CN101611028B - Substituted oxindole derivatives and their use as vasopressin receptor ligands - Google Patents

Substituted oxindole derivatives and their use as vasopressin receptor ligands Download PDF

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Publication number
CN101611028B
CN101611028B CN200780051459.2A CN200780051459A CN101611028B CN 101611028 B CN101611028 B CN 101611028B CN 200780051459 A CN200780051459 A CN 200780051459A CN 101611028 B CN101611028 B CN 101611028B
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compound
acceptable salt
pharmacy acceptable
tautomeric forms
general formula
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CN101611028A (en
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A·尼茨
T·乌斯特
H·格尼斯特
W·M·布拉杰
W·沃内特
L·昂杰
W·霍恩伯格
W·卢比希
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Abert & Co KG GmbH
Abbott GmbH and Co KG
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Abstract

The present invention relates to novel oxindole derivatives of the general formula (I) to medicaments comprising them and to their use for the prophylaxis and/or treatment of diseases vasopressin dependent.

Description

The oxindole derivatives that replaces and they are used as the purposes of vasopressin receptor ligands
The present invention relates to the oxindole derivatives of new replacement, comprise their medicine and the purposes of their treatment diseases.
Vassopressin is a kind of endogenous hormone, and it has different widely effects to organ with tissue.People suspect that the vassopressin system relates to multiple pathological state, for example, and heart failure and hypertension.Known three kinds of acceptors (V1a, V1b or V3 and V2) are regulated its many effects by these acceptor vassopressins at present.Therefore, study the antagonist of these acceptors, so as to provide as much as possible the treatment disease new treatment (M.Thibonnier, Exp.Opin.Invest.Drugs1998,7 (5), 729-740).
The application has described the new replacement oxindole that has aryl sulfonyl at 1.Be described to the part of vasopressin receptor before the 1-benzenesulfonyl-1,3-dihydro-2H-indol-2-one.Described derivative in WO 93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO01/55134, WO 01/64668 and WO 01/98295, described derivative stems from the oxindole skeleton and has aryl sulfonyl at 1.These compounds are significantly different 3 replacement.
Especially; WO 93/15051 and WO 98/25901 have described 1-benzenesulfonyl-1; 3-dihydro-2H-indol-2-one is as the part of vasopressin receptor, and wherein this oxindole structure is replaced by two alkyl at 3, and described alkyl is formal ring alkyl (spiral shell connection) together.Perhaps, described volution can comprise heteroatoms such as oxygen and nitrogen (choose wantonly and have substituting group).
WO 95/18105 has described 1-benzenesulfonyl-1, and 3-dihydro-2H-indol-2-one is as the part of vasopressin receptor, and it has nitrogen-atoms at 3.In addition, the group that is selected from alkyl, cycloalkyl, phenyl and benzyl (in each case optional have substituting group) is connected at 3.
WO 03/008407 has described 1-phenyl sulfonyl oxindole compounds, wherein is connected on the oxindole by the oxygen carbonyl at 3 pyridyl piperazines.
The embodiment 108 of WO 2005/030755 has described carbamate compounds 4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid 5-cyano group-1-(2; 4-dimethoxy-benzenesulfonyl)-3-(2-methoxypyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl ester (is named according to IUPAC: 5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-methoxypyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methyl piperidine-4-yl) piperazine-1-carboxylicesters).
WO 06/005609 has described described 2-ethoxyl phenenyl carbamide compounds N-[5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxyl phenenyl)-2-oxo-2; 3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides (as embodiment 119) and N-[5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxyl phenenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides (as embodiment 128).
Except the binding affinity to vassopressin V1b acceptor, other character also may be favourable to treating and/or preventing vassopressin-dependence disease, for example:
1.) with respect to vassopressin V1a acceptor, vassopressin V1b acceptor had selectivity, namely to the binding affinity of V1a acceptor (Ki (V1a) (measuring with unit " nmole (nM) ") and to the merchant of the binding affinity (Ki (V1b)) (measuring with unit " nmole (nM) ") of V1b acceptor.Merchant Ki (V1a)/Ki (V1b) is more big, and the V1b selectivity is more big;
2.) with respect to vassopressin V2 acceptor, vassopressin V1b acceptor had selectivity, namely to the binding affinity of V2 acceptor (Ki (V2) (measuring with unit " nmole (nM) ") and to the merchant of the binding affinity (Ki (V1b)) (measuring with unit " nmole (nM) ") of V1b acceptor.Merchant Ki (V2)/Ki (V1b) is more big, and the V1b selectivity is more big;
3.) with respect to pitocin OT acceptor, vassopressin V1b acceptor had selectivity, namely to the binding affinity of OT acceptor (Ki (OT) (measuring with unit " nmole (nM) ") and to the merchant of the binding affinity (Ki (V1b)) (measuring with unit " nmole (nM) ") of V1b acceptor.Merchant Ki (OT)/Ki (V1b) is more big, and the V1b selectivity is more big;
4.) metabolic stability for example uses in each species (for example rat or people's) liver microsomes the external transformation period that records to determine;
5.) even have, also be less, the inhibition of Cytochrome P450 (CYP) enzyme: Cytochrome P450 (CYP) is the title with superfamily of the active reduced hematin of enzyme (oxydase).They are to foreign matter in the Mammals organism, and for example the degraded of medicine or xenobiotics (metabolism) also is particularly important.The most important representative of CYP type and hypotype is in people's organism: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4.When giving CYP 3A4 inhibitor (for example grapefruit juice, Cimetidine Type AB, erythromycin) simultaneously and by the degraded of this kind of enzyme system and when competing the medicine in this identical combination site, enzyme place thus, their degraded may be delayed, and the effect of institute's administered agents and side effect may increase in a kind of undesirable mode;
6.) suitable solubleness (representing with mg/ml) in water;
7.) appropriate drug kinetics (at blood plasma or tissue as the time curve of the The compounds of this invention concentration in the brain).Pharmacokinetics can be explained by following parameters: transformation period, volume of distribution, plasma clearance, AUC (" area under curve ", the area under concentration-time curve), oral administration biaavailability, brain/blood plasma ratio;
8.) existence is attached to the active substance (medicine/plasma proteins is in conjunction with (PPB) value) of a certain ratio of plasma proteins;
9.) do not have or only have a spot of hERG channel blocking: the compound of retardance hERG passage may prolong the QT timed interval, causes serious irregularity of pulse (for example " swinging pattern of ventricular tachycardia ") thus.Use described displacement test in the literature, use dofetilide (G.J.Diaz etc., Journal of Pharmacological and ToxicologicalMethods, 50 (2004) of radioactivity mark, 187-199), might measure the potentiality of the compound of retardance hERG passage.IC50 in this " dofetilide test " is more low, and the hERG retardance is more effective.In addition, the retardance of hERG passage can be used by hERG passage cells transfected and measure (G.J.Diaz etc., Journal ofPharmacological and Toxicological Methods by " full cell patch pincers " by electric Physical Experiment, 50 (2004), 187-199).
An object of the present invention is to provide a kind of compound with high reactivity and selective active, preferably particularly have high reactivity and selective active for vassopressin v1b acceptor, be used for the treatment of or prevent various vassopressin-dependence diseases.In addition, material of the present invention will have above-mentioned 1.)-9.) in one or more advantages, particularly with respect to the V1a acceptor V1b acceptor is had suitable selectivity.
Purpose of the present invention realizes by the compound of general formula (I)
Wherein
Figure G2007800514592D00031
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen, methoxy or ethoxy;
R6 is hydrogen or methoxyl group;
R7 is hydrogen, methyl, ethyl, n-propyl or sec.-propyl;
X1 is-NH-;
X2 is N or CH;
X3 is N or CH;
Wherein X2 and X3 can not be N (that is to say that having only one at most is nitrogen-atoms) simultaneously; And pharmacy acceptable salt, tautomeric forms and prodrug.
Therefore, the present invention relates to the compound (hereinafter being also referred to as " compound (I) ") of general formula (I), comprise its tautomeric forms, and the prodrug of the pharmacy acceptable salt of compound (I) and compound (I).
A compound that preferred theme is general formula (I) of the present invention,
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen or methoxyl group, particularly methoxyl group;
R6 is hydrogen or methoxyl group, particularly methoxyl group;
R7 is hydrogen, methyl, ethyl, n-propyl or sec.-propyl;
X1 is-NH-;
X2 is N or CH;
X3 is N or CH;
Wherein X2 and X3 can not be nitrogen-atoms simultaneously;
And pharmacy acceptable salt, tautomeric forms and prodrug.
A preferred especially theme of the present invention is the compound of general formula (I),
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen or methoxyl group, particularly methoxyl group;
R6 is hydrogen or methoxyl group, particularly methoxyl group, particularly methyl or ethyl;
R7 is hydrogen, methyl or ethyl;
X1 is-NH-;
X2 is N;
X3 is CH;
And pharmacy acceptable salt, tautomeric forms and prodrug.
Another preferred especially theme of the present invention is the compound of general formula (I),
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen or methoxyl group, particularly methoxyl group;
R6 is hydrogen or methoxyl group, particularly methoxyl group;
R7 is hydrogen, methyl or ethyl, particularly methyl or ethyl;
X1 is-NH-;
X2 is CH;
X3 is N;
And pharmacy acceptable salt, tautomeric forms and prodrug.
Another preferred especially theme of the present invention is the compound of general formula (I),
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen or methoxyl group, particularly methoxyl group;
R6 is hydrogen or methoxyl group, particularly methoxyl group;
R7 is hydrogen, methyl or ethyl, particularly methyl or ethyl;
X1 is-NH-;
X2 is CH;
X3 is CH;
And pharmacy acceptable salt, tautomeric forms and prodrug.
Another preferred especially theme of the present invention is the compound of general formula (I),
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is methoxyl group;
R6 is methoxyl group;
R7 is methyl or ethyl;
X1 is-NH-;
X2 is that CH and X3 are N; Or
X2 is that N and X3 are CH;
And pharmacy acceptable salt, tautomeric forms and prodrug.
The example of the preferred embodiments of the invention is compounds of general formula (I), and pharmacy acceptable salt, tautomeric forms and prodrug, wherein
R1 is oxyethyl group,
R2 is hydrogen,
R3 is cyano group,
R4 is hydrogen,
X1 is NH,
And wherein radicals X 2, X3, R5, R6 and R7 have listed implication in following table 1 every row in each case.
Table 1:
Embodiment number X2 X3 R5 R6 R7
1 N CH Methoxyl group Methoxyl group Methyl
2 N CH Methoxyl group H Methyl
3 N CH Oxyethyl group H Methyl
4 N CH H H Methyl
5 N CH H Methoxyl group Methyl
6 N CH Oxyethyl group Methoxyl group Methyl
7 N CH Methoxyl group Methoxyl group Ethyl
8 N CH Methoxyl group H Ethyl
9 N CH Oxyethyl group H Ethyl
10 N CH H H Ethyl
11 N CH H Methoxyl group Ethyl
12 N CH Oxyethyl group Methoxyl group Ethyl
13 N CH Methoxyl group Methoxyl group N-propyl
14 N CH Methoxyl group H N-propyl
15 N CH Oxyethyl group H N-propyl
16 N CH H H N-propyl
17 N CH H Methoxyl group N-propyl
18 N CH Oxyethyl group Methoxyl group N-propyl
19 N CH Methoxyl group Methoxyl group Sec.-propyl
20 N CH Methoxyl group H Sec.-propyl
21 N CH Oxyethyl group H Sec.-propyl
22 N CH H H Sec.-propyl
23 N CH H Methoxyl group Sec.-propyl
24 N CH Oxyethyl group Methoxyl group Sec.-propyl
25 N CH Methoxyl group Methoxyl group H
26 N CH Methoxyl group H H
27 N CH Oxyethyl group H H
28 N CH H H H
29 N CH H Methoxyl group H
30 N CH Oxyethyl group Methoxyl group H
31 CH N Methoxyl group Methoxyl group Methyl
Embodiment number X2 X3 R5 R6 R7
32 CH N Methoxyl group H Methyl
33 CH N Oxyethyl group H Methyl
34 CH N H H Methyl
35 CH N H Methoxyl group Methyl
36 CH N Oxyethyl group Methoxyl group Methyl
37 CH N Methoxyl group Methoxyl group Ethyl
38 CH N Methoxyl group H Ethyl
39 CH N Oxyethyl group H Ethyl
40 CH N H H Ethyl
41 CH N H Methoxyl group Ethyl
42 CH N Oxyethyl group Methoxyl group Ethyl
43 CH N Methoxyl group Methoxyl group N-propyl
44 CH N Methoxyl group H N-propyl
45 CH N Oxyethyl group H N-propyl
46 CH N H H N-propyl
47 CH N H Methoxyl group N-propyl
48 CH N Oxyethyl group Methoxyl group N-propyl
49 CH N Methoxyl group Methoxyl group Sec.-propyl
50 CH N Methoxyl group H Sec.-propyl
51 CH N Oxyethyl group H Sec.-propyl
52 CH N H H Sec.-propyl
53 CH N H Methoxyl group Sec.-propyl
54 CH N Oxyethyl group Methoxyl group Sec.-propyl
55 CH N Methoxyl group Methoxyl group H
56 CH N Methoxyl group H H
57 CH N Oxyethyl group H H
58 CH N H H H
59 CH N H Methoxyl group H
60 CH N Oxyethyl group Methoxyl group H
61 CH CH Methoxyl group Methoxyl group Methyl
62 CH CH Methoxyl group H Methyl
63 CH CH Oxyethyl group H Methyl
Embodiment number X2 X3 R5 R6 R7
64 CH CH H H Methyl
65 CH CH H Methoxyl group Methyl
66 CH CH Oxyethyl group Methoxyl group Methyl
67 CH CH Methoxyl group Methoxyl group Ethyl
68 CH CH Methoxyl group H Ethyl
69 CH CH Oxyethyl group H Ethyl
70 CH CH H H Ethyl
71 CH CH H Methoxyl group Ethyl
72 CH CH Oxyethyl group Methoxyl group Ethyl
73 CH CH Methoxyl group Methoxyl group N-propyl
74 CH CH Methoxyl group H N-propyl
75 CH CH Oxyethyl group H N-propyl
76 CH CH H H N-propyl
77 CH CH H Methoxyl group N-propyl
78 CH CH Oxyethyl group Methoxyl group N-propyl
79 CH CH Methoxyl group Methoxyl group Sec.-propyl
80 CH CH Methoxyl group H Sec.-propyl
81 CH CH Oxyethyl group H Sec.-propyl
82 CH CH H H Sec.-propyl
83 CH CH H Methoxyl group Sec.-propyl
84 CH CH Oxyethyl group Methoxyl group Sec.-propyl
85 CH CH Methoxyl group Methoxyl group H
86 CH CH Methoxyl group H H
87 CH CH Oxyethyl group H H
88 CH CH H H H
89 CH CH H Methoxyl group H
90 CH CH Oxyethyl group Methoxyl group H
Especially, the present invention relates to the compound (it is equivalent to embodiment 1 compound of table 1) of following formula Ia
Figure G2007800514592D00101
And pharmacy acceptable salt, tautomeric forms and the prodrug of Ia.
Especially, the invention still further relates to compound and pharmacy acceptable salt, tautomeric forms and the prodrug of table 1 embodiment 7.
Especially, the invention still further relates to compound and pharmacy acceptable salt, tautomeric forms and the prodrug of table 1 embodiment 31.
Especially, the invention still further relates to compound and pharmacy acceptable salt, tautomeric forms and the prodrug of table 1 embodiment 37.
Compound of the present invention (I) or (Ia) have chiral centre 3 of 2-oxindole ring.Therefore, general formula of the present invention (I) or (Ia) compound can exist with the form of 1: 1 mixture of enantiomer (racemic modification), or can have that (wherein one of two enantiomers are by enrichment with the non-racemic mixture form of enantiomer, namely or be (left-handed) enantiomer, it makes the plane of polarization port (calling (-)-enantiomer in the following text) of line polarized light, or (dextrorotation) enantiomer, it makes the plane of polarization of line polarized light turn to the right side (calling (+)-enantiomer in the following text)), or with the form existence of the compound of enantiomeric pure (the excessive ee of enantiomer＞90%) basically, namely so that (-)-enantiomer of enantiomeric pure or the form of (+)-enantiomer exist basically.Preferably, described compound exists with the form of the compound of enantiomeric pure basically.Particularly preferably be (ee＞90%) compound of enantiomeric pure basically.
Therefore, the present invention not only provides pure enantiomer and their mixture, for example, and the mixture that a kind of enantiomer exists with enriched form, and described racemic modification is provided.The present invention also provides pharmacy acceptable salt, tautomer and the prodrug of (I) or pure enantiomer (Ia), and the enantiomeric mixture that exists with the form of (I) or pharmacy acceptable salt (Ia), tautomer and prodrug.
The preferred embodiments of the invention are general formula (I) or compound (Ia) as defined above, it is characterized in that they exist with optically active form, and in each case, they all are the enantiomers of described general formula (I) compound of free alkali form, or its pharmacy acceptable salt, tautomeric forms or prodrug, this enantiomer makes the plane of polarization of polarized light to left-handed (being left-handed enantiomer).Hereinafter, compound (I) or left-handed enantiomer (Ia) are also referred to as (-)-enantiomer.
The preferred embodiments of the invention are general formula (I) or compound (Ia) as defined above, it is characterized in that they exist with the optically active form form, wherein the absolute configuration of the chirality C-3 ring carbon atom of these compounds is equivalent to the absolute configuration at C-3 place of (-)-enantiomer of formula (Ia) compound of free alkali form.This configuration is also referred to as " preferred configuration " hereinafter.The X-ray structure analysis shows that with respect to the asymmetry center at 3 carbon atom places of oxindole ring, (-)-enantiomer of formula (Ia) compound has the S configuration.
According to the present invention, preferably general formula (I) or compound (Ia), its tautomer, its pharmacy acceptable salt and its prodrug as defined above, wherein (enantiomer is excessive, ee) exists greater than 50% with optical purity for corresponding (-)-enantiomer.
According to the present invention, preferably general formula (I) or compound (Ia), its tautomer, its pharmacy acceptable salt and its prodrug as defined above, the enantiomer that wherein has preferred absolute configuration at C-3 ring carbon atom place is so that (enantiomer is excessive, ee) exists greater than 50% optical purity.
According to the present invention, preferably general formula (I) or compound (Ia), its tautomer, its pharmacy acceptable salt and its prodrug as defined above, wherein (enantiomer is excessive, ee) exists greater than 90% with optical purity for corresponding (-)-enantiomer.
According to the present invention, preferably general formula (I) or compound (Ia), its tautomer, its pharmacy acceptable salt and its prodrug as defined above, the enantiomer that wherein has preferred absolute configuration at C-3 ring carbon atom place is so that (enantiomer is excessive, ee) exists greater than 90% optical purity.
Same preferred embodiment of the present invention is general formula (I) or compound (Ia) as defined above, it is characterized in that they exist with non-optically active form form, just the form with racemic modification exists, and perhaps the form with pharmacy acceptable salt, tautomeric forms or the prodrug of this racemic modification exists.
Another theme of the present invention relates to the medicine that comprises at least a general formula as defined above (I) or compound (Ia) and/or its pharmacy acceptable salt or prodrug.
Another theme of the present invention relates to as defined above general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or prodrug as medicine.
Another theme of the present invention relates to as defined above formula (I) or compound (Ia) and/or its pharmacy acceptable salt or prodrug is used for the treatment of or preventing disease, and described disease is vassopressin dependence disease or the disease mentioned in this article particularly.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of and/or prevents at least a vassopressin dependence disease and/or for the preparation of the medicine that is used for the treatment of and/or prevents at least a vassopressin dependence disease.Vassopressin-dependence disease is those, and wherein vassopressin is depended in advancing of disease at least to a certain extent, i.e. such disease, and wherein the vassopressin level raises, and vassopressin can be facilitated disease picture (disease picture) directly or indirectly.
The invention still further relates to compound of the present invention (I) or (Ia) and/or its pharmacy acceptable salt or prodrug is used for the treatment of and/or prophylactic purposes, vassopressin is depended in wherein said advancing of disease at least to a certain extent, it is such disease, wherein the vassopressin level raises, and vassopressin can be facilitated the disease picture directly or indirectly.The invention still further relates to compound of the present invention (I) or (Ia) and/or its pharmacy acceptable salt or prodrug for the preparation of the purposes in the medicine that treats and/or prevents such disease.
The present invention be more particularly directed at least a general formula as defined above (I) or compound (Ia) and/or its pharmacy acceptable salt or prodrug and be used for the treatment of and/or prevent the purposes of at least a disease, described disease is selected from diabetes, diabetes insipidus, insulin resistance, nocturnal enuresis, incontinence, the disease that blood coagulation disorders occurs and/or the delay disease of urinating particularly, and for the preparation of the purposes in the medicine that treats and/or prevents at least a described disease.
The present invention be more particularly directed at least a general formula as defined above (I) or compound (Ia) and/or its pharmacy acceptable salt or prodrug and be used for the treatment of and/or prevent the purposes of at least a disease, described disease is selected from hypertension, pulmonary hypertension, in heart failure, myocardial infarction, coronary vasospasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), heart ischemia, the disorder of kidney system, edema, kidney vasospasm, cortical necrosis of kidney, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, gastrointestinal disturbance, gastritis vasospasm (gestritic vasospasm), liver cirrhosis, gastroenteritic ulcer, vomiting, the vomiting of chemotherapeutic period and/or travel sickness (travel sickness), and for the preparation of the purposes in the medicine that treats and/or prevents at least a described disease.
Compound of the present invention (I) or (Ia), their salt, their tautomer and their prodrug can also be used for the treatment of various vassopressin-dependence diseases, its show the central neuropathy because of or hpa axis (hypothalamus pituitary gland hypothalamic pituitary adrenal axis) change, for example be used for the treatment of affective disorder such as dysthymia disorders and bipolar disorder.These for example comprise stress (spirit) obstacle after depression (dythymicdisorders), phobia, the wound, generalized anxiety disorder, panic disorder, seasonal depression disease and somnopathy.
Compound of the present invention (I) or (Ia), their salt, their tautomer and their prodrug can be used in treatment anxiety disorder and the anxiety disorder relevant with stress reaction equally, for example, generalized anxiety disorder, phobia, post-traumatic anxiety disorder, terrified property anxiety disorder, mandatory anxiety disorder, anxiety disorder and the social phobia relevant with gross stress reaction.Compound of the present invention can also be used for the treatment of memory impairment, Alzheimer, psychosis, mental disorder, somnopathy and/or CS and disease that all are relevant with stress reaction.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of affective disorder and/or for the preparation of the medicine that is used for the treatment of affective disorder.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of anxiety disorder and/or the anxiety disorder relevant with stress reaction and/or for the preparation of being used for the treatment of anxiety disorder and/or the medicine of relevant anxiety disorder with stress reaction.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of memory impairment and/or Alzheimer and/or for the preparation of the medicine that is used for the treatment of memory impairment and/or Alzheimer.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of psychosis and/or mental disorder and/or for the preparation of the medicine that is used for the treatment of psychosis and/or mental disorder.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of CS or other and stress reaction diseases associated and/or for the preparation of the medicine that is used for the treatment of CS or other and stress reaction diseases associated.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of somnopathy and/or for the preparation of the medicine that is used for the treatment of somnopathy.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of dysthymia disorders and/or for the preparation of the medicine that is used for the treatment of dysthymia disorders.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, the Childhood of being used for the treatment of the mood disorder of onset and/or for the preparation of be used for the treatment of the Childhood medicine of the mood disorder of onset.The term mood disorder of onset " Childhood " be understood to mean as far back as the Childhood mood disorder and the dysthymia disorders that just begin.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, be used for the treatment of vasomotor symptoms and/or thermoregulation dysfunction, for example, " hot flush " symptom.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, be used for the treatment of and/or prevent mentation substance depilatory (drug dependencies), pharmacological dependence (medicamentdependencies), and/or by the dependency of other factors mediation, be used for the treatment of and/or prevent by the caused stress reaction of withdrawal of regulating dependent one or more factors, and/or be used for the treatment of and/or prevent the mentation substance depilatory that stress reaction causes, pharmacological dependence and/or the dependent recurrence that is mediated by other factors.
Another theme of the present invention relates to the purposes of at least a general formula (I) as defined above or compound (Ia) and/or its pharmacy acceptable salt or prodrug, is used for the treatment of and/or prevents schizophrenia and/or psychosis.
Another theme of the present invention relate in the patient, treat and/or prevent below the method for at least a disease, described disease is selected from diabetes, particularly diabetes insipidus (diabetes insipidus), insulin resistance, nocturnal enuresis, incontinence, the disease that blood coagulation disorders occurs and delay are urinated, and it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relate in the patient, treat and/or prevent below the method for at least a disease, described disease is selected from hypertension, pulmonary hypertension, in heart failure, myocardial infarction, coronary vasospasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), heart ischemia, the disorder of kidney system, edema, kidney vasospasm, cortical necrosis of kidney, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, gastrointestinal disturbance, gastritis vasospasm, liver cirrhosis, gastroenteritic ulcer, vomiting, the vomiting of chemotherapeutic period and travel sickness is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to the method that treats and/or prevents affective disorder in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to the method that treats and/or prevents anxiety disorder and/or the anxiety disorder relevant with stress reaction in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to the method that treats and/or prevents memory impairment and/or Alzheimer in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to the method that treats and/or prevents psychosis and/or mental disorder in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to the method for the treatment of CS in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of this patient's significant quantity.
Another theme of the present invention relates to the method for the treatment of somnopathy in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of this patient's significant quantity.
Another theme of the present invention relates to the method for the treatment of dysthymia disorders in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of this patient's significant quantity.
Another theme of the present invention relates to treat and/or prevent for example method of " hot flush " symptom of vasomotor symptoms and/or temp regulating function obstacle in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of this patient's significant quantity.
Another theme of the present invention relates to treat and/or prevent the mentation substance depilatory in the patient, pharmacological dependence and/or the dependent method that is mediated by other factors, be used for the treatment of and/or prevent method by the stress reaction that withdrawal causes of regulating dependent one or more factors, and/or be used for the treatment of and/or prevent at the mentation substance depilatory, pharmacological dependence and/or by the method for the recurrence that is caused by stress reaction in the dependency of other factors mediation is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to treat and/or prevent schizophrenia and/or psychotic method in the patient, it is characterized in that giving at least a general formula (I) or compound (Ia) and/or its pharmacy acceptable salt or the prodrug of described patient's significant quantity.
Another theme of the present invention relates to method as defined above, it is characterized in that described patient is Mammals, preferably people or non-human mammal or non-human transgene mammal.
General formula (I) or compound (Ia) as defined above, their pharmacy acceptable salt and prodrug can be taught in the equipment of known method steps itself and/or the similar devices by those skilled in the art's technology according to the present invention and be prepared.
Another preferred embodiment relates to aforesaid general formula (I) or compound (Ia), their tautomer, their prodrug and their pharmacy acceptable salt, it is characterized in that they are optionally to vasopressin receptor hypotype V1b with respect at least a closely-related vassopressin/ocytocin receptor hypotype (for example vassopressin V1a, vassopressin V2 and/or pitocin).
Another preferred embodiment relates to aforesaid general formula (I) or compound (Ia), their tautomer, their prodrug and their pharmacy acceptable salt, it is characterized in that they have the metabolic stability of improvement.
The metabolic stability of compound can be determined, for example, the solution of this compound is cultivated with the hepatomicrosome of specific species (for example rat, dog or the mankind), measure transformation period (the RS Obach of described compound then under these conditions, Curr Opin Drug Discov Devel.2001,4,36-44).Observe the improved conclusion of metabolic stability that the long transformation period might draw this compound.Stability in the presence of people's hepatomicrosome is to make the people interested especially, because it can predict the metabolism decomposition of this compound in people's liver.Therefore, have the compound (measuring) that increases metabolic stability in the hepatomicrosome test perhaps also can decompose in liver slowlyer.The concentration (level of significance) that can cause compound higher and/or longer time maintenance in vivo, the elimination transformation period (elimination half-life) of improving The compounds of this invention are thus decomposed in slow metabolism in liver.Level of significance that improve and/or that the longer time continues can cause this compound in treatment or prevent better effect in the various diseases relevant with vassopressin.In addition, the metabolic stability of improvement can also cause improving at oral administration artifact availability, and this is because described compound absorbs the back in intestines lower metabolism decomposition (so-called first pass effect) to take place in liver.Because this compound concentrations (level of significance) has improved, the oral administration biaavailability of raising can cause the better effects if of this compound behind the oral administration.
Another preferred embodiment relates to the compound of aforesaid general formula (I), it is characterized in that, with compared by the known oxindole compounds of prior art, described compound is in the patient or can have the pharmacological activity of improvement in the relevant animal models for the treatment of the applied forcasting report.
Each of the preferred definition of described these variablees can with the combinations of definitions of any other variable.
The present invention be more particularly directed to be selected from the compound of the general formula (I) of the following example, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89 and 90, and their tautomeric forms, acceptable salt and their salt-independent shape such as hydrate and/or solvate on their prodrug, particularly their physiology.The above-claimed cpd of preferred especially free alkali form or acid salt form.
The present invention also is particularly related to (-)-enantiomer of the following embodiment 1-90 compound of being selected from of general formula (I), 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B, and the tautomeric forms of formula (I) compound, acceptable salt and salt-independent shape such as hydrate and/or solvate on the prodrug, particularly their physiology.The above-claimed cpd of preferred especially free alkali form or acid salt form.
Term " prodrug " is understood to mean those compounds, and it is metabolised to compound of the present invention in vivo.The exemplary of prodrug is described in C.G.Wermeth (Ed.): The Practice ofMedicinal Chemistry, and Academic Press, San Diego is in 1996, the 671-715 pages or leaves.They comprise, for example, and phosphoric acid ester, carbamate or amino acid, ester etc.In the present invention; the suitable prodrug of formula I compound is the compound of formula I; the nitrogen-atoms that wherein carries R7 is the part of acid amides/peptide group, and namely described nitrogen carries acyl group such as C1-C4-alkyl-carbonyl such as ethanoyl, propionyl, positive butyryl radicals (n-propyl carbonyl), isobutyryl, normal-butyl carbonyl or tertiary butyl carbonyl (valeryl), benzoyl, derives from the CO conjugated group that amino acid whose CO conjugated group for example derives from glycine, L-Ala, Serine, phenylalanine etc.Suitable prodrug also comprises the alkyl carbonyl oxy alkyl carbamate, the radicals R 7 among its Chinese style I be formula-C (=O)-O-CHR a-O-C (=O)-R bPart, wherein R aAnd R bBe selected from the C1-C4-alkyl independently of each other.These carbamates are by J.Alexander, R.Cargill, and S.R.Michelson, H.Schwam, J.Medicinal Chem.1988,31 (2), 318-322 has done the generality description.These groups are cleaved under the metabolism condition, obtain the compound of formula I, and wherein R7 is hydrogen.
In addition, the present invention relates to the pharmacy acceptable salt of formula I compound, it is also referred to as acceptable salt on the physiology.Described salt usually can be by the free alkali of The compounds of this invention (I) and suitable acid-respons acquisition.Suitable acid for example is listed in Fortschritte derArzneimittelforschung " [Advances in Drug Research], 1966, Verlag, Vol.10 is among the pp.224-285.They comprise, for example, and hydrochloric acid, citric acid, tartrate, lactic acid, phosphoric acid, methylsulfonic acid, acetic acid, formic acid, toxilic acid and fumaric acid.
Compound of the present invention all is effective after the administration by all means.Described route of administration for example can be in intravenously, intramuscular, subcutaneous, local, the tracheae, in the nose, through skin, vagina, rectum, hypogloeeis, oral cavity or oral, and can be intravenously, intramuscular or particularly oral usually.
The invention still further relates to pharmaceutical composition, it comprises compound of the present invention (I) and/or its tautomer and/or its pharmacy acceptable salt and/or its prodrug and suitable pharmacy carrier (pharmaceutical carrier).The quantity of compound I in pharmaceutical composition can depend on the formulation of said composition and for example can be in the scope of 0.0001mg/g-1g/g said composition, particularly can be in scope 0.001mg/g-0.5g/g said composition.
These pharmaceutical carriers are selected according to medicament forms and desired administering mode.
General formula of the present invention (I) compound or, if it is suitable, the suitable salt of these compounds can be used in that preparation is oral, in hypogloeeis, oral cavity, subcutaneous, intramuscular, intravenously, part, the tracheae, in the nose, through the pharmaceutical composition of skin, vagina or rectal administration, described pharmaceutical composition can mix with the conventional medicine carrier with the form of unit dosage and gives the animal or human, is used for prevention or treats above-mentioned obstacle or disease.
Suitable consistent form of medication (unit dosage) comprises the form for oral administration, the for example solution of tablet, capsule, pulvis, granula, orally ingestible or suspension, be used in hypogloeeis, oral cavity, the tracheae or the form of intranasal administration, aerosol, implant, subcutaneous, intramuscular or the form of intravenous administration and the form of rectal administration.
For topical, compound of the present invention can use with the form of emulsion, paste or lotion.
In order to reach required prevention or result for the treatment of, the dosage of this active compound can change in the scope of 0.01 to 50mg/kg body weight/day.
Per unit dosage can comprise 0.05 to 5000mg, active compound and the pharmaceutical carrier of preferred 1-1000mg.This unitary dose can the administration every day 1-5 time, gives 0.5-25000mg like this, the per daily dose of preferred 1-5000mg.
If preparation is the solids composition of tablet form, so this active compound and pharmaceutical carrier such as gelatin, starch, lactose, Magnesium Stearate, talcum, silicon-dioxide etc. are mixed.
Described tablet can or carry out other and handle with sucrose, derivatived cellulose or other suitable substance dressing, so that it has activity lasting or that postpone, and the feasible active compound that discharges predetermined amount continuously.
The capsule form preparation by active compound is mixed with extender and be contained in the gained mixture soft or hard capsule in obtain.
The preparation of syrup or elixir form or can contain active compound and sweeting agent with the preparation of drops form administration does not preferably contain caloric sweeting agent, as methyl p-hydroxybenzoate or propylparaben, seasonings and the suitable tinting material of sanitas.
Water-dispersible pulvis or granula can comprise the active compound that mixes with dispersion agent, wetting agent or suspension agent such as polyvinylpyrrolidone and sweeting agent or correctives.
Rectum or vagina administration realize that by using suppository suppository uses the tackiness agent that melts in the anus temperature to be prepared, and described tackiness agent for example is theobroma oil or polyoxyethylene glycol.Administered parenterally by use aq suspension, etc. ooze salts solution or aseptic and Injectable solution works, it comprises pharmacology suitable dispersion agent and/or wetting agent, for example propylene glycol or polyoxyethylene glycol.
Described active compound can also be mixed with the form of microcapsule or centrosome (centrosomes), if appropriate, prepares with one or more carriers or additive.
Except the compound or their pharmacy acceptable salt or prodrug of general formula (I), composition of the present invention can comprise other active compound, and described other active compound is useful to treating aforesaid infringement or disease.
Therefore, the invention still further relates to pharmaceutical composition, it comprises the various active compound, and wherein at least a in these active compounds is compound of the present invention (I) or its tautomer, salt or prodrug.
The preparation of The compounds of this invention
The example for preparing the synthetic route of oxindole derivatives of the present invention is described below.
The preparation of oxindole of the present invention can be undertaken by the different approaches as shown in synthetic schemes 1 and 2.In these synthetic schemess, described variable has as identical implication in the general formula (I).
Described 3-hydroxyl-1,3-Indolin-2-one IV can be by obtaining in the 3-ketone group that metallized heterocycle III is joined isatin (isatins) II.This metallized heterocycle, for example, corresponding Ge Liya (Mg) compound or organolithium compound can be obtained by halogen or hydrocarbon compound in a usual manner.Exemplary method can be at Houben-Weyl, Methoden derOrganischen Chemie[Methods of organic chemistry], Vol.13,1-2 finds in Chap.Mg and the Li compound.Described isatin II or commercially available or to be similar to document (Advances in Heterocyclic Chemistry, A.R.Katritzky and A.J.Boulton, Academic Press, New York, 1975,18,2-58; J.Brazil.Chem.Soc.12,273-324,2001) described in the method preparation.
Use KCN or Zn (CN) 2And Pd (0) catalyzer is in solvent such as dimethyl formamide or tetrahydrofuran (THF), if the suitable for example K of alkali that also adds 2CO 3Or other carbonate and amine, at high temperature, might will in 6-unit aromatic ring, contain the iodine substituting group, for example radicals R 3Or R 43-hydroxyl oxindole IV be converted into similar cyano-containing-3-hydroxyl-oxindole IV.What be suitable as that Pd (0) salt uses is, for example, and by PdCl 2Or PdOAc 2By adding phosphine, three (o-tolyl) phosphine for example, the transition metal complex that original position makes.Also may use commercial palladium complex, for example, catalyzer tetrakis triphenylphosphine palladium (0) and/or additional phosphine part.
Described 3-hydroxyl oxindole IV can be converted into the compound V that carries leavings group LG ' at 3, and wherein said leavings group LG ' can be conventional leavings group, for example, and halogenide, methylsulfonic acid ester group (mesylate) or toluenesulphonic acids ester group (tosylate).Described intermediate V wherein, for example, LG '=chlorine can handle being prepared by pure IV in the presence of alkali such as pyridine with thionyl chloride.Perhaps, the use methylsulfonyl chloride by changing into methanesulfonates, may obtain pure IV in the presence of alkali such as triethylamine.Subsequently, compound V and amine such as ammoniacal liquor react, and after substitution reaction, obtain similar amine VI.Then, by handling with SULPHURYL CHLORIDE VII, compound such as VI are using highly basic such as potassium tert.-butoxide or sodium hydride after the hydrogenation reaction, to be converted into product VII I in DMF.Employed SULPHURYL CHLORIDE VII or commercially available, perhaps can be prepared with the similar mode of currently known methods (referring to, for example, J.Med.Chem.40,1149 (1997)).
By reacting by ordinary method with derive amino reagent such as chloro-formic ester, isocyanic ester or urea chloride, compound VIII be converted into compound I X (referring to J.March, Advanced Organic Chemistry, 1992,4 ThVersion, Wiley, New York, p.417-421; 499; 903).For example, can be the O phenyl in compound I X as the LG of leavings group, it reacts acquisition by VIII and phenyl chloroformate in the presence of alkali such as pyridine.
Subsequently with amine X reaction, if suitable at high temperature and add auxiliary alkali such as triethylamine or diisopropylethylamine, obtain the compound of general formula of the present invention (I).This amine X or commercially available or can be by method preparation known in the reference.
The another kind of method of preparation amine X is that amine and aldehydes or ketones react in the presence of reductive agent such as sodium cyanoborohydride or acetoxyl group sodium borohydride, namely carries out reductive amination reaction (J.March, AdvancedOrganic Chemistry, 1992,4 ThVersion, Wiley, New York, the 411st; 898 pages).
Synthetic schemes 1
Described in synthetic schemes 2, be similar to top synthetic schemes 1, the order for preparing the synthesis step of compound I of the present invention can be rearranged.Therefore, at first, the amino in the compound VI for example uses phenyl chloroformate to carry out derivative reaction, obtains compounds X Ia and/or XIb.In the presence of excess amine X or by means of auxiliary alkali, can make urea derivatives XII, this urea derivatives XII is in subsequent reaction, under normal condition by using highly basic such as sodium hydride or potassium tert.-butoxide to make compounds X II deprotonation, and the SULPHURYL CHLORIDE VII that is used in subsequently among the DMF handles, and can be converted into compound I of the present invention.
Synthetic schemes 2
Figure G2007800514592D00221
Below, the present invention uses embodiment to illustrate in greater detail, and described embodiment does not constitute limitation of the scope of the invention.
Compound of the present invention can be by multiple route of synthesis preparation.Therefore, the method described in synthetic schemes 1 and 2 only illustrates in more detail based on mentioned embodiment, and is not subjected to route of synthesis 1 or 2 or the restriction of mentioned similar approach.
Experimental section
Embodiment 1
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
1a) 3-(2-ethoxy pyridine-3-yl)-3-hydroxyl-5-iodo-1,3-dihydro-2H-indol-2-one
Under the ice bath cooling, 20.86g (76.40mmol) 5-iodine isatin is stirred in 400ml anhydrous tetrahydro furan (THF), (80.50mmol, 60%w/w) sodium hydride add a little at every turn, and temperature is remained between 0-10 ℃ then to add 3.22g.Under the ice bath cooling, described suspension was stirred 1 hour, during this period, make the pyridine Grignard reagent.At room temperature, 20g (80.30mmol) 2-oxyethyl group-3-iodine pyridine is dissolved among the anhydrous THF of 400ml, and then with 5-10 minute time, cooling down, (the 1M solution in THF, 95.60mmol) ethyl-magnesium-bromide joins in this solution with 95.6ml between 22 to 15 ℃.With described solution stirring 20 minutes, during this period, solution colour from colourless become slightly light yellow.
Then, divide clock time with 5-10, the solution of described pyridine Grignard reagent is joined in the solution of this 5-iodine isatin sodium salt that cools off in ice bath, described temperature fluctuates between 5 to 18 ℃.After described Grignard reagent finishes, remove ice bath, then again reaction mixture was at room temperature stirred 2 hours.Add excessive saturated ammonium chloride solution, add ethyl acetate subsequently, with this mixture restir 5 minutes.Shift out water and use ethyl acetate extraction (2x).With organic phase water (2x) washing that merges, then desolventizing under reduced pressure.At first, unreacted 5-iodine isatin precipitates from dilute solution to be separated out and is removed, and after further concentrating, product also crystallization is separated out.This suspension was stored in 5 ℃ of refrigerators 2 hours, leaches slightly lurid solid then and wash with amount of ethyl acetate.After 40 ℃ of dryings, separate obtaining required 3-(2-ethoxy pyridine-3-yl)-3-hydroxyl-5-iodo-1,3-dihydro-2H-indol-2-one (17.1g, 43.16mmol, 57%).
ESI-MS[M+H +]=397.05 calculated value C 15H 13IN 2O 3=396.19
1b) 5-cyano-3-hydroxy-3-(2-ethoxy pyridine-3-yl)-1, the 3-Indolin-2-one
In nitrogen atmosphere, with 7.1g (17.92mmol) 3-(2-ethoxy pyridine-3-yl)-3-hydroxyl-5-iodo-1,3-dihydro-2H-indol-2-one at room temperature stirs in the anhydrous THF of 100ml.Add 2.1g (17.92mmol) zinc cyanide, then add 0.51g (0.45mmol) tetrakis triphenylphosphine palladium (0).Described reaction mixture is directly transferred in the oil bath of 100 ℃ of preheatings.Described mixture after 100 ℃ (oil bath temperature) stirs 30 minutes, is added the catalyzer of other 0.51g (0.45mmol).Described mixture was stirred 2 hours altogether.Reaction mixture is cooled to room temperature, and adds excessive water.Described mixture is with ethyl acetate (3x) extraction, with organic phase water (3x) washing that merges.Under reduced pressure solvent evaporation is extremely done, then made resistates become slurry with a spot of ethyl acetate.Filter out slightly lurid solid, with ethyl acetate washing and dry in vacuum drying oven.Can separate and obtain the required product 5-cyano-3-hydroxy-3-of 3.7g (12.44mmol, 69.4%) (2-ethoxy pyridine-3-yl)-1,3-Indolin-2-one.
ESI-MS[M+H +]=296.05 calculated value C 16H 13N 3O 3=295.30
1c) 3-chloro-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile
In nitrogen atmosphere, with 6.00g (20.32mmol) 5-cyano-3-hydroxy-3-(2-ethoxy pyridine-3-yl)-1, the 3-Indolin-2-one is suspended in the 60ml anhydrous methylene chloride (molecular sieve drying is crossed).Then, add 2.30ml (28.45mmol) pyridine.Reaction mixture is cooled to 0 ℃, drips the pure thionyl chloride (thermopositive reaction) of 2.06ml (28.45mmol) then.Described mixture was at room temperature stirred 1 hour.Observe and generate a kind of yellow suspension.Reaction process is by thin-layer chromatography (TLC) monitoring (silica gel, 95: 5 methylene chloride).Described reaction mixture is poured in ice-water carefully.Stir after 15 minutes, shift out organic phase.Water extracts with methylene dichloride (2x).Merge all organic phases, use dried over mgso, filter, and desolventizing under reduced pressure.Obtain 5.70g (18.17mmol, 89%) product 3-chloro-3-(2-ethoxy pyridine-3-the yl)-2-oxoindoline-5-nitrile of amorphous solid, it is not having just to be used for next step reaction under the situation of further purifying.
ESI-MS[M+H +]=314.1 calculated value C 16H 12ClN 3O 2=313.75
1d) 3-amino-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile
5.70g (18.17mmol) 3-chloro-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile is dissolved in the 50ml methylene dichloride.In nitrogen atmosphere, 14ml (98.11mmol) 7N methanol ammonia solution slowly is added drop-wise in the reaction soln of cooling.The color of solution becomes faint yellow, then described solution is at room temperature stirred and spends the night, and product crystallizes out lentamente during this period.Reaction process is by TLC monitoring (silica gel, 9: 1 methylene chloride).Desolventizing is under reduced pressure derived resistates again and is dissolved in the methylene dichloride.Then, mixture water extraction.Separate phase, then the grease that will generate between phase is added to aqueous phase.The water ethyl acetate extraction is till the grease phased soln.Merge all organic phases that obtain, then desolventizing under reduced pressure.Described resistates is developed with ether, forms a kind of solid matter, this solid matter is leached and carries out drying in moderate temperature (35 ℃) in vacuum drying oven.Obtain 3-amino-3-(2-ethoxy pyridine-3-the yl)-2-oxoindoline-5-nitrile of 4.54g (15.43mmol, 85%) solid form.
ESI-MS[M+H +]=295.3 calculated value C 16H 14N 4O 2=294.32
1e) 3-amino-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile
3.54g (12.03mmol) 3-amino-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile is dissolved in the 80ml anhydrous dimethyl formamide (molecular sieve drying is crossed).In nitrogen atmosphere and use under the ice bath cooling, add 1.49g (13.23mmol) potassium tert.-butoxide slightly at every turn.The color of reaction mixture changes, and this brown solution is complete to guarantee hydrogenation reaction 0 ℃ of following restir 1 hour.At low temperatures, add 3.16g (13.23mmol) 2,4-dimethoxy benzene sulfonyl chloride, with this mixture 0 ℃ of following restir 2 hours.Reaction process is by TLC monitoring (silica gel, 9: 1 methylene chloride).Described reaction mixture is poured in ice-water, uses ethyl acetate extraction then.Organic phase is washed with saturated nacl aqueous solution, uses dried over mgso, and steaming desolventizes.Resistates is suspended in the ether, stirs till the product of separating out solid form, and can shift out by filtration.After the desolventizing; mother liquor uses ether (2x) to handle till final again, after the drying, obtains 4.67g (9.44mmol; 79%) the 3-amino-1-[(2 of required solid form, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile.
ESI-MS[M+H +]=495.15 calculated value C 24H 22N 4O 6S=494.53
1f) [5-cyano group-1-[(2,4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl] phenyl carbamate
With 4.67g (9.44mmol) 3-amino-1-[(2,4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile is dissolved in the 120ml pyridine and uses ice bath to be cooled to 0 ℃.Add the pure phenyl chloroformate of 1.30ml (10.39mmol), and reaction mixture was stirred 2 hours down at 0 ℃.Reaction process is by TLC monitoring (silica gel, 95: 5 methylene chloride).Desolventizing under reduced pressure, especially pyridine extract with residue diluted with water and with ethyl acetate (3x).The organic phase that merges is washed with saturated nacl aqueous solution, with dried over mgso and filtration, then desolventizing under reduced pressure.By adding toluene repeatedly and evaporating at Rotary Evaporators, remove the pyridine of trace.Ether is joined in the resistates of separation; solid crystal spends the night, and obtains the required product of 5.62g (9.14mmol, 97%) [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl] phenyl carbamate.
ESI-MS[M+H +]=615.15 calculated value C 31H 26N 4O 8S=614.64
1g) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
With 1.00g (1.63mmol) [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] phenyl carbamate; 596mg (3.25mmol) 1-(1-methyl piperidine-4-yl) piperazine and 8ml dry THF are mixed, and this mixture was at room temperature stirred 24 hours.(0.01%TFA) whether detection reaction finishes for RP, elutriant acetonitrile/water by means of analyzing HPLC.Desolventizing, resistates are gone up at Chromolith post (positive is from Merck) with preparation property HPLC and are purified, and use methylene dichloride and 6% methyl alcohol as elutriant.After repeating column chromatography; can separate 230mg (0.33mmol; 21%) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides.
Perhaps, reaction can followingly be carried out aftertreatment and purification: desolventizing after finishing.Thick material is dissolved in the ethyl acetate, and extracts with 1N HCl.Detect impurity in organic phase, product is at acid aqueous phase.Therefore, water neutralizes with 2N NaOH solution and uses ethyl acetate extraction.After dried over mgso, filter also and under reduced pressure remove ethyl acetate, described product can be used the ether crystallization.Obtain the N-[5-cyano group-1-[(2 of yield＞50%, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides.
ESI-MS[M+H +]=704.2 calculated value C 35H 41N 7O 7S=703.82
1H-NMR([D6]-DMSO，400MHz)δ[ppm]＝8.12(d，1H，J＝4.8Hz)，7.88(d，1H，J＝8.8Hz)，7.87(d，1H，J＝8.7Hz)，7.81(d，1H，J＝8.5Hz)，7.72(d，1H，J＝7.6Hz)，7.67(s，1H)，7.64(s，1H)，7.02(dd，1H，J＝5.0Hz，J＝7.5Hz)，6.69(d，1H，J＝8.9Hz)，6.65(s，1H)，4.15(m，2H)，3.85(s，3H)，3.44(s，3H)，3.20(m，4H)，2.76(m，2H，J＝11.1Hz)，2.34(m，4H)，2.11(m，4H)，1.81(m，2H，J＝11.3Hz)，1.64(m，2H，J＝10.7Hz)，1.37(m，2H)，1.06(t，1H，J＝7.0Hz)。
Embodiment 5:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl) alkylsulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl }-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
5a) 5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-3-[(carbobenzoxy) amino] indoline-2-carboxylic acid phenyl ester
With 2.78g (9.43mmol) 3-amino-3-(2-ethoxy pyridine-3-yl)-2-oxoindoline-5-nitrile (according to embodiment 1, method steps 1a)-1c) preparation) be suspended in the 25ml methylene dichloride, and be cooled to 0 ℃ with ice bath.Add 7.63ml (94.34mmol) pyridine, slowly drip 2.37ml (18.87mmol) phenyl chloroformate then, so that temperature is no more than 5-10 ℃.Under the situation that ice bath melts, will react at room temperature to stir and spend the night, precipitation is separated out the slightly solid of color then.Reaction mixture dilutes with methylene dichloride, and after adding water, solid turns back in the solution.Separate phase, water is used methylene dichloride (1x) extraction again.Saturated nacl aqueous solution (1x) washing is used at first water (3x) washing of the organic phase that merges then.After dried over mgso, filter also steaming under reduced pressure and desolventize, resistates is dissolved in the ether, add the pentane of 10 times of quantity.Generate a kind of white precipitate, should precipitate suction and leach, with pentane washing, and in vacuum drying oven 40 ℃ of dryings.Behind the fractional crystallization, separate obtaining 4.46g (8.35mmol, 89%) 5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-3-[(carbobenzoxy altogether) amino] indoline-1-carboxylic acid phenyl ester.
ESI-MS[M+H +]=535.15 calculated value C 30H 22N 4O 6=534.53
5b) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
At room temperature, at first with 760mg (1.42mmol) 5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-3-[(carbobenzoxy) amino] indoline-1-carboxylic acid phenyl ester joins among the 5ml THF, and at undiluted 1.42g (5.69mmol) 1-(1-methyl piperidine-4-yl) piperazine that adds down.The reaction mixture stirring is spent the night, and reaction detects (silica gel, methylene chloride 15: 5) to determine reaction process by TLC.This reaction is diluted with ethyl acetate and water (1x) and saturated nacl aqueous solution (1x) washing.Organic phase is also filtered with dried over mgso, and desolventizing under reduced pressure.Resistates is imported in a small amount of ether, add the hexanaphthene of 6 times of quantity.Precipitation is separated out a kind of colorless solid, and it comprises the pure N-[5-cyano group-3-of 615mg (1.22mmol, 86%) (2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides.
ESI-MS[M+H +]=504.25 calculated value C 27H 33N 7O 3=503.61
5c) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl) alkylsulfonyl]-2-oxo-2,3-dihydro-lH-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
80.0mg (0.16mmol) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides is dissolved in the dimethyl formamide, and at 0 ℃ of following 7.63mg (0.19mmol, 60%w/w) sodium hydride of adding.For making 1,3-dihydro-2H-indol-2-one derivates deprotonation, mixture was stirred 10 minutes, add 39.4mg (0.19mmol) 4-anisole SULPHURYL CHLORIDE then.Then, mixture is warmed to room temperature and stirring 30 minutes.Reaction process is by TLC monitoring (silica gel, methylene chloride 1: 1).Saturated sodium bicarbonate solution and ethyl acetate are joined in this reaction mixture, separate phase then.Water is used ethyl acetate (1x) extraction again.Dried over mgso is used in the organic phase water (1x) that merges and saturated nacl aqueous solution (1x) washing, filters, and desolventizing under reduced pressure.Resistates uses mobile phase methylene chloride (5-20%) to purify with preparation property MPLC (ISCO Companion, 4g NP post).Separate and obtain 27.3mg (0.04mmol; 23% yield; 90% purity) alkylsulfonyl N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl)]-2-oxo-2,3-dihydro-lH-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides.
ESI-MS[M+H +]=674.2 calculated value C 34H 39N 7O 6S=673.80
Alternative method of purification of crude mixture crystallization comprises the conventional column chromatography (NP-SiO of positive 2Post Chromabond) uses mobile phase dichloromethane/methyl alcohol to purify, and perhaps purifies by preparation property HPLC (RP, moving phase acetonitrile/water, 0.01%TFA or 0.01% acetic acid).
Embodiment 2-4 and 6-30:
The compound of embodiment 2-4 and 6-30 can be to use suitable starting raw material to be prepared with embodiment 1 and/or embodiment 5 similar preparation methods.
Embodiment 2:
N-{5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(2-p-methoxy-phenyl) alkylsulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl }-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
ESI-MS[M+H +]=674.05 calculated value C 34H 39N 7O 6S=673.80
Embodiment 3:
N-[5-cyano group-1-[(2-ethoxyl phenenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=688.3 calculated value C 35H 41N 7O 6S=687.82
Embodiment 4:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
ESI-MS[M+H +]=644.2 calculated value C 33H 37N 7O 5S=643.77
Embodiment 31:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
At first with 100mg (0.16mmol) [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] phenyl carbamate is (according to embodiment 1; method steps 1a)-1f) preparation) join in the 8ml anhydrous tetrahydro furan (molecular sieve drying is crossed), and add 44.7mg (0.24mmol) 1-methyl-4-(piperidin-4-yl) piperazine.Reaction mixture at room temperature stirred spend the night.Reaction process is by TLC (silica gel, 9: 1 methylene chloride) and LCMS (RP, acetonitrile/water is as elutriant and 0.01%TFA) monitoring.Desolventizing under reduced pressure imports in the methylene dichloride resistates also with 2N sodium hydroxide solution (1x) extraction.The organic phase that merges is also filtered with dried over mgso, and desolventizing under reduced pressure.Described crude mixture column chromatography (5g NP-SiO 2Cylinder Chromabond) purify twice, use 99: 1-80: 20 methylene chloride is as elutriant.Separate and obtain 53.8mg (0.08mmol; 47%) pure N-[5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides.
ESI-MS[M+H +]=704.25 calculated value C 35H 41N 7O 7S=703.82
1H-NMR([D6]-DMSO，400MHz)δ[ppm]＝8.13(dd，1H，J＝1.4Hz，J＝4.8Hz)，7.88(d，1H，J＝8.5Hz)，7.87(d，1H，J＝8.8Hz)，7.81(dd，1H，J＝1.6Hz，J＝8.6Hz)，7.71(dd，1H，J＝1.4Hz，J＝7.6Hz)，7.68(d，1H，J＝1.3Hz)，7.65(s，1H)，7.02(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.68(d，1H，J＝8.9Hz)，6.65(s，1H)，4.17(m，2H)，3.85(s，3H)，3.80(m，2H)，3.44(s，3H)，2.62(m，2H)，2.41-2.12(m，9H)，2.12(s，3H)，1.61(m，2H)，1.16(m，2H)，1.09(t，3H，J＝7.0Hz).
Embodiment 32-36:
The compound of embodiment 32-36 can be to use suitable starting raw material to be prepared with embodiment 1,5 and/or 31 similar preparation methods.
Embodiment 32:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(2-p-methoxy-phenyl) alkylsulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=674.8 calculated value C 34H 39N 7O 6S=673.80
Embodiment 33:
N-[5-cyano group-1-[(2-ethoxyl phenenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=688.2 calculated value C 35H 41N 7O 6S=687.82
Embodiment 34:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=644.7 calculated value C 33H 37N 7O 5S=643.77
Embodiment 35:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl) alkylsulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=674.2 calculated value C 34H 39N 7O 6S=673.80
Embodiment 37:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides
At first add 100mg (the 0.16mmol) [5-cyano group-1-[(2 that is dissolved in the 8ml anhydrous tetrahydro furan (molecular sieve drying is crossed); the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] phenyl carbamate (according to embodiment 1, method steps 1a)-1f) preparation).74.9mg (0.24mmol) 1-ethyl-4-piperidin-4-yl piperazine and 0.07ml triethylamine are joined in the reaction mixture together, it is at room temperature stirred spend the night then.For accelerated reaction and realization conversion completely, described mixture is heated to 50 ℃ again.Reaction process is by TLC (silica gel, 9: 1 methylene chloride) and LCMS (RP, acetonitrile/water is as elutriant and 0.01%TFA) monitoring.Desolventizing under reduced pressure imports in the methylene dichloride resistates also with 2N sodium hydroxide solution (1x) extraction.The organic phase that merges is also filtered with dried over mgso, and desolventizing under reduced pressure.Crude mixture is at first purified with silica gel column chromatography, and (pillar 20 * 200mm) uses methylene dichloride and 2% methyl alcohol as elutriant.With merge, have the product cut of an impurity to purify again on Chromolith post (positive is from Merck) with preparation property HPLC a little, use methylene dichloride and methyl alcohol (with the gradient 0-10% volume of 15min methyl alcohol) wash-out.Obtain the required N-[5-cyano group-1-[(2 of 20mg (0.03mmol, 17%), the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides.
ESI-MS[M+H +]=718.25 calculated value C 36H 43N 7O 7S=717.85
1H-NMR([D6]-DMSO，400MHz)δ[ppm]＝8.13(dd，1H，J＝1.2Hz，J＝4.6Hz)，7.88(d，1H，J＝8.2Hz)，7.87(d，1H，J＝8.7Hz)，7.81(dd，1H，J＝1.4Hz，J＝8.6Hz)，7.72(dd，1H，J＝1.3Hz，J＝7.6Hz)，7.68(d，1H，J＝1.1Hz)，7.66(s，1H)，7.02(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.68(dd，1H，J＝2.0Hz，J＝8.8Hz)，6.65(d，1H，J＝2.2Hz)，4.17(m，2H)，3.85(s，3H)，3.81(m，2H)，3.44(s，3H)，2.62(m，2H)，2.43-2.29(m，11H)，1.61(m，2H)，1.15(m，2H)，1.09(t，3H，J＝7.0Hz)，0.97(t，3H，J＝7.1Hz).
Embodiment 38-90:
The compound of embodiment 38-90 can be to use suitable starting raw material to be prepared with embodiment 1,5,31,37,55,61 and/or 67 similar preparation methods.
Embodiment 40:
N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=658.25 calculated value C 34H 39N 7O 5S=657.79
Embodiment 43:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propyl group piperazine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=732.3 calculated value C 37H 45N 7O 7S=731.88
Embodiment 55:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazine-1-phenylpiperidines-1-carboxylic acid amides
55a) 4-[1-({ [5-cyano group-1-[(2,4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl] amino } carbonyl) piperidin-4-yl] piperazine-1-carboxylic acid tert-butyl ester
At first with 100mg (0.16mmol) [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] phenyl carbamate is (according to embodiment 1; method steps 1a)-1f) preparation) join in the 8ml anhydrous tetrahydro furan (molecular sieve drying is crossed), and add 65.8mg (0.24mmol) 4-piperidin-4-yl piperazine-1-carboxylic acid tert-butyl ester.Then, mixture at room temperature stirs and spends the night.Reaction process is by TLC (silica gel, CH 2Cl 2/ MeOH 9: 1) and LCMS (RP, mobile phase acetonitrile/water and 0.01%TFA) monitoring.Desolventizing under reduced pressure imports in the methylene dichloride resistates also with 2N sodium hydroxide solution (1x) extraction.The organic phase that merges is also filtered with dried over mgso, and desolventizing under reduced pressure.Crude mixture is with column chromatography (the 5g NP-SiO that purifies 2Post, Chromabond) 98: 2 methylene chloride of use is as moving phase.Obtain the required product of 55.3mg (0.07mmol, 43%), it is directly used in next step reaction and carries out the Boc deprotection.
ESI-MS[M+H +]=790.30 calculated value C 39H 47N 7O 9S=789.91
55b) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazine-1-phenylpiperidines-1-carboxylic acid amides
At first; with 55.3mg (0.07mmol) 4-[1-({ [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] amino } carbonyl) piperidin-4-yl] piperazine-1-carboxylic acid tert-butyl ester joins in the 4ml methyl alcohol, and the hydrochloric acid of adding 1.0ml5-6M in Virahol.Described mixture is at room temperature stirred.Reaction process is by TLC monitoring (silica gel, CH 2Cl 2/ MeOH 9: 1).After transforming fully, remove alcoholic solvent, then resistates is imported in the methylene dichloride, use the 1N aqueous sodium hydroxide solution by extraction the pH value to be adjusted to 9.Organic phase and aqueous phase separation, water extracts (2x) again with methylene dichloride.With the organic phase dried over mgso that merges, and desolventizing under reduced pressure.With resistates ether crystallization.Perhaps, this resistates can also be by the conventional column chromatography (NP-SiO of positive 2Post Chromabond) uses methylene chloride to purify as mobile phase, and perhaps (RP, mobile phase acetonitrile/water 0.01%TFA) are purified by preparation property HPLC.After the crystallization, separate obtaining 15.9mg (0.023mmol, 33%) N-[5-cyano group-1-[(2,4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazine-1-phenylpiperidines-1-carboxylic acid amides.
ESI-MS[M+H +]=690.45 calculated value C 34H 39N 7O 7S=689.80
Embodiment 25-30 and 56-60 and 85-90:
The compound of embodiment 25-30 and 56-60 and 85-90 can also be to use suitable starting raw material to be prepared with embodiment 1,5,31, the similar mode of 37 and/or 55 preparation methods.
Embodiment 25:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-yl piperazine-1-carboxylic acid amides two (trifluoroacetate)
ESI-MS[M+H +]=690.15 calculated value C 34H 39N 7O 7S=689.80
Embodiment 85:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4 '-Lian piperidines-1-carboxylic acid amides two (trifluoroacetate)
ESI-MS[M+H +]=689.25 calculated value C 35H 40N 6O 7S=688.81
In compound of the present invention (I), can also introduce substituent R 7 by the reductive amination reaction subsequently according to synthetic schemes 1 or 2, it uses embodiment 61 and 67 to be illustrated by way of example:
Embodiment 61:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-methyl-4,4 '-Lian piperidines-1-carboxylic acid amides
At first with 100mg (0.138mmol) 4-[1-({ [5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl] amino } carbonyl) piperidin-4-yl] piperidinium chloride (chloride salt that is equivalent to embodiment 85) is (according to embodiment 1; method steps 1a)-1f) preparation method steps 55a and embodiment 55)-55b)) join in the 10ml methylene dichloride.Add 20 μ l (0.207mmol) formalins (37% concentration), and reaction mixture was stirred 5 minutes.This solution becomes gets muddy a little.Add 98mg (0.69mmol) sodium sulfate and 20 μ l (0.279mmol) glacial acetic acids, and this mixture is stirred 1.5h.Each a small amount of 48.7mg (0.207mmol) hydroborating reagent acetoxyl group sodium borohydride that adds, after 15 minutes, the clarification that becomes of this reaction mixture, the reaction mixture muddiness that becomes again soon then.With mixture at room temperature stir spend the night and be warmed to 40 ℃ 1 hour again.Reaction mixture at first with the dilution of 30ml methylene dichloride, is used saturated sodium bicarbonate solution (3x) extraction then.The organic phase that merges is also filtered with dried over mgso, and the vapourisation under reduced pressure solvent.Separate to obtain the 75mg crude product, this crude product is gone up and is purified at Chromolith post (RP-18e, from Merck, mobile phase acetonitrile/water, 0.01% acetic acid) with preparation property HPLC.Separate and obtain 5mg (0.007mmol; 5%) required N-[5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl]-1 '-methyl-4,4 '-Lian piperidines-1-carboxylic acid amides (correspondingly the form with acetate exists).
ESI-MS[M+H +]=703.2 calculated value C 36H 42N 6O 7S=702.83
Embodiment 67:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-ethyl-4,4 '-Lian piperidines-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=717.30 calculated value C 37H 44N 6O 7S=716.86
The racemic modification of the racemic compound of embodiment 1-90 splits:
In a kind of exemplary manner, use embodiment 1, by separating described racemic modification such as the following enantiomer (embodiment 1A and 1B) that is separated into it at preparation property chiral column:
A.) racemic modification of the racemic compound of embodiment 1 splits:
The racemic N-[5-cyano group-1-[(2 of 100mg (0.14mmol); the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides (embodiment 1) (Chiralcell OD, flow velocity 55ml/min) on the chirality preparative column uses normal heptane/ethanol (700: 300) to separate as elutriant.Can separate obtaining the at first enantiomer that goes out of wash-out of 19mg (0.03mmol, 19%), have the enantiomer (embodiment 1B) that dextrorotation luminosity (embodiment 1A) and 8mg subsequently (0.01mmol, 8%) have negative rotation luminosity.
Embodiment 1A:
(+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
ESI-MS[M+H +]=704.25 calculated value C 35H 41N 7O 7S=703.82
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=9.04min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=dextrorotation
1H-NMR([D6]-DMSO，500MHz)δ[ppm]＝8.13(dd，1H，J＝1.6Hz，J＝4.9Hz)，7.89(d，1H，J＝8.9Hz)，7.88(d，1H，J＝8.6Hz)，7.82(dd，1H，J＝1.7Hz，J＝8.6Hz)，7.72(dd，1H，J＝1.5Hz，J＝7.7Hz)，7.68(d，1H，J＝1.6Hz)，7.65(s，1H)，7.02(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.69(dd，1H，J＝2.2Hz，J＝8.9Hz)，6.66(d，1H，J＝2.1Hz)，4.17(m，2H)，3.86(s，3H)，3.45(s，3H)，3.21(m，4H)，2.77(m，2H，J＝11.0Hz)，2.34(m，4H)，2.12(m，4H)，1.82(m，2H，J＝10.9Hz)，1.64(m，2H，J＝10.8Hz)，1.37(m，2H)，1.08(t，3H，J＝7.0Hz).
Embodiment 1B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides
ESI-MS[M+H +]=704.25 calculated value C 35H 41N 7O 7S=703.82
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=25.73min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=left-handed
1H-NMR([D6]-DMSO，500MHz)δ[ppm]＝8.13(dd，1H，J＝1.2Hz，J＝4.7Hz)，7.88(d，1H，J＝8.9Hz)，7.87(d，1H，J＝8.5Hz)，7.81(dd，1H，J＝1.5Hz，J＝8.5Hz)，7.72(dd，1H，J＝1.1Hz，J＝7.6Hz)，7.68(s，1H)，7.64(s，1H)，7.01(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.69(dd，1H，J＝1.9Hz，J＝9.0Hz)，6.66(d，1H，J＝1.9Hz)，4.16(m，2H)，3.85(s，3H)，3.45(s，3H)，3.20(m，4H)，2.77(m，2H，J＝11.5Hz)，2.34(m，4H)，2.12(m，4H)，1.82(m，2H，J＝11.3Hz)，1.64(m，2H，J＝11.5Hz)，1.37(m，2H)，1.07(t，3H，J＝7.0Hz)。
B.) racemic modification of the racemic compound of embodiment 31 splits:
N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
(embodiment 31) on the chirality preparative column (Chiralcell OD, flow velocity 55ml/min) uses normal heptane/ethanol (700: 300) to separate as elutriant.At first the enantiomer that goes out of wash-out has dextrorotation luminosity (embodiment 31A), and the enantiomer that goes out of wash-out has negative rotation luminosity (embodiment 31B) subsequently.
Embodiment 31A:
(+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=704.80 calculated value C 35H 41N 7O 7S=703.82
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=9.60min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=dextrorotation
1H-NMR([D6]-DMSO，500MHz)δ.[ppm]＝8.12(dd，1H，J＝1.6Hz，J＝4.8Hz)，7.87(d，1H，J＝8.5Hz)，7.86(d，1H，J＝8.8Hz)，7.81(dd，1H，J＝1.7Hz，J＝8.6Hz)，7.73(dd，1H，J＝1.5Hz，J＝7.7Hz)，7.69(s，1H)，7.67(d，1H，J＝1.5Hz)，7.02(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.67(dd，1H，J＝2.2Hz，J＝8.9Hz)，6.65(d，1H，J＝2.1Hz)，4.14(m，2H)，3.83(s，3H)，3.80(m，2H)，3.42(s，3H)，2.60(m，2H)，2.39-2.10(m，9H)，2.10(s，3H)，1.60(m，2H)，1.12(m，2H)，1.06(t，3H，J＝7.0Hz).
Embodiment 31B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=704.80 calculated value C 35H 41N 7O 7S=703.82
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=34.31min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=left-handed
1H-NMR([D6]-DMSO，500MHz)δ[ppm]＝8.12(dd，1H，J＝1.6Hz，J＝4.9Hz)，7.86(d，1H，J＝8.7Hz)，7.85(d，1H，J＝8.8Hz)，7.81(dd，1H，J＝1.6Hz，J＝8.6Hz)，7.72(dd，1H，J＝1.4Hz，J＝7.6Hz)，7.69(s，1H)，7.67(d，1H，J＝1.6Hz)，7.02(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.67(dd，1H，J＝2.2Hz，J＝8.9Hz)，6.64(d，1H，J＝2.0Hz)，4.13(m，2H)，3.83(s，3H)，3.80(m，2H)，3.42(s，3H)，2.60(m，2H)，2.42-2.10(m，9H)，2.10(s，3H)，1.60(m，2H)，1.12(m，2H)，1.06(t，3H，J＝7.0Hz).
C.) racemic modification of the racemic compound of embodiment 37 splits:
N-[5-cyano group-1-[(2; the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2; 3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides (embodiment 37) (Chiralcell OD, flow velocity 55ml/min) on the chirality preparative column uses normal heptane/ethanol (700: 300) to separate as elutriant.At first the enantiomer that goes out of wash-out has dextrorotation luminosity (embodiment 37A), and the enantiomer that goes out of wash-out has negative rotation luminosity (embodiment 37B) subsequently.
Embodiment 37A:
(+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=718.30 calculated value C 36H 43F 3N 7O 7S=717.85
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=7.29min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=dextrorotation
1H-NMR([D6]-DMSO，500MHz)δ[ppm]＝8.13(dd，1H，J＝1.7Hz，J＝4.9Hz)，7.89(d，1H，J＝8.6Hz)，7.88(d，1H，J＝8.8Hz)，7.82(dd，1H，J＝1.8Hz，J＝8.6Hz)，7.72(dd，1H，J＝1.7Hz，J＝7.7Hz)，7.69(d，1H，J＝1.7Hz)，7.67(s，1H)，7.02(dd，1H，J＝4.9Hz，J＝7.7Hz)，6.69(dd，1H，J＝2.2Hz，J＝8.9Hz)，6.66(d，1H，J＝2.2Hz)，4.18(m，2H)，3.85(s，3H)，3.81(m，2H)，3.44(s，3H)，2.62(m，2H)，2.42-2.24(m，11H)，1.62(m，2H)，1.15(m，2H)，1.09(t，3H，J＝7.1Hz)，0.96(t，3H，J＝7.2Hz).
Embodiment 37B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=718.25 calculated value C 36H 43F 3N 7O 7S=717.85
HPLC (Chiralcel OD 0.46cm * 25cm; Normal heptane/ethanol 7: 3) R f=12.41min
Specific rotation α (22 ℃, 589nm, CHCl 3, 1mg/ml)=left-handed
1H-NMR([D6]-DMSO，500MHz)δ[ppm]＝8.12(dd，1H，J＝1.6Hz，J＝4.9Hz)，7.88(d，1H，J＝8.5Hz)，7.87(d，1H，J＝8.8Hz)，7.80(dd，1H，J＝1.7Hz，J＝8.6Hz)，7.71(dd，1H，J＝1.5Hz，J＝7.7Hz)，7.68(d，1H，J＝1.5Hz)，7.66(s，1H)，7.00(dd，1H，J＝4.9Hz，J＝7.6Hz)，6.67(dd，1H，J＝2.2Hz，J＝8.9Hz)，6.65(d，1H，J＝2.1Hz)，4.16(m，2H)，3.84(s，3H)，3.80(m，2H)，3.44(s，3H)，2.61(m，2H)，2.41-2.23(m，11H)，1.60(m，2H)，1.14(m，2H)，1.08(t，3H，J＝7.1Hz)，0.95(t，3H，J＝7.2Hz).
D.) racemic modification of racemic compound 2-30,21-36 and 38-90 splits:
With with racemic compound 1,31 and 37 racemic modification splits similar mode, can carry out racemic modification 2-30,32-36 and 38-90 separate, and obtain corresponding (+)-enantiomer 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A and 32A, 33A, 34A, 35A and 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A, 87A, 88A, 89A and 90A
And corresponding (-)-enantiomer 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B and 32B, 33B, 34B, 35B and 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.
Enantiomer A and B also can use the precursor of enantiomeric pure and intermediate to be prepared, and for example are similar to synthetic schemes 1 or 2, preferably by synthetic schemes 1.Racemic mixture is separated into (+)-enantiomer and (-)-enantiomer can be undertaken by the chirality preparative chromatography, preferably by corresponding amine structure unit VI.
Embodiment 7B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethyl piperidine-4-yl) piperazine-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=718.25 calculated value C 36H 43N 7O 7S=717.85
Embodiment 40B:
(-)-N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides
ESI-MS[M+H +]=658.25 calculated value C 34H 39N 7O 5S=657.79
Embodiment 61B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl)-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-methyl-4,4 '-Lian piperidines-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=703.30 calculated value C 36H 42N 6O 7S=702.83
1H-NMR ([D6]-DMSO, 500MHz) δ [ppm]=9.26 (1H, TFA's is protonated, 8.12 (dd, 1H, J=1.7Hz, J=4.9Hz), 7.87 (dd, 2H, J=1.3Hz, J=8.7Hz), 7.80 (dd, 1H, J=1.8Hz, J=8.5Hz), 7.80 (m, 2H), 7.66 (s, 1H), 7.00 (dd, 1H, J=4.9Hz, J=7.6Hz), 6.68 (dd, 1H, J=2.2Hz, J=8.9Hz), 6.65 (d, 1H, J=2.1Hz), 4.16 (m, 2H), 3.85 (s, 6H), and 3.44-3.41 (m, 5H), 2.85 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 1.81 (m, 2H), 1.55 (m, 2H), and 1.34-1.22 (m, 4H), 1.08 (t, 3H, J=7.0Hz), 0.92 (m, 2H).
Embodiment 67B:
(-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-ethyl-4,4 '-Lian piperidines-1-carboxylic acid amides trifluoroacetate
ESI-MS[M+H +]=717.35 calculated value C 37H 44N 6O 7S=716.86
The amine of general formula X can be prepared by the reductive amination reaction according to synthetic schemes 1 or 2.Hereinafter, use the preparation of amine compound 1-ethyl-4-piperidin-4-yl piperazine to describe as an example:
Embodiment 91:1-ethyl-4-piperidin-4-yl piperazine
91a) 4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
At first 29.2g (256mmol) N-ethyl piperazidine and 50.0g (256mmol) 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (being equivalent to the 1-Boc-4-piperidone) are joined in the 800ml ethanol down ice-cooled, and add 15.4g (256mmol) glacial acetic acid.Then, slightly the acetoxyl group sodium borohydride of 16.1g (256mmol) is joined in the reaction mixture of cooling at every turn.Beginning has gas to emit a little, behind the reductive agent of adding 2/3, can observe foam.Reaction mixture at room temperature stirred spend the night.For aftertreatment, cooling joins 200ml 2N aqueous sodium hydroxide solution in the reaction soln down, steams to desolventize ethanol, then with remaining reaction mixture dilute with water.Described mixture washs (1x) with ether (2x) extraction and with saturated nacl aqueous solution, and the organic phase dried over mgso of merging is filtered, and desolventizing under reduced pressure.Obtain the required product of yellow oily, it separates in the enterprising circumstances in which people get things ready for a trip spectrum of the 41 Nutsche strainers that are filled with silica gel subsequently, uses methylene dichloride and 10% methyl alcohol as elutriant.Obtain 40g (135mmol, 53%) 4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester altogether.
91b) the 1-of chloride salt form ethyl-4-piperidin-4-yl piperazine:
In order to remove protecting group, at first 40g (135mmol) 4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester is joined in 200ml methyl alcohol and the 1.8L methylene dichloride, and add the 5-6M HCl solution of 100ml in Virahol.Described solution becomes a kind of suspension, and has observed slight gas and emitted.Reaction mixture was stirred 1 hour at 40 ℃ (bath temperature), then at room temperature stirred weekend.In order to finish deprotection to obtain required product, add the 5-6M HCl solution in Virahol of other 50ml, then this mixture is stirred at 40 ℃.Steam methylene dichloride at Rotary Evaporators, add other 200ml methyl alcohol and the 30ml 5-6M HCl solution in Virahol.Under refluxing, stir after 1 hour, emit at strong gas and generate a kind of white suspension down.Subsequently, generate a kind of low-viscosity suspension, it is cooled to room temperature.Suction leaches precipitation, with methyl alcohol and ether washing.After the drying, separate 36g (117mmol, the 87%) 1-ethyl-4-piperidin-4-yl piperazine that obtains the chloride salt form.
1H-NMR(D 2O，400MHz)δ[ppm]＝3.74-3.47(m，11H)，3.28(q，2H，J＝7.3Hz)，3.06(dt，2H，J＝2.2Hz，J＝13.2Hz)，2.38(m，2H，J＝13.6Hz)，1.89(dq，2H，J＝4.1Hz，J＝13.3Hz)，1.30(t，3H，J＝7.3Hz).
(embodiment 1-90 also for example has letter " A " for embodiment 1-90 compound (racemic modification) and corresponding dextrorotation (+)-enantiomer, 1A, 2A etc.) and accordingly the chemical structure of left-handed (-)-enantiomer (embodiment 1-90 and with letter " B ", for example 1B, 2B etc.) be illustrated in the following table 2:
Figure G2007800514592D00411
Figure G2007800514592D00421
Figure G2007800514592D00431
Figure G2007800514592D00441
Figure G2007800514592D00451
Figure G2007800514592D00461
Figure G2007800514592D00471
Figure G2007800514592D00481
Figure G2007800514592D00491
Figure G2007800514592D00501
Figure G2007800514592D00511
Figure G2007800514592D00541
Figure G2007800514592D00551
Figure G2007800514592D00561
Figure G2007800514592D00571
Figure G2007800514592D00611
Figure G2007800514592D00621
Figure G2007800514592D00631
Figure G2007800514592D00641
Figure G2007800514592D00651
Figure G2007800514592D00661
Figure G2007800514592D00671
Figure G2007800514592D00681
Figure G2007800514592D00691
Figure G2007800514592D00701
Figure G2007800514592D00711
The measuring method of biologic activity
Vassopressin V1b receptor binding assays:
Material:
With substances with 10 -2The concentration of M is dissolved among the DMSO, and further is diluted to 5 * 10 in DMSO -4M to 5 * 10 -9The concentration of M.The pre-dilution series of these DMSO is diluted with 1: 10 with the test damping fluid.In test mixture (2%DMSO is in this mixture), material concentration was diluted with 1: 5 again.
Membrane prepare:
Collection has the CHO-K1 cell of people's vassopressin V1b acceptor (clone 3H2) of stably express, and in 50mM Tris-HCl and in the presence of proteinase inhibitor (Roche complete Mini#1836170), use the Polytron homogenizer mid-way homogenize 2 * 10 seconds, subsequently with the centrifugal 1h of 40000xg.Described film precipitation is carried out homogenize and centrifugal again as mentioned above, imports to 50mM Tris-HCl then, among the pH 7.4, and homogenize and-190 ℃ of freezing being kept in the liquid nitrogen of equal portions.
In conjunction with testing:
Carry out based on people's such as Tahara people such as (, Brit.J.Pharmacol.125,1463-1470 (1998)) Tahara A method in conjunction with test.This cultivation damping fluid is: 50mM Tris, 10mMMgCl 2, 0.1% BSA, pH 7.4.
In this test mixture (250 μ l), have the film (50 μ g/ml albumen are in cultivating damping fluid) of the CHO-K1 cell of stably express people V1b acceptor (clone hV1b_3H2_CHO) and cultivating damping fluid (50mMTris, 10mM MgCl 2, 0.1% BSA, pH7.4) 1.5nM in 3H-AVP (the 8-Arg-vassopressin, PerkinElmer#18479) cultivate together, perhaps adds the substances (replacing experiment) that increases concentration in addition and cultivate by (fully in conjunction with).Non-specific binding is measured with 1 μ M AVP (Bachem #H1780).All measure triplicate.After cultivating (at room temperature 60 minutes), pass Wathman GF/B glass fiber filter paper pad by vacuum filtration (Skatron cell harvestor 7000) and filter out free radioligand, and filter paper is transferred in the scintillation vial.Liquid scintillation is determined in Tricarb type 2000 or the 2200CA instrument (Packard) to be carried out.By means of standard quencher series the cpm that records is converted into dpm.
Estimate:
Incorporating parametric calculates by the nonlinear regression analysis among the SAS.Programmed algorithm is similar to the LIGAND routine analyzer and carries out (Munson PJ and Rodbard D, AnalyticalBiochem.107,220-239 (1980)).For recombinant chou people V1b acceptor 3The Kd of H-AVP is 0.4nM, and it is used for determining the Ki value.
This test shows that compound of the present invention has high avidity to the V1b acceptor usually, and it is with K i(h-V1b) value representation, and be usually less than 150nM, particularly 50nM, 10nM especially at the most at the most.The result provides in table 3.
Vassopressin V1a receptor binding assays:
Material:
This test substances is with 10 -2M concentration is dissolved among the DMSO.These DMSO solution are being cultivated damping fluid (50mM Tris, 10mM MgCl 2, 0.1% BSA, pH 7.4) in further dilution.
Membrane prepare:
Collection has the CHO-K1 cell of people's vassopressin V1a acceptor (clone 5) of stably express, and in 50mM Tris-HCl and in the presence of proteinase inhibitor (Roche complete Mini#1836170), use the Polytron homogenizer mid-way homogenize 2 * 10 seconds, subsequently with the centrifugal 1h of 40000xg.Described film precipitation is carried out homogenize and centrifugal again as mentioned above, imports to 50mM Tris-HCl then, among the pH 7.4, and homogenize and-190 ℃ of freezing being kept in the liquid nitrogen of equal portions.
In conjunction with testing:
Carry out people such as (, Brit.J.Pharmacol.125,1463-1470 (1998)) Tahara A in conjunction with test based on people's such as Tahara method.
This cultivation damping fluid is: 50mM Tris, 10mM MgCl 2, 0.1% BSA, pH 7.4.
In this test mixture (250 μ l), have the film (20 μ g/ml albumen are in cultivating damping fluid) of the CHO-K1 cell of stably express people V1a acceptor (clone hV1a_5_CHO) and cultivating damping fluid (50mM Tris, 10mM MgCl 2, 0.1% BSA, pH7.4) 0.04nM in 125I-AVP (8-Arg-vassopressin, NEX 128) (combination fully) cultivates together, perhaps adds the substances (replace and test) that increases concentration in addition and cultivates.Non-specific binding is measured with 1 μ M AVP (Bachem #H1780).Measure in triplicate.
After cultivating (at room temperature 60 minutes), pass Wathman GF/B glass fiber filter paper pad by vacuum filtration (Skatron cell harvestor 7000) and filter out free radioligand, and filter paper is transferred in the scintillation vial.
Liquid scintillation is determined in Tricarb type 2000 or the 2200CA instrument (Packard) to be carried out.By means of standard quencher series the cpm that records is converted into dpm.
Estimate:
Incorporating parametric calculates by the nonlinear regression analysis among the SAS.Programmed algorithm is similar to the LIGAND routine analyzer and carries out (Munson PJ and Rodbard D, AnalyticalBiochem.107,220-239 (1980)).At recombinant chou hV1a acceptor 125The Kd of I-AVP measures in saturation experiments.1.33nM Kd be used for determining the Ki value.
This test shows, compares with the V1a acceptor, and compound of the present invention has selectivity usually to the V1b acceptor, and it is with K i(h-V1a)/K i(h-V1b) value representation surpasses 10 usually, and often at least 15, and particularly at least 50, and especially at least 100.The result provides in table 3.
Vassopressin V2 receptor binding assays:
Material:
This test substances is with 10 -2M concentration is dissolved among the DMSO.This DMSO solution is being cultivated damping fluid (50mM Tris, 10mM MgCl 2, 0.1% BSA, pH 7.4) in further dilution.
Membrane prepare:
Collection has the CHO-K1 cell of people's vassopressin V2 acceptor (clone 23) of stably express, and in 50mM Tris-HCl and in the presence of proteinase inhibitor (Roche complete Mini#1836170), use the Polytron homogenizer mid-way homogenize 2 * 10 seconds, subsequently with the centrifugal 1h of 40000xg.Described film precipitation is carried out homogenize and centrifugal again as mentioned above, imports to 50mM Tris-HCl then, among the pH 7.4, and homogenize and-190 ℃ of freezing being kept in the liquid nitrogen of equal portions.
In conjunction with testing:
Carry out people such as (, Brit.J.Pharmacol.125,1463-1470 (1998)) Tahara A in conjunction with test based on people's such as Tahara method.
This cultivation damping fluid is: 50mM Tris, 10mM MgCl 2, 0.1% BSA, pH 7.4.
In this test mixture (250 μ l), have the film (50 μ g/mi albumen are in cultivating damping fluid) of the CHO-K1 cell of stably express people V2 acceptor (clone hV2_23_CHO) and cultivating damping fluid (50mM Tris, 10mM MgCl 2, 0.1% BSA, pH7.4) 1-2nM in 3H-AVP (8-Arg-vassopressin, PerkinElmer #18479) (combination fully) cultivates together, perhaps adds the substances (replace and test) that increases concentration in addition and cultivates.Non-specific binding is measured with 1 μ M AVP (Bachem #H1780).All measure triplicate.
After cultivating (at room temperature 60 minutes), pass Wathman GF/B glass fiber filter paper pad by vacuum filtration (Skatron cell harvestor 7000) and filter out free radioligand, and filter paper is transferred in the scintillation vial.
Liquid scintillation is determined in Tricarb type 2000 or the 2200CA instrument (Packard) to be carried out.By means of standard quencher series the cpm that records is converted into dpm.
Estimate:
Incorporating parametric calculates by the nonlinear regression analysis among the SAS.Programmed algorithm is similar to the LIGAND routine analyzer and carries out (Munson PJ and Rodbard D, AnalyticalBiochem.107,220-239 (1980)).For recombinant chou hV2 acceptor 3The Kd of H-AVP is 2.4nM, and it is used for determining the Ki value.
This test shows, compares with the V2 acceptor, and compound of the present invention has selectivity usually to the V1b acceptor, and it is with K i(h-V2)/K i(h-V1b) value representation surpasses 10 usually, and often at least 15, and particularly at least 25, and especially at least 50.
Ocytocin receptor is in conjunction with test
Material:
With material with 10 -2The concentration of M is dissolved among the DMSO and uses and cultivate damping fluid (50mMTris, 10mM MgCl 2, 0.1% BSA, pH 7.4) dilution.
Cell preparation:
Has the fusion HEK-293 cell of recombinant human ocytocin receptor of transient expression with 750xg at room temperature centrifugal 5 minutes.Resistates is exported in ice-cold molten born of the same parents' damping fluid (50mMTris-HCl, 10% glycerine, pH 7.4 and Roche Complete proteinase inhibitor), and experience osmotic shocks 20 minutes at 4 ℃.Then, with the cell among the molten born of the same parents with 750xg 4 ℃ centrifugal 20 minutes, resistates exported to cultivates in the damping fluid, make the aliquots containig of 107 cells/ml.This five equilibrium sample is frozen under-80 ℃ before use.
In conjunction with testing:
On the same day of experiment, with cell thawing, with cultivating the damping fluid dilution and using MultipetteCombitip (Eppendorf, Hamburg) homogenize.0.250ml reaction mixture by 2-5 * 10 4Reconstitution cell, 3-4nM 3H-pitocin (PerkinElmer, NET 858) is at test substances (suppress figure) composition in the presence of cultivation damping fluid (all in conjunction with) down or only.Non-specific binding is with 10 -6(Bachem AG H2510) measures the M pitocin.Measure and carry out in triplicate.In conjunction with the radioligand with free use the filtration of Skatron cell harvestor 7000 usefulness Whatman GF/B glass fiber filter paper to separate by vacuum filtration.Binding radioactivity is measured by the liquid scintillation of Tricarb β counter 2000 types or 2200CA (Packard).
Estimate:
Incorporating parametric calculates by nonlinear regression analysis (SAS), is similar to LIGAND program (the Analytical Biochem 1980 of Munson and Rodbard; 107:220-239).For recombinant chou hOT acceptor 3The Kd of H-pitocin is 7.6nM, and it is used for determining the Ki value.
This test shows, compares with ocytocin receptor, and compound of the present invention has selectivity usually to the V1b acceptor, and it is with K i(h-OT)/K i(h-V1b) value representation surpasses 10 usually, and often at least 15, and particularly at least 25, and especially at least 50.The result provides in table 3.
Table 3
Embodiment K i(h-V1b)*[nM] K i(h-V1a)/K i(h-V1b)* K i(h-OT)/K i(h-V1b)*
1 +++ +++ +++
1B +++ +++ +++
2 ++ +++ +++
3 ++ +++ +++
4 ++ ++ ++
7B +++ +++ +++
25 +++ +++ ++
31 +++ +++ +++
31B +++ +++ +++
32 ++ + +++
35 +++ + ++
37 +++ +++ +++
37B +++ +++ +++
40 +++ ++ +++
40B +++ + +++
43 +++ +++ +++
55 +++ +++ ++
61 +++ +++ +++
61B +++ +++ +++
67 +++ +++ +++
67B +++ +++ +++
85 +++ +++ ++
K i(h-V1b) K i(h-V1a)/K i(h-V1b) K i(h-OT)/K i(h-V1b)
+ ＞50-150nM 15-50 15-25
++ 10-50nM ＞50-100 ＞25-50
+++ ＜10nM ＞100 ＞50
The microsome half life determination:
The metabolic stability of The compounds of this invention is measured in testing below.
Substances is with the following cultivation of 0.5 μ M concentration:
0.5 μ M substances is with hepatomicrosome (the 0.25mg microsomal protein/ml) cultivate 5min in advance in 37 ℃ in microtiter plate in 0.05M potassium phosphate buffer pH 7.4 of various species (rat, people or other species).Begin reaction by adding NADPH (1mg/ml).0,5,10,15,20 and 30min after, take out 50 μ l aliquots containigs, and immediately through isopyknic acetonitrile termination reaction and the cooling.Sample is freezing till analyzing.Use MSMS, measure the residual concentration of undecomposed substances.Measure the transformation period (T1/2) by the increase of substances signal/time unit's curve, wherein suppose first order kinetics, the transformation period that can calculate substances by the minimizing of compound concentration in time.Microsome clearance rate (mCl) is with mCl=ln2/T1/2/ (the content mg/ml of microsomal protein) * 1000[ml/min/mg] form calculate and (to make amendment according to reference: Di, The Society for BiomoleculaurScreening, 2003,453-462; Obach, DMD, 1999 vol 27.N 11,1350-1359).
This test shows that compound of the present invention has high metabolic stability usually, and it causes people's microsome clearance rate value 220 μ lmin at the most usually -1Mg -1, frequent 120 μ lmin -1Mg -1, and 60 μ lmin at the most particularly -1Mg -1The result provides in table 4.
Table 4
Embodiment People's microsome clearance rate [μ lmin -1mg -1]
1 +++
1B +++
4 +++
5 +++
7B +++
25 +++
31 ++
31B +++
34 +++
35 ++
37 ++
37B +++
Embodiment People's microsome clearance rate [μ lmin -1mg -1]
40 ++
40B ++
55 ++
61B +++
85 ++
People's microsome clearance rate
+ ＞120-220μlmin -1mg -1
++ 60-120μlmin -1mg -1
+++ ＜60μlmin -1mg -1
Measure plasma proteins combination (PPB) by equilibrium dialysis:
To add 150 μ l rats of 1 or 10 μ M substances or the side that human plasma is moved into 96 hole dialysate chambers, 150 μ l PPS damping fluids are moved into the opposite side of this 96 hole dialysate chamber.Described dialysate chamber separates by the dialysis membrane of 6-8000 dalton molecular weight cut-off.
This 96 hole dialysate chamber covered and shaken over night lightly.
The next morning, pipette 10 μ l blood plasma and with the dilution of 90 μ l PPS damping fluids, then use 200 μ l acetonitriles to separate out albumen.Centrifugally remove the albumen that this is separated out, 100 μ l supernatant liquors are used for MSMS and analyze.Get 100 μ l from damping fluid one sidesway and carry out the MSMS analysis.Also referring to following reference: Banker, Journal of Pharmaceutical Sciences Vol.92,5,967-974,2003.
The external test method that Cytochrome P450 (CYP) suppresses
The fluorogenic substrate of 2C9 and 3A4:
0.4mg/ml people's hepatomicrosome was cultivated 10 minutes at 37 ℃ in 0.05M potassium phosphate buffer pH 7.4 in advance with material to be tested (0-20 μ M), CYP specific substrate.The Cyp-specific substrate of CYP2C9 is fluorescein H, and the Cyp-specific substrate of CYP 3A4 is fluorescein BE.Begin reaction by adding NADPH.After RT cultivates 30min, add the fluorescein detection reagent, and measure the gained fluorescent signal and (make amendment according to reference: Promega, Technical Bulletin P450-GLO TMAssays).
The midazolam CYP 3A4 inhibition relevant with the time
This test is made up of two portions.In first part, this substances is cultivated=pre-the cultivation in advance with hepatomicrosome (containing NADPH), then adds described substrate; In second section, substrate and substances add=are total to cultivation simultaneously.
The pre-cultivation:
0.05mg/ml microsomal protein (people's hepatomicrosome) is cultivated 5min in advance with 0-10 μ M (or 50 μ M) substances in the 50mM potassium phosphate buffer.Use NADPH to begin reaction.Behind the 30min, add 4 μ M midazolams (ultimate density), this mixture is cultivated 10min again.Behind the 10min, pipette 75 μ l reaction solns also with 150 μ l acetonitrile solution cancellation.
Cultivate altogether:
With 0.05mg/ml microsomal protein (people's hepatomicrosome), 4 μ M midazolams (ultimate density) and 0-10 μ M (or 50 μ M) the substances pre-5min that cultivates in the 50mM potassium phosphate buffer.Use NADPH to begin reaction.Behind the 10min, pipette 75 μ l reaction solns also with 150 μ l acetonitrile solution cancellation.Before analyzing with MSMS with sample always freezing (change according to reference:
Obdach，Journal of Pharmacology & Experimental Therapeutics，Vol316，1，336-348，2006；Walsky，Drug Metabolism and Disposition Vol 32，6，647-660，2004)。
The measuring method of water solubility (mg/ml)
The water solubility of The compounds of this invention for example can be according to so-called " shake flask " method (according to ASTM International:E 1148-02, Standard test methods formeasurement of aqueous solubility, Book of Standards Volume 11.05.) measure.At this, excessive solid chemical compound is joined in the buffered soln with a certain pH value (for example phosphate buffered saline buffer pH 7.4), and the gained mixture is shaken or stir till reaching steady state (typically 24 or 48 hours, sometimes even until 7 days).Then, filter or the centrifugal insoluble solids of removing, use the concentration of suitable calibrating curve determining dissolved compound by UV spectrum or high pressure liquid chromatographic analysis (HPLC).

Claims (41)

1. the compound of general formula (I)
Wherein
R1 is oxyethyl group;
R2 is hydrogen;
R3 is cyano group;
R4 is hydrogen;
R5 is hydrogen, methoxy or ethoxy;
R6 is hydrogen or methoxyl group;
R7 is hydrogen, methyl, ethyl, n-propyl or sec.-propyl;
X1 is-NH-;
X2 is N or CH;
X3 is N or CH;
Wherein X2 and X3 are not N simultaneously;
And pharmacy acceptable salt and tautomeric forms.
2. the compound of claim 1, wherein R5 is hydrogen or methoxyl group.
3. the compound of claim 1, wherein R7 is hydrogen, methyl or ethyl.
4. each compound of claim 1-3, wherein
R5 is hydrogen or methoxyl group;
R7 is hydrogen, methyl or ethyl;
X1 is-NH-;
X2 is N; With
X3 is CH.
5. each compound of claim 1-3, wherein
R5 is hydrogen or methoxyl group;
R7 is hydrogen, methyl or ethyl;
X1 is-NH-;
X2 is CH; With
X3 is N.
6. each compound of claim 1-3, wherein
R5 is methoxyl group;
R6 is methoxyl group;
R7 is methyl or ethyl;
X1 is-NH-;
X2 is that CH and X3 are N; Or
X2 is that N and X3 are CH.
7. each compound of claim 1-3, wherein
R5 is methoxyl group;
R6 is methoxyl group;
R7 is methyl;
X1 is-NH-;
X2 is N; With
X3 is CH.
8. each compound of claim 1-3, wherein
R5 is methoxyl group;
R6 is methoxyl group;
R7 is methyl;
X1 is-NH-;
X2 is CH; With
X3 is N.
9. each compound of claim 1-3, wherein
R5 is methoxyl group;
R6 is methoxyl group;
R7 is ethyl;
X1 is-NH-;
X2 is CH; With
X3 is N.
10. each the compound of general formula (I) of claim 1-3, it is characterized in that they exist with the optically active form form and they are left-handed (-)-enantiomers of described general formula (I) compound of free alkali form, this left-handed (-)-enantiomer makes the plane of polarization of line polarized light to left-handed, and pharmacy acceptable salt and/or tautomeric forms.
11. each the compound of general formula (I) of claim 1-3, it is characterized in that they exist with the optically active form form, wherein the absolute configuration of chirality C-3 ring carbon atom is equivalent to the absolute configuration at C-3 place of left-handed (-)-enantiomer of formula (Ia) compound of free alkali form
Figure FSB00001080797400031
This left-handed (-)-enantiomer makes the plane of polarization of line polarized light to left-handed, and pharmacy acceptable salt and tautomeric forms.
12. the compound of the general formula of claim 10 (I), it is the optically active form form, it is characterized in that this corresponding left-handed (-)-enantiomer is so that (enantiomer is excessive, ee) exists, and pharmacy acceptable salt and tautomeric forms greater than 50% optical purity.
13. the compound of the general formula of claim 11 (I), it is the optically active form form, the enantiomer that it is characterized in that having at C-3 ring carbon atom place preferred absolute configuration is so that (enantiomer is excessive greater than 50% optical purity, ee) exist, and pharmacy acceptable salt and tautomeric forms.
14. the compound of the general formula of claim 10 (I), it is the optically active form form, it is characterized in that corresponding left-handed (-)-enantiomer is so that (enantiomer is excessive, ee) exists, and pharmacy acceptable salt and tautomeric forms greater than 90% optical purity.
15. the compound of the general formula of claim 11 (I), it is the optically active form form, the enantiomer that it is characterized in that having at C-3 ring carbon atom place preferred absolute configuration is so that (enantiomer is excessive greater than 90% optical purity, ee) exist, and pharmacy acceptable salt and tautomeric forms.
16. each the compound of general formula (I) of claim 1-3, it is the racemic modification form, and pharmacy acceptable salt and the tautomeric forms of the racemic modification of general formula (I) compound.
17. the compound of the general formula of claim 1 (I), it is selected from following compound:
(1) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(2) (+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(3) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(4) alkylsulfonyl N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl)]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(5) alkylsulfonyl N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(2-p-methoxy-phenyl)]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(6) alkylsulfonyl N-[5-cyano group-1-[(2-ethoxyl phenenyl)]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(7) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
(8) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(9) (+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(10) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(11) alkylsulfonyl N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(2-p-methoxy-phenyl)]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(12) alkylsulfonyl N-[5-cyano group-1-[(2-ethoxyl phenenyl)]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(13) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(14) alkylsulfonyl N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-1-[(4-p-methoxy-phenyl)]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid amides;
(15) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides;
(16) (+)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides;
(17) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides;
(18) N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides;
(19) (-)-N-[5-cyano group-3-(2-ethoxy pyridine-3-yl)-2-oxo-1-(benzenesulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethyl piperazidine-1-yl) piperidines-1-carboxylic acid amides;
(20) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propyl group piperazine-1-yl) piperidines-1-carboxylic acid amides;
(21) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazine-1-phenylpiperidines-1-carboxylic acid amides;
(22) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-yl piperazine-1-carboxylic acid amides;
(23) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4 '-Lian piperidines-1-carboxylic acid amides;
(24) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-methyl-4,4 '-Lian piperidines-1-carboxylic acid amides;
(25) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-methyl-4,4 '-Lian piperidines-1-carboxylic acid amides;
(26) N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-ethyl-4,4 '-Lian piperidines-1-carboxylic acid amides;
(27) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1 '-ethyl-4,4 '-Lian piperidines-1-carboxylic acid amides;
(28) (-)-N-[5-cyano group-1-[(2, the 4-Dimethoxyphenyl) alkylsulfonyl]-3-(2-ethoxy pyridine-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethyl piperidine-4-yl) piperazine-1-carboxylic acid amides;
Or its at least a pharmacy acceptable salt or a kind of tautomeric forms.
18. medicine, comprise each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms.
19. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: at least a vassopressin-dependence disease.
20. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: at least a disease, described disease are selected from diabetes, insulin resistance, nocturnal enuresis, incontinence, the disease that blood coagulation disorders occurs and/or delay and urinate.
21. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: at least a disease, and described disease is selected from hypertension, in heart failure, myocardial infarction, coronary vasospasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), heart ischemia, the disorder of kidney system, edema, kidney vasospasm, cortical necrosis of kidney, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, gastrointestinal disturbance, gastritis vasospasm, liver cirrhosis, gastroenteritic ulcer, vomiting and/or travel sickness.
22. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: pulmonary hypertension.
23. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: the vomiting of chemotherapeutic period.
24. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: affective disorder.
25. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: anxiety disorder.
26. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: memory impairment and/or Alzheimer.
27. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: mental disorder.
28. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: CS.
29. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: somnopathy.
30. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: dysthymia disorders.
31. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: the Childhood morbidity mood disorder.
32. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: vasomotor symptoms and/or temp regulating function obstacle.
33. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: " hot flush " symptom.
34. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: mentation substance depilatory and/or pharmacological dependence, by the stress reaction that withdrawal causes of regulating dependent one or more factors, and/or the recurrence that is caused by stress reaction in mentation substance depilatory and/or the pharmacological dependence.
35. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: schizophrenia.
36. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: the anxiety disorder relevant with stress reaction.
37. each compound or its at least a pharmacy acceptable salt or a kind of tautomeric forms of general formula (I) of at least a claim 1-16, or the compound of at least a claim 17 or its at least a pharmacy acceptable salt or a kind of tautomeric forms are in being used for the treatment of and/or preventing purposes in the medicine of following disease for the preparation of the patient: psychosis.
38. each purposes of claim 19-37 is characterized in that described patient is a kind of Mammals.
39. each purposes of claim 19-37 is characterized in that described patient is the people.
40. each purposes of claim 19-30 and 32-37 is characterized in that described patient is the non-human Mammals.
41. each purposes of claim 19-30 and 32-37 is characterized in that described patient is the non-human transgene mammal.
CN200780051459.2A 2006-12-30 2007-12-28 Substituted oxindole derivatives and their use as vasopressin receptor ligands Expired - Fee Related CN101611028B (en)

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CN1533387A (en) * 2001-07-17 2004-09-29 ����ɳŵ��-����������˾ 1-phenysulfonyl-1,3-dihydro-2H-indole-2-one derivatives, their preparation and their therapeutic use

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