (C
1-5-alkyl) ,-S (C
1-5-alkyl) ,-NH (C
1-5-alkyl) ,-N (C
1-5-alkyl) (C
1-5-alkyl) ,-OCF
3, C
3-8-cycloalkyl and-SCF
3Thiazolinyl have at least one, the two keys of preferred 1,2,3 or 4 C-C and alkynyl have at least one, preferred 1,2,3 or 4 C-C triple bonds.
Alkyl is preferably selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, neo-pentyl and n-hexyl, and it may optionally be 1,2,3,4,5,6,7,8 or 9 substituting group and replaces, described substituting group be selected from independently of each other F, Cl, Br, I ,-CN ,-NO
2,-OH ,-NH
2,-SH ,-OCH
3,-O-C
2H
5,-SCH
3,-S-C
2H
5,-OCF
3,-SCF
3,-NH-CH
3,-N (CH
3)
2,-N (C
2H
5)
2With-N (CH
3) (C
2H
5).
In addition, thiazolinyl also is preferably selected from vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl-butene-2-Ji, 1-pentenyl, pentenyl, 3-pentenyl and 4-pentenyl, and they may optionally be 1,2 or 3 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br, I ,-CN ,-NO
2,-OH ,-NH
2,-SH ,-OCH
3,-O-C
2H
5,-SCH
3,-S-C
2H
5,-OCF
3,-SCF
3,-NH-CH
3,-N (CH
3)
2,-N (C
2H
5)
2With-N (CH
3) (C
2H
5).
In addition, also preferred alkynyl is selected from ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base and 3-butynyl, and they can choose wantonly by 1,2 or 3 substituting group and replace, described substituting group be selected from independently of each other F, Cl, Br, I ,-CN ,-NO
2,-OH ,-NH
2,-SH ,-OCH
3,-O-C
2H
5,-SCH
3,-S-C
2H
5,-OCF
3,-SCF
3,-NH-CH
3,-N (CH
3)
2,-N (C
2H
5)
2With-N (CH
3) (C
2H
5).
The different azoles of benzo [the d]-3-base-amine compound that preferably has the replacement of general formula I, wherein
R
1, R
2, R
3And R
4Expression respectively independently of each other
H；F；Cl；Br；I；-CN；-NO
2；-SF
5；-NR
7R
8；-OR
9；-SR
10；-C(＝O)OR
11；
-(C=O) NR
12R
13-S (=O)
2R
14-C (=O) R
15-NR
16-S (=O)
2R
17C
1-10-alkyl;
C
2-10-thiazolinyl; C
2-10-alkynyl;
R
5Expression
-C (=S) NR
21R
22Or (CHR
6)
n-R
25,
And n=1,2 or 3,
R wherein
6Expression H, C
3-8-cycloalkyl or C
1-6-alkyl,
And R
25Expression aryl or heteroaryl,
R
7And R
8Expression respectively independently of each other
H ,-C (=O) R
14Or C
1-10-alkyl, perhaps
R
7And R
8With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
9, R
10, R
11And R
16Expression respectively independently of each other
H; C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
R
12And R
13Expression respectively independently of each other
H or expression C
1-10-alkyl; Or
R
12And R
13With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
14Expression
-NR
7R
8C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl; R
15And R
17Expression respectively independently of each other
C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
R
21And R
22Represent H independently of each other respectively,
C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
Wherein,
Aforesaid C
1-10-alkyl, C
2-10-thiazolinyl and C
2-10It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is straight or branched and optional, and described substituting group is selected from F independently of each other; Cl; Br; COOH; COOC
1-4-alkyl;-CN;-OH;-SH;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Above-mentioned C
3-8-cycloalkyl all may optionally be 1,2,3,4 or 5 substituting group and replaces, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Above-mentioned Heterocyclylalkyl is respectively 4,5,6 or 7 yuan of rings, and they have 1 or 2 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group replacement, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2
Above-mentioned aryl is represented phenyl, anthryl or naphthyl respectively, and it can be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is selected from F independently of each other; Cl; Br; I;-CF
3-OCF
3-SCF
3C (=O) C
1-5-alkyl;
-NO
2Cyclohexyl;-O (C=O) C
1-2-alkyl;-SF
5-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-5-alkyl;-S-C
1-5-alkyl;-C (=O)-OH;-C (=O)-OC
1-5-alkyl;-NH
2-N (H) (C
1-5-alkyl);-N (C
1-5-alkyl) (C
1-5-alkyl);-C (=O) NH
2-C (=O) N (H) (C
1-5-alkyl);-C (=O) N (C
1-5-alkyl) (C
1-5-alkyl) ,-S (=O)
2NH
2-S (=O)
2N (H) (C
1-5-alkyl);-S (=O)
2N (C
1-5-alkyl) (C
1-5-alkyl);-S (=O)
2-phenyl;-S (=O)
2-C
1-5-alkyl; Phenyl; Phenoxy group; Benzyl; Benzyloxy; Thienyl (thienyl); Furyl and pyridyl,
Above-mentioned heteroaryl is respectively 5 or 6 yuan of rings, and they have 1,2 or 3 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group and replace, and described substituting group is selected from F independently of each other; Cl; Br; I;-CF
3-OCF
3-SCF
3-SF
5-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-5-alkyl;-S-C
1-5-alkyl;-C (=O)-OH;-C (=O)-OC
1-5-alkyl;-NH
2-N (H) (C
1-5-alkyl);-N (C
1-5-alkyl) (C
1-5-alkyl);-C (=O) NH
2-C (=O) N (H) (C
1-5-alkyl);-C (=O) N (C
1-5-alkyl) (C
1-5-alkyl) ,-S (=O)
2NH
2-S (=O)
2N (H) (C
1-5-alkyl);-S (=O)
2N (C
1-5-alkyl) (C
1-5-alkyl);-S (=O)
2Phenyl;-S (=O)
2-C
1-5-alkyl; Phenyl; Phenoxy group; Benzyl; Thienyl (thienyl); Furyl and pyridyl,
And described compound is racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
Particularly preferably be the compound of formula I of the present invention,
R
1, R
2, R
3And R
4, expression respectively independently of each other
H; F; Cl; Br; I;-CN;-NR
7R
8-OR
9-SR
10C
1-4-alkyl; C
2-4-thiazolinyl or C
2-4-alkynyl;
R
5Expression
-C(＝S)NR
21R
22，
Or
-(CHR
6)
n-R
25，
And n=1,2 or 3,
R wherein
6Expression H or C
1-6-alkyl,
And R
25Expression aryl or heteroaryl,
R
7And R
8Expression respectively independently of each other
H ,-C (=O) R
15Or C
1-4-alkyl, perhaps
R
7And R
8With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
9, R
10Expression respectively independently of each other
H; C
1-4-alkyl, C
2-4-thiazolinyl, C
2-4-alkynyl; C
3-8-cycloalkyl;-(C
1,2 or 3-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1,2 or 3-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1,2 or 3-alkylidene group)-aryl;-(C
1,2 or 3-alkylidene group)-heteroaryl; R
21And R
22Expression respectively independently of each other
H; C
1-10-alkyl; C
2-10-thiazolinyl, C
2-4-alkynyl; C
3-8-cycloalkyl;-(C
1,2 or 3-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1,2 or 3-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1,2 orThe 3-alkylidene group)-aryl;-(C
1,2 or 3-alkylidene group)-heteroaryl;
Wherein,
Aforesaid C
1-10-alkyl, C
2-10-thiazolinyl and C
2-10It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is straight or branched and optional, and described substituting group is selected from F independently of each other; Cl; Br;-CN; COOH; COOC
1-4-alkyl;-OH;-SH;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Aforesaid C
1-4-alkyl, C
2-4-thiazolinyl and C
2-4It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is straight or branched and optional, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-OCH
3With-NH
2,
Above-mentioned C
3-8-cycloalkyl all may optionally be 1,2,3,4 or 5 substituting group and replaces, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-CH
3-C
2H
5-OCH
3With-NH
2,
Above-mentioned Heterocyclylalkyl is respectively 4,5,6 or 7 yuan of rings, and they have 1 or 2 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group replacement, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-CH
3-C
2H
5-OCH
3With-NH
2
Above-mentioned aryl is represented phenyl, anthryl or naphthyl respectively, and it can be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is selected from F independently of each other; Cl; Br;-CF
3-OCF
3-SCF
3 
-NO
2-C (=O) C
1-2-alkyl; Cyclohexyl;-O (C=O) C
1-2Alkyl;
-SF
5-CN;-OH; Methyl; Ethyl; N-propyl; Sec.-propyl; Normal-butyl; Isobutyl-; Sec-butyl; The tertiary butyl; Methoxyl group; Oxyethyl group;-NH
2-N (CH
3)
2-N (C
2H
5)
2Phenyl; Benzyloxy; Phenoxy group; Benzyl; Thienyl (thienyl); Furyl and pyridyl,
Above-mentioned heteroaryl is represented furyl, thienyl (thienyl (Thiophenyl)) or pyridyl respectively and may optionally be 1,2,3,4 or 5 substituting group to replace, and described substituting group is selected from F independently of each other; Cl; Br;-CF
3-OCF
3-SCF
3-SF
5-CN;-OH; Methyl; Ethyl; N-propyl; Sec.-propyl; Normal-butyl; Isobutyl-; Sec-butyl; The tertiary butyl; Methoxyl group; Oxyethyl group;-NH
2-N (CH
3)
2-N (C
2H
5)
2Phenyl; Phenoxy group; Benzyl; Thienyl (thienyl); Furyl and pyridyl,
And described compound is racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
Preferred R wherein
5Expression-C (=S) NR
21R
22Compound.
Also preferred R wherein
5Expression-(CHR
6)
n-R
25Compound.
Also preferred in addition wherein n represents 1 compound.
Particularly preferred compound, wherein R
21Represent H and R
22Expression benzyl, phenyl, pyridyl, naphthyl and styroyl, and it can be unsubstituted or with methyl, ethyl, sec.-propyl, Cl, F, Br, NO
2, ethanoyl, CN, COOH, COOC
1-4-alkyl, methoxyl group, oxyethyl group, N (CH
3)
2, N (C
2H
5)
2,
CF
3, SCH
3One replacement or polysubstituted; Perhaps represent C
1-10-alkyl, and it can be side chain or non-side chain, saturated or undersaturated, do not replace or with OCH
3, COOCH
3And COOC
2H
5Replace; Expression C
3-6-cycloalkyl, wherein said cycloalkyl can be via CH
2Group bonding; Expression C
5-6-Heterocyclylalkyl, wherein said Heterocyclylalkyl can be via CH
2Group bonding.
Extremely preferred compound, wherein R
21Represent H and R
22Expression benzyl, phenyl, 2-aminomethyl phenyl, styroyl, 2-isopropyl phenyl, 2-chloro-phenyl-, 4-fluoro benzyl, 1-(4-fluoro phenyl) ethyl, 4-chloro benzyl, 4-chloro-styroyl, 4-nitrophenyl, 4-acetylphenyl, 3-carboxyl phenyl, 3-methyl benzoic acid ester, 4-ethylamino benzonitrile acid esters, 2,6-diethyl phenyl, 3-chloro-4-methyl-phenyl, 2-methoxy ethyl, 3-methoxy-propyl, cyclopentyl, cyclohexyl, 3-pyridyl, 4-dimethylaminophenyl, 4-diethylamino phenyl, CH
2COOCH
3, CH (CH
3) COOC
2H
5, CH (CH
3) CH
2COOC
2H
5Cyclohexyl methyl, the 4-ethoxyl phenenyl, 3, the 4-Dimethoxyphenyl, the 1-naphthyl, 3,4, the 5-trimethoxyphenyl, 2,3,4,5, the 6-pentafluorophenyl group, the benzo dioxolyl, 4-fluoro phenyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, allyl group, 2-methyl-prop-2-thiazolinyl, the 2-nitrophenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, the 4-trifluoromethyl, cyclopropyl, 2-methyl sulfane base phenyl, 3-methyl sulfane base phenyl, 4-methyl sulfane base phenyl, 3, the 5-3,5-dimethylphenyl, ethyl morpholine, ((4-propyl group)-cyclohexyl) phenyl, 4-bromo-2-trifluoromethyl, n-octyl, n-nonyl, the tetrahydrofuran (THF) ylmethyl, the 2-ethylphenyl, the 4-cyano-phenyl, the 3-cyano-phenyl, 2, the 6-diisopropyl phenyl, n-pentyl, n-hexyl, sec-butyl, the propyl group morpholine, 5-chloro-2-p-methoxy-phenyl, 4-chloro-3-trifluoromethyl, the 3-chloro-phenyl-, the 1-phenylethyl, CH (CH
3) COOCH
3, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, CH
2CH
2COOC
2H
5, 2-methyl benzoic acid ester, 4-methyl benzoic acid ester, 2-ethylamino benzonitrile acid esters, 2-fluoro phenyl, 2-methoxyl group-5-chlorophenyl or 2, the 4-Dimethoxyphenyl.
In addition, also preferred compound, wherein R
6Expression H.
Preferred R wherein equally also
6Expression CH
3Compound.
Special also preferred compound, R wherein
25Expression phenyl, anthryl, pyridyl, thienyl or furyl, and all be unsubstituted or with CF
3, SCF
3, C
1-4-alkyl, Cl, NO
2, O-ethanoyl, OCH
3, F, O-phenyl, OCF
3, Br, O-benzyl, O-allyl group, phenyl, I, CN or OH one or polysubstituted, the phenyl that does not preferably replace or replace with above-mentioned group.
Extremely particularly preferred compound, wherein R
25Expression 4-three fluoro aminomethyl phenyls, 4-SCF
3-phenyl, 2-aminomethyl phenyl, phenyl, anthryl, 4-Cl-phenyl, 4-OCF
3-phenyl, 4-n-butylphenyl, 3 (3-CF
3-phenoxy group)-phenyl, 4-OCHF
2-phenyl; 3; the 5-3,5-dimethylphenyl; 3-bromo-4-p-methoxy-phenyl; 4-benzyloxy-3; the 5-3,5-dimethylphenyl; the 3-nitrophenyl; 3-methoxyl group-4-(ethanoyl methyl)-phenyl; 2; 4; the 5-trimethoxyphenyl; the 4-ethylphenyl; 3; the 4-dichlorophenyl; 2; 3; the 5-trifluorophenyl; the 4-Phenoxyphenyl; 3-chloro-4-fluoro phenyl; 3-benzyloxy-phenyl; 3-bromo-4; the 5-Dimethoxyphenyl; 3-fluoro-2-aminomethyl phenyl; 2-chloro-3-trifluoromethyl; 3-chloro-2-fluoro-5-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 4-(allyloxy)-phenyl; 2-(benzyloxy)-4; the 5-Dimethoxyphenyl; 2-phenyl-phenyl; 2; 3; 4-trifluoro-benzene base; 2-fluoro-5-trifluorophenyl; 4-methoxyl group-3-aminomethyl phenyl; 2-fluoro-3-chloro-phenyl-; 3; 4-phenyl-difluoride base; 2; the 6-dichlorophenyl; the 3-iodine substituted phenyl; 3-iodo-4, the 5-Dimethoxyphenyl; the 2-cyano-phenyl; the 4-hydroxy phenyl; 3,4-3,5-dimethylphenyl or 3-OCF
3-phenyl.
Highly preferred The compounds of this invention is selected from following material:
The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl-phenyl)-ethyl]-amine
The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl sulphur alkyl-phenyl)-ethyl]-amine
The different azoles of 1-benzo [d]-3-base-3-benzyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-phenyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-o-tolyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-styroyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-sec.-propyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-chloro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-benzyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-[1-(4-fluoro-phenyl)-ethyl]-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-chloro-benzyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-[2-(4-chloro-phenyl)-ethyl]-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-nitrophenyl)-thiocarbamide
The different azoles of 1-(4-ethanoyl-phenyl)-3-benzo [d]-3-base-thiocarbamide
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-phenylformic acid
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-methyl benzoate
4-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl benzoate
The different azoles of 1-benzo [d]-3-base-3-(2,6-diethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3-chloro-4-methyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-methoxyl group-ethyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3-methoxyl group-propyl group)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-cyclopentyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-encircles not hexyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-pyridin-3-yl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-dimethylamino-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-diethylamino-phenyl)-thiocarbamide
(the different azoles of 3-benzo [d]-3-base-thioureido)-ritalin
2-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl propionate
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl butyrate
The different azoles of 1-benzo [d]-3-base-3-cyclohexyl methyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-oxyethyl group-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3,4-dimethoxy-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-pentafluorophenyl group-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-naphthalene-1-base-thiocarbamide
The different azoles of 1-benzo [1,3] dioxole-5-ylmethyl-3-benzo [d]-3-base-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-methyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-ethyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-propyl group-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-sec.-propyl-thiocarbamide
The different azoles of 1-benzo [the d]-3-base-3-tertiary butyl-thiocarbamide
The different azoles of 1-allyl group-3-benzo [d]-3-base-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-methyl-allyl group)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-nitro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-cyclopropyl-thiocarbamide
2-[3-(the different azoles of 4-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate
1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-o-tolyl-thiocarbamide
1-benzyl-3-(the different azoles of 4-chloro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-isobutyl--thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-is to phenmethyl-thiocarbamide
1-(3-chloro-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3,5-dimethyl-phenyl)-thiocarbamide
1-benzyl-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-propyl group)-thiocarbamide
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl butyrate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-phenylformic acid
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-oxyethyl group-phenyl)-thiocarbamide
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl benzoate
4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-sulfonyl urea]-ethyl benzoate
1-(4-ethanoyl-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(2-chloro-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(4-diethylin-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide
2-{3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thioureido }-methyl propionate
1-benzo [1,3] dioxolyl-5-ylmethyl-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-[4-(4-propyl group-cyclohexyl)-phenyl]-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-(4-bromo-2-trifluoromethyl-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-(4-methoxyl group-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
3-{3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thioureido }-ethyl propionate
The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-octyl group-thiocarbamide
The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-nonyl-thiocarbamide
The different azoles of 1-cyclopropyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclopentyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclohexyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclohexyl methyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
1-(4-dimethylamino-phenyl)-3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-allyl group-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide
[3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thioureido]-ritalin
1-(2-sec.-propyl-phenyl)-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 5-methyl-benzo [d]-3-yl)-3-(4-trifluoromethyl)-thiocarbamide
2-[3-(the different azoles of 5-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate
1-(the different azoles of 5-fluoro-benzo [d]-3-yl)-3-(tetrahydrofuran (THF)-2-ylmethyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-fluorophenyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-ethylphenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-fluoro-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(2-fluoro-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-cyclopentyl-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-cyano group-phenyl)-thiocarbamide
3-[3-(the different azoles of 6-chloro-benzo [d]-3-yl)-thioureido]-phenylformic acid
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-(3,4-dimethoxy-phenyl)-thiocarbamide
1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-naphthalene-1-base-thiocarbamide
1-benzo [1,3] dioxolyl-5-ylmethyl-3-(the different azoles of 6-bromo-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 6-fluoro-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(3-cyano group-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(2-chloro-6-methyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(2,6-di-isopropyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-methyl-thiocarbamide
1-ethyl-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-propyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-amyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-hexyl-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-octyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-nonyl-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-isobutyl--thiocarbamide
1-allyl group-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-p-methylphenyl-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(3-morpholine-4-base-propyl group)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide
1-(4-chloro-benzyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide
1-(5-chloro-2-methoxyl group-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(4-chloro-3-trifluoromethyl-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(2,4-dimethoxy-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide
The different azoles of benzo [d]-3-base-(3-methyl-butyl)-amine
(the different azoles of 5-fluoro-benzo [d]-3-yl)-(2-methyl-benzyl)-amine
N4, N4-dimethyl-N3-(3-phenyl-propyl group)-different azoles-3 of benzo [d], 4-diamines
N3-butyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
Anthracene-9-ylmethyl-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(4-chloro-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-nitro-benzyl)-amine
The different azoles of acetic acid-4-[(6-chloro-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester
The different azoles of acetic acid-4-[(6-bromo-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester
The different azoles of benzo [d]-3-base-(3,4-two chloro-benzyls)-amine
The different azoles of benzo [d]-3-base-(2,4,5-trimethoxy-benzyl)-amine
The different azoles of benzo [d]-3-base-(4-ethyl-benzyl)-amine
(the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-two chloro-benzyls)-amine
The different azoles of benzo [d]-3-base-(2,3,5-three fluoro-benzyls)-amine
(the different azoles of 6-chloro-benzo [d]-3-yl)-(4-phenoxy group-benzyl)-amine
(3-chloro-4-fluoro-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine
The different azoles of benzo [d]-3-base-(4-trifluoromethyl-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-methyl-amyl group)-amine
N4, N4-dimethyl-N3-(2,3,4-three fluoro-the benzyls)-different azoles-3 of benzo [d], 4-diamines
N3-(2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
The different azoles of benzo [d]-3-base-(4-trifluoromethoxy-benzyl)-amine
(the different azoles of 5-fluoro-benzo [d]-3-yl)-(4-trifluoromethoxy-benzyl)-amine
The different azoles of benzo [d]-3-base-(4-trifluoromethyl sulfane base-benzyl)-amine
(4-butyl-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine
The different azoles of (the different azoles of 5-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine benzo [d]-3-base-(2-fluoro-4-trifluoromethyl-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(4-trifluoromethoxy-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-[3-(3-trifluoromethyl-phenoxy group)-benzyl]-amine
(4-difluoro-methoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(3,5-dimethyl-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine
(3-bromo-4-methoxyl group-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(4-benzyloxy-3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(4-butyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine
(3-benzyloxy-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
N3-(3,5-dimethyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
N3-(4-butyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
(the different azoles of 5-bromo-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine
(3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine
N3-(3-fluoro-2-methyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(2-chloro-3-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(3-chloro-2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine
(4-allyl group oxygen base-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
The different azoles of benzo [d]-3-base-(2-benzyloxy-4,5-dimethoxy-benzyl)-amine
(2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine
N3-(2-benzyloxy-4,5-dimethoxy-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-biphenyl-2-ylmethyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-iodo-benzyl)-amine
(2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(the different azoles of 4-fluoro-benzo [d]-3-yl)-(3-iodo-4,5-dimethoxy-benzyl)-amine
The different azoles of 2-[(5-methyl-benzo [d]-3-base is amino)-methyl]-benzonitrile
Butyl-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-amine
(3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 5-methyl-benzo [d]-3-yl)-amine
The different azoles of 4-[(4-chloro-benzo [d]-3-base is amino)-methyl]-phenol
(the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-dimethyl-benzyl)-amine
(the different azoles of 4-chloro-benzo [d]-3-yl)-(3-chloro-2-fluoro-benzyl)-amine
(3,4-two fluoro-benzyls)-(the different azoles of 5-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 6-bromo-benzo [d]-3-yl)-(2,6-two chloro-benzyls)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(3-trifluoromethoxy-benzyl)-amine,
And their corresponding separately salt, particularly their hydrogenchloride (Hydrochlorid) additive salt and their optional respectively solvates.
Another theme of the present invention is a kind of method that is used to prepare the different azoles of benzo [the d]-3-ylamine compounds of replacement of the present invention, according to this method, be preferably selected from diethyl ether, tetrahydrofuran (THF), acetonitrile, methyl-sulphoxide, in the reaction medium of dimethyl formamide and methylene dichloride, there is alkali, preferably there is at least a alkali metal alcoholates, be selected from potassium methylate particularly preferably in existence, sodium methylate, under the condition of the alkali metal alcoholates of the tertiary butyl (tert-butylat) potassium and tertiary butyl sodium, preferably under 20 ℃ to 100 ℃ temperature, make the 2-fluoro-benzonitrile compound of the optional general formula I I that replaces and acethydroximic acid (the Acethydroxams ure) reaction of formula III, generate the compound of general formula I
Radicals R wherein
1, R
2, R
3And R
4Has above-mentioned implication
Radicals R wherein
1-R
4Have above-mentioned implication and radicals R
5The expression hydrogen group,
It is then optional with its purification and/or optionally separating,
It is chosen wantonly in the reaction medium that is preferably selected from acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol and respective mixtures, make itself and at least a wherein R
22General formula with above-mentioned implication is S=C=N-R
22Lsothiocyanates optional have at least a alkali, preferably there being at least a triethylamine, 4 that is selected from, react under the condition of the alkali of 4-dimethylaminopyridine and diisopropylethylamine, generate at least a compound, R wherein with general formula I
1, R
2, R
3, R
4Have above-mentioned implication and R
5Expression-C (=S)-NR
21R
22, and R
22Have above-mentioned implication and R
21The expression hydrogen group, then with they optional purifications and/or optionally separating,
Make optional at least a have general formula I and R wherein
1, R
2, R
3, R
4Have above-mentioned implication and R
5Expression-C (=S)-NR
21R
22And R
22Have above-mentioned implication and R
21The compound of expression hydrogen group, and in the reaction medium that is preferably selected from acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol and respective mixtures, there is at least a alkali, preferably under the condition that has at least a metal hydride salt or metal alkoxide, be selected from particularly preferably in existence under the condition of the metal hydride salt of sodium hydride, potassium hydride KH, potassium tert.-butoxide, sodium tert-butoxide, potassium methylate, sodium methylate, sodium ethylate and potassium ethylate or metal alkoxide, have a general formula LG-R with at least a
21And wherein LG represent leavings group, preferably represent halogen atom, especially preferably represent chlorine atom and R
21Had the compound reaction of the above-mentioned implication outside the hydrogen, generated the compound of at least a general formula I, and with its optional purification and/or optionally separating,
Perhaps
Make optional at least a have general formula I and R wherein
1, R
2, R
3, R
4Have above-mentioned implication and R
5The compound of expression H, in the reaction medium that is preferably selected from by acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol, DCM, trifluoroacetic acid and respective mixtures, there is at least a alkali, preferably under the condition that has at least a metal hydride salt or metal alkoxide or triethyl silicane, particularly preferably in there being triethyl silicane, be selected under the condition of the metal hydride salt of sodium hydride, potassium hydride KH, potassium tert.-butoxide, sodium tert-butoxide, potassium methylate, sodium methylate, sodium ethylate and potassium ethylate or metal alkoxide, have a general formula R with at least a
30C (=O) H or R
6C (O) R
25And R wherein
6And R
25Has above-mentioned implication and R
30The expression straight or branched, saturated or unsaturated, do not replace or monobasic at least aliphatic group; Represent that more not replacement or monobasic at least aryl or heteroaryl and its can or encircle member ring systems with monocycle and condense; Expression does not replace or monobasic at least aryl or heteroaryl and its can be with monocycles or encircle that member ring systems condenses more and react via the compound that the alkylidene group of straight or branched is connected, generate at least a compound with general formula I, and optional with its purification and/or optionally separating.
If radicals R in certain compound
30Definition is arranged, then just mean in this case, R in the structure of general formula I
5Expression CH
2R
30
Be used for the chemical reagent of above-mentioned reaction and reacted constituent and all be commercially available or all can make according to method routine, that the technician knows separately.
In addition, above-mentioned reaction also can be all routine, under the known condition of technician, for example carrying out aspect pressure, temperature, protective atmosphere or the composition interpolation order.Choose the technological process that under each condition, to determine the best by simple test in advance wantonly by the technician.
If wish and/or need, can be separately according to routine, the known method of technician is purified and/or separate according to resulting intermediates of above-mentioned reaction and finished product.Suitable method of purification is for example extraction process and chromatography such as column chromatography or prefabricated chromatography and HPLC.
Each purification and/or the sepn process of all above-mentioned those method stepss and intermediate product or end product can preferably be carried out in nitrogen atmosphere or in the argon atmospher partially or completely in inert atmosphere.
The different azoles of the benzo of replacement of the present invention [d]-3-base-amine compound can be separated into its free alkali, acceptable salt on the form, particularly physiology of its free acid and corresponding separately salt.
The free alkali of the different azoles of the benzo of each replacement of the present invention [d]-3-base-amine compound can be for example by reacting with inorganic or organic acid, preferably be converted into corresponding salt, the form of acceptable salt on the preferred physiology with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, carbonic acid, formic acid, acetic acid, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid, tartrate, amygdalic acid, fumaric acid, lactic acid, citric acid, L-glutamic acid or l-asparagine acid-respons.
The free alkali of the different azoles of the benzo of each replacement of the present invention [d]-3-base-amine compound equally can be with free acid or for the salt of sugar substance (Zuckerersatzstoff), as asccharin, encircle sulfonate or Acesulfam reaction and change acceptable salt on the corresponding physiology into.
Correspondingly, the free acid of the different azoles of benzo [d]-3-base-amine compound of replacing of the present invention can be by changing acceptable salt on the corresponding physiology into suitable alkali reaction.The example of being worth mentioning is an alkali metal salt, alkaline earth salt or ammonium salt [NH
xR
4-x]
+, x=0 wherein, 1,2,3 or 4 and R represents the C of straight or branched
1-4-alkyl.
The different azoles of benzo [d]-3-base-amine compound that the present invention replaces can be chosen wantonly equally as the corresponding acid of these compounds, corresponding alkali or salt, according to routine, the known method of technician and with its solvate forms, preferably the form of its hydrate obtains.
If what the different azoles of benzo [d]-3-base-amine compound that the present invention replaces obtained after its preparation is the form of mixtures of its steric isomer, the form of mixtures of its racemic modification form or other various enantiomorphs and/or diastereomer preferably, then can according to routine, the known method of technician separates it and optionally separating.The example of being worth mentioning is a chromatography, the liquid chromatography under normal pressure or the elevated pressures particularly, preferred MPLC-and HPLC-method, and fractionation crystallization.And, can for example utilize HPLC on the stationary phase of chirality or utilize crystallization process with each enantiomorph and chiral acid, the diastereoisomeric salt that forms as (+)-tartrate, (-)-tartrate or (+)-10-camphorsulfonic acid is separated from each other.
The different azoles of the benzo of replacement of the present invention [d]-3-base-amine compound and each corresponding acid, alkali, salt and solvate all are suitable as the active constituents of medicine in the medicine.
Therefore, another theme of the present invention is to contain the different azoles of at least a replacement benzo of the present invention [d]-3-base-amine compound and chooses any one kind of them or the medicine of multiple pharmaceutically acceptable auxiliary agent.
Described medicine of the present invention is applicable to be influenced the KCNQ2/3-passage and particularly plays agonism.
Medicine of the present invention preferably is applicable to treats to small part because the disorder or the disease of the mediation of KCNQ2/3-passage.
Medicine of the present invention also preferably is applicable to one or more diseases of treatment, and it is selected from pain; Epilepsy; The anxiety disorder and the urinary incontinence, described pain are preferably selected from pain, the migraine that acute pain, chronic pain, neurodynia, myalgia and inflammation cause.The suitable especially pain that is used for the treatment of of medicine of the present invention, pain and myalgia that more preferred suitable treatment chronic pain, neurodynia, inflammation cause.
Theme more of the present invention be the different azoles of at least a replacement benzo of the present invention [d]-3-base-amine compound and optional one or more pharmaceutically acceptable auxiliary agents preparation in order to treat to small part be purposes aspect the medicine of the disorder of KCNQ2/3-passage mediation or disease.
The different azoles of preferably at least a replacement benzo of the present invention [d]-3-base-amine compound and one or more optional pharmaceutically acceptable auxiliary agents are used for the treatment of pain in preparation, are preferably selected from the pain that acute pain, chronic pain, neurodynia, myalgia and inflammation cause; Migraine; The purposes of the medicine aspect of epilepsy, anxiety disorder and the urinary incontinence.
The different azoles of particularly preferred at least a replacement benzo of the present invention [d]-3-base-amine compound and one or more optional pharmaceutically acceptable auxiliary agents are used for the treatment of pain in preparation, extremely preferably the purposes of the medicine aspect of the pain that causes of chronic pain, neurodynia, inflammation and myalgia.
Medicine of the present invention can be used as liquid, semisolid or solid pharmaceutical dosage formulation, for example injection solution, drops, juice, syrup, spray, suspension, tablet, application, capsule, patch, suppository, ointment, creme, lotion, gel, emulsion, aerocolloidal form or many particle form, for example as pill or particulate form, choose wantonly and can be pressed into tablet, be filled in the capsule or be suspended in the liquid, and also can itself form administration.Except the different azoles of at least a replacement benzo of the present invention [d]-3-base-amine compound; medicine of the present invention also contains acceptable drug auxiliary agent on other the physiology usually, and it preferably can be selected from solid support material, filler, solvent, thinner, surfactant, pigment, sanitas, disintegrating agent, antiseize paste, lubricant, perfume compound and binding agent.
The selection of acceptable assistant and consumption thereof is depended in oral, subcutaneous, the parenteral, intravenously, intraperitoneal, intracutaneous, intramuscular, nose of medicament on the physiology, cheek, rectum or part ( rtlich) be as being applied in infection site on the skin, mucous membrane or being applied in the method for application of eye.For Orally administered, preferred suitable be the preparation of tablet, sugar-pill, capsule, particle, pill, drops, juice and syrup form, for using of parenteral, part and suction form suitable be solution, suspension, the drying agent and the sprays of (rekonstituierbare) that can be easy to prepare again.
The different azoles of replacement benzo [the d]-3-base-amine compound that is used for medicine of the present invention can sustained release dosage (Depot), solubilized form or paste form, and chooses wantonly under the situation of having added the medicament that promotes dermal osmosis and exist as suitable percutaneous drug administration preparation.The dosage form of oral or percutaneous dosing also can each replacement of the present invention of slowly-releasing the different azoles of benzo [d]-3-base-amine compound.
Medicament drug utilization routine of the present invention, well known in the prior art, equipment, method and technology are prepared, for example be recorded in " Remingtons Pharmaceutical Sciences ", Herausgeber A.R.Gennaro, the 17th edition, Mack publishing company, Easton, Pa, 1985, particularly in the 8th part, those in 76 to 93 chapters.Corresponding record content is incorporated herein by reference and as the part of disclosure.
The amount that the different azoles of each replacement benzo of the present invention [d]-3-base-amine compound is applied to the patient can different and for example depend on patient's body weight or the age and depend on method of application, the symptom of disease and severity.Usually, the dosage of at least a such The compounds of this invention is 0.005 to 100mg/kg, preferred 0.05 to 75mg/kg weight in patients.
Below will utilize some embodiment to set forth the present invention.These set forth are exemplary and be not to be restriction to whole inventive concept.
Embodiment
Embodiment:
The yield of obtained compound is not an optimization.
All temperature all are without gauged.
Abbreviation:
Aq. aqueous
The APCI atmospheric pressure chemical ionization
The DCM methylene dichloride
The DMF dimethyl formamide
The DMSO methyl-sulphoxide
The EtOAc ethyl acetate
Ges. saturated
H hour
The min branch
The NMR nuclear magnetic resonance spectrum
The RT room temperature
Used chemical reagent and solvent all are that can buy from traditional supplier (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCl etc.) or synthetic according to the known method of technician.
Use E.Merck, the Kieselgel 60 (0.040-0.063mm) of Darmstadt company is as the stationary phase of column chromatography.
Utilize the HPTLC-matrix band, E.Merck, the Kieselgel 60F 254 of Darmstadt company carry out the thin-layer chromatography test.
The mixing ratio of solvent, dispersion agent is always represented with the volume/volume ratio for chromatography test.
Analyze by HPLC-MS or NMR.The purity that in most of the cases obtains is＞80%.
The general process of preparation benzisoxa azoles basic structure:
The basic structure of benzisoxa azoles of the present invention is similar to rules content (M.G.Palermo, the Tetrahedron Lett.1996 of Palermo; 37; 17; 2885-2886) be prepared.The corresponding content of describing is introduced the part that therefore this also also regard the disclosure of invention as a reference as.Different with described rules, at least can be by the precipitation of the corresponding HCl-salt benzisoxa azole compounds of purifying.Process:
In three-necked flask, acethydroximic acid (1.1 equivalent) is suspended in DMF (1.45ml/mmol acethydroximic acid).In rare gas element, add tertiary butyl sylvite (1.1 equivalent).The 30min that stirs the mixture under the room temperature also then adds the optional 2-fluoro-benzonitrile (1 equivalent) that replaces.Reaction mass is warming to 50 ℃ and stir 1h under this temperature.Join in the mixture of forming by the saturated NaCl solution and the vinyl acetic monomer of equal volume amounts (1.8ml/mmol acethydroximic acid) reaction mixture and the good 30min of stirring after the cooling.Separate each mutually also with acetic ester aqueous phase extracted 3 times (respectively being the 0.8ml/mmol acethydroximic acid).The purification organic phase is also washed 3 times with saturated NaCl solution (respectively being the 0.8ml/mmol acethydroximic acid) and is also followed via dried over mgso.Filter sal epsom and filtrate is at first then being concentrated on oil pump on the rotatory evaporator.
Preferably precipitate the hydrochloride of gained in order further to purify under some situation.
For this reason, residue is dissolved in the methylethylketone (8.7ml/g residue).Added that water (0.1ml/g residue) is slowly stirring afterwards and the frozen water cooling conditions under dripping trimethylchlorosilane (0.7ml/g residue).In refrigerator, the flask placement is spent the night, filter formed throw out and in water trap (Exikkator), utilize five phosphorus oxide to come dry as siccative.
Prepare following intermediate product according to this process:
The amino benzisoxa azoles-basic structure body that replaces of reduction amination prepares the general rule of the benzisoxa azoles amine of alpha-alkyl replacement:
Process:
Each benzisoxa azoles (4.55mmol, 1 equivalent) is dissolved among the DCM (11ml), mixed with corresponding alkyl phenyl ketone (4.55mmol, 1 equivalent) and in rare gas element, under room temperature, stir 1h.Then under inert conditions, drip triethyl silicane (4.5mmol, 1 equivalent) and trifluoracetic acid (13.65mmol, 3 equivalents) and stirring reaction material 4-12h under refluxad.The saturated NaHCO in cooling back
3The pH that-solution is regulated material is 8-9 and with DCM aqueous phase extracted 4 times.Via MgSO
4The organic phase of dry and concentrated merger.The crude product of gained is purified by quick-chromatography (diethyl ether/hexane).
Obtain following alkyl phenyl ketone according to this rule reaction:
According to the synthetic following examples of above-mentioned rule.Raw materials used numbering is recorded in the table.
Raw materials used
| Embodiment | Benzisoxa azoles | Alkyl phenyl ketone | Molar mass | Discriminating means: (purity) | Title |
| 1 | A | Z1 | 306,286992 | NMR | The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl-phenyl)-ethyl]-amine |
| 2 | A | Z2 | 338,350991 | NMR | The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl sulphur alkyl-phenyl)-ethyl]-amine |
The general rule of the benzisoxa azoles-basic structure body of reduction amination amino-replacement:
Wherein, R
30The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Expression does not replace or monobasic at least aryl or heteroaryl, and more it can or encircle member ring systems with monocycle and condense;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can be with monocycle or encircle that member ring systems condenses more and be connected via the alkylidene group of straight or branched.
Process:
Automatization is synthetic
(solution I, 0.05M is in DCM, 2ml) and sneak into the corresponding aldehyde of 100 μ mol (solution II, 0.15M is in DCM, 0.66ml) to insert the benzisoxa azoles solution of 100 μ mol in an exsiccant Gewindeglas under room temperature in advance.Moving liquid in reaction soln adds the solution that the mixture by the trifluoroacetic acid of 120 μ mol triethyl silicanes and 300 μ mol forms (solution III, 0.1M triethyl silicane is in DCM, and the 0.25M trifluoroacetic acid is in DCM, 1.2ml).With barrier film cover sealing Gewindeglas, and under 60 ℃ of reflux conditionss stirring reaction solution 16h.Reaction soln is placed under the room temperature and with the 7% concentration NaCO of 1.5ml
3-solution is adjusted to alkalescence and fully mixed 30min.Elimination R ü hrfisch also uses 1.5ml DCM washed container.
Take off and collect organic phase.Contain aqueous phase and sneak into the DCM of 2ml, its eddy current is stirred and fully mixed 15min.After centrifugal, separate organic phase and divide merging to be in the same place with the first step.Similarly, for the second time with the DCM aqueous phase extracted.Then via MgSO
4The dry organic phase that merges of-tube also concentrates in GeneVac.
Utilize HPLC to purify.
React following aldehyde according to above-mentioned rules:
Synthesize following examples according to above-mentioned rules.Raw materials used numbering is listed in the table.
Raw materials used
| Embodiment | Benzisoxa azoles | Aldehyde | Molar mass | Discriminating means: (purity) | Title |
| 136 | A | Z3 | 204,272996 | MS | The different azoles of benzo [d]-3-base (3-methyl-butyl)-amine |
| 137 | K | Z4 | 256,279994 | MS(＞80％) | (the different azoles of 5-fluoro-benzo [d]-3-yl)-(2-methyl-benzyl)-amine |
| 138 | D | Z5 | 295,385994 | MS(＞80％) | N4, N4-dimethyl-N3-(3-phenyl-propyl group)-different azoles-3 of benzo [d], 4-diamines |
| 139 | D | Z6 | 233,314996 | MS | N3-butyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 140 | E | Z7 | 354,408992 | MS | Anthracene-9-ylmethyl-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine |
| 141 | E | Z8 | 288,733994 | MS(＞80％) | (4-chloro-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine |
| 142 | O | Z9 | 287,249994 | MS(＞80％) | (the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-nitro-benzyl)-amine |
| 143 | M | Z10 | 346,769992 | MS(＞80％) | The different azoles of acetate-4-[(6-chloro-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester |
| 144 | N | Z10 | 391,22599 | MS(＞80％) | The different azoles of acetate-4-[(6-bromo-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester |
| 145 | A | Z13 | 293,152993 | MS(＞80％) | The different azoles of benzo [d]-3-base-(3,4-two chloro-benzyls)-amine |
| 146 | A | Z11 | 314,340993 | MS | The different azoles of benzo [d]-3-base-(2,4,5-trimethoxy-benzyl)-amine |
| 147 | A | Z12 | 252,316995 | MS(＞80％) | The different azoles of benzo [d]-3-base-(4-ethyl-benzyl)-amine |
| 148 | M | Z13 | 327,597993 | MS(＞80％) | (the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-two chloro-benzyls)-amine |
Raw materials used
| Embodiment | Benzisoxa azoles | Aldehyde | Molar mass | Discriminating means: (purity) | Title |
| 149 | A | Z14 | 278,232993 | MS(＞80％) | The different azoles of benzo [d]-3-base-(2,3,5-three fluoro-benzyls)-amine |
| 150 | M | Z15 | 350,804992 | MS(＞80％) | (the different azoles of 6-chloro-benzo [d]-3-yl)-(4-phenoxy group-benzyl)-amine |
| 151 | G | Z16 | 294,687993 | MS(＞80％) | (3-chloro-4-fluoro-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine |
| 152 | A | Z17 | 292,259992 | MS(＞80％) | The different azoles of benzo [d]-3-base-(4-trifluoromethyl-benzyl)-amine |
| 153 | G | Z18 | 236,289995 | MS(＞80％) | (the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-methyl-amyl group)-amine |
| 154 | D | Z19 | 321,301992 | MS(＞80％) | N4, N4-dimethyl-N3-(2,3,4-three fluoro-the benzyls)-different azoles-3 of benzo [d], 4-diamines |
| 155 | D | Z20 | 353,318991 | MS(＞80％) | N3-(2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 156 | H | Z21 | 283,330994 | MS(＞80％) | N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines |
| 157 | H | Z21 | 283,330994 | MS | N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines |
| 158 | A | Z25 | 308,258992 | MS(＞80％) | The different azoles of benzo [d]-3-base-(4-trifluoromethoxy-benzyl)-amine |
| 159 | K | Z25 | 326,248991 | MS(＞80％) | (the different azoles of 5-fluoro-benzo [d]-3-yl)-(4-trifluoromethoxy-benzyl)-amine |
| 160 | A | Z26 | 324,323992 | MS(＞80％) | The different azoles of benzo [d]-3-base-(4-trifluoromethyl sulfane base-benzyl)-amine |
| 161 | M | Z27 | 314,815993 | MS(＞80％) | (4-butyl-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine |
Raw materials used
| Embodiment | Benzisoxa azoles | Aldehyde | Molar mass | Discriminating means: (purity) | Title |
| 162 | K | Z26 | 342,313991 | MS(＞80％) | (the different azoles of 5-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine |
| 163 | A | Z38 | 310,249992 | MS(＞80％) | The different azoles of benzo [d]-3-base-(2-fluoro-4-trifluoromethyl-benzyl)-amine |
| 164 | G | Z25 | 326,248991 | MS(＞80％) | (the different azoles of 7-fluoro-benzo [d]-3-yl)-(4-trifluoromethoxy-benzyl)-amine |
| 165 | G | Z28 | 402,346989 | MS(＞80％) | (the different azoles of 7-fluoro-benzo [d]-3-yl)-[3-(3-trifluoromethyl-phenoxy group)-benzyl]-amine |
| 166 | E | Z29 | 320,294992 | MS(＞80％) | (4-difluoro-methoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine |
| 167 | G | Z30 | 270,306994 | MS(＞80％) | (3,5-dimethyl-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine |
| 168 | O | Z31 | 351,17999 | MS(＞80％) | (3-bromo-4-methoxyl group-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 169 | O | Z30 | 270,306994 | MS(＞80％) | (3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 170 | O | Z32 | 376,430991 | MS | (4-benzyloxy-3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 171 | O | Z27 | 298,360993 | MS(＞80％) | (4-butyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 172 | O | Z26 | 342,313991 | MS(＞80％) | (the different azoles of 6-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine |
| 173 | O | Z33 | 348,376992 | MS(＞80％) | (3-benzyloxy-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 174 | H | Z30 | 267,331995 | MS | N3-(3,5-dimethyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines |
| 175 | H | Z27 | 295,385994 | MS | N3-(4-butyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines |
Raw materials used
| Embodiment | Benzisoxa azoles | Aldehyde | Molar mass | Discriminating means: (purity) | Title |
| 176 | L | Z26 | 403,224988 | MS(＞80％) | (the different azoles of 5-bromo-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine |
| 177 | G | Z34 | 381,20599 | MS(＞80％) | (3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine |
| 178 | G | Z38 | 328,239991 | MS(＞80％) | (the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine |
| 179 | D | Z35 | 299,348994 | MS(＞80％) | N3-(3-fluoro-2-methyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 180 | D | Z36 | 369,773991 | MS(＞80％) | N3-(2-chloro-3-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 181 | D | Z37 | 387,76399 | MS | N3-(3-chloro-2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 182 | O | Z38 | 328,239991 | MS(＞80％) | (the different azoles of 6-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine |
| 183 | O | Z39 | 298,316993 | MS(＞80％) | (4-allyloxy-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine |
| 184 | A | Z40 | 390,438991 | MS(＞80％) | The different azoles of benzo [d]-3-base-(2-benzyloxy-4,5-dimethoxy-benzyl)-amine |
| 185 | M | Z40 | 424,88399 | MS | (2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine |
| 186 | D | Z40 | 433,507991 | MS(＞80％) | N3-(2-benzyloxy-4,5-dimethoxy-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 187 | D | Z41 | 343,429993 | MS | N3-biphenyl-2-ylmethyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines |
| 188 | O | Z42 | 368,148994 | MS(＞80％) | (the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-iodo-benzyl)-amine |
Raw materials used
| Embodiment | Benzisoxa azoles | Aldehyde | Molar mass | Discriminating means: (purity) | Title |
| 189 | E | Z40 | 420,464991 | MS(＞80％) | (2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine |
| 190 | B | Z43 | 428,200992 | MS(＞80％) | (the different azoles of 4-fluoro-benzo [d]-3-yl)-(3-iodo-4,5-dimethoxy-benzyl)-amine |
| 191 | J | Z44 | 263,299995 | MS | The different azoles of 2-[(5-methyl-benzo [d]-3-base is amino)-methyl]-benzonitrile |
| 192 | F | Z6 | 288,268993 | MS(＞80％) | Butyl-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-amine |
| 193 | J | Z34 | 377,24299 | MS(＞80％) | (3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 5-methyl-benzo [d]-3-yl)-amine |
| 198 | C | Z45 | 274,706994 | MS(＞80％) | The different azoles of 4-[(4-chloro-benzo [d]-3-base is amino)-methyl]-phenol |
| 199 | M | Z46 | 286,761994 | MS(＞80％) | (the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-dimethyl-benzyl)-amine |
| 200 | C | Z22 | 311,142993 | MS(＞80％) | (the different azoles of 4-chloro-benzo [d]-3-yl)-(3-chloro-2-fluoro-benzyl)-amine |
| 201 | K | Z23 | 278,232993 | MS(＞80％) | (3,4-two fluoro-benzyls)-(the different azoles of 5-fluoro-benzo [d]-3-yl)-amine |
| 202 | N | Z24 | 372,05399 | MS(＞80％) | (the different azoles of 6-bromo-benzo [d]-3-yl)-(2,6-two chloro-benzyls)-amine |
| 203 | G | Z47 | 326,248991 | MS(＞80％) | (the different azoles of 7-fluoro-benzo [d]-3-yl)-(3-trifluoromethoxy-benzyl)-amine |
Synthesizing of thiocarbamide
Automatization is synthetic
In having the dry Gewindeglas of barrier film cover, under room temperature, insert the benzisoxa oxazole derivatives solution (solution I of 100 μ mol in advance; 0.1M in pyridine, 1ml) and be mixed into the lsothiocyanates derivative solution (solution II of 100 μ mol; 0.1M in pyridine, 1ml).Stirring reaction solution 24h under the reflux conditions.Elimination R ü hrfisch also uses the CH of 2ml
2Cl
2Washed container.
Rock suspension and direct GHP filter funnel casting fast via 0.45 μ m.DCM with 7.5ml cleans reagent bottle and then utilize the pressurized air filtering suspension liquid in filter funnel.The organic phase of concentrating clarifying in Gene-Vac.Purify by HPLC.
Adopt following lsothiocyanates:
According to the synthetic following examples of above-mentioned rules.
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 3 | A | I1 | 283,352994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-benzyl-thiocarbamide |
| 4 | A | I2 | 269,325994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-phenyl-thiocarbamide |
| 5 | A | I3 | 283,352994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-o-tolyl-thiocarbamide |
| 6 | A | I4 | 297,379994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-styroyl-thiocarbamide |
| 7 | A | I5 | 311,406994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2-sec.-propyl-phenyl)-thiocarbamide |
| 8 | A | I6 | 303,770993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2-chloro-phenyl)-thiocarbamide |
| 9 | A | I7 | 301,342993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-benzyl)-thiocarbamide |
| 10 | A | I8 | 315,369993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-[1-(4-fluoro-phenyl)-ethyl]-thiocarbamide |
| 11 | A | I9 | 317,797993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-chloro-benzyl)-thiocarbamide |
| 12 | A | I10 | 331,824993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-[2-(4-chloro-phenyl)-ethyl]-thiocarbamide |
| 13 | A | I11 | 314,322994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-nitro-phenyl)-thiocarbamide |
| 14 | A | I12 | 311,362993 | MS(＞80％) | The different azoles of 1-(4-ethanoyl-phenyl)-3-benzo [d]-3-base-thiocarbamide |
| 15 | A | I13 | 313,334993 | MS(＞80％) | 3-(the different azoles of 3-benzo [d]-3-base-thioureido)-phenylformic acid |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 16 | A | I14 | 327,361993 | MS(＞80％) | 3-(the different azoles of 3-benzo [d]-3-base-thioureido)-methyl benzoate |
| 17 | A | I15 | 341,388993 | MS(＞80％) | 4-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl benzoate |
| 18 | A | I16 | 325,433993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2,6-diethyl-phenyl)-thiocarbamide |
| 19 | A | I17 | 317,797993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(3-chloro-4-methyl-phenyl)-thiocarbamide |
| 20 | A | I18 | 251,307995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2-methoxyl group-ethyl)-thiocarbamide |
| 21 | A | I19 | 265,334995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(3-methoxyl group-propyl group)-thiocarbamide |
| 22 | A | I20 | 261,346995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-cyclopentyl-thiocarbamide |
| 23 | A | I21 | 275,373994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-cyclohexyl-thiocarbamide |
| 24 | A | I22 | 270,313995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-pyridin-3-yl-thiocarbamide |
| 25 | A | I23 | 312,394994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-dimethylamino-phenyl)-thiocarbamide |
| 26 | A | I24 | 340,448993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-diethylamino-phenyl)-thiocarbamide |
| 27 | A | I25 | 265,290995 | MS(＞80％) | (the different azoles of 3-benzo [d]-3-base-thioureido)-methyl acetate |
| 28 | A | I26 | 293,344994 | MS(＞80％) | 2-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl propionate |
| 29 | A | I27 | 307,371994 | MS(＞80％) | 3-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl butyrate |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 30 | A | I80 | 289,400994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-cyclohexyl methyl-thiocarbamide |
| 31 | A | I28 | 313,378993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-oxyethyl group-phenyl)-thiocarbamide |
| 32 | A | I29 | 329,377993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(3,4-dimethoxy-phenyl)-thiocarbamide |
| 33 | A | I30 | 359,403992 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide |
| 34 | A | I31 | 359,27599 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-pentafluorophenyl group-thiocarbamide |
| 35 | A | I32 | 319,385993 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-naphthalene-1-base-thiocarbamide |
| 36 | A | I33 | 327,361993 | MS(＞80％) | The different azoles of 1-benzo [1,3] dioxole-5-ylmethyl-3-benzo [d]-3-base-thiocarbamide |
| 37 | A | I34 | 287,315994 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-phenyl)-thiocarbamide |
| 38 | A | I35 | 207,254996 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-methyl-thiocarbamide |
| 39 | A | I36 | 221,281996 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-ethyl-thiocarbamide |
| 40 | A | I37 | 235,308995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-propyl group-thiocarbamide |
| 41 | A | I38 | 235,308995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-sec.-propyl-thiocarbamide |
| 42 | A | I39 | 249.335995 | MS(＞80％) | The different azoles of 1-benzo [the d]-3-base-3-tertiary butyl-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 43 | A | I40 | 233,292995 | MS | The different azoles of 1-allyl group-3-benzo [d]-3-base-thiocarbamide |
| 44 | A | I41 | 247,319995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2-methyl-allyl group)-thiocarbamide |
| 45 | A | I42 | 314,322994 | NMR | The different azoles of 1-benzo [d]-3-base-3-(2-nitro-phenyl)-thiocarbamide |
| 46 | A | I43 | 337,322992 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(2-trifluoromethyl-phenyl)-thiocarbamide |
| 47 | A | I44 | 337,322992 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(3-trifluoromethyl-phenyl)-thiocarbamide |
| 48 | A | I45 | 337,322992 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-(4-trifluoromethyl-phenyl)-thiocarbamide |
| 49 | A | I46 | 233,292995 | MS(＞80％) | The different azoles of 1-benzo [d]-3-base-3-cyclopropyl-thiocarbamide |
| 50 | B | I82 | 297,307993 | MS(＞80％) | 2-[3-(the different azoles of 4-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate |
| 51 | C | I3 | 317,797993 | MS | 1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-o-tolyl-thiocarbamide |
| 52 | C | I1 | 317,797993 | MS(＞80％) | 1-benzyl-3-(the different azoles of 4-chloro-benzo [d]-3-yl)-thiocarbamide |
| 53 | C | I47 | 331,824993 | MS(＞80％) | 1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide |
| 54 | D | I48 | 292,404994 | MS | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-isobutyl--thiocarbamide |
| 55 | D | I49 | 326,421993 | MS | 1-(the different azoles of 4-dimethylamino-benzo [d]--base)-3-o-tolyl-thiocarbamide |
| 56 | D | I50 | 346,839993 | MS(＞80％) | 1-(3-chloro-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 57 | D | I51 | 342,420993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide |
| 58 | D | I52 | 358,485993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide |
| 59 | D | I53 | 358,485993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methyl sulphur alkyl-phenyl)-thiocarbamide |
| 60 | D | I54 | 358,485993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methyl sulphur alkyl-phenyl)-thiocarbamide |
| 61 | D | I81 | 342,420993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide |
| 62 | D | I55 | 342,420993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide |
| 63 | D | I56 | 340,448993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3,5-dimethyl-phenyl)-thiocarbamide |
| 64 | D | I1 | 326,421993 | MS(＞80％) | 1-benzyl-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide |
| 65 | D | I19 | 308,403994 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-propyl group)-thiocarbamide |
| 66 | D | I57 | 336,413993 | MS(＞80％) | 3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 67 | D | I26 | 336,413993 | MS(＞80％) | 2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate |
| 68 | D | I27 | 350,440993 | MS(＞80％) | 3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl butyrate |
| 69 | D | I13 | 356,403993 | MS(＞80％) | 3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-phenylformic acid |
| 70 | D | I28 | 356,447993 | MS(＞80％) | 1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-oxyethyl group-phenyl)-thiocarbamide |
| 71 | D | I58 | 370,430992 | MS(＞80％) | 2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate |
| 72 | D | I14 | 370,430992 | MS | 3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate |
| 73 | D | I59 | 370,430992 | MS(＞80％) | 4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate |
| 74 | D | I60 | 384,457992 | MS(＞80％) | 2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl benzoate |
| 75 | D | I15 | 384,457992 | MS(＞80％) | 4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-sulfonyl urea]-ethyl benzoate |
| 76 | D | I12 | 354,431993 | MS | 1-(4-ethanoyl-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide |
| 77 | E | I6 | 333,796993 | MS(＞80％) | 1-(2-chloro-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 78 | E | I24 | 370,474993 | MS(＞80％) | 1-(4-diethylamino-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
| 79 | E | I61 | 336,413993 | MS(＞80％) | 1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide |
| 80 | F | I82 | 377,340991 | MS(＞80％) | 2-{3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thioureido }-methyl propionate |
| 81 | F | I33 | 425,38499 | MS(＞80％) | 1-benzo [1,3] dioxolyl-5-ylmethyl-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide |
| 82 | F | I62 | 491,575988 | MS(＞80％) | 1-[4-(4-propyl group-cyclohexyl)-phenyl]-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide |
| 83 | F | I63 | 514,246985 | MS(＞80％) | 1-(4-bromo-2-trifluoromethyl-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide |
| 84 | F | I55 | 397,37499 | MS(＞80％) | 1-(4-methoxyl group-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide |
| 85 | F | I57 | 391,36799 | MS(＞80％) | 3-{3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thioureido }-ethyl propionate |
| 86 | I | I64 | 425,594991 | MS(＞80％) | The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-octyl group-thiocarbamide |
| 87 | I | I65 | 439,621991 | MS(＞80％) | The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-nonyl-thiocarbamide |
| 88 | I | I46 | 353,443992 | MS(＞80％) | The different azoles of 1-cyclopropyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 89 | I | I20 | 381,497992 | MS(＞80％) | The different azoles of 1-cyclopentyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide |
| 90 | I | I21 | 395,524992 | MS(＞80％) | The different azoles of 1-cyclohexyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide |
| 91 | I | I80 | 409,551991 | MS(＞80％) | The different azoles of 1-cyclohexyl methyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide |
| 92 | F | I23 | 410,41799 | MS(＞80％) | 1-(4-dimethylamino-phenyl)-3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thiocarbamide |
| 93 | J | I40 | 247,319995 | MS | 1-allyl group-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide |
| 94 | J | I25 | 279,317994 | MS(＞80％) | [3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thioureido]-methyl acetate |
| 95 | J | I5 | 325,433993 | MS(＞80％) | 1-(2-sec.-propyl-phenyl)-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide |
| 96 | J | I45 | 351,349991 | MS(＞80％) | 1-(the different azoles of 5-methyl-benzo [d]-3-yl)-3-(4-trifluoromethyl-phenyl)-thiocarbamide |
| 97 | K | I82 | 297,307993 | MS(＞80％) | 2-[3-(the different azoles of 5-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate |
| 98 | K | I66 | 295,335994 | MS(＞80％) | 1-(the different azoles of 5-fluoro-benzo [d]-3-yl)-3-(tetrahydrofuran (THF)-2-ylmethyl)-thiocarbamide |
| 99 | L | I67 | 366,21699 | MS(＞80％) | 1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-fluoro-phenyl)-thiocarbamide |
| 100 | L | I68 | 376,28099 | MS(＞80％) | 1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-ethyl-phenyl)-thiocarbamide |
| 101 | M | I34 | 321,760993 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-fluoro-phenyl)-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 102 | M | I67 | 321,760993 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(2-fluoro-phenyl)-thiocarbamide |
| 103 | M | I20 | 295,791994 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-cyclopentyl-thiocarbamide |
| 104 | M | I69 | 328,780993 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-cyano group-phenyl)-thiocarbamide |
| 105 | M | I13 | 347,779992 | MS(＞80％) | 3-[3-(the different azoles of 6-chloro-benzo [d]-3-yl)-thioureido]-phenylformic acid |
| 106 | M | I55 | 333,796993 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide |
| 107 | M | I51 | 333,796993 | MS(＞80％) | 1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide |
| 108 | N | I29 | 408,27899 | MS(＞80％) | 1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-(3,4-dimethoxy-phenyl)-thiocarbamide |
| 109 | N | I32 | 398,28699 | MS | 1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-naphthalene-1-base-thiocarbamide |
| 110 | N | I33 | 406,26299 | MS | 1-benzo [1,3] dioxolyl-5-ylmethyl-3-(the different azoles of 6-bromo-benzo [d]-3-yl)-thiocarbamide |
| 111 | O | I52 | 333,406992 | MS(＞80％) | 1-(the different azoles of 6-fluoro-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide |
| 112 | O | I70 | 312,325993 | MS(＞80％) | 1-(3-cyano group-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide |
| 113 | O | I71 | 335,787992 | MS(＞80％) | 1-(2-chloro-6-methyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide |
| 114 | O | I72 | 371,477992 | MS(＞80％) | 1-(2,6-di-isopropyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 115 | G | I35 | 225,244995 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-methyl-thiocarbamide |
| 116 | G | I36 | 239,271995 | MS(＞80％) | 1-ethyl-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide |
| 117 | G | I37 | 253,298995 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-propyl group-thiocarbamide |
| 118 | G | I73 | 281,352994 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-amyl group-thiocarbamide |
| 119 | G | I79 | 295,379994 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-hexyl-thiocarbamide |
| 120 | G | I64 | 323,433993 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-octyl group-thiocarbamide |
| 121 | G | I65 | 337,460993 | MS | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-nonyl-thiocarbamide |
| 122 | G | I48 | 267,325994 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-isobutyl--thiocarbamide |
| 123 | G | I40 | 251,282995 | MS | 1-allyl group-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide |
| 124 | G | I49 | 301,342993 | MS | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-p-methylphenyl-thiocarbamide |
| 125 | L | I23 | 391,29599 | MS(＞80％) | 1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide |
| 126 | G | I61 | 324,377993 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide |
| 127 | G | I77 | 338,404993 | MS(＞80％) | 1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(3-morpholine-4-base-propyl group)-thiocarbamide |
Raw materials used
| Embodiment | Benzisoxa azoles | Lsothiocyanates | Accurate mass | Discriminating means: (purity) | Title |
| 128 | E | I78 | 327,405993 | MS(＞80％) | 1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide |
| 129 | E | I9 | 347,823992 | MS(＞80％) | 1-(4-chloro-benzyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
| 130 | E | I81 | 329,377993 | MS(＞80％) | 1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide |
| 131 | L | I23 | 391,29599 | MS | 1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide |
| 132 | E | I75 | 363,822992 | MS(＞80％) | 1-(5-chloro-2-methoxyl group-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
| 133 | E | I74 | 401,79399 | MS(＞80％) | 1-(4-chloro-3-trifluoromethyl-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
| 134 | E | I76 | 359,403992 | MS(＞80％) | 1-(2,4-dimethoxy-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide |
| 135 | F | I30 | 457,426989 | MS(＞80％) | 1-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide |
Pharmacological method:
I. florescence analysis (FLIPR
TM-instrument), in order to differentiate the material that on ionic channel KCNQ2/3, has agonism
CHO-K1-cell or the blank strain cell of CHO-K1-with expressing K CNQ2/3 before the test were implanted to through gathering-D-Methionin plate black/clear (Falcon/BD company of applying; Order goods number: 356640) go up and concentration is 20000 cells/100 μ l MEM alpha, 50ml FCS, 5.5mlP/S/G solution (100x), and then in incubator, cultivate 20-24h (37 ℃, 5%CO
2).
In test day, at first prepare HBSS/Hepes-working solution and FMP/HBSS/Hepes-mixture ((membrane potential test kit red (FMP)) according to following scheme
(Membranpotential Assay Kit Red(FMP)，Bulk Format CatNr.R8123)：
1.HBSS/Hepes：
1000ml 1xHBSS-damping fluid (Hank ' s Balanced Salt Solution (1X) (Gibco; Nr.14025)+and 10ml HEPES (1M bacterial strain solution, pH 7.4; Hepes-Na-salt (Sigma company; Nr.H7006-500g; Deposit under 4 ℃ in the refrigerator)
2.1x FMP/HBSS/Hepes-working solution: make to be stored in-20 ℃ FMP-solution by 5ml (preparation process is as follows; Room temperature is melted method) mix with 6ml HBSS/Hepes-buffering liquid phase.
To be positioned at the medicine plate (Costar 96 orifice plates, Katnr.3795) to be diluted to concentration be 30 μ M (3x is spissated) to Nei test substances (bacterial strain solution 2mM is in 100%DMSO) by adding the HBSS/Hepes-damping fluid then.
Once (the residual volume thing Katnr.5161550) and by the plate that twice bat turns is only removed by CellwashWasher, Labsystems company along with the test panel of cell enlargement with 200 μ l HBSS/Hepes washing.The then FMP/HBSS/Hepes-working solution of 100 μ l and in addition respectively on cell plate at CO
2Cultivate in the cabinet in 37 ℃ and 5%CO
2Condition under cultivate 1h.
Then at the equipment FLIPR of Molecular Devices company III (96 Format; The bandpass filter of employing 540-590nm in the #2-positioning area) measures on.Selective filter #2 in the test of FLIPR software is provided with.In input magazine, alternately place cell plate and material plate.Before adding, material carries out signal testing respectively by cell plate.The cumulative volume that reaches 150 μ l/ holes in the hole that the liquid unit is added into test substances (add volume 50 μ l, 3x concentrates, final concentration 10 μ M) cell plate that moves by FLIPR then.
The general data of FLIPR program is:
It is long-pending to move liquid: 50 μ l
Move the liquid height: 225 μ l
Move liquid speed: 50 μ l/sec
Camera configuration: exposure=0.4; Multiplying power=50
Transfer pipet after moving the liquid process at every turn with 1% DMSO solution washing 3 times.
It is as follows to add test substances interval time of measurement afterwards:
Sequence 1:60x1sec
Sequence 2:15x20sec
The overall measurement time: 6min/ plate.
Form according to the difference between maximum value and the minimum value and to estimate.Adopt Graph Pad Prim-computed in software EC
50/ IC
50Value.
Solution:
Explanation according to the manufacturer prepares membrane potential load buffer (membrane potential test kit red (FMP), Bulk Format Cat Nr.R8123):
10x assay buffer (composition B) with 90ml sterilized water dilution 10ml is also then regulated pH7.4 (1x assay buffer) with 1.0NNaOH.Dissolve the FLIPR membrane potential test composition A of 1 container fully and fully mixed 10min on magnetic stirrer with 100ml 1x assay buffer.Then the 5ml-sample aliquot is positioned over (about 2 weeks of persistence) under-20 ℃ of temperature.
From-40 (with low value more) just can observe agonism.
| Embodiment | FLIPR Δ F % suppresses |
| 55 | -84 |
| 107 | -80 |
| 65 | -79 |
| 200 | -74 |
| 172 | -68 |
| 52 | -67.5 |
| 87 | -66.5 |
| 54 | -64 |
| 95 | -64 |
| 169 | -63.25 |
| 167 | -61 |
| 50 | -59.5 |
| 106 | -59 |
| 97 | -58.5 |
| 103 | -58 |
| 160 | -58 |
| 175 | -57.7 |
| 96 | -57 |
| 63 | -56 |
| 163 | -56 |
| 113 | -55 |
| 123 | -55 |
| 173 | -55 |
| 56 | -55 |
| 114 | -54 |
| 108 | -53.5 |
| 158 | -53 |
| 171 | -53 |
| 64 | -52 |
| 92 | -51 |
| 51 | -50 |
| 124 | -50 |
| 152 | -49 |
| 31 | -49 |
| 203 | -49 |
| 135 | -47.5 |
| 94 | -47 |
| 128 | -47 |
| 93 | -45.5 |
| 174 | -45.5 |
| 132 | -45 |
| 98 | -43.5 |
| 53 | -42.5 |
| 100 | -42 |
| 134 | -42 |
| 129 | -42 |
| Embodiment | FLIPR Δ F % suppresses |
| 90 | -41.5 |
| 159 | -41 |
| 23 | -40 |
| 84 | -40 |
| 161 | -40 |
II. electricity pincers test
In order to confirm the KCNQ2/3 agonism of material with electrophysiological method, in electricity pincers module people such as (, 1981) Hamill, on the hKCNQ2/3CHO-K1 of stable delivery clone, carry out the patch clamp test.After having formed Ji Jia and sealing, at first on the fixed potential of-60mV, clamp cell.Then applying a unpolarized abrupt change of voltage until electromotive force is+20mV (increment: 20mV, time length: 1 second), thereby confirms the functional expression of KCNQ2/3 exemplary currents.The substance testing process is carried out under the electromotive force of-40mV.Under-40mV condition, on each cell, at first write down inductive current increment by Retigabin (10 μ M) as forward control.Increase the back (time length: 80s) apply test substances (10 μ M) fully in the Retigabin effect.Note (referring to down) for Retigabin effect regulation by test substances institute inductive current increment and as relative effectivenes.
Hamill OP,
Marty A,
Neher E,
Sakmann B,
Sigworth FJ.Improved patch-clamptechniques for high-resolution current recording from cells and cell-free membranepatches.
Pflugers Arch.1981 Augusts; 391 (2): 85-100.
| Embodiment | Electricity pincers: for the relative effectivenes [10 μ M] of Retigabin |
| 163 | 1.29 |
| 173 | 0.84 |
| 174 | 0.8 |
| 162 | 0.79 |
| 170 | 0.72 |
| 171 | 0.68 |
| Embodiment | Electricity pincers: for the relative effectivenes [10 μ M] of Retigabin |
| 176 | 0,62 |
| 161 | 0,61 |
| 175 | 0,59 |
| 160 | 0,45 |
| 159 | 0,42 |
| 1 | 0,42 |
| 2 | 0,37 |
| 168 | 0,35 |
| 112 | 0,3 |
| 167 | 0,25 |
| 152 | 0,22 |
| 130 | 0,2 |
Claims (16)
1. the different azoles of replacement benzo [the d]-3-base-amine compound that has general formula I,
Wherein,
R
1, R
2, R
3And R
4Expression respectively independently of each other
H；F，Cl，Br，I；-CN；-NO
2；-SF
5；-NR
7R
8；-OR
9；-SR
10；-C(＝O)OR
11；
-(C＝O)NR
12R
13；-S(＝O)
2R
14；-C(＝O)R
15；-NR
16-S(＝O)
2R
17；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Represent saturated or undersaturated, do not replace or monobasic at least and optional alicyclic group with at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via alkylidene group, alkenylene or the alkynylene of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or be connected via alkylidene group, alkenylene or the alkynylene of straight or branched,
R
5Expression
-C(＝S)NR
21R
22，
Perhaps represent straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems or is connected R via the alkylidene group of straight or branched
7And R
8Expression respectively independently of each other
H ,-C (=O) R
15Or the expression straight or branched, saturated or undersaturated, do not replace or
At least monobasic aliphatic group, perhaps
R
7And R
8With their nitrogen-atoms of connection as ring members form saturated or undersaturated, do not replace or monobasic at least, optionally have the heterocycle aliphatic group of at least one other heteroatoms as ring members,
R
9, R
10, R
11And R
16Expression respectively independently of each other
H；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group;
Represent saturated or undersaturated, do not replace or monobasic at least, optionally have the alicyclic group of at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
12And R
13Expression respectively independently of each other
H or expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group, perhaps
R
12And R
13With their nitrogen-atoms of connection as ring members form saturated or undersaturated, do not replace or monobasic at least, optionally have the heterocycle aliphatic group of at least one other heteroatoms as ring members,
R
14Expression
-NR
7R
8；
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least, optionally have at least
Heteroatoms is as the alicyclic group of ring members, and its can with monocycle or polycyclic ring
System condenses and/or connects via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
15And R
17Expression respectively independently of each other
Straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least, optionally have the alicyclic group of at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
R
21And R
22Represent H independently of each other respectively,
The expression straight or branched, saturated or undersaturated, do not replace or monobasic at least aliphatic group,
Represent saturated or undersaturated, do not replace or monobasic at least also, optionally have the alicyclic group of at least one heteroatoms as ring members, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
Perhaps expression does not replace or monobasic at least aryl or heteroaryl, and it can condense with monocycle or polycyclic member ring systems and/or is connected via the alkylidene group of straight or branched;
And described compound is racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
2. compound as claimed in claim 1 is characterized in that,
R
1, R
2, R
3And R
4Expression respectively independently of each other
H; F; Cl; Br; I;-CN;-NO
2-SF
5-NR
7R
8-OR
9-SR
10-C (=O) OR
11-(C=O) NR
12R
13-S (=O)
2R
14-C (=O) R
15-NR
16-S (=O)
2R
17C
1-10-alkyl; C
2-10-thiazolinyl; C
2-10-alkynyl;
R
5Expression
-C (=S) NR
21R
22Or (CHR
6)
n-R
25,
And n=1,2 or 3,
R wherein
6Expression H, C
3-8-cycloalkyl or C
1-6-alkyl,
And R
25Expression aryl or heteroaryl,
R
7And R
8Expression respectively independently of each other
H ,-C (=O) R
14Or C
1-10-alkyl, perhaps
R
7And R
8With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
9, R
10, R
11And R
16Expression respectively independently of each other
H; C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
R
12And R
13Expression respectively independently of each other
H or expression C
1-10-alkyl; Or
R
12And R
13With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
14Expression
-NR
7R
8C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl;
Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
R
15And R
17Expression respectively independently of each other
C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
R
21And R
22Represent H independently of each other respectively,
C
1-10-alkyl, C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1-5-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1-5-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1-5-alkylidene group)-aryl;-(C
1-5-alkylidene group)-heteroaryl;
Wherein, aforesaid C
1-10-alkyl, C
2-10-thiazolinyl and C
2-10It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is respectively done for oneself straight or branched and optional, and described substituting group is F independently of each other; Cl; Br; COOH; COOC
1-4-alkyl;-CN;-OH;-SH;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Above-mentioned C
3-8-cycloalkyl may optionally be 1,2,3,4 or 5 substituting group separately and replaces, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Above-mentioned Heterocyclylalkyl is respectively 4,5,6 or 7 yuan of rings, and they have 1 or 2 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group replacement, and described substituting group base is independently selected from F; Cl; Br;-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2
Above-mentioned aryl is represented phenyl, anthryl or naphthyl respectively, and it can be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is selected from F independently of each other; Cl; Br; I;-CF
3-OCF
3-SCF
3C (=O) C
1-5-Alkyl;
-NO
2Cyclohexyl;-SF
5-CN;
-OH;-SH;-C
1-5-alkyl;-O-C
1-5-alkyl;-S-C
1-5-alkyl;-C (=O)-OH;-O (C=O) C
1-2Alkyl;-C (=O)-OC
1-5-alkyl;-NH
2-N (H) (C
1-5-alkyl);-N (C
1-5-alkyl) (C
1-5-alkyl);-C (=O) NH
2-C (=O) N (H) (C
1-5-alkyl);-C (=O) N (C
1-5-alkyl) (C
1-5-alkyl) ,-S (=O)
2NH
2-S (=O)
2N (H) (C
1-5-alkyl);-S (=O)
2N (C
1-5-alkyl) (C
1-5-alkyl);-S (=O)
2-phenyl;-S (=O)
2-C
1-5-alkyl; Phenyl; Phenoxy group; Benzyl; Benzyloxy; Thienyl (Thiophenyl) (thienyl); Furyl and pyridyl,
Above-mentioned heteroaryl is respectively 5 or 6 yuan of rings, and they have 1,2 or 3 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group and replace, and described substituting group is selected from F independently of each other; Cl; Br; I;-CF
3-OCF
3-SCF
3-SF
5-CN;-OH;-SH;-C
1-5-alkyl;-O-C
1-5-alkyl;-S-C
1-5-alkyl;-C (=O)-OH;-C (=O)-OC
1-5-alkyl;-NH
2-N (H) (C
1-5-alkyl);-N (C
1-5-alkyl) (C
1-5-alkyl);-C (=O) NH
2-C (=O) N (H) (C
1-5-alkyl);-C (=O) N (C
1-5-alkyl) (C
1-5-alkyl) ,-S (=O)
2NH
2-S (=O)
2N (H) (C
1-5-alkyl);-S (=O)
2N (C
1-5-alkyl) (C
1-5-alkyl);-S (=O)
2-phenyl;-S (=O)
2-C
1-5-alkyl; Phenyl; Phenoxy group; Benzyl; Thienyl (thienyl); Furyl and pyridyl,
And described compound is racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
3. compound as claimed in claim 1, wherein
R
1, R
2, R
3And R
4, expression respectively independently of each other
H; F; Cl; Br; I;-CN;-NR
7R
8-OR
9-SR
10C
1-4-alkyl; C
2-4-thiazolinyl or C
2-4-alkynyl;
R
5Expression
-C(＝S)NR
21R
22
Or
-(CHR
6)
n-R
25
And n=1,2 or 3,
R wherein
6Expression H or C
1-6-alkyl
And R
25Expression aryl or heteroaryl;
R
7And R
8Expression respectively independently of each other
H ,-C (=O) R
15Or C
1-4-alkyl, perhaps
R
7And R
8With the nitrogen-atoms primordial group as ring members that connects them, and this group is selected from morpholine, piperidines or tetramethyleneimine;
R
9, R
10Expression respectively independently of each other
H; C
1-4-alkyl, C
2-4-thiazolinyl, C
2-4-alkynyl; C
3-8-cycloalkyl;-(C
1,2 or 3-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1,2 or 3-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1,2 or 3-alkylidene group)-aryl;-(C
1,2 or 3-alkylidene group)-heteroaryl;
R
21And R
22Expression respectively independently of each other
H; C
1-10-alkyl; C
2-10-thiazolinyl, C
2-10-alkynyl; C
3-8-cycloalkyl;-(C
1,2 or 3-alkylidene group)-C
3-8-cycloalkyl; Heterocyclylalkyl;-(C
1,2 or 3-alkylidene group)-Heterocyclylalkyl; Aryl; Heteroaryl;-(C
1,2 or 3-alkylidene group)-aryl;-(C
1,2 or 3-alkylidene group)-heteroaryl;
Wherein,
Aforesaid C
1-10-alkyl, C
2-10-thiazolinyl and C
2-10It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is respectively done for oneself straight or branched and optional, and described substituting group is selected from F independently of each other; Cl; Br;-CN; COOH; COOC
1-4-alkyl;-OH;-SH;-O-C
1-2-alkyl;-S-C
1-2-alkyl and-NH
2,
Aforesaid C
1-4-alkyl, C
2-4-thiazolinyl and C
2-4It can be that 1,2,3,4 or 5 substituting group replaces that-alkynyl is respectively done for oneself straight or branched and optional, and described substituting group is selected from F independently of each other;
Cl; Br;-CN;-OH;-OCH
3With-NH
2,
Above-mentioned C
3-8-cycloalkyl may optionally be 1,2,3,4 or 5 substituting group separately and replaces, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-CH
3-C
2H
5-OCH
3With-NH
2,
Above-mentioned Heterocyclylalkyl is respectively 4,5,6 or 7 yuan of rings, and they have 1 or 2 heteroatoms that is selected from oxygen, sulphur and nitrogen independently of each other as ring members, and may optionally be 1,2,3,4 or 5 substituting group replacement, and described substituting group is selected from F independently of each other; Cl; Br;-CN;-OH;-CH
3-C
2H
5-OCH
3With-NH
2
Above-mentioned aryl is represented phenyl, anthryl or naphthyl respectively, and it can be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is selected from F independently of each other; Cl; Br;-CF
3-OCF
3-SCF
3 
-NO
2-C (=O) C
1-2-alkyl; Cyclohexyl;-O (C=O) C
1-2-alkyl;-SF
5-CN;-OH; Methyl; Ethyl; N-propyl; Sec.-propyl; Normal-butyl; Isobutyl-; Sec-butyl; The tertiary butyl; Methoxyl group; Oxyethyl group;-NH
2-N (CH
3)
2-N (C
2H
5)
2Phenyl; Benzyloxy; Phenoxy group; Benzyl; Thienyl (thienyl); Furyl and pyridyl,
Above-mentioned heteroaryl is represented furyl, thienyl (thienyl) or pyridyl respectively and may optionally be 1,2,3,4 or 5 substituting group to replace, and described substituting group is selected from F independently of each other; Cl; Br;-CF
3-OCF
3-SCF
3-SF
5-CN;-OH; Methyl; Ethyl; N-propyl; Sec.-propyl; Normal-butyl; Isobutyl-; Sec-butyl; The tertiary butyl; Methoxyl group; Oxyethyl group;-NH
2-N (CH
3)
2-N (C
2H
5)
2Phenyl; Phenoxy group; Benzyl; Thienyl (thienyl); One group of forming of furyl and pyridyl,
And described compound is a racemic object form; The mixture of the mixture of enantiomer, diastereomer, enantiomer or diastereomer or each enantiomer or diastereomer; The form of the alkali of acceptable acid and/or salt on the physiology.
4. as the described compound of one of claim 1 to 3, wherein R
5Expression-C (=S) NR
21R
22
5. as the described compound of one of claim 1 to 3, wherein R
5Expression-(CHR
6)
n-R
25
6. compound as claimed in claim 4, wherein R
21Represent H and R
22Expression benzyl, phenyl, pyridyl, naphthyl or styroyl, and it can be unsubstituted or with methyl, ethyl, sec.-propyl, Cl, F, Br, NO
2, ethanoyl, CN, COOH, COOC
1-4-alkyl, methoxyl group, oxyethyl group, N (CH
3)
2, N (C
2H
5)
2,
CF
3, SCH
3One replacement or polysubstituted; Perhaps represent C
1-10-alkyl, and it can be side chain or non-side chain, saturated or undersaturated, do not replace or with OCH
3, COOCH
3Or COOC
2H
5Replace; Expression C
3-6-cycloalkyl, wherein said cycloalkyl can be via CH
2Group bonding; Expression C
5-6-Heterocyclylalkyl, wherein said Heterocyclylalkyl can be via CH
2Group bonding.
7. compound as claimed in claim 6, wherein R
21Represent H and R
22Expression benzyl, phenyl, 2-aminomethyl phenyl, styroyl, 2-isopropyl phenyl, 2-chloro-phenyl-, 4-fluoro benzyl, 1-(4-fluoro phenyl) ethyl, 4-chloro benzyl, 4-chloro-styroyl, 4-nitrophenyl, 4-acetylphenyl, 3-carboxyl phenyl, 3-methyl benzoic acid ester, 4-ethylamino benzonitrile acid esters, 2,6-diethyl phenyl, 3-chloro-4-methyl-phenyl, 2-methoxy ethyl, 3-methoxy-propyl, cyclopentyl, cyclohexyl, 3-pyridyl, 4-dimethylaminophenyl, 4-diethylamino phenyl, CH
2COOCH
3, CH (CH
3) COOC
2H
5, CH (CH
3) CH
2COOC
2H
5Cyclohexyl methyl, the 4-ethoxyl phenenyl, 3, the 4-Dimethoxyphenyl, the 1-naphthyl, 3,4, the 5-trimethoxyphenyl, 2,3,4,5, the 6-pentafluorophenyl group, the benzo dioxolyl, 4-fluoro phenyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, allyl group, 2-methyl-prop-2-thiazolinyl, the 2-nitrophenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, the 4-trifluoromethyl, cyclopropyl, 2-methyl sulfane base phenyl, 3-methyl sulfane base phenyl, 4-methyl sulphur alkylbenzene, 3, the 5-3,5-dimethylphenyl, ethyl morpholine, ((4-propyl group)-cyclohexyl) phenyl, 4-bromo-2-trifluoromethyl, n-octyl, n-nonyl, the tetrahydrofuran (THF) ylmethyl, the 2-ethylphenyl, the 4-cyano-phenyl, the 3-cyano-phenyl, 2, the 6-diisopropyl phenyl, n-pentyl, n-hexyl, sec-butyl, the propyl group morpholine, 5-chloro-2-p-methoxy-phenyl, 4-chloro-3-trifluoromethyl, the 3-chloro-phenyl-, the 1-phenylethyl, CH (CH
3) COOCH
3, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, CH
2CH
2COOC
2H
5, 2-methyl benzoic acid ester, 4-methyl benzoic acid ester, 2-ethylamino benzonitrile acid esters, 2-fluoro phenyl, 2-methoxyl group-5-chlorophenyl or 2, the 4-Dimethoxyphenyl.
8. compound as claimed in claim 5, wherein R
6Expression H.
9. compound as claimed in claim 5, wherein R
6Expression CH
3
10. as claim 5, one of 8 or 9 described compounds, wherein R
25Expression phenyl, pyridyl, thienyl or furyl, and each is unsubstituted naturally or with CF
3, SCF
3, C
1-4-alkyl, Cl, NO
2, O-ethanoyl, OCH
3, F, O-phenyl, OCF
3, Br, O-benzyl, O-allyl group, phenyl, I, CN or OH one or polysubstituted.
11. compound as claimed in claim 10, wherein R
25Expression 4-three fluoro aminomethyl phenyls, 4-SCF
3-phenyl, 2-aminomethyl phenyl, phenyl, anthryl, 4-Cl-phenyl, 4-OCF
3-phenyl, 4-n-butylphenyl, 3 (3-CF
3-phenoxy group)-phenyl, 4-OCHF
2-phenyl; 3; the 5-3,5-dimethylphenyl; 3-bromo-4-p-methoxy-phenyl; 4-benzyloxy-3; the 5-3,5-dimethylphenyl; the 3-nitrophenyl; 3-methoxyl group-4-(ethanoyl methyl)-phenyl; 2; 4; the 5-trimethoxyphenyl; the 4-ethylphenyl; 3; the 4-dichlorophenyl; 2; 3; the 5-trifluorophenyl; the 4-Phenoxyphenyl; 3-chloro-4-fluoro phenyl; 3-benzyloxy-phenyl; 3-bromo-4; the 5-Dimethoxyphenyl; 3-fluoro-2-aminomethyl phenyl; 2-chloro-3-trifluoromethyl; 3-chloro-2-fluoro-5-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 4-(allyloxy)-phenyl; 2-(benzyloxy)-4; the 5-Dimethoxyphenyl; 2-phenyl-phenyl; 2; 3; 4-trifluoro-benzene base; 2-fluoro-5-trifluorophenyl; 4-methoxyl group-3-aminomethyl phenyl; 2-fluoro-3-chloro-phenyl-; 3; 4-phenyl-difluoride base; 2; the 6-dichlorophenyl; the 3-iodine substituted phenyl; 3-iodo-4, the 5-Dimethoxyphenyl; the 2-cyano-phenyl; the 4-hydroxy phenyl; 3,4-3,5-dimethylphenyl or 3-OCF
3-phenyl.
12. compound as claimed in claim 1, it is selected from by following material:
The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl-phenyl)-ethyl]-amine
The different azoles of benzo [d]-3-base-[1-(4-trifluoromethyl sulphur alkyl-phenyl)-ethyl]-amine
The different azoles of 1-benzo [d]-3-base-3-benzyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-phenyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-o-tolyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-styroyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-sec.-propyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-chloro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-benzyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-[1-(4-fluoro-phenyl)-ethyl]-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-chloro-benzyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-[2-(4-chloro-phenyl)-ethyl]-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-nitrophenyl)-thiocarbamide
The different azoles of 1-(4-ethanoyl-phenyl)-3-benzo [d]-3-base-thiocarbamide
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-phenylformic acid
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-methyl benzoate
4-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl benzoate
The different azoles of 1-benzo [d]-3-base-3-(2,6-diethyl-phenyl)-thiocarbamide
1-benzo [the different azoles of dl-3-base-3-(3-chloro-4-methyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-methoxyl group-ethyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3-methoxyl group-propyl group)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-cyclopentyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-cyclohexyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-pyridin-3-yl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-dimethylamino-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-diethylamino-phenyl)-thiocarbamide
(the different azoles of 3-benzo [d]-3-base-thioureido)-ritalin
2-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl propionate
3-(the different azoles of 3-benzo [d]-3-base-thioureido)-ethyl butyrate
The different azoles of 1-benzo [d]-3-base-3-cyclohexyl methyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-oxyethyl group-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3,4-dimethoxy-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-pentafluorophenyl group-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-naphthalene-1-base-thiocarbamide
The different azoles of 1-benzo [1,3] dioxole-5-ylmethyl-3-benzo [d]-3-base-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-fluoro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-methyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-ethyl-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-propyl group-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-sec.-propyl-thiocarbamide
The different azoles of 1-benzo [the d]-3-base-3-tertiary butyl-thiocarbamide
The different azoles of 1-allyl group-3-benzo [d]-3-base-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-methyl-allyl group)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-nitro-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(2-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(3-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-(4-trifluoromethyl-phenyl)-thiocarbamide
The different azoles of 1-benzo [d]-3-base-3-cyclopropyl-thiocarbamide
2-[3-(the different azoles of 4-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate
1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-o-tolyl-thiocarbamide
1-benzyl-3-(the different azoles of 4-chloro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-chloro-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-isobutyl--thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-p-methylphenyl-thiocarbamide
1-(3-chloro-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3,5-dimethyl-phenyl)-thiocarbamide
1-benzyl-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(3-methoxyl group-propyl group)-thiocarbamide
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl propionate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl butyrate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-phenylformic acid
1-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-3-(4-oxyethyl group-phenyl)-thiocarbamide
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
3-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-methyl benzoate
2-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl benzoate
4-[3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thioureido]-ethyl benzoate
1-(4-ethanoyl-phenyl)-3-(the different azoles of 4-dimethylamino-benzo [d]-3-yl)-thiocarbamide
1-(2-chloro-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(4-diethylin-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide
2-{3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thioureido }-methyl propionate
1-benzo [1,3] dioxole-5-ylmethyl-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-[4-(4-propyl group-cyclohexyl)-phenyl]-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-(4-bromo-2-trifluoromethyl-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-(4-methoxyl group-phenyl)-3-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-thiocarbamide
3-{3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thioureido }-ethyl propionate
The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-octyl group-thiocarbamide
The different azoles of 1-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-3-nonyl-thiocarbamide
The different azoles of 1-cyclopropyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclopentyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclohexyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
The different azoles of 1-cyclohexyl methyl-3-[4-(4-methyl-benzyloxy)-benzo [d]-3-yl]-thiocarbamide
1-(4-dimethylamino-phenyl)-3-[4-(2,2, the 2-the trifluoro ethoxy)-different azoles of benzo [d]-3-yl]-thiocarbamide
1-allyl group-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide
[3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thioureido]-ritalin
1-(2-sec.-propyl-phenyl)-3-(the different azoles of 5-methyl-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 5-methyl-benzo [d]-3-yl)-3-(4-trifluoromethyl)-thiocarbamide
2-[3-(the different azoles of 5-fluoro-benzo [d]-3-yl)-thioureido]-methyl propionate
1-(the different azoles of 5-fluoro-benzo [d]-3-yl)-3-(tetrahydrofuran (THF)-2-ylmethyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-fluorophenyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(2-ethylphenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-fluoro-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(2-fluoro-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-cyclopentyl-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-cyano group-phenyl)-thiocarbamide
3-[3-(the different azoles of 6-chloro-benzo [d]-3-yl)-thioureido]-phenylformic acid
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(4-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 6-chloro-benzo [d]-3-yl)-3-(3-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-(3,4-dimethoxy-phenyl)-thiocarbamide
1-(the different azoles of 6-bromo-benzo [d]-3-yl)-3-naphthalene-1-base-thiocarbamide
1-benzo [1,3] dioxole-5-ylmethyl-3-(the different azoles of 6-bromo-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 6-fluoro-benzo [d]-3-yl)-3-(2-methyl sulphur alkyl-phenyl)-thiocarbamide
1-(3-cyano group-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(2-chloro-6-methyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(2,6-di-isopropyl-phenyl)-3-(the different azoles of 6-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-methyl-thiocarbamide
1-ethyl-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-propyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-amyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-hexyl-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-octyl group-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-nonyl-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-isobutyl--thiocarbamide
1-allyl group-3-(the different azoles of 7-fluoro-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-p-methylphenyl-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(2-morpholine-4-base-ethyl)-thiocarbamide
1-(the different azoles of 7-fluoro-benzo [d]-3-yl)-3-(3-morpholine-4-base-propyl group)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(1-phenyl-ethyl)-thiocarbamide
1-(4-chloro-benzyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-3-(2-methoxyl group-phenyl)-thiocarbamide
1-(the different azoles of 5-bromo-benzo [d]-3-yl)-3-(4-dimethylamino-phenyl)-thiocarbamide
1-(5-chloro-2-methoxyl group-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(4-chloro-3-trifluoromethyl-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-(2,4-dimethoxy-phenyl)-3-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-thiocarbamide
1-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-3-(3,4,5-trimethoxy-phenyl)-thiocarbamide
The different azoles of benzo [d]-3-base-(3-methyl-butyl)-amine
(the different azoles of 5-fluoro-benzo [d]-3-yl)-(2-methyl-benzyl)-amine
N4, N4-dimethyl-N3-(3-phenyl-propyl group)-different azoles-3 of benzo [d], 4-diamines
N3-butyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
Anthracene-9-ylmethyl-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(4-chloro-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-nitro-benzyl)-amine
The different azoles of acetic acid-4-[(6-chloro-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester
The different azoles of acetic acid-4-[(6-bromo-benzo [d]-3-base is amino)-methyl]-2-methoxyl group phenyl ester
The different azoles of benzo [d]-3-base-(3,4-two chloro-benzyls)-amine
The different azoles of benzo [d]-3-base-(2,4,5-trimethoxy-benzyl)-amine
The different azoles of benzo [d]-3-base-(4-ethyl-benzyl)-amine
(the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-two chloro-benzyls)-amine
The different azoles of benzo [d]-3-base-(2,3,5-three fluoro-benzyls)-amine
(the different azoles of 6-chloro-benzo [d]-3-yl)-(4-phenoxy group-benzyl)-amine
(3-chloro-4-fluoro-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-the yl)-different azoles of amine benzo [d]-3-base-(4-trifluoromethyl-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-methyl-amyl group)-amine
N4, N4-dimethyl-N3-(2,3,4-three fluoro-the benzyls)-different azoles-3 of benzo [d], 4-diamines
N3-(2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
N3-(4-methoxyl group-3-methyl-benzyl)-different azoles-3 of benzo [d], the different azoles of 4-diamines benzo [d]-3-base-(4-trifluoromethoxy-benzyl)-amine
(the different azoles of 5-fluoro-benzo [d]-3-the yl)-different azoles of (4-trifluoromethoxy-benzyl)-amine benzo [d]-3-base-(4-trifluoromethyl sulfane base-benzyl)-amine
(4-butyl-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine
The different azoles of (the different azoles of 5-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine benzo [d]-3-base-(2-fluoro-4-trifluoromethyl-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(4-trifluoromethoxy-benzyl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-[3-(3-trifluoromethyl-phenoxy group)-benzyl]-amine
(4-difluoro-methoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(3,5-dimethyl-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine
(3-bromo-4-methoxyl group-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(4-benzyloxy-3,5-dimethyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(4-butyl-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine
(3-benzyloxy-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
N3-(3,5-dimethyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
N3-(4-butyl-benzyl)-different azoles-3 of benzo [d], the 4-diamines
(the different azoles of 5-bromo-benzo [d]-3-yl)-(4-trifluoromethyl sulfane base-benzyl)-amine
(3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 7-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine
N3-(3-fluoro-2-methyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(2-chloro-3-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-(3-fluoro-2-fluoro-5-trifluoromethyl-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(2-fluoro-4-trifluoromethyl-benzyl)-amine
(4-allyl group oxygen base-benzyl)-(the different azoles of 6-fluoro-benzo [d]-3-yl)-amine
The different azoles of benzo [d]-3-base-(2-benzyloxy-4,5-dimethoxy-benzyl)-amine
(2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 6-chloro-benzo [d]-3-yl)-amine
N3-(2-benzyloxy-4,5-dimethoxy-benzyl)-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
N3-biphenyl-2-ylmethyl-N4, the different azoles-3 of N4-dimethyl-benzo [d], 4-diamines
(the different azoles of 6-fluoro-benzo [d]-3-yl)-(3-iodo-benzyl)-amine
(2-benzyloxy-4,5-dimethoxy-benzyl)-(the different azoles of 4-methoxyl group-benzo [d]-3-yl)-amine
(the different azoles of 4-fluoro-benzo [d]-3-yl)-(3-iodo-4,5-dimethoxy-benzyl)-amine
The different azoles of 2-[(5-methyl-benzo [d]-3-base is amino)-methyl]-benzonitrile
Butyl-[4-(2,2,2-three fluoro-the oxyethyl groups)-different azoles of benzo [d]-3-yl]-amine
(3-bromo-4,5-dimethoxy-benzyl)-(the different azoles of 5-methyl-benzo [d]-3-yl)-amine
The different azoles of 4-[(4-chloro-benzo [d]-3-base is amino)-methyl]-phenol
(the different azoles of 6-chloro-benzo [d]-3-yl)-(3,4-dimethyl-benzyl)-amine
(the different azoles of 4-chloro-benzo [d]-3-yl)-(3-chloro-2-fluoro-benzyl)-amine
(3,4-two fluoro-benzyls)-(the different azoles of 5-fluoro-benzo [d]-3-yl)-amine
(the different azoles of 6-bromo-benzo [d]-3-yl)-(2,6-two chloro-benzyls)-amine
(the different azoles of 7-fluoro-benzo [d]-3-yl)-(3-trifluoromethoxy-benzyl)-amine
And their corresponding separately salt, particularly their hydrogenchloride additive salt and their optional respectively solvates.
13. method that is used to prepare the different azoles of replacement benzo of the present invention [d]-3-ylamine compounds, according to this method, be preferably selected from diethyl ether, tetrahydrofuran (THF), acetonitrile, methyl-sulphoxide, in the reaction medium of dimethyl formamide and methylene dichloride, there is alkali, preferably there is at least a alkali metal alcoholates, be selected from potassium methylate particularly preferably in existence, sodium methylate, under the condition of the alkali metal alcoholates of tertiary butyl potassium and tertiary butyl sodium, preferably under 20 ℃ to 100 ℃ temperature, make the acethydroximic acid reaction of optional 2-fluoro-benzonitrile compound that replaces and formula III with general formula I I, generate the compound of general formula I
Radicals R wherein
1, R
2, R
3And R
4Has above-mentioned implication;
Radicals R wherein
1-R
4Have above-mentioned implication and radicals R
5The expression hydrogen group,
It is then optional with its purification and/or optionally separating,
Choose wantonly then in the reaction medium that is preferably selected from acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol and respective mixtures, make itself and at least a wherein R
22General formula S=C=N-R with above-mentioned implication
22Lsothiocyanates optional have at least a alkali, preferably there being at least a triethylamine, 4 that is selected from, react under the condition of the alkali of 4-dimethylaminopyridine and diisopropylethylamine, generate at least a compound, R wherein with general formula I
1, R
2, R
3, R
4Have above-mentioned implication and R
5Expression-C (=S)-NR
21R
22, R wherein
22Have above-mentioned implication and R
21The expression hydrogen group, then with they optional purifications and/or optionally separating,
And in the reaction medium that is preferably selected from acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol and respective mixtures, there is at least a alkali, preferably under the condition that has at least a metal hydride salt or metal alkoxide, be selected from particularly preferably in existence under the condition of the metal hydride salt of sodium hydride, potassium hydride KH, potassium tert.-butoxide, sodium tert-butoxide, potassium methylate, sodium methylate, sodium ethylate and potassium methylate or metal alkoxide, make optional at least a wherein R
1, R
2, R
3, R
4Have above-mentioned implication and R
5Expression-C (=S)-NR
21R
22, R wherein
22Have above-mentioned implication and R
21The compound of Formula I of expression hydrogen group, with at least a wherein LG represent leavings group, preferably represent halogen atom, especially preferably represent chlorine atom and R
21Had the general formula LG-R of the above-mentioned implication outside the hydrogen
21Compound reacts, and generates the compound of at least a general formula I, and with its optional purification and/or optionally separating,
Perhaps
In the reaction medium that is preferably selected from acetonitrile, toluene, dimethyl formamide, benzene, ethanol, methyl alcohol, DCM, trifluoroacetic acid and respective mixtures, there is at least a alkali, preferably under the condition that has at least a metal hydride salt or metal alkoxide or triethyl silicane, particularly preferably in there being triethyl silicane, be selected under the condition of the metal hydride salt of sodium hydride, potassium hydride KH, potassium tert.-butoxide, sodium tert-butoxide, potassium methylate, sodium methylate, sodium ethylate and potassium ethylate or metal alkoxide, make optional at least a wherein R
1, R
2, R
3, R
4Have above-mentioned implication and R
5The compound of Formula I of expression H is with at least a wherein R
6And R
25Has above-mentioned implication and R
30The expression straight or branched, saturated or unsaturated, do not replace or monobasic at least aliphatic group; Represent that more not replacement or monobasic at least aryl or heteroaryl and its can or encircle member ring systems with monocycle and condense; Expression does not replace or monobasic at least aryl or heteroaryl and its can be with monocycles or the general formula R that encircles that member ring systems condenses more and be connected via the alkylidene group of straight or branched
30C (=O) H or R
6C (O) R
25The compound reaction generates the compound of at least a general formula I, and chooses wantonly its purification and/or optionally separating.
14. medicine, its contain at least a compound according to claim 1 and choose any one kind of them or multiple physiology on acceptable assistant.
15. at least a compound according to claim 1 is used for the treatment of the purposes aspect the medicine of pain, migraine, anxiety disorder, the urinary incontinence or epilepsy in preparation.
16. at least a compound according to claim 1 is used for the treatment of the purposes aspect the medicine of the pain that is selected from the pain that acute pain, chronic pain, neurodynia, myalgia and inflammation cause in preparation.
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| DE102005023589.1 | 2005-05-18 | ||
| DE102005023589 | 2005-05-18 | ||
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829303A (en) * | 2013-12-20 | 2016-08-03 | 吉利德科学公司 | Fused heterocyclic compounds as ion channel modulators |
| CN111481548A (en) * | 2019-01-29 | 2020-08-04 | 复旦大学 | Application of 4- (2, 6-dichlorobenzyloxy) -3- (3-aminopyridine) benzo [ d ] isoxazole in pharmacy |
-
2006
- 2006-05-18 CN CNA2006800264751A patent/CN101228139A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829303A (en) * | 2013-12-20 | 2016-08-03 | 吉利德科学公司 | Fused heterocyclic compounds as ion channel modulators |
| US9920018B2 (en) | 2013-12-20 | 2018-03-20 | Gilead Sciences, Inc. | Fused heterocyclic compounds as ion channel modulators |
| CN105829303B (en) * | 2013-12-20 | 2018-11-06 | 吉利德科学公司 | Condensed heterocyclic compouds as ion channel modulators |
| CN111481548A (en) * | 2019-01-29 | 2020-08-04 | 复旦大学 | Application of 4- (2, 6-dichlorobenzyloxy) -3- (3-aminopyridine) benzo [ d ] isoxazole in pharmacy |
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