CN101528230A - Indoloquinoline compounds as calcium channel blockers - Google Patents

Indoloquinoline compounds as calcium channel blockers Download PDF

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CN101528230A
CN101528230A CNA2007800392241A CN200780039224A CN101528230A CN 101528230 A CN101528230 A CN 101528230A CN A2007800392241 A CNA2007800392241 A CN A2007800392241A CN 200780039224 A CN200780039224 A CN 200780039224A CN 101528230 A CN101528230 A CN 101528230A
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quinoline
ketone
tetrahydro indole
trimethyl
chemical compound
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伊琳娜·谢尔巴科娃
尤里·尼科利尤金
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Medipropharma Inc
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Abstract

The invention discloses various calcium channel blockers and pharmaceutical compositions containing these compounds. Calcium channel blockers are compounds capable of inhibiting calcium ion channels. Methods for preparing calcium channel blockers and their use as calcium channel antagonists are also disclosed.

Description

Indoloquinoline compounds as calcium channel blocker
The cross reference of related application
The application requires the priority in the U.S. Provisional Patent Application 60/840,596 of submission on August 28th, 2006 by the inventor.
Technical field
The disclosure relates to can block the substituted 2,3,4 of calcium channel, and the 7-tetrahydro indole is [2,3-c] quinoline compound also, and the preparation of this chemical compound and application.Chemical compound as herein described is administered to the patient to realize therapeutic effect.
Background technology
It is novel 2,3,4 that the disclosure relates to, and the 7-tetrahydro indole is [2,3-c] quinoline compound also, and the preparation method of these chemical compounds comprises the pharmaceutical composition of these chemical compounds, and as calcium (Ca 2+) channel blocker or calcium (Ca 2+) application of channel antagonist.
The disclosure relates to the novel indoloquinoline chemical compound with B-carboline center primitive.Be well known that from document many 'Beta '-carboline compounds are at γ-An Jidingsuan (GABA) receptor (GABA that promptly takes on positive allosteric modulator AComplex) benzene phenodiazine
Figure A20078003922400061
(BDZ) binding site has high affinity, that is, increasing GABA can be active.(for example, referring to WO 92/21679; WO93/06100).Some 'Beta '-carboline compounds are the inhibitor [referring to GB 2,355,659A (2001)] that absorbed by the GABA that GABA transport protein GAT-3/4 carries out.Some other 'Beta '-carboline compound is that hiv inhibitor is [referring to WO 2004/067531 A1; US 2005/0165040 A1; US 7,001,912 B2 (2006)], 1 κ B-kinase complex (IKK) inhibitor is (referring to WO01/68648 A1; WO 2004/092167; US 2005/0239781 A1); The antagonist of intestinal hormones glucagon-like peptide 1 (GLP-1) (referring to WO 00/33839), interleukin II (IL-2) formation inhibitor (referring to WO 98/06719) maybe can bring out and periodically amplify calcium (Ca in the β cell 2+) release (referring to WO 03/065036).Yet, before the disclosure, do not think or recognize the effectiveness of B-carboline analog as calcium channel blocker.
Chemical compound of the present disclosure is used in particular for treating mammiferous by valtage-gated calcium (Ca 2+) disease and the patient's condition of passage mediation.Valtage-gated calcium channel is present in neuron, heart, smooth muscle and skeletal muscle and other excitable cell.The change of these channel response transmembrane potentials and mediate Ca 2+In flow in the cell.Because the important function of these passages in gas ions inner equilibrium and cell signal granting incident, these passages participate in film irritability, muscle contraction and emiocytosis, such as; The exocytosis synapse is transmitted.Calcium channel is divided into low pressure activation (LVA) passage and high pressure activation (HVA) passage according to their electrophysiology character usually.The HVA passage is the known at least three group passages that comprise at present, are called L-, N-and P/Q-type passage.These passages are being had any different aspect electrophysiology and the biochemistry in conjunction with character based on their pharmacology and part each other.The HVA calcium channel is by comprising at least three subunit α (α 1, α 2), the memebrane protein of δ and β (in skeletal muscle, being also referred to as γ) assorted coalescent close formation [referring to people such as T.P.Snatch, Proc.Natl..Acad.Sci.87:3391-3395 (1990); People such as R.W.Tsien, Trends Neurosci.12:349-354 (1991); People such as M.E.Williams, Neuron 8:71-84 (1992); People such as Y.Fujita, Neuron 10:585 (1993)].Independent α 1Subunit enough forms the function passage, although the functional modification of experiencing the β subunit especially of this passage.Calcium channel exists with static (closing), (opening) or deactivation (sensitivity reduction) state that activates.The depolarization of static channel response film and opening transfers the deactivation sexual state then to.Need repolarization to return resting state.
Calcium channel is considered to the important target of pharmacotherapy.Calcium channel blocker is powerful vasodilation and involves many pathology patient's condition, comprises essential hypertension, congestive heart failure, angor, arrhythmia, migraine and pain.
The calcium channel blocker that is approved for clinical practice in the U.S. belongs to several different chemical classes: dihydropyridines (for example amlodipine, felodipine, nifedipine, nicardipine, isradipine, nimodipine), benzene phenodiazine
Figure A20078003922400071
Class (for example diltiazem), phenylalkylamine class (for example verapamil) and ammonia diaryl base propyl group amidogen ether class (for example bepridil).
Dihydropyridines, the tall and erect class of benzimidazole thiophanate nitrogen and phenylalkylamine class are incorporated into the α of L type calcium channel 1On the position of the different still functional connection on the subunit; High affinity Ca in the medicine that belongs in other two types and the passage can allosteric be regulated in the combination of the medicine of any kind 2+The combination of binding site.[referring to people such as G.H.Hockerman, Ann.Rev.Phanvacol.Toxicol.37:361-396 (1997)].
The pharmacophoric group of these types seems to the considerable selectivity that has of the L type passage in the cardiovascular system, therefore illustrated that they generally do not have activity [referring to D.J.Triggle, Biochem.Pharmacol.74:1-9 (2007)] in neuron and secretory tissue.For example, carry out in the clinical research in part brain injury patients with subarachnoid hemorrhage, the effect of nimodipine is to show beneficial effect, although the increase of the adverse reaction that is suffered by the intervention group may show that this medicine is deleterious [referring to people such as J.Langham to some patients, The CochraneDatabase of Systematic Reviews, 4:1-17 (2003)].
Blocking-up calcium channel and the chemical compound with cardiovascular effect of reduction can be used for treating neurological's disease, such as traumatic brain injury, and traumatic shock (accompanied by tissue damage hemorrhage), apoplexy, acute and chronic pain, migraine, Alzheimer, epilepsy, multiple sclerosis, parkinson disease, amyotrophic lateral sclerosis and depression are [for example, referring to J.Hatton, CNS Drugs 15:553-581 (2001); People such as J.Fritze, J.Neural Tramsm Suppl.46:539-543 (1995); People such as T.Yagami, Biochem.Pharmacol.67:1153-1165 (2004); People such as S.Moosmang, J.Neurosci.25:9883-9892 (2005); People such as I.Nomura, Neurosci.Lett.391:1-6 (2005); People such as D.Lowe, ICAD 2006, summary, P4-437, Madrid).
The use of calcium channel blocker is known to be useful to ischemia or traumatic brain injury.Ischemic injury to brain in shock or traumatic brain injury makes from the excessive release glutamate of depolarization teleneuron.This excessive glutamic acid discharges and stimulates a large amount of calcium to enter neurocyte again, activates the biochemistry cascade, causes cell death.The main path that calcium enters the depolarization neurocyte is undertaken by valtage-gated calcium channel.
This calcium enters and can be blocked by calcium channel blocker.Having data to show for the liquid knockout in the rat (fluid percussion) damages, treat with the calcium channel blocker verapamil, cause the remarkable improvement and the vasoactive recovery [referring to people such as T.Maeda, J.Neurotrauma 22:763-771 (2005)] of hematodinamics depression after the wound.The use of calcium channel blocker has hinted the cerebral vasospasm that can prevent or treat after the acute injury brain injury.This application that is hinted out is based on following hypothesis: these medicines can be offset extracellular calcium current and be gone in the smooth muscle cell of blood vessel and prevent vasoconstriction [referring to people such as D.I.Graham, J.Neurology Neurosurgery Psychiatry 52:346-350 (1989)].
Recently; calcium-channel antagonists such as DP b99, the CNS 1145, LOE 908, MN 153 and the MEM 1003 that have shown other have neuroprotective and are in [referring to J.Hatton, CNSDrugs 15:553-581 (2001)] in the clinical trial at present in animal model.
In the use of the medicine that goes through at present, there is considerable shortcoming.Some calcium channel blockers cause reflex tachycardia, vasodilation is excessive and gastrointestinal problems.Modal side effect comprises headache, and hypopiesia is felt sick, and flushing is dizzy, fatigue, edema, stomachache and constipation.Some exception, the drug treating time that uses is short at present, and must be by frequent drug administration to realize lasting effect.
Therefore, need be as the novel chemical compound of calcium channel blocker, it has bigger tissue selectivity, and rendeing a service increases, and side effect reduces and more favourable acting duration.
Summary of the invention
The disclosure relates to following discovery, that is, by the indoloquinoline chemical compound of structure (I) expression as calcium (Ca 2+) channel blocker.
In addition, the disclosure relates in one aspect to following discovery,, is shown the α of blocking-up L type calcium channel by the indoloquinoline chemical compound of structure (I) expression that is 1The selectivity of subunit.
Another aspect of the present disclosure relates to following discovery, that is, and and by the indoloquinoline chemical compound of structure (I) expression α to neuron L type calcium channel 1The dihydropyridine of subunit and benzene phenodiazine Binding site has highly to be renderd a service and selectivity.
Another aspect of the present disclosure relates to following discovery, that is, by the indoloquinoline chemical compound of structure (I) expression as gamma aminobutyric acid (GABA) chloride ion (Cl -) passage is at the inhibitor at the positive benzoate of tert-butyl group dicyclo (TBOB) binding site place.
The disclosure also relates in the mammal that suffers the calcium channel overactivity disease that the compounds for treating by structure (I) expression as herein described by effective dosage responds to the blocking-up of calcium channel.
Other aspect of the present disclosure provides by the mammal administration of needs treatment or application is used for the method for following aspect by the chemical compound of structure (I) expression: treat, prevent or improve neuronal damage after global brain ischemia and focal ischemia; Treat, prevent or improve ischemia reperfusion injury; Treat, prevent or improve cognitive disorder; Treatment, prevention or improvement are fainted from fear and the neural degeneration patient's condition; Treatment, prevention or improvement comprise the pain of acute pain and chronic pain, and neuropathic pain; Treat, prevent or improve depression; As anesthetics and anti-arrhythmic.
Another aspect of the present disclosure relates to by the application as calcium channel blocker of the indoloquinoline chemical compound of structure (I) expression.
The disclosure also relates to the application that is used for following aspect by the chemical compound of structure (I) expression: mammal people particularly, the treatment neuronal damage, be used in particular for treating apoplexy or brain injury, it is hemorrhage that accompanied by tissue damages, chronic neurodegenerative disease such as Alzheimer, parkinson disease, Huntington Chorea or amyotrophic lateral sclerosis (ALS), epilepsy, the convulsibility disease, pain, anxiety neurosis, depression, schizophrenia, the anesthesia back is cognitive to descend the opioid toleration, drug dependence spills smart abuse etc.
In addition, one side of the present disclosure provides the pharmaceutical composition that can be used for treating the disease that the blocking-up to calcium channel responds, and comprises chemical compound and the pharmaceutically useful salt and the complex by structure (I) expression of effective dose.
Detailed Description Of The Invention
The disclosure is feature with the calcium channel blocker." calcium channel blocker " is meant the chemical compound that can block calcium channel.The ability that chemical compound can " be blocked calcium channel " is meant that this chemical compound prevents that calcium from entering the intracellular main path of depolarization via valtage-gated calcium channel.
Calcium channel blocker stops calcium channel and/or realizes that the application of beneficial effect is as follows in the patient.The following technology that can be used for obtaining other calcium channel blocker of also having described.
Represent 2,3,4, the 7-tetrahydro indole also example of the distinctive calcium channel blocker of [2,3-c] quinolines is described by following structure (I) and officinal salt, hydrate, tautomer, solvate and complex and explanation subsequently:
Structure (I)
Figure A20078003922400111
Wherein:
R 1For one of following: H, lower alkyl, cyclic hydrocarbon radical, aryl, aryl alkyl.Preferably, R 1Be H or low alkyl group;
R 2And R 3Be selected from one of following independently of one another: H, low alkyl group, cyclic hydrocarbon radical, aryl, aryl alkyl; Perhaps R 2And R 3Formation-(CH together 2) n-and n be 6,5 or 4; Perhaps R 2And R 3Formation-CH (low alkyl group) (CH together 2) n-and n be 5,4 or 3.Preferably, R 2And R 3Be selected from one of following independently of one another: H, low alkyl group, aryl or aryl alkyl; Perhaps R 2And R 3Formation-(CH together 2) n-and n be 6,5 or 4.More preferably, R 2And R 3Be selected from one of following independently of one another: H, low alkyl group or aryl; Perhaps R 2And R 3Formation-(CH together 2)-and n be 5 or 4;
R 4And R 5Be selected from one of following independently of one another: H, NH 2, OH or lower alkyl; Or R 4And R 5Be O, S or NOH together.Preferably, R 4And R 5Be selected from one of following independently of one another: H or OH; Or R 4And R 5Be O or NOH together;
R 6, R 7, R 8And R 9Be selected from independently of one another: H, halogen, CN, CF 3, OCF 3, low alkyl group, cyclic hydrocarbon radical, lower alkoxy, NH-low alkyl group, NH-alkylaryl, N (low alkyl group) 2, C (O) OH, C (O) O-low alkyl group, OH, OC (O)-low alkyl group.Preferably, R 6, R 7, R 8And R 9Be selected from independently of one another: H, halogen, CN, CF 3, OCF 3, low alkyl group, lower alkoxy;
R 10For one of following: H, low alkyl group, cyclic hydrocarbon radical, aryl alkyl, aryl.Preferably, R 10Be selected from one of following: H, low alkyl group or aryl alkyl.
About functional group (such as R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9) " being independently selected from " of indication be meant that described functional group can select with being same to each other or different to each other.
" alkyl " is meant alkyl or alkenyl." lower alkyl " is meant low alkyl group or low-grade alkenyl, preferred low alkyl group.
" thiazolinyl " is meant optional substituted alkyl, its comprise at least one between carbon atom carbon-to-carbon double bond and comprise 2-6 carbon atom that combines.The thiazolinyl alkyl can be a straight chain.Straight-chain alkenyl preferably contains 2-4 carbon.
" alkyl " is meant optional substituted alkyl, and it is by the connection of carbon-to-carbon singly-bound and have 1-6 carbon atom that links together.The alkyl alkyl can be straight chain or comprise one or more side chains.Side chain and straight chained alkyl preferably contain 1-4 carbon, can choose wantonly separately to be substituted.Alkyl substituent is selected from independently of one another: low alkyl group, unsubstituted aryl, OH, NH 2, NH-low alkyl group and N (low alkyl group) 2-.Preferably, there are two substituent groups at the most.Even more preferably, alkyl is the low alkyl group of the alkyl that contains 2-4 carbon of unsubstituted side chain or straight chain.
" cyclic hydrocarbon radical " is meant optional substituted cyclic alkyl or chooses substituted non-aromatics ring-type thiazolinyl wantonly and comprise monocycle and multiring structure, such as bicyclo-or three rings.Cycloalkyl has 3-15 atom.Preferably, cycloalkyl has 3-6 carbon.The optional substituent group of cyclic hydrocarbon radical is independently selected from about alkyl and the described substituent group of thiazolinyl.
" aryl " is meant optional substituted aryl, and it has at least one ring, has bonded or condensed loop systems.Aryl comprises isocyclic aryl, heterocyclic aryl and biaryl, and all these can be chosen wantonly and be substituted.Preferably, aryl is optional substituted phenyl.
" aryl alkyl " is meant aryl-(C 1-C 6) alkyl substituent, wherein alkyl is a straight chain, such as benzyl or phenethyl; Or side chain.Moieties with the junction point place bonding of parent molecule.
" alkoxyl " is meant the oxygen that is connected with the alkyl of the unsubstituted 1-4 of containing carbon length, preferred 1-2 carbon length.More preferably, alkoxyl is a methoxyl group.
" halogen " is meant fluorine, chlorine, bromine or iodine.Preferably, halogen is a fluorine or chlorine.
By the indoloquinoline chemical compound of structure (I) expression can comprise one or more asymmetric carbon atoms and can racemic form and the optical activity form exist.All these chemical compounds and diastereomer covered in the scope of the present invention.
Chemical compound as useful especially embodiment comprises:
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also.
Verbose Listing as the chemical compound of useful especially embodiment comprises:
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydrochysene-indole be [2,3-c] quinoline-1-ketone also.
More Verbose Listing as the chemical compound of useful especially embodiment comprises:
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3-isopropyl-6-methyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9,10-two fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole are [2,3-c] quinoline-1-ketone also;
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydrochysene-indole be [2,3-c] quinoline-1-ketone also;
10-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydrochysene-1H-indole be [2,3-c] quinoline also.
The further Verbose Listing of chemical compound comprises:
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline also;
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-fluoro-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3-isopropyl-6-methyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone also;
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3-phenyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
9,10-two fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole are [2,3-c] quinoline-1-ketone also;
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydrochysene-indole be [2,3-c] quinoline-1-ketone also;
10-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydrochysene-1H-indole be [2,3-c] quinoline also;
7-N-ethyl-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also.
The more detailed tabulation of chemical compound comprises:
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline also;
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-fluoro-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-chloro-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3-isopropyl-6-methyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3-phenyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
9,10-two fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole are [2,3-c] quinoline-1-ketone also;
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydrochysene-indole be [2,3-c] quinoline-1-ketone also;
6-isopropyl-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydrochysene-1H-indole be [2,3-c] quinoline also;
7-N-ethyl-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
7-N-propyl group-3,3,6-trimethyl 2,3,4I7-tetrahydro indole be [2,3-c] quinoline-1-ketone also.
Officinal salt is nontoxic salt at it under by the amount of administration and concentration.
Officinal salt comprises acid-addition salts, such as comprising sulfate, hydrochlorate, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esilate, benzene sulfonate, tosilate, cyclohexyl-n-sulfonate and quinate.Hydrochlorate is useful especially officinal salt.Officinal salt can be from obtaining such as following acid: hydrochloric acid, maleic acid, sulphuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, cyclohexyl sulfamic acid, fumaric acid and quinic acid.
When having the phenol etc. of acidic functionality such as alcohol, carboxylic acid, officinal salt also can comprise base addition salts, such as comprising dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkyl ammonia and zinc.
For example, by the calcium channel blocker of structure (I) expression, wherein R 1Be hydrogen or low alkyl group, R 4And R 5Form oxygen together, and R 10Be hydrogen, can comprise making suitable 1-oxo-2,3,4, the method that 7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes and ammonium hydroxide react in isopropyl alcohol or reacts in water with ammonium acetate according to reaction scheme I preparation.
By the calcium channel blocker of structure (I) expression, wherein R 1Be hydrogen or low alkyl group, and R 4, R 5And R 10Each hydrogen naturally can be according to reaction scheme I, and is suitable to 2,3 of structure (I) expression by making, 4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone reduction preparation also, comprises making suitable 2,3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone and the hydrazine hydrate method of reacting in ethylene glycol also.
By the calcium channel blocker of structure (I) expression, wherein R 1Be hydrogen or low alkyl group, R 4And R 5Form the N-hydroxyl amino together, and R 10Be hydrogen, can be according to reaction scheme I preparation, comprise making suitably that the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone and the oxammonium hydrochloride. method of reacting also in pyridine and ethanol by 2,3,4 of structure (I) expression.
By the calcium channel blocker of structure (I) expression, wherein R 1Be hydrogen or low alkyl group, R 4And R 5Form oxygen together, and R 10Be low alkyl group, can be according to reaction scheme I, suitable by making by 2 of structure (I) expression, 3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketoalkylation preparation also, comprise and make suitable 2,3,4,7-tetrahydro indole also [2,3-c] quinoline-1-ketone and sodium hydride and alkyl halide be at anhydrous N, the method for reacting in the dinethylformamide.
1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes can be according to reaction scheme 1 preparation, comprise making suitable 2-(1H-indol-3-yl) cyclohexane extraction-1,3-diketone and suitable carboxylic acid anhydrides and perchloric acid or phosphorous acid reaction or with the method for diethoxy Ethyl Methyl Ether and Tetrafluoroboric acid reaction.
2-(1H-indol-3-yl) cyclohexane extraction-1,3-diketone can comprise making suitable 2-(1-acetyl group-1H-indol-3-yl) cyclohexane extraction-1 according to reaction scheme I preparation, the method for 3-diketone and sodium hydroxide reaction.
2-(1-acetyl group-1H-indol-3-yl) cyclohexane extraction-1,3-diketone can comprise making suitable 1-acetyl group-1 according to reaction scheme I preparation, and 2-indoline-3-ketone is with suitable cyclohexane extraction-1, the method that 3-diketone and triethylamine react in acetic acid.
1-acetyl group-1,2-indoline-3-ketone can comprise the method that suitable acetic acid 1-acetyl group-1H-indol-3-yl ester and sodium sulfite are reacted according to reaction scheme I preparation in water.
Acetic acid 1-acetyl group-1H-indol-3-yl ester can comprise the method that makes suitable 2-(N-acetyl group carboxyl methylamino) benzoic acid and acetic anhydride according to reaction scheme I preparation.
2-(N-acetyl group carboxyl methylamino) benzoic acid can adopt the method preparation that makes suitable 2-(carboxyl methylamino) benzoic acid and sodium carbonate or acetic anhydride adopt standard technique to react.
2-(carboxyl methylamino) benzoic acid can adopt the method preparation that makes suitable 2-amino benzoic Acid and monoxone adopt standard technique to react.[for example, referring to people such as S.Holt, Proc.Roy.Soc.B 148:481-494 (1958); People such as S.Holt, J.Chem.Soc.1217-1223 (1958); People such as E.Tighineanu, Tetrahedron 36:1385-1397 (1980); People such as V.I.Dulenko, Chem.Heterocycl.Comp. (Engl.Transl.) 3:302-305 (1985); People such as I.V.Komissarov, Chem.Heterocycl.Comp. (Engl.Transl.) 19:187-191 (1986); People such as I.V.Komissarov, Chem.Heterocycl.Comp. (Engl.Transl.) 23:471-474 (1989); People such as M.Kollmar, Org.Synth.Coll.Vol.10:23 (2004)].
Reaction scheme I
Figure A20078003922400191
To treat people and other mammal in order using, according to standard medicine pharmacy practice it to be mixed with pharmaceutical composition usually by the compound or pharmaceutically acceptable salt thereof or the complex of structure (I) expression.
Calcium channel blocker can be by comprising following different approaches administration: intravenous, and intraperitoneal, subcutaneous, intramuscular, per os, local (transdermal), or transmucosal administration.For being administered systemically, oral administration is preferred.For oral administration, for example, chemical compound can be formulated into conventional peroral dosage form, and such as capsule, tablet and liquid preparation be such as syrup, elixir and dense drop.
As an alternative, can use injecting pathway (parenterai administration), for example, intramuscular, intravenous, intraperitoneal and subcutaneous.For injection, chemical compound of the present invention is formulated in the liquid solution, preferably, be formulated in the physiology compatible buffer agent or solution, and such as saline solution, Hank ' s solution or ringer's solution.In addition, this chemical compound can be formulated into solid form, and dissolving or suspension more immediately before use.Also can make lyophilized form.
Be administered systemically and also can realize by saturating mucosa or transdermal methods.For saturating mucosa or transdermal administration, the penetrating agent that matches with barrier to be infiltrated is used in the said preparation.This penetrating agent is normally known in the art, and for example comprises that bile salts and fusidic acid derivatives are used for transmucosal administration.In addition, can use detergent to help to see through.Transmucosal administration for example, can be undertaken by nasal spray, rectal suppository or vaginal suppository.
For topical, chemical compound of the present invention can be formulated into unguentum, ointment, gel or cream, and this is that this area is known usually.
The amount for the treatment of the various calcium channel blockers of administration can be following all multifactor next definite according to standardization program and consideration: Compound I C 50, EC 50, the biological half-life of chemical compound, patient's age, volume and body weight are with patient's diseases associated or disease.The importance of these and other factor that is considered is known for those of ordinary skill.
Dosage is different and different according to route of administration and oral administration biaavailability also.For example, for chemical compound, can give higher dosage relatively with low oral administration biaavailability.
Compositions can be unit dosage forms.For oral administration, for example, but administration tablet or capsule, for the per nasal application, but the aerosol of administration metering, for the transdermal application, but administration topical formulations or patch, for saturating mucosal delivery, but administration cheek patch.In all cases, can be to the patient dose administration to give single dosage.
For oral administration, each dosage unit suitably comprises 0.01 to 500mg/kg, preferred 0.1 to 50mg/kg compound or pharmaceutically acceptable salt thereof or complex by structure (I) expression, calculates with free alkali.Daily dose for non-intestinal, per nasal, per os suction, saturating mucosa or transdermal route suitably comprises 0.01 to 100mg/kg the chemical compound by structure (I) expression.Topical formulations suitably comprises 0.01 to 5.0% the chemical compound by structure (I) expression.Active component can be used as single dose or multiple dose form administration, for example gives 2-6 time every day, enough shows required activity, and this can easily be predicted by those skilled in the art.
" treatment " of disease used herein includes but not limited to the preventing of disease, postponement and diseases prevention.
Disease and the disease that can be treated or prevent based on the cell that is affected, comprise central nervous system disease or disease, such as epilepsy, apoplexy, head trauma, spinal cord injury, it is hemorrhage that accompanied by tissue damages, the neural cell injury of hypoxia inducible, such as betiding cardiac arrest or neonate is poverty-stricken, epilepsy, neurodegenerative disease is such as Alzheimer, Huntington Chorea and parkinson disease, dementia, muscular tone, pain, depression, anxiety neurosis, paranoid fears, obsession, post-traumatic stress disorder, the anesthesia back is cognitive to descend, the opioid toleration, drug dependence spills smart abuse, schizophrenia, neuroleptic malignant syndrome, and tourette's syndrome; The resorbent disease of excessive water that involves kidney is such as the ADH secretion syndrome (SIADH) of imbalance, liver cirrhosis, congestive heart failure and nephrosis; Hypertension; The toxicity of the cation antibiotic (aminoglycoside antibiotics) of prevention and/or reduction kidney; The internal organs motion sickness is such as diarrhoea and spastic colon; The GI Peptic Ulcers; With the GI disease of excessive calcium absorption, such as sarcoidosis; Autoimmune disease and organ-graft refection; Squamous cell carcinoma; And pancreatitis.
Chemical compound and officinal salt and/or complex by structure (I) expression when oral administration, can be formulated into syrup, tablet, capsule and rhombus agent.Syrup suspension or the solution composition in liquid-carrier by chemical compound or salt usually, described liquid-carrier be such as for example being ethanol, Oleum Arachidis hypogaeae semen, and olive oil, glycerol or water, and contain flavoring agent or coloring agent.When compositions is tablet form, can use any pharmaceutical carrier that can be used to prepare solid dosage forms routinely.The example of this carrier comprises magnesium stearate, Gypsum Fibrosum powder, Talcum, gelatin, arabic gum, stearic acid, starch, lactose and sucrose.When compositions was capsule form, sealing of any routine was suitable, for example, used above-mentioned carrier in the hard gelatin capsule shell.When compositions is soft gelatin shell capsule, can adopt any pharmaceutical carrier that is used to prepare dispersant or suspending agent routinely.For example, can make use natural gum, cellulose, silicate or oils form the Perle shell.
Typical non-intestinal compositions by chemical compound or salt solution or the suspension in the carrier of aseptic moisture or non-water form, randomly comprise the acceptable oils of non-intestinal, for example Polyethylene Glycol, polyvinylpyrrolidone, lecithin, Oleum Arachidis hypogaeae semen or Oleum sesami.
Typically sucking with compositions is solution, suspension or Emulsion form, and it can be used as dry powder doses or aerosol by administration, and described aerosol adopts the conventional propellant such as dichlorodifluoromethane or Arcton 11.
Typical suppository comprises compound or pharmaceutically acceptable salt thereof or the complex by structure (I) expression, and it is when having activity when for example diol polymer, gelatin, cocoa-butter or other low melting point vegetable wax or fat or its synthetic analogues are by administration with binding agent and/or lubricant by this way.
Typical skin and preparation capable of permeating skin comprise the vehicle of conventional moisture or non-water, for example cream, unguentum, lotion or paste, or be medical form of smearing agent, patch or film.
Preferably low, said composition is a unit dosage forms, for example, be tablet, capsule or metered aerosol dosage form, thereby the patient can give single dosage.
Expection does not have unwelcome toxicology effect when giving chemical compound of the present invention according to the present invention.
Embodiment
Comprise that following specific embodiment only is used for the illustrative purpose, is not construed as limiting the disclosure.Reagent that uses in following examples and intermediate are commercially available or can be synthetic by the technical staff of organic synthesis according to the normative document record.
NMR (nuclear magnetic resonance, NMR) spectroscopy is carried out on Varian Gemini spectrometer.Mass spectrum under 300MHz at deuterochloroform (CDCl 3), dimethyl sulfoxide-d 6(DMSO-d 6) or trifluoroacetic acid (CF 3COOH) record in the solution.NMR resonance is used following the description for observed multiplicity: s (unimodal), d (doublet), t (triplet), q (quartet), dd (double doublet), and m (multiplet) with respect to being in the news with δ (ppm) as interior target tetramethylsilane (TMS).
Embodiment 1
3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-] quinoline-1-ketone also
A) 2-(carboxyl methylamino) benzoic acid
Figure A20078003922400231
In room temperature and under stirring to monoxone (347g, 3.67mol) add sodium carbonate (200g carefully in the solution in water (500mL), 4.72mol), the solution that forms is heated to 40-45 ℃ and also promptly joins from ortho-aminobenzoic acid (500g, 3.65mol) in the mixture of the suspension in water (340mL) and 35% sodium hydrate aqueous solution (320mL) preparation, and be heated to 40-45 ℃, reactant mixture remains on 40 ℃ and reaches 4 days, solid reaction mixture sodium hydroxide (150g, 3.75mol) solution-treated in water (4L).With mixture heated to 60 ℃ and by carrying out heat filtering, solid residue aqueous sodium hydroxide washes with 20% on filter is washed, and up to the solid residue dissolving, the filtrate that merges is acidified to pH3 with 37% aqueous hydrochloric acid solution, leaches precipitate; From filtrate, be settled out the product of other amount after spending the night, and collect this product.Product obtains 567g (80%) altogether, m.p.220 ℃ 100 ℃ of dryings.
B) 2-(N-acetyl group carboxyl methylamino) benzoic acid
Figure A20078003922400232
In room temperature with under stirring, to sodium carbonate (89g, 0.84mol) divide aliquot to add 2-(carboxyl methylamino) benzoic acid (100g of embodiment 1a in the solution in water (830mL), 0.84mol), form clear solution, drip acetic anhydride (85.68g in room temperature with under stirring, 0.84mol), reactant mixture was stirred 30 minutes, and drip 37% aqueous hydrochloric acid solution (140mL), product slowly precipitation is separated out, in 12 hours, leach solid product, wash that (3 * 150mL) the line space air dry of going forward side by side obtain 110g (91%), m.p.206 ℃ with water.
C) acetic acid 1-acetyl group-1H-indol-3-yl ester
Figure A20078003922400241
At room temperature to the acetic anhydride (46.29g that stirs; 0.45mol) and triethylamine (13.77g; 0.14mol) mixture in add 2-(the N-acetyl group carboxyl methylamino) benzoic acid (11.36g of embodiment 1b; 0.048mol); mixture refluxed 20 minutes; and vacuum concentration; obtain the oily residue; under strong agitation, add entry (350mL), mixture cold preservation is spent the night, collect solid product; wash with water; the line space of going forward side by side air dry obtains the product of 9.0g (86%), and it need not purification can be directly used in next step.
D) 1-acetyl group-1,2-indoline-3-ketone
Figure A20078003922400242
Under agitation with sodium sulfite (12.6g, 0.1mol) solution in water (180mL) is heated to 70-75 ℃, and divide aliquot to add acetic acid 1-acetyl group-1H-indol-3-yl ester (9.0g of embodiment 1c, 0.041mol), mixture stirred 1.5 hours at 70-75 ℃, keep then at room temperature spending the night, leach solid product, dry, and be dissolved in the dichloromethane (40mL), use dichloromethane on aluminium oxide, to carry out hurried chromatographic isolation, obtain the faint yellow product of 5.25g (71%) as eluent; M.p.138 ℃.
E) 2-(1-acetyl group-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone
Figure A20078003922400251
In room temperature with under stirring, the 1-acetyl group-1 of embodiment 1d, 2-indoline-3-ketone (131.3g, 0.75mol) and 5,5-dimethyl-cyclohexane extraction-1,3-diketone (105g, 0.75mol) be added into acetic acid (700mL) and triethylamine (105mL, in mixture 0.75mol), reaction mixture refluxed 6 hours, vacuum is removed the solvent of about 1/3rd volumes, with mixture cooling and dilute with water (50mL), leach precipitate, with alcohol-water washing in 1: 1, and dry, obtain the clear crystal of 169.4g (76%); M.p.225-227 ℃.
F) 2-(1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone
Figure A20078003922400252
In room temperature with under stirring, to the 2-of embodiment 1e (1-acetyl group-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone (74.8g, 0.25mol) and the mixture of methanol (30mL) in add sodium hydroxide (30g, 0.75mol) solution in water (300mL), reactant mixture heats and stirred 2 hours at 60 ℃, add active carbon (10g) and water (300mL) then, mixture stirred 10 minutes, leached active carbon, filtrate is arrived pH2 with hcl acidifying, leach solid product, wash with water and drying, obtain the colorless solid of 38.3g (60%); M.p.173 ℃.
G) 3,3-dimethyl-1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes tetrafluoroborate
Under agitation to the 2-of embodiment 1f (1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone (2.5g, 9.8mmol) divide two parts to add the Tetrafluoroboric acid (diethyl ether solutions of 54wt% in the suspension in diethoxy Ethyl Methyl Ether (20mL), 2mL, 14.5mmol), mixture at room temperature stirred 2 hours, with ether (20mL) dilution, leach solid product, wash with ether, at room temperature carry out air drying, obtain 2.4g (70%) product, be red crystallization, it need not purification can be directly used in next step.
H) 3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also
Figure A20078003922400261
To 3 of embodiment 1g, 3-dimethyl-1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes tetrafluoroborate (2.4g; 6.8mmol) and the mixture of acetic acid (35mL) in add ammonium acetate (30g), mixture refluxed 30 minutes, with the reactant mixture cooling, add entry (40mL), add ammonium hydroxide aqueous solution then and make that pH is 8, leach solid product, wash with water and at room temperature carry out air drying, at room temperature product is dissolved in the mixture of ethanol (15mL) and ether (15mL), drip 37% aqueous hydrochloric acid solution (0.72mL), mixture at room temperature kept 2 hours, leach crystallized product, use alcohol-ether, 1: 3 (2mL) washing, wash with ether then, and dry, obtain the colourless crystallization of 1.64g, this product is dissolved in the water (30mL), and the adding ammonium hydroxide aqueous solution makes that pH is 9, leach precipitate, wash with water, drying, from the toluene crystallization, obtain the colourless crystallization of 1.4g (78%); M.p.224-225 ℃. 1HNMR(DMSO-d 6)：δ1.09(s，6H)，2.70(s，2H)，3.16(s，2H)，7.22-7.25(m，1H)，7.59-7.62(m，2H)，9.05(s，1H)，9.22(d，1H)，11.96(s，1H)。
Embodiment 2
3,3-dimethyl-2.3,4.7-tetrahydro indole be the preparation of [2,3-c] quinoline also
Figure A20078003922400271
In room temperature and under stirring with 3 of embodiment 1h, 3-dimethyl-2,3,4, the 7-tetrahydro indole also [2,3-c] quinoline-1-ketone (1.36g 5.14mmol) joins in the mixture of an ethylene glycol (8mL) and a hydrazine hydrate (5mL), mixture refluxed 1 hour, cooling added potassium hydroxide (1g), with reaction mixture refluxed 2 hours, under 1psi, slowly distill out excessive hydrazine and water, reach 190 ℃ up to vapor (steam) temperature, with residue cooling, dilute with water (60mL), leach solid product, wash with water,, isolate product from 1: 1 recrystallization of alcohol-water, be colorless solid (0.59g, 46%).Obtain analytically pure sample from the toluene crystallization; M.p.275-277 ℃. 1H NMR (DMSO-d 6) δ 1.03 (S, 6H), 1.72 (t, 2H), 2.76 (s, 2H), 3,30 (t, 2H), 7.20-7.23 (m, 1H), 7.49-7.60 (m, 2H), 8.17 (d, 1H), 8.66 (S 11H), 11.45 (S 11H).
Embodiment 3
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400272
A) 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone
Adopt process described in the embodiment 1a-e, difference is to replace ortho-aminobenzoic acid with 2-amino-4-fluobenzoic acid in step 1a, has prepared title compound and crystallization from alcohol-water 1: 1.
B) the 9-fluoro-3,3,6-trimethyl-1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes perchlorate
Figure A20078003922400281
In room temperature and under stirring with the 2-(6-fluoro-1H-indol-3-yl)-5 of embodiment 3a, 5-dimethyl cyclohexane-1,3-diketone (0.575g, 2.1mmol) slowly join in freshly prepd acetic acid (2mL), acetic anhydride (2.1mL) and 70% high chloro acid solution's (0.17mL) the mixture, reactant mixture at room temperature stirred 4 hours, add ether (5mL), leach product, with ether washing and at room temperature dry, obtain the bright yellow crystal of 0.72g (89%), this product need not purification can be directly used in next step.
C) the 9-fluoro-3,3, and 6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also
Ammonium hydroxide aqueous solution (3mL) is joined the 9-fluoro-3 of embodiment 3b, 3,6-trimethyl-1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes perchlorate (0.72g, 1.88mmol) in the suspension in isopropyl alcohol (2mL), reaction mixture refluxed 1 hour, cooling, add entry (5mL), in mixture, add ammonium hydroxide aqueous solution and make that pH is 9, leach precipitate, wash with water and drying, crude product is dissolved in the acetone, the aqueous hydrochloric acid solution (0.2mL) of adding 37% leaches precipitate, is suspended in the hot water, use ammonium hydroxide that mixture is basified to pH9, leach product, wash with water, drying, from the toluene crystallization, obtain the colourless crystallization of 0.26g (50%); M.p.244-246 ℃.
Embodiment 4
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400291
Adopt process described in the embodiment 3a-c, difference is to use the 2-(1H-indol-3-yl)-5 of embodiment 1f in step 3a, 5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone, preparation title compound and from the toluene crystallization; M.p.176-177 ℃. 1H?NMR(CF 3COOH)：δ1.3(s，6H)，2.07(s，2H)，3.17(s，3H)，3，37(s，2H)，7.33-7.9(m，4H)，9.27(d，1H)。
Embodiment 5
9-fluoro-3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400292
Adopt the described process of embodiment 1a-h, difference is to replace ortho-aminobenzoic acid with 2-amino-4-fluobenzoic acid in step 1a, preparation title compound and from the toluene crystallization; M.p.271-273 ℃.
Embodiment 6
10-methoxyl group-3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400293
Adopt the described process of embodiment 1a-h, difference is to replace ortho-aminobenzoic acid with 2-amino-5-methoxybenzoic acid in step 1a, preparation title compound and from the toluene crystallization; M.p.230-231 ℃.
Embodiment 7
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400301
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(5-methoxyl group-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and replace ortho-aminobenzoic acid among the step 1a of embodiment 1 with 2-amino-5-methoxybenzoic acid, preparation title compound and from the toluene crystallization; M.p.241-243 ℃.
Embodiment 8
9-chloro-3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400302
Adopt the described process of embodiment 1a-h, difference is to replace ortho-aminobenzoic acid with 2-amino-4-chlorobenzoic acid in step 1a, preparation title compound and from the toluene crystallization; M.p.257-259 ℃.
Embodiment 9
9-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400303
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(6-chloro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and replace ortho-aminobenzoic acid among the step 1a of embodiment 1 with 2-amino-4-chlorobenzoic acid, preparation title compound and from the toluene crystallization; M.p.248-250 ℃.
Embodiment 10
9-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400311
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(6-methoxyl group-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and replace ortho-aminobenzoic acid among the step 1a of embodiment 1 with 2-amino-4-methoxybenzoic acid, preparation title compound and from the toluene crystallization; M.p.250-252 ℃.
Embodiment 11
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400312
Use process described in the embodiment 3a-c, difference is in step 3a with 2-(4-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and replace ortho-aminobenzoic acid among the step 1a of embodiment 1 with 2-amino-6-fluobenzoic acid, preparation title compound and from the toluene crystallization; M.p.246-247 ℃.
Embodiment 12
3,6-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Use process described in the embodiment 3a-c, difference is in step 3a with 2-(1H-indol-3-yl)-5-hexahydrotoluene-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone adopts 5-hexahydrotoluene-1, among the step 1a of 3-diketone replacement embodiment 15,5-dimethyl cyclohexane-1,3-diketone, preparation title compound and from the toluene crystallization; M.p.218-219 ℃.
Embodiment 13
3-isopropyl-6-methyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400322
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(1H-indol-3-yl)-5-isopropyl-cyclohexane extraction-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone is with 5-isopropyl cyclohexane-1, among the step 1e of 3-diketone replacement embodiment 15,5-dimethyl cyclohexane-1,3-diketone, preparation title compound and from the toluene crystallization; M.p.248-249 ℃.
Embodiment 14
6-methyl-3 ' H-volution hexane-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400323
Use process described in the embodiment 3a-c, difference is to use 3-(1H-indol-3-yl)-spiral shell [5,5] hendecane-2 in step 3a, and the 4-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone, and with [5,5] hendecane-2, among the step 1e of 4-diketone replacement embodiment 15,5-dimethyl cyclohexane-1,3-diketone, preparation title compound and from the toluene crystallization; M.p.245-246 ℃.
Embodiment 15
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400331
Method A. uses process described in the embodiment 3a-c, difference is in step 3a with 2-(5-chloro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and replace ortho-aminobenzoic acid among the step 1a of embodiment 1 with 2-amino-5-chlorobenzoic acid, preparation title compound and from the toluene crystallization; M.p.244-246 ℃.
Method B. by 5-10 ℃ and stir under add 85% phosphorous acid (1.7mL; 25mmol) to acetic anhydride (21.6mL; prepared mixture 200mmol); adopt process described in the embodiment 1a-e to prepare 2-(1-acetyl group-5-chloro-1H-indol-3-yl)-5 then; 5-dimethyl cyclohexane-1; 3-diketone (2.6g; 10mmol); difference is to replace ortho-aminobenzoic acid with 2-amino-5-chlorobenzoic acid in step 1a, is added in the mixture, and reactant mixture was 95-100 ℃ of heating 3 minutes; be cooled to 60-70 ℃; and in 15 minutes, drip water (1.8mL) at 60-70 ℃, add then ammonium acetate (7.71g, 100mmol); mixture was 100-120 ℃ of following heated and stirred 1 hour; the acetic acid (12mL) that during reaction generates is gone out by vacuum distilling then, with residue cooling and adding ammonia (15mL), leaches precipitate; wash with water; drying, and recrystallization carries out purification from the toluene (110mL) that is added with neutral alumina, obtains the pale yellow crystallization of 2.5g (80%).The fusing point of chemical compound is identical with the fusing point of the product for preparing by method A.
Embodiment 16
6-methyl-3-phenyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400341
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(1H-indol-3-yl)-5-phenyl-cyclohexane--1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and with 5-Phenylcyclohexane-1, among the step 1e of 3-diketone replacement embodiment 15,5-dimethyl cyclohexane-1,3-diketone, preparation title compound and from the toluene crystallization; M.p.246-248 ℃.
Embodiment 17
3,6-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketoxime also
Figure A20078003922400342
3 of embodiment 12,6-dimethyl-2,3,4,7-tetrahydro indole also [2,3-c] quinoline-1-ketone 0.26g, 1mmol), ethanol (4mL), pyridine (0.15mL, 1.85mmol) and oxammonium hydrochloride. (0.1g, 1.5mmol) mixture refluxed 3 hours, mixture is cooled, and leaches solid product, uses washing with alcohol, dry, and be dissolved in the hot water (20mL), add ammonium hydroxide aqueous solution and make that pH is 9, the collecting precipitation thing, wash with water, drying and crystallization from alcohol-water 1: 1 obtain the colourless crystallization of 0.17g (61%); M.p.282-283 ℃.
Embodiment 18
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketoxime also
Figure A20078003922400343
Adopt process described in the embodiment 17, difference is in step 3a with 3,3,6-trimethyl-2,3,4, also [2,3-c3 quinoline-1-ketone replaces 3 to the 7-tetrahydro indole, 6-dimethyl-2,3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone also, preparation title compound and crystallization from alcohol-water 1: 1, m.p.293-294 ℃.
Embodiment 19
9,10-two fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole are the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400351
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(5,6-two fluoro-1H-indol-3-yls)-5,5-dimethyl-cyclohexane extraction-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone, with 2-amino-4, the 5-difluoro-benzoic acid replaces the ortho-aminobenzoic acid among the step 1a of embodiment 1, preparation title compound and from the toluene crystallization; M.p.260-252 ℃.
Embodiment 20
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400352
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl-cyclohexane extraction-1,3-diketone and in step 3b, replace acetic anhydride with propionic andydride, preparation title compound and from the toluene crystallization; M.p.188-190 ℃.
Embodiment 21
6-isopropyl-3,3-dimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400361
Adopt process described in the embodiment 3a-c, difference is in step 3a with 2-(1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl-cyclohexane extraction-1, the 3-diketone replaces acetic anhydride with isobutyric anhydride in step 3b, preparation title compound and from the toluene crystallization; M.p.176-178 ℃.
Embodiment 22
10-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400362
Use process described in the embodiment 3a-c, difference is in the step 3a of embodiment 1 with 2-(5-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1, the 3-diketone replaces 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethyl cyclohexane-1,3-diketone and in the step 1a of embodiment 1, replace ortho-aminobenzoic acid with 2-amino-5-fluobenzoic acid, preparation title compound and from the toluene crystallization; M.p.229-230 ℃.
Embodiment 23
3,3,6-trimethyl-2,3,4,7-tetrahydrochysene-1H-indole be the preparation of [2,3-c] quinoline also
Figure A20078003922400363
Adopt embodiment 2 described processes, difference is with 3,3 of embodiment 4,6-trimethyl-2,3,4,7-tetrahydro indole also [2,3-c] quinoline-1-ketone replaces 3,3-dimethyl-2,3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone also, preparation title compound and from the toluene crystallization; M.p.241-243 ℃.
Embodiment 24
7-N-ethyl-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400371
In room temperature with under stirring, with 3 of embodiment 4,3,6-trimethyl-2,3,4, the 7-tetrahydro indole also [2,3-c] quinoline-1-ketone (0.28g is 1mmol) at anhydrous N, drips of solution in the dinethylformamide (4mL) is added to sodium hydride (60% dispersion in mineral oil, 0.051g, 1.3mmol) at anhydrous N, in the suspension in the dinethylformamide (4mL), reactant mixture at room temperature stirred 2 hours, drip then the 1-iodoethane (0.19g, 1.2mmol), mixture at room temperature stirs up to reaction and finished (4 hours, thin layer chromatography control), the dilution of reactant mixture water (25) and saline (10mL), use then ethyl acetate extraction (3 * 15mL), the organic layer anhydrous sodium sulfate drying of merging, vacuum distilling goes out ethyl acetate, obtain crude product (0.18g, 60%), from the hexane crystallization, obtain pure products, be the light orange crystallization; M.p.174-177 ℃.
Embodiment 25
7-N-propyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be the preparation of [2,3-c] quinoline-1-ketone also
Figure A20078003922400372
Adopt embodiment 24 described processes, difference is to replace the 1-iodoethane with propyl iodide, preparation title compound and from the hexane crystallization; M.p.123-125 ℃.
Biological activity by the chemical compound of structure (I) expression uses analyzing in conjunction with test of standard.Calcium channel and GABA AChloride channel in conjunction with the test example be well known in the art [for example, referring to people such as R.Gloud, Molecular Pharmacology 25:235-241 (1984); People such as F.J.Ehlert, Life Sci.30:2191-2202 (1982); People such as H.Schoemaker, Eur.J.Pharmacol.111:273-277 (1985); People such as L.Lawrence, J.Neurochem.45:798-804 (1986); People such as L.M.Cole, Life Sci.35:1755-1762 (1984)].The method of describing in these publications is incorporated herein by reference.
Biological activity by the chemical compound of structure (I) expression confirms that by following test described test is at NovaScreen, and a Caliper Life Science Company (Hanover, MD 1U.S.A.) is undertaken by standard technique known in the art and process:
(I) L type calcium channel (dihydropyridine site).[ 3H] the nitrendipine radioligand is in conjunction with test
K D(binding affinity): 0.20nM.B Max(acceptor number): 166fmol/mg organizes (weight in wet base).Receptor source: rat layer film.Radioligand: [ 3H] nitrendipine (70-80Ci/mmol).Final ligand concentration: [0.2nM].Non-specific determiner: nifedipine [1.0 μ M].Reference compound: nifedipine.Positive control: nifedipine.
This process is following carries out: (Tromethamine hydrochloride reacted 60 minutes at 25 ℃ in (pH 7) at 50mM TRISHCl.Vacuum filtration makes reaction terminating by carrying out rapidly on glass fiber filter.Mensuration is trapped within the radioactivity on the filter and compares with control value, thereby determines any interaction of test compound and nitrendipine binding site.[referring to people such as R.Gould, Tissue Heterogenecity of Calcium Channel AntagonistBinding Sites Labeled by[ 3H] Nitrendipine.Molecular Pharmacology, 25:235-241 (1984); People such as F.J.Ehlert, The Binding of[ 3H] N itrendipine toReceptors for Calcium Channel Antagonists in the Heart, Cerebral Cortex, and Ileum ofRats.Life Sci.30:2191-2202 (1982)].
(II) L type calcium channel (benzimidazole thiophanate nitrogen
Figure A20078003922400381
The site).[ 3H] the diltiazem radioligand is in conjunction with test
K D(binding affinity): 34nM.Bmax (acceptor number): 24.2fmol/mg organizes (weight in wet base).Receptor source: rat layer film.Radioligand: [ 3H] diltiazem, cis (+) is (70-87Ci/mmol).Final ligand concentration: [5.0nM].Non-specific determiner: diltiazem hydrochloride [10 μ M].Reference compound: diltiazem hydrochloride.Positive control: diltiazem hydrochloride.
This process is following carries out: (Tromethamine hydrochloride reacted 90 minutes at 25 ℃ in (pH 7) at 50mM TRISHCl.Vacuum filtration makes reaction terminating by carrying out rapidly on glass fiber filter.Mensuration is trapped within the radioactivity on the filter and compares with control value, thereby any interaction of determining test compound and diltiazem binding site is [referring to H.Schoemaker and S.Z.Langer.[ 3H] Diltiazem Binding to Calcium ChannelAntagonists Recognition Sites in Rat Cerebral Cortex.Eur.J.Pharnacol.111:273-277 (1985)].
III) GABA A. chloride channel (the positive benzoate of tert-butyl group ring (TBOB) site).[ 3H] TBOB diltiazem radioligand is in conjunction with test
K D(binding affinity): 45nM.B Max(acceptor number): 116.7fmol/mg organizes (weight in wet base).Receptor source: rat layer film.Radioligand: [ 3H] TBOB (20-60Ci/mmol).Final ligand concentration: [20nM].Non-specific determiner: tert-butyl group dicyclo thiophosphate (TBPS) [10 μ M].Reference compound: tert-butyl group dicyclo thiophosphate (TBPS).Positive control: tert-butyl group dicyclo thiophosphate (TBPS).
This process is following carries out: at 20mM NaKPO 4/ 500mM NaCI reacted 75 minutes at 25 ℃ in (pH 7).Vacuum filtration makes reaction terminating by carrying out rapidly on glass fiber filter.Mensuration is trapped within the radioactivity on the filter and compares with control value, thereby determines any interaction of test compound and TBOB binding site.[referring to people such as L.Lawrence, [ 3H] butylbicycloorthobenzoate:A New Radioligand Probe forGamma-aminobutyric Acid-regulated Chloride lonophore.J.Neurochem.45:798-804 (1986); People such as L.M.Cole, Similar Propertiesof[ 35S] t-butylbicyclophosphothionate Receptor and Coupled Compounentsof the GABA Receptor-lonophore Complex in Brains of Human, Cow, Rat, Chicken, and Fish.Life Sci.35:1755-1762 (1984)].
All chemical compounds are tested under the concentration that is up to 50 μ M in duplicate with 5 concentration.
Usually, [ 3H] nitrendipine and [ 3H] diltiazem in conjunction with the test in have lower IC 50The value and [ 3H] TBOB in conjunction with the test in have higher IC 50These chemical compounds of value are the chemical compounds that are more preferably.Spendable in the present invention chemical compound [ 3H] nitrendipine and [ 3H] diltiazem is in conjunction with the IC that has in the test 50Value is lower than 50 μ M.Preferred chemical compound be those [ 3H] nitrendipine and [ 3H] diltiazem in conjunction with the test in IC 50Be 10 μ M or lower and [ 3H] TBOB in conjunction with the test in IC 50Be 3 μ M or those higher chemical compounds.Preferred chemical compound be those [ 3H] nitrendipine and [ 3H] diltiazem in conjunction with the test in IC 50Be 6 μ M or lower and [ 3H] TBOB in conjunction with the test in IC 50Be 3 μ M or those higher chemical compounds.Preferred chemical compound be [ 3H] nitrendipine and [ 3H] diltiazem in conjunction with the test in IC 50Be 3 μ M or lower and [ 3H] TBOB in conjunction with the test in IC 50Be 3 μ M or those higher chemical compounds.Most preferred be those [ 3H] nitrendipine and [ 3H] diltiazem in conjunction with the test in IC 50Be 1 μ M or lower and [ 3H] TBOB in conjunction with the test in IC 50Be 3 μ M or those higher chemical compounds.
All publications of being quoted in this manual include but not limited to patent and patent application, and are incorporated herein by reference, just like each independent publication by clearly and individually pointed out to be used for incorporated herein by reference and as if described fully.
Above-described description fully discloses the present invention who comprises preferred version of the present invention.In the scope that the modification and the improvement of the concrete disclosed embodiment of this paper is in claims.Need not to describe in further detail, it is believed that those skilled in the art can use previous description to adopt the present invention to reach the degree of its fullest.Therefore, it is exemplary that the embodiment of this paper only is considered to, and never in any form scope of the present invention is construed as limiting.Wherein embodiment of the present invention of monopoly of Yao Qiuing or privilege are as giving a definition.
The technical staff obviously can carry out many changes and not break away from basic principle of the present invention above-mentioned embodiment.Therefore scope of the present invention is through only being determined by claims.

Claims (20)

1. the compound or pharmaceutically acceptable salt thereof, hydrate, tautomer, solvate or the complex that have structure shown in the following chemical formula:
Structure (I)
Figure A2007800392240002C1
Wherein
R 1For one of following: H, lower alkyl, cyclic hydrocarbon radical, aryl, aryl alkyl;
R 2And R 3Be selected from one of following independently of one another: H, low alkyl group, cyclic hydrocarbon radical, aryl, aryl alkyl; Perhaps R 2And R 3Formation-(CH together 2) n-and n be 6,5 or 4; Perhaps R 2And R 3Formation-CH (low alkyl group) (CH together 2) n-and n be 5,4 or 3;
R 4And R 5Be selected from one of following independently of one another: H, NH 2, OH or lower alkyl; Perhaps R 4And R 5Form O together, S or NOH;
R 6, R 7, R 8And R 9Be selected from independently of one another: H, halogen, CN, CF 3, OCF 3, low alkyl group, cyclic hydrocarbon radical, lower alkoxy, NH-lower alkyl, NH-alkylaryl, N (low alkyl group) 2, C (O) OH, C (O) O-lower alkyl, OH, OC (O)-low alkyl group;
R 10For one of following: H, low alkyl group, cyclic hydrocarbon radical, aryl, aryl alkyl.
2. the chemical compound of representing by structure I of claim 1, wherein R 1Be hydrogen or low alkyl group.
3. the chemical compound of claim 2, wherein said low alkyl group is methyl or ethyl.
4. the chemical compound of representing by structure I of claim 1, wherein R 2And R 3Be selected from independently of one another: hydrogen, low alkyl group or aryl.
5. the chemical compound of claim 4, wherein said low alkyl group is one of methyl and isopropyl.
6. the chemical compound of claim 4, wherein said aryl is a phenyl.
7. the chemical compound of representing by structure I of claim 1, wherein R 2And R 3Formation-(CH together 2) n-and n be 5.
8. the chemical compound of representing by structure I of claim 1, wherein R 4And R 5Each is hydrogen naturally.
9. the chemical compound of representing by structure I of claim 1, wherein R 4And R 5Form oxygen or NOH together.
10. the chemical compound of representing by structure I of claim 1, wherein R 6, R 7, R 8And R 9Be selected from independently of one another: hydrogen, halogen or lower alkoxy.
11. the chemical compound of claim 10, wherein said halogen is a fluorine or chlorine.
12. the chemical compound of claim 10, wherein said lower alkoxy is a methoxyl group.
13. the chemical compound of representing by structure I of claim 1, wherein R 10Be hydrogen or low alkyl group.
14. the chemical compound of claim 13, wherein said low alkyl group are one of ethyl and propyl group.
15. the chemical compound of representing by structure I of claim 1, wherein said chemical compound be following one of at least:
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline also;
9-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-fluoro-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-chloro-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
9-methoxyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
11-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3-isopropyl-6-methyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3 ' H-volution hexane-2,3,4, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone also;
10-chloro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-methyl-3-phenyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
3,6-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketoxime also;
9,10-two fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole are [2,3-c] quinoline-1-ketone also;
6-ethyl-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
6-isopropyl-3,3-dimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
10-fluoro-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
3,3,6-trimethyl-2,3,4,7-tetrahydrochysene-1H-indole be [2,3-c] quinoline also;
7-N-ethyl-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also;
7-N-propyl group-3,3,6-trimethyl-2,3,4,7-tetrahydro indole be [2,3-c] quinoline-1-ketone also.
16. pharmaceutical composition comprises chemical compound and the acceptable diluents or the excipient represented by structure I of claim 1.
17. prepare substituted 2,3,4, the 7-tetrahydro indole is the method for [2,3-c] quinoline-1-ketone also, comprises making substituted 1-oxo-2,3,4,7-tetrahydrochysene-1H-5-oxygen-7-azepine benzo [c] fluorenes perchlorate, dihydric phosphate or tetrafluoroborate and ammonium hydroxide or ammonium acetate reaction.
18. prepare substitutedly 2,3,4, the 7-tetrahydro indole is the method for [2,3-c] quinoline also, comprises making the substituted 2,3,4 of claim 17, the 7-tetrahydro indole is [2,3-c] quinoline-1-ketone and hydrazine hydrate reaction also.
19. treatment, comprises the chemical compound of being represented by structure I to the claim 1 of experimenter's effective dosage that needs are arranged by the central nervous system disease of calcium channel mediation or the method for disease.
20. the method for claim 19, wherein said central nervous system disease be selected from following at least a: apoplexy, head trauma, spinal cord injury, traumatic shock, Alzheimer, parkinson disease, Huntington Chorea, amyotrophic lateral sclerosis, epilepsy, epilepsy, convulsibility disease, the neural cell injury of hypoxia inducible, pain, depression, anxiety neurosis, paranoid fears, obsession, post-traumatic stress disorder, the anesthesia back is cognitive to descend the opioid toleration, drug dependence spills smart abuse or schizophrenia.
CNA2007800392241A 2006-08-28 2007-08-13 Indoloquinoline compounds as calcium channel blockers Pending CN101528230A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103249878A (en) * 2010-08-23 2013-08-14 Irm有限责任公司，特拉华有限责任公司 Mechanically-activated cation channels
CN109942479A (en) * 2019-04-24 2019-06-28 常州工程职业技术学院 A kind of purifying technique of N, O-1,3- diacetyl indoles
CN115160310A (en) * 2022-05-10 2022-10-11 中国人民解放军北部战区总医院 Sinomenine derivatives as CDK2/Topo I inhibitor, and preparation method and anti-tumor application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103249878A (en) * 2010-08-23 2013-08-14 Irm有限责任公司，特拉华有限责任公司 Mechanically-activated cation channels
CN109942479A (en) * 2019-04-24 2019-06-28 常州工程职业技术学院 A kind of purifying technique of N, O-1,3- diacetyl indoles
CN109942479B (en) * 2019-04-24 2022-05-31 常州工程职业技术学院 Purification process of N, O-1, 3-diacetylindole
CN115160310A (en) * 2022-05-10 2022-10-11 中国人民解放军北部战区总医院 Sinomenine derivatives as CDK2/Topo I inhibitor, and preparation method and anti-tumor application thereof

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