CN105949203A - Octahydropyrrole[3, 4-c]pyrrole derivative and using method and application thereof - Google Patents
Octahydropyrrole[3, 4-c]pyrrole derivative and using method and application thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to an ctahydropyrrole[3, 4-c]pyrrole derivative and a using method and application thereof. A compound and a drug composition containing the same are used for resisting orexin receptors. The invention further relates to methods of preparing the compound and the drug composition and application of the compound and the drug composition in treating or preventing diseases related to the orexin receptors.
Description
Invention field
The invention belongs to technical field of pharmaceuticals, be specifically related to substituted (octahydro pyrrolo-[3, the 4-c] pyrroles-2 of a class
(1H)-yl) phenyl ketone compound, comprise the pharmaceutical composition of this compounds, and their using method and purposes.More
Specifically, compound of the present invention and pharmaceutical composition can be used for treating as orexin receptor antagonists, prevent or
Alleviate the disease relevant to orexin receptor.
Background of invention
Orexin (orexin) also referred to as hypothalamus secretin, appetite peptide, it includes orexin-A and orexin B (or inferior colliculus
Krinin-1 and hypothalamus secretin-2), it is a kind of neuropeptide secreted by hypothalamus, its main physiological action has: 1. regulation
Ingesting, orexin can be obviously promoted feed, and reacts in dose-dependant, and have activated the neuron of regulation feed；2. participate in
The regulation of energy metabolism, orexin can dramatically increase metabolic rate；3. participating in the regulation of Sleep-Wake, orexin can suppress quick
Eye Movement Sleep, extends the awakening time, and the effect blocking orexin can hypnotic；4. participate in endocrine regulation, orexin
Impact endocrine on pituitary hormone is clearly；5. relevant to remuneration sense, learning and memory；6. gastric acid secretion；7. promote
Drinking-water increases；8. raising blood pressure；9. play an important role in reward system and drug dependence mechanism, wait (Piper et al.,
The novel brain neuropeptide,orexin-A,modulates the sleep-wake cycle of
rats.Eur.J.Neuroscience,2000,12(2),726-730；and Sakurai,T.,et al.,The neural
circuit of orexin(hypocretin):Maintaining sleep and wakefulness.Nature Review
Neuroscience,2007,8:171181)。
Orexin produces physiological effect by acting on orexin receptor (orexin receptor, OXR).Orexin
Receptor is a kind of G-G-protein linked receptor, has two types, is called OX1Receptor and OX2Receptor, wherein OX1Receptor is to appetite
Element A has a selectivity, and OX2Receptor for orexin-A and orexin B be non-selective receptor (Sakurai T.et al.,
Orexins and orexin receptors:a family of hypothalamic neuropeptides and G
protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573-
585)。OX1Receptor and OX2Receptor almost exists only in cerebral tissue, and is optionally expressed in brain, wherein OX1Receptor with
High Cell Density And High Expression is in locus coeruleus (locus coeruleus), and it is the nuclei of origin of noradrenergic neuron, and OX2Receptor
With High Cell Density And High Expression in tuberomammillary nucleus, it is the nuclei of origin of histaminergic neuron.OX1Receptor and OX2The expression of both receptors can
Seeing in rapheal nuclei, it is the nuclei of origin of serotoninergic nerve unit, and is found in ventral tegmental area, and it is dopaminergic neuron
Nuclei of origin.Additionally, OX2Expression of receptor is also seen in the brain stem cholinergic neuron of responsible regulation rapid-eye-movement sleep (REM sleep) and to it
Nuclear activity has impact (Marcus, J.N.et al., Differential expression of orexin receptors
1and 2in the rat brain.J.Comp.Neurol.,2001,435(1):6-25；and Trivedi,P.et al.,
Distribution oforexin receptormRNA in the ratbrain.FEBSLett.,1998,438(1-2):
71-75)。
As can be seen here, orexin receptor has great importance on pathology, relates to relevant to multiple disease, such as, sleeps
Dormancy obstacle, depression, anxiety neurosis, Panic disorder, obsession, affective disease, depressibility neuropathy, anxious neuropathy, the heart
Border obstacle, panic attack obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sexual dysfunction, psychosis, spirit point
Split disease, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer, parkinson
Disease, the dyskinesia, drinking and eating irregularly, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, glycosuria
Disease, metabolic disease, immune correlated disease, endocrine relevant disease and hypertension etc..But, in the market with orexin receptor
Relevant medicine only has anti-insomnia medicine Su Woleisheng (Suvorexant) of Merck company research and development, and it is that orexin receptor is short of money
Anti-agent, this medicine was the most once suffering because of safety issue that the refusal of U.S. FDA was ratified.
In consideration of it, the invention provides a class there is the compound of orexin receptor antagonistic activity, with existing similarization
Compound is compared, and the compound of the present invention has more preferable drug activity, and toxic and side effects is less, and safety is higher, also simultaneously
There is excellent physicochemical property, medicine for character and toxicological characteristics, therefore, possess preferable potential applicability in clinical practice.
Summary of the invention
Hereinafter some aspects of the present invention are only summarized, it is not limited to this.These aspects and other parts are later
There is more complete explanation.All lists of references in this specification are incorporated in this by entirety.Work as the disclosure of the specification
With quote document variant time, be as the criterion with the disclosure of the specification.
The invention provides a class and there is the compound of orexin receptor antagonistic activity, be specifically related to octahydro pyrrolo-[3,
4-c] azole derivatives, and pharmaceutical composition, described compound and pharmaceutical composition may be used for preparation prevention or treatment with
The disease that orexin receptor is relevant.
The compounds of this invention shows good antagonistic activity to orexin receptor, has more preferable drug effect, medicine for character
And/or toxicological characteristics, the best brain/blood plasma ratio (brain plasma ratio), good bioavailability, good
Metabolic stability, low toxic and side effects and high security etc..Meanwhile, the good characteristic of some parameter of the compounds of this invention, as partly declined
The excellent spy of phase, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, permeability of the membrane, dissolubility etc.
Property, it is possible to promote the reduction of side effect, the expansion of therapeutic index or the improvement of toleration.
Specifically:
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I)
Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein, Hy, R1、R2、R3、R4、R5、R6、R7And R8There is implication as described in the present invention.
In one embodiment, Hy be phenyl or 5-6 unit heteroaryl, described phenyl and 5-6 unit heteroaryl individually optionally
It is independently selected from D, F, Cl, Br, I, C by one or more1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy or
The substituent group of benzyl is replaced.
In one embodiment, Hy is thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals or comprises two nitrogen-atoms
5-6 unit heteroaryl, described thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals and to comprise the 5-6 unit of two nitrogen-atoms miscellaneous
Aryl is independently selected from D, F, Cl, Br, I, C by one or more individually optionally1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl,
C1-6The substituent group of halogenated alkoxy or benzyl is replaced.
In another embodiment, Hy is thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals or to comprise two nitrogen former
Son 5-6 unit heteroaryl, described thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals and comprise two nitrogen-atoms 5-6 unit
Heteroaryl individually optionally by one or more selected from D, F, Cl, Br, I, methyl, ethyl, isopropyl, the tert-butyl group, trifluoromethyl,
The substituent group of difluoromethyl, 1,2-bis-fluoro ethyl, methoxyl group, ethyoxyl, isopropoxy, trifluoromethoxy or benzyl is replaced.
In one embodiment, Hy is triazolyl, is chosen in particular from the subformula shown in i-1 to i-14:
Wherein each subformula shown in i-1 to i-14 is the most one or more
It is independently selected from D, F, Cl, Br, I, methyl, ethyl, isopropyl, the tert-butyl group, trifluoromethyl, methoxyl group, isopropoxy, trifluoro methoxy
The substituent group of base or benzyl is replaced.
In one embodiment, the compound that the present invention relates to, it is for shown in the compound shown in formula (II) or formula (II)
The stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or front
Medicine,
Wherein, R1、R2、R3、R4、R5、R6、R7And R8There is implication as described in the present invention.
In one embodiment, the R in formula (I) or formula (II)1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、
Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl,
C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6The substituted alkyl of hydroxyl, (C1-6Alkyl)-C (=O)-, (C1-6Alkane
Epoxide)-C (=O)-, (C1-6Alkylamino)-C (=O)-, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl.
In one embodiment, the R in formula (I) or formula (II)5、R6、R7And R8Be each independently H, D, F, Cl, Br,
I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkane
Epoxide, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6The substituted alkyl of hydroxyl, (C1-6Alkyl)-C (=O)-, (C1-6Alkoxyl)-
C (=O)-, (C1-6Alkylamino)-C (=O)-, C3-6Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl.
In one embodiment, the R in formula (I) or formula (II)1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、
Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl,
C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The substituted alkyl of hydroxyl, (C1-4Alkyl)-C (=O)-, (C1-4Alkane
Epoxide)-C (=O)-or (C1-4Alkylamino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)5、R6、R7And R8Be each independently H, D, F, Cl, Br,
I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkane
Epoxide, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The substituted alkyl of hydroxyl, (C1-4Alkyl)-C (=O)-, (C1-4Alkoxyl)-
C (=O)-or (C1-4Alkylamino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、
Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3、-
CF2CF3, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3
Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)5、R6、R7And R8Be each independently H, D, F, Cl, Br,
I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3、-
CF2CF3, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2Or-CH2OH。
In one embodiment, compound of the present invention, it is to have the compound of one of following structure or have
One of the following stereoisomer of compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically
Acceptable salt or prodrug,
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound of the present invention.
In one embodiment, pharmaceutical composition of the present invention optionally comprises pharmaceutically acceptable carrier, tax
Shape agent, adjuvant or their combination in any.
On the other hand, the present invention relates to compound of the present invention or the pharmaceutical composition purposes in preparing medicine,
Described medicine is for preventing, treat or alleviate the disease relevant to orexin receptor.
In one embodiment, the described disease relevant to orexin receptor is sleep disorder, depression, anxiety neurosis, fears
Flurried disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorders, panic attack obstacle, behavior
Not normal, emotionally disturbed, posttraumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, spirit are wrong
Unrest, dementia, drug dependence, addiction, cognitive disorder, Alzheimer, parkinson, the dyskinesia, drinking and eating irregularly, head
Bitterly, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, the relevant disease of immunity
Disease, endocrine relevant disease or hypertension.
On the other hand, the present invention relates to compound of the present invention or the pharmaceutical composition purposes in preparing medicine,
Described medicine is used for antagonism orexin receptor.
On the other hand, the present invention relates to formula (I) or the side of the preparation of compound, separation and purification that formula (II) is comprised
Method.
Biological results shows, the compound that the present invention provides can be as preferable orexin receptor antagonists.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not
There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other
Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and
The content of his aspect will make more specific complete description below.
Summary of the invention
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This
Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition
In the range of.Those skilled in the art will appreciate that many similar with the of the present invention or method of equivalent and material can be used in
Put into practice the present invention.The present invention is not limited to method of the present invention and material.At the document combined, patent and similar material
One or more different from the application or conflicting in the case of (include but not limited to defined term, term application, institute
The technology described, etc.), it is as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments
Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity,
Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference
Bright.
Context except as otherwise noted or has significantly conflict, article used in the present invention " ", "
(kind) " and " described " be intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to
The article of one or more than one (i.e. at least one) object.Such as, " embodiment " refers to one or more embodiment.
Term " optionally " or " optionally " refer to the event described subsequently or situation can but not necessarily occur, and this is retouched
State and include situation that wherein said event or situation occur and wherein its absent variable situation.
Term " optionally by ... replaced ", can with term " unsubstituted or quilt ... replaced " exchange use, i.e.
Described structure or group are unsubstituted or are replaced by one or more substituent groups of the present invention, and wherein said replacement anticipates
Taste occur in structure or group any quantivalence allow rational position.Substituent group of the present invention includes,
But it is not limited to D, F, Cl, Br, I ,-N3、-CN、-NO2、-OH、-SH、-NH2, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyl,
Alkylthio group, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
It is said that in general, term " substituted " represents that the one or more hydrogen atoms in given structure or group are specifically replaced
Base is replaced.Unless other aspects show, a substituent group can replace in each commutable rational position of group.
The one or more concrete substituent group being selected from when more than one position in given structural formula is replaced, then substituent group
Can identical or differently in structural formula each rational position replace.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise
Content.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special
Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term
“C1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " represents single D-atom.
Term " hetero atom " represents one or more oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N),
Sulfur (S) and the form of phosphorus (P) any oxidation state；Primary, secondary, tertiary amine and the form of quaternary ammonium salt；Or the hydrogen on nitrogen-atoms in heterocycle
The form being replaced, such as, N (as 3, the N in 4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidinyl) or NR is (as N-
NR in substituted pyrrolidinyl).
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine
(I)。
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1-20 carbon atom, saturated straight chain or
Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention
Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4
Individual carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but does not limit
In, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH
(CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH
(CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
Term " thiazolinyl " expression straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which carbon-
Carbon sp2Double bond, wherein, described alkenyl group is optionally replaced by one or more substituent groups described in the invention, its bag
Include " cis " and the location of " trans ", or " E " and the location of " Z ".
Term " alkynyl " expression straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which carbon-
Carbon sp tri-key, wherein, described alkynyl group is optionally replaced by one or more substituent groups described in the invention.
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has
Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party
In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；?
In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more
The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-
OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH
(CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen
Base ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t-
BuO, t-butoxy ,-OC (CH3)3), etc..
Term " haloalkyl " represents that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has
Implication as described in the present invention, such example comprises, but is not limited to ,-CF3、-CF2CF3、-CH2CF2CHF2Deng.Real one
Executing in scheme, " haloalkyl " is the C of lower level1-4Haloalkyl, wherein said " C1-4Haloalkyl " comprise the substituted C of fluorine1-4
The substituted C of alkyl, chlorine1-4The substituted C of alkyl, bromine1-4The substituted C of alkyl, iodine1-4Alkyl, etc..Concrete, halogen atom replaces
C1-4Alkyl comprises-CH2F、-CHF2、-CF3、-CH2Cl、-CHCl2、-CCl3、-CH2Br、-CHBr2、-CBr3、-CH2CH2F、-
CH2CHF2、-CH2CF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-CHFCF3、-CHFCHF2、-CHFCH2F、-CH2CH2CF3、-
CH2CF2CHF2Etc..Described haloalkyl is optionally replaced by one or more substituent groups described in the invention.
Term " halogenated alkoxy " represents that alkoxy base is replaced by one or more halogen atoms, wherein alkoxyl base
Group has implication as described in the present invention, and such example comprises, but is not limited to ,-OCF3、-OCF2CF3、-OCH2CF2CHF2
Deng.Described halogenated alkoxy is optionally replaced by one or more substituent groups described in the invention.
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base
Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.
Term " the substituted alkyl of hydroxyl " represents that alkyl group is replaced by one or more oh groups, wherein alkyl base
Group has implication of the present invention.Such example comprises, but is not limited to methylol, ethoxy, 1,2-dihydroxy ethyl,
Etc..
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably herein, represent containing 3-12 ring carbon atom, unit price or
The monocycle of multivalence, dicyclo or three-ring system, its medium ring can be fully saturated or comprise one or more degree of unsaturation, but
One armaticity ring all can not have.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, represent and comprise 3-12 annular atoms, unit price or many
The monocycle of valency, dicyclo or three-ring system, on its medium ring, one or more atoms are replaced by hetero atom independently, described hetero atom
Having implication as described in the present invention, ring can be fully saturated or comprise one or more degree of unsaturation, but a fragrance
Property ring all can not have.
Term " cycloalkyl " represents containing 3-12 ring carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three rings
System.
Term " aryl " represents containing 6-14 annular atoms, or 6-10 annular atoms, or 6 annular atomses, unit price or many
The monocycle of valency, dicyclo or the carbocyclic ring system of three rings, at least one of which ring is aromatic.Aromatic yl group is usual, but necessarily
Ground is connected with parent molecule by the armaticity ring of aromatic yl group.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring "
Change use.The example of aromatic yl group can include phenyl, naphthyl, anthracene, etc..Described aromatic yl group is the most one or more
Substituent group described in the invention is replaced.
Term " heteroaryl " represents containing 5-14 annular atoms, or 5-10 annular atoms, or (the i.e. 5-6 of 5-6 annular atoms
Unit), unit price or the monocycle of multivalence, dicyclo or three-ring system, at least one of which ring is aromatic, and at least one ring comprises
One or more hetero atoms.Heteroaryl groups is usual, but necessarily by armaticity ring and the parent molecule of heteroaryl groups
Connect.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups is appointed
Selection of land is replaced by one or more substituent groups described in the invention.
The example of heteroaryl groups includes, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals,
4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-azoles
Base, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-
Pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazole radical (such as 5-tetrazole radical), triazole
Base (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-
Di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3-triazolyl, 1,2,3-thio biphosphole base, 1,3,4-sulfur
For di azoly, 1,2,5-thio biphosphole base, pyrazinyl, cyanuro 1,3,5；Also include following dicyclo, but be not limited to these
Dicyclo: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2-indyl), purine radicals, quinolyl are (such as 2-quinoline
Quinoline base, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo
[1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,
2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine
Base, etc..
As described in the present invention, attachment point can be connected with molecule remainder any attachable position on ring.
Such as, the Hy in the present invention can be triazolyl, on described triazolyl any attachable position all can as with molecule remaining
The junction point that part is connected, specifically comprises the subformula shown in i-1 to i-14:
Term " stereoisomer " refers to have identical chemical constitution, but atom or group spatially arrangement mode is different
Compound.Stereoisomer includes that enantiomer, diastereomer, conformer (rotamer), geometry are different
Structure body (cis/trans) isomer, atropisomer, etc..
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and
Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,
Inc,NewYork,1994.Many organic compound exist with optical active forms, and i.e. they have and make the flat of linearly polarized light
The ability that face rotates.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one
Individual or the absolute configuration of mulitiple chiral centers.Prefix d and l or (+) and (-) are to revolve for linearly polarized light caused by appointed compound
Turn symbol, wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete
Stereoisomer is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer:
50 mixture are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or three-dimensional special
During the opposite sex, may occur in which this situation.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties
Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization
Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art
The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product
Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping
Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates
and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric
Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,
E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables
of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.ofNotre
Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical
Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,
2007)。
What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low
Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach
The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually
Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and
Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to so some compounds, raw material, compositions and/or dosage form, and they are rationally doctor
Learn in the range of judging, it is adaptable to patient tissue contacts and without excessive toxicity, zest, allergy or with reasonably profit
Other problems that benefit/Hazard ratio is symmetrical and complication, and it is effective to given application.
Term used in the present invention " prodrug ", represents a compound and is converted in vivo shown in formula (I) or (II)
Compound.Such conversion hydrolyzed in blood by prodrug or blood or tissue in through enzymatic conversion be the shadow of precursor structure
Ring.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class as prodrug,
Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention
A compound comprise hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug shape
Formula includes phosphate ester, if these phosphate compounds are that the di on parent obtains.Complete about prodrug
Whole discussion is referred to documents below: Higuchi et al., Pro-drugs as Novel Delivery Systems,
Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug
Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et
al.,Prodrugs:Design and Clinical Applications,NatureReviews Drug Discovery,
2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,
J.Med.Chem., 2008,51,2328-2345, every document is incorporated herein by this.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention
Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound
Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound
Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base
The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid
Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document
Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist
Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur
Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal
Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid
Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2-naphthalene sulfonate, nicotinic acid
Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, special penta
Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By suitable alkali
The salt obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any comprised N's
The quaternary ammonium salt that the compound of group is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali
Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is suitable, nontoxic that pharmaceutically acceptable salt farther includes
Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid
Compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed
Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention
Molecule can combine with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule
Can combine with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention divides
Son can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with non-
The biological effectiveness of the described compound of hydrated form.
Term " therapeutically effective amount " or " treatment effective dose " refer to cause individual life as used in the present invention
Thing or medicinal response (such as reduce or inhibitory enzyme or protein active, or improve symptom, alleviate disease, slow down or postpone disease
Sick development, or prevention disease etc.) the amount of the compounds of this invention.
The present invention relates to substituted (octahydro pyrrolo-[3,4-c] pyrroles-2 (1H)-yl) phenyl ketone compound, its pharmacy
Going up acceptable salt, its pharmaceutical composition and pharmaceutical preparation thereof, they have orexin receptor antagonism, can be as orexin
Receptor antagonist is for prevention or treats the disease relevant to orexin receptor, such as sleep disorder, psychiatry, neurological
With neural degeneration obstacle, drug dependence, addiction, cognitive disorder, the dyskinesia, drinking and eating irregularly, etc..
Unless otherwise mentioned, all suitable isotope changes of the compound of the present invention, stereoisomer, tautomerism
Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Compound shown in formula (I) or formula (II) can exist with different tautomeric forms, and all these mutually
Tautomeric is included within the scope of the present invention.
Within the nitrogen oxides of the compounds of this invention is also contained in the scope of the present invention.Can be by often using at an elevated temperature
With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, aoxidize corresponding nitrogen-containing basic material, or pass through
With acid reaction excessively in applicable solvent, such as, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or
Chloroform or dichloromethane react with 3-chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Additionally, when the compound of the present invention forms hydrate or solvate, they are also included within the scope of the present invention
In.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within the model of the present invention
In enclosing.
Compound shown in formula (I) or formula (II) can exist in a salt form.In one embodiment, described salt refers to medicine
Acceptable salt on.The pharmaceutically acceptable salt of the present invention can with conventional chemical processes by parent compound, alkalescence or
Acidic moiety synthesizes.It is said that in general, such salt can be by making free acid form and the stoichiometry of these compounds
Suitable alkali (such as the hydroxide of Na, Ca, Mg or K, carbonate, bicarbonate etc.) reaction, or by making these compounds
Free alkali form is prepared with the suitable acid reaction of stoichiometry.Such reaction generally water or organic solvent or the two
Mixture in carry out.Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol,
Isopropanol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, Mack Publishing
Company,Easton,Pa.,(1985)；" pharmaceutical salts handbook: character, select and apply (Handbook
ofPharmaceutical Salts:Properties,Selection,andUse)”,Stahl and Wermuth(Wiley-
VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
The compounds of this invention is alkaline, is therefore generally possible to by being formed pharmaceutically acceptable with suitable acid treatment
Acid-addition salts.Suitably acid includes pharmaceutically acceptable mineral acid and pharmaceutically acceptable organic acid.Representational medicine
On, acceptable acid-addition salts includes hydrochlorate, hydrobromate, nitrate, methyl nitrate, sulfate, disulfate, ammonia
Base sulfonate, phosphate, acetate, hydroxyl acetate, phenyl acetate salt, propionate, butyrate, isobutyrate, valerate, horse
Carry out hydrochlorate, hydroxymaleic acid salt, acrylates, fumarate, malate, tartrate, citrate, salicylate, right
Aminosalicylate, glycollate, lactate, enanthate, phthalate, oxalates, succinate, benzoate, neighbour
Acetoxy-benzoic acid salt, chloro benzoate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzene
Formates, mandelate, tannate, formates, stearate, Ascorbate, palmitate, oleate, pyruvate,
Pamoate, malonate, laruate, glutarate, glutamate, Glu, estolate, mesylate, sulfonate, 2-hydroxyl
Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with
The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many
Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced
Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, such as, and its
In there is radiosiotope, as3H、14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (uses such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread
SPECT (single photon emission computed tomography) (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or
It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment or formula (II) can pass through this area skill
Embodiment in routine techniques that art personnel are familiar with or the present invention and preparation process is described uses the examination of suitable isotope labelling
Agent substitutes original used unmarked reagent and prepares.
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I) or formula (II).
On the other hand, the present invention relates to the preparation of compound shown in formula (I) or formula (II), separation and the method for purification.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or formula (II) or formula (I) or formula (II) institute
Show the stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or
Prodrug.Described pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient further, and optionally
Ground, other treatment and/or prevention composition.
Suitably carrier, adjuvant and excipient be well known to those skilled in the art and be described in detail in such as
Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；GennaroA.R.et al.,
Remington:The Science and Practice ofPharmacy (2000) Lippincott, Williams&
Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005)
Pharmaceutical Press, in Chicago.
The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition concordance
Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing
Split-phase is held, and can be substantially reduced the interaction of effect of the compounds of this invention and can cause not being medicine during to avoid being administered patient
The interaction of acceptable pharmaceutical composition on.Additionally, every kind of excipient must be pharmaceutically acceptable, such as, tool
There is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, can be according to them in group
Specific function in compound selects pharmaceutically acceptable excipient.Such as, optional can help to produce equal one dosage type low temperature
Some pharmaceutically acceptable excipient.Optional some pharmaceutically acceptable figuration that can help to produce stabilizer type
Agent.May select and contribute to when patient is administered carrying or transport the compounds of this invention from health organ or partly to health
Another organ or part some pharmaceutically acceptable excipient.Some of optional enhancing patient compliance is pharmaceutically
Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent,
Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify
Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable
Agent, surfactant and buffer agent.One skilled in the art will recognize that, some pharmaceutically acceptable excipient can provide not
A kind of function, and alternative function is provided, this depends on having in how many these excipient and preparation which there is in preparation
Other excipient a little.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention
Pharmaceutically acceptable excipient.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable
Excipient, and be used for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's
Pharmaceutical Sciences(Mack Publishing Company),The Handbook of
Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of
Pharmaceutical Excipients(theAmerican PharmaceuticalAssociation and the
Pharmaceutical Press)。
At Remington:The Science and Practice ofPharmacy, 21st edition, 2005,
ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of
Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel
Dekker, NewYork disclose the various carriers for configuring pharmaceutically acceptable compositions, and for its public affairs prepared
Knowing technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable biology
Effect, or so that other composition any in harmful way and pharmaceutically acceptable compositions occurs to interact with of the present inventionization
Outside any commonly employed carrier that compound is incompatible, pay close attention to its application and belong to the scope of the present invention.
The compounds of this invention is usually formulated as being adapted to pass through the dosage form that patient is administered by required approach.Such as, dosage form
It is suitable for the dosage form of following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, pill, buccal tablet including those
Agent, powder, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, the most aseptic
Solution, suspensoid and redissolution powder；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as suppository；(5) inhale
Enter, such as aerosol, solution and dry powder doses；(6) topical, such as ointment, ointment, lotion, solution, paste
Agent, spray, foam and gel.
It will also be appreciated that some compound of the present invention can exist in a free form for treating, if or suitably
Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivant
Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or
Compound of the present invention or its metabolite or any other adduct of residue or derivant are provided indirectly.
In one embodiment, the compounds of this invention can be configured to peroral dosage form.In another embodiment, the present invention
Compound can be configured to inhalant dosage form.In another embodiment, the compounds of this invention can be configured to nose administration dosage form.
In yet another embodiment, the compounds of this invention can be configured to transdermal administration.The most in one embodiment, of the present inventionization
Compound can be configured to Topical dosage forms.
The present invention provide pharmaceutical composition can with compressed tablet, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or
Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are to dissolve or the material bag of disintegrate in intestinal with being resistant to gastric acid effect
The compressed tablet of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to fatty acid, fat
Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Coated tablet is the compacting that sugar-coat surrounds
Sheet, it can be beneficial to cover taste beastly or abnormal smells from the patient and can prevent tablet from aoxidizing.Thin membrane coated tablet is for using water solublity
The compressed tablet that the thin layer of material or thin film cover.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose
Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple
Tabletting is the compressed tablet through preparing more than a press cycles, including multilayer tablet and pressed coated or dry coated tablet.
Tabules can by powder, the one that individually or describes with the present invention of crystallization or granular active component
Or prepared by variety carrier or excipient composition, described carrier and excipient include binding agent, disintegrating agent, controlled release polymer, profit
Lubrication prescription, diluent and/or coloring agent.Fumet and sweeting agent are particularly useful when forming chewable tablet and lozenge.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, methyl fibre
Prepared by dimension element, starch or calcium alginate.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section
Fill in another section, enclose active component the most completely.SEC (SEC) is soft, spherical shell, such as gelatin shell,
It plastifies by adding glycerol, sorbitol or similar polyhydric alcohol.Soft gelatin shell can comprise preservative and carry out prophylaxis of microbial life
Long.Suitably preservative be as described in the present invention those, including methyl hydroxybenzoate and propylparaben, and sorbic acid.This
Liquid, semisolid and solid dosage forms that invention provides can be encapsulated in capsule.Suitably liquid and semisolid dosage form is included in
Solution in Allyl carbonate, vegetable oil or triglyceride and suspensoid.The capsule comprising such solution can be as in the U.S.
Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.Described capsule can also be adopted
Use coating as is known to persons skilled in the art, thus improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible
Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of liquid in pellet form,
It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and
Preservative.Suspensoid can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used
The acetal accepted, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there is one or many
The water-soluble solvent of individual hydroxyl, such as propylene glycol and ethanol.Elixir is transparent, the water-alcohol solution of sweet taste.Syrup is dense
The aqueous solution of sugar such as sucrose, and also preservative can be comprised.For liquid dosage form, such as, the solution in Polyethylene Glycol
Can be with enough pharmaceutically acceptable liquid-carrier such as water dilutions, to be accurately, conveniently administered.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form to patient's inhalation, such as dry powder
Agent, aerosol, suspensoid or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared
Become to be suitable to by the dry powder doses dosage form to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention
Can be configured to be suitable to by the aerosol apparatus dosage form to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual
Comprise fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes
Shape agent.Being especially suitable for use as the pharmaceutically acceptable excipient dawn known to those skilled in the art of dry powder doses, it includes breast
Sugar, starch, mannitol and single-, two-and polysaccharide.Fine powder can be prepared by such as micronization and grinding.General next
Saying, reduced size of (as micronized) compound can be by the D of about 1 to 10 micron50Value (such as, is surveyed with laser diffractometry
Amount) define.
The pharmaceutical composition being suitable for transdermal administration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient
It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as
Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of topical can be formulated into ointment, ointment, suspensoid, lotion, powder,
Solution, paste, gel, spray, aerosol or oil preparation.Such as, ointment, ointment and gel can be with water or oil
Substrate, and the thickening agent and/or gel and/or the solvent that are suitable for configure.Such substrate can include, water, and/or oil example
Such as liquid-liquid paraffin and vegetable oil (such as Oleum Arachidis hypogaeae semen or Oleum Ricini), or solvent such as Polyethylene Glycol.Make according to medium property
Thickening agent and gel include soft paraffin, aluminium stearate, cetearyl alcohol, Polyethylene Glycol, lanoline, Cera Flava, poly-carboxylic second
Alkene and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.
The compounds of this invention can also be combined with the soluble polymer as target medicine carrier.Such polymer bag
Include polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or
The substituted oxide polylysine of palmitoyl residues.Additionally, compound disclosed in this invention can with realizing medicine
Control release in use one class Biodegradable polymeric combine, such as, polylactic acid, poly-epsilon-caprolactone, poly butyric,
Poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block copolymer.
The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete
Body is administered.As the present invention use parenteral include intravenous, intra-arterial, intraperitoneal, sheath in, in ventricle, in urethra, breast
In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes
Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid
Bodily form formula.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees
Remington:The Science and Practice of Pharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and
Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or anti-micro-life
Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer agent, antioxidant, local anesthetic, suspending agent and the dispersion of thing growth
Agent, wetting agent or emulsifying agent, chelating agent, sequestering agent or chelating agen, antifreezing agent, cryoprotective agent, thickening agent, pH adjusting agent
And noble gas.
The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, arteries and veins
Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations is wrapped
It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro-of antibacterial or fungistatic concentrations
Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.
The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutical effect
Preparation, or with supplement the material co-formulation of intended effect.
In one embodiment, the Therapeutic Method of the present invention includes giving patient in need this of safe and effective amount
Bright compound or comprise the pharmaceutical composition of the compounds of this invention.The each embodiment of the present invention includes by patient in need
Give the compounds of this invention of safe and effective amount or comprise the pharmaceutical composition of the compounds of this invention, treating what the present invention mentioned
Disease.
In one embodiment, the compounds of this invention or comprise the pharmaceutical composition of the compounds of this invention can be by any
The route of administration being suitable for is administered, including Formulations for systemic administration and topical.Formulations for systemic administration include oral administration, parenteral,
Transdermal administration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular and skin
Hemostasis or administered by infusion.Topical includes being applied to skin and ophthalmic, ear, intravaginal, suction and intranasal administration.One
In individual embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administrations.At another
In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.Also have one in fact
Execute in example, the compounds of this invention or to comprise the compounds of this invention can be intranasal administration.
In one embodiment, the compounds of this invention or comprise the compounds of this invention pharmaceutical composition can disposably to
Medicine, or according to dosage regimen, at the appointed time in section, be administered several times in different time intervals.Such as, it is administered one every day
Secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily.
Can be administered until reaching the therapeutic effect wanted or maintaining the therapeutic effect wanted indefinitely.The compounds of this invention or comprise
The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of this compound, such as, inhale
Receiving, be distributed and the half-life, these can be by determination of technical staff.Additionally, the compounds of this invention or comprise the compounds of this invention
The appropriate dosage regimen of pharmaceutical composition, including the persistent period of the enforcement program, depends on the disease being treated, treated disease
The sick order of severity, the age of patient under consideration and health, the character of the medical history of patient under consideration, simultaneously therapy, think
The factor in the range of technical staff's knowledge and experience such as the therapeutic effect wanted.Such technical staff be also to be understood that for
The individual patient reaction to dosage regimen, or when passage individual patient needs change over time, in order to be sufficiently accurate it may be desired to adjust giving of matters
Regimen.
The compounds of this invention can, or be administered before it or afterwards with one or more other therapeutic agents simultaneously.This
Bright compound can be administered by identical or different route of administration respectively with other therapeutic agents, or therewith with pharmaceutical composition
Form is administered.
The compounds of this invention can be with tranquilizer, sleeping pill, antianxiety drugs, psychosis, antianxiety drug, cyclopyrrole
Ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, fading element can medicament, benzene phenodiazine
Leather, barbiturate, 5HT-2 antagonist etc. are used in combination, such as: adinazolam, allobarbital, alonimid,
Alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, BUP, fourth
Spirocyclic ketone, cloth tower barbital, cloth tower are than appropriate, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, chlorine miboplatin
Bright, clonazepam, Domperidone, Decacil, cloretate, clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine
Aldehyde willow amine, double valproic acid, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west
Dissolve, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, chlorine hydroxyl nor-
Stable, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles
Logical sequence, Buddhist nun's method oxazolone, nisobamate, nitrodiazepam, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, pentobarbital, piperazine
Even up, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, auspicious chlorine
West is dissolved, rolipram, quinalbarbitone, Sertraline, suproclone, temazepam, thioridazine, tracazolate, anti-phenyl ring third
Amine, trazodone, triazole benzene phenodiazine, trepipam, tricetamide, trichloroethyl phosphate, trifluoperazine, trimethoxy benzoyl
Quinoline, trimeprimine, uldazepam, venlafaxine, Zaleplon, zolazepam, zolpidem and their salt and compositions
Etc., or the compounds of this invention can be administered while physical method such as phototherapy or electricity irritation are used in combination.
Additionally, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is
When patient is administered, finally can discharge the functional derivatives of the compounds of this invention in vivo.This is given with prodrug forms
During bright compound, those skilled in the art can implement the one in following manner and more than: the internal onset of (a) modification compound
Time；The internal acting duration of (b) modification compound；The internal conveying of (c) modification compound or distribution；(d) modification
The internal dissolubility of compound；And (e) overcomes the side effect or other difficult points that compound faced.For preparing the typical of prodrug
Functional derivatives, be included in internal chemically or the variant of compound that cracks of the mode of enzyme.Comprise prepare phosphate,
These variants of amide, ester, monothioester, carbonate and carbaminate are well-known to those skilled in the art.
The compounds of this invention and the purposes of pharmaceutical composition
Compound of the present invention and pharmaceutical composition are as orexin receptor antagonists, to preventing or treating and appetite
The disease that element receptor is relevant is effective, can be used for preparing the medicine of antagonism orexin receptor.
The disease relevant to orexin receptor is selected from all types of sleep disorder, all types of psychiatry, god
Through disease and neural degeneration obstacle, all types of pressure correlation syndrome, all types of addiction (especially psychotropic activity thing
The use of matter, abuse, seek and recover), all types of in healthy population and in psychiatric patient and nervous system disease
Cognitive dysfunction in patient, all types of feed or drinking-water obstacle, etc..
In one embodiment, relevant to orexin receptor disease comprises sleep disorder, depression, anxiety neurosis, fear
Disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorders, panic attack obstacle, behavior are lost
Often, emotionally disturbed, posttraumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder,
Dementia, drug dependence, addiction, cognitive disorder, Alzheimer, parkinson, the dyskinesia, drinking and eating irregularly, headache,
Migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune correlated disease, interior
Secretion related disorders or hypertension.
In one embodiment, the disease relevant to orexin receptor is selected from sleep disorder, and it comprises all types of
Insomnia, Narcolepsy and other excessive sleepiness disease, parasomnia, the myodystonia that sleep is relevant, not peaceful lower limb
Syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome and sleep phases
Insomnia that syndrome or mental sickness relevant is retarded or advanced, etc..
In one embodiment, relevant to orexin receptor disease is selected from psychiatry, neurological and neural change
Sexual disorders, it comprises depression, anxiety neurosis, Panic disorder, obsession, affective disease, depressibility neuropathy, anxious nerve
Disease, mood disorders, panic attack obstacle, posttraumatic stress disorder, sexual dysfunction, psychosis, parkinson, dull-witted or smart
God's hypoevolutism, etc..
In one embodiment, the disease relevant to orexin receptor is selected from cognitive dysfunction, and it is included in normally
, healthy, young, adult's or transient episodes or all types of attentions of chronic seizures, in the crowd in old age
Practise and memory function declines, or transient episodes or chronic in psychosis, neuropathy, cardiovascular and disease of immune system patient
All types of attentions of outbreak, learning and memory function reduction, etc..
It should be appreciated that in such as some environmental condition such as pressure or fear, (wherein, pressure is likely to be of society source such as
Social pressure or there is physiological sources such as physical stress, the pressure including being produced by fear) promote or accelerate any as previously mentioned
Disease or disease in the case of, the compound of the present invention to treat these environment regulation disease or disease be particularly useful
's.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on
Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.?
This, the compound of the present invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply
The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment are for lifting further
Example explanation present disclosure.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably
Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention
Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art
Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention
, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou
Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning
Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase
Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride
It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N-
Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects
Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record.1H H NMR spectroscopy is with CDC13、
DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), mark as reference with TMS (0ppm) or chloroform (7.26ppm)
Accurate.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t
(triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-MS (pillar model:
Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% in flowing
The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in, uses electron spray ionisation (ESI), under 210nm/254nm,
Detect with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type
Number: NOVASEP 50/80mm DAC), under 210nm/254nm, detect with UV.
The use of brief word below runs through the present invention:
Boc tertbutyloxycarbonyl
CH2Cl2, DCM dichloromethane
Cs2CO3Cesium carbonate
CDC13Deuterochloroform
CuI Hydro-Giene (Water Science).
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
EtOH ethanol
G gram
H hour
KOH potassium hydroxide
K2CO3Potassium carbonate
MeCN、CH3CN acetonitrile
Na2CO3Sodium carbonate
NaOH sodium hydroxide
Na2SO4Sodium sulfate
MgSO4Magnesium sulfate
ML, ml milliliter
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Following synthetic schemes describes the step preparing the compounds of this invention.Unless otherwise indicated, R1、R2、R3、R4、R5、
R6、R7And R8There is definition as described in the present invention.
Intermediate synthetic schemes 1
Midbody compound of the present invention (5) can be prepared by the method described in intermediate synthetic schemes 1: different
The substituted o-iodobenzoic acid of substituent group (1) exist and under heating condition at [Cu] catalysis, suitable alkali with 1H-1,2,3-triazole
Reaction obtain intermediate (2).Compound (2) with chlorinating agent react in a heated condition obtain compound (3), compound (3)
React in the basic conditions with 2-Boc-hexahydropyrrolo also [3,4-c] pyrroles obtain compound (4), compound (4) at acid bar
Under part deprotection obtain compound (5)。
Intermediate synthetic schemes 2
Midbody compound of the present invention (10) can be prepared by the method that intermediate synthetic schemes 2 describes: different
The substituted ortho-aminobenzoic acid of substituent group (6) and carbamide (7) in a heated condition cyclization obtain intermediate (8), intermediate (8) with
Suitably chlorinating agent react in a heated condition obtain the double chloro of 2,4-quinazoline intermediate (9), intermediate (9) suitably
Hydrolyzed under basic conditions obtain intermediate (10)。
Synthetic schemes 1
The compounds of this invention (11) can be prepared by the method that synthetic schemes 1 describes: midbody compound (5) with
Midbody compound (10) direct reaction i.e. obtain compound (11)。
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment
(hexahydropyrrolo is also for 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) for the fluoro-2-of embodiment 1:6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinazoline-4 (3H)-one
Step 1) synthesis of 6-Fluquinconazole quinoline-2,4 (1H, 3H)-diketone
Carbamide (29.0g, 482.9mmol) and 2-amino-5-fluorobenzoic acid (5.0g, 32.2mmol) are added sequentially to
In the airtight tube sealing of 200mL, it is stirred vigorously down and is gradually heating to 160 DEG C, after 4 hours, be warming up to 180 DEG C again, after 4 hours, the coldest
But to room temperature, in reactant liquor, tap water (150mL), after stirring 1 hour under room temperature, sucking filtration, a large amount of tap water of filtering residue are added
Washing colourless to filtrate, filtering residue with acetone (150mL), methanol washing (70mL), obtains title compound the most successively after filter residue and drying
Thing (brick-red solid, 5.041g, 86.8%).
MS(ESI,neg.ion)m/z:179.1[M-H]-；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.29 (s, 2H), 7.57 (dd, J=8.4Hz, 2.7Hz, 1H),
7.53 (td, J=8.7Hz, 2.8Hz, 1H), 7.19 (dd, J=8.8Hz, 4.3Hz, 1H).
Step 2) synthesis of 2,4-bis-chloro-6-Fluquinconazole quinoline
Phosphorus pentachloride (12.5g, 60.0mmol), phosphorus oxychloride (46.0mL, 502.5mmol) are added sequentially to 250mL
In single port bottle, it is slowly added into 6-Fluquinconazole quinoline-2,4 (1H, 3H)-diketone (3.6g, 20.0mmol) under stirring, is gradually heating to back
Stream reaction, stopped reaction after 9 hours, cooling, remove solvent under reduced pressure, residue is slowly poured in 400mL mixture of ice and water, stirring
After 0.5 hour, extract (250mL × 3) with dichloromethane, combined dichloromethane layer, directly carry out silica gel column chromatography separating purification
(petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (white solid, 3.735g, 86.0%).
MS(ESI,pos.ion)m/z:216.9[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.03 (dd, J=9.2Hz, 4.9Hz, 1H), 7.86 (dd, J=
8.1Hz, 2.7Hz, 1H), 7.79～7.73 (m, 1H).
Step 3) synthesis of 2-chloro-6-Fluquinconazole quinoline-4 (3H)-one
By 2,4-bis-chloro-6-Fluquinconazole quinoline (0.21g, 0.97mmol) joins in 50mL single port bottle, uses oxolane
(1mL) after making it the most molten, sodium hydrate aqueous solution (1M, 8mL) is added, the lower room temperature reaction of nitrogen protection 12 hours.Stopped reaction,
Reactant liquor glacial acetic acid regulates pH to 5～6, extracts by ethyl acetate (10mL × 2), combined ethyl acetate layer, directly carries out silicon
Plastic column chromatography isolated and purified (petrol ether/ethyl acetate (v/v)=4/1) obtain title compound (white solid, 0.159g,
83.0%).
MS(ESI,pos.ion)m/z:199.1[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 10.93 (s, 1H), 7.92 (dd, J=8.0Hz, 3.0Hz, 1H), 7.71
(dd, J=9.0Hz, 4.8Hz, 1H), 7.53 (td, J=8.4Hz, 3.0Hz, 1H).
Step 4) 5-methyl-2-(2H-1,2,3-triazole-2-base) benzoic synthesis
By 1,2,3-triazoles (3.45g, 50mmol), 2-iodo-5-ar-Toluic acid (5.24g, 20mmol), cesium carbonate
(11.72g, 36mmol), trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51g, 3.6mmol), Hydro-Giene (Water Science). (0.38g,
2mmol), DMF (30mL) is added sequentially in 100mL single necked round bottom flask, gradually heats up under nitrogen protection
React 4 hours to 100 DEG C.Stopped reaction, cooling, dilute with tap water and use ethyl acetate (200mL × 2) to extract.Water layer is used
Concentrated hydrochloric acid acidifying (pH=1～2) extracts by ethyl acetate (200mL × 2) afterwards, merges organic layer below and uses anhydrous sodium sulfate
Being dried, filter, filtrate decompression is evaporated and carries out column chromatographic isolation and purification (methylene chloride/methanol (v/v)=50/1) and obtains title
Compound (yellow solid, 2.76g, 68%).
MS(ESI,neg.ion)m/z:202.1[M-H]-；
1H NMR (MeOD, 600MHz) δ (ppm): 7.88 (s, 2H), 7.66 (d, 1H), 7.59 (d, J=8.2Hz, 1H),
7.50～7.48 (dd, J=8.1Hz, 1.1Hz, 1H), 2.45 (s, 3H)；
13C NMR(MeOD,151MHz)δ(ppm):169.8,140.7,137.5,136.7,133.5,131.5,129.3,
126.0,21.0.
Step 5) synthesis of 5-methyl-2-(2H-1,2,3-triazole-2-base) Benzenecarbonyl chloride.
5-methyl-2-(2H-1,2,3-triazole-2-base) benzoic acid (2.03g, 10mmol) is joined 100mL single port
In round-bottomed flask, dissolve with anhydrous methylene chloride (20mL), then be slowly added into thionyl chloride (15mL, 200mmol) and pyridine
(0.15mL, 2mmol), is gradually heating to back flow reaction 3 hours.Stopped reaction, cooling, decompression slowly boils off solvent, and gained produces
Thing is directly used in next step.
Step 6) 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c] pyrrole
Cough up the synthesis of-2 (1H)-t-butyl formates
By 2-Boc-hexahydropyrrolo during also [3,4-c] pyrroles (0.990g, 4.66mmol) joins 100mL single port bottle, use
Dry methylene chloride (20mL) is dissolved and is placed in cold-trap (-8 DEG C), is slowly added into triethylamine (5mL), adds dichloromethane
(15mL) 5-methyl-2-(1,2, the 3-triazole-2-base) Benzenecarbonyl chloride. (1.250g, 5.640mmol) dissolved, after 10 minutes,
It is transferred to room temperature reaction 14 hours.Stopped reaction, reactant liquor adds dchloromethane, and saturated aqueous common salt washs, and collects organic
Layer, water layer uses dichloromethane extraction (20mL × 3), merges organic layer, and anhydrous sodium sulfate is dried, and filters, and filtrate decompression is evaporated
And carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/6) obtain title compound (clear yellow viscous thing,
1.793g, 96.7%).
MS(ESI,pos.ion)m/z:398.1[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 7.84 (d, J=7.4Hz, 1H), 7.77 (s, 2H), 7.30 (d, J=
8.0Hz, 1H), 7.20 (s, 1H), 3.77 (d, J=7.4Hz, 1H), 3.65～3.51 (m, 2H), 3.42 (d, J=40.6Hz,
1H), 3.26 (d, J=5.8Hz, 2H), 3.17～3.06 (m, 1H), 2.90 (d, J=31.5Hz, 2H), 2.76 (s, 1H), 2.39
(s, 3H), 1.44 (d, J=19.2Hz, 9H).
Step 7) (hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-yl) (5-methyl-2-(2H-1,2,3-triazole-2-
Base) phenyl) synthesis of ketone
By 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-2
(1H)-t-butyl formate (1.79g, 4.50mmol) joins in 100mL single port bottle, makes it the most molten with dichloromethane (15mL)
After, it is slowly added into the ethyl acetate solution (3.5M, 30mL) of hydrogen chloride, room temperature reaction 0.5 hour.After reaction terminates, wherein
It is slowly added into aqueous sodium carbonate and is adjusted to alkalescence, dichloromethane extraction (30mL × 3), collected organic layer, use saturated aqueous common salt
(30mL) washing, decompression solvent is distilled off, gained crude by column chromatography isolated and purified (methylene chloride/methanol (v/v)=
10/1) title compound (yellow oil, 1.28g, 95.6%) is obtained.
MS(ESI,pos.ion)m/z:298.4[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 7.81～7.79 (m, 3H), 7.29 (dd, J=8.3Hz, 0.8Hz,
1H), 7.17 (s, 1H), 3.72～3.64 (m, 2H), 3.38～3.31 (m, 2H), 3.21～3.18 (m, 1H), 3.09～3.06
(m, 1H), 2.97～2.95 (m, 2H), 2.85～2.77 (m, 2H), 2.38 (s, 3H).
Step 8) (hexahydropyrrolo is also for 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) for the fluoro-2-of 6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinazoline-4 (3H)-one
By chloro-for 2-6-Fluquinconazole quinoline-4 (3H)-one (0.151g, 0.827mmol), (hexahydropyrrolo also [3,4-c] pyrroles-2
(1H)-yl) (5-methyl-2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.271g, 0.911mmol), triethylamine
(0.25g, 2.48mmol), Isosorbide-5-Nitrae-dioxane (10mL) are added sequentially in 50mL mono-neck bottle, gradually heat up under nitrogen protection
To back flow reaction 4 hours.Stopped reaction, is cooled to room temperature, and decompression boils off solvent, and remaining solid uses dichloromethane (30mL) molten
Solving, successively with tap water (20mL), saturated aqueous common salt (20mL) washing, organic layer directly carries out silica gel column chromatography separation after concentrating
Purification (petrol ether/ethyl acetate (v/v)=1/1) obtains title compound (yellow solid, 0.295g, 80.4%).
MS(ESI,pos.ion)m/z:460.2[M+H]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.46～11.14 (m, 1H), 7.99 (s, 2H), 7.75 (d, J=
8.2Hz, 1H), 7.57 (dd, J=8.5,2.4Hz, 1H), 7.46 (td, J=8.7,2.9Hz, 1H), 7.40 (d, J=7.7Hz,
1H), 7.30 (s, 2H), 3.70～3.56 (m, 2H), 3.45～3.33 (m, 6H), 2.95 (s, 2H), 2.38 (s, 3H).
The fluoro-2-of embodiment 2:6-(5-(2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c]
Pyrroles-2 (1H)-yl) synthesis of quinazoline-4 (3H)-one
Step 1) 2-(2H-1,2,3-triazole-2-base) benzoic synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, will 1,2,3-triazoles
(0.7g, 10.08mmol), 2-iodo-benzoic acid (1g, 4.03mmol), cesium carbonate (2.36g, 7.2mmol), trans-N, N'-diformazan
Base-1,2-cyclohexanediamine (0.103g, 0.752mmol), Hydro-Giene (Water Science). (0.077g, 0.403mmol) is at N, N-dimethyl formyl
Reaction preparation in amine (18mL), thick product is marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1)
Topic compound (yellow solid, 0.511g, 67%).
MS(ESI,neg.ion)m/z:188.1[M-H]-；
1H NMR(DMSO-d6, 600MHz) and δ (ppm): 13.06 (w, 1H), 8.08 (s, 2H), 7.78～7.75 (m, 2H),
7.72～7.68 (m, 1H), 7.60～7.57 (m, 1H).
13C NMR(DMSO-d6,151MHz)δ(ppm):167.7,137.5,136.3,131.7,129.6,128.9,
128.5,124.4.
Step 2) synthesis of 2-(2H-1,2,3-triazole-2-base) Benzenecarbonyl chloride.
This step title compound prepares with reference to the method described by embodiment 1 step 5, will 2-(2H-1,2,3-
Triazole-2-base) benzoic acid (0.37g, 1.96mmol) anhydrous methylene chloride (20mL) dissolving, then it is slowly added into thionyl chloride
(6mL, 82.7mmol) and pyridine (0.04mL, 0.5mmol), be gradually heating to back flow reaction 3 hours.Stopped reaction, cooling, subtract
Pressure slowly boils off solvent, and products therefrom is directly used in next step.
Step 3) 5-(2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-2
(1H) synthesis of-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 6, will 2-Boc-hexahydro pyrrole
Cough up also [3,4-c] pyrroles (0.96g, 4.52mmol), triethylamine (2.55mL), 2-(2H-1,2,3-triazole-2-bases) Benzenecarbonyl chloride.
(1.12g, 5.39mmol) be reaction preparation in anhydrous methylene chloride (30mL), and thick product is through silica gel column chromatography separating purification (stone
Oil ether/ethyl acetate (v/v)=2/1) obtain title compound (brown color viscous liquid, 1.33g, 76.5%).
MS(ESI,pos.ion)m/z:384.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 8.00 (d, J=8.1Hz, 1H), 7.81 (s, 2H), 7.55～7.50
(m, 1H), 7.45～7.42 (m, 2H), 3.79 (d, J=7.4Hz, 1H), 3.63 (d, J=10.9Hz, 2H), 3.46 (d, J=
8.4Hz, 1H), 3.29 (dd, J=11.2,5.0Hz, 2H), 3.20～3.11 (m, 1H), 2.90 (s, 2H), 2.80 (dd, J=
11.0,5.6Hz, 1H), 1.46～1.44 (m, 9H).
Step 4) (2-(2H-1,2,3-triazole-2-base) phenyl) (hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-yl) first
The synthesis of ketone
This step title compound prepares with reference to the method described by embodiment 1 step 7, will 5-(2-(2H-1,
2,3-triazole-2-bases) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-t-butyl formate (1.31g,
3.42mmol) ethyl acetate solution (3.5M, 15mL) and the middle reaction of anhydrous methylene chloride (30mL) being dried at hydrogen chloride are made
Standby, thick product obtains title compound (brown color through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1)
Viscous liquid, 0.94g, 97.10%).
MS(ESI,pos.ion)m/z:284.2[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 7.97 (d, J=8.1Hz, 1H), 7.83 (s, 2H), 7.54～7.50
(m, 1H), 7.41 (q, J=7.7Hz, 2H), 3.79～3.67 (m, 2H), 3.29 (dd, J=13.1,9.0Hz, 2H), 3.15
(dd, J=11.2,7.3Hz, 1H), 3.08 (dd, J=11.4,3.4Hz, 1H), 2.95 (d, J=8.4Hz, 2H), 2.83～
2.75(m,2H).
Step 5) 2-(5-(2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-2
(1H)-yl) synthesis of-6-Fluquinconazole quinoline-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (2-(2H-1,2,
3-triazole-2-base) phenyl) (hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-yl) ketone (0.23g, 0.812mmol), 2-be chloro-
6-fluoro-3H-quinazoline-4-one (0.21g, 1.06mmol) and triethylamine (0.45m, 3.20mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (white slightly light yellow solid, 0.229g, 63.19%).
MS(ESI,pos.ion)m/z:446.2[M+H]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.02 (s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.74 (s, 2H),
7.56 (d, J=6.3Hz, 1H), 7.54～7.51 (m, 1H), 7.42 (d, J=4.0Hz, 2H), 7.37～7.32 (m, 2H),
3.95 (dd, J=21.0,12.8Hz, 2H), 3.81～3.69 (m, 4H), 3.63～3.61 (m, 2H), 3.13 (s, 2H).
(hexahydropyrrolo is also for 5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) for the fluoro-2-of embodiment 3:6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
Step 1) the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoic synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 4, will 1,2,3-triazoles
(6.9g, 100mmol), 2-Fluoro-6-iodobenzoic acid (10.64g, 40mmol), cesium carbonate (23.4g, 71.7mmol), trans-N,
N'-dimethyl-1,2-cyclohexanediamine (1.02g, 7.04mmol) and Hydro-Giene (Water Science). (0.76g, 4.0mmol) are at N, N-dimethyl methyl
Reaction preparation in amide (50mL), thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (yellow solid, 5.62g, 67.90%).
MS(ESI,pos.ion)m/z:208.10[M+H]+；
1H NMR(d6-DMSO, 400MHz) δ (ppm): 13.66 (s, 1H), 8.16 (s, 2H), 7.79 (d, J=8.2Hz,
1H), 7.68 (td, J=8.2,6.2Hz, 1H), 7.44 (t, J=8.8Hz, 1H).
Step 2) synthesis of the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) Benzenecarbonyl chloride.
Fluoro-for 2-6-(2H-1,2,3-triazole-2-base) benzoic acid (0.69g, 3.33mmol) is used anhydrous methylene chloride
(20mL) dissolve, then be slowly added into thionyl chloride (8mL, 109.0mmol) and DMF (0.04mL, 0.5mmol), be gradually heating to
Back flow reaction 3 hours.Stopped reaction, cooling, decompression slowly boils off solvent, and products therefrom is directly used in next step.
Step 3) 5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-
The synthesis of 2 (1H)-t-butyl formates
This step title compound prepares with reference to the method described by embodiment 1 step 6, will 2-Boc-hexahydro pyrrole
Cough up also [3,4-c] pyrroles (0.426g, 2.01mmol), triethylamine (0.8mL), the fluoro-6-of 2-(2H-1,2,3-triazole-2-bases)
Benzenecarbonyl chloride. (0.54g, 2.39mmol) is reaction preparation in dry anhydrous methylene chloride (30mL), and thick product is through silica gel column layer
Analyse isolated and purified (petroleum ether/acetone (v/v)=4/1) obtain title compound (brown color viscous liquid, 0.705g,
87.5%).
MS(ESI,pos.ion)m/z:346.20[M-56]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 7.89～7.76 (m, 3H), 7.48 (dd, J=14.3,8.4Hz, 1H),
7.15 (td, J=8.4,3.0Hz, 1H), 3.90～2.86 (m, 10H), 1.47 (s, 9H).
Step 4) (the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) phenyl) (hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-
Base) synthesis of ketone
This step title compound prepares with reference to the method described by embodiment 1 step 7, will 5-(the fluoro-6-of 2-
(2H-1,2,3-triazole-2-bases) benzoyl) hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-t-butyl formate (0.913g,
2.27mmol) ethyl acetate solution (3.5M, 4mL) and the middle reaction of anhydrous methylene chloride (10mL) being dried at hydrogen chloride are made
Standby, thick product obtains title compound (brown color through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1)
Viscous liquid, 0.604g, 88%).
MS(ESI,pos.ion)m/z:302.1[M+1]+；
1H NMR(d6-DMSO,400MHz)δ(ppm):9.91(s,1H),9.50(s,1H),8.23(s,1H),8.14(s,
1H), 7.82 (t, J=8.2Hz, 1H), 7.68 (tdd, J=8.4,6.4,2.0Hz, 1H), 7.44 (t, J=9.2Hz, 1H),
3.62 (d, J=6.2Hz, 1H), 3.57～3.42 (m, 2H), 3.41～3.14 (m, 3H), 3.13～2.85 (m, 4H).
Step 5) the fluoro-2-of 6-(5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,
4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (2-fluoro-6-(2H-
1,2,3-triazole-2-base) phenyl) (hexahydropyrrolo also [3,4-c] pyrroles-2 (1H)-yl) ketone (0.50g, 1.48mmol), 2-
Chloro-6-fluoro-3H-quinazoline-4-one (0.45g, 2.27mmol) and triethylamine (0.8mL, 6.0mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (pale yellow oil, 0.757g, 51.1%).
MS(ESI,pos.ion)m/z:464.2[M+1]+；
1HNMR(CDCl3, 600MHz) and δ (ppm): 11.04 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.74 (s, 2H),
7.55 (d, J=6.5Hz, 1H), 7.54～7.51 (m, 1H), 7.42 (d, J=3.9Hz, 2H), 7.39～7.35 (m, 1H),
3.91 (dd, J=21.0,12.8Hz, 2H), 3.80～3.67 (m, 4H), 3.63～3.59 (m, 2H), 3.13 (s, 2H).
(hexahydropyrrolo is also for 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) for the chloro-2-of embodiment 4:6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
Step 1) synthesis of 6-chloro-quinazoline-2,4 (1H, 3H)-diketone
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 2-amino-5-chlorine
Benzoic acid (3.432g, 20.0mmol) and carbamide (18.016g, 300.0mmol) react preparation in 100mL tube sealing, after drying
Obtain title compound (gray solid, 3.272g, 83.2%).
MS(ESI,neg.ion)m/z:195.1[M-H]-；
1HNMR(d6-DMSO, 600MHz) δ (ppm): 11.34 (s, 2H), 7.81 (d, J=2.5Hz, 1H), 7.67 (dd, J
=8.7Hz, 2.5Hz, 1H), 7.18 (d, J=8.7H, 1H).
Step 2) synthesis of 2,4,6-tri-chloro-quinazoline
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 6-chloro-quinazoline-
2,4 (1H, 3H)-diketone (2.66g, 13.51mmol), phosphorus pentachloride (8.43g, 40.5mmol) phosphorus oxychloride (30.9mL,
Reaction preparation in 338mmol), thick product obtains through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=50/1)
Title compound (white solid, 0.881g, 27.9%).
MS(ESI,pos.ion)m/z:232.9[M+H]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 8.02 (d, J=2.5Hz, 1H), 7.86 (dd, J=8.7Hz,
2.5Hz, 1H), 7.64 (d, J=8.7H, 1H).
Step 3) synthesis of 2,6-dichloroquinazoline-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 2,4,6-tri-chloroquines
Oxazoline (0.864g, 3.70mmol) is reaction preparation in sodium hydrate aqueous solution (1M, 22.2mL) and oxolane (3.5mL),
Thick product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=10/1), and (white is solid
Body, 0.703g, 88.3%).
MS(ESI,pos.ion)m/z:215.1[M+H]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 8.04 (d, J=2.5Hz, 1H), 7.88 (dd, J=8.7Hz,
2.5Hz, 1H), 7.66 (d, J=8.7H, 1H).
Step 4) (hexahydropyrrolo is also for 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) for the chloro-2-of 6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (5-methyl-2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.50g, 1.68mmol),
2,6-dichloroquinazoline-4 (3H)-one (0.54g, 2.52mmol) and triethylamine (0.93ml, 6.72mmol) are at 1,4-dioxy six
In ring (20mL) prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
To title compound (pale yellow oil, 0.51g, 63.0%).
MS(ESI,pos.ion)m/z:476.24[M+1]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.36 (s, 1H), 7.98 (s, 2H), 7.87 (d, J=8.4Hz,
1H), 7.67 (dd, J=8.5,2.5Hz, 1H), 7.56 (td, J=8.7,2.7Hz, 1H), 7.39 (d, J=7.7Hz, 1H),
7.30 (s, 2H), 3.70～3.56 (m, 2H), 3.45～3.31 (m, 6H), 2.99 (s, 2H), 2.36 (s, 3H).
The chloro-2-of embodiment 5:6-(5-(2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-c]
Pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.45g, 1.59mmol), 2,6-bis-
Chloro-quinazoline-4 (3H)-one (0.38g, 1.75mmol) and triethylamine (0.88mL, 6.35mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (pale yellow oil, 0.476g, 64.98%).
MS(ESI,pos.ion)m/z:462.16[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.05 (s, 1H), 7.96 (d, J=8.0Hz, 1H), 7.72 (s, 2H),
7.58 (d, J=6.5Hz, 1H), 7.68～7.61 (m, 1H), 7.52 (d, J=4.0Hz, 2H), 7.37～7.32 (m, 2H),
3.96 (dd, J=21.0,12.8Hz, 2H), 3.89～3.69 (m, 4H), 3.63～3.61 (m, 2H), 3.13 (s, 2H).
(hexahydropyrrolo is also for 5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) for the chloro-2-of embodiment 6:6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.40g, 1.33mmol), 2,
6-dichloroquinazoline-4 (3H)-one (0.31g, 1.46mmol) and triethylamine (0.74mL, 5.31mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (faint yellow dope, 0.39g, 62.1%).
MS(ESI,pos.ion)m/z:480.14[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.04 (s, 1H), 7.95 (d, J=8.1Hz, 1H), 7.73 (s, 2H),
7.51 (d, J=6.7Hz, 1H), 7.49～7.45 (m, 1H), 7.41 (d, J=3.8Hz, 2H), 7.39～7.36 (m, 1H),
3.95 (dd, J=21.0,12.8Hz, 2H), 3.76～3.67 (m, 4H), 3.65～3.59 (m, 2H), 3.12 (s, 2H).
(hexahydropyrrolo is also for 5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) for the chloro-2-of embodiment 7:6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
Step 1) synthesis of 6-methylquinazolin-2,4 (1H, 3H)-diketone
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 2-amino-5-first
Yl benzoic acid (5.0g, 33.08mmol), carbamide (29.80g, 496.15mmol) react preparation in 100mL tube sealing, after drying
Obtain title compound (gray solid, 4.84g, 82.89%).
MS(ESI,neg.ion)m/z:175.16[M-H]-；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.26 (s, 2H), 7.59 (dd, J=8.5Hz, 2.8Hz, 1H),
7.52 (td, J=8.8Hz, 2.7Hz, 1H), 7.16 (dd, J=8.7Hz, 4.4Hz, 1H), 2.32 (s, 3H).
Step 2) synthesis of 2,4-bis-chloro-6-methylquinazolin
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 6-methyl quinoline azoles
Quinoline-2,4 (1H, 3H)-diketone (2.88g, 16.35mmol), phosphorus pentachloride (10.21g, 49.04mmol) are in phosphorus oxychloride
Reaction preparation in (37.4mL, 408mmol), thick product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=
50/1) title compound (white solid, 2.89g, 83.0%) is obtained.
MS(ESI,pos.ion)m/z:213.08[M+H]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 8.04 (dd, J=9.1Hz, 4.9Hz, 1H), 7.84 (dd, J=
8.3Hz, 2.5Hz, 1H), 7.78～7.73 (m, 1H), 2.32 (s, 3H).
Step 3) synthesis of 2-chloro-6-methylquinazolin-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 2, the chloro-6-of 4-bis-
Methylquinazolin (0.72g, 3.70mmol) is reaction in sodium hydrate aqueous solution (1M, 22.2mL) and oxolane (3.5mL)
Preparation, it is (white that thick product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=10/1)
Color solid, 0.59g, 90.51%).
MS(ESI,pos.ion)m/z:195.10[M+H]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 8.10 (d, J=2.7Hz, 1H), 7.89 (dd, J=8.7Hz,
2.5Hz, 1H), 7.68 (d, J=8.5H, 1H), 2.34 (s, 3H).
Step 4) (hexahydropyrrolo is also for 5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) for the chloro-2-of 6-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (5-methyl-2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.38g, 1.28mmol),
2-chloro-6-methylquinazolin-4 (3H)-one (0.27g, 1.41mmol) and triethylamine (0.71mL, 5.11mmol) are at 1,4-dioxy
In six rings (20mL) prepared by back flow reaction, and thick product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Obtain title compound (faint yellow dope, 0.38g, 65.12%).
MS(ESI,pos.ion)m/z:456.21[M+1]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.14 (s, 1H), 8.03 (s, 2H), 7.79 (d, J=8.2Hz,
1H), 7.55 (dd, J=8.7,2.4Hz, 1H), 7.42 (td, J=8.5,2.7Hz, 1H), 7.40 (d, J=7.7Hz, 1H),
7.32 (s, 2H), 3.71～3.63 (m, 2H), 3.45～3.29 (m, 6H), 2.93 (s, 2H), 2.42 (s, 3H), 2.34 (s,
3H).
Embodiment 8:6-methyl-2-(5-(2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo also [3,4-
C] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.45g, 1.59mmol), the chloro-6-of 2-
Methylquinazolin-4 (3H)-one (0.34g, 1.75mmol) and triethylamine (0.88mL, 6.35mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (faint yellow dope, 0.485g, 69.26%).
MS(ESI,pos.ion)m/z:442.21[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.13 (s, 1H), 7.97 (d, J=7.9Hz, 1H), 7.76 (s, 2H),
7.58 (d, J=6.3Hz, 1H), 7.64～7.51 (m, 1H), 7.52 (d, J=4.0Hz, 2H), 7.37～7.32 (m, 2H),
3.97 (dd, J=21.0,12.8Hz, 2H), 3.81～3.69 (m, 4H), 3.63～3.61 (m, 2H), 3.13 (s, 2H), 2.34
(s,3H).
(hexahydropyrrolo is also for 5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) for embodiment 9:6-methyl-2-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.45g, 1.49mmol), 2-
Chloro-6-methylquinazolin-4 (3H)-one (0.32g, 1.64mmol) and triethylamine (0.83mL, 5.97mmol) are at 1,4-dioxy six
In ring (20mL) prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
To title compound (clear yellow viscous thing, 0.403g, 58.76%).
MS(ESI,pos.ion)m/z:460.18[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 10.98 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.76 (s, 2H),
7.57 (d, J=6.7Hz, 1H), 7.53～7.51 (m, 1H), 7.42 (d, J=3.7Hz, 2H), 7.39～7.31 (m, 1H),
3.93 (dd, J=20.9,12.8Hz, 2H), 3.81～3.67 (m, 4H), 3.63～3.59 (m, 2H), 3.13 (s, 2H), 2.32
(s,3H).
Embodiment 10:6-methoxyl group-2-(5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydro
Pyrrolo-[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
Step 1) synthesis of 6-methoxyquinazoline hydrochloride-2,4 (1H, 3H)-diketone
This step title compound prepares with reference to the method described by embodiment 1 step 1, will 2-amino-5-first
P-methoxybenzoic acid (2.51g, 15.0mmol), carbamide (13.51g, 225.0mmol) react preparation in 200mL tube sealing, after drying
Obtain title compound (gray solid, 2.30g, 79.7%).
MS(ESI,neg.ion)m/z:191.0[M-H]-；
1H NMR(d6-DMSO, 400MHz) δ (ppm): 11.24 (s, 1H), 11.06 (s, 1H), 7.36 (d, J=2.9Hz,
1H), 7.32 (dd, J=8.8Hz, 2.9Hz, 1H), 7.16 (d, J=8.8Hz, 1H), 3.82 (s, 3H).
Step 2) synthesis of 2,4-bis-chloro-6-methoxyquinazoline hydrochloride
This step title compound prepares with reference to the method described by embodiment 1 step 2, will 6-methoxyl group quinoline azoles
Quinoline-2,4 (1H, 3H)-diketone (1.84g, 9.57mmol), phosphorus pentachloride (5.97g, 28.65mmol) are in phosphorus oxychloride
Reaction preparation in (21.9mL, 239mmol), thick product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=
10/1) title compound (white solid, 1.78g, 81.2%) is obtained.
MS(ESI,pos.ion)m/z:229.1[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm): 7.89 (d, J=9.2Hz, 1H), 7.61 (dd, J=9.2Hz, 2.8Hz,
1H), 7.40 (d, J=2.7Hz, 1H), 3.99 (s, 3H).
Step 3) synthesis of 2-chloro-6-methoxyquinazoline hydrochloride-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 3, will 2, the chloro-6-of 4-bis-
Methoxyquinazoline hydrochloride (2.11g, 9.21mmol) is anti-in sodium hydrate aqueous solution (1M, 55.3mL) and oxolane (20.0mL)
Should prepare, it is (white that thick product obtains title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1)
Color solid, 1.91g, 98.3%).
MS(ESI,pos.ion)m/z:211.0[M+H]+；
1HNMR(CDCl3, 600MHz) and δ (ppm): 7.63～7.60 (m, 2H), 7.38 (dd, J=8.9Hz, 3.0Hz, 1H),
3.93(s,3H).
Step 4) 6-methoxyl group-2-(5-(5-methyl-2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydropyrrolo
And [3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (5-methyl-2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.50g, 1.68mmol),
2-chloro-6-methoxyquinazoline hydrochloride-4 (3H)-one (0.39g, 1.85mmol) and triethylamine (0.93mL, 6.73mmol) are at 1,4-bis-
In oxygen six ring (20mL) prepared by back flow reaction, and thick product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/
1) title compound (pale yellow oil, 0.58g, 72.61%) is obtained.
MS(ESI,pos.ion)m/z:472.35[M+1]+；
1H NMR(d6-DMSO, 600MHz) δ (ppm): 11.26 (s, 1H), 7.99 (s, 2H), 7.75 (d, J=8.2Hz,
1H), 7.57 (dd, J=8.6,2.5Hz, 1H), 7.48 (td, J=8.5,2.9Hz, 1H), 7.36 (d, J=7.7Hz, 1H),
7.31 (s, 2H), 3.85 (s, 3H), 3.72～3.46 (m, 2H), 3.49～3.35 (m, 6H), 2.95 (s, 2H), 2.38 (s,
3H).
(hexahydropyrrolo is also for 5-(2-(2H-1,2,3-triazole-2-base) benzoyl) for embodiment 11:6-methoxyl group-2-
[3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.50g, 1.76mmol), the chloro-6-of 2-
Methoxyquinazoline hydrochloride-4 (3H)-one (0.41g, 1.94mmol) and triethylamine (0.98mL, 7.06mmol) are at 1,4-dioxane
(20mL) in prepared by back flow reaction, and thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Title compound (faint yellow dope, 0.55g, 68.1%).
MS(ESI,pos.ion)m/z:458.36[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.08 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.74 (s, 2H),
7.66 (d, J=6.5Hz, 1H), 7.58～7.49 (m, 1H), 7.42 (d, J=4.0Hz, 2H), 7.37～7.32 (m, 2H),
3.89 (dd, J=21.1,12.6Hz, 2H), 3.81～3.69 (m, 4H), 3.63～3.61 (m, 2H), 3.82 (s, 3H), 3.13
(s,2H).
Embodiment 12:6-methoxyl group-2-(5-(the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) benzoyl) hexahydro pyrrole
Cough up also [3,4-c] pyrroles-2 (1H)-yl) synthesis of quinoline azoles-4 (3H)-one
This step title compound prepares with reference to the method described by embodiment 1 step 8, will (hexahydropyrrolo is also
[3,4-c] pyrroles-2 (1H)-yl) (the fluoro-6-of 2-(2H-1,2,3-triazole-2-base) phenyl) ketone (0.50g, 1.66mmol), 2-
Chloro-6-methoxyquinazoline hydrochloride-4 (3H)-one (0.38g, 1.83mmol) and triethylamine (0.92mL, 6.64mmol) are at 1,4-dioxy
In six rings (20mL) prepared by back flow reaction, and thick product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1)
Obtain title compound (faint yellow dope, 0.50g, 63.58%).
MS(ESI,pos.ion)m/z:476.35[M+1]+；
1H NMR(CDCl3, 600MHz) and δ (ppm): 11.02 (s, 1H), 7.97 (d, J=7.9Hz, 1H), 7.72 (s, 2H),
7.49 (d, J=6.5Hz, 1H), 7.47～7.43 (m, 1H), 7.40 (d, J=3.7Hz, 2H), 7.36～7.31 (m, 1H),
3.91 (dd, J=21.0,12.6Hz, 2H), 3.85 (s, 3H), 3.81～3.69 (m, 4H), 3.61～3.57 (m, 2H), 3.15
(s,2H).
Biologic test
Embodiment A the compounds of this invention is to humanization OX
1
The antagonism experiment of receptor
Test method
Use fluorescence detection detection the compounds of this invention that the impact of the cell calcium current of agonist induction is evaluated this
Bright compound is to expressing the humanization OX on Chinese hamster ovary cell (CHO)1The antagonistic ability of receptor.By cell suspension in
In DMEM culture medium (invitrogen), then with 2 × 104The Density Distribution of cells/well is in micro reaction plate.Will be containing glimmering
Light probe (Fluo4NW, Invitrogen), probenecid are flat with the Hank of 20mM hydroxyethyl piperazine second sulfacid (invitrogen)
Weighing apparatus saline solution (HBSS, invitrogen) (pH=7.4) joins in above-mentioned micro reaction plate, then arises from 37 DEG C with cell one
Hatch 60min, hatch 15min then at 22 DEG C.Sptting plate is placed in cell fluorescence work station (CellLux,
PerkinElmer), and add test compound or with reference to antagonist or Hank balanced salt solution, after 5min, add 3nM appetite
Element A or Hank balanced salt solution (blank), then measures the change of fluorescence intensity, and it is dense with free intracellular calcium
That spends is changing into positive correlation.Experimental result represents with the suppression percentage ratio relative to matched group 3nM orexin-A.
Obtain amount effect curve by the experiment test of series concentration, thus calculate IC50Value.Experimental result is shown in Table 1.
Table 1 the compounds of this invention is to OX1The antagonism of receptor
| Embodiment is numbered | OX1IC50(μM) |
| Embodiment 1 | 0.658 |
| Embodiment 2 | 0.766 |
| Embodiment 3 | 0.884 |
| Embodiment 4 | 1.061 |
Test result indicate that, the compounds of this invention is to OX1Receptor shows preferable antagonism.
Embodiment B the compounds of this invention is to humanization OX
2
The antagonism experiment of receptor
Test method
Use fluorescence detection detection the compounds of this invention that the impact of the cell calcium current of agonist induction is evaluated this
Bright compound is to expressing the humanization OX on HEK-293 cell2The antagonistic ability of receptor.By cell suspension in DMEM culture medium
(invitrogen) in, then with 3 × 104The Density Distribution of cells/well is in micro reaction plate.Will be containing fluorescent probe
The Hank balanced salt solution of (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second sulfacid (HBSS,
Invitrogen), during (PH=7.4) joins above-mentioned micro reaction plate, then arise from 37 DEG C with cell one and hatch 60min, then at
Hatch 15min for 22 DEG C.Sptting plate is placed in (CellLux, PerkinElmer) in cell fluorescence work station, and adds testization
Compound or with reference to antagonist or Hank balanced salt solution, adds 10nM orexin B or Hank balanced salt solution is (empty after 5min
White comparison), then measure the change of fluorescence intensity, it is changing into positive correlation with free intracellular calcium concentration.Experiment knot
Fruit represents with the suppression percentage ratio relative to matched group 10nM orexin B.
Obtain amount effect curve by the experiment test of series concentration, thus calculate IC50Value.Experimental result is as shown in table 2.
Table 2 the compounds of this invention is to OX2The antagonism of receptor
| Embodiment is numbered | OX2IC50(μM) |
| Embodiment 1 | 0.588 |
| Embodiment 2 | 0.436 |
| Embodiment 3 | 0.423 |
| Embodiment 4 | 0.575 |
Test result indicate that, the compounds of this invention is to OX2Receptor show preferable antagonism.
Pharmacokinetic Evaluation after embodiment C rat, dog and monkey intravenous or the quantitative the compounds of this invention of gavage
The compounds of this invention pharmacokinetic in rat, dog and monkey body is assessed by the present invention, dynamic
Thing information refers to Table A.
Table A animal subject of the present invention information table
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline
Aqueous solution or the form of 10%DMSO+10%Kolliphor HS 15+80% normal saline solution, animal subject is carried out to
Medicine.For intravenous administration group, dosage is 1mg/kg or 2mg/kg, time point the most upon administration is 0.083,
0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 little venous blood sampling constantly (0.3mL), and 3,000 or 4, under 000rpm from
The heart 10 minutes, collects plasma solutions, and preserves at-20 DEG C or-70 DEG C.For gastric infusion group, dosage is 2.5mg/
Kg or 5mg/kg, time point the most upon administration is that the little vein constantly in 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 takes
Blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm, collect plasma solutions, and protect at-20 DEG C or-70 DEG C
Deposit.Positive control is suvorexant.
Collect, to above-mentioned each group, the plasma solutions obtained and carry out LC/MS/MS analysis.Result is as shown in table 3.
Table 3 the compounds of this invention pharmacokinetic studies result in rat body
Result of the test shows, the compounds of this invention has good pharmacokinetic property in rat body.
The assessment of the cause QT interval prolongation effect that embodiment D the compounds of this invention is potential
Test method
Whether block hERG passage by detection the compounds of this invention and assess the phase between the cause QT that the compounds of this invention is potential
Prolongation effect, specific experiment method is as follows:
The compounds of this invention accurately weighed is dissolved in dimethyl sulfoxide (DMSO), is configured to the most highly concentrated of 10.0mM
The solution of degree, is then diluted to, with hERG FP Assay Buffer (Invitrogen), the solution that initial concentration is 120.0 μMs；
HERG Tracer Red stock solution (Invitrogen) and positive reference substance E-4031 stock solution (Invitrogen) are used hERG respectively
It is 4.0nM and the solution of 120.0 μMs that FPAssay Buffer (Invitrogen) is diluted to initial concentration.In 384 orifice plates, add
Enter the compounds of this invention of 2.5 μ L initial concentrations or the positive reference substance E-4031 (positive controls) of 2.5 μ L initial concentrations or
2.5 μ L hERG FPAssay Buffer (negative control group), 5 μ L hERG Membrane and 2.5 μ L hERG Tracer
Red solution, blank group adds 5 μ L hERG FPAssay Buffer and 5 μ L hERG Membrane so that of the present inventionization
Compound, the test final concentration of E-4031 and hERG Tracer Red are respectively 30.0 μMs, 30.0 μMs and 1.0nM, each group of test
Do 4 multiple holes.Then 384 orifice plates are put into 25 DEG C, the concussion instrument (PHMP-4, Grant-sio) of 250rpm are hatched 4 hours,
Measure the fluorescence polarization value in each hole by multi-functional microplate reader (PHERAStarFS, BMG LABTECH), computerized compound is to hERG
The relative inhibition of passage and 50% inhibition concentration (IC50)。
In the case of E-4031 is as positive control, if the compounds of this invention of 30.0 μMs relatively pressing down hERG passage
Rate processed is less than 50%, then the compounds of this invention IC to hERG passage50More than 30.0 μMs.If the compounds of this invention pair of 30.0 μMs
The relative inhibition of hERG passage is more than 50%, then need the compounds of this invention does dose curve titration, and concrete grammar is as follows:
By the compounds of this invention solution that above-mentioned initial concentration is 120 μMs and E-4031 solution, use hERG respectively
FPAssay Buffer carries out 5 times of gradient dilutions, be diluted to 120.0 μMs, 24.0 μMs, 4.8 μMs, 960.0nM, 192.0nM,
38.4nM, 7.7nM and 1.5nM totally 8 concentration to be measured, each concentration to be measured does 2 multiple holes.In 384 orifice plates, add 2.5 μ L treat
Survey the compounds of this invention or the positive reference substance E-4031 (positive controls) of 2.5 μ L concentration to be measured or 2.5 μ L hERG of concentration
FP Assay Buffer (negative control group), 5 μ L hERG FP Membrane and 2.5 μ L hERG Tracer Red solution,
Blank group adds 5 μ L hERG FP Assay Buffer and 5 μ L hERG Membrane.Then 384 orifice plates are put into 25
DEG C, the concussion instrument (PHMP-4, Grant-sio) of 250rpm is hatched 4 hours, with multi-functional microplate reader (PHERAStarFS, BMG
LABTECH) measuring the fluorescence polarization value in each hole, maximum and minima with E-4031 fluorescence polarization value are corrected,
The IC of GraphPad computed in software the compounds of this invention50。
Test result indicate that, the compounds of this invention does not has inhibitory activity substantially to hERG passage, points out this compound to cause
The risk of QT interval prolongation is little.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show
Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature
It is contained at least one embodiment or the example of the present invention.In this manual, need not to the schematic representation of above-mentioned term
Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be arbitrary
Individual or multiple embodiment or example combine in an appropriate manner.Additionally, in the case of the most conflicting, the technology of this area
The feature of the different embodiments described in this specification or example and different embodiment or example can be combined by personnel
And combination.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example
Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, revises, replaces and modification.
Claims (10)
1. a compound, it is the stereoisomer of compound, tautomerism shown in the compound shown in formula (I) or formula (I)
Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Hy be phenyl or 5-6 unit heteroaryl, described phenyl and 5-6 unit heteroaryl individually optionally by one or more selected from D, F,
Cl、Br、I、C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6The substituent group of halogenated alkoxy or benzyl is replaced；
R1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O)
NH2、C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6
The substituted alkyl of hydroxyl, (C1-6Alkyl)-C (=O)-, (C1-6Alkoxyl)-C (=O)-, (C1-6Alkylamino)-C (=O)-, C3-6
Cycloalkyl, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；With
R5、R6、R7And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6
Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Hydroxyl takes
The alkyl in generation, (C1-6Alkyl)-C (=O)-, (C1-6Alkoxyl)-C (=O)-, (C1-6Alkylamino)-C (=O)-, C3-6Cycloalkyl,
C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl.
Compound the most according to claim 1, wherein, Hy be thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals or
Comprise the 5-6 unit heteroaryl of two nitrogen-atoms, described thienyl, furyl, pyrrole radicals, triazolyl, pyridine radicals and comprise two
The 5-6 unit heteroaryl of nitrogen-atoms individually optionally by one or more selected from D, F, Cl, Br, I, methyl, ethyl, isopropyl, uncle
The substituent group of butyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy or benzyl is replaced.
Compound the most according to claim 2, what it was compound shown in the compound shown in formula (II) or formula (II) is vertical
Body isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
4. according to the compound described in claim 1 or 3, wherein R1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、
Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl,
C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The substituted alkyl of hydroxyl, (C1-4Alkyl)-C (=O)-, (C1-4Alkane
Epoxide)-C (=O)-or (C1-4Alkylamino)-C (=O)-.
5. according to the compound described in claim 1 or 3, wherein R5、R6、R7And R8Be each independently H, D, F, Cl, Br, I ,-
CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alcoxyl
Base, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The substituted alkyl of hydroxyl, (C1-4Alkyl)-C (=O)-, (C1-4Alkoxyl)-C
(=O)-or (C1-4Alkylamino)-C (=O)-.
6. according to the compound described in claim 1 or 3, wherein R1、R2、R3And R4It is each independently H, D ,-CD3、F、Cl、
Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3、-
CF2CF3, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3
Or-C (=O) N (CH3)2。
7. according to the compound described in claim 1 or 3, wherein R5、R6、R7And R8Be each independently H, D, F, Cl, Br, I ,-
CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3、
Methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-NHCH3、-N(CH3)2Or-CH2OH。
8., according to the compound described in claim 1 or 3, it is to have the compound of one of following structure or have one of following
The stereoisomer of the compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable
Salt or prodrug,
9. a pharmaceutical composition, it comprises the compound described in claim 1-8 any one；
Described pharmaceutical composition optionally comprises pharmaceutically acceptable carrier, excipient, adjuvant or their combination in any.
10. the compound described in claim 1-8 any one or the pharmaceutical composition described in claim 9 are in preparing medicine
Purposes, described medicine is for preventing, treat or alleviate the disease relevant to orexin receptor；
Wherein, the described disease relevant to orexin receptor is sleep disorder, depression, anxiety neurosis, Panic disorder, obsession, feelings
Perception neuropathy, depressibility neuropathy, anxious neuropathy, mood disorders, panic attack obstacle, behavioral disorder, emotionally disturbed,
Posttraumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, medicine depend on
Rely, addiction, cognitive disorder, Alzheimer, parkinson, the dyskinesia, drinking and eating irregularly, headache, migraine, pain
Bitterly, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune correlated disease, endocrine are correlated with
Disease or hypertension.
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| CN108299437A (en) * | 2017-01-13 | 2018-07-20 | 广东东阳光药业有限公司 | Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof |
| CN109988171A (en) * | 2017-12-29 | 2019-07-09 | 广东东阳光药业有限公司 | Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof |
| WO2022194122A1 (en) * | 2021-03-16 | 2022-09-22 | 上海翰森生物医药科技有限公司 | Nitrogen-containing heterocyclic polycyclic compound, preparation method therefor, and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299437A (en) * | 2017-01-13 | 2018-07-20 | 广东东阳光药业有限公司 | Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof |
| CN108299437B (en) * | 2017-01-13 | 2022-07-08 | 广东东阳光药业有限公司 | Octahydropyrrolo [3,4-c ] pyrrole derivatives and uses thereof |
| CN109988171A (en) * | 2017-12-29 | 2019-07-09 | 广东东阳光药业有限公司 | Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof |
| WO2022194122A1 (en) * | 2021-03-16 | 2022-09-22 | 上海翰森生物医药科技有限公司 | Nitrogen-containing heterocyclic polycyclic compound, preparation method therefor, and application thereof |
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| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |