CN1635998A - Tricyclic analgesics - Google Patents
Tricyclic analgesics Download PDFInfo
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- CN1635998A CN1635998A CNA008086427A CN00808642A CN1635998A CN 1635998 A CN1635998 A CN 1635998A CN A008086427 A CNA008086427 A CN A008086427A CN 00808642 A CN00808642 A CN 00808642A CN 1635998 A CN1635998 A CN 1635998A
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- piperidines
- naphthalene
- dihydro
- spiral shell
- oxo spiral
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
A tricyclic compound of Formula (I): wherein: R<1> is hydrogen or hydroxy; R<2> is hydrogen or hydroxy; or R<1> and R<2> together are oxygen; A is a bond, CH2, CH CH3, CH2 CH2 or C(CH3)2; R<3> and R<4> are the same or different and are hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy, trifluoromethyl, NO2, COR<6>, COOR<6> or NR<6>R<7>, wherein R<6> and R<7> are the same or different and are hydrogen, C1-C6 alkyl or benzyl; R<5> is hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, (O=C)-C1-6 alkyl, (O=C)-C2-6 alkenyl, (O=C)-C3-6 cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl groups can be substituted by 1, 2 or 3 groups selected from halogen, C3-C6 cycloalkyl, phenyl or substituted phenyl.
Description
Invention field
The present invention relates to have by the 3rd nitrogenous cyclosubstituted condensed-bicyclic of spiral shell is the organic compound of feature.These compounds can be treated Mammals epileptic seizures and chronic pain effectively.
Background of invention
Although chronic pain is a disease common among the crowd, its physiopathology is not fully understood as yet.A kind of possibility is that the spinal sensory nerve unit that comes to harm after damage produces unsuitable activity.Become super excited and produce spontaneity and beat laboratory animal and in the human body back spinal cord Sensory neurone that sustains damage.Matzner is relevant with the chronic pain that is caused by Na channel density increase on the damage location with this hyperexcitability of Devor (1992) proposition.Infer in addition that after nerve injury kinetics changes and the voltage-dependent feature generation ectopic beat of Na electric current and the hyperexcitability of spinal sensory nerve unit.Dorsal root ganglion (DRG) neurone has the compound mixture of Na electric current, comprises quick tetraodontoxin sensitivity (TTX-S) electric current and slow TTX-resistance (TTX-R) electric current.In rat drg neuron, produce hyperalgesic three kinds of promoting agent PGE in vivo
2, adenosine and serotonin increased the magnitude of current of TTX-R and make its electricity lead/voltage dependence moves (Gold etc., 1996) to the hyperpolarization direction.After nerve injury, the TTX-R electric current is subjected to decrement and regulates in the DRG neurone, and in identical animal body, the TTX-S electric current is subjected to incremental adjustments (Cummings and Waxman, 1997).Devor etc. (1993) use Na passage specific antibody confirmed that the Na passage accumulate, the accumulation of Na passage on impaired aixs cylinder tip can be explained the dystopy passage in the neuroma that is partly produced by nerve the excitability and the pain and the paresthesia that make peripheral nerve injury deterioration in the human body usually of generation.
Damage to spinal sensory nerve unit aixs cylinder seems to have changed the Na electric current, thereby has changed its excitability basically.Therefore, the selective exclusion agent of Na passage can be used for preventing or treating mammiferous chronic pain.Confirmed that sodium channel blockers is effective to chronic pain syndrome, the pain that comprises trigeminal nerve neurodynia, diabetic neuropathy, migrainous prevention and cancer is (by McQuay etc. at 1995 " BMJs " (British Medical Journal) 1995; The reference of summarizing among the 311:1047-1052 and wherein quoting).
Yet the pain that causes because of acute or chronic nerve injury is difficult to treat and usually anodyne commonly used is produced tolerance.This compounds comprises some local anesthetics and anticonvulsive drug, for example lignocaine, Etidocaine, Benzocaine, tetracaine, Riluzole, Phenytoin Sodium Salt and gabapentin.In them, although this class promoting agent modulation Na passage, they have limited clinical application because of high-risk untoward reaction.For example, lignocaine can cause the heartbeat of cardiovascular atrophy and generation to stop.Benzocaine can cause respiratory distress and fash, erythema and oedema.The Phenytoin Sodium Salt that is used for the epileptic seizures disease can cause hyperglycemia.
Because the such neuropathic pain of for example chronic pain is not had the effective chemical treatment means and because this class pain is general and relevant such as such disease of cancer and serious somatic damage and diabetic neuropathy, so can use clinically and can not produce the lasting demand of existence of the compound of serious adverse reaction to seeking.
Invention is summarized
The inventor has had been found that at present a series of is tricyclic compounds of effective antagonist of neurone Na passage.These compounds are feature to have spiral shell the 3rd cyclosubstituted condensed-bicyclic.
The present invention provides the tricyclic compound and the pharmaceutically acceptable salt thereof of general formula I thus:
Wherein:
R
1Be hydrogen or hydroxyl;
R
2Be hydrogen or hydroxyl; Or
R
1And R
2Be oxygen jointly;
A is key, CH
2, CHCH
3, CH
2CH
2Or C (CH
3)
2
R
3And R
4Identical or different and be hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, trifluoromethyl, NO
2, COR
6, COOR
6Or NR
6R
7, R wherein
6And R
7Identical or different and be hydrogen, C
1-C
6Alkyl or benzyl;
R
5Be hydrogen, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
3-C
6Cycloalkyl, (O=C)-C
1-6Alkyl, (O=C)-C
2-6Alkenyl, (O=C)-C
3-6Cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl can be selected from halogen, C by 1,2 or 3
3-C
6The group of cycloalkyl, phenyl or substituted-phenyl replaces.
Compound of the present invention is used for controlling clinically and treating such as epileptic seizures disease, the such various diseases of epilepsy; Play neuroprotective, be preferred for such as cerebral ischemia, anoxic and injury of head, local anesthesia, pain, preferably acute, chronic, neuropathic, internal organ and body pain, irritable bowel portion syndrome (IBS); Medicine dependency, migraine and obsessive-compulsive disorder.
Preferred compound is the compound of those general formula Is, wherein R
5Be hydrogen, C
1-C
6Alkyl can be by phenyl or C
3-C
6Cycloalkyl substituted or do not replaced by them.
Other preferred compound is the compound of those general formula Is, wherein R
5Be can be by phenyl or C
3-C
6Cycloalkyl substituted or the C that is not replaced by them
1-C
6Alkyl.
Other preferred compound is the compound of those general formula Is, wherein R
5Be hydrogen, can be by phenyl or C
3-C
6Cycloalkyl substituted or the C that is not replaced by them
1-C
6Alkyl; And R
3Be hydrogen or C
1-C
4Alkoxyl group.
Most preferred of the present invention is the compound of general formula I, wherein R
1And R
3Common is that oxygen and A are CH
2
Other most preferred is the compound of those general formula Is, wherein R
5Be H, C
1-C
6Alkyl can be by phenyl or C
3-C
6Cycloalkyl substituted or do not replaced by them; And R
3Be hydrogen or C
1-C
4Alkoxyl group.
Another embodiment of the invention is a kind of compound that comprises general formula I and is used for the pharmaceutically acceptable carrier of blended with it or the pharmaceutical composition of thinner.
Another embodiment of the invention is a kind of mammiferous method of suffering from pain and needs treatment that is used for the treatment of, and this method comprises the step of the compound of the general formula I that gives significant quantity.
Another embodiment of the invention is a kind of method that is used for the treatment of the Mammals epileptic seizures disease of needs treatment, and this method comprises the step of the compound that gives general formula I.
The methods of treatment that relates to above-mentioned all other indications also belongs to scope of the present invention.
Detailed Description Of The Invention
Term " C used herein
1-C
6Alkyl " refer to the carbochain of the straight or branched that constitutes by 1-6 carbon atom.C
1-C
6The example of alkyl comprises methyl, ethyl, sec.-propyl, sec-butyl, the tertiary butyl, isopentyl and n-hexyl.
" C
1-C
6Alkoxyl group " refer to the abovementioned alkyl that connects by oxygen, for example methoxyl group, isopropoxy and positive hexyloxy.
" C
2-C
6Alkenyl " refer to the straight or branched carbochain that has 2-6 carbon atom, one of them carbon-to-carbon double bond is present on the described chain.Example comprises vinyl, 2-propenyl, 1-methyl-3-pentenyl, 1-ethyl-crotyl and 5-hexenyl.
" C
3-C
6Cycloalkyl " refer to the ring of the non-aromatic ring that has 3-6 carbon atom, example has cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Abovementioned alkyl, alkenyl and cycloalkyl can be replaced by 1,2 or 3 group, and these groups are selected from halogen, unsubstituted C
3-C
6The phenyl of cycloalkyl, phenyl or replacement." halogen " refers to chlorine, bromine, fluorine and iodine." phenyl of replacement " refers to and has 1,2 or 3 substituent phenyl, and described substituting group is selected from halogen, hydroxyl, nitro, unsubstituted C
1-C
6Alkyl, unsubstituted C
1-C
6Alkoxyl group and NH
2
The C that is substituted by cycloalkyl
1-C
6The example of alkyl comprises cyclopropyl methyl, 1-cyclobutyl ethyl, 3-cyclohexyl butyl and 3,3-dicyclohexyl propyl group thus.The alkyl that is replaced by halogen comprises chloromethyl, 1,2-two bromotrifluoromethanes, trifluoromethyl and 1-bromo-3-chloro-6-iodine hexyl.Comprised benzyl, 1-phenyl propyl, 1-methyl-3-phenyl-butyl, 3-Chlorophenylmethyl, 2 by the alkyl that phenyl or substituted phenyl replaced, 3-dimethoxy-benzyl, 3-(2-methyl-5-fluoro-6-nitrophenyl)-butyl and 3,3-diphenyl propyl.
The C that replaces
2-C
6Non-limiting examples of alkenyls comprises 2-cyclobutyl vinyl, 3-phenyl-crotyl, 1,1-dimethyl-3-chloro-3-butenyl, 4,4-phenylbenzene-3-butenyl, 2-(3-chloro-phenyl-)-3-cyclobutyl-4-hexenyl and 1,2-two fluoro-3-(2-phenyl-cyclobutyl)-4-pentenyl.
The C that replaces
3-C
6The example of cycloalkyl comprises 3-cyclopentyl cyclohexyl, 2-benzyl ring butyl, 3-chlorine cyclopentyl, 2,2-two bromo-3-nitro-cyclohexyl and 2,2-two-(3-p-methoxy-phenyl)-cyclopropyl.
The C that replaces
1-C
6The example of alkoxyl group comprises trifluoromethoxy, cyclo propyl methoxy, 1-methyl-2-phenyl propoxy-and 2,3-two-(2, the 4-dinitrophenyl)-hexyloxy.
Described alkyl, alkenyl and naphthenic substituent can be connected by carbonyl (O=C).Example comprises ethanoyl, valeryl, 1-oxo-3-pentenyl, 1-oxo cyclobutylmethyl, 1-oxo-3-phenyl-4-cyclohexyl amyl group and 1-oxo-(3-benzyl ring amyl group)-methyl.
With " A-" in the general formula I be defined as key ,-CH
2-,-CH-CH
3,-CH-(CH
3)
2With-CH
2CH
2-; That compound of the present invention has thus is following-as structure:
Preferred compound of the present invention comprises following compounds:
3,4-dihydro-1-oxo spiral shell (oxospiro) [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclobutylmethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclohexyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-styroyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-amino-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-chloro-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
3,4-dihydro-1 '-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-allyl group-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1 '-(2-methyl-propyl)-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-ring propionyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines)-1 ' (trans-2-phenyl-methyl cyclopropyl);
3,4-dihydro-1 '-benzyl-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1 '-(two-right-fluorine diphenyl-methyl)-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3,4-three hydrogen-1-hydroxyl-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3-dihydro-1-hydroxyl-spiral shell-[2H-indenes-2,4 '-piperidines];
1 '-(cyclopropyl methyl)-8,9-dihydro spiral shell [6H-benzocyclohepta alkene-6,4 '-piperidines]-5 (7H)-ketone;
1 '-cyclopropyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
6-chloro-1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6-fluoro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6,7-dimethoxy-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(1-cyclopropyl-1-ethyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(3-amylene)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-phenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclobutylmethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclohexyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(2-styroyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
With
6-chloro-1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines.
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
The more preferred compound of the present invention comprises following compounds:
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-amino-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-chloro-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl methyl isophthalic acid, 3,4-three hydrogen-1-hydroxyl-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3-dihydro-1-oxo spiral shell [2H-indenes-2,4 '-piperidines];
1 '-(cyclopropyl methyl)-8,9-dihydro spiral shell [6H-benzocyclohepta alkene-6,4 '-piperidines]-5 (7H)-ketone;
1 '-cyclopropyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
6-chloro-1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6-fluoro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6,7-dimethoxy-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(1-cyclopropyl-1-ethyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(3-amylene)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
With
6-chloro-1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines.
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Most preferred of the present invention comprises following compounds:
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines].
The compound of general formula I is characterised in that it belongs to and has volution as substituent dicyclo.It (is N-R that described volution contains a nitrogen-atoms
5), work as R
5Be during such as the such group of alkyl, alkenyl or cycloalkyl, it can be alkaline in nature.This class basic cpd is by being easy to form pharmaceutically acceptable salt with the inorganic and organic acid reaction of using always.The common acid that is used to form the pharmaceutically acceptable salt of the present invention comprises hydrochloric acid, sulfuric acid, thionamic acid, phosphoric acid, citric acid, succsinic acid, L-glutamic acid, toxilic acid, lactic acid, tartrate, tosic acid, phenylformic acid, oxalic acid and Whitfield's ointment.Generally in the solvent such such as methyl alcohol or ether by making murexine prepare salt with simple contact of suitable acid.This salt generally is the highly crystalline form, is easy to precipitation and passes through filtered and recycled.If desired, can be with them further by from such as recrystallization the such common solvent of methyl alcohol, ethyl acetate, acetone and tetrahydrofuran (THF) and purifying.
Be easy to prepare the compound of general formula I of the present invention by well-known method in the organic chemistry filed.Preferably at first a kind of compound of easy manufacture, wherein R
5Be hydrogen, and make this compound and R then
5-alkylation or-acylation reaction.Shown in the following diagram 1 of this class reaction:
Reaction scheme 1
R wherein
1, R
2, R
3, R
4Have the above-mentioned implication that provides with A, and " L " is common leavings group (for example such as the such halogen of chlorine or bromine or such as the such silyl of trimethylsilyl).
Generally such as tetrahydrofuran (THF), methyl-sulphoxide or N, in the such organic solvent that does not participate in reacting of dinethylformamide by (being N-R with the spiral shell amine of suitable molar weight and alkylation or acylating agent
5) mix and carry out above-mentioned reaction.If desired, can be with such as triethylamine or NaHCO
3Such alkali has been used for the effect of acid scavenger.If react under about 25 ℃-Yue 60 ℃ temperature, this reaction was generally finished after about 2-20 hour basically so.The separated product and if desired by carrying out further purifying easily by removing reaction solvent such as the such general method of salify, crystallization and chromatography.
Can use following any several method is synthesized required raw material, is spiral shell amine by the reagent that is easy to obtain.
-in one approach, make N-by the deutero-diethylamine of the form of protecting and dicyclo reactive ketone according to diagram 2:
Reaction scheme 2
In above-mentioned diagram 2, P is the amine protecting group that is easy to remove, for example ethoxy carbonyl or benzyl.Be easy under the situation that has the highly basic such to exist and the dicyclo reactive ketone by the diethylamine derivative that protected such as NaH.This reaction produces the spiral shell sulfonamide derivatives, and it is easy to by ordinary method, for example by the deprotection with hydrochloric acid reaction.
Carbonyl 2 has been explained the preparation method of the raw material that ketone group replaces, i.e. R wherein
1And R
2Be oxygen.This compounds usually in the solvent such such as methyl alcohol or ethanol by with such as NaBH
4Such reductive agent reaction and be easy to be converted to corresponding alcohol (R
1Be H, R
2Be OH).
By catalytic hydrogenation, for example by under the situation that has 10% palladium-carbon to exist, can further described alcohol being reduced with hydrogen reaction.These are reflected in the diagram 3 and explain:
Reaction scheme 3
On the other hand, can be by using suitable substituted piperidine derivative to prepare the compound of general formula I of the present invention as raw material as shown in diagram 4:
Reaction scheme 4
Generally the piperidines by making replacement is finished cyclization with reacting such as the so strong dewatering agent of phosphorus pentachloride and titanium tetrachloride in the organic solvent that does not participate in reacting such such as benzene,toluene,xylene or chloroform.When carrying out under 30 ℃-60 ℃ temperature, this reaction was finished in 2 hours usually.
Cyclisation product is a kind of compound of general formula I, wherein R
1And R
2Be oxygen; Shown in diagram 3, it can be reduced into corresponding alcohol or alkane (R
1And R
2Be hydrogen).
As shown in diagram 5, be easy to prepare the required substituted piperidine of above-mentioned reaction:
Reaction scheme 5
In diagram 5, make 4-piperidine methyl formate and amine protective material reaction (promptly inserting P).Typical amine protecting group comprises tert-butoxycarbonyl, benzyl and trimethylsilyl.Next under the situation that has the highly basic such such as NaH or LDA (LDA) to exist, (wherein A is CH with for example phenethyl bromide generally to make the piperidine derivative that is protected in the solvent that does not participate in reacting such such as tetrahydrofuran (THF) or benzene
2) or 2-phenyl propyl iodine (wherein A is CH-CH
3) or 3-phenyl propyl iodine (wherein A is CH
2CH
2) such phenylalkyl halide reaction.After being reflected at about 2-4 hour, finish basically this that carries out under about-20 ℃.Can make then alkylated piperidines deprotection (removing the L-protecting group) and by with PCl
5And TiCl
4React and cyclisation; Or can be at first with its cyclisation and remove the L-protecting group subsequently.
Following specific embodiment has illustrated the synthetic method by special compound provided by the invention.These embodiment only are that where face representational and not in office has been used for the qualification effect.
Embodiment 1
3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Step 1:Two (2-bromotrifluoromethane) amine hydrobromate.
With the 48%HBr of 157.5g (1.5mol) diethanolamine and 1.35l (stirring simultaneously) (thermo-negative reaction) import successively 21 can be used for reflux or the distillatory three-necked flask.Heating this solution under 180-200 ℃ the bath temperature so that under 122 ℃ vapour temperature, distill out the volume of 350ml.This device is adjusted to the backflow position and kept 1 hour.Further distill as mentioned above so that collect the distillate of 465ml.This device regulated once more be used to reflux 3.75 hours and distill out 400ml then.This mixture is cooled off and adding 300ml ethyl acetate in resistates.This suspension was stirred on ice bath 1 hour.Filter out the precipitation and wash with ethyl acetate then.Obtain the white crystals product of 367g.Yd＝78.5％，M.p.(℃)＝130-135℃。
Step 2:Two (2-bromotrifluoromethane) urethanum.
Adding the product and the 108ml that obtain in 367g (1.17mol) above-mentioned steps in 4l is equipped with the reactor of 1.8l water/ice mixture successively is the Vinyl chloroformate of 122.6g (1.13mol), stirs simultaneously.2N sodium hydroxide solution that will about 1.3l in 5 minutes adds above-mentioned solution so that make pH be continuously 11, simultaneously with temperature maintenance below 5 ℃.This mixture was stirred 5 minutes and was acidified to pH with dense HCl then is 1.With 3 * 1l ether extraction.Na is washed and used then to organic phase with 3 * 500ml softening water
2SO
4Dry.Evaporating solvent.Resistates is carried out chromatography, use CH
2Cl
2Wash-out.Obtain the product of 208.5g.Yd＝58％，TLC(CH
2Cl
2)：R
f＝0.6，
N.M.R.：CDCl
3?
1H((ppm)：1.2(t，3H)，3.4-3.55(m，4H)，3.6-3.7(m，4H)，4.1-4.2(q，2H)).
Step 3:3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]-1 '-carboxylic acid, ethyl ester.
The DMF that uses the 1-Tetralone an intermediate of Sertraline of 69g (0.472mol) of molecular sieve drying and 234ml in advance imported moisture-free and be in the reactor in the inert gas environment.With dry ice/acetone batch this solution is cooled to-15 ℃ and to 80% sodium hydride of the 34.6g that wherein adds the mineral oil dispersion (1.15mol).Temperature is risen to about 20-25 ℃ (thermo-negative reaction).This reaction mixture was stirred 1.5 hours being lower than under 30 ℃ the temperature.
Simultaneously with dry ice/acetone batch with moisture-free be in 208g (0.69mol) two (2-bromotrifluoromethane) urethanum in the reactor in the inert gas environment and be dissolved in the resulting solution of 234ml DMF (using molecular sieve drying in advance) and be cooled to-25 ℃.Undertaken by in nitrogen, shifting to import in the reaction solution for preparing simultaneously and under-25 ℃ temperature 10 minutes.(this temperature being risen to 45 ℃ thermo-negative reaction) elevates the temperature.Then this reaction mixture is cooled off so that it is maintained under about 30 ℃.Rise to subsequently 50 ℃ 2 hours and under 50 ℃, be lower than evaporating solvent in the vacuum of 1mmHg then.Resistates is dissolved in the ice cold water of 1.2l also with 3 * 600ml ether extraction.Na is washed and used then to organic phase with 3 * 500ml softening water
2SO
4Dry.Behind evaporating solvent, obtain dark-brown oily resistates, it by the flash chromatography purifying, is used the CH that is rich in acetone
2Cl
2Wash-out progressively.Obtain the product (Yd=42.5%) of 57.7g (0.2mol), TLC (97/3 CH
2Cl
2/ acetone): R
f=0.45,
N.M.R.：CDCl
3?
1H((ppm)：1.15(t，3H)，1.4(m，2H)，1.8-2.0(m，4H)，2.85-2.95(m，2H)，3.45-3.55(m，4H)，4.0-4.1(q，2H)，7.1(d，1H)，7.2(dd，1H)，7.35(dd，1H)，7.9(d，1H)).
Step 4:3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines).
With 57.7g (0.2mol) 3, the 6N HCl of 4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]-1 '-carboxylic acid, ethyl ester and 1.6l imports in the reactor successively.This mixture is stirred and lasting the backflow 14 hours.Then with its cooling and with 2 * 500ml ether extraction.Simultaneously with water with cold NaOH alkalization and with 3 * 500ml ether extraction.The washing organic phase is also used Na
2SO
4Dry.Behind evaporating solvent, it by chromatography purification, is comprised 10%NH with being rich in
4The CH of the methyl alcohol of OH
2Cl
2Wash-out progressively.
Weight: 31g, Yd=72%, TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.2-0.35.
N.M.R.:CDCl
3 1H ((ppm) base peak: 1.35-1.45 (m, 2H), 1.8-1.9 (m, 2H), 2.0 (t, 2H), 2.1 (s, 1H), 2.75-2.85 (m, 2H), 2.85-3.0 (m, 4H), 7.1 (d, 1H), 7.2 (dd, 1H), 7.35 (dd, 1H), 7.9 (d, 1H)).
By CH to described product
2Cl
2The concentrated hydrochloric acid that adds about 5N in the solution prepares hydrochloride.This mixture is concentrated into does and make then product crystallization from the methanol mixture.
White powder, M.p.=235 ℃, TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.35.
Analyze and C
14H
18The ClNO unanimity.
IR：2995，2700，1675，1600，1440，1395，1210，1090，990，750，740cm
-1
Embodiment 2
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
With 10g (46.4mol) 3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines] and the DMF of 80ml and the THF of 36.2ml import three-necked flask successively.(brooethyl) cyclopropane and 7.8g (92.8mmol) NaHCO that add 6.89g (51mmol)
3This suspension is continued to reflux and kept then 1.5 hours.Under 50 ℃, be lower than evaporating solvent in the vacuum of 1mmHg.Resistates is dissolved in 200ml water also with 3 * 100ml ether extraction.Ether is extracted and uses then 2 * 50ml water extraction with the 1N HCl of 100ml mutually.Simultaneously with water with cold dense NaOH alkalization and with 3 * 100ml ether extraction.With NaCl solution washing organic phase and use Na
2SO
4Dry.In case, then obtain the oily resistates of 12g with evaporating solvent.By CH to crude product
2Cl
2The concentrated hydrochloric acid that adds about 5N in the solution prepares hydrochloride.This mixture is concentrated into does and make the product crystallization by in the methanol solution of product, adding the 20ml ether then, crystallization is spent the night under 20-25 ℃ and filter out product then and wash with water.After the drying, obtain the product of 8.4g.
White powder, M.p.=243 ℃, TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.55.
Analyze and C
18H
24The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.55(m，2H)，0.75-0.8(m，2H)，1.3-1.4(m，1H)，2.1-2.2(m，4H)，2.4-2.55(m，2H)，2.85-2.9(m，2H)，3.0-3.05(m，2H)，3.2-3.3(m，2H)，3.5-3.6(m，2H)，7.2-7.25(m，1H)，7.3-7.35(m，1H)，7.5-7.6(m，1H)，7.95-8.0(m，1H)，12.0-12.2(m，1H).
IR：2990，2700，1675，1600，1420，1395，1320，1080，980，900，760，740cm
-1
Also obtained corresponding iodomethylation thing.MP：162℃。
Embodiment 3
1 '-cyclobutylmethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Use the cyclobutylmethyl bromide, embodiment 2 described methods have produced the product of hydrochloride form.Light brown powder, M.p.=235 ℃.
TLC (92/8 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.7.
Analyze and C
19H
26The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：1.8-2.25(m，10H)，2.4-2.5(m，2H)，2.95-3.1(m，5H)，3.1-3.25(m，2H)，3.25-3.35(m，2H)，7.2-7.35(m，2H)，7.45-7.55(m，1H)，7.9-8.0(m，1H)，11.95-12.15(m，1H))
IR：3400，2900，2650，2500，1680，1590，1430，1360，1300，1220，1140，1100，1040，960，930，900，800，770，740，640cm
-1
Embodiment 4
1 '-cyclohexyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Use the cyclohexyl methyl bromide, embodiment 2 described methods have produced the product of hydrochloride form.The beige powder, M.p.=265 ℃.
TLC (93/87CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.8.
Analyze and C
21H
30The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.95-1.3(m，5H)，1.6-2.1(m，10H)，2.5-2.65(m，2H)，2.7-2.8(m，2H)，2.9-3.0(m，2H)，3.1-3.2(m，2H)，3.3-3.4(m，2H)，7.15-7.3(m，2H)，7.4-7.5(m，1H)，7.9-7.95(m，1H)，11.6-11.8(m，1H))
IR：3400，2900，2500，1680，1600，1440，1360，1300，1220，1150，1110，1060，980，910，760，735cm
-1
Embodiment 5
1 '-styroyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Use styroyl bromination thing, embodiment 2 described methods have produced the product of hydrochloride form.The beige powder, M.p.=＞275 ℃, Yd=55%.
TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.85.
Analyze and C
22H
26The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：2.0-2.15(m，4H)，2.3-2.45(m，2H)，2.9-3.0(m，2H)，3.05-3.25(m，6H)，3.4-3.5(m，2H)，7.1-7.3(m，7H)，7.4-7.45(m，1H)，7.85-7.9(m，1H)，12.25-12.45(m，1H))
IR：3400，2900，2500，1670，1600，1450，1360，1290，1220，1110，1010，960，820，800，740，700cm
-1
Embodiment 6
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
With 0.94g (4.36mmol) 3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines] and the DMF of 10ml import three-necked flask successively.(brooethyl) cyclopropane that adds 1.3g (8.7mmol) then in the solution of gained is dissolved in resulting solution of 2ml DMF and 0.73g (8.7mmol) NaHCO
3This suspension is reached reflux state and kept then 1.5 hours.Under 50 ℃, be lower than evaporating solvent in the vacuum of 1mmHg.Resistates is dissolved in 50ml water also with 3 * 50ml ether extraction.Ether is extracted and uses then 2 * 50ml water extraction with the 1N HCl of 100ml mutually.Simultaneously with water with cold dense NaOH alkalization and with 3 * 50ml ether extraction.With NaCl solution washing organic phase and use Na
2SO
4Dry.Remove and desolvate.The oily resistates by the flash chromatography purifying, is used the CH that is rich in methyl alcohol
2Cl
2Wash-out.Obtain 0.6g, by CH to crude product
2Cl
2The concentrated hydrochloric acid that adds about 5N in the solution prepares its hydrochloride.With this mixture concentrate as for and add the 30ml ether in the resulting solution of 5ml Virahol and make the product crystallization by being dissolved in then to product.Crystallization was carried out under 20-25 ℃ 14 hours and filtered out product then and wash with water.After the drying, obtain the white powder of 0.5g.M.p.=244 ℃, TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.35.Analyze and C
19H
26The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.1-0.3(m，2H)，0.45-0.65(m，2H)，0.7-0.8(m，1H)，1.6-2.6(m，8H)，2.9-3.5(m，8H)，7.2-7.4(m，2H)，7.4-7.6(t，1H)，7.9-8.05(d，1H)，12.15(1H))
IR：2900，2450，1670，1600，1430，1290，1220，950，890，740cm
-1
Embodiment 7
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Use the cinnamyl bromide, prepare according to embodiment 2 described methods, then by chromatography purification and crystal of hydrochloride.White powder, M.p.=228 ℃.
TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.55.
Analyze and C
23H
26The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：2.0-2.25(m，4H)，2.3-2.5(m，2H)，2.9-3.85(m，8H)，6.4-6.6(m，1H)，6.6-6.8(d，1H)，7.1-7.6(m，8H)，7.9-8.0(d，lH)，12.1(1H))
IR：2900，2400，1670，1590，1420，1290，1220，970，730，690cm
-1
Embodiment 8
1 '-(3,3 '-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Use 3,3 '-diphenyl propyl bromide, according to embodiment 6 described methods preparation and preparation hydrochlorides.Obtain white powder, M.p.=257 ℃, TLC (95/5 CH
2Cl
2/ MeOH): R
f=0.35.Analyze and C
29H
32The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：2.0-2.2(m，4H)，2.4-3.5(m，12H)，3.9-4.05(m，1H)，7.2-7.4(m，12H)，7.4-7.6(m，1H)，7.9-8.0(m，1H)，12.3(1H))
IR：2900，2350，1670，1590，1450，1300，1220，910，740，700cm
-1
Embodiment 9
1 '-(cyclopropyl methyl)-3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
According to embodiment 1 described synthetic method preparation 3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines].The alkylation of " N " is identical with the step described in the embodiment 6.Obtain the hydrochloride of white powder form, M.p.＞260 ℃.
TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.5.Analyze and C
20H
28The ClNO unanimity.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.3-0.4(m，2H)，0.7-0.8(m，2H)，1.1-1.3(m，1H)，2.0-2.1(m，4H)，2.2(s，3H)，2.3(s，3H)，2.35-2.45(m，2H)，2.7-2.85(m，4H)，3.0-3.2(m，2H)，3.4-3.5(m，2H)，7.15(s，1H)，7.6(s，1H)，12.15(1H))
IR：3400，2900，2500，1670，1605，1470，1430，1280，1180，1020，970，950，880，830cm
-1
Embodiment 10
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Method by embodiment 9 obtains hydrochloride.
White powder, M.p.＞255 ℃.
TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.35.Analyze and C
19H
26ClNO
2Consistent.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.5(m，2H)，0.75-0.85(m，2H)，1.25-1.4(m，1H)，2.05-2.2(m，4H)，2.35-2.5(m，2H)，2.8-2.95(m，2H)，2.95-3.05(m，2H)，3.2-3.4(m，2H)，3.45-3.6(m，2H)，3.85(s，3H)，6.7(s，1H)，6.85(d，1H)，7.9-8.0(d，1H)，12.15(1H))
IR：2900，2420，1660，1590，1430，1250，1220，960，830，600cm
1
Embodiment 11
1 '-(cyclopropyl methyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Obtain hydrochloride according to the method identical with embodiment 10.
White powder, M.p.=244 ℃.
TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.75.Analyze and C
19H
26ClNO
2Consistent.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.5(m，2H)，0.75-0.85(m，2H)，1.25-1.4(m，1H)，2.05-2.2(m，4H)，2.35-2.5(m，2H)，2.8-3.0(m，4H)，3.1-3.3(m，2H)，3.5-3.6(m，2H)，3.85(s，3H)，7.0-7.1(m，1H)，7.25-7.35(m，1H)，7.5-7.6(m，1H)，12.1-12.2(1H))
IR：2930，2560，2360，1680，1580，1470，1435，1260，1060，970，750cm
-1
Embodiment 12
1 '-(methyl cyclopropyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
By using the method acquisition hydrochloride identical with embodiment 10.
White powder, M.p.=235 ℃.
TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.70-0.75.Analyze and C
19H
26ClNO
2Consistent.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.5(m，2H)，0.75-0.85(m，2H)，1.25-1.4(m，1H)，2.05-2.2(m，4H)，2.35-2.5(m，2H)，2.8-3.0(m，4H)，3.2-3.3(m，2H)，3.5-3.6(m，2H)，3.80(s，3H)，7.0-7.1(m，1H)，7.15-7.25(m，1H)，7.4(s，1H)，12.1-12.2(1H))
IR：2930，2510，2445，1670，1610，1495，1415，1250，1025cm
-1
Embodiment 13
1 '-(cyclopropyl methyl)-3,4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Step 1:Will be according to the 2.4g (8.35mmol) 3 of the preparation of method described in the step 3 of embodiment 1,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]-the 1 '-carboxylic acid, ethyl ester and the 35ml vitriol oil import three-necked flask.The nitrosonitric acid that in being cooled to this solution of 0 ℃, adds 0.79g (12.5mmol).Under 0 ℃, this mixture was stirred 1 hour and stirred 2 hours down at 20-25 ℃ then.Make this solution from 100ml water and ice, precipitate and use then the CH of 3 * 100ml
2Cl
2Extract.With organic phase water successively and saturated NaCl solution washing.Using Na
2SO
4Behind the dry also evaporating solvent, obtain the oily matter of 2.75g, this oily matter is carried out chromatography, with the CH that is rich in acetone
2Cl
2Wash-out progressively.Obtain the 1.5g 3 of crystallizable oily resistates form, 4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]-1 '-carboxylic acid, ethyl ester.Yd=54%, TLC (98/2 CH
2Cl
2/ acetone): R
f=0.3.
N.M.R.：CDCl
3?
1H((ppm)：1.15(t，3H)，1.4(m，2H)，1.8-2.0(m，4H)，2.9-3.0(m，2H)，3.45-3.55(m，4H)，4.0-4.1(q，2H)，7.3(d，1H)，8.2(d，1H)，8.8(s，1H))
Step 2:Make the 1.5g product hydrolysis of above-mentioned steps by the method described in embodiment 1 step 4.Comprise 10%NH using to be rich in
4The CH of the methyl alcohol of OH
2Cl
2Progressively behind the chromatography of wash-out, isolate 0.45g.TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.1.
Step 3:With 3 of the 0.22g (0.845mmol) that obtains in the above-mentioned steps, 4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines] is suspended in the 3ml acetonitrile.Add 0.343g (2.54mmol) cyclopropyl MB and be dissolved in the resulting solution of 0.5ml acetonitrile, stir simultaneously.To make reaction mixture reach reflux state and keep about 5 hours.
Remove the CH that desolvates and resistates is dissolved in 20ml
2Cl
2And extract with 20ml N/1 HCl.With cold diluted sodium hydroxide solution acid is alkalized mutually to pH 12 and with 3 * 20ml CH simultaneously
2Cl
2Extract.Washing, dry and remove desolvate after, resistates is carried out chromatography, comprise 10%NH with being rich in
4The CH of the methyl alcohol of OH
2Cl
2Progressively wash-out obtains 3 of 0.130g, 4-dihydro-1 '-(cyclopropyl methyl)-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines].TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.7.
Prepare hydrochloride as mentioned above.White powder, M.p.=256 ℃.
TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.7.
Analyze and C
18H
23ClN
2O
3Consistent.
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.5(m，2H)，0.7-0.8(m，2H)，1.2-1.4(m，1H)，2-2.25(m，4H)，2.4-2.6(m，2H)，2.8-2.9(m，2H)，3.05-3.3(m，4H)，4.5-4.6(m，2H)，7.45(d，1H)，8.3(d，1H)，8.8(s，1H)，12.1(1H))
IR：2940，2500，2440，1690，1610，1520，1410，1345，1220，1105，960cm
-1
Embodiment 14
1 '-(cyclopropyl methyl)-7-amino-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
With 3 of the 60mg (0.19mmol) that obtains as described in example 13 above, 4-dihydro-1 '-(methyl cyclopropyl)-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines] is dissolved in the THF of 1ml and imports the tin chloride hydrate of 0.21g then when stirring.This solution is continued to reflux 1 hour.Reaction solution is joined saturated NaHCO
3In the solution and with 3 * CH
2Cl
2Extract.The washing organic phase is also used Na
2SO
4Dry.Evaporating solvent also carries out chromatography to the resistates that obtains, and comprises 10%NH with being rich in
4The CH of the methyl alcohol of OH
2Cl
2Wash-out progressively.Obtain the product of 29mg.
N.M.R.：CDCl
3?
1H((ppm)：0.1-0.2(m，2H)，0.4-0.55(m，2H)，0.85-1.0(m，1H)，1.6-1.7(m，2H)，1.9-2.1(m，4H)，2.3-2.4(m，2H)，2.5-2.75(m，4H)，2.8-2.9(m，2H)，3.6-3.8(2H)，6.8(d，1H)，7.0(d，1H)，7.2(s，1H))
Crystallization goes out hydrochloride from ether.Obtain the yellow powder of 26mg.
M.p.=200 ℃, decompose.TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.45.
Embodiment 15
1 '-(cyclopropyl methyl)-7-chloro-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Step 1:Piperidines-1,4-dicarboxylic acid 4-ethyl 1-tertiary butyl diester.
The THF of the different piperidine ethyl formate of 60g (0.381mol) and 400ml placed moisture-free and be in the three-necked flask of inert gas environment and add the sodium hydrate particle of 18.3g (0.458mol).In 1 hour, add 100g (0.458mol) tert-Butyl dicarbonate and be dissolved in the resulting solution of 170ml THF, simultaneously it is stirred into suspension.Temperature reaches 45 ℃.Under 20-25 ℃, this reaction mixture continue stirred 14 hours and then in impouring 2l water and the ice and with 3 * 500ml ether extraction.With organic phase with the saturated NaCl solution washing of 3 * 250ml, use Na
2SO
4Dry and concentrated.Resistates is carried out chromatography, with the CH that is rich in acetone
2Cl
2Wash-out and in the vacuum of 0.09mmHg and under 95-102 ℃ the vapour temperature, distilling then progressively.Obtain 82g (0.2mol) (Yd=83.6%), TLC (95/5 CH
2Cl
2/ acetone): R
f=0.60.
N.M.R.：CDCl
3?
1H((ppm)：1.2-1.3(t，3H)，1.4(s，9H)，1.5-1.6(m，2H)，1.8-1.9(m，2H)，2.35-2.45(m，1H)，2.7-2.85(m，2H)，3.9-4.0(m，2H)，4.05-4.15(q，2H))
Step 2:4-(4-chlorobenzene ethyl) piperidines-1,4-dicarboxylic acid 4-ethyl 1-tertiary butyl diester.
To import moisture-free and be in the three-necked flask in the inert gas environment by in nitrogen, shifting with the Diisopropylamine of the 6.16g (60.9mmol) of molecular sieve drying and 174ml THF.This solution is cooled to-10 ℃ and add the hexane solution (60.9mmol) of the 2.5N n-Butyl Lithium of 24.3ml.Down this mixture was stirred 15 minutes and was cooled to-70 ℃ and in about 20 minutes, add 10.4g (40.6mmol) and be dissolved in the resulting solution of 86mlTHF at-10 ℃ from the product in the above-mentioned steps 1.At-70 ℃ of HMPT that down this mixture stirred 10 minutes and added then 10.9g (60.9mmol).-70 ℃ this mixture is continued to stir 1.5 hours down and-70 ℃ under 20 minutes in adding 4-chlorobenzene ethyl bromine (10.7g 48.7mmol) is dissolved in the solution of 86ml THF.It is waterborne and with ether extraction 3 times that this mixture was stirred 14 hours down and be poured on then 350ml at 20-25 ℃.With N/1 HCl and use saturated NaCl solution washing organic phase then.In drying with after concentrating, obtain the orange of 17g, this oily matter is carried out chromatography, with the CH that is rich in hexane
2Cl
2Wash-out and use the acetone wash-out then progressively.Obtain 11.8g (Yd=80%).TLC (95/5 CH
2Cl
2/ acetone): R
f=0.70.
NMR：CDCl
3?
1H((ppm)：1.2-1.3(t，3H)，1.4(s，9H)，1.3-1.4(m，2H)，1.7-1.8(m，2H)，2.0-2.1(m，2H)，2.3-2.4(m，2H)，2.7-2.9(m，2H)，3.7-3.9(m，2H)，4.05-4.15(q，2H)，6.9-7.0(m，2H)，7.1-7.2(m，2H))
Step 3:4-(4-chlorobenzene ethyl) piperidines-4-carboxylic acid, ethyl ester
With product and the 50ml CH of 10.8g from above-mentioned steps 2
2Cl
2Import moisture free three-necked flask.Stir this solution down and add the 25ml trifluoroacetic acid at 20-25 ℃.This mixture is continued to stir 30 minutes and be concentrated into dry doubling then resistates is dissolved in ether.With 10% sodium hydroxide solution and be dissolved in the washing organic phase with saturated NaCl then.Dry and concentrate after obtain the oily matter of 9g, this oily matter crystallization.
TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.45.
NMR：CDCl
3?
1H((ppm)：1.1-1.25(t，3H)，1.3-1.4(m，2H)，1.7-1.8(m，2H)，2.1-2.2(m，2H)，2.35-2.45(m，2H)，2.6-2.7(m，2H)，2.9-3.0(m，2H)，3.3(1H)，4.1-4.2(q，2H)，6.9-7.0(dd，2H)，7.1-7.2(dd，2H))
Step 4:1-(cyclopropyl methyl)-4-(4-chlorobenzene ethyl) piperidines-4-carboxylic acid, ethyl ester
To import moisture-free successively from 85% (brooethyl) cyclopropane of product, 85mlTHF and the 14.9ml triethylamine of above-mentioned steps 3 and 2.4ml (20.9mmol) and be in the round-bottomed flask in the nitrogen environment with the 3.4g (11.5mmol) of molecular sieve drying, stir simultaneously.This mixture continue refluxed 14 hours and to be concentrated into dry doubling then water-soluble and with twice of ether extraction with resistates.Concentrate with saturated NaCl solution washing and exsiccant organic phase.Obtain the 3g crude product, this product is carried out chromatography (eluent: be rich in and comprise 10%NH
4The CH of the methyl alcohol of OH
2Cl
2Wash-out progressively).Obtain 2.6g oily product.Yd＝65％。
TLC (95/5 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.50.
N.M.R.：CDCl
3?
1H((ppm)：0.0-0.1(m，2H)，0.35-0.45(m，2H)，0.7-0.8(m，1H)，1.1-1.2(t，3H)，1.4-1.5(m，2H)，1.7-1.8(m，2H)，1.9-2.1(m，2H)，2.1-2.2(m，2H)，2.3-2.4(m，2H)，2.7-2.85(m，2H)，4.1-4.2(q，2H)，6.9-7.0(dd，2H)，7.1-7.2(dd，2H))
Step 5:1-(cyclopropyl methyl)-4-(4-chlorobenzene ethyl) piperidines-4-carboxylic acid
The above-mentioned ester of 2.2g (6.28mmol) and 6.6ml anhydrous dimethyl sulfoxide imported moisture-free and be in the round-bottomed flask in the nitrogen environment.(4.4g 39mmol) is dissolved in the resulting solution of 30ml methyl-sulphoxide to add potassium tert.-butoxide when stirring.Under 20-25 ℃, this mixture is continued to stir 2 hours.Join this reaction mixture in the 200ml water and wash with ether then.With 10%HCl with aqueous phase as acidified to pH 5-7.Filter out the precipitation and wash with water.The acid that makes acquisition is from CH
2Cl
2Crystallization in the/carbinol mixture.M.p.＝250℃。
NMR：CDCl
3?
1H((ppm)：0.2-0.3(m，2H)，0.5-0.6(m，2H)，1.07-1.1(m，1H)，1.6-1.9(m，4H)，2.25-2.35(m，2H)，2.5-2.6(m，2H)，2.65-2.75(m，2H)，2.8-2.9(m，2H)，3.3-3.4(m，2H)，6.9-7.0(dd，2H)，7.1-7.2(dd，2H))
IR：3370，1490，1445，1380，1240，1170，1095，965，805cm
-1.
Step 6:7-chloro-3,4-dihydro-1 '-(cyclopropyl methyl)-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines].
The acid of the 0.3g (0.9mmol) of above-mentioned acquisition and 6ml benzene imported moisture-free and be in the round-bottomed flask in the nitrogen environment.The PCl that adds 0.24g
5CH with 6ml
2Cl
2, add the PCl of 0.24g subsequently again
5Under 20-25 ℃, this mixture was stirred 2 hours.This mixture is cooled to 0 ℃, imports the tin tetrachloride (a large amount of precipitation) of 0.44ml, the CH of adding 12ml
2Cl
2And with this mixture maintain 0 ℃ following 1 hour and maintain then 20-25 ℃ following 14 hours.Remove and to desolvate and resistates is water-soluble.With water with ether washing and alkalize to pH 12 with NaOH then and use ether extraction.With organic phase washing, dry and concentrated.Crude product is carried out chromatography, comprise 10%NH with being rich in
4The CH of the methyl alcohol of OH
2Cl
2Wash-out progressively.Obtain the product of 22mg, with this product at CH
2Cl
2Handle with the 5N concentrated hydrochloric acid in the solution.Go out in product and the vacuum under 50 ℃ dry in crystallization and filtration from ethyl acetate.
White powder, TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.55.
M.p.＝263℃。
N.M.R.：CDCl
3?
1H((ppm)HCl：0.4-0.5(m，2H)，0.7-0.8(m，2H)，1.2-1.3(m，1H)，2.0-2.15(m，4H)，2.4-2.55(m，2H)，2.8-2.9(m，2H)，2.95-3.05(m，2H)，3.1-3.3(m，2H)，3.5-3.6(m，2H)，7.2-7.3(m，1H)，7.4-7.5(m，1H)，7.9(s，1H)，12.2(1H))
IR：2930，2440，1720，1490，1230，1185，1095，1025，810cm
-1.
Embodiment 16-34
According to above-mentioned general step, listed following other compound in the preparation table 1.
Table 1
Table 1 (continuing)
The following institute of the MP of the compound of embodiment 16-34 and NMR data provides:
Embodiment 16
MP＝240-243℃
R.M.N.CDCl
3 1H δ (ppm) base peak: 1,5-1,6 (m, 2H); 1,95-2,05 (m, 4H); 2,25 (s, 3H); 2,3-2,4 (m, 2H); 2,45-2,55 (m, 2H); 2,9-2,95 (m, 2H); 7,1-7,15 (m, 1H); 7,2-7,25 (m, 1H); 7,35-7,4 (m, 1H); 7, and 9-7.95 (m, 1H)
Embodiment 17
MP＝242-244℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：2,05-2,15(m，4H)；2,3-2,45(m，2H)；3,0-3,1(m，2H)；3,1-3,25(m，2H)；3,35-3,5(m，2H)；3,55-3,6(m，2H)；5,4-5,55(m，2H)；6,1-6,25(m，1H)；7,2-7,35(m，2H)；7,45-7.5(m，1H)；7,9-7,95(m，1H)；12,3-12,45(m，1H)
Embodiment 18
MP＝244-245℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：1,15(d，6H)；2,0-2,1(m，4H)；2,15-2,3(m，1H)；2,55-2,65(m，2H)；2,75-2,8(m，2H)；2,95-3,0(m，2H)；3,1-3,25(m，2H)；3,35-3,45(m，2H)；7,2-7,35(m，2H)；7,45-7.5(m，1H)；7,9-7,95(m，1H)；11,7-11,8(m，1H)
Embodiment 19
MP＝95-97℃
R.M.N.CDCl
3 1H δ (ppm) base peak: 0,6-0,7 (m, 2H); 0,8-0,95 (m, 2H); 1,4-1,5 (m, 2H); 1,6-1,7 (m, 1H); 1,8-2,1 (m, 4H); 2,9-3,5 (m, 2H); 3,4-3,8 (m, 4H); 7,1-7,3 (m, 2H); 7, and 35-7.45 (m, 1H); 7,9-8,0 (m, 1H);
Embodiment 20
MP＝220-221℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：1,05-1,3(m，2H)；1,5-1,9(m，1H)；2,0-2,2(m，5H)；2,3-2,55(m，2H)；2,9-3,4(m，6H)；3,4-3,6(m，2H)；7,0-7,6(m，8H)；7,9-8,1(m，1H)；12,2-12,4(m，1H)
Embodiment 21
MP＝261-262℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：2,0-2,1(m，4H)；2,4-2,5(m，2H)；2,95-3,05(m，2H)；3,1-3,25(m，2H)；3,3-3,4(m，2H)；4,1-4,15(m，2H)；7,2-7,35(m，2H)；7,4-7,5(m，4H)；7,65-7,7(m，2H)；7,9-7,95(m，1H)；12,25-12,5(m，1H)
Embodiment 22
MP＝＞250℃
R.M.N.CDCl
3 1H δ (ppm) base peak: 1,4-1,55 (m, 2H); 1,9-2,05 (m, 4H); 2,2-2,35 (m, 2H); 2,4-2,55 (m, 2H); 2,8-2,95 (m, 2H); 4,2 (s, 1H); 6,8-7,0 (m, 4H); 7,15 (d, 1H); 7,2-7,35 (m, 5H); 7,4 (t, 1H); 7,9 (d, 1H)
Embodiment 23
MP＝91-93℃
R.M.N.CDCl
3 1H δ (ppm) base peak :-0,05-0,05 (m, 2H); 0,35-0,45 (m, 2H); 0,7-0,85 (m, 1H); 1,25-1,85 (m, 7H); 2,2 (d, 2H); 2,2-2,4 (m, 2H); 2,5-2,6 (m, 1H); 2,6-2,7 (m, 3H); 4,2 (s, 1H); 7,0-7,3 (m, 4H)
Embodiment 24
MP＝256-258℃
R.M.N.CDCl
3 1H δ (ppm) base peak: 0,0-0,1 (m, 2H); 0,4-0,5 (m, 2H); 0,75-0,85 (m, 1H); 1,45-1,55 (m, 4H); 1,6-1,65 (m, 2H); 2,2 (d, 2H); 2,35-2,6 (m, 6H); 2,7-2,8 (m, 2H); 6,9-7,05 (m, 4H)
Embodiment 25
MP＝241℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,0-0,15(m，2H)；0,4-0,55(m，2H)；0,75-0,9(m，1H)；1,35(d，2H)；1,9-2,15(m，4H)；2,25(d，2H)；2,9(s，2H)；3,0(d，2H)；7,25(t，1H)；7,35(d?1H)；7,5(t，1H)；7,65(d，1H)；12,1-12,2(1H)
Embodiment 26
MP＝242-243℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,4-0,5(m，2H)；0,7-0,8(m，2H)；1,2-1,35(m，1H)；1,85-2,0(m，4H)；2,2-2,3(m，2H)；2,3-2,4(m，2H)；2,7-2,9(m，6H)；3,4-3,5(m，2H)；7,15-7,4(m，4H)；12,1-12,3(1H)
Embodiment 27 MP=234 ℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,45(m，2H)；0,75(m，2H)；1,35(m，1H)；1,4(dd，3H)；1,85(m，2H)；2,1(m，3H)；2,3(m，1H)；2,75(m，2H)；2,9(m，2H)3,25(m，1H)；3,45-3,8(m，3H)；7,3-7,45(m，2H)；7,6(m，1H)；8,0(dd，1H)；12,1(1H)
Embodiment 28
MP＝＞250℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,4-0,5(m，2H)；0,75-0,85(m，2H)；1,3-1,4(m，1H)；2,1-2,2(m，4H)；2,42,55(m，2H)；2,9-2,95(m，2H)；3,0-3,05(m，2H)；3,2-3,3(m，2H)；3,5-3,6(m，2H)；7,25-7,3(m，2H)；7,9，7,95(m，1H)；12,2(1H)
Embodiment 29
MP＝227℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,4-0,5(m，2H)；0,75-0,85(m，2H)；1,3-1,4(m，1H)；2,0-2,2(m，4H)；2,4-2,6(m，2H)；2,85-2,95(m，2H)；3,0-3,1(m，2H)；3,2-3,3(m，2H)；3,5-3,6(m，2H)；6,9-7,0(m，1H)；7,0-7,1(m，1H)；7,95-8,05(m，1H)；12,1(1H)
Embodiment 30
MP＝229℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,45(m，2H)；0,75(m，2H)；1,35(m，1H)；2,15(m，4H)；2,45(td，2H)；2,9(m，2H)；2,95(m，2H)；3,3(m，2H)；3,55(m，2H)；4,85(s，3H)；4,95(s，3H)；6,65(s，1H)；7,45(s，1H)；12,05(1H)
Embodiment 31
MP＝189-192℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：0,2-0,3(m，1H)；0,6-0,7(m，1H)；0,7-0,8(m，1H)；0,8-0,9(m，1H)；1,1-1,2(m，1H)；1,55(d，3H)；1,6-1,7(m，1H)；2,1-2,2(m，4H)；2,5-2,7(m，2H)；3,0-3,1(m，2H)；3,3-3,6(m，4H)；7,2-7,25(m，1H)；7,3-7,35(m，1H)；7,45-7,5(m1H)；8,0-8,05(m，1H)；11,85(1F)
Embodiment 32
MP＝＞235℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：1,7(d，3H)；2,1-2,2(m，4H)；2,4-2,5(m，2H)；2,6-2,7(m，2H)；2,9-3,1(m，4H)；3,2-3,3(m，2H)；3,4-3,5(m，2H)；5,3-5,4(m，1H)；5,6-5,7(m，1H)；7,2-7,3(m，1H)；7,3-7,35(m，1H)；7,5-7,6(m1H)；7,95-8,0(m，1H)；12,2(1H)
Embodiment 33
MP＝209℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：2,1(m，4H)；2,25(m，2H)；2,45(m，2H)；2,7(m，2H)；2,9(m，2H)；3,0(m，2H)；3,15(m，2H)；3,4(m，2H)；7,1-7,35(m，7H)；7,5(m，1H)；7,95(m，1H)；11,95(1H)
Embodiment 34
MP＝228℃
R.M.N.CDCl
3?
1Hδ(ppm)HCl：2,0-2,2(m，4H)；2,4(td，2H)；3,0(m，2H)；3,3(qd，2H)；3,45(m，2H)；3,75(t，2H)；3,85(s，3H)；6,55(qt，1H)；6,7(m，2H)；6,85(dd，1H)；7,35(m，3H)；7,45(d，2H)；7,95(d，1H)；11,95(1H).
Embodiment 35-69
According to step as known in the art, make some alkylation in the above-mentioned naphthane ketone so that listed following other compound in the generation table 2
Table 2
| Embodiment | ??R 1-R 2 | ?R 3 | ????R 4 | ????R 5 | ????A | ????Rf |
| ????35 | ????＝O | ?5：OCH 3 | ????H | ????(CH 2) 2-c-C 3H 5 | ????CH 2 | ????0.7 |
| ????36 | ????＝O | ?5：OCH 3 | ????H | ????CH 2-c-C 4H 7 | ????CH 2 | ????0.5 |
| ????37 | ????＝O | ?5：OCH 3 | ????H | ????CH 2-c-C 6H 11 | ????CH 2 | ????0.8 |
| ????38 | ????＝O | ?5：OCH 3 | ????H | ????CH 2-CH＝CH-C 6H 6 | ????CH 2 | ????0.7 |
| ????39 | ????＝O | ?5：OCH 3 | ????H | ????CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.7 |
| ????40 | ????＝O | ?5：OCH 3 | ????H | ????CH 2-CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.55 |
| ????41 | ????＝O | ?5：OCH 3 | ????H | ????(CH 2) 2-CH-(C 6H 6) 2 | ????CH 2 | ????0.90 |
| ????42 | ????＝O | ?6：OCH 3 | ????H | ????(CH 2) 2-c-C 3H 5 | ????CH 2 | ????0.4 |
| ????43 | ????＝O | ?6：OCH 3 | ????H | ????CH 2-c-C 4H 7 | ????CH 2 | ????0.3 |
| ????44 | ????＝O | ?6：OCH 3 | ????H | ????CH 2-c-C 6H 11 | ????CH 2 | ????0.55 |
| ????45 | ????＝O | ?6：OCH 3 | ????H | ????CH 2-CH＝CH-C 6H 6 | ????CH 2 | ????0.5 |
| ????46 | ????＝O | ?6：OCH 3 | ????H | ????CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.5 |
| ????47 | ????＝O | ?6：OCH 3 | ????H | ????CH 2-CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.4 |
| ????48 | ????＝O | ?6：OCH 3 | ????H | ????(CH 2) 2-CH-(C 6H 6) 2 | ????CH 2 | ????0.7 |
| ????49 | ????＝O | ?7：OCH 3 | ????H | ????(CH 2) 2-c-C 3H 5 | ????CH 2 | ????0.5 |
| ????50 | ????＝O | ?7：OCH 3 | ????H | ????CH 2-c-C 4H 7 | ????CH 2 | ????0.2 |
| ????51 | ????＝O | ?7：OCH 3 | ????H | ????CH 2-c-C 6H 11 | ????CH 2 | ????0.4 |
| ????52 | ????＝O | ?7：OCH 3 | ????H | ????CH 2-CH＝CH-C 6H 6 | ????CH 2 | ????O.4 |
| ????53 | ????＝O | ?7：OCH 3 | ????H | ????CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.4 |
| ????54 | ????＝O | ?7：OCH 3 | ????H | ????CH 2-CH 2-CH 2-C 6H 6 | ????CH 2 | ????0.3 |
| ????55 | ????＝O | ?7：OCH 3 | ????H | ????(CH 2) 2-CH-(C 6H 6) 2 | ????CH 2 | ????0.65 |
Table 2 (continuing)
| Embodiment | ??R 1-R 2 | ????R 3 | ????R 4 | ????R 5 | ????A | ????Rf |
| ????56 | ????＝O | ????H | ????H | ????(CH 2) 2-c-C 3H 5 | ??CHCH 3 | ????0.4 |
| ????57 | ????＝O | ????H | ????H | ????CH 2-c-C 4H 7 | ??CHCH 3 | ????0.2 |
| ????58 | ????＝O | ????H | ????H | ????CH 2-c-C 6H 11 | ??CHCH 3 | ????0.5 |
| ????59 | ????＝O | ????H | ????H | ????CH 2-CH＝CH-C 6H 6 | ??CHCH 3 | ????0.45 |
| ????60 | ????＝O | ????H | ????H | ????CH 2-CH 2-C 6H 6 | ??CHCH 3 | ????0.5 |
| ????61 | ????＝O | ????H | ????H | ????CH 2-CH 2-CH 2-C 6H 6 | ??CHCH 3 | ????0.4 |
| ????62 | ????＝O | ????H | ????H | ????(CH 2) 2-CH-(C 6H 6) 2 | ??CHCH 3 | ????0.7 |
| ????63 | ????＝O | ????6：Cl | ????H | ????(CH 2) 2-c-C 3H 5 | ??CH 2 | ????0.5 |
| ??64 | ??＝O | ??6：Cl | ??H | ??CH 2-c-C 4H 7 | ??CH 2 | ??0.3 |
| ??65 | ??＝O | ??6：Cl | ??H | ??CH 2-c-C 6H 11 | ??CH 2 | ??0.65 |
| ??66 | ??＝O | ??6：Cl | ??H | ??CH 2-CH＝CH-C 6H 6 | ??CH 2 | ??0.55 |
| ??67 | ??＝O | ??6：Cl | ??H | ??CH 2-CH 2-C 6H 6 | ??CH 2 | ??0.65 |
| ??68 | ??＝O | ??6：Cl | ??H | ??CH 2-CH 2-CH 2-C 6H 6 | ??CH 2 | ??0.5 |
| ??69 | ??＝O | ??6：Cl | ??H | ??(CH 2) 2-CH-(C 6H 6) 2 | ??CH 2 | ??0.85 |
Embodiment 70
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
Except that step 3, synthetic method wherein is used to replace the 1-Tetralone an intermediate of Sertraline with the 6-methoxytetralone to similar described in the embodiment 1.
N.M.R.:CDCl
3 1H ((ppm) base peak: 1.9-2.3 (m, 6H); 2.9-3.1 (m, 2H); 3.3-3.6 (m, 4H); 3.85 (s, 3H); 6.65 (s, 1H); 6.8-6.9 (m, 1H); 7.9-8.0 (dd, 1H); (9.5 bs, 2H)).
M.P.=236-237 ℃, TLC (90/10 CH
2Cl
2/ contain 10%NH
4The MeOH of OH): R
f=0.25.
IR：2724，1657，1595，1446，1258，1223，1086，978，906，839cm
-1
As mentioned above, the compound of general formula I of the present invention is used for the treatment of chronic pain and such as epileptic seizures, other such CNS disease of for example epilepsy.At ability and the antagonism PGE of measuring the isolating Mammals Na neurone passage of blocking-up
2(PGE
2) estimated described compound in the standard test test that produces.Two kinds of determination tests all are generally used for showing the clinical application of compound in treatment chronic pain and other CNS disease (referring to (Anethesiology) 24:949-951 of Tonelian etc. " (narcology ", 1991).
Embodiment 71
The sodium channel [
3
-H] batrachotoxin (BTX) combination test
Will be from ice-cold 0.32M sucrose, the 5mM K of 10 volumes of pallium in glass-teflon homogenizer of male Sprague-Dawley rat
2HPO
4Homogenize in (4 ℃ of following pH 7.4)., will precipitation be suspended in the sucrose of equal volume again and carry out centrifugal again centrifugal 10 minutes of this homogenize thing with 1000g.Discard precipitation and collect from two portions of supernatant liquors of two times centrifugal and centrifugal 10 minutes with 20000g.With gained precipitation be suspended in again do not contain Na contain 50mMHEPES, 5.4mM KCl, 0.8mM MgSO
4, 5.5mM glucose and 130mM choline chloride 60 test damping fluid (25 ℃ of following pH 7.4) in.Be with or without under the situation that the unmarked medicine of different concns (250 μ l final volume) exists by to contain 25 μ g scorpion venoms (
Leirus Quinquestriatus), 0.1%BSA and 10nM[
3-H] (40Ci/mmol adds 150-200 μ g synaptosome albumen and starts in conjunction with test batrachotoxin in test damping fluid NEN).Under the situation that has the 0.3mM veratridine to exist, measure the non-specific binding situation.Under 25 ℃, reactant cultivated 90 minutes and by through the isolated by vacuum filtration of Whatman GF/B filter membrane by the binding partner that discharges; With this filter membrane with 2 * 5ml damping fluid (5mM HEPES, 1.8mM CaCl
2, 0.8mMMgSO
4, 130mM choline chloride 60,0.1%BSA; 25 ℃ of following pH 7.4) washing and by liquid-scintillation spectrometry method estimation bonded part.
Embodiment 72
Enter SK-N-SH neuroblast oncocyte 22Na
+ Stream
End user SK-N-SH cell carries out Na on 96 hole culture plates
+The characterization of channel activity.The evaluation test compound is to passing through Na under veratridine stimulates
+The Na of passage
+The influence of stream.
Under 37 ℃ and the situation that has test compounds to exist, containing 5.4mM KCl, 0.8mMMgSO
4, 1.8mM CaCl
2, 5mM glucose, 140mM choline chloride 60 25mM hepes/TrispH 7.5 damping fluids in cultivated 15 minutes the SK-N-SH cell is pre-.By 37 ℃ and have under the situation that test compounds and veratridine exist replenished 1 μ M unabain, 10mM NaCl, 130mM choline chloride 60 and
22Na
+The cultivation damping fluid in cultivate and to induce Na in 10 minutes
+Flow into (Jacques, Y.Fosset, M. and Lazdunski, M., (1978), " the ionophoric molecular characterization of action potential Na+ in the neuroblast oncocyte " (Molecularproperties of the action potential Na+ ionophore inneuroblastoma cells)-" biology and The Chemicals " (J.Biol.Chem.) 253,7383-7392).
This
22Na
+After the absorption, use 0.1mM MgCl
2Washed cell.Next (Microscint 40, and Packard) (Topcount Packard) measures radioactivity to back microtest plate reader adding scintillation solution.
Reference compound is 10
-10M-10
-7The pure toxin of testing under 7 kinds of concentration in the scope in river is so that measure IC
50Value.
Embodiment 73
Anodyne is to PGE in the rat body
2
The chronic hyperalgesic activity of bringing out
The purpose of this test is to use the analgesic effect of Randall and Selitto test determination rat body build-in test compound, wherein passes through in 4 days PGE according to the scheme (" pain " is 63:33-37 (Pain), 1995) of employings such as Nakamura-Craig
2In the vola, inject shank and bring out chronic hyperpathia.
This research is carried out at the Sprague-Dawley rat that 120-140g criticizes, by the vola approach to they 100ng PGE with 100 μ l volumes
2Give 4 days, every day continuously twice; It produced chronic hyperpathia since the 5th day in shank, continue a week at least.In morning this day of test with Randall and Selitto test check to the threshold value of pain reaction and to select threshold value be the animals of ψ 100 arbitrarily definite units.At noon, giving to repeat mensuration before and after the test compounds solution by subcutaneous route; Before measuring pain threshold, this administration was carried out 30 minutes.Concerning every batch of animal, compare with the control animal of only accepting carrier, calculate analgesic activity (%) according to the threshold value form that before the treatment and treatment back is measured.
3 combination of Na passage and the analgesic activities of having listed in above-mentioned test the representative compound of the present invention when measuring of tabulating down.
Table 3: pharmacologically active
| Embodiment number compound | ??[ 3H] BTX detection: Na +Passage is in conjunction with Ki (nM) | ???? 22Na influx IC50 (μ M) | ????PGE 2Detect: analgesic activity 10mg/kg S.C. (%) |
| ????2 ????6 ????7 ????8 ????10 ????33 ????36 ????42 ????43 ????47 ????49 ????70 | ????876 ????1435 ????366 ????397 ????3890 ????291 ????475 ????ND ????ND ????ND ????2183 ????ND | ????10.7 ????3.4 ????0.94 ????0.97 ????30 ????1.2 ????3.4 ????4.3 ????6 ????0.6 ????7.6 ????ND | ????49 ????67 ????57 ????47 ????100 ????81 ????51 ????46 ????39 ????66 ????38 ????46 |
The compound that above-mentioned biological data has been established general formula I is used in particular for treating Mammals intravital CNS disease, especially neuropathic pain, trigeminal nerve neurodynia, diabetic neuropathy, sciatica and epileptic seizures.These compounds especially fully are suitable for treating diabetic neuropathy, and it is a most common complication of following diabetes.These compounds also are used for prevention and treatment migraine.
Can give compound of the present invention by people oral and that parenteral route is treated chronic pain disease or epileptic seizures disease to needs, for example they be made tablet or capsule administration or make subcutaneous or intravenous injection administration.Give these compounds with effective control and treatment epileptic seizures amount sick or that the alleviation neuropathic pain is felt.This class significant quantity is generally in the scope of the about 2000mg/kg weight of mammal of about 0.1-.Common prescribed dose is at the about 500mg/kg of about 5mg/kg-.For alleviating neuropathic pain and epileptic seizures, this class dosage can be given 1-4 time the grownup every day.Used prescribed dose depends on the specific compound of used general formula I, the patient's that treats particular case and generally should abide by the doctor's advice of doctor on duty or other specialist.
Can prepare the oral or parenterai administration of described compound by general method for use in routine.Typical oral dosage form is tablet, capsule, lozenge, elixir, syrup, suspensoid and for example controlled release form by osmotic pump.Described compound can be mixed with the formulation that to pass through intraperitoneal, subcutaneous, intramuscular, hypogloeeis or intravenous administration equally.Can prepare described compound by thinner commonly used, vehicle, carrier and tackiness agent that use is generally used for pharmacy field.For example, can with compound with such as such carrier, thinner and the vehicle of starch, Mierocrystalline cellulose, PVP, methylcellulose gum, sugar, wax, talcum and such as Magnesium Stearate, MgO, CaCO
3, such stablizer and the tackiness agent of methyl p-Hydroxybenzoate (para methyl paraben) and n-propyl p-hydroxybenzoate (propylparaben) mix.
Following other embodiment has illustrated by typical medicaments preparation provided by the invention.
Embodiment 74
Tablet
The compound 25.0mg of embodiment 10
Microcrystalline Cellulose 50.0mg
The food W-Gum 50.0mg of modification
Magnesium Stearate 1.0mg
Mixing said ingredients is to evenly and be pressed into tablet.With every day 1-4 time frequency this class tablet is suffered from the people of chronic pain.
Embodiment 75
Iv formulation
The compound 400mg of embodiment 2
Acetate buffer 20ml
The distilled water solution of HCl or NaOH is to pH 6.5
Sterile isotonic salt solution capacity is to 1000ml
Compound of the present invention is dissolved in acetate buffer and with pH regulator to 6.5.Isotonic saline solution is added to the 1000ml volume.This solution packed into be equipped with in the aseptic Flesible plastic container of dropper.The patient who this solution is suffered from diabetic neuropathy by intravenous injection.
Claims (13)
1. the tricyclic compound of a general formula I and pharmaceutically acceptable salt thereof:
Wherein:
R
1Be hydrogen or hydroxyl;
R
2Be hydrogen or hydroxyl; Or
R
1And R
2Be oxygen jointly;
A is key, CH
2, CHCH
3, CH
2CH
2Or C (CH
3)
2
R
3And R
4Identical or different and be hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, trifluoromethyl, NO
2, COR
6, COOR
6Or NR
6R
7, R wherein
6And R
7Identical or different and be hydrogen, C
1-C
6Alkyl or benzyl;
R
5Be hydrogen, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
3-C
6Cycloalkyl, (O=C)-C
1-6Alkyl, (O=C)-C
2-6Alkenyl, (O=C)-C
3-6Cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl can be selected from halogen, C by 1,2 or 3
3-C
6The group of cycloalkyl, phenyl or substituted-phenyl replaces.
2. the compound according to claim 1, wherein R
5By phenyl or C
3-C
6Cycloalkyl substituted or the C that is not replaced by them
1-C
6Alkyl.
3. the compound according to claim 1 or 2, wherein R
3Be hydrogen, halogen or C
1-C
4Alkoxyl group.
4. one kind according to compound any among the claim 1-3, wherein R
1Be C
1-C
6Alkyl, C
2-C
6Alkenyl or C
3-C
6Cycloalkyl, they are selected from halogen, C by 1,2 or 3
3-C
6The group of cycloalkyl, phenyl or substituted-phenyl replaces or is not replaced by them; And R
2Be hydrogen.
5. one kind according to compound any among the claim 1-4, wherein R
4Be hydrogen.
6. compound that is selected from the group that following compounds forms:
3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclobutylmethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclohexyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-styroyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4 dihydros-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-amino-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-chloro-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
3,4-dihydro-1 '-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-allyl group-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1 '-(2-methyl-propyl)-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-ring propionyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines)-1 ' (trans-2-phenyl-methyl cyclopropyl);
3,4-dihydro-1 '-benzyl-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
3,4-dihydro-1 '-(two-right-fluorine diphenyl-methyl)-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3,4-three hydrogen-1-hydroxyl-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3-dihydro-1-hydroxyl-spiral shell-[2H-indenes-2,4 '-piperidines];
1 '-(cyclopropyl methyl)-8,9-dihydro spiral shell [6H-benzocyclohepta alkene-6,4 '-piperidines]-5 (7H)-ketone;
1 '-cyclopropyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
6-chloro-1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6-fluoro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6,7-dimethoxy-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(1-cyclopropyl-1-ethyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(3-amylene)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-phenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene--2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclohexyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(2-styroyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclobutylmethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclohexyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(2-styroyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines; With
6-chloro-1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines.
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
7. the compound of a group of forming by following compounds:
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5,7-dimethyl-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-7-nitro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-amino-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-7-chloro-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl methyl isophthalic acid, 3,4-three hydrogen-1-hydroxyl-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl isophthalic acid, 3-hydrogen-1-oxo spiral shell [2H-indenes-2,4 '-piperidines];
1 '-(cyclopropyl methyl)-8,9-dihydro spiral shell [6H-benzocyclohepta alkene-6,4 '-piperidines]-5 (7H)-ketone;
1 '-cyclopropyl methyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
6-chloro-1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6-fluoro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-cyclopropyl methyl-3,4-dihydro-6,7-dimethoxy-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(1-cyclopropyl-1-ethyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines);
1 '-(3-amylene)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1 H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cinnamyl-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-4-methyl isophthalic acid-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
6-chloro-1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines; With
6-chloro-1 '-(3,3 ' diphenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines.
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines]
8. the compound of a group of forming by following compounds:
1 '-cyclopropyl methyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cyclopropyl ethyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-cinnamyl-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3, the 3-diphenyl propyl)-3,4-dihydro-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(cyclopropyl methyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines];
1 '-(3-phenyl propyl)-3,4-dihydro-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-5-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclobutylmethyl-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-(3-phenyl propyl)-3,4-dihydro-6-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
1 '-cyclopropyl ethyl-3,4-dihydro-7-methoxyl group-1-oxo spiral shell (naphthalene-2 (1H), 4 '-piperidines;
3,4-dihydro-6-methoxyl group-1-oxo spiral shell [naphthalene-2 (1H), 4 '-piperidines].
9. one kind comprises compound any among the claim 1-8 and is used for the pharmaceutical composition of the pharmaceutically acceptable carrier of blended, diluent or carrier with it.
10. one kind is used for the treatment of the mammiferous method of suffering from pain and needs treatment, and this method comprises the step of compound any among the claim 1-8 that gives significant quantity.
11. the method according to claim 10, wherein said pain is neuropathic pain.
12. the method according to claim 10, wherein said pain is diabetic neuropathy.
13. one kind is used for the treatment of the mammiferous method of suffering from the epileptic seizures disease, this method comprises the step of compound any among the claim 1-8 that gives significant quantity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13786899P | 1999-06-07 | 1999-06-07 | |
| US60/137,868 | 1999-06-07 |
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| Publication Number | Publication Date |
|---|---|
| CN1635998A true CN1635998A (en) | 2005-07-06 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA008086427A Pending CN1635998A (en) | 1999-06-07 | 2000-06-07 | Tricyclic analgesics |
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| Country | Link |
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| EP (1) | EP1235808A2 (en) |
| JP (1) | JP2003513006A (en) |
| KR (1) | KR20020010923A (en) |
| CN (1) | CN1635998A (en) |
| AP (1) | AP2001002356A0 (en) |
| AU (1) | AU6428400A (en) |
| BG (1) | BG106162A (en) |
| BR (1) | BR0011427A (en) |
| CA (1) | CA2376076A1 (en) |
| EA (1) | EA200101117A1 (en) |
| HR (1) | HRP20010913A2 (en) |
| HU (1) | HUP0203317A2 (en) |
| IL (1) | IL146755A0 (en) |
| IS (1) | IS6175A (en) |
| MA (1) | MA26795A1 (en) |
| MX (1) | MXPA01012694A (en) |
| NO (1) | NO20015966L (en) |
| PL (1) | PL357340A1 (en) |
| SK (1) | SK17512001A3 (en) |
| TR (1) | TR200103531T2 (en) |
| WO (1) | WO2000075116A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103403004A (en) * | 2011-02-02 | 2013-11-20 | 沃泰克斯药物股份有限公司 | Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045449A1 (en) * | 2001-08-15 | 2003-03-06 | Pfizer, Inc. | Pharmaceutical combinations for the treatment of neurodegenerative diseases |
| FR2915099B1 (en) * | 2007-04-19 | 2009-06-05 | Sanofi Aventis Sa | USE OF 4-CYCLOPROPYLMETHOXY-N- (3,5-DICHLORO-1-OXYDO-PYRIDIN-4-YL) -5- (METHOXY) PYRIDINE-2-CARBOXAMIDE FOR THE TREATMENT OF CRANIAL TRAUMATISM |
| GB201416346D0 (en) * | 2014-09-16 | 2014-10-29 | Shire Internat Gmbh | Spirocyclic derivatives |
| CN115872873A (en) * | 2022-12-29 | 2023-03-31 | 上海泰坦科技股份有限公司 | Recrystallization purification method of bis (2-bromoethyl) amine hydrobromide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8917069D0 (en) * | 1989-07-26 | 1989-09-13 | Merck Sharp & Dohme | Therapeutic agents |
| IL96507A0 (en) * | 1989-12-08 | 1991-08-16 | Merck & Co Inc | Nitrogen-containing spirocycles and pharmaceutical compositions containing them |
| DK0681571T3 (en) * | 1993-01-28 | 1998-11-23 | Merck & Co Inc | Spiro-substituted azacyclic compounds as tachykinin receptor antagonists |
| US5439914A (en) * | 1994-02-18 | 1995-08-08 | Merck & Co., Inc. | Spirocycles |
| WO1998025604A1 (en) * | 1996-12-13 | 1998-06-18 | Merck & Co., Inc. | Spiro-substituted azacycles as modulators of chemokine receptor activity |
| US6013644A (en) * | 1997-12-12 | 2000-01-11 | Merck & Co., Inc. | Spiro-substituted azacycles as modulators of chemokine receptor activity |
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2000
- 2000-06-07 IL IL14675500A patent/IL146755A0/en unknown
- 2000-06-07 CA CA002376076A patent/CA2376076A1/en not_active Abandoned
- 2000-06-07 WO PCT/EP2000/005783 patent/WO2000075116A2/en not_active Application Discontinuation
- 2000-06-07 JP JP2001501597A patent/JP2003513006A/en active Pending
- 2000-06-07 HU HU0203317A patent/HUP0203317A2/en unknown
- 2000-06-07 SK SK1751-2001A patent/SK17512001A3/en unknown
- 2000-06-07 EP EP00951290A patent/EP1235808A2/en not_active Withdrawn
- 2000-06-07 AU AU64284/00A patent/AU6428400A/en not_active Abandoned
- 2000-06-07 AP APAP/P/2001/002356A patent/AP2001002356A0/en unknown
- 2000-06-07 KR KR1020017015730A patent/KR20020010923A/en not_active Application Discontinuation
- 2000-06-07 BR BR0011427-8A patent/BR0011427A/en not_active IP Right Cessation
- 2000-06-07 PL PL00357340A patent/PL357340A1/en not_active Application Discontinuation
- 2000-06-07 MX MXPA01012694A patent/MXPA01012694A/en unknown
- 2000-06-07 CN CNA008086427A patent/CN1635998A/en active Pending
- 2000-06-07 TR TR2001/03531T patent/TR200103531T2/en unknown
- 2000-06-07 EA EA200101117A patent/EA200101117A1/en unknown
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- 2001-11-23 IS IS6175A patent/IS6175A/en unknown
- 2001-11-30 BG BG106162A patent/BG106162A/en unknown
- 2001-11-30 MA MA26431A patent/MA26795A1/en unknown
- 2001-12-06 NO NO20015966A patent/NO20015966L/en not_active Application Discontinuation
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103403004A (en) * | 2011-02-02 | 2013-11-20 | 沃泰克斯药物股份有限公司 | Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels |
| CN103403004B (en) * | 2011-02-02 | 2016-06-01 | 沃泰克斯药物股份有限公司 | As the Pyrrolopyrazine-spirocyclic piperidine acid amides of ion channel modulators |
| CN106008504A (en) * | 2011-02-02 | 2016-10-12 | 沃泰克斯药物股份有限公司 | Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels |
Also Published As
| Publication number | Publication date |
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| IS6175A (en) | 2001-11-23 |
| WO2000075116A2 (en) | 2000-12-14 |
| MA26795A1 (en) | 2004-12-20 |
| CA2376076A1 (en) | 2000-12-14 |
| HRP20010913A2 (en) | 2003-04-30 |
| AU6428400A (en) | 2000-12-28 |
| AP2001002356A0 (en) | 2001-12-31 |
| MXPA01012694A (en) | 2003-10-15 |
| HUP0203317A2 (en) | 2003-02-28 |
| NO20015966D0 (en) | 2001-12-06 |
| NO20015966L (en) | 2001-12-06 |
| TR200103531T2 (en) | 2002-06-21 |
| BR0011427A (en) | 2002-03-26 |
| JP2003513006A (en) | 2003-04-08 |
| EA200101117A1 (en) | 2002-06-27 |
| KR20020010923A (en) | 2002-02-06 |
| BG106162A (en) | 2002-05-31 |
| SK17512001A3 (en) | 2002-11-06 |
| WO2000075116A3 (en) | 2002-07-04 |
| PL357340A1 (en) | 2004-07-26 |
| EP1235808A2 (en) | 2002-09-04 |
| IL146755A0 (en) | 2002-07-25 |
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