CN102131790A - Novel phenolic and catecholic amines and prodrugs thereof - Google Patents
Novel phenolic and catecholic amines and prodrugs thereof Download PDFInfo
- Publication number
- CN102131790A CN102131790A CN200980133807XA CN200980133807A CN102131790A CN 102131790 A CN102131790 A CN 102131790A CN 200980133807X A CN200980133807X A CN 200980133807XA CN 200980133807 A CN200980133807 A CN 200980133807A CN 102131790 A CN102131790 A CN 102131790A
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- naphtho
- piperazine
- compound
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC1OC(Cc2c3OCOc3ccc2C2)C2*(*)C1 Chemical compound CC1OC(Cc2c3OCOc3ccc2C2)C2*(*)C1 0.000 description 11
- KSKBWQQTIDXDSS-OJHOYRSXSA-N C/C=C\C=C(\C[C@@H]12)/C(CO)=CC1OCCN2C=C=C Chemical compound C/C=C\C=C(\C[C@@H]12)/C(CO)=CC1OCCN2C=C=C KSKBWQQTIDXDSS-OJHOYRSXSA-N 0.000 description 1
- AQCDKWSWCPPOGH-UHFFFAOYSA-N C=CC(CC(C=C)O)CC1Cc2ccc3OCOc3c2CC1 Chemical compound C=CC(CC(C=C)O)CC1Cc2ccc3OCOc3c2CC1 AQCDKWSWCPPOGH-UHFFFAOYSA-N 0.000 description 1
- QLKPRKDKJGAABJ-PZORYLMUSA-N CC(C)(C)OC(N[C@H](Cc1c(C2)c(OC)ccc1)C2O)=O Chemical compound CC(C)(C)OC(N[C@H](Cc1c(C2)c(OC)ccc1)C2O)=O QLKPRKDKJGAABJ-PZORYLMUSA-N 0.000 description 1
- BAYNYPRASVIHDW-DYESRHJHSA-N CCCN(C[C@H](C[n]1nccc1)[O]([C@@H]1C2)#C)C1=Cc1c2c(OC)ccc1 Chemical compound CCCN(C[C@H](C[n]1nccc1)[O]([C@@H]1C2)#C)C1=Cc1c2c(OC)ccc1 BAYNYPRASVIHDW-DYESRHJHSA-N 0.000 description 1
- FXDZJDBJFDAFKP-SZVBFZGTSA-N CCCN(C[C@H](C[n]1ncnc1)O)[C@H](C1)[C@H](C)Cc2c1cccc2OC Chemical compound CCCN(C[C@H](C[n]1ncnc1)O)[C@H](C1)[C@H](C)Cc2c1cccc2OC FXDZJDBJFDAFKP-SZVBFZGTSA-N 0.000 description 1
- QOQUSKNLFACPNO-MRCUYLHHSA-N CCCN1[C@H](C)[C@@H](Cc(c(C)ccc2)c2OC)O[C@H](C[n](cc2)nc2-c2ccccc2)C1 Chemical compound CCCN1[C@H](C)[C@@H](Cc(c(C)ccc2)c2OC)O[C@H](C[n](cc2)nc2-c2ccccc2)C1 QOQUSKNLFACPNO-MRCUYLHHSA-N 0.000 description 1
- IRDVUBIIDODAJH-FRFSOERESA-N CCCN1[C@H](Cc2c(C3)c(OC)ccc2)[C@@H]3O[C@@H](CO)C1 Chemical compound CCCN1[C@H](Cc2c(C3)c(OC)ccc2)[C@@H]3O[C@@H](CO)C1 IRDVUBIIDODAJH-FRFSOERESA-N 0.000 description 1
- KDJBZCDQLOZHFD-ZKYQVNSYSA-N COc1c(C[C@H]2O[C@H](CO)CN[C@@H]2C2)c2ccc1 Chemical compound COc1c(C[C@H]2O[C@H](CO)CN[C@@H]2C2)c2ccc1 KDJBZCDQLOZHFD-ZKYQVNSYSA-N 0.000 description 1
- PNTJEDOPDLAXFJ-UHFFFAOYSA-N COc1cccc(CC2N)c1CC2O Chemical compound COc1cccc(CC2N)c1CC2O PNTJEDOPDLAXFJ-UHFFFAOYSA-N 0.000 description 1
- PNTJEDOPDLAXFJ-YHMJZVADSA-N COc1cccc(C[C@H]2N)c1CC2O Chemical compound COc1cccc(C[C@H]2N)c1CC2O PNTJEDOPDLAXFJ-YHMJZVADSA-N 0.000 description 1
- WWAZVPMMUTVWMG-RDJZCZTQSA-N COc1cccc2c1C[C@@H]1OCCN(CC3CC3)[C@H]1C2 Chemical compound COc1cccc2c1C[C@@H]1OCCN(CC3CC3)[C@H]1C2 WWAZVPMMUTVWMG-RDJZCZTQSA-N 0.000 description 1
- RRMVJAIXDIXHPN-AAEUAGOBSA-N COc1cccc2c1C[C@@H]1OCCN[C@H]1C2 Chemical compound COc1cccc2c1C[C@@H]1OCCN[C@H]1C2 RRMVJAIXDIXHPN-AAEUAGOBSA-N 0.000 description 1
- KDJBZCDQLOZHFD-MPKXVKKWSA-N COc1cccc2c1C[C@H]1O[C@@H](CO)CN[C@@H]1C2 Chemical compound COc1cccc2c1C[C@H]1O[C@@H](CO)CN[C@@H]1C2 KDJBZCDQLOZHFD-MPKXVKKWSA-N 0.000 description 1
- KBZGDKJNTQRXGO-FBBABVLZSA-N COc1cccc2c1C[C@H]1O[C@H](CO)CN(Cc3ccccc3)[C@@H]1C2 Chemical compound COc1cccc2c1C[C@H]1O[C@H](CO)CN(Cc3ccccc3)[C@@H]1C2 KBZGDKJNTQRXGO-FBBABVLZSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to novel phenolic and catecholic amines of Formula 1, to processes for their preparation, pharmaceutical compositions containing them, to their use in therapy and to their use in radiolabeled form as PET or SPECT ligands.
Description
Invention field
The present invention relates to New Phenol type and catechol type amine and form their prodrug derivant in vivo; The method for preparing them; The pharmaceutical composition and their purposes in treatment that comprise them.
Background of invention
Along with aging population, it is more general that neurodegenerative disease becomes.A kind of concrete neurodegenerative disease is Parkinson's disease (PD), and it is usually in the morbidity of the age in 50-80 year.PD is an encephalopathy, it is characterized in that trembling and walking, motion and difficult coordination.
What Parkinson's disease seemingly contained dopamine neuron in the SNc by brain carries out that sexual involution causes.Dopamine HCL (DA) is chemical neurotransmitter, and it is used for transmitting impulsion by brain cell and controls or regulate muscular movement on every side.The disappearance that contains dopamine neuron causes the minimizing of available Dopamine HCL amount in the body.This process is considered to disturb the neurocyte function, so that impulsion can not correctly be transmitted, causes the disappearance of muscle control and function.
The method of still not knowing to cure PD at present.Treatment at control PD symptom, mainly is metabolized to the L-DOPA of Dopamine HCL or stimulates the chemical agent of Dopamine Receptors to substitute Dopamine HCL by using usually.These acceptors are divided into two big classes (D1-type and D2-receptor).The former is divided into D1 and D5 acceptor, and the D2 receptor family is made up of D2, D3 and D4 acceptor.
All main method that are used for the treatment of PD are recovered the DA tensity of losing owing to carrying out property midbrain dopaminergic nerve sexual involution.L-DOPA is inexpensive and effective medicine, causes dyskinesia and other reaction fluctuations (response fluctuations) but have relatively poor PK curve.D optionally
2-agonist (for example pramipexole) produces less dyskinesia, is the line medicine of preferred treatment PD.
The phenyl-ethyl amine of known some hydroxylation (phenols or pyrocatechol) (former state or form the part of semi-rigid/rigidity ring system) has useful dopaminergic activity at least in animal model.But their clinical use is restricted, and reason is that they have low or do not have oral administration biaavailability.Clinical use Apomorphine [for clinical trial, for example seeing: Manson etc., Brain 124,331 (2001) and Neef and van Laar, Clin.Pharmacokinet, 37,257 (1999)].Carrying out several alternative clinical studyes of passing regimen of Apomorphine, for example using in the nose and sublingual formulation; But these effort do not become the selection [summary is seen: Stacy and Factor (editor) Neurology, 62 (supplementary issues 4), S1 (2004) and Neef and van Laar, Clin.Pharmacokinet., 37,257 (1999)] of the clinical treatment of PD as yet.
The DA receptor stimulant can activate DA autoreceptor and postsynaptic DA receptor.For example when Apomorphine gave with low dosage, the effect that autoreceptor stimulates was preponderated, but when higher dosage, the enhancement that stimulates by postsynaptic receptor is preponderated weakening of DA transmission.For example for example during Apomorphine, anti-anxiety and anti-dyskinesia effect might be because the autoreceptor-stimulant character of this DA receptor stimulant to the low dosage administration of human.This health general knowledge show nervus centralis DA autoreceptor is had the DA receptor stimulators of high selectivity will be useful in the mental disorder in treatment.
Dopaminergic turnover increase comprises geriatric disease and bradykinesia to its useful disease.The DA receptor stimulators can be to depressive patient effectively and can be used as fenisorex and be used for the treatment of obesity.The DA receptor stimulators can improve MBD (MBD), hypnolepsy and schizoid passive paresthesia and cognitive symptom.Restless leg syndrome and Periodic limb movement disorder carry out the indication [discussion is seen: Lesage and Hening, Seminars in Neurology, 24,249 (2004)] of clinical treatment for other with the DA-agonist.In addition, impotence and erective dysfunction also can by improve with the DA-agonist treatment (to women and the male sex all can).In this article, it should be noted that when the hypogloeeis gives Apomorphine that it is used to improve male erectile dysfunction clinically.
In Huntington Chorea, use the clinical study [trinucleotide by the 5 ' expansion of holding that is positioned at the 1T15 gene repeats the neurodegenerative disease that (CAG) causes] of L-DOPA and the treatment of D2 agonist pramipexole to show promising result; Therefore treat another potential use that Huntington Chorea is a The compounds of this invention.Also can treat by other neurodegenerative diseases that the CAG trinucleotide of expanding repeats to cause by The compounds of this invention.
DA participates in the adjusting of cardiovascular and kidney system, so renal failure and hypertension can be considered to other indications of The compounds of this invention.
In addition, in the treatment hyperprolactinemia, use the DA receptor stimulant to reduce the amount [nearest summary is seen: Chanson, P. etc., Annales d ' Endocrinologie 68 (2-3), 113 (2007)] of prolactin in the blood.An example of these DA receptor stimulants is selective d 2 agonist quinagolide (Norprolac
).Therefore, hyperprolactinemia also can be considered as other indications of The compounds of this invention.
Summary of the invention
A target of the present invention be provided as dopamine receptor ligands can itself be metabolized to free phenol type in vivo or its corresponding alkoxyl group, acyloxy and the methylene-dioxy derivative form of catechol type amine as the New Phenol type or the catechol type amine of medicine.
Therefore, relate to formula I compound in one aspect of the invention:
Wherein
● X does not exist or is oxygen
Zero when X is oxygen, R
1And R
2Be independently selected from hydrogen; C
1-C
6Alkyloyl; C
6-C
10Aryl-C
1-C
6Alkyloyl such as phenyl acetyl or benzoyl; Or R
1With R
2Condense and form methylene radical (CH
2).
Zero when X does not exist, R
1Be selected from hydrogen; C
1-C
6Alkyl; C
1-C
6Alkyloyl; C
6-C
10Aryl-C
1-C
6Alkyloyl such as phenyl acetyl or benzoyl; And R
2Be hydrogen.
● R
3Be selected from hydrogen; C
1-C
4Alkyl such as methyl, ethyl, n-propyl, cyclopropyl-methyl, allyl group or propargyl; C
3-C
4Cycloalkyl such as cyclopropyl and cyclobutyl; Hydroxyalkyl such as hydroxyethyl; C
2-C
3Fluoroalkyl such as 3-fluoro-n-propyl and 2-fluoro ethyl,
● R
4Be selected from hydrogen; C
1-C
6Alkyl such as methyl; C
6-C
10Aryl-C
1-C
6Alkyl such as benzyl; Heteroaryl-C
1-C
6Alkyl such as 1-imidazolyl-methyl; Two (C
1-C
6Alkyl) amino-C
1-C
6Alkyl such as dimethylamino methyl; C
1-C
6Alkylthio-C
1-C
6Alkyl such as methylthiomethyl; C
1-C
6Hydroxyalkyl such as methylol; And C
1-C
6Haloalkyl such as methyl fluoride, wherein each C
6-C
10Aryl and heteroaryl can be selected from halogen such as fluorine, bromine or chlorine; C
1-C
6Alkyl such as methyl; C
1-C
6Alkoxyl group such as methoxyl group; Or the replacement of the substituting group of phenyl,
With its enantiomer, diastereomer, tautomer and pharmaceutically acceptable addition salt, with and polymorphic forms.
In a special embodiment, the present invention relates to the formula I compound of pure basically single enantiomer or single diastereomeric form.
In another special embodiment, the present invention relates to the formula I compound of enantiomeric mixture, non-enantiomer mixture or pure basically polymorphic forms.
In a special embodiment, the present invention relates to have the trans formula I compound that condenses ring system.
In another embodiment of the present invention, R
1With R
2Be hydrogen and X, R
3And R
4As above definition.
In another embodiment of the present invention, R
1With R
2Condense and form methylene radical (CH
2), X, R
3And R
4As above definition.
In another embodiment of the present invention, R
1And R
2In at least one is C
1-C
6Alkyloyl, phenyl acetyl or benzoyl, X, R
3And R
4As above definition.
In another embodiment of the present invention, R
1Be hydrogen and X, R
2, R
3And R
4As above definition.
In another embodiment of the present invention, R
1Be C
1-C
6Alkyloyl, phenyl acetyl or benzoyl, X, R
2, R
3And R
4As above definition.
In an independent embodiment of the present invention, R
4Be hydrogen, X, R
1, R
2, R
3As above definition.
In an independent embodiment of the present invention, R
4Be not hydrogen, X, R
1, R
2, R
3As above definition.
In an independent embodiment of the present invention, R
3Be C
1-C
4Alkyl, as methyl, ethyl or n-propyl, X, R
1, R
2And R
4As above definition.
In an independent embodiment of the present invention, X is an oxygen, R
1, R
2, R
3And R
4As above definition.
In another embodiment of the present invention, X does not exist, R
1, R
2, R
3And R
4As above definition.
In an independent embodiment of the present invention, R
4Be heteroaryl-C
1-C
6Alkyl, wherein said heteroaryl are the pyrazoles of pyrazoles or replacement.In yet another embodiment of the present invention, R
4Be heteroaryl-C
1-C
6Alkyl, wherein said heteroaryl are imidazoles.In another embodiment of the present invention, R
4Be heteroaryl-C
1-C
6Alkyl, wherein said heteroaryl are 1,2, the 4-triazole.
In an independent embodiment of the present invention, formula I compound is the form of pure basically enantiomer.In another embodiment, formula I compound is the form of pure basically diastereomer.
In an independent embodiment of the present invention, R
4Be hydrogen, formula I compound be pure basically (4aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be hydrogen, formula I compound be pure basically (4aS, 10aS)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, formula I compound be pure basically (2R, 4aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, formula I compound be pure basically (2S, 4aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, formula I compound be pure basically (2R, 4aS, 10aS)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, formula I compound be pure basically (2S, 4aS, 10aS)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be hydrogen, R
1With R
2Condense and form methylene radical (CH
2), formula I compound be pure basically (6aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be hydrogen, R
1With R
2Condense and form methylene radical (CH
2), and formula I compound be pure basically (6aS, 10aS)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, R
1With R
2Condense and form methylene radical (CH
2), formula I compound be pure basically (2R, 6aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, R
1With R
2Condense and form methylene radical (CH
2), formula I compound be pure basically (2R, 6aS, 10aS)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, R
1With R
2Condense and form methylene radical (CH
2), formula I compound be pure basically (2S, 6aR, 10aR)-form of enantiomer.
In an independent embodiment of the present invention, R
4Be not hydrogen, R
1With R
2Condense and form methylene radical (CH
2), formula I compound be pure basically (2S, 6aS, 10aS)-form of enantiomer.
In the further embodiment of the present invention, formula I compound is selected from following particular compound, no matter is with its free alkali, tautomeric forms or its pharmaceutically-acceptable acid addition form.Each compound has constituted each embodiment of the present invention:
1) (4aR, 10aR)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
2) (4aS, 10aS)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
3) (4aR, 10aR)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
4) (4aS, 10aS)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
5) (4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
6) (4aS, 10aS)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
7) (4aR, 10aR)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
8) (4aS, 10aS)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
9) (4aR, 10aR)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
10) (4aS, 10aS)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
11) (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
12) (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
13) (2S, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
14) (2R, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
15) (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
16) (2R, 4aR, 10aR)-and 9-methoxyl group-2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
17) ((2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-ylmethyl)-dimethyl amine;
18) (2R, 4aR, 10aR)-and 2-methyl fluoride-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
19) (2S, 4aR, 10aR)-and 9-methoxyl group-2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
20) (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
21) (2S, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
22) (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
23) (2R, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
24) (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
25) (2S, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
26) (2R, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
27) (2S, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
28) (4aR, 10aR)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
29) (4aS, 10aS)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
30) (4aR, 10aR)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
31) (4aS, 10aS)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
32) (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
33) (4aS, 10aS)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
34) (4aR, 10aR)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
35) (4aS, 10aS)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
36) (4aR, 10aR)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
37) (4aS, 10aS)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
38) (2R, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
39) (2S, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
40) (2S, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
41) (2R, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
42) (2S, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
43) (2R, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
44) (2S, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
45) (2R, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
46) (2S, 4aR, 10aR)-and 2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
47) (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
48) (2R, 4aR, 10aR)-and 2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
49) (2S, 4aR, 10aR)-and 2-dimethylamino methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
50) (2R, 4aR, 10aR)-and 2-methyl fluoride-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
51) (2R, 4aR, 10aR)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
52) (2S, 4aS, 10aS)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
53) (2S, 4aR, 10aR)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
54) (2R, 4aS, 10aS)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
55) (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
56) (2S, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
57) (2R, 4aR, 10aR)-and 2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
58) (2S, 4aR, 10aR)-and 2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
59) (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-8, the 9-glycol;
60) (6aR, 10aR)-7-methyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene;
61) (6aR, 10aR)-7-ethyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene; With
62) (6aR, 10aR)-7-n-propyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene.
In another aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition purposes as medicine.
Formula I compound, with free alkali, or with pharmaceutically-acceptable acid addition, or with the form of its pharmaceutical composition, can give in any suitable manner, in for example oral, the cheek, hypogloeeis, non-oral or parenteral, and the suitable form that described compound can anyly be used for these administering modes exists, for example with the orally give of tablet, capsule, powder, syrup, solution or dispersion agent form, for for example giving through the non-orally give of skin patch form or with the form parenteral of injection dispersion or solution.In one embodiment, formula I compound gives with the solid pharmaceutical entity form that is suitably tablet or capsule.
Formula I compound and various organic and mineral acid formation pharmaceutically-acceptable acid addition.These salt also constitute each side of the present invention.
As well known in the art, the pharmaceutically-acceptable acid addition of formula I compound is formed by pharmaceutically acceptable acid.These salt comprise Journal of Pharmaceutical Science, 66, and pharmacy acceptable salt listed among the 2-19 (1977) is also known by the technician.The mineral acid that is used to form these salt comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid, diphosphanetetroic acid, metaphosphoric acid, tetra-sodium etc.Also can use by mineral acid (paraffinic acid, hydroxyl alkane acid and hydroxyl chain docosandioic acid, aromatic acid, aliphatics and the aromatic sulphonic acid of single and dicarboxylic acid, phenyl replacement) deutero-salt as aliphatics.Therefore these pharmacy acceptable salts comprise muriate, bromide, iodide, nitrate, acetate, phenylacetic acid salt, trifluoroacetate, acrylate, ascorbate salt, benzoate, chloro benzoate, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, tolyl acid salt, acetoxybenzoic acid salt, isobutyrate, phenylbutyric acid salt, the Alpha-hydroxy butyrates, butine-1, the 4-diformate, hexin-1, the 4-dioctyl phthalate, caprate, octylate, cinnamate, Citrate trianion, formate, fumarate, glycollate, enanthate, hippurate, lactic acid salt, malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, Yi Yansuan salt, oxalate, phthalate, the terephthalic acid speech, propiolate, propionic salt, phenylpropionic acid salt, salicylate, sebacate, succinate, suberate, benzene sulfonate, p-bromobenzenesulfonate, closilate, ethyl sulfonate, the 2-isethionate, metilsulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, naphthalene-1,5-sulfonate, tosilate, xylenesulfonate, tartrate etc.
The method for preparing solid composite medicament is also well-known for this area.Therefore can be by with activeconstituents and common auxiliary material, weighting agent and mixing diluents, subsequently this mixture compressing tablet in conventional tabletting machine be prepared tablet.The example of auxiliary material, weighting agent and thinner comprises Microcrystalline Cellulose, W-Gum, yam starch, lactose, N.F,USP MANNITOL, sorbyl alcohol, talcum powder, Magnesium Stearate, gelatin, lactose, natural gum etc.Also can use any other auxiliary material or additive such as tinting material, perfume compound, sanitas etc., condition is they and activeconstituents compatibility.
Particularly, tablet composition of the present invention can be by preparing with the auxiliary material of routine or the formula I compound direct compression of mixing diluents.Perhaps, the wet granular or the melt particle of the formula I compound of optional and conventional auxiliary material or mixing diluents can be used for compressed tablets.
The formula I compound solution that is used for injecting can be by being dissolved in the part solvent for injection with activeconstituents and possible additive, and preferred sterilized water, regulator solution be to volume required, with solution sterilization and can in suitable ampoule or bottle.Can add the conventional any suitable additive that uses in this area, as tonicity agent (tonicity agent), sanitas, antioxidant, solubilizing agent etc.Perhaps, can be with active ingredient, for example with free alkali form, be dissolved in and can digest or indigestion oil, in its mixture or the analogue, prepare and can prolong the activeconstituents storage storehouse formula intramuscular composition of time of releasing.
Being used for applied dermally comprises the osmotically active agent and promotes activeconstituents to pass skin as choosing wantonly through the pharmaceutical composition of the formula I of skin patch compound.
In a particular of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition comprises the formula I compound for the treatment of significant quantity (X=oxygen wherein, R
1With R
2Condense and form methylene radical (CH
2), R
4As above define) and pharmaceutically acceptable carrier or thinner.
In another embodiment of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition comprises the formula I compound for the treatment of significant quantity (X=oxygen wherein, R
1And R
2Be C
1-C
6Alkyloyl or aryl-C
1-C
6Alkyloyl such as phenylacetyl or benzoyl, R
4As above define) and pharmaceutically acceptable carrier or thinner.
In another embodiment of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition comprises the formula I compound for the treatment of significant quantity (X=oxygen wherein, R
1And R
2Be hydrogen and R
4As above define) and pharmaceutically acceptable carrier or thinner.
In another embodiment of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition comprises the formula I compound for the treatment of significant quantity, and (wherein X does not exist, R
1Be selected from hydrogen; C
1-C
6Alkyl, C
1-C
6Alkyloyl and aryl-C
1-C
6Alkyloyl such as phenylacetyl or benzoyl; R
2Be hydrogen) and pharmaceutically acceptable carrier or thinner.
In another particular of the present invention, provide be used for non-oral administration (as in skin, nose, cheek, outside the intramuscular, gi tract or subcutaneous administration) pharmaceutical composition, described pharmaceutical composition comprises formula I compound and the pharmaceutically acceptable carrier or the thinner for the treatment of significant quantity.
In a particular of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition comprises formula I compound and the pharmaceutically acceptable carrier or the thinner for the treatment of significant quantity, and its Chinese style I compound is the form of pure basically diastereomer or pure basically enantiomer.
In another aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of purposes in the medicine of neurodegenerative disease (as Parkinson's disease and Huntington Chorea) in preparation.
In another aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of purposes in psychosis, impotence, renal failure, heart failure, hyperprolactinemia or the hypertensive medicine in preparation.
In another aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of purposes in the medicine of cognitive impairment that Mammals suffers from preparation.In a particular, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of purposes in the medicine of the cognitive impairment relevant: schizophrenia, Parkinson's disease, dull-witted as AIDS dementia, anxiety disorder, relevant memory defects, dysthymia disorders, alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) of age with being selected from following obstacle or disease in preparation.
More on the one hand in, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of purposes in the medicine of restless leg syndrome (RLS) or Periodic limb movement disorder (PLMD) in preparation.
In a different aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition preparation be used for the treatment of dyskinesia that Mammals suffers from, motion can not, purposes in the medicine of gait disorder or intention tremor.
In another aspect, the invention provides the purposes that formula I compound or its pharmaceutically-acceptable acid addition are used for the treatment of neurodegenerative disease such as Parkinson's disease and Huntington Chorea.
In another aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be used for the treatment of psychosis, impotence, renal failure, heart failure, hyperprolactinemia or hypertensive purposes.
In another aspect, the invention provides the purposes that formula I compound or its pharmaceutically-acceptable acid addition are used for the treatment of cognitive impairment that Mammals suffers from.In a particular, the invention provides the purposes that formula I compound or its pharmaceutically-acceptable acid addition are used for the treatment of the cognitive impairment relevant with being selected from following obstacle or disease: schizophrenia, Parkinson's disease, dull-witted as AIDS dementia, anxiety disorder, relevant memory defects, dysthymia disorders, alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) of age.
In aspect another, the invention provides the purposes that formula I compound or its pharmaceutically-acceptable acid addition are used for the treatment of restless leg syndrome (RLS) or Periodic limb movement disorder (PLMD).
In other aspect, the invention provides formula I compound or its pharmaceutically-acceptable acid addition be used for the treatment of dyskinesia that Mammals suffers from, motion can not, the purposes of gait disorder or intention tremor.
In aspect independent, the invention provides formula I compound or its pharmaceutically-acceptable acid addition and be intended to oral administration or be used for the purposes of the medicine of non-oral administration in preparation.
The present invention also provides the method for a kind of treatment neurodegenerative disease that Mammals suffers from (as Parkinson's disease and Huntington Chorea), and described method comprises formula I compound or its pharmaceutically-acceptable acid addition that gives Mammals treatment significant quantity.
In another aspect, the present invention provides also that a kind of treatment Mammals is mentally ill, impotence, renal failure, heart failure, hyperprolactinemia or hypertensive method, and described method comprises formula I compound or its pharmaceutically-acceptable acid addition that gives Mammals treatment significant quantity.
In another aspect, the invention provides a kind of method for the treatment of cognitive impairment that Mammals suffers from, described method comprises formula I compound or its pharmaceutically-acceptable acid addition that gives the Mammals significant quantity.
The invention still further relates to the method for a kind of treatment restless leg syndrome that Mammals suffers from (RLS) or Periodic limb movement disorder (PLMD), described method comprises formula I compound or its pharmaceutically-acceptable acid addition that gives Mammals treatment significant quantity.
The invention still further relates to a kind of treat dyskinesia that Mammals suffers from, motion can not, the method for gait disorder or intention tremor, described method comprises formula I compound or its pharmaceutically-acceptable acid addition that gives Mammals treatment significant quantity.
In a particular of the present invention, Mammals is the human experimenter.
The treatment significant quantity of formula I compound is calculated with the per daily dose of formula (I) compound of free alkali form, is suitably 0.01-125mg/ days, is 0.05-100mg/ days, for example preferably at 0.1-50mg/ days preferablyly.
In a specific embodiment, the per daily dose of formula I compound is between 1-10mg/ days.
In another embodiment, the per daily dose of formula I compound was less than about 1mg/ days.
In an independent embodiment, the per daily dose of formula I compound is about 0.1mg/ days.
In further embodiment, the invention provides oral compositions, described composition comprises 0.001mg to 125mg formula I compound.
In further embodiment, the invention provides oral compositions, described composition comprises 0.001mg to 0.1mg formula I compound.
In further embodiment, the invention provides oral compositions, described composition comprises 0.01mg to 1mg formula I compound.
In further embodiment, the invention provides oral compositions, described composition comprises 0.1mg to 10mg formula I compound.
Summary of drawings
Fig. 1: (+)-(4aS, 10aS)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The crystalline structure of piperazine-9-alcohol hydrochloride (embodiment 5d2).The absolute configuration of measuring by the anomalous scattering of " weight " chlorine atom.
Fig. 2: (2R, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The crystalline structure of piperazine-9-alcohol hydrochloride (embodiment 5j).
Fig. 3: toluene-4-sulfonic acid (2R, 4aS, 10aS)-and 9-methoxyl group-4-propyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The crystalline structure of piperazine-2-base methyl esters (intermediate VB).
Detailed Description Of The Invention
Substituent definition
Term " the C that uses among the present invention1-C
6Alkyl " refer to have 1-6 the carbon atom straight or branched saturated hydrocarbons of (comprising 1 and 6 carbon atom). The example of these groups includes but not limited to methyl, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butene base and n-hexyl.
Term " the C that uses among the present invention1-C
4Alkyl " refer to have 14 carbon atoms straight or branched saturated hydrocarbons of (comprising 1 and 4 carbon atom). The example of these groups includes but not limited to methyl, ethyl, n-pro-pyl, 2-propyl group, 1-butyl and 2-butyl.
Term " C1-C
6Alkanoyl " refer to comprise the straight or branched alkanoyl of 1-6 carbon atom, the example comprises formoxyl, acetyl group, pivaloyl group etc.
Term " C1-C
6Alkoxyl " refer to have 1-6 the carbon atom saturated alkoxyl of straight or branched of (comprising 1 and 6 carbon atom) and open chemical valence be on oxygen. The example of these groups includes but not limited to methoxyl group, ethyoxyl, n-butoxy, 2-methyl-amoxy and just own oxygen base.
Term " C1-C
6Alkylthio group " refer to have 1-6 the carbon atom saturated alkylthio group of straight or branched of (comprising 1 and 6 carbon atom) and open chemical valence be on sulphur. The example of these groups includes but not limited to methyl mercapto and ethylmercapto group.
Term " C6-C
10Aryl " refer to comprise the list of 6-10 ring carbon atom-or polycyclic aromatic group, and the variant of fractional saturation. Typical example, it should not be considered to restrictive, comprises phenyl, indenyl, indanyl, naphthyl and tetralyl.
Term " C6-C
10Aryl-C1-C
6Alkanoyl " refer to and C as defined above6-C
10The as defined above C that aromatic yl group connects1-C
6Alkanoyl. Typical example, it should not be considered to restrictive, comprises benzoyl and phenylacetyl group.
Term " C1-C
6-C
6-C
10Aryl " refer to and C as defined above6-C
10The as defined above C that aromatic yl group connects1-C
6Group.
Term " C1-C
6Alkylthio group-C1-C
6Alkyl " refer to and C as defined above1-C
6The as defined above C that alkyl group connects1-C
6The alkylthio group group. The example of these groups includes but not limited to methylthiomethyl and ethylmercapto group methyl.
Term " heteroaryl " refers to comprise the list of 10 annular atomses at the most-or the variant of polycyclic aromatic group and fractional saturation thereof, wherein 1-4 annular atoms is selected from N, O or S, and all the other atoms are carbon, and the annular atoms that wherein is selected from N, O or S can place one or more rings. Typical example, it should not be considered to restrictive, comprises pyridine radicals, thienyl, furyl, indyl, pyranose, benzofuranyl, benzothienyl, quinoline, isoquinolin, naphthyridines base, EEDQ base, benzopyranyl, sulfo-benzopyranyl, benzoquinoline base and acridinyl.
Term " C1-C
6Alkyl-heteroaryl " refer to and C as defined above1-C
6The as defined above heteroaryl groups that alkyl group connects.
The compounds of this invention is the morpholine of trans-fused, and it contains at least two chiral centres (following usefulness*Mark), while R4Also do not have the 3rd chiral centre (following usefulness for the The compounds of this invention of H
Mark).
Work as R1With R2During uncondensed, the annular atoms of The compounds of this invention numbering is as follows:
Work as R1With R2Condense when forming methylene, the annular atoms of The compounds of this invention numbering is as follows:
The compounds of this invention can 23=8 different enantiomeric forms exist, and wherein the present invention only comprises the morpholine derivative of (R, R) and (S, S) trans-fused, that is:
Discoverable type I function of chemical compound is identical with the apomorphine of Orally active, and this is so that potential Parkinson's and the other diseases/obstacle of being used for the treatment of of this compound, and these diseases advantageously respond the dopaminergic turnover of increase.
In measuring, hepatocyte found that wherein the formula I compound of X=oxygen can be metabolized to common wherein R1And R2Be the catecholamine parent compound of hydrogen:
Concrete metabolic pathway is difference with the replacement form, and does not come to understand fully yet. Therefore for wherein X=oxygen and R1And R2Be ester group such as C1-C
6Alkanoyl and C6-C
10-aryl-C1-C
6The formula I compound of alkanoyl, metabolism means the hydrolysis of ester group. For wherein X=oxygen and R1With R2Condense and form methylene (CH2) the formula I compound of group, the oxidation by methylene group, infer that the step that is hydrolyzed subsequently changes into catecholamine.
A particular of the present invention relates to formula I compound or its pharmaceutically acceptable addition salt is used for the purposes that improvement suffers from the mammal cognition of cognitive impairment illness, and wherein said illness is relevant with schizophrenia. In another embodiment of the present invention, described illness is relevant with Parkinson's. In another embodiment of the present invention, described illness is relevant with dull-witted (such as the AIDS dementia). In another embodiment of the present invention, described illness is relevant with anxiety disorder. In another embodiment of the present invention, the described illness memory defects relevant with the age is relevant. In another embodiment of the present invention, described illness and depression, comprise adult depression, particularly the elderly's depression is relevant. In another embodiment of the present invention, described illness and benzodiazepine *
Use relevant. In another embodiment of the present invention, described illness is relevant with the use of tricyclics. In another embodiment of the present invention, described illness Ahl tribulus sea silent sickness is relevant. In another embodiment of the present invention, described illness is relevant with attention deficit hyperactivity disorder (ADHD). In another embodiment of the present invention, described illness is relevant with post-traumatic stress disorder (PTSD).
In another embodiment, the present invention relates to the purposes that formula I compound or its pharmaceutically acceptable addition salt are used for the treatment of depression that mammal suffers from such as adult's depression, bipolar disorder or anxiety disorder.
The invention still further relates to as the video picture part formula I compound of PET and SPECT part or its precursor particularly. Required radioactive label can (comprise by precursor and the radioactive label reactant that makes PET or SPECT part11The reactant of C-mark as [11C] methyl iodide, [11C] the TFMS methyl esters etc.) react and introduce. This compound is also available3H、
18F or123The I mark. Therefore in a particular of the present invention, provide radiolabeled formula I compound, wherein radioactive label is selected from11C、
3H、
18F or123I。
R wherein1And R2Be the radiolabeled formula I compound of hydrogen especially preferably as radioligand.
In a specific embodiment, the present invention relates to radiolabeled formula I compound, X=oxygen wherein, R1And R2Be hydrogen and R3For 3-(18F)-fluoropropyl or 2-(18F)-fluoro ethyl.
In another specific embodiment, the present invention relates to radiolabeled formula I compound, wherein X is key, R1Be hydrogen and R3Be selected from 3-(18F)-fluoropropyl, 2-(18F)-fluoro ethyl, (11CH
3)-、(
11CH
3CH
2)-or (11CH
3CH
2CH
2)-。
In a preferred embodiment, the present invention relates to radiolabeled formula I compound, X=oxygen wherein, R1And R2Be hydrogen, R3Be n-pro-pyl and R4Comprise and be selected from11C、
3H and18The radioactive label of F. In one embodiment, R4Be selected from 3-(18F)-fluoropropyl, 2-(18F)-fluoro ethyl, (11CH
3)-、(
11CH
3CH
2)-or (11CH
3CH
2CH
2)-。
Further embodiment relates to free alkali or its salt or its pharmaceutical composition of formula I compound and relates to the purposes described in the literary composition, its Chinese style I compound has at least 10%, at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, preferred at least 98% trans-diastereoisomer excessive (trans-diastereoisomer excessive 10% refers to that the ratio of trans in the mixture of referring to-diastereoisomer and cis-diastereoisomer is 55: 45). As used herein, term " cis " be connected trans " relate to exclusively two carbon atom (following usefulness that connect morpholine ring and formula I compound center ring*Mark) configuration:
Of the present invention trans-diastereoisomer always has (R, R) or (S, S) configuration, and cis-diastereoisomer (it is not included in the present invention) has (R, S) or (S, R) configuration.
Further embodiment relates to free alkali or its salt of formula I compound, or its pharmaceutical composition and relate to the purposes described in the literary composition, its Chinese style I compound has at least 10%, at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, preferred at least 98% enantiomter is excessive, and (enantiomter excessive 10% that for example has the formula I compound of (4aR, 10aR) configuration refers to (4aR in the mixture of referring to, 10aR)-enantiomter is 55: 45 with the ratio of (4aS, 10aS)-enantiomter).
In another aspect, the present invention relates to formula I compound, wherein catechol is partly sheltered and is methylene-dioxy (MDO) prodrug derivant, but this derivative in vivo metabolism generate free catecholamine:
Therefore the invention still further relates to formula I compound, X=oxygen wherein, R1With R2Condense and form methylene (CH2) group.
In another aspect of this invention, relate to this type of formula I compound, wherein catechol is partly sheltered and is diester deriv, this derivative also in vivo cracking produce free catecholamine (below illustrate X=oxygen wherein, R1And R2=acetyl group):
The present invention also comprises the asymmetric diester deriv of formula I compound, wherein R1And R2Be two kinds of different substituting groups.
The invention still further relates to basically pure formula I compound trans-diastereoisomer, X=oxygen wherein, R1With R2Condense and form methylene (CH2) group, R3Be selected from hydrogen, methyl, ethyl and n-pro-pyl.
The invention still further relates to basically (6aR, 10aR) enantiomter of pure formula I compound, X=oxygen wherein, R1And R2Condense and form methylene (CH2) group, R3Be selected from hydrogen, methyl, ethyl and n-pro-pyl.
In independent embodiment, the present invention relates to formula I compound, X=oxygen wherein, R3Be selected from hydrogen, methyl, ethyl and n-pro-pyl, R1And R2In at least one is C1-C
6Alkanoyl, or R1And R2In at least one is benzoyl, or R1And R2In at least one is phenylacetyl group.
The invention still further relates to basically pure formula I compound trans-diastereoisomer, X=oxygen wherein, R3Be selected from hydrogen, methyl, ethyl and n-pro-pyl, R1And R2In at least one is C1-C
6Alkanoyl such as pivaloyl group, or R1And R2In at least one is benzoyl, or R1And R2In at least one is phenylacetyl group.
The invention still further relates to (4aR, 10aR) enantiomter of basically pure formula I, X=oxygen wherein, R3Be selected from hydrogen, methyl, ethyl and n-pro-pyl, R1And R2In at least one is C1-C
6Alkanoyl such as pivaloyl group, or R1And R2In at least one is benzoyl, or R1And R2In at least one is phenylacetyl group.
In content of the present invention, for disclosed pharmaceutical use in the literary composition, should be understood that particularly when regulation formula (I) compound was basically pure enantiomter or diastereoisomer, then described compound had relative purity in spatial chemistry. Preferred enantiomter or diastereoisomer is excessive is at least 60%, at least 70%, and preferably at least 80%, at least 90%, at least 96%, or preferably at least 98% (80% enantiomter is excessive to refer to that in the mixture of referring to for example the ratio of (4aR, 10aR) and (4aS, 10aS) is 90: 10).
Universal synthesis method
By known racemization trans-3-azido-8-methoxyl group-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol initial [Nozulak, J.; Vigouret, J.M.; Jaton, A.L.; Hofmann, A.; Dravid, A.R.; Weber, H.P.; Kalkman, H.O.; Walkinshaw, M.D.; J.Med.Chem.1992,35,480-489] (compound 1), and with the azido reduction, obtain accordingly trans-amino alcohol, it is used the chloro-acetyl chloride acidylate. Subsequently cyclization under alkali condition, subsequently reduction of amide and Boc-protection obtains the key compound 6 into pure diastereoisomer. Split compound 6 by chromatogram, deprotection obtains two kinds of enantiomter 6A and 6B subsequently.
The preparation of Markush 1A: 6A is initial by compound, and the The compounds of this invention with (4aR, 10aR) configuration can prepare by several methods. With LAH reducing compound 6A, produce Markush 1A, wherein R3＝CH
3 Perhaps, BOC group usable acid cracking. Subsequently, can prepare Markush 1A, for example use alkyl iodide or alkyl bromide to carry out the N-alkylation. Other method is the acidylate of secondary amine, subsequently with for example LAH reduction. The third method is for using aldehyde, ketone or ketone substitute such as (1-ethyoxyl-cyclopropyl)-oxygen base] the trimethyl silane reduction amination.
The preparation of Markush 2A: the cracking that example is the methoxy group of Markush 1A of preparation Markush 2A. A kind of method of cracking methoxy group is at high temperature by using the L-Selectride in THF. Other method relates at high temperature to be processed with benzenethiol and KF in DMA.
6B is initial by compound, can prepare similarly the The compounds of this invention with (4aS, 10aS) configuration.
Adopt and prepare the described similar method of compound 6A by compound 5 and prepare pure enantiomter compound 7A by compound 2. For example by make the cracking of BOC group with acid, use subsequently the chlorobenzoyl chloride acidylate, with midbody acid amide LAH reduction, compound 7A can be changed into compound 8A subsequently. Compound 8A subsequently by boiling, obtains compound 9A and compound 10A with R-(-)-chloropropylene oxide alkanisation in rare NaOH, it can pass through chromatographic isolation.
The preparation of Markush 4A and Markush 5A:
Markush 3A can [for example be passed through such as the blocking group (Protective Groups in Organic Synthesis) in organic synthesizing by compound 9A preparation; T.W.Greene and P.G.M.Wuts; Wiley Interscience, hydrogenolysis benzyl described in (1991) ISBN 0471623016]. Be used for as previously discussed subsequently Markush 1A and prepare Markush 3A by the compound 11A that obtains. Markush 4A can be by Markush 3A preparation, for example by replacing leaving group with nucleopilic reagent subsequently with the toluene sulfochloride reaction. This nucleopilic reagent can be for example alkoxide, alkyl sulfide alkoxide or amine. Markush 5A can be used the L-Selectride preparation or at high temperature for example use benzenethiol and KF preparation among the DMA as described in Markush 2A by Markush 4A.
Can prepare Markush 6A, Markush 7A and Markush 8A by compound 10A through compound 12A similarly.
7B is initial by compound, can prepare similarly the The compounds of this invention with (4aS, 10aS) configuration.
Markush 3A and 6A, wherein R3=n-pro-pyl (intermediate III A and IIA) also can be prepared by compound 7A as describing in the flow process 3. The propionyl chloride acidylate is used in the acid cleavage of BOC group subsequently, makes subsequently midbody acid amide LAH reduction, preparation compound 14A. Compound 14A boils in rare NaOH subsequently with R-(-)-chloropropylene oxide or with S-(+)-chloropropylene oxide alkylation, obtains the mixture of intermediate II A and IIIA. These two kinds of diastereoisomers can pass through chromatographic isolation.
7B is initial by compound, can prepare similarly the The compounds of this invention with (4aS, 10aS) configuration.
The preparation of Markush 9A and Markush 10A: 6A is initial by compound, and Markush 9A and Markush 10A can prepare, for example by prepare compound 15A with L-Selectride cracking methoxyl group under the THF medium and high temperature. Under appropraite condition as described herein, this Substance Transformation can be become compound 16A with paraformaldehyde with Grignard reagent. The Dakin oxidation obtains intermediate VI, and it can be converted to intermediate VII, for example by use bromochloromethane and alkali in suitable solvent. Method by described Markush 1A for being prepared by compound 6A can prepare Markush 9A and Markush 10A subsequently.
Adopt similar method can prepare Markush 11A, 12A, 13A and 14A.
Experimental section
Universal method
Obtain analyzing the LC/MS data at the PE Sciex API 150EX instrument that atmospheric pressure photoionization (atmospheric pressure photo ionization) and Shimadzu LC-8A/SLC-10A LC system are housed. Measure purity by UV (254nm) and ELSD spike integration. The MS instrument derives from PESciex (API), the APPI-source is housed and operates under positive ion mode. Retention time (RT) in the UV-spike (UV-trace) is with a minute expression. By 0.05%TFA/ water preparation solvent orange 2 A, and by the 0.035%TFA in acetonitrile and 5% water preparation solvent B. Used several diverse ways:
Method 25:API 150EX and Shimadzu LC10AD/SLC-10A LC system. Post: dC-18 4.6x 30mm, 3 μ m (Atlantis, Waters). Column temperature: 40 ℃. Gradient elution: carry out with ion pair is anti-phase. Flow velocity: 3.3mL/ minute. Sampling volume: 15 μ L. Gradient: through 2.4 minutes 2%B/A to 100%B, 2%B/A kept 0.4 minute subsequently. Total run time: 2.8 minutes.
Method 101:API 150EX and Shimadzu LC8/SLC-10A LC system. Post: C-184.6x 30mm, 3.5 μ m (Symmetry, Waters). Column temperature: 60 ℃. Gradient elution: carry out with ion pair is anti-phase. Flow velocity: 3.3mL/ minute. Sampling volume: 15 μ L. Gradient: through 2.4 minutes 10%B/A to 100%B, 10%B/A kept 0.4 minute subsequently. Total run time: 2.8 minutes.
Method 102:API 150EX and Shimadzu LC8/SLC-10A LC system. Post: dC-18 4.6x 30mm, 3 μ m (Atlantis, Waters). Column temperature: 40 ℃. Gradient elution: carry out with ion pair is anti-phase. Flow velocity: 3.3mL/ minute. Sampling volume: 15 μ L. Gradient: through 2.4 minutes 2%B/A to 100%B, 2%B/A kept 0.4 minute subsequently. Total run time: 2.8 minutes.
Method 111:API 150EX and Shimadzu LC8/SLC-10A LC system. Post: C-184.6x 30mm, 3.5 μ m (Symmetry, Waters). Column temperature: 60 ℃. Gradient elution: carry out with ion pair is anti-phase. Flow velocity: 3.3mL/ minute. Sampling volume: 10 μ L (1 μ L sample introduction is to post). Gradient: through 2.4 minutes 10%B/A to 100%B, 10%B/A kept 0.4 minute subsequently. Total run time: 2.8 minutes.
Method 350:API 300 and waters UPLC system. Post: Acquity UPLC BEH C-18 2.1x 50mm, 1.7 μ m (Waters). Column temperature: 60 ℃. Flow velocity: 1.2mL/ minute. Sampling volume: 1 μ L. Gradient: through 1 minute 10%B/A to 100%B, 10%B/A kept 0.15 minute subsequently. Total run time: 1.15 minutes.
Application standard Parr rocker carries out hydrogenation (1-3 clings to Hydrogen Vapor Pressure).
Except as otherwise noted, otherwise term " chromatogram " refers to HPLC, " silica gel chromatograph " or " chirality SFC ".
" chirality SFC " carries out at the Berger SFC multigram II instrument that chiral column is housed, and usually uses postcritical CO2With the mixture of various modifier as eluent.
Preparation HPLC-purifying carries out at the identical instrument with APCI. Post: 50x 20mm YMC ODS-A, particle diameter: 5-μ m. Method: 80%A to 100%B linear gradient elution and flow velocity are 22.7mL/ minute in 7 minutes. Carrying out flow point by the monitoring of shunting mass spectrum collects.
Term " silica gel chromatograph (EtOAc/ heptane) " has following implication: usually be dissolved in compound to be purified among a small amount of DCM and load on that prepackage is filled with on the post of silica gel and with the mixture wash-out of EtOAc and heptane, in degree mode such as grades or with such as 0 to 100%EtOAc/ heptane gradient mode. A used example that is filled with the post of silica gel is " ISOLUTE SPE COLUMNS " [for example 20g FLASH Si 70mL derives from International sorbent technology]. Alternatively, use silica gel to carry out classical manual chromatogram purification [Machery-Nagel 60M for example; 0.04-0.063mm, the 230-400 order], compound is analyzed to differentiate by the enterprising column criterion TLC of aluminium sheet that is covered with silica gel [for example Merck 60 F254] in precoating. By use UV lamp (254nm) irradiation or by immerse ammonium molybdate (6.25g) and cerous sulfate (IV) (2.5g) in the solution in 10% aqueous sulfuric acid (250mL) afterwards charing make compound as seen.
In the microwave reaction bottle of sealing, carry out the microwave accelerated reaction. This experiment is carried out at Smith synthesizer (Personal Chemistry).
Term " freeze-drying " refers to use Christ Alpha 2-4 LSC instrument (deriving from WWR International) with the raw material freeze-drying.
Term " dry (Na2SO
4) " and " dry (Mg2SO
4) " refer to by adding respectively anhydrous Na2SO
4Or Mg2SO
4Stirring subsequently the time of the suitable length that is enough to the efficient drying processing removes water from organic layer. Subsequently this solid filtering is removed, usually with filtrate Vacuum Concentration (seeing lower).
Term " Vacuum Concentration " has following implication: the Rotary Evaporators of Application standard is under reduced pressure removed volatile component from mixture. Term " 40 ℃ of lower vacuum drying " refers to use 40 ℃ the standard vacuum case of being heated to that is connected with oil pump. Term " vacuum drying " refers to dry the processing, wherein material to be dried is placed with the sufficiently long time of the direct-connected flask of oil pump and removes volatile component.
The X-ray crystal structure is measured following carrying out. Use Cryostream nitrogen cooler system that the crystal of described compound is cooled to 120K. Collect data at the Siemens SMART Platform diffractometer with CCD area sensitive detector. Also pass through the complete matrix least square method based on F by the direct method analytic structure2All data are carried out refine. Hydrogen atom in the structure can measure in the electron density disparity map. Non-hydrogen atom is anisotropically carried out refine. All hydrogen atoms use the riding model to be positioned at calculating location, O-H=0.84, and C-H=0.99-1.00,
For all hydrogen atoms, stationary heat parameter [for connecting atom U (H)=1.2U]. Flack x-parameter area is 0.0 (1)-0.05 (1), shows that absolute configuration is correct. Be used for data acquisition, the program of data reduction and fusion (absorption) is SMART, SAINT and SADABS[are with reference to " SMART and SAINT; Area Detector Control and Integration Software (area detector control and integration software) ", Version 5.054, Bruker Analytical X-Ray Instruments Inc., Madison, USA (1998), Sheldrick " SADABS; Program for Empirical Correction of Area Detector Data (experience of area detector data is proofreaied and correct) " Version 2.03, University of
Germany (2001)]. Program SHELXTL[is with reference to Sheldrick " SHELXTL; Structure Determination Programs (structure determine procedures) ", Version 6.12, Bruker Analytical X-Ray Instruments Inc., Madison, USA (2001)] for analytic structure and molecular modeling.
The preparation of intermediate of the present invention
The following intermediate that consists of other aspects of the present invention is for the preparation of The compounds of this invention:
Intermediate compound I-VII
The preparation of intermediate compound I A and IB
Racemization trans-3-amino-8-methoxyl group-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 2)
With compound 1 (6.17g; Such as [Nozulak, J. such as Nozulak; Vigouret, J.M.; Jaton, A.L.; Hofmann, A.; Dravid, A.R.; Weber, H.P.; Kalkman, H.O.; Walkinshaw, M.D.J.Med.Chem.1992,35,480-489] described preparation) be dissolved in and add 10%Pd/C (617mg) among the 99%EtOH (280mL) and under argon gas atmosphere. At room temperature, 2.5 bar H2Under the pressure with this mixture hydrogenation 3 hours. Crude mixture is through the Celite diatomite filtration, concentrates, and vacuum drying obtains the compound 2 of white solid. Obtain 5.24g.
Racemization trans-2-chloro-N-3-hydroxy-5-methyl Oxy-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-acetamide (compound 3)
Under 0 ℃, the past compound 2 (5.22g) that stirs was at THF (260mL) and Et through 2-3 minute3Be added in the ClAcCl (2.90mL) among the THF (14mL) in the solution among the N (6.30mL). At room temperature this mixture was stirred 2 hours. Add EtOAc (500mL) and 1M HCl (500mL), organic layer water (500mL) extraction. The water layer that merges extracts with EtOAc (500mL). The organic layer that merges salt water washing (500mL), dry (MgSO4), filtering, Vacuum Concentration obtains 7.57g compound 3 subsequently, is light yellow solid.
Racemization trans-9-methoxyl group-4a, 5,10,10a-, six hydrogen-4H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]Piperazine-3-ketone (compound 4)
60%NaH dispersion (1.29g) and TBAI (1.05g) be suspended among the THF (46mL) [form hard solid, be cut into small pieces]. In 20 minutes, drip the compound 3 (7.57g) in THF (300mL). At room temperature this mixture is stirred and spend the night. With this solution for vacuum concentration, residue is dissolved among the DCM also with ice-cooled water washing subsequently. Organic layer is used the salt water washing with 1M HCl washing, dry (MgSO4), Vacuum Concentration obtains 2.83g compound 4 behind silica gel chromatograph purifying (EtOAc) subsequently, is colorless solid.
Racemization trans-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine (compound 5)
In the mixture of compound 4 (1.61g) in THF (83mL) that stirs, drip the LAH (15mL) of 1M in THF. At room temperature this mixture was stirred 3 hours. This solution is with ice-cooled water quencher and add Et2O. Water layer Et2The O extraction. The organic layer salt water washing that merges, dry (MgSO4), filtering, Vacuum Concentration obtains compound 5 subsequently, is yellow oil. This material is directly used in next step.
Racemization trans-9-methoxyl group-2,3,4a, 5,10,10a-, six hydrogen-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine-4-t-butyl formate (compound 6)
The compound 5 that derives from previous step is dissolved among the THF (70mL), adds Et3N (1.45mL) and Boc2O (1.52g) at room temperature stirs this mixture 3 days subsequently. With this solution for vacuum concentration, behind silica gel chromatograph purifying (EtOAc/ heptane), obtaining 1.45g compound 6, light yellow oil.
Racemization trans-9-methoxyl group-2,3,4a, 5,10,10a-, six hydrogen-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
The fractionation of piperazine-4-t-butyl formate (compound 6 is split into 6A and 6B)
Compound 6 (1.38g) is split by chirality SFC at the Berger SFC multigram II instrument that Chiralpak AD 21.2x 250mm post is housed. Solvent system: CO2/EtOH/Et
2NH (70: 29.9: 0.1); Method: continuous gradient, flow velocity are 50mL/ minute. Carry out the collection of flow point by UV 230nm monitoring. Enantiomter (4aS, 10aS enantiomter that wash-out is fast; Compound 6B): 0.622g is white solid. Mp=89-90 ℃.D+ 190.1 (C=0.25, MeOH). Enantiomter (4aR, 10aR enantiomter that wash-out is slow; Compound 6A): 0.633g, white solid. Mp=89-90 ℃.D-184.8 (C=0.25, MeOH). The configuration of stereocenter is measured (embodiment 5d2) by X-ray diffraction crystal analysis method.
(4aR, 10aR)-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine hydrochloride (intermediate compound I A)
(14mL, 5M is at Et to add HCl in the solution of compound 6A (545mg) in MeOH (11mL) that stirs2Among the O). After stirring 45 minutes, with this mixture Vacuum Concentration. Obtain 418mg intermediate compound I A, be white solid. Mp decomposes＞280 ℃; LC/MS:ELSD:99.6%; UV:99.2%; MH+: 220.2. The NMR data are identical with the data that intermediate compound I B reports.
C
13H
17NO
2HCl: calculated value: C, 61.05; H, 7.09; N, 5.48; Measured value: C, 60.93; H, 7.26; N, 5.42.
(4aS, 10aS)-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine hydrochloride (intermediate compound I B)
(14mL, 5M is at Et to add HCl in the solution of compound 6B (543mg) in MeOH (11mL) that stirs2Among the O). After stirring 45 minutes, with this mixture Vacuum Concentration. Obtain 436mg, intermediate compound I B is white solid. Mp decomposes＞280 ℃; LC/MS:ELSD:98.7%; UV:93.7%; MH+：220.2。
1H NMR(500MHz，DMSO)δ2.40(dd，1H)，3.00-3.20(br m，4H)，3.30(m，1H)，3.75(s，3H)，3.90(m，2H)，4.00(dd，1H)，6.75(d，1H)，6.80(d，1H)，7.15(t，1H)，9.75(b，1H).
13C NMR(DMSO)δ：157.0，133.3，127.6，121.6，120.8，108.6，73.2，63.1，55.7，54.3，43.2，31.4，29.1.
C
13H
17NO
2HCl: calculated value: C, 61.05; H, 7.09; N, 5.48; Measured value: C, 61.11; H, 7.25; N, 5.41.
The preparation of intermediate II A, IIIA, IVA, VA, VI and VII
Racemization trans-3-hydroxy-5-methyl Oxy-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-t-butyl carbamate (compound 7)
Compound 2 (7.36g) is dissolved among the THF (175mL), adds Et3N (7.7mL) and Boc2O (7.74g). At room temperature this mixture is stirred and spend the night Vacuum Concentration. Crude product obtains 6.90g compound 7 through silica gel chromatograph purifying (EtOAc/ hexane), is white solid.
Racemization trans-3-hydroxy-5-methyl Oxy-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-fractionation (compound 7 splits into compound 7A and 7B) of t-butyl carbamate
Compound 7 (13g) is split by chirality SFC at the Berger SFC multigram II instrument that Chiralpak AD 21.2x 250mm post is housed. Solvent system: CO2/EtOH/Et
2NH (70: 29.9: 0.1); Method: continuous gradient, flow velocity are 50mL/ minute. Carry out the collection of flow point by UV 230nm monitoring. Enantiomter (2S, 3S enantiomter that wash-out is fast; Compound 7B): 5.14g is white solid. Mp=161-162 ℃. Enantiomter (2R, 3R enantiomter that wash-out is slow; Compound 7A): 5.17g is white solid. Mp=161-162 ℃.
(2R, 3R)-3-benzylamino-8-methoxyl group-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 8A)
(70mL, 5M is at Et to add HCl in the solution of compound 7A (5.10g) in MeOH (35mL) that stirs2Among the O). After at room temperature stirring is spent the night, with this mixture Vacuum Concentration. Obtain (2R, 3R)-3-amino of 4.09g white solid-8-methoxyl group-1,2,3, the hydrochloride of 4-tetrahydrochysene-naphthalene-2-alcohol. This material of 3.84g is suspended among the THF (140mL), adds Et3N (4.6mL) and chlorobenzoyl chloride (2.58g). At room temperature this mixture is stirred 3.5 hours nights, subsequently by adding EtOAc (400mL) and 2M HCl (300mL) quencher. Organic phase salt water washing, Vacuum Concentration. (1M is in THF, 20mL) to add LAH in 5 ℃ of lower past these materials (4.63g). In the microwave treatment bottle of sealing, reactant mixture is heated to 100 ℃ and kept 1200 seconds, subsequently by adding wet Na2SO
4Quencher. This solution dilutes by adding ether (60mL) and THF (60mL), with by anhydrous Na2SO
4Filter, subsequently Vacuum Concentration. Obtain 3.69g white solid compound 8A.
((2S, 4aR, 10aR)-4-benzyl-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine-2-yl)-methyl alcohol (compound 9A) and ((2R, 4aR, 10aR)-4-benzyl-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine-2-yl)-methyl alcohol (compound 10A)
Add R-(-)-chloropropylene oxide (1.95mL is dissolved in the 10mL heptane) toward being suspended among the compound 8A (1.42g) among 1, the 2-DCE (5mL) of stirring. Under 115 ℃, reaction mixture refluxed is spent the night. Solvent is boiled off, and residue is through the silica gel chromatograph purifying (heptane of 10-50%/EtOAc). Obtain this intermediate 1.60g, LC/MS (m102): 1.15 minutes (MH 376.1), ELSD 99%, and UV 76%. Toward this intermediate (1.60g) adding 2M NaOH (50mL) and under 130 ℃ this solution backflow is spent the night, be cooled to room temperature, subsequently by adding THF (75mL) quencher. The salt water washing of separation of phases, organic phase, subsequently Vacuum Concentration. Crude product obtains the compound 9A (isomers that wash-out is fast) of 0.457g white solid and the compound 10A (isomers that wash-out is slow) of 0.340g white solid through silica gel chromatograph purifying (EtOAc/ heptane).
((2S,, 4aR, 10aR)-9-methoxyl group-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]
Piperazine-2-yl)-methyl alcohol (compound 11A)
Compound 9A (447mg) is dissolved among the EtOH (56mL). Adding 10%Pd/C (110mg) also spends the night this solution hydrogenation. With the catalyst filtering, solvent is boiled off. Obtain compound 11A316mg.
((2S, 4aR, 10aR)-9-methoxyl group-4-n-pro-pyl-3,4,4a, 5,10,10a-, six hydrogen-2H-naphtho-[2,3-b] [Isosorbide-5-Nitrae]Piperazine-2-yl)-methyl alcohol (intermediate III A)
In the solution of compound 11A (316mg) in DMF (6.3mL) that stirs, add K
2CO
3(369mg), add n-propyl iodide (0.11mL) subsequently.At room temperature reaction mixture is stirred and spend the night, subsequently by adding EtOAc (40mL) and salt solution (25mL) quencher.Organic phase boils off solvent with more salt water washing.Crude product obtains 196mg intermediate III A through silica gel chromatography purifying (EtOAc/ heptane).
Toluene-4-sulfonic acid (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-base methyl esters (intermediate VA)
In the solution of intermediate III A (160mg) in pyridine (3mL) that stirs, add TsCl (160mg).At room temperature reaction mixture was stirred 5 hours, subsequently by adding entry (0.2mL) quencher.After 20 minutes, add EtOAc (25mL) and saturated NaHCO
3The aqueous solution (10mL).Organic phase is with saturated NaHCO
3(10mL) the salt water washing is used in washing subsequently, and solvent is boiled off, and obtains 187mg intermediate VA, is solid.LC/MS (method 101): RT 1.12 minutes, ELSD 98.4%, UV 73.5%.MH
+: 446.7.
((2R, 4aR, 10aR)-and 9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-yl)-methyl alcohol (compound 12A)
Adopt and the described similar method of compound 11A that is used for, prepare this material by compound 10A (340mg).Obtain 288mg.
Adopt with described to be used for method like the intermediate II category-A, by compound 12A preparation ((2R, 4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-yl)-methyl alcohol (intermediate II A).Obtain 149mg.
Toluene-4-sulfonic acid (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-base methyl esters (intermediate compound IV A)
Adopt and the described similar method of intermediate VA that is used for, prepare this material, obtain 238mg by intermediate II A.LC/MS (method 101): RT 1.09 minutes, ELSD 98%, UV 65%.MH
+: 446.7.
(2R, 3R)-3-amino-8-methoxyl group-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 13A)
(99mL, 2M is at Et to add HCl in the solution of compound 7A (7.19g) in MeOH (100mL) that stirs
2Among the O).After stirring 2 hours, solution is filtered, obtain compound 13A, be white solid.Obtain 5.05g.LC/MS (method 350): RT 0.32 minute, ELSD 97.0%, UV 100%.MH
+: 194.1. α
D-105.5 (C=0.25, MeOH)
1H?NMR(500MHz，DMSO)δ：2.41(dd，1H)，2.95(dd，1H)，3.09-3,17(m，3H)，3.77(s，3H)，3.87(m，1H)，5.75(1，1H)，6.71(d，1H)，6.79(d，1H)，7.13(t，1H)，8.32(s，3H).
13C?NMR(DMSO)δ：157.0，133.8，127.3，122.7，120.7，108.3，67.2，55.7，52.3，32.6，31.9.
(2S, 3S)-3-amino-8-methoxyl group-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 13B)
Adopt and the described similar method of compound 13A that is used for, by synthetic this material of compound 7B (7.44g).Obtain 5.34g compound 13B, be white solid.LC/MS (method 350): RT 0.32 minute, ELSD 100%, UV 100%.MH
+: 194.1. α
D+ 104,6 (C=0.25, MeOH) .NMR data and the compound 13A data consistent of being reported.
(2R, 3R)-8-methoxyl group-3-n-propyl amino-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 14A)
Compound 13A (1.50g) is suspended in THF (15mL) and Et
3Among the N (1.80mL), add propionyl chloride (0.60mL).With this solution stirring 20 minutes.Under room temperature, stirring, (1M in THF, 10mL), is heated to 90 ℃ with reaction mixture and kept 1200 seconds in the microwave treatment bottle of sealing to drip LAH.The wet Na of this reaction
2SO
4Quencher.This mixture dilutes with THF (50mL), the Na of drying
2SO
4Filter, subsequently vacuum concentration.Obtain 1.21g compound 14A, be oily matter.LC/MS (method 350): RT 0.40 minute, ELSD 100%, UV 100%.MH
+: 235.9.
1H?NMR(500MHz，CDCl
3)δ0.89(t，J＝7,6Hz，3H)，1.43-1.52(m，2H)，2.37-2.51(m，3H)，2.61-2.68(m，1H)，2.74-2.80(m，1H)，3.14(dd?,J＝4.93，J＝16.0，1H)，3.22-3.29(dd，J＝16.9，J＝5.9，1H)，3.56-3.63(m，1H)，3.73(s，1H)，6.60(d，J＝8.05，1H)，6.62(d，J＝7.89，1H)，7.03(t，J＝7.86，1H).
13C?NMR(500MHz，CDCl
3)δ：157.7?136.4，127.0，123.8，121.2，107.7，71.0，59.8，55.7，49.5，35,7，32.1，24.1，12.2.
(2S, 3S)-8-methoxyl group-3-n-propyl amino-1,2,3,4-tetrahydrochysene-naphthalene-2-alcohol (compound 14B)
By synthetic this material of compound 13B (1.15g).Obtain 960mg compound 14B, be oily matter.LC/MS (method 350): RT 0.40 minute, ELSD 99.2%, UV 100%.MH
+: 235.9.
Intermediate II A and intermediate III A.Be dissolved in 1 toward what stir, add S-(+)-Epicholorohydrin (1.22mL) among the compound 14A (751mg) among the 2-DCE (3.2mL).Under 120 ℃, reaction mixture refluxed is spent the night, subsequently vacuum concentration.(8.7mL 2M), refluxes this mixture under 130 ℃ and spends the night to add NaOH in the resistates.Solution is cooled to room temperature, adds THF (17.5mL) subsequently.Organic phase is washed with salt solution (5mL), subsequently vacuum concentration.Two kinds of isomer separate (0-100%EtOAc/ heptane) with silica gel chromatography, obtain the fast isomer of 116mg wash-out ((2S, 4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-yl)-methyl alcohol (intermediate III A): LC/MS:ELSD:100.0%; UV:90.4%; MH
+291.8.
1H?NMR(500MHz，CDCl
3)δ0.87(t，J＝7.48，3H)，1.38-1.59(m，2H)，2.09-2.15(m，1H)，2.30-2.40(m，1H)，2.59(dd，J＝15.86，J＝11.69，1H)，2.65(dd，J＝11.87，J＝3.99，1H)，2.99(d，J＝11.81，1H)，3.11(t，J＝5.59，1H)，3.14(t，J＝5.14，1H)，3.74(s，3H)，3.83-3.92(m，2H)，4.07-4.14(m，2H)，6.60(d，J＝8.21，1H)，6.63(d，J＝7.86，1H)，7.04(t，J＝8.03，1H).
13C?NMR(500MHz，CDCl
3)δ：157.5?135.5，127.1，123.4，121.1，107.7，72.4，72.3，67.0，60.9，55,7，55.1，53.2，33.9，30.7，19.1，12.3.
With the slow isomer of 76mg wash-out ((2R, 4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-yl)-methyl alcohol (intermediate II A) LC/MS:ELSD:100.0%; UV:100.0%; MH
+291.8; R
t=0.41.
1H?NMR(500MHz，CDCl
3)δ0.85(t，J＝7,3Hz，3H)，1.45-1.59(m，2H)，2.24-2.32(m，3H)，2.43(dd，J＝16.9，J＝10.6，1H)，2.60(dd，J＝11.8，J＝15.4，1H)，2.73(m，1H)，2.79(d，J＝11.18，1H)，3.10-3.19(m，2H)，3,55(dd，J＝6.35，J＝11.64，1H)，(3.58-3.66(m，2H)，3.74(s，3H)，3.78(bs，1H)，6.61(d，J＝8.21，1H)，6.66(d，J＝7.92，1H)，7.05(t，J＝7.88，1H).
13C?NMR(500MHz，CDCl
3)δ：157.5?135.8，127.1，123.4，121.2，107.7，76.9，76.0，64.7，60.9，55,7，55.6，53.4，33.9，30.1，18.7，12.4.
Under these conditions by compound 14A (1.1g) and R-(-)-Epicholorohydrin (1.76ml) preparation intermediate II A and IIIA.Obtain 338mg intermediate III A and 247mg intermediate II A.
The preparation of intermediate II B and IIIB
Adopt and the described similar method of enantiomer 7A that is used for, use S-(+)-Epicholorohydrin to prepare intermediate II B and IIIB by compound 7B through the number step.Adopt and the described similar method of enantiomer 14A that is used for, use S-(+)-Epicholorohydrin or R-(-)-Epicholorohydrin also to prepare intermediate II B and IIIB by compound 14B.
The preparation of intermediate compound IV B and VB
Adopt and the described similar method of enantiomer that is used for, prepare intermediate compound IV B and VB by intermediate II b and IIIB.
The preparation of intermediate VI and VII
(4aR, 10aR)-9-hydroxyl-2,3,4a, 5,10,10a-six hydrogen-naphtho-[2,3-b] [1,4]
Piperazine-4-t-butyl formate (compound 15A)
At room temperature in compound 6A (901mg), add L-Selectride (13.5mL, 1M is in THF).In 110 ℃, sealing microwave reaction bottle with solution heating 6 hours.Add more L-Selectride (1.5mL, 1M is in THF) and under 110 ℃ with this solution heating 1 hour.With xanchromatic solution impouring ice/water mixture (45mL) and saturated NaHCO
3(45mL).This mixture Et
2O (3x 90mL) extraction.The organic layer salt water washing that merges, dry (Na
2SO
4), vacuum concentration subsequently.Crude product obtains 530mg compound 15A through silica gel chromatography purifying (MeOH/EtOAc/ heptane), is white solid.
(4aR, 10aR)-8-formyl radical-9-hydroxyl-2,3,4a, 5,10,10a-six hydrogen-naphtho-[2,3-b] [1,4]
Piperazine-4-t-butyl formate (compound 14A)
Compound 15A (375mg) is dissolved in the dry toluene (4mL).The toluene vacuum concentration is removed, added more toluene (20mL).At room temperature drip ethylmagnesium bromide (0.45mL; 3M is at Et
2Among the O) and with this solution stirring 15 minutes.Remove about 1/4 solvent by vacuum concentration, add Paraformaldehyde 96 (95mg) and HMPA (0.21mL) subsequently.Under 90 ℃,, be transferred in the microwave reaction bottle of sealing with syringe subsequently this solution stirring 2 hours, under 120 ℃ with this solution heating 0.5 hour.At room temperature this solution was kept 3 days.With solution at saturated NH
4Cl (30mL) and Et
2Distribute between O (120mL).Organic layer salt water washing, dry (Na
2SO
4), vacuum concentration subsequently.Crude product obtains 230mg compound 16A through silica gel chromatography purifying (EtOAc/ heptane), is white solid.
(4aR, 10aR)-8,9-dihydroxyl-2,3,4a, 5,10,10a-six hydrogen-naphtho-[2,3-b] [1,4]
Piperazine-4-t-butyl formate (intermediate VI)
With the solution degassing of compound 16A (225mg) in MeOH (3.4mL).Drip 1MNaOH (0.67mL) and 35%H
2O
2(0.28mL) and at room temperature with the solution stirring of redness 10 minutes.(10mL, 2M is at Et to add HCl
2Among the O) and the mixture of MeOH (20mL), this solution becomes yellow.Add Et immediately
2O (30mL) and salt solution (5mL).Organic layer salt water washing, dry (Na
2SO
4), vacuum concentration obtains intermediate VI subsequently, is brown powder.
(6aR, 10aR)-6,6a, 8,9,10a, 11-six hydrogen-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene-7-t-butyl formate (intermediate VII)
The sealing the microwave reaction bottle in intermediate VI (60mg), Cs
2CO
3(33mg), CH
2BrCl (48mg) and DMF (1mL) are heated to 110 ℃ and kept 0.5 hour.Add more CH
2BrCl (33mg is in 0.2mL DMF) was with this mixture heating up to 110 ℃ maintenance 0.5 hour.Reaction mixture is through silica gel chromatography purifying (EtOAc/ heptane).Obtain 18mg intermediate VII.
The preparation of The compounds of this invention
Invention disclosed in coming furtherly expressly by following indefiniteness embodiment.
1a1. (4aR, 10aR)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Compound 6A is dissolved among the anhydrous THF (5mL).(1M in THF, 1.5mL) and in the microwave method bottle of sealing is heated to 90 ℃ and kept 15 minutes with this solution at room temperature to drip LAH.After being cooled to room temperature, slowly add MeOH (0.3mL) and ice-cooled water (10mL), product Et
2O (3x 20mL) extraction.The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration subsequently obtains the compound of embodiment 1a1.Obtain 107mg.TLC：Rf＝0.19(EtOAc)。
1a2. (4aS, 10aS)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 1a1, obtain embodiment 1a2 compound by compound 6B (160mg).Obtain 78mg.
2a1. (4aR, 10aR)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
In the solution of intermediate compound I A (0.39mmol) in DMF (9mL) that stirs, add K
2CO
3(1.50mmol) and iodoethane (2.2mmol).Under 55 ℃, this mixture was stirred 3 hours.Add entry (20mL), product is extracted to Et
2O (3x 10mL).The organic phase that merges salt solution and saturated NH
4The Cl washing, dry (MgSO
4), vacuum concentration obtains embodiment 2a1 compound subsequently.
2a2. (4aS, 10aS)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
In the solution of intermediate compound I B (0.39mmol) in DMF (9mL) that stirs, add K
2CO
3(1.50mmol) and iodoethane (2.2mmol).Under 55 ℃, this mixture was stirred 3 hours.Add entry (20mL), product is extracted to Et
2Among the O (3x 10mL).The organic phase that merges salt solution and saturated NH
4The Cl washing, dry (MgSO
4), vacuum concentration obtains embodiment 2a2 compound subsequently.
2b1. (4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
(100mg 0.39mmol) adds K in the solution in DMF (9mL) toward the intermediate compound I A that stirs
2CO
3(1.50mmol) and n-propyl iodide (375mg, 2.2mmol).Under 55 ℃, this mixture was stirred 3 hours.Add entry (20mL) and product is extracted to Et
2O (3x 10mL).The organic phase that merges salt solution and saturated NH
4The Cl washing, dry (MgSO
4), vacuum concentration obtains embodiment 2b1 compound subsequently, is white solid.Obtain 93mg.LC/MS (method 25): RT0.58 minute, ELSD 100%, UV 92%.TLC:Rf=0.51 (EtOAC)
2b2. (4aS, 10aS)-9-methoxyl group-4-n-propyl--3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 2b1, initial by intermediate compound I B (100mg), obtain embodiment 2b2 compound.Obtain 102mg.LC/MS (method 25): RT 0.60 minute, ELSD 100%, UV 93%.TLC:Rf=0.51 (EtOAc).
2c1. (4aR, 10aR)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
In the solution of intermediate compound I A (115mg) in DMF (10mL) that stirs, add K
2CO
3(202mg) and allyl bromide 98 (300mg).Under 55 ℃, this mixture was stirred 5 hours.Add entry (20mL) and saturated NaHCO
3(10mL) and with product be extracted to Et
2O (3x 20mL).The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration obtains embodiment 2c1 compound subsequently, is white solid.Obtain 117mg.LC/MS (method 25): RT 0.97 minute, ELSD 97%, UV 48%.MH
+: 260.3.
2c2. (4aS, 10aS)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 2c1, initial by intermediate compound I B (115mg), obtain embodiment 2c2 compound.Obtain 117mg.LC/MS (method 25): RT 0.97 minute, ELSD98%, UV 47%.MH
+: 260.3.
2d1. (4aR, 10aR)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
In the solution of intermediate compound I A (100mg) in DMF (9mL) that stirs, add K
2CO
3(176mg) and allyl bromide 98 (292mg).Under 55 ℃, this mixture was stirred 3 hours.Add entry (20mL) and saturated NaHCO
3(10mL), product is extracted to Et
2O (3x 20mL).The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration obtains embodiment 2d1 compound subsequently, is white solid.Obtain 107mg.LC/MS (method 25): RT 0.72 minute, ELSD 100%, UV 92%.MH
+: 274.3.
2d2. (4aS, 10aS)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 2d1, initial by intermediate compound I B (100mg), obtain embodiment 2d2 compound.Obtain 107mg.LC/MS (method 25): RT 0.72 minute, ELSD 99%, UV 90%.MH
+: 274.1.
3a. (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
(60% oil dispersion 4mg) adds intermediate compound IV (21mg) in the solution in DMF at room temperature past 1.2.4-triazole (11mg) that stirs and NaH.In the microwave treatment bottle of sealing this solution is heated to 100 ℃ and kept 30 minutes, postheating to 130 ℃ also kept 30 minutes.After being cooled to room temperature, add EtOAc (5mL), organic phase is washed with salt solution (2x 5mL), dry (MgSO
4), vacuum concentration subsequently.Crude product is through silica gel chromatography purifying (wash-out: the 0-30%MeOH in EtOAc).Obtain 6mg embodiment 3a compound, be clarifying oily matter.LC/MS (method 101): RT 0.69 minute, ELSD 100%, UV 55%.MH
+: 343.2
3b. (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3a, initial by intermediate compound IV A (21mg), obtain embodiment 3b compound.LC/MS (method 111): RT 0.59 minute, ELSD 100%, UV100%.MH
+: 343.1.
3c. (2S, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3d, VA is initial by intermediate, obtains embodiment 3c compound.
3d. (2R, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
In the suspension of KOH (20mg) in MeOH (0.6mL) that stirs, add S-methyl-isourea (25mg).At room temperature this mixture was stirred 10 minutes, add intermediate compound IV A (21mg).Under 65 ℃ with this solution stirring 3 hours.After being cooled to room temperature, add 1,2-DCE (4mL), organic phase water (2mL) washing, dry (MgSO
4), vacuum concentration subsequently.Crude product is through the HPLC purifying.Obtain 5mg embodiment 3d compound, be clarifying oily matter.LC/MS (method 101): RT 0.84 minute, ELSD 100%, UV 70%.MH
+: 322.1
3e. (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3a, initial by intermediate compound IV A (21mg) and imidazoles (11mg), obtain embodiment 3e compound.Obtain 10mg.LC/MS (method 111): RT 0.49 minute, ELSD 100%, UV 79%.MH
+: 342.3.
3f. (2R, 4aR, 10aR)-and 9-methoxyl group-2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
(5M is in MeOH, 0.1mL) to add sodium methylate in the solution of intermediate compound IV A (11mg) in MeOH (0.4mL) that stirs.In the microwave treatment bottle of sealing, this solution is heated to 100 ℃ and kept 15 minutes.After being cooled to room temperature, add EtOAc (1mL), organic phase is washed with salt solution (0.5mL).Separate each phase, crude product is through chromatogram purification.
3g. ((2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-ylmethyl)-dimethyl amine
In the solution of intermediate compound IV A (11mg) in MeOH (0.4mL) that stirs, add dimethyl amine (0.1mL, 8M is in MeOH).In the microwave treatment bottle of sealing this solution being heated to 120 ℃ kept 30 minutes.After being cooled to room temperature, add EtOAc (1mL), organic phase is washed with salt solution (0.5mL).Separate each phase, crude product is through chromatogram purification.
3h. (2R, 4aR, 10aR)-and 2-methyl fluoride-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
(1M is in THF, 0.5mL) toward the middle adding of intermediate compound IV A (11mg) TBAF.In the microwave treatment bottle of sealing this solution being heated to 100 ℃ kept 15 minutes.After being cooled to room temperature, add EtOAc (1mL), organic phase is washed with salt solution (0.5mL).Separate each phase, crude product is through chromatogram purification.
3i. (2S, 4aR, 10aR)-and 9-methoxyl group-2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine
(1M is in THF, 0.5mL) to add LAH in the solution of intermediate compound IV A (11mg) in THF (0.5mL) that stirs.In the microwave treatment bottle of sealing this solution being heated to 100 ℃ kept 15 minutes.After being cooled to room temperature, add EtOAc (1mL), organic phase is washed with salt solution (0.5mL).Separate each phase, crude product is through chromatogram purification subsequently.
3j1. (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The piperazine hydrochloride
Adopt the described method that is used for embodiment 3a, initial by intermediate compound IV A (42mg) and pyrazoles (19mg), obtain embodiment 3j1 compound.(2mL, 2M is at Et to add HCl
2Among the O), the volatile constituent vacuum is removed, obtain embodiment 3j1 compound, be white solid.Obtain 20mg.LC/MS (method 350): RT 0.41 minute, ELSD 100%, UV 100%.MH
+: 342.1.
C
20H
28N
3O
2Cl·2H
2O：
Calculated value: C, 58.00; H, 7.73; N, 10.14; Measured value: C, 58.47; H, 7.39; N, 10.04.
1H?NMR(500MHz，DMSO)δ0.95(t，J＝7,34Hz，3H)，1.63-1.81(m，2H)，2.39(dd，J＝16.71，J＝10.83，1H)，2.90-3.06(mm，2H)，3.07-3.19(m，2H)，3.30-3.40(m，3H)，3.48(dd，J＝16.03，J＝5.34，1H)，3.65(s，1H)3.76(s，3H)，4.08-4.16(m，1H)，4.29(dd，J＝14.32，J＝6.74，1H)，4.39(dd，J＝14.32，J＝4.29，1H)，4.43-4.49(m，1H)，6.28(t，J＝2.04，1H)，6.76(d，J＝7.93，1H)，6.82(d，J＝8.21，1H)，7.17(t，J＝8.00，1H)，7.50(d，J＝1.89，1H)，7.74(d，J＝2.23，1H).
3j2. (2S, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The piperazine hydrochloride
Adopt the described method that is used for embodiment 3a, by intermediate compound IV B (42mg, 0.09mmol) and pyrazoles (19mg) initial, obtain embodiment 3j2 compound.(2mL, 2M is at Et to add HCl
2Among the O), the volatile constituent vacuum is removed, obtain embodiment 3j2 compound, be white solid.Obtain 16.1mg.LC/MS (method 350): RT 0.41 minute, ELSD 100%, UV 100%.MH
+: 342.1.
C
20H
28N
3O
2Cl·6H
2O：
Calculated value: C, 49.40; H, 8.23; N, 8.64; Measured value: C, 49.13; H, 7.34; N, 8.46.
1The data consistent that H NMR data and embodiment 3j1 are reported.
3k1. (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The piperazine hydrochloride
Adopt the described method that is used for embodiment 3a, initial by intermediate VA (42mg) and pyrazoles (19mg), obtain embodiment 3k1 compound, be oily matter, (2mL, 2M is at Et to add HCl
2Among the O), the volatile constituent vacuum is removed, obtain embodiment 3k1 compound, be white solid.Obtain 33mg.LC/MS (method 350): RT 0.41 minute, ELSD 100%, UV 100%.MH
+: 342.1.
C
20H
28N
3O
2Cl·3.5H
2O：
Calculated value: C, 54.42; H, 7.90; N, 9.52; Measured value: C, 54.35; H, 7.57; N, 9.25.
1H?NMR(500MHz，DMSO)δ0.95(t，J＝7,34Hz，3H)，1.67-1.82(m，2H)，2.33(dd，J＝16.80，J＝10.21，1H)，2.99-3.08(mm，2H)，3.32-3.52(m，7H)，3.77(s，3H)，4.35-4.42(m，1H)，4.44-4.51(m，1H)，4.69(dd，J＝14.29，J＝6.06，1H)，5.13(dd，J＝14.33，J＝9.29，1H)，6.27(t，J＝1.87，1H)，6.78(d，J＝7.60，1H)，6.82(d，J＝7.98，1H)，7.18(t，J＝7.78，1H)，7.50(d，J＝1.70，1H)，7.92(d，J＝2.08，1H).
3k2. (2R, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
The piperazine hydrochloride
Adopt the described method that is used for embodiment 3a, initial by intermediate VB (42mg) and pyrazoles (19mg), obtain embodiment 3k2 compound, be oily matter.(2mL, 2M is at Et to add HCl
2Among the O), the volatile constituent vacuum is removed, obtain embodiment 3k2 compound, be white solid.Obtain 20mg.LC/MS (method 350): RT 0.41 minute, ELSD 100%, UV 100%.MH
+: 342.1.
C
20H
28N
3O
2Cl
2·5H
2O：
Calculated value: C, 56.79; H, 7.88; N, 9.94; Measured value: C, 56.99; H, 7.49; N, 9.90.
1The data consistent that H NMR data and embodiment 3k1 are reported.
3l. (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3a, initial by intermediate compound IV A (42mg) and pyrazoles (28mg), obtain 13mg embodiment 3l compound, be white solid.LC/MS (method 350): RT 0.60 minute, ELSD 100%, UV 100%.MH
+: 376.3.
1H?NMR(500MHz，CDCl
3)δ1.05(t，J＝7,20Hz，3H)，1.69-1.83(m，1H)，1.88-2.04(m，1H)，2.50(dd，J＝17.01，J＝10.40，1H)，2.57(dd，J＝18.94，J＝9.44，1H)，2.90(bs，2H)，3.21(dd，J＝15.56，J＝4.75，1H)，3.29(t，J＝11.30，1H)，3.37(dd，J＝17.08，J＝6.31，1H)，3.54(d，J＝11.18，1H)，3.67(t，J＝13.14，1H)，3.84(s，3H)，4.29-4.41(m，2H)，4.55-4.66(m，1H)，4.91(d，J＝8.33，1H)，6.69(d，J＝7.74，1H)，6.72(d，J＝8.17，1H)，6.82(d，J＝8.21，1H)，7.15(t，J＝8.00，1H)，7.44(s，1H)，7.52(s，1H).
13C?NMR(500MHz，CDCl
3)δ：157.3?138.6，132.3，129.6，128.0，121.4，121.0，111.0，108.4，73.7，70.6，62.3，55.8，54.9，54.6，52.4，30.1，29.9，16.4，11.6.
3m. (2S, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described embodiment 3a method that is used for, initial by intermediate VA (42mg) and pyrazoles (28mgl), obtain embodiment 3m compound, be oily matter.Obtain 43mg.LC/MS (method 350): RT 0.58 minute, ELSD 100%, UV 100%.MH
+: 376.1.
1H NMR (500MHz, CDCl
3) δ 1.08 (bs, 3H), 1.73 (bs, 1H), 1.99 (bs, 1H), 2.51 (dd, J=9.25, J=16.47,1H), 2.97-3.44 (m, 7H), 3.83 (s, 3H), 3.94 (m, 1H), 4.51 (bs, 1H), 4.80 (bs, 1H), 5.57 (bs, 1H), 6.72 (d, J=8.21,2H), 7.17 (bs, 1H), 7.52 (s, 1H), 8.23 (s, 1H).
13C NMR (500MHz, CDCl
3) δ: 157.3 138.3,132.3,131.2,128.1,121.2,121.0,110.9,108.4,69.5,68.5,62.9,55.8,55.5,51.7,49.2,30.1,29.8,16.5,11.8.
3n. (2R, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3a, initial by intermediate compound IV A (42mg) and 3-phenylpyrazole (39mg), obtain embodiment 3n compound, be oily matter.Obtain 60mg.LC/MS (method 350): RT 0.67 minute, ELSD 99.9%, UV 71.5%.MH
+: 418.1.
3o. (2S, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine
Adopt the described method that is used for embodiment 3a, initial by intermediate VA (42mg) and 3-phenylpyrazole (39mg), obtain embodiment 3o compound, be oily matter.Obtain 66mg.LC/MS (method 350): RT 0.67 minute, ELSD 91.9%, UV 79.7%.MH
+: 418.1.
4a1. (4aR, 10aR)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
(1M is in THF, 18mL) at room temperature to drip L-Selectride in the solution of compound 6A (577mg) in THF (5mL).This solution is heated to 100 ℃ and kept 6 hours in the microwave treatment bottle of sealing.After being cooled to 0 ℃, slowly add ice-cooled water (125mL) and saturated NaHCO
3(50mL), product Et
2O (3x 75mL) extraction.The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration subsequently.Resistates is through the silica gel chromatography purifying, obtain (4aR, 10aR)-9-hydroxyl-2,3,4a, 5,10,10a-six hydrogen-naphtho-[2,3-b] [1,4]
Piperazine-4-t-butyl formate is white solid.Obtain 297mg.Mp：203-205℃。With this substance dissolves of 141mg in MeOH (4mL) and add HCl (5M is at Et
2Among the O).At room temperature with this solution stirring 45 minutes vacuum concentration subsequently.Resistates is dissolved among the anhydrous EtOH (2.3mL).Add NaCNBH
3(129mg), acetate (0.3mL) and acetaldehyde (122mg) and this solution is heated to 90 ℃ and kept 15 minutes in the microwave treatment bottle of sealing.After being cooled to 0 ℃, slowly add ice-cooled water (25mL) and saturated NaHCO
3(10mL), product Et
2O (3x15mL) extraction.The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration subsequently.Crude product obtains 49mg through chromatogram purification.Be dissolved in product among the MeOH (1mL) and add HCl (1.5mL, 5M is at Et
2Among the O).The HCl salt that produces is separated and vacuum-drying.Obtain embodiment 4a1 compound 38mg, be white solid.Record mp＞280 ℃; LC/MS (method 25): RT 0.66 minute, ELSD 99%, UV 100%.MH
+: 234.1.
1H?NMR(500MHz，DMSO)δ1.25(t，3H)，2.40(dd，1H)，3.05-3.20(br?m，4H)，3.35-3.50(m，3H)，4.00-4.10(br?m，3H)，6.60(d，1H)，6.65(d，1H)，7.00(t，1H)，9.55(s，1H)，11.45-11.55(b，1H).
C
14H
19NO
2·HCl
Calculated value: C, 61.31; H, 7.53; N, 5.11, (1/4H2O); Measured value: C, 61.69; H, 7.57; N, 5.12. α
D:-116.6
4a2. (4aS, 10aS)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 4a1, initial by compound 6B (191mg), obtain embodiment 4a2 compound.Obtain 73mg, be white solid.Mp dec.＞280 ℃; LC/MS (method 25): RT 0.66 minute, ELSD 99%, UV 100%.MH
+: 234.1.
1The data consistent that H NMR data and embodiment 4a1 are reported.
C
14H
19NO
2·HCl：
Calculated value: C, 61.31; H, 7.53; N, 5.11; Measured value: C, 61.97; H, 7.55; N, 5.13. α
D+ 122.2 (C=0.5, DMSO).
5a1. (4aR, 10aR)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
At room temperature (1M is in THF, 4.6mL) toward the middle dropping of embodiment 1a1 (107mg) L-Selectride.This solution is heated to 100 ℃ and kept 6 hours in the microwave treatment bottle of sealing.After being cooled to 0 ℃, slowly add ice-cooled water (25mL) and saturated NaHCO
3(10mL), with after product Et
2O (3x 15mL) extraction.The organic phase salt water washing that merges, dry (MgSO
4), vacuum concentration subsequently.Crude product is through the silica gel chromatography purifying.Be dissolved in free alkali among the MeOH (1mL) and use 5M HCl/Et
2O (1.5mL) precipitates with the HCl salt form.Obtain 49mg embodiment 5a1 compound, be white solid.Mp decomposes＞280 ℃; LC/MS (method 25): ELSD:99.0%, UV:100.0%, MH
+: 220.3.
1H?NMR(500MHz，DMSO)δ2.40(dd，1H)，2.85(s，3H)，3.05-3.20(br?m，2H)，3.25(m，1H)，3.35-3.50(br?m，2H)，3.95-4.05(br?m，3H)，6.60(d，1H)，6.65(d，1H)，7.00(t，1H)，9.55(s，1H)，11.30-11.40(b，1H).
C
13H
17NO
2·HCl：
Calculated value: C, 61.05; H, 7.09; N, 5.48; Measured value: C, 60.46; H, 7.18; N, 5.28. α
D-122.9 (C=0.5, DMSO).
5a2. (4aS, 10aS)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 1a2 compound (78mg), obtain embodiment 5a2 compound.Obtain 50mg, be white solid.Mp decomposes＞280 ℃; LC/MS (method 25): RT 0.56 minute, ELSD 99%, UV 100%.MH
+: 220.2.
1The data consistent that H NMR data and embodiment 5a1 are reported.
C
14H
19NO
2·HCl：
Calculated value: C, 61.05; H, 7.09; N, 5.48; Measured value: C, 60.49; H, 7.16; N, 5.31. α
D+ 117 (C=0.5, DMSO).
5b1. (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2b1 compound (102mg), obtain embodiment 5b1 compound.Obtain 61mg, be white solid.Mp decomposes＞300 ℃; LC/MS (method 25): RT 0.56 minute, ELSD 100%, UV 98%.MH
+: 248.2.
1H?NMR(500MHz，DMSO)δ0.95(t，3H)，1.73(m，2H)，2.40(dd，1H)，3.00(m，1H)，3.10-3.20(br?m，4H)，3.35-3.50(br?m，2H)，4.05(m，3H)，6.60(d，1H)，6.65(d，1H)，7.00(t，1H)，9.55(s，1H)，11.30-11.40(b，1H)；
C
15H
21NO
2·HCl·0.25H
2O：
Calculated value: C, 62.48; H, 7.88; N, 4.86; Measured value: C, 62.71; H, 7.99; N, 5.05. α
D+ 117 (C=0.5, DMSO).
5b2. (4aS, 10aS)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2b2 compound (102mg), obtain embodiment 5b2 compound.Obtain 60mg, be white solid.Mp decomposes＞300 ℃;
1The data consistent that H NMR data and embodiment 5b1 are reported.
C
15H
21NO
2·HCl·0.25H
2O：
Calculated value: C, 62.48; H, 7.88; N, 4.86; Measured value: C, 62.67; H, 7.78; N, 5.00. α
D+ 111.4 (C=0.5, DMSO).
5c1. (4aR, 10aR)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2c1 compound (117mg), obtain embodiment 5c1 compound.Obtain 28mg, be white solid.Record mp＞280 ℃; LC/MS (method 25): RT 0.74 minute, ELSD 99%, UV 96%.MH
+: 246.2.
1H?NMR(500MHz，DMSO)δ2.40(dd，1H)，3.10-3.20(br?m，3H)，3.40(m，1H)，3.45(dd，1H)，3.75(m，1H)，4.00-4.10(br?m，4H)，5.55(d，1H)，5.65(d，1H)，6.05(m，1H)，6.60(d，1H)，6.65(d，1H)，7.00(t，1H)，9.55(s，1H)，11.65-11.75(b，1H).
C
15H
19NO
2·HCl·0.25H
2O：
Calculated value: C, 62.93; H, 7.22; N, 4.89; Measured value: C, 62.53; H, 7.48; N, 4.71. α
D+ 111.4 (C=0.5, DMSO).
5c2. (4aS, 10aS)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2c2 compound (117mg), obtain embodiment 5c2 compound.Obtain 22mg, be white solid.Record mp＞280 ℃; LC/MS (method 25): RT 0.75 minute, ELSD 99%, UV 95%.MH
+: 246.3.
1The data consistent that HNMR data and embodiment 5c1 are reported.
C
15H
21NO
2·HCl·0.25H
2O：
Calculated value: C, 61.96; H, 7.28; N, 4.82; Measured value: C, 62.26; H, 7.51; N, 4.57. α
D+ 118.4 (C=0.5, DMSO).
5d1. (4aR, 10aR)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2d1 compound (107mg), obtain embodiment 5d1 compound.Obtain 79mg, be white solid.Record mp＞280 ℃; LC/MS (method 25): RT 0.80 minute, ELSD 99%, UV 98%.MH
+: 260.2.
1H?NMR(500MHz，DMSO)δ0.45(m，2H)，0.65(m，2H)，1.15(m，1H)，2.40(dd，1H)，3.05-3.20(br?m，3H)，3.25(m，1H)，3.35-3.45(br?m，2H)，3.70(d，1H)，4.00-4.10(br?m，3H)，6.60(d，1H)，6.65(d，1H)，7.00(t，1H)，9.55(s，1H)，11.10-11.20(b，1H).α
D-109.5(C＝0.5，DMSO).
5d2. (4aS, 10aS)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol hydrochloride
Adopt the described method that is used for embodiment 5a1, initial by embodiment 2d2 compound (107mg), obtain embodiment 5d2 compound.Obtain 73mg, be white solid.Record mp＞280 ℃; LC/MS (method 25): RT 0.77 minute, ELSD 99%, UV 96%.MH
+: 260.2.
1The data consistent that H NMR data and embodiment 5d1 are reported.
C
16H
21NO
2·HCl：
Calculated value: C, 64,48; H, 7.52; N, 4.70. (1/8H
2O); Measured value: C, 64.32; H, 7.66; N, 4.64. α
D+ 114.9 (C=0.5, DMSO).
In order to measure the absolute configuration of two kinds of stereocenters, measure the compound (referring to Fig. 1) of embodiment 5d2 with x-ray analysis.
5e1. (2R, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
(1M is in THF, 0.75mL) toward the middle adding of intermediate II A (20mg) L-Selectride.This solution is heated to 120 ℃ and kept 8 hours in the microwave treatment bottle of sealing.After being cooled to room temperature, slowly add ice-cooled water (0.3mL) and saturated NaHCO
3(1mL).With the pH value of this solution with rare HCl be adjusted to～8.5.Product is extracted to 1, among the 2-DCE (2x 5mL).The organic phase salt water washing that merges, vacuum concentration.Crude product is through silica gel chromatography purifying (0-30%MeOH/EtOAc), and further through the HPLC purifying.The output of 5e1 is 3.7mg, is clarifying oily matter.LC/MS (method 101): 0.47 minute ELSD:100% of RT, UV:96%, MH
+=278.2.
5e2. (2S, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 5e1, initial by intermediate II B (12mg), obtain embodiment 5e2 compound.Obtain 5.0mg, be clarifying oily matter.LC/MS (method 101): RT 0.47 minute, ELSD 98%, UV 92%.MH
+=278.2.
5f1. (2S, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 5e1, initial by intermediate III A (25mg), obtain embodiment 5f1 compound.Obtain 5.8mg, be clarifying oily matter.LC/MS (method 101): RT 0.47 minute, ELSD 100%, UV 92%.MH
+=278.2.
5f2. (2R, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described embodiment 5e1 method that is used for, initial by intermediate III B (25mg), obtain embodiment 5f2 compound.Obtain 4.3mg, be clarifying oily matter.LC/MS (method 101): RT0.47 minute, ELSD 100%, UV 88%.MH
+=278.2.
5g. (2S, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
(1M is in THF, 1mL) to add L-Selectride in embodiment 3a (6mg) compound.This solution is heated to 100 ℃ and kept 6 hours in the microwave treatment bottle of sealing.After being cooled to room temperature, slowly add a small amount of wet Na
2SO
4This solution dilutes with THF (2mL), the Na of drying
2SO
4Filter.Solvent is boiled off, and resistates is through the HPLC purifying.Obtain 4.3mg embodiment 5g compound, be clarifying oily matter.LC/MS (method 101): RT=0.43 minute.ELSD：100％，UV：93％，MH
+＝329.4.
5h. (2R, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described embodiment 5g method that is used for, initial by embodiment 3b compound (12mg), obtain embodiment 5h compound.Obtain 1.7mg, be white oily matter.LC/MS (method 111): RT 0.44 minute, ELSD 100%, UV 100%.MH
+=329.5.
5i. (2S, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Use the described method that is used to prepare embodiment 5g, can be by embodiment 3c compound embodiment 5i compound.
5j. (2R, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 5g, initial by embodiment 3d compound (2.3mg), obtain embodiment 5j compound.Obtain 0.8mg, be clarifying oily matter.LC/MS (method 350): RT 0.43 minute, ELSD 100%, UV 100%.MH
+=308.3.
In order to measure the absolute configuration of two kinds of stereocenters, be determined as the compound (referring to Fig. 1) of the embodiment 5j of hydrochloride form with x-ray analysis.
5k. (2S, 4aR, 10aR)-and 2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 5g, initial by intermediate compound IV A (3.9mg), obtain embodiment 5k compound.Obtain 1.4mg, be clarifying oily matter.LC/MS (method 111): RT 0.43 minute, ELSD 84%, UV 62%.MH
+=262.1.
5l. (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 5g, initial by embodiment 3e compound (10mg), obtain embodiment 5l compound.Obtain 5.8mg, be clarifying oily matter.LC/MS (method 350): RT 0.29 minute, ELSD 100%, UV 100%.MH
+=328.0.
5m. (2R, 4aR, 10aR)-and 2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Use the described method that is used to prepare embodiment 5g, can be by embodiment 3f compound embodiment 5m compound.
5n. (2S, 4aR, 10aR)-and 2-dimethylaminomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Use the described method that is used to prepare embodiment 5g, can be by embodiment 3g compound embodiment 5n compound.
5o. (2R, 4aR, 10aR)-and 2-methyl fluoride-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Use the described method that is used to prepare embodiment 5g, can be by embodiment 3h compound embodiment 5o compound.
6a1. (2R, 4aR, 10aR)-and 2-pyrazol-1-yl methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
With embodiment 3j1 compound (27mg 0.08mmol) is dissolved among the DMA (2.5mL), add KF (9mg, 0.16mmol) and thiophenol (0.04mL, 0.40mmol).In the microwave treatment bottle of sealing, this solution is heated to 210 ℃ and kept 1 hour.After being cooled to room temperature, crude product through the silica gel chromatography purifying (eluent: the 0-100%EtOAc/ heptane, 0-10%MeOH/EtOAc), subsequently by the HPLC purifying.Obtain 7.5mg 6a1, be oily matter.LC/MS (method 350): RT 0.40 minute, ELSD 99.9%, UV 100%.MH
+: 328.0.
1H?NMR(500MHz，DMSO)δ0.96(t，J＝7,27Hz，3H)，1.54-1.67(m，1H)，1.70-1.82(m，1H)2.41(dd，J＝16.92，J＝10.69，1H)，2.51(bs，1H)，2.85(t，J＝13.90，2H)，2.97-3.14(m，2H)，3.34-3.71(m，3H)，3.92-3.99(m，1H)，4.25-4.42(m，3H)，6.29(s，1H)，6.60(dd，J＝7.45，1H)，6.66(d，J＝7.66，1H)，6.99(t，J＝7.89，1H)，7.51(s，1H)，7.75(d，J＝1.53，1H)；
C
19H
26N
3O
2：
HRMS calculated value: 328.2020[M+H
+]; Measured value 328.2011.
6a2. (2S, 4aS, 10aS)-and 2-pyrazol-1-yl methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 6a1, initial by embodiment 3j2, obtain embodiment 6a2 compound.Obtain 8.0mg, be oily matter.LC/MS (method 350): RT 0.41 minute, ELSD 100%, UV 100%.MH
+: 328.0.
1The data consistent that H NMR data and embodiment 6a1 are reported.
C
19H
26N
3O
2：
HRMS calculated value: 328.2020[M+H
+]; Measured value: 328.2020.
6b1. (2S, 4aR, 10aR)-and 2-pyrazol-1-yl methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 6a1, initial by embodiment 3k1 compound, obtain embodiment 6b1 compound.Obtain 12mg, be oily matter.LC/MS (method 350): RT 0.39 minute, ELSD 99.4%, UV 100%.MH
+: 328.0.
1H?NMR(500MHz，DMSO)δ0.77(t，J＝7,27Hz，3H)，1.41-1.62(m，2H)，2.14(dd，J＝16.67，J＝10.24，1H)，2.31(bs，1H)，2.77-2.94(m，3H)，3.19-3.32(m，4H)，3.38(d，J＝13.28，3H)，4.15(dd，J＝16.23，J＝10.05，1H)，4.22-4.34(m，2H)，4.70(dd，J＝14.11，J＝9.45?1H)，6.09(s，1H)，6.43(dd，J＝7.62，1H)，6.48(d，J＝7.99，1H)，6.81(t，J＝7.62，1H)，7.31(s，1H)，7.63(s，1H)；
C
19H
26N
3O
2：
HRMS calculated value: 328.2020[M+H
+]; Measured value: 328.2016.
6b2. (2R, 4aS, 10aS)-and 2-pyrazol-1-yl methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 6b2, initial by embodiment 3k2 compound (40mg), obtain embodiment 6b2 compound.Obtain 7mg, be oily matter.LC/MS (method 350): RT 0.40 minute, ELSD 100%, UV 100%.MH
+: 328.0.
1The data consistent that H NMR data and embodiment 6a2 are reported.
C
19H
26N
3O
2：
HRMS calculated value: 328.2020[M+H
+]; Measured value: 328.2012.
6c. (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
With embodiment 3l compound (8mg, 0.02mmol) be dissolved among the DMA (0.7mL) and add KF (2mg, 0.04mmol) and thiophenol (0.01mL, 0.11mmol).In the microwave treatment bottle of sealing, this solution is heated to 220 ℃ and kept 1 hour.After being cooled to room temperature, solvent to be removed, resistates is through the silica gel chromatography purifying, with after HPLC.Obtain 2.6mg embodiment 6c compound, be white solid.LC/MS (method 350): RT 0.48 minute, ELSD 100%, UV 100%.MH
+: 362.4.
1H?NMR(500MHz，DMSO)δ0.95(t，J＝7,26Hz，3H)，1.55-1.68(m，1H)，1.69-1.81(m，1H)，2.40(dd，J＝16.60，J＝10.62，1H)，2.51(bs，1H)，2.82-3.05(m，2H)，3.10(dd，J＝16.71，J＝5.83，1H)，3.25-3.72(m，2H)，3.95(d，J＝5.99，1H)，(dd，J＝15.78，J＝10.27，1H)，4.24-4.40(m，3H)，4.44-4.50(m，1H)，6.60(d，J＝7.67，1H)，6.66(d，J＝7.67，1H)，6.99(t，J＝7.82，1H)，7.61(s，1H)，7.99(s，1H)；9.66(bs，1H).
C
19H
25Cl
1N
3O
2：
HRMS calculated value: 362.1630[M+H
+]; Measured value 362.1628.
6d. (2S, 4aR, 10aR)-2-(4-chloro-pyrazol-1-yl methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 6c, initial by embodiment 3m compound (26mg), obtain embodiment 6d compound.Obtain 6.4mg compound 6d, be white solid.LC/MS (method 350): RT 0.47 minute, ELSD 100%, UV 100%.MH
+: 362.4.
1H?NMR(500MHz，DMSO)δ0.96(t，J＝7,27Hz，3H)，1.57-1.81(m，2H)，2.32(dd，J＝16.32，J＝10.42，1H)，2.51(bs，1H)，2.93-3.06(m，3H)，3.42-3.60(bs，4H)，4.30(dd，J＝15.78，J＝10.27，1H)，4.39(dd，J＝14.50，J＝4.50，1H)，4.44-4.50(m，1H)，4.89(dd，J＝14.32，J＝10.321H)，6.63(d，J＝7.67，1H)，6.67(d，J＝7.67，1H)，7.00(t，J＝7.82，1H)，7.61(s，1H)，8.10(s，1H)；9.67(bs，1H).
C
19H
25Cl
1N
3O
2：
HRMS calculated value: 362.1630[M+H
+]; Measured value 362.1624.
6e. (2R, 4aR, 10aR)-and 2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
With embodiment 3n compound (60mg, 0.14mmol) be dissolved among the DMA (0.7mL) and add KF (16mg, 0.28mmol) and thiophenol (0.07mL, 0.70mmol).In the microwave treatment bottle of sealing this solution being heated to 220 ℃ kept 1 hour.After being cooled to room temperature, solvent steamed removes, resistates through chromatogram purification (wash-out: the 0-100%EtOAc/ heptane), with after the HPLC purifying.Obtain 15.6mg embodiment 6e, be oily matter.LC/MS (method 350): RT0.57 minute, ELSD 99.5%, UV 85.6%.MH
+: 404.3.
1H?NMR(500MHz，DMSO)δ0.79(t，J＝7,16Hz，3H)，1.57-1.69(m，1H)，1.70-1.84(m，1H)，2.44(dd，J＝16.74，J＝10.37，1H)，2.51(bs，2H)，2.55(s，1H)，2.87(dd，J＝14.88，J＝12.08，1H)，3.00-3.09(m，1H)，3.12(dd，J＝16.57，J＝6.15，1H)(s，1H)3.73(d，J＝12.23，3H)，3.99(m，1H)，4.31-4.48(m，3H)，6.61(d，J＝7.60，1H)，6.67(d，J＝8.00，1H)，6.77(d，J＝2.13，1H)，6.99(t，J＝7.74，1H)，7.31(t，J＝7.27，1H)，7.41(t，J＝7.55，1H)，7.79-7.83(m，3H)，9.67(bs，1H).
C
25H
30N
3O
2：
HRMS calculated value: 404.2333[M+H
+]; Measured value 404.2339.
6f. (2S, 4aR, 10aR)-and 2-(4-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol trifluoroacetate
Adopt the described method that is used for embodiment 6e, initial by embodiment 3o compound (66mg), obtain embodiment 6f compound.Obtain 4.9mg, be oily matter.LC/MS (method 350): RT 0.58 minute, ELSD 100%, UV 88.7%.MH
+: 404.3.
1H?NMR(500MHz，DMSO)δ0.79(t，J＝7,22Hz，3H)，1.39-1.65(m，2H)，2.16(dd，J＝16.74，J＝10.37，1H)，2.32(bs，2H)，2.36(s，1H)，2.80-2.98(m，3H)，3.11-3.47(m，3H)，4.10-4.30(m，1H)，4.31-4.40(m，1H)，4.76(dd，J＝15.23，J＝11.563.58，1H)，6.45(d，J＝7.82，1H)，6.49(d，J＝7.48，1H)，6.57(d，J＝2.25，1H)，6.82(t，J＝7.80，1H)，7.12(t，J＝7.33，1H)，7.22(t，J＝7.62，2H)，7.62(d，J＝7.33，2H)，7.73(d，J＝1.89，1H)，9.43(bs，1H).
C
25H
30N
3O
2
HRMS calculated value: 404.2333[M+H
+]; Measured value 404.2330.
7 (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-8,9-glycol trifluoroacetate
(1.5mL, 2M is at Et to add HCl in the solution of intermediate VI (16mg) in MeOH (1mL) that stirs
2Among the O).At room temperature with this solution stirring 15 minutes, vacuum concentration subsequently.This resistates is suspended among the MeOH (1mL).Add propionic aldehyde (18mg), NaCNBH
3(18mg) and AcOH (1), at room temperature with this solution stirring 0.5 hour.Add more NaCNBH
3(18mg), solution leniently is heated to 40 ℃ and kept 2 minutes.With the crude mixture vacuum concentration, resistates is through the HPLC purifying.Obtain 4mg embodiment 7 compounds, be oily matter.LC/MS (method 102): RT 0.59 minute, ELSD 100%, UV89.3%.MH
+: 264.1.
8a (6aR, 10aR)-7-methyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene trifluoroacetate
At room temperature, in the microwave reaction bottle, in intermediate VII (9mg), add LAH (1mL, 1M is in THF).With bottle sealing, under 90 ℃, microwave radiation, this mixture was stirred 0.5 hour.This reaction is by adding wet Na
2SO
4Come quencher.The Na of suspension drying
2SO
4Filter, and with the filtrate vacuum concentration.Resistates is through the HPLC purifying.Obtain 1.4mg embodiment 8a compound, be oily matter.LC/MS (method 102): RT 0.75 minute, ELSD 100%, UV 90.6%.MH
+: 248.1.
8b (6aR, 10aR)-7-ethyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene trifluoroacetate
(1.5mL, 2M is at Et to add HCl in the solution of intermediate VII (3mg) in MeOH (1.5mL) that stirs
2Among the O).At room temperature with this solution stirring 5 minutes, subsequently with its vacuum concentration.Be dissolved in resistates among the DMF (0.5mL) and add K
2CO
3(22mg) and iodoethane (30 μ L).Under 70 ℃, this suspension was stirred 0.25 hour, will extract in its impouring water (5mL) and with EtOAc (2x 10mL) subsequently.The organic extract liquid salt water washing that merges, dry (Na
2SO
4).With rough mixture vacuum concentration, resistates is through the HPLC purifying.Obtain 0.8mg embodiment 8b compound, be oily matter.LC/MS (method 101): RT 0.52 minute, ELSD 100%, and UV 90.0%, MH
+: 262.2.
8c (6aR, 10aR)-7-n-propyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene trifluoroacetate
(1.5mL, 2M is at, Et to add HCl in the solution of intermediate VII (9mg) in MeOH (1.5mL) that stirs
2Among the O).At room temperature with this solution stirring 1.5 hours, subsequently with its vacuum concentration.Be dissolved in resistates among the DMF (1mL) and add K
2CO
3(45mg) and propyl iodide (0.055mL).Under 70 ℃, this suspension was stirred 1 hour, will extract in its impouring water (5mL) and with EtOAc (2x 10mL) subsequently.The organic extraction layer salt water washing that merges, dry (Na
2SO
4), vacuum concentration subsequently, resistates is through the HPLC purifying.Obtaining 4.6mg embodiment 8c compound is white solid.LC/MS (method 102): RT 0.92 minute, ELSD 100%, UV 95.2%.MH
+: 276.3.
The abbreviation of used chemical and tabulation
Use following abbreviation.This paragraph has also been listed chemical and their commercial source (not comprising standard solvent) used.
AcOH=acetate.Allyl bromide 98 (for example Fluka 05870).α
D=specific optical rotation.Boc
2(for example Aldrich 19,913-3) for O=Boc acid anhydrides/tert-Butyl dicarbonate.Salt solution=saturated sodium chloride aqueous solution.The BSA=bovine serum albumin.The cAMP=cAMP.CH
2(Aldrich 13,526-7) for the BrCl=bromochloromethane.CH
3(for example Aldrich 28,956-6) for I=methyl-iodide/methyl iodide.Chinese hamster ovary celI=Chinese hamster ovary cell.(for example Aldrich 10,449-3) for the ClAcCl=chloroacetyl chloride.Cs
2CO
3=cesium carbonate (Aldrich 441902).(Aldrich 24,240-3) for cyclopropyl monobromomethane/(brooethyl)-cyclopropane.The DA=Dopamine HCL.The D1=d1 dopamine receptor.The D2=d2 dopamine receptor.The D3=dopamine D 3 receptor.The D4=dopamine d 4 receptor.D5=dopamine D 5 acceptors.DCM=methylene dichloride/METHYLENE CHLORIDE.The DMF=dimethyl formamide.The DMSO=dimethyl sulfoxide (DMSO).L-DOPA=(left-handed)-3, the 4-dopa.EC
50=cause that half responds required concentration between baseline and the testing compound peak response.The scattering of light of ELSD=vapo(u)rability detects.Et
3The N=triethylamine.Et
2The NH=diethylamine.The EtOAc=ethyl acetate.The 99%EtOH=dehydrated alcohol.Ethylmagnesium bromide is (with at Et
23M solution among the O uses; For example Aldrich 18,987-1).Et
2The O=ether.[(1-oxyethyl group-cyclopropyl)-oxygen base] trimethyl silane (Aldrich 332739).35%H
2O
2(for example Aldrich 34,988-7) for=35% aqueous hydrogen peroxide solution.The FSB=foetal calf serum.H=hour.The HCl=hydrochloride aqueous solution (as not specifying, is Et
2O solution, it is commercially available, for example Aldrich 45,518-0).The HMPA=hexamethyl phosphoric triamide.The HRMS=high resolution mass spectrometry.I=is different.IBMX=3-isobutyl--1-methyl xanthine.The i.d.=internal diameter.(for example Aldrich 17,188-3) for propyl iodide.K
2CO
3(for example Aldrich 20,961-9) for=salt of wormwood.KMnO
4(for example Aldrich 39,912-4) for=potassium permanganate.KO=knocks out.LC/MS=high performance liquid phase/mass spectrum.The LAH=lithium aluminum hydride (uses with 1M THF solution; For example Aldrich 21,277-6).The L-Selectride=3-sec-butyl lithium borohydride (uses with 1M THF solution; Aldrich 17,849-7).The MDO=methylene-dioxy.The MED=minimal effective dose.MED
Nemonapride=minimal effective dose in the presence of nemonapride.MeOH=methyl alcohol.Methoxyacetyl chloride (for example Aldrich M965-3).Min=minute.The MBD=minimal brain dysfunction (MBD).N=just.NaCNBH
3(for example Aldrich 15,615-9) for=sodium cyanoborohydride.(use with 60% dispersion, for example Aldrich 45,291-2) for the NaH=sodium hydride.1M/9M NaOH=1M/9M aqueous sodium hydroxide solution.The NaOMe=sodium methylate (uses with the solution of about 5M in methyl alcohol; For example Aldrich 15,625-6).The 6-OHDA=6-hydroxydopamine.PBS=phosphate buffer salt (the 0.02M sodium phosphate buffer that contains 0.15M sodium-chlor, pH regulator to 7.4).The PD=Parkinson's disease.The PFC=prefrontal cortex.(for example Aldrich 20,569-9) for Pd/C=palladium/carbon.The PK=pharmacokinetics.The PLMD=Periodic limb movement disorder.(for example Aldrich 58,812-4) for propionic aldehyde.The RLS=restless leg syndrome.The rt=room temperature.The RT=retention time.Saturated NaHCO
3=saturated sodium bicarbonate aqueous solution.Saturated NH
4The aqueous ammonium chloride solution that Cl=is saturated.SC=is subcutaneous.The overcritical flash chromatography of SFC=.Uncle tert=.(for example Aldrich 14,077-5) for the TBAI=tetrabutylammonium iodide.The TFA=trifluoroacetic acid.THF=tetrahydrofuran (THF) (warp
Molecular sieve drying).UV=ultraviolet purity (except as otherwise noted, otherwise under 254nm, measure).
Pharmacology test
D1 cAMP analyzes
Following mensuration compound the stably express people recombinate the D1 acceptor the Chinese hamster ovary celI moderate stimulation or suppress the ability that the receptor-mediated cAMP of D1 forms.In test preceding 3 days, the concentration of cell with 11000 cells/well is seeded in 96 orifice plates.Testing the same day, with G damping fluid (the 1mM MgCl among PBSs (phosphate-buffered salt) of cell with preheating
2, 0.9mM CaCl
2, 1mMIBMX (3-isobutyl-1-methylxanthine)) in washing once and the mixture by test compound (antagonism) that adds 100 μ L 30nMA68930 and in the G damping fluid, dilute or the test compound (excitement) that in the G damping fluid, dilutes start mensuration.Under 37 ℃ with cell cultures 20 minutes, by adding 100 μ L S damping fluid (0.1M HCl and 0.1mM CaCl
2) stop this reaction, with this plate place 4 ℃ following 1 hour.Add 68 μ L N damping fluids (0.15M NaOH and 60mMNaOAc) also with this plate jolting 10 minutes.60 μ L reaction solutions are transferred to the cAMP FlashPlates (DuPont NEN) that contains 40 μ L 60mM sodium acetates (pH 6.2) and add 100 μ L IC mixture (50mM sodium acetate (pH 6.2), 0.1% sodiumazide, 12mM CaCl
2, 1%BSA (bovine serum albumin) and 0.15 μ-Ci/mL
125I-cAMP).Cultivation is after 18 hours down at 4 ℃, and the plate washing once and in Wallac TriLux counter is counted.
D2cAMP measures
Following mensuration compound has the Chinese hamster ovary celI moderate stimulation of people D2 acceptor or suppresses the ability that the receptor-mediated inhibition of D2 cAMP forms in transfection.In test preceding 3 days, the concentration of cell with 8000 cells/well is seeded in 96 orifice plates.Testing the same day, with G damping fluid (the 1mM MgCl of cell with preheating
2, 0.9mM CaCl
2, 1mM IBMX, in PBS) in washing once, this mensurations starts mensuration by adding 100 μ L 1 μ M quinpirole, 10 μ M forskolins in the G damping fluid and the mixture of test compound (antagonism) or 10m M forskolin in the G damping fluid and test compound (excitement).Under 37 ℃ with cell cultures 20 minutes, by adding 100 μ l S damping fluid (0.1M HCl and 0.1mM CaCl
2) stop this reaction, with this plate place 4 ℃ following 1 hour.Add 68 μ L N damping fluids (0.15M NaOH and 60mM sodium acetate) also with this plate jolting 10 minutes.60 μ L reaction solutions are transferred among the cAMP FlashPlates (DuPont NEN) that contains 40 μ L 60mM NaOAc (pH6.2), and add 100 μ L IC mixture (50mM NaOAc (pH 6.2), 0.1% sodiumazide, 12mM CaCl
2, 1%BSA and 0.15 μ-Ci/ml
125I-cAMP)., after 18 hours the plate washing once and on the WallacTriLux counter is counted 4 ℃ of cultivations.
D1/D2 analyzes (dissections)
Dopamine agonist can have activity to D1-sample acceptor, D2-sample acceptor or the two.We have used rotation to reply assessing compound to stimulate two kinds of acceptor types and have induced ability [Ungerstedt, the Arbuthnott of rotation in the rat of the one-sided infringement of 6-OHDA; Brain Res., 24,485 (1970); Setler, Sarau, Zirkle, Saunders; Eur.J.Pharmacol., 50 (4), 419 (1978); Ungerstedt, Herrera-Marschitz, Jungnelius,
Tossman,
In " Advances in Dopamine Research (Dopamine HCL progress) " (Kohsaka, Ed.), Pergamon Press, Oxford, p.219 (1982)].Experiment comprises measures the minimal effective dose (MED) that testing compound brings out rotation.In case determined MED, carried out second experiment and measure the MED (MED that compound overcomes the nemonapride blocking-up
Nemonapride).Nemonapride is the D2-sample antagonist of blocking-up D2-sample acceptor, and therefore any observed rotation will be depended on the activity to D1-sample acceptor.At last, in case MED
NemonaprideFor known, then use MED
Nai Mobi SharpThe effect that dosage carries out the 3rd experiment and observes independent D1-sample antagonist SCH 23390, independent D2-sample antagonist, the effect of last SCH 23390 and nemonapride combination therapy.The activity of described compound to two kinds of acceptors proved conclusively in this 3rd experiment, because independent antagonist only can partly suppress to be replied by the rotation that test compound brings out, and whole rotations [Arnt, the Hytell of rat have been blocked in combination therapy fully; Psychopharmacology, 85 (3), 346 (1985); Sonsalla, Manzino, Heikkila; J.Pharmacol Exp.Ther., 247 (1), 180 (1988)].Use Apomorphine this model to be come into force as principle proof property (proof-of-principle) compound of Combination D1-sample/D2-sample agonist.
D5 measures
Use the pEXJ carrier of improvement to produce people D5 (hD5) expression construct.Express hybridization people's proteic stable cell lines of Galpha16 G (CHO-Ga16) available from (Molecular Devices, Sunnyvale, CA).Under 37 ℃, 5%CO
2In, (Invitrogen, Carlsbad cultivate in CA) at the HAMS F-12 substratum that contains 10%FSB, 1%L-glutamine and 1% penicillin/streptomycin (P/S) with cell.In mensuration preceding 48 hours, the CHO-Ga16 cell uses lipofectamine Plus method, and (Invitrogen, Carlsbad CA), and were allowed to condition in the substratum of serum and no P/S and grew 1 day with the of short duration transfection of hD5 receptor dna.In mensuration preceding 24 hours, with the density of 10,000 cells in every hole with the CHO-Ga16 cell inoculation of hD5 transfection with poly--(Becton Dickinson is USA) in the 384-orifice plate of pretreated black wall clear bottom for D-Methionin.Subsequently under 37 ℃, 5%CO
2In cell is cultivated in the HAMS F-12 cell growth medium that contains 1.5%FBS, 1%L-glutamine and 1% penicillin/streptomycin (P/S).
External liver cell is measured
The male rat liver cell of cryopreserved merging (Sprague Dawley) and from the human liver cell of 10 contributors' (masculinity and femininity) merging available from In Vitro Technologies Inc., BA, USA.In 37 ℃ of water-baths with cell thawing, viable count and the 100 μ L altogether that are seeded in 96 orifice plates contain in the Eagle substratum (high sugar) of the Dulbecco ' s improvement of 5mM Hepes buffer reagent, contain 250.000 and 500.000 every milliliter respectively for rat hepatocytes and each hole of human liver cell., begin cultivation and stopped cultivation in time point termination cultivation in 0,5,15,30 and 60 minutes with for human liver cell in 0,30,60,90 and 120 minutes at time point after 15 minutes in pre-cultivation for rat hepatocytes.Stop cultivating by adding isopyknic ice-cooled acetone that contains 10%1M HCl.Centrifugal subsequently, the supernatant liquor of 20 μ L is injected HPLC post Atlantis dC18 3 μ m, 150x 2.1mm i.d. (Waters, MA, USA) on.Moving phase has following composition: A:5% acetone, 95%H
2O, 3.7ml/l 25%NH
3The aqueous solution, 1.8mL/L formic acid.Mobile phase B: 100% acetone and 0.1% formic acid.Flow velocity is 0.3ml/ minute.Becoming 75%B by 0% between 5 minutes to 20 minutes carries out gradient elution and uses Q-TOFmicro mass spectrograph (Waters, MA, USA) analysis elutriant.Compare by the formation of accurate mass measurement affirmation product/metabolite and with the synthetic standard substance that obtains consistent retention time.
Radioligand is in conjunction with measurement result
For the EC50 value of most compounds among the present invention, as above illustrational, for people D1 and D2 acceptor, be about 5.0 μ M or lower.The binding affinity that records chemical compound lot is about 1.0 μ M or lower.The binding affinity that records several compound is about 500nM or lower.The binding affinity that records several compounds is 100nM or lower.
Table I: EC 50 values of selected compounds
Claims (24)
1. compound with structure I
Wherein
● X does not exist or is oxygen
Zero when X is oxygen, R
1And R
2Be independently selected from hydrogen; C
1-C
6Alkyloyl; C
6-C
10Aryl-C
1-C
6Alkyloyl; Or R
1With R
2Condense and form methylene radical (CH
2),
Zero when X does not exist, R
1Be selected from hydrogen; C
1-C
6Alkyl; C
1-C
6Alkyloyl; C
6-C
10Aryl-C
1-C
6Alkyloyl; And R
2Be hydrogen,
● R
3Be selected from hydrogen; C
1-C
4Alkyl; Allyl group; Propargyl; C
3-C
4Cycloalkyl; Hydroxyalkyl; C
2-C
3Haloalkyl;
● R
4Be selected from hydrogen; C
1-C
6Alkyl; C
6-C
10Aryl-C
1-C
6Alkyl; Heteroaryl-C
1-C
6Alkyl; Two (C
1-C
6Alkyl) amino-C
1-C
6Alkyl; C
1-C
6Alkylthio-C
1-C
6Alkyl; C
1-C
6Hydroxyalkyl; And C
1-C
6Haloalkyl,
Each C wherein
6-C
10Aryl and heteroaryl can be selected from halogen, C
1-C
6Alkyl, C
1-C
6The substituting group of alkoxyl group replaces;
And enantiomer, diastereomer, tautomer and pharmaceutically acceptable addition salt, with and polymorphic forms.
2. the compound of claim 1, wherein X is an oxygen, R
1, R
2, R
3And R
4As definition in the claim 1.
3. the compound of claim 1, wherein X does not exist, R
1, R
2, R
3And R
4As definition in the claim 1.
4. the compound of claim 2, wherein R
1And R
2Be hydrogen, R
3And R
4As definition in the claim 1.
5. the compound of claim 2, wherein R
1And R
2Condense and form methylene radical (CH
2), R
3And R
4As definition in the claim 1.
6. the compound of claim 2, wherein R
1And R
2In at least one is C
1-C
6Alkyloyl, phenyl acetyl or benzoyl, R
3And R
4As definition in the claim 1.
7. the compound of claim 3, wherein R
1Be hydrogen, R
2, R
3And R
4As definition in the claim 1.
8. the compound of claim 3, wherein R
1Be C
1-C
6Alkyloyl, phenyl acetyl or benzoyl, R
2, R
3And R
4As definition in the claim 1.
9. each compound, wherein R during aforesaid right requires
4Be hydrogen.
10. each compound, wherein R among the claim 1-8
4Be not hydrogen.
Each compound, wherein R during 11. aforesaid right requires
3Be C
1-C
4Alkyl.
12. the compound of claim 11, wherein R
3Be methyl, ethyl or n-propyl.
Each compound during 13. aforesaid right requires, wherein said heteroaryl is selected from pyrazolyl, imidazolyl and 1,2,4-triazolyl.
14. each compound, wherein R among the claim 2-4
4Be hydrogen, the feature of described compound also be into basically pure (4aR, 10aR)-enantiomer.
15. each compound, wherein R among the claim 2-4
4Be not hydrogen, the feature of described compound also be into basically pure (2R, 4aR, 10aR)-enantiomer.
16. each compound, wherein R among the claim 2-4
4Be not hydrogen, the feature of described compound also be into basically pure (2S, 4aR, 10aR)-enantiomer.
17. the compound of claim 5, wherein R
4Be hydrogen, the feature of described compound also be into basically pure (6aR, 10aR)-enantiomer.
18. the compound of claim 5, wherein R
4Be not hydrogen, the feature of described compound also be into basically pure (2R, 6aR, 10aR)-enantiomer.
19. the compound of claim 5, wherein R
4Be not hydrogen, the feature of described compound also be into basically pure (2S, 6aR, 10aR)-enantiomer.
20. the compound of claim 1, wherein said compound is selected from:
1) (4aR, 10aR)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
2) (4aS, 10aS)-9-methoxyl group-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
3) (4aR, 10aR)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
4) (4aS, 10aS)-4-ethyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
5) (4aR, 10aR)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
6) (4aS, 10aS)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
7) (4aR, 10aR)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
8) (4aS, 10aS)-4-allyl group-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
9) (4aR, 10aR)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
10) (4aS, 10aS)-4-cyclopropyl methyl-9-methoxyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
11) (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
12) (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
13) (2S, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
14) (2R, 4aR, 10aR)-and 9-methoxyl group-2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
15) (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
16) (2R, 4aR, 10aR)-and 9-methoxyl group-2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
17) ((2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-2-ylmethyl)-dimethyl amine;
18) (2R, 4aR, 10aR)-and 2-methyl fluoride-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
19) (2S, 4aR, 10aR)-and 9-methoxyl group-2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
20) (2R, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
21) (2S, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
22) (2S, 4aR, 10aR)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
23) (2R, 4aS, 10aS)-and 9-methoxyl group-4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
24) (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
25) (2S, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-9-methoxyl group-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
26) (2R, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
27) (2S, 4aR, 10aR)-and 9-methoxyl group-2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine;
28) (4aR, 10aR)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
29) (4aS, 10aS)-4-ethyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
30) (4aR, 10aR)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
31) (4aS, 10aS)-4-methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
32) (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
33) (4aS, 10aS)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
34) (4aR, 10aR)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
35) (4aS, 10aS)-4-allyl group-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
36) (4aR, 10aR)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
37) (4aS, 10aS)-4-cyclopropyl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
38) (2R, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
39) (2S, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
40) (2S, 4aR, 10aR)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
41) (2R, 4aS, 10aS)-and 2-methylol-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
42) (2S, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
43) (2R, 4aR, 10aR)-and 4-n-propyl-2-[1,2,4] triazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
44) (2S, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
45) (2R, 4aR, 10aR)-and 2-methylthiomethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
46) (2S, 4aR, 10aR)-and 2-methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
47) (2R, 4aR, 10aR)-and 2-imidazoles-1-ylmethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
48) (2R, 4aR, 10aR)-and 2-methoxymethyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
49) (2S, 4aR, 10aR)-and 2-dimethylamino methyl-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
50) (2R, 4aR, 10aR)-and 2-methyl fluoride-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
51) (2R, 4aR, 10aR)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
52) (2S, 4aS, 10aS)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
53) (2S, 4aR, 10aR)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
54) (2R, 4aS, 10aS)-and 4-n-propyl-2-pyrazol-1-yl methyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
55) (2R, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
56) (2S, 4aR, 10aR)-and 2-(4-chloro-pyrazol-1-yl methyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
57) (2R, 4aR, 10aR)-and 2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
58) (2S, 4aR, 10aR)-and 2-(3-phenyl-pyrazole-1-ylmethyl)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-9-alcohol;
59) (4aR, 10aR)-4-n-propyl-3,4,4a, 5,10,10a-six hydrogen-2H-naphtho-[2,3-b] [1,4]
Piperazine-8, the 9-glycol;
60) (6aR, 10aR)-7-methyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene;
61) (6aR, 10aR)-7-ethyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene; With
62) (6aR, 10aR)-7-n-propyl-6a, 7,8,9,10a, 11-six hydrogen-6H-1,3,10-trioxa-7-azepine-cyclopenta [a] anthracene,
Or its pharmaceutically acceptable addition salt.
21. a pharmaceutical composition, described pharmaceutical composition comprise compound and the pharmaceutically acceptable carrier or the thinner of the claim 1 for the treatment of significant quantity.
22. each compound or its pharmaceutical acceptable acid additive salt are used for the treatment of purposes in the medicine of neurodegenerative disease that Mammals suffers from preparation in the claim 1 to 20.
23. the purposes of claim 22, wherein said neurodegenerative disease are Parkinson's disease.
24. the purposes of claim 22, wherein said neurodegenerative disease are Huntington Chorea.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200800887 | 2008-06-27 | ||
| DKPA200800887 | 2008-06-27 | ||
| PCT/EP2009/057928 WO2009156458A1 (en) | 2008-06-27 | 2009-06-24 | Novel phenolic and catecholic amines and prodrugs thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102131790A true CN102131790A (en) | 2011-07-20 |
Family
ID=41066579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200980133807XA Pending CN102131790A (en) | 2008-06-27 | 2009-06-24 | Novel phenolic and catecholic amines and prodrugs thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2303851A1 (en) |
| JP (1) | JP2011525893A (en) |
| CN (1) | CN102131790A (en) |
| WO (1) | WO2009156458A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077754A2 (en) * | 1981-10-16 | 1983-04-27 | Sandoz Ag | Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivatives |
| CN1222516A (en) * | 1997-09-01 | 1999-07-14 | 阿迪尔公司 | Naphth oxazines derivvs., process for their preparation and pharmaceutical compositions containing them |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2093837B (en) * | 1981-03-02 | 1985-04-24 | Abbott Lab | Aminoalkyl subsituted 1,2,3,4-tetrahydronaphtalenes |
| ZA827062B (en) * | 1981-09-28 | 1983-07-27 | Beecham Group Plc | Active compounds |
| JPH0227988B2 (en) * | 1981-10-16 | 1990-06-20 | Sandoz Ag | YAKURIGAKUTEKINIKATSUSEINASHINKI1 * 2 * 3 * 4 * 4A * 5 * 10 * 10AAOKUTAHIDOROOBENZO * G * KINORINJUDOTAI |
| PH22782A (en) * | 1983-02-01 | 1988-12-12 | Sandoz Ltd | Novel pharmaceutical active 1,2,3,4,4a,5,10,10a octahydrobenzo(g)quinoline derivatives |
| HU193979B (en) * | 1984-06-12 | 1987-12-28 | Sandoz Ag | Process for producing naphtoxazine derivatives and pharmaceutical compositions containing them |
| US5614526A (en) * | 1995-06-09 | 1997-03-25 | Hoffmann-La Roche Inc. | Use of phenoxy-piperzine derivatives |
| FR2747386B1 (en) * | 1996-04-12 | 1998-05-15 | Synthelabo | DERIVATIVES OF 3 - [(1,2,3,4-TETRAHYDROISOQUINOLEIN-2-YL) METHYL] -8-AZABICYCLO [3.2.1] OCTANE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| TWI404702B (en) * | 2007-08-31 | 2013-08-11 | Lundbeck & Co As H | Catecholamine derivatives and prodrugs thereof |
-
2009
- 2009-06-24 CN CN200980133807XA patent/CN102131790A/en active Pending
- 2009-06-24 JP JP2011515379A patent/JP2011525893A/en active Pending
- 2009-06-24 WO PCT/EP2009/057928 patent/WO2009156458A1/en active Application Filing
- 2009-06-24 EP EP09769306A patent/EP2303851A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077754A2 (en) * | 1981-10-16 | 1983-04-27 | Sandoz Ag | Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivatives |
| US4565818A (en) * | 1981-10-16 | 1986-01-21 | Sandoz Ltd. | Pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline derivatives |
| CN1222516A (en) * | 1997-09-01 | 1999-07-14 | 阿迪尔公司 | Naphth oxazines derivvs., process for their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (2)
| Title |
|---|
| ROBERTO PERRONE，等: "Dopaminergic and serotoninergic activity of p-dimethoxy-derivatives of octahydrobenzo[g]quinoline isosteres", 《MEDICINAL CHEMISTRY RESEARCH》 * |
| 苏胜 等: "抗帕金森病药物的研究进展", 《中国药物应用与监测》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2011525893A (en) | 2011-09-29 |
| WO2009156458A1 (en) | 2009-12-30 |
| EP2303851A1 (en) | 2011-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5802792B2 (en) | Catecholamine derivatives useful for the treatment of Parkinson's disease | |
| US8129530B2 (en) | Catecholamine derivatives and prodrugs thereof | |
| RU2542103C2 (en) | 5-ht receptor modulators and methods for using them | |
| CN102131790A (en) | Novel phenolic and catecholic amines and prodrugs thereof | |
| CN115677719A (en) | Aryl heterocyclic compound and preparation method and application thereof | |
| ZA200403454B (en) | Novel mandelate salts of substituted tetracyclic tetrahydrofuran derivatives. | |
| US8067410B2 (en) | Phenolic and catecholic amines and prodrugs thereof | |
| CN101935305B (en) | Method for preparing trans-4-(IR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and salt thereof and use as a medicament | |
| Seidel et al. | Synthesis of [14C]‐labelled repinotan hydrochloride and its major metabolite M‐6 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1160121 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110720 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1160121 Country of ref document: HK |