CN109988171A - Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof - Google Patents

Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof Download PDF

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CN109988171A
CN109988171A CN201711468833.0A CN201711468833A CN109988171A CN 109988171 A CN109988171 A CN 109988171A CN 201711468833 A CN201711468833 A CN 201711468833A CN 109988171 A CN109988171 A CN 109988171A
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alkyl
alkoxy
compound
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alkylamino
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金传飞
梁海平
薛亚萍
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems

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Abstract

The present invention relates to octahydro pyrrolo- [3,4-c] azole derivatives and application thereof.Compound of the present invention and pharmaceutical composition comprising the compound are used for antagonism orexin receptor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they treat or prevent with orexin receptor related disease in purposes.

Description

Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof
Invention field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of octahydro pyrrolo- [3,4-c] azole derivatives include this The pharmaceutical composition of class compound and their application method and purposes.More specifically, compound of the present invention and Pharmaceutical composition can be used as orexin receptor antagonists for treating, preventing or mitigating disease relevant to orexin receptor.
Background of invention
Orexin (orexin) is also referred to as inferior colliculus krinin, appetite peptide comprising orexin-A and orexin B (or inferior colliculus Krinin -1 and inferior colliculus krinin -2), be a kind of neuropeptide secreted by hypothalamus, main physiological action has: 1. are adjusted It ingests, orexin can be obviously promoted feed, and react in dose-dependant, and have activated the neuron for adjusting feed；2. participating in The adjusting of energetic supersession, orexin can dramatically increase metabolic rate；3. participating in the adjusting of Sleep-Wake, orexin be can inhibit quickly Eye Movement Sleep extends the awakening time, the effect of orexin is blocked to can promote sleep；4. participating in endocrine metabolic diseases, orexin It is endocrine on pituitrin to influence clearly；5. related to remuneration sense, learning and memory；6. promoting gastric acid secretion；7. promoting Drinking-water increases；8. increasing blood pressure；9. it plays an important role in reward system and drug habit 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 generates physiological effect by acting on orexin receptor (orexin receptor, OXR).Orexin Receptor is a kind of G- G-protein linked receptor, and there are two types of types, is referred to as OX1Receptor and OX2Receptor, wherein OX1Receptor is to appetite Plain A has selectively, and OX2Receptor be for orexin-A and orexin B 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 brain tissue, and is selectively expressed in brain, wherein OX1Receptor with High Cell Density And High Expression is the nuclei of origin of noradrenergic neuron in locus coeruleus (locus coeruleus), and OX2Receptor It is the nuclei of origin of histaminergic neuron with High Cell Density And High Expression in nodular nipple nucleus.OX1Receptor and OX2The expression of both receptors can It sees in nuclei of median raphe, is the nuclei of origin of serotoninergic nerve member, and be found in ventral tegmental area, be dopaminergic neuron Nuclei of origin.In addition, OX2Expression of receptor is also seen in the responsible brain stem cholinergic neuron for adjusting rapid-eye-movement sleep and to it Nuclear activity has influence (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 of orexin receptor mRNA in the rat brain.FEBS Lett.,1998,438(1- 2):71-75)。
It can be seen that orexin receptor has great importance on pathology, it is related to a variety of diseases, such as sleep Obstacle, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mental state Obstacle, panic attack obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia Disease, manic depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, Dyskinesia, feeding desorder, headache, migraine, pain, disease of digestive system, epilepsy, inflammation, cardiovascular disease, diabetes, Metabolic disease, immune correlated disease, endocrine related disease and hypertension etc..But currently on the market with orexin receptor phase The drug of pass only has the anti-insomnia medicine Su Woleisheng (Suvorexant) of United States Merck company research and development, is orexin receptor antagonism Agent, the drug were also once once ratified because of safety issue by the refusal of U.S. FDA.
In consideration of it, the present invention provides a kind of compound with orexin receptor antagonistic activity, the compound of the present invention With preferable drug activity, and toxic side effect is smaller, and safety is higher, while also having excellent physicochemical property, medicine generation Therefore property and toxicological characteristics have preferable potential applicability in clinical practice.
Summary of the invention
Only summarize some aspects of the invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification When variant with citation, it is subject to the disclosure of the specification.
The present invention provides a kind of compounds with orexin receptor antagonistic activity, and in particular to octahydro pyrrolo- [3, 4-c] azole derivatives and its pharmaceutical composition, the compound and pharmaceutical composition can be used for preventing or treating and appetite The relevant disease of plain receptor.
The compounds of this invention shows good antagonistic activity to orexin receptor, has good drug effect, medicine for property And/or toxicological characteristics, such as it is good brain/blood plasma ratio (brain plasma ratio), good bioavilability, good Metabolic stability, less toxic side effect and high security etc..Meanwhile the good characteristic of the certain parameters of the compounds of this invention, such as partly decline The excellent spy of phase, clearance rate, selectivity, bioavilability, chemical stability, metabolic stability, permeability of the membrane, dissolubility etc. Property, the reduction of side effect, the expansion of therapeutic index or the improvement of tolerance can be promoted.
Specifically:
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein: X, R1、R2、R3、R4、R5And R6With meaning as described in the present invention.
In one embodiment, X is N or CRx。
In one embodiment, R1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、 C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkane ammonia Base, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkane ammonia Base).
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、 C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkane ammonia Base, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkane ammonia Base).
In one embodiment, R3、R4、R5And RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Haloalkoxy Base, C1-6Alkylthio group, C1-6Alkylamino, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alcoxyl Base) or-C (=O)-(C1-6Alkylamino).
In one embodiment, R6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、 C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkane ammonia Base, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkane ammonia Base).
In one embodiment, compound of the present invention is shown in formula (II) compound represented or formula (II) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt or preceding of compound Medicine,
Wherein, R1、R2、R3、R4、R5And R6With meaning as described in the present invention.
In one embodiment, the R in formula (I) or formula (II)1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) Or-C (=O)-(C1-4Alkylamino).
In one embodiment, the R in formula (I) or formula (II)2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) Or-C (=O)-(C1-4Alkylamino).
In one embodiment, the R in formula (I) or formula (II)3、R4、R5And RxBe each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkane Oxygroup, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) or-C (=O)-(C1-4Alkylamino).
In one embodiment, the R in formula (I) or formula (II)6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) Or-C (=O)-(C1-4Alkylamino).
In one embodiment, the R in formula (I) or formula (II)1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、- OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3、-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、- OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3、-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)3、R4、R5And RxBe each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,- CHF2、-CF3、-CH2CHF2、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、- OCF3、-OCH2CHF2、-OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、- OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3、-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, compound of the present invention for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds of the present invention.
In one embodiment, pharmaceutical composition of the present invention optionally includes pharmaceutically acceptable carrier, assigns Shape agent, adjuvant or their any combination.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine preparation, The drug is for preventing, treating or mitigating disease relevant to orexin receptor.
In one embodiment, the disease relevant to orexin receptor is sleep disturbance, depression, anxiety disorder, fears Flurried disease, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior Not normal, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, spirit are wrong Unrest, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, feeding desorder, head Bitterly, migraine, pain, disease of digestive system, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune related disease Disease, endocrine related disease or hypertension.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine preparation, The drug is used for antagonism orexin receptor.
On the other hand, the side of preparation, separation and the purifying of the compound for being included the present invention relates to formula (I) or formula (II) Method.
Biological results show that compound provided by the invention can be used as preferable orexin receptor antagonists.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, 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 identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one (kind) " and " described " are 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.For example, " embodiment " refers to one or more embodiments.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched It states and includes the case where the case where wherein event or situation occur and wherein it does not occur.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced " The structure or group are unsubstituted or are replaced by one or more substituent groups of the present invention, wherein the substitution is anticipated Taste the reasonable position of any chemical valence permission in give structure or group occurs.Substituent group of the present invention includes, But it is not limited to D, F, Cl, Br, I ,-N3、-CN、-NH2、-OH、-SH、-NO2,-COOH ,-C (=O) NH2,-C (=O)-alkyl ,-C (=O)-alkoxy ,-C (=O)-alkylamino, alkyl, alkenyl, alkynyl, halogenated alkyl, halogenated alkoxy, alkoxy, alkylthio group, Alkylamino, the alkyl of hydroxyl substitution, naphthenic base, carbocylic radical, heterocycle, aryl, heteroaryl, etc..
In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.For example, structural formula "-C (=O) NR9R9a" and structural formula " R9R9aN-S (=O)2" R between the two9And R9aSpecific option it is unaffected from each other.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " indicates single D-atom.
Term " hetero atom " indicates one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), The form of sulphur (S) and phosphorus (P) any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the hydrogen in heterocycle on nitrogen-atoms Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole base), NH (as the NH in pyrrolidinyl) or NR are (as N- NR in substituted pyrrolidinyl).
Term " halogen " and " halogenated " 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 ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally 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 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (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), tert-butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one carbon- Carbon sp2Double bond, wherein the alkenyl group optionally replaced one or more substituent groups described in the invention, wraps Include the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one carbon- Tri- key of carbon sp, wherein the alkynyl group is optionally replaced one or more substituent groups described in the invention.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In 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.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
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 " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF3、-CF2CF3、-CH2CF2CHF2Deng.It is real one It applies in scheme, " halogenated alkyl " is the C of lower level1-4Halogenated alkyl the, wherein " C1-4Halogenated alkyl " includes fluorine-substituted C1-4 The C that alkyl, chlorine replace1-4The C that alkyl, bromine replace1-4The C that alkyl, iodine replace1-4Alkyl, etc..Specifically, halogen atom replaces C1-4Alkyl includes-CH2F、-CHF2、-CF3、-CH2Cl、-CHCl2、-CCl3、-CH2Br、-CHBr2、-CBr3、-CH2CH2F、- CH2CHF2、-CH2CF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-CHFCF3、-CHFCHF2、-CHFCH2F、-CH2CH2CF3、- CH2CF2CHF2Etc..The halogenated alkyl is optionally replaced one or more substituent groups described in the invention.
Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF3、-OCF2CF3、-OCH2CF2CHF2 Deng.The halogenated alkoxy is optionally replaced one or more substituent groups described in the invention.
Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.
The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), ethylmercapto group (EtS ,- SCH2CH3), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH2CH2CH3), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH (CH3)2), 1- butylthio (n-BuS, n- butylthio ,-SCH2CH2CH2CH3), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur Base ,-SCH2CH(CH3)2), 2- butylthio (s-BuS, s- butylthio ,-SCH (CH3)CH2CH3), 2- methyl -2- rosickyite base (t- BuS, t- butylthio ,-SC (CH3)3), etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets It invents replaced described substituent group.
Term " hydroxyl replace alkyl " indicate alkyl group replaced one or more hydroxyl groups, wherein alkyl base Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl, Etc..
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, indicate containing 3-12 ring carbon atom, it is monovalent or The monocycle of multivalence, bicyclic or three-ring system, middle ring can be it is fully saturated or comprising one or more degrees of unsaturation, but One armaticity ring cannot all have.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitable carbocylic radical group packet It includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3-8 ring carbon atom；? In another embodiment, carbocylic radical includes 3-6 ring carbon atom.The example of carbocylic radical group includes, but are not limited to: cyclopropyl, Cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- hexamethylene Base -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, etc..The carbocylic radical group can be with It is independently unsubstituted or replaced one or more substituent groups described in the invention.
Term " heterocycle " and " heterocycle " are used interchangeably here, indicate to include 3-12 annular atom, unit price or more The monocyclic, bicyclic or tricyclic system of valence, one or more atoms are independently replaced by hetero atom in middle ring, the hetero atom With meaning as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, a but fragrance Property ring cannot all have.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.The example of heterocycle includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, etc..It is miscellaneous - CH in ring group2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles by-C (=the O)-example substituted Alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl and hybar X base.The example that sulphur atom is oxidized in heterocycle includes, But it is not limited to, sulfolane base, 1,1- dioxothiomorpholinyl.The heterocyclyl groups can be optionally one or more Replaced substituent group described in the invention.
Term " naphthenic base " indicates containing 3-12 ring carbon atom, monovalent or multivalence saturation monocyclic, bicyclic or tricyclic System.The example of naphthenic base includes, but are not limited to cyclopropyl, cyclopenta, cyclohexyl, etc..The group of naphthene base is optionally Replaced one or more substituent groups described in the invention.
Term " aryl " is indicated containing 6-14 annular atom or 6-10 annular atom or 6 annular atoms, monovalent or more The carbocyclic ring system of the monocyclic, bicyclic or tricyclic of valence, wherein at least one ring are aromatic.Aryl group is in general, but necessarily Ground is connect by the armaticity ring of aryl group with parent molecule.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring " Change use.The example of aryl group may include phenyl, naphthalene, anthryl, etc..The aryl group is optionally by one or more Replaced a substituent group described in the invention.
Term " heteroaryl " indicates (the i.e. 5-6 containing 5-14 annular atom or 5-10 annular atom or 5-6 annular atom Member), the monocyclic, bicyclic or tricyclic system of unit price or multivalence, wherein at least one ring is aromatic, and at least one ring includes One or more hetero atoms.Heteroaryl groups are in general, but unnecessarily pass through the armaticity ring and parent molecule of heteroaryl groups Connection.Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is replaced 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- oxazole Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 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- Oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulphur For di azoly, 1,2,5- thio biphosphole base, pyrazinyl, cyanuro 1,3,5；Also include below bicyclic, but be not limited to these It is bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinoline Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, 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..
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Stereochemical definitions used in the present invention and rule generally 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,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate compound be it is left-handed, prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer 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.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " prodrug " used in the present invention represents a compound and is converted into shown in formula (I) or (II) in vivo Compound.Such conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for precursor structure It rings.Pro-drug compounds of the present invention can be ester, and what ester can be used as pro-drug in existing invention has phenyl ester class, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound include hydroxyl, it can be acylated to obtain the compound of prodrug form.Other pro-drug shapes Formula includes phosphate, if these phosphate compounds are obtaining through the di on parent.It is complete about pro-drug Whole discussion can refer to following documents: 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,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document are included herein by reference.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.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 hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor 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, niacin Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through alkali appropriate Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The compound of group is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to cause individual Object or medicinal response (such as enzyme or protein active are reduced or inhibit, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevention disease etc.) the compounds of this invention amount.
The present invention relates to substituted (octahydro pyrrolo- [3,4-c] pyrroles -2 (1H)-yl) phenyl ketone compounds, its pharmacy Upper acceptable salt, its pharmaceutical composition and its pharmaceutical preparation, they have orexin receptor antagonism, can be used as orexin Receptor antagonist is for preventing or treating disease relevant to orexin receptor, such as sleep disturbance, psychiatry, neurology With neurodegeneration obstacle, pharmacological dependence, habituation, cognitive disorder, dyskinesia, feeding desorder, etc..
Unless otherwise mentioned, all suitable isotope variations 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 mutual Tautomeric is included within the scope of the present invention.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
In addition, they are also included within the scope of the present invention when the compound of the present invention forms hydrate or solvate It is interior.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within model of the invention In enclosing.
Compound shown in formula (I) or formula (II) can exist in a salt form.In one embodiment, the salt refers to medicine Acceptable salt on.Pharmaceutically acceptable salt of the invention can with conventional chemical processes by parent compound, alkalinity or Acidic moiety synthesizes.In general, such salt can be by making the free acid form and stoichiometry of these compounds It is suitable for alkali (hydroxide, carbonate, the bicarbonate of such as Na, Ca, Mg or K) reaction, or by making these compounds Free alkali form reacts to be prepared with the suitable acid of stoichiometry.Such reaction is usually in water or organic solvent or both Mixture in carry out.Generally, in appropriate cases, need using non-aqueous medium for example ether, ethyl acetate, ethyl alcohol, Isopropanol or acetonitrile.At such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth The list that other is suitable for salt can be found in (Wiley-VCH, Weinheim, Germany, 2002).
The compounds of this invention is alkaline, therefore is generally possible to by pharmaceutically acceptable to be formed with suitable acid processing Acid-addition salts.Suitable acid includes pharmaceutically acceptable inorganic acid and pharmaceutically acceptable organic acid.Representative medicine Acceptable acid-addition salts include hydrochloride, hydrobromate, nitrate, methyl nitrate, sulfate, disulfate, ammonia on 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, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzene Formates, mandelate, tannate, formates, stearate, ascorbate, palmitate, oleate, acetonate, Pamoate, malonate, laruate, glutarate, glutamate, estolate, mesylate, sulfonate, 2- hydroxyl Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such 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, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread 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) or formula (II) of isotope enrichment can pass through this field skill It is tried described by routine techniques known to art personnel or the embodiment in the present invention and preparation process using suitable isotope labelling Agent substitutes original used unmarked reagent to prepare.
On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I) or formula (II).
Pharmaceutical composition, preparation and the administration of the compounds of this invention
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 further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, interaction the effect of to avoid will be greatly reduced the compounds of this invention when administering to a patient and to will lead to be not medicine The interaction of acceptable pharmaceutical composition on.In addition, every kind of excipient must be pharmaceutically acceptable, for example, tool There is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.One skilled in the art will recognize that certain pharmaceutically acceptable excipient can provide not A kind of only function, and alternative function is provided, this is depended in preparation in the presence of there are which in how much excipient and preparation Other a little excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and 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(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy, 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 The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.
The compounds of this invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.For example, dosage form It is suitable for the dosage form of following administration route including those: (1) is administered orally, such as tablet, capsule, caplet agent, pill, lozenge Agent, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, for example, it is sterile Solution, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as suppository；(5) it inhales Enter, such as aerosol, solution and dry powder doses；(6) local administration, such as cream, ointment, lotion, solution, paste Agent, spray, foaming agent and gelling agent.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
In one embodiment, the compounds of this invention can be configured to peroral dosage form.In another embodiment, of the 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.Also in one embodiment, of the present inventionization Topical dosage forms can be configured to by closing object.
Pharmaceutical composition provided by the invention can be with compressed tablets, development piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet, intestines Molten, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance coating for being resistant to gastric acid effect but dissolving or being disintegrated in intestines Compressed tablets, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating include, but are not limited to fatty acid, fat, Phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compressed tablets that sugar-coat surrounds, It can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is to use water-soluble substances Thin layer or film covering compressed tablets.Film coating includes, but are not limited to hydroxyethyl cellulose, sodium carboxymethylcellulose, gathers Ethylene glycol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.Multiple compressed tablet For by the compressed tablets prepared more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared At be suitable for dry powder doses to the dosage form of patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Include fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising cream Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next It says, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed Amount) Lai Dingyi.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
The compounds of this invention can also be in conjunction with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine that palmitoyl residues replace.In addition, compound disclosed in this invention can with realizing drug Control release used in one kind Biodegradable polymeric combination, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel crosslinking or amphiphilic block copolymer.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.
In one embodiment, treatment method of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.
In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administration.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administration.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is 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. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, the duration including implementing the program are treated disease depending on treated disease The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs to change as time goes by it may require that adjust it is suitable to Prescription case.
The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.
The compounds of this invention can be with sedative, hypnotic, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole Ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the element that fades can medicaments, benzene phenodiazineBarbiturate, 5HT-2 antagonist etc. are used in combination, such as: Adinazolam, allobarbital, alonimid, Alprazolam, amitriptyline, amytal, amoxapine, bentazepam, benzoctamine, brotizolam, biphenylacetone, fourth Spirocyclic ketone, cloth tower barbital, cloth tower are than appropriate, capuride, Carbocloral, chloral betaine, chloraldurate, librium, chlorine rice pa Bright, Clonazepam, Domperidone, chlorine nitrogenCloretate, Clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine Aldehyde willow amine, double valproic acids, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west It dissolves, Flurazepam, Fluvoxamine, fluoxetine, fosazepam, glutethimide, Halazepam, hydroxyzine, imipramine, chlorine hydroxyl go first to pacify Fixed, Lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles Logical sequence Buddhist nun's method oxazolone, Nisobamate, intrazepam, nortriptyline, is oxazepaned, paraaldehyde, Paro former times spit of fland, amobarbital, piperazine It evens up, perphenazine, nardil, phenobarbital, verstranFenazil, propofol, protriptyline, quazepam, auspicious chlorine West dissolves, rolipram, quinalbarbitone, Sertraline, Suproclone, Temazepam, thioridazine, Tracazolate, anti-phenyl ring third Amine, Trazodone, triazole benzene phenodiazine, Trepipam, trimeglamide, trichloroethyl phosphate, triperazine, trimethoxy benzoyl Quinoline, trimeprimine, uldazepam, venlafaxine new, Zaleplon, Zolazepam, zolpidem and their salt and composition Etc. or the compounds of this invention can administration while physical method such as light therapy or electro photoluminescence be used in combination.
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound of the present invention and pharmaceutical composition are as orexin receptor antagonists, to preventing, treating or mitigate Disease relevant to orexin receptor is effectively, to can be used for preparing the drug of antagonism orexin receptor.
Disease relevant to orexin receptor can be selected from all types of sleep disturbance, all types of psychiatry, mind It is learned and neurodegeneration obstacle, all types of pressure related syndromes, all types of habituation (especially psychotropic activity object through disease The use of matter is abused, seeks and is restored), it is all types of in healthy population and in psychiatric patient and nervous system disease Cognition dysfunction, all types of feeds or drinking-water obstacle in patient, etc..
In one embodiment, disease relevant to orexin receptor includes sleep disturbance, depression, anxiety disorder, fear Disease, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior are lost Often, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, amentia, Dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, feeding desorder, headache, It is migraine, pain, disease of digestive system, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune correlated disease, interior Secrete related disease or hypertension.
In one embodiment, disease relevant to orexin receptor can be selected from sleep disturbance, and it includes all types of Insomnia, Narcolepsy and other hyper somnolence diseases, parasomnia, the relevant myodystony of sleep, uneasy leg Syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome and sleep phases Syndrome or the relevant insomnia of mental disease is retarded or advanced, etc..
In one embodiment, disease relevant to orexin receptor can be selected from psychiatry, neurology and nerve change Sexual dysfunction, it includes depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective diseases, depressibility neuropathy, anxiety nerve Disease, mood disorder, panic attack obstacle, posttraumatic stress disorder, sex dysfunction, mental disease, Parkinson's disease, dementia or essence Refreshing hypoevolutism, etc..
In one embodiment, disease relevant to orexin receptor can be selected from cognition dysfunction, and it includes normal , in healthy, young, adult or old crowd transient episodes or chronic seizures all types of attentions, It practises and memory function declines, or the transient episodes or chronic in mental disease, neuropathy, angiocarpy and disease of immune system patient All types of attentions of breaking-out, learning and memory function reduction, etc..
It should be understood that in certain environmental conditions such as such as pressure or fear, (wherein, pressure may have social source such as Social pressures or have physiological sources such as physical stress, including by fear generate pressure) promote or accelerate it is any as previously described Conditions or diseases in the case where, the compound of the present invention to treat these environment adjust conditions or diseases be useful.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog 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 the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through 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 is for further lifting Example illustrates the contents of the present invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、 DMSO-d6、D2O、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0 ppm) or chloroform (7.26ppm) as Reference standard.When there is multiplet, following abbreviation: s (singlet, unimodal) will be used, d (doublet, bimodal), T (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), Brs (broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet Of doublet of doublets, in pairs doublet), and tdd (triplet of doublet of doublets, three pairs two Weight peak), dt (doublet of triplets, double triplets), td (triplet of doublets, three doublets), tt (triplet of triplets, three triplets).Coupling constant J is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-MS of Agilent (column model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), at 210nm/254nm, detected with UV.
The use of logogram word below is through the present invention:
CH2Cl2, DCM methylene chloride
CDC13Deuterated chloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
EtOAc, EA ethyl acetate
CH3CN acetonitrile
CH3OH, MeOH methanol
H2O water
D2O deuterium-oxide, heavy water
Et3N triethylamine
DMF N,N-dimethylformamide
DIPEA N, N- diisopropylethylamine
HATU 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
Mmol, mM mM
NM nanomole
μM micromole
G grams
Min minutes
H hours
NaH sodium hydride
K2CO3Potassium carbonate
Na2CO3Sodium carbonate
NaHCO3Sodium bicarbonate
Na2SO4Sodium sulphate
NaCl sodium chloride
μ L, μ l microlitres
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Boc, BOC tertbutyloxycarbonyl
HCl hydrochloric acid
The ethyl acetate solution of HCl in EA hydrogen chloride-ethyl acetate, hydrochloric acid
Saline physiological saline
Following synthetic schemes describes the step of preparing the compounds of this invention.Unless otherwise stated, R1And R2With such as this hair The bright definition.
Synthetic schemes 1
Step 1:
Step 2:
Step 3:
The compounds of this invention (6) can be prepared by the method that synthetic schemes 1 describes:
Step 1: compound (1) with 2,2,2 tfifluoroethyl alcohol or 2,2- difluoroethanol nucleophilic substitution occurs Conjunction object (2)；
Step 2: 2- bromethiazole compound containing different substituents (3) and hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate by necleophilic reaction obtain compound (4), compound (4) slough Boc protecting group obtain compound (5)；
Step 3: compound (5) and compound (2) by condensation reaction obtain target compound (6)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
1 4- methyl -2- of embodiment (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up -2 (1H)-yls) synthesis of thiazole -5- nitrile
The synthesis of step 1) 2- (2,2,2- trifluoro ethoxy) niacin
In 50mL there-necked flask, n,N-Dimethylformamide (10mL), 2,2,2- trifluoroethanols are added under nitrogen protection (435 μ L, 6mmol) is added sodium hydride (180mg, 60% is scattered in liquid paraffin, 4.5mmol) at 0 DEG C, maintains and stir at 0 DEG C It mixes 0.5 hour.By sodium hydride (180mg, 60% is scattered in liquid paraffin, 4.5mmol) and 2- fluorine pyridine-3-carboxylic acid (423mg, It 3mmol) is dissolved in n,N-Dimethylformamide (5mL) (turbid solution), is added drop-wise to the reaction system at 0 DEG C, is risen after being added dropwise To being stirred overnight at room temperature.TLC detection stops reaction after the reaction was completed, and slowly plus water quenching is gone out, and 1N HCl to pH=2 is added, and uses Ethyl acetate extracts (3 × 30mL), collects organic phase, and anhydrous sodium sulfate is dry, and it is isolated that column chromatographs (ethyl acetate elution) Title compound is pale solid (611mg, 92%).
MS(ESI,pos.ion)m/z:222.15[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.46 (d, J=7.6Hz, 1H), 8.39 (dd, J=3.9,0.8Hz, 1H), 7.19 (dd, J=7.2,5.3Hz, 1H), 4.98 (q, J=8.3Hz, 2H)
Step 2) 5- (5- cyano -4- methylthiazol -2- base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-tertiary fourth of carboxylic acid The synthesis of ester
Weigh the bromo- 4- methylthiazol -5- formonitrile HCN (0.65g, 3.2mmol) of 2-, hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 Acetonitrile is added in 50mL single port bottle in (1H)-t-butyl formate (0.75g, 3.5mmol), potassium carbonate (1.3g, 9.3mmol) (15mL) is placed at 95 DEG C and starts to be refluxed overnight, and TLC detects raw material point and disappears.Add water (20mL) quenching reaction, ethyl acetate extraction It takes (3 × 20mL), is concentrated after anhydrous sodium sulfate is dry, column chromatography (petrol ether/ethyl acetate (v/v)=3/1) obtains title Compound is light yellow solid (0.87g, 81%).
MS(ESI,pos.ion)m/z:279.20[M+H-56]+；
1H NMR(400MHz,CDCl3) δ (ppm): 3.72 (dd, J=21.8,14.8Hz, 4H), 3.37 (dd, J=39.0, 16.0Hz,4H),3.08(s,2H),2.42(s,3H),1.47(s,9H).
The synthesis of step 3) 2- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol -5- nitrile hydrochloride
To filling 5- (5- cyano -4- methylthiazol -2- base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-tertiary fourth of carboxylic acid The single port bottle of ester is added methylene chloride (6mL), and the ethyl acetate solution (6mL, 3mol/L, 18mmol) of hydrochloric acid is then added dropwise.About After 3 hours, TLC detects raw material almost fully reacting, and it is yellow solid that solvent, which is removed under vacuum, and is dried to obtain title compound (0.89g, 99%).
MS(ESI,pos.ion)m/z:235.10[M+H]+；
1H NMR(400MHz,D2O) δ (ppm): 3.87 (dd, J=11.4,7.4Hz, 2H), 3.74-3.48 (m, 4H), 3.40 (dd, J=11.3,8.8Hz, 2H), 3.26 (dd, J=12.3,4.5Hz, 2H), 2.37 (s, 3H)
Step 4) 4- methyl -2- (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) thiazole -5- nitrile synthesis
It weighs 2- (2,2,2- trifluoro ethoxy) niacin (377mg, 1.524mmol) and dichloromethane is added at single port bottle, 0 DEG C Alkane (30mL), n,N-diisopropylethylamine (0.5mL, 2.9mmol) are then added HATU (557mg, 1.457mmol), return to room The hydrochloride of 2- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol -5- nitrile is added in temperature stirring after 1 hour (325mg, 1.387mmol), which is placed in, to be stirred overnight at room temperature.TLC detects a small amount of raw material and does not react, after continuing stirring 3 hours, Sodium bicarbonate solution quenching reaction is added, methylene chloride extracts (3 × 20mL), and the dry organic phase of anhydrous sodium sulfate is spin-dried for solvent, It is white solid (0.31g, 51%) that column chromatography (ethyl acetate elution), which obtains title compound,.
MS(ESI,pos.ion)m/z:438.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.19 (dd, J=4.8,1.6Hz, 1H), 7.70 (dd, J=7.3, 1.6Hz, 1H), 7.05 (dd, J=7.2,5.1Hz, 1H), 4.98-4.54 (m, 2H), 3.95 (dd, J=12.9,7.7Hz, 1H), 3.84-3.55 (m, 4H), 3.45 (dd, J=10.6,4.4Hz, 1H), 3.38-3.03 (m, 4H), 2.39 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):168.1,165.4,163.6,156.4,148.0,138.3,123.5 (d, J=276.0Hz), 120.5,118.6,114.3,87.8,61.9 (q, J=36.0Hz), 53.5,52.8,50.4,49.6, 42.4,41.1,17.1；
HPLC:99.78%.
Embodiment 22- (5- (2- (2,2- difluoroethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) -4- methylthiazol -5- formonitrile HCN synthesis
The synthesis of step 1) 2- (2,2- difluoroethoxy) niacin
This step title compound method referring to described in 1 step 1 of embodiment is prepared, in 50mL there-necked flask, N,N-Dimethylformamide (20mL), 2,2- difluoroethanol (0.9mL, 14mmol) are added under nitrogen protection, hydrogenation is added at 0 DEG C Sodium (425mg, 60% is scattered in liquid paraffin, 10.6mmol) is maintained and is stirred 0.5 hour at 0 DEG C.Then by sodium hydride (425mg, 60% is scattered in liquid paraffin, 10.6mmol) and 2- fluorine pyridine-3-carboxylic acid (1g, 7.1mmol) are dissolved in N, N- diformazan In base formamide (10mL) (turbid solution), it is added drop-wise to the reaction system at 0 DEG C, is warmed to room temperature and is stirred overnight after being added dropwise.TLC Detection stops reaction after the reaction was completed, and slowly plus water quenching is gone out, and 1N HCl to pH=2 is added, make to be extracted with ethyl acetate (3 × 30mL), organic phase is collected, anhydrous sodium sulfate is dry, and it is white that column, which chromatographs (ethyl acetate elution) isolated title compound, Solid (0.96g, 67%).
MS(ESI,pos.ion)m/z:204.10[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.46 (d, J=7.4Hz, 1H), 8.41-8.31 (m, 1H), 7.17 (dd, J=7.4,5.0Hz, 1H), 6.23 (dt, J=55.2,3.9Hz, 1H), 4.78 (td, J=13.4,3.9Hz, 2H)
Step 2) 2- (5- (2- (2,2- difluoroethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) - The synthesis of 4- methylthiazol -5- formonitrile HCN
This step title compound method referring to described in 1 step 4 of embodiment is prepared, that is, weighs 2- (2,2- bis- Fluorine ethyoxyl) methylene chloride (30mL), N, N- diisopropyl second is added in niacin (310mg, 1.526mmol) at single port bottle, 0 DEG C Then HATU (554mg, 1.457mmol) is added in amine (0.5mL, 2.9mmol), returns to addition 2- (six after being stirred at room temperature 1 hour Hydrogen pyrrolo- [3,4-c] pyrroles -2 (1H)-yl) hydrochloride (325mg, 1.387mmol) of -4- methylthiazol -5- nitrile is placed in It is stirred overnight at room temperature.TLC detects raw material and does not react there are also a small amount of, after continuing stirring 3 hours, sodium bicarbonate solution is added and is quenched instead It answers, methylene chloride extracts (3 × 20mL), and the dry organic phase of anhydrous sodium sulfate is spin-dried for solvent, and column chromatographs (ethyl acetate elutes) and obtains It is white solid (0.28g, 48%) to title compound.
MS(ESI,pos.ion)m/z:420.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.39-8.00 (m, 1H), 7.67 (dd, J=7.2,1.4Hz, 1H), 7.01 (dd, J=7.1,5.1Hz, 1H), 6.11 (tt, J=55.4,3.9Hz, 1H), 4.55 (dd, J=26.1,13.2Hz, 2H), 3.94 (dd, J=12.9,7.8Hz, 1H), 3.87-3.52 (m, 4H), 3.46 (dd, J=10.5,4.0Hz, 1H), 3.39- 2.98(m,4H),2.38(s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):168.1,165.6,163.7,157.2,148.1,138.0,120.4, (118.1,114.3,113.1 q, J=240.0Hz), 87.7,64.2 (t, J=30.0Hz), 53.6,52.8,50.5,49.6, 42.4,41.1,17.1；
HPLC:99.67%.
3 4- methyl -2- of embodiment (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up -2 (1H)-yls) synthesis of thiazole-5-carboxylic acid ethyl ester
Step 1) 2- (5- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol - The synthesis of 5- carboxylic acid, ethyl ester
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., to 100mL's Sequentially added in eggplant-shape bottle cis-2-Boc- hexahydropyrrolo simultaneously [3,4-c] pyrroles (0.53g, 2.50mmol), sodium carbonate (1.06g, 10.00mmol), the bromo- 4- methyl thiazole-5-carboxyl acid ethyl ester (0.66g, 2.64mmol) of 2- and acetonitrile (15mL), then heat to Reflux is reacted 15 hours.After the reaction was completed, be spin-dried for solvent, add methylene chloride and water, be layered, with methylene chloride (3 × 50mL) aqueous phase extracted merges organic phase, is washed, then cleaned with saturated salt solution (50mL), obtained light yellow with water (3 × 100mL) Liquid.Obtaining target compound by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) is thick pale yellow shape liquid Body (0.77g, 81%).
MS(ESI,pos.ion)m/z:382.30[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 4.25 (q, J=7.0Hz, 2H), 3.70 (d, J=6.9Hz, 2H), 3.64 (s, 2H), 3.32 (d, J=53.0Hz, 4H), 3.03 (s, 2H), 2.56 (s, 3H), 1.44 (s, 9H), 1.32 (t, J= 7.1Hz,3H).
Step 2) 2- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochloride Synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., to 100mL's 2- (5- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methyl thiazolium is sequentially added in eggplant-shape bottle Ethyl acetate solution (7mL, the 3mol/ of azoles -5- carboxylic acid, ethyl ester (0.765g, 2.00mmol), methylene chloride (15mL) and hydrogen chloride L, 21mmol), it reacts at room temperature 1.5 hours.After the reaction was completed, it is thick pale yellow shape that solvent evaporated, which obtains target compound, Liquid (0.64g, 99%).
MS(ESI,pos.ion)m/z:318.7[M+H]+.
Step 3) 4- methyl -2- (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) thiazole-5-carboxylic acid ethyl ester synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., to 100mL's 2- (2,2,2- trifluoro ethoxy) niacin (0.244g, 1.10mmol) and methylene chloride (10mL) are sequentially added in eggplant-shape bottle, so Reaction flask is put into cryogenic thermostat reactive bath technique afterwards, temperature is controlled at 0 DEG C -5 DEG C, adds n,N-diisopropylethylamine (0.7mL, 4.00mmol) and HATU (0.412g, 1.05mmol) after finishing, moves to room temperature and adds 2- after stirring 1 hour (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (0.318g, 1.00mmol), it then reacts at room temperature 15 hours.After the reaction was completed, adding water stratification, water phase is extracted with methylene chloride (3 × 30mL), Organic phase is washed with water (3 × 100mL), then is washed with saturated salt solution (50mL), and light yellow liquid is obtained, then dry with anhydrous sodium sulfate After dry, solvent evaporated, it is light yellow for obtaining target compound by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) Viscous liquid (0.38g, 78%).
MS(ESI,pos.ion)m/z:485.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20 (dd, J=4.9,1.7Hz, 1H), 7.71 (dd, J=7.3, 1.7Hz, 1H), 7.06 (dd, J=7.3,5.0Hz, 1H), 4.83 (dd, J=18.9,8.8Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 3.97 (dd, J=12.9,7.7Hz, 1H), 3.78 (dd, J=10.6,7.6Hz, 1H), 3.72-3.60 (m, 3H), 3.45 (dd, J=10.8,4.8Hz, 1H), 3.34 (dd, J=10.9,4.3Hz, 1H), 3.24 (dd, J=11.0,5.1Hz, 1H), 3.18-3.06 (m, 2H), 2.56 (s, 3H), 1.33 (t, J=7.1Hz, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):167.6,165.4,162.8,156.6,148.0,138.4,123.5 (q, J=271.8Hz), 120.7,118.7,110.1,62.1 (q, J=45.3Hz), 60.5,53.4,52.6,50.6,49.7, 42.5,41.2,17.5,14.5；
HPLC:99.27%.
4 2- of embodiment (5- (2- (2,2- difluoroethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) -4- methyl thiazole-5-carboxyl acid ethyl ester synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., to 100mL's 2- (2,2- difluoroethoxy) niacin (0.224g, 1.10mmol) and methylene chloride (10mL) are sequentially added in eggplant-shape bottle, then Reaction flask is put into cryogenic thermostat reactive bath technique, control temperature at 0 DEG C -5 DEG C, add n,N-diisopropylethylamine (0.7mL, 4.00mmol) with HATU (0.412g, 1.05mmol), after finishing, moves to room temperature and add 2- (hexahydro pyrrole after stirring 1 hour Cough up simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (0.318g, 1.00mmol), then room Temperature reaction 16 hours.After the reaction was completed, add water stratification, water phase is extracted with methylene chloride (3 × 30mL), organic phase with water (3 × 100mL) wash, then washed with saturated salt solution (50mL), obtain light yellow liquid, then with anhydrous sodium sulfate it is dry after, solvent evaporated, Obtaining target compound by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) is thick pale yellow shape liquid (0.28g, 60%).
MS(ESI,pos.ion)m/z:467.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.16 (dd, J=4.8,1.6Hz, 1H), 7.65 (dd, J=7.3, 1.6Hz, 1H), 6.99 (dd, J=7.2,5.1Hz, 1H), 6.10 (tt, J=55.5,4.0Hz, 1H), 4.54 (td, J=13.5, 3.5Hz, 2H), 4.22 (q, J=7.1Hz, 2H), 3.92 (dd, J=12.8,7.8Hz, 1H), 3.74 (dd, J=10.5, 7.6Hz, 1H), 3.69-3.56 (m, 3H), 3.43 (dd, J=10.7,4.3Hz, 1H), 3.31 (dd, J=10.8,4.4Hz, 1H), 3.22 (dd, J=11.0,4.6Hz, 1H), 3.09 (ddd, J=29.4,11.8,4.9Hz, 2H), 2.52 (s, 3H), 1.29 (t, J=7.1Hz, 3H)；
13C NMR(101MHz,CDCl3)δ(ppm):167.6,165.6,162.7,160.3,157.3,148.0,138.0, (120.6,118.1,113.2 t, J=242.4Hz), 110.1,64.3 (t, J=29.29Hz), 60.3,53.4,52.6,50.7, 49.7,42.5,41.2,17.5,14.4；
HPLC:99.44%.
Embodiment 54- methyl -2- (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles - 2 (1H)-yls) thiazole -5- formamide synthesis
Step 1) 5- (5- carbamoyl -4- methylthiazol -2- base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic The synthesis of tert-butyl acrylate
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., to 100mL's Sequentially added in eggplant-shape bottle cis-2-Boc- hexahydropyrrolo simultaneously [3,4-c] pyrroles (0.53g, 2.50mmol), sodium carbonate (1.06g, 10.00mmol), the bromo- 4- methylthiazol -5- formamide (0.581g, 2.63mmol) of 2- and acetonitrile (15mL), then heat to back Stream reacts 12 hours.After the reaction was completed, it is spin-dried for solvent, adds methylene chloride and water, is layered, with methylene chloride (3 × 50mL) Aqueous phase extracted merges organic phase, is washed, then cleaned with saturated salt solution (50mL) with water (3 × 100mL), obtain light yellow liquid. By silica gel column chromatography (methylene chloride/methanol (v/v)=40/1) obtain target compound be light yellow solid (0.60g, 70%).
MS(ESI,pos.ion)m/z:353.30[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 5.42 (s, 2H), 3.70 (d, J=6.8Hz, 2H), 3.64 (s, 2H), 3.38(s,3H),3.26(s,1H),3.04(s,2H),2.54(s,3H),1.45(s,9H).
Step 2) 2- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol -5- carboxamide hydrochloride Synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., to 100mL's 5- (5- carbamoyl -4- methylthiazol -2- base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-is sequentially added in eggplant-shape bottle Carboxylic acid tert-butyl ester (0.61g, 1.73mmol), methylene chloride (15mL) and hydrogen chloride ethyl acetate solution (4mL, 3mol/L, 12mmol), it reacts at room temperature 1 hour.After the reaction was completed, it filters, filter cake adds a small amount of methylene chloride to clean, and is evaporated at 30 DEG C of filter cake Methylene chloride (20mL) is added to light yellow solid, then into solid, adds triethylamine (5mL), is stirred at room temperature 30 minutes, until Solid all after dissolution, stops stirring, pours into separatory funnel, washed with water (100mL), then is washed with the saline solution (50mL) of saturation, It is finally dry with anhydrous sodium sulfate, obtain colourless liquid, solvent evaporated obtain target compound be white solid (0.44g, 99%).
MS(ESI,pos.ion)m/z:253.10[M+H]+.
Step 3) 4- methyl -2- (5- (2- (2,2,2- trifluoro ethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) thiazole -5- formamide synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., to 100mL's 2- (2,2,2- trifluoro ethoxy) niacin (0.21g, 0.95mmol) and methylene chloride (10mL) are sequentially added in eggplant-shape bottle, then Reaction flask is put into cryogenic thermostat reactive bath technique, control temperature at 0 DEG C -5 DEG C, add n,N-diisopropylethylamine (0.222g, 1.70mmol) with HATU (0.35g, 0.893mmol), after finishing, moves to room temperature and add 2- (hexahydro pyrrole after stirring 1 hour Cough up simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol -5- formamide (0.215g, 0.852mmol), then react at room temperature 24 hours.After the reaction was completed, add water stratification, water phase is extracted with methylene chloride (3 × 30mL), and organic phase is with water (3 × 100mL) It washes, then is washed with saturated salt solution (50mL), obtain light yellow liquid, then with after anhydrous sodium sulfate drying, solvent evaporated passes through silicon It is light yellow solid (0.37g, 95%) that plastic column chromatography (methylene chloride/methanol (v/v)=40/1), which obtains target compound,.
MS(ESI,pos.ion)m/z:456.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.20 (dd, J=4.9,1.4Hz, 1H), 7.71 (dd, J=7.3, 1.4Hz, 1H), 7.06 (dd, J=7.1,5.1Hz, 1H), 5.53 (s, 2H), 3.97 (dd, J=12.9,7.7Hz, 1H), 3.78 (dd, J=10.7,7.6Hz, 1H), 3.71-3.59 (m, 3H), 3.45 (dd, J=10.8,4.7Hz, 1H), 3.33 (dd, J= 10.8,4.5Hz, 1H), 3.25 (dd, J=11.1,5.1Hz, 1H), 3.18-3.07 (m, 2H), 2.54 (s, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):166.2,165.5,164.5,156.6,155.6,148.0,138.4, 123.5 (q, J=271.8Hz), 120.6,118.7,62.1 (q, J=45.3Hz), 53.4,52.6,50.6,49.7,42.5, 41.2,17.7；
HPLC:99.05%.
6 2- of embodiment (5- (2- (2,2- difluoroethoxy) nicotinoyl base) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) -4- methylthiazol -5- formamide synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., to 100mL's 2- (2,2- difluoroethoxy) niacin (0.193g, 0.95mmol) and methylene chloride (10mL) are sequentially added in eggplant-shape bottle, then Reaction flask is put into cryogenic thermostat reactive bath technique, control temperature at 0 DEG C -5 DEG C, add n,N-diisopropylethylamine (0.225g, 1.72mmol) with HATU (0.355g, 0.906mmol), after finishing, moves to room temperature and add 2- (hexahydro pyrrole after stirring 1 hour Cough up simultaneously [3,4-c] pyrroles -2 (1H)-yl) -4- methylthiazol -5- formamide (0.217g, 0.86mmol), then react at room temperature 15 Hour.After the reaction was completed, adding water stratification, water phase is extracted with methylene chloride (3 × 30mL), and organic phase is washed with water (3 × 100mL), It is washed again with saturated salt solution (50mL), obtains light yellow liquid, then with after anhydrous sodium sulfate drying, solvent evaporated passes through silica gel It is light yellow solid (0.34g, 90%) that column chromatography (methylene chloride/methanol (v/v)=40/1), which obtains target compound,.
MS(ESI,pos.ion)m/z:438.10[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.19 (dd, J=4.8,1.6Hz, 1H), 7.68 (dd, J=7.2, 1.6Hz, 1H), 7.02 (dd, J=7.2,5.1Hz, 1H), 6.12 (tt, J=55.5,4.0Hz, 1H), 5.57 (s, 2H), 4.57 (dd, J=13.4,10.9Hz, 2H), 3.95 (dd, J=12.9,7.8Hz, 1H), 3.77 (dd, J=10.6,7.5Hz, 1H), 3.65 (tdd, J=18.2,11.0,7.4Hz, 3H), 3.45 (dd, J=10.7,4.4Hz, 1H), 3.33 (dd, J=10.8, 4.5Hz, 1H), 3.25 (dd, J=11.0,4.5Hz, 1H), 3.16-3.07 (m, 2H), 2.53 (s, 3H)；
13C NMR(101MHz,CDCl3)δ(ppm):166.2,165.7,164.3,157.3,155.6,148.1,138.1, (120.6,118.2,114.0,113.2 t, J=242.4Hz), 110.8,77.3,77.0,76.7,64.3 (t, J= 29.29Hz),53.5,52.7,50.7,49.8,42.5,41.2,17.6；
HPLC:98.71%.
Biologic test
Embodiment A the compounds of this invention is to humanization OX1The antagonism of receptor is tested
Test method
Influence of the compounds of this invention to the cell calcium current of agonist induction is detected with fluorescence detection to evaluate this hair Humanization OX of the bright compound to expression on Chinese hamster ovary cell (CHO)1The antagonistic ability of receptor.Cell is suspended in In DMEM culture medium (invitrogen), then with 2 × 104The Density Distribution of cells/well is in micro reaction plate.It will contain glimmering The Hank of light probe (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acid (invitrogen) is flat Weighing apparatus salting liquid (HBSS, invitrogen) (pH=7.4) is added in above-mentioned micro reaction plate, then arises from 37 DEG C with cell one It is incubated for 60min, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and test compound is added or referring to antagonist or Hank balanced salt solution, adds 3nM appetite after 5min Plain A or Hank balanced salt solution (blank control) then measures the variation of fluorescence intensity, dense with free intracellular calcium The variation of degree is positively correlated.Experimental result is indicated with the suppression percentage relative to control group 3nM orexin-A.
Amount effect curve is obtained by the experiment test of series of concentrations, to calculate IC50Value.
The experimental results showed that the compounds of this invention is to OX1Receptor shows preferable antagonism.
Embodiment B the compounds of this invention is to humanization OX2The antagonism of receptor is tested
Test method
Influence of the compounds of this invention to the cell calcium current of agonist induction is detected with fluorescence detection to evaluate this hair Humanization OX of the bright compound to expression on HEK-293 cell2The antagonistic ability of receptor.Cell is suspended in DMEM culture medium (invitrogen) in, then with 3 × 104The Density Distribution of cells/well is in micro reaction plate.Fluorescence probe will be contained (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acid Hank balanced salt solution (HBSS, Invitrogen) (PH=7.4) is added in above-mentioned micro reaction plate, and 37 DEG C of incubation 60min are then arised from cell one, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and testization is added It closes object or referring to antagonist or Hank balanced salt solution, it is (empty that 10nM orexin B or Hank balanced salt solution is added after 5min White control), the variation of fluorescence intensity is then measured, the variation with free intracellular calcium concentration is positively correlated.Experiment knot Fruit is indicated with the suppression percentage relative to control group 10nM orexin B.
Amount effect curve is obtained by the experiment test of series of concentrations, to calculate IC50Value.Experimental result is as shown in table 1.
The compound provided in an embodiment of the present invention of table 1 is to OX2The antagonism experimental result of receptor
The experimental results showed that the compounds of this invention is to OX2Receptor shows preferable antagonism.
Embodiment C rat, dog and monkey intravenous or stomach-filling quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses the compounds of this invention in rat, dog and the intracorporal pharmacokinetic of monkey, moves Object information is detailed in Table A.
Table A animal subject information table of the present invention
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solution, to animal subject carry out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm from The heart 10 minutes, plasma solutions are collected, and save at -20 DEG C or -70 DEG C.For gastric infusion group, dosage 2.5mg/ Kg or 5mg/kg, vein takes when then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour Blood (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, plasma solutions are collected, and protect at -20 DEG C or -70 DEG C It deposits.Positive control is suvorexant.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analysis.
Test result shows that the compounds of this invention has preferable pharmacokinetic property in rat, dog or monkey body.
The assessment that embodiment D the compounds of this invention potentially causes QT interval prolongation to act on
Test method
QT interphase is potentially caused by the way that whether detection the compounds of this invention blocks the channel hERG to assess the compounds of this invention Extension effect, specific experimental method is as follows:
Accurate weighed the compounds of this invention is dissolved in dimethyl sulfoxide (DMSO), the most highly concentrated of 10.0mM is configured to Then the solution of degree is diluted to the solution that initial concentration is 120.0 μM with hERG FP Assay Buffer (Invitrogen)； HERG Tracer Red stoste (Invitrogen) and positive reference substance E-4031 stoste (Invitrogen) are used into hERG respectively FP Assay Buffer (Invitrogen) is diluted to the solution that initial concentration is 4.0nM and 120.0 μM.Into 384 orifice plates, 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 is added Or 2.5 μ L hERG FP Assay Buffer (negative control group), 5 μ L hERG Membrane and 2.5 μ L hERG Tracer Red solution, 5 μ L hERG FP Assay Buffer and 5 μ L hERG Membrane are added in blank control group, so that of the invention Compound, E-4031 and hERG Tracer Red test final concentration be respectively 30.0 μM, 30.0 μM and 1.0nM, each group of survey Have a fling at 4 multiple holes.Then 384 orifice plates are put into 25 DEG C, it is small to be incubated for 4 in the concussion instrument (PHMP-4, Grant-sio) of 250rpm When, the fluorescence polarization value in each hole is measured with multi-function microplate reader (PHERAStarFS, BMG LABTECH), calculates compound pair The relative inhibition in the channel hERG and 50% inhibition concentration (IC50)。
In the case where E-4031 is as positive control, if opposite suppression of 30.0 μM of the compounds of this invention to the channel hERG Rate processed is less than 50%, then IC of the compounds of this invention to the channel hERG50Greater than 30.0 μM.If 30.0 μM of the compounds of this invention pair The relative inhibition in the channel hERG is greater than 50%, then needs to do the compounds of this invention dose curve titration, the specific method is as follows:
The compounds of this invention solution and E-4031 solution for being 120 μM by above-mentioned initial concentration use hERG FP respectively Assay Buffer carry out 5 times of gradient dilutions, be diluted to 120.0 μM, 24.0 μM, 4.8 μM, 960.0nM, 192.0nM, Totally 8 concentration to be measured, each concentration to be measured do 2 multiple holes by 38.4nM, 7.7nM and 1.5nM.2.5 μ L are added into 384 orifice plates to wait for Survey the compounds of this invention of concentration or the positive reference substance E-4031 (positive controls) or 2.5 μ L hERG of 2.5 μ L concentration to be measured FP Assay Buffer (negative control group), 5 μ L hERG FP Membrane and 2.5 μ L hERG Tracer Red solution, 5 μ L hERG FP Assay Buffer and 5 μ L hERG Membrane are added in blank control group.Then 384 orifice plates are put into 25 DEG C, it is incubated for 4 hours in the concussion instrument (PHMP-4, Grant-sio) of 250rpm, with multi-function microplate reader (PHERAStarFS, BMG LABTECH the fluorescence polarization value for) measuring each hole, is corrected with the maximum value and minimum value of E-4031 fluorescence polarization value, The IC of GraphPad software calculating the compounds of this invention50。
The experimental results showed that the compounds of this invention to the channel hERG substantially without inhibitory activity, prompt the compound to cause The risk of QT interval prolongation is small.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (10)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
X is N or CRx；
R1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkylamino, C1-6The alkane that hydroxyl replaces Base ,-C (=O)-(C1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkylamino)；
R2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkylamino, C1-6The alkane that hydroxyl replaces Base ,-C (=O)-(C1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkylamino)；
R3、R4、R5And RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkylamino, C1-6Alkyl ,-C (=O)-(C of hydroxyl substitution1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkylamino)； With
R6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylthio group, C1-6Alkylamino, C1-6The alkane that hydroxyl replaces Base ,-C (=O)-(C1-6Alkyl) ,-C (=O)-(C1-6Alkoxy) or-C (=O)-(C1-6Alkylamino).
2. compound according to claim 1 is the vertical of compound shown in formula (II) compound represented or formula (II) Body isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
3. compound according to claim 1 or 2, wherein R1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) Or-C (=O)-(C1-4Alkylamino)；
R2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynes Base, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4The alkane that hydroxyl replaces Base ,-C (=O)-(C1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) or-C (=O)-(C1-4Alkylamino).
4. compound according to claim 1 or 2, wherein R3、R4、R5And RxBe each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alcoxyl Base, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4Alkyl ,-C (=O)-(C of hydroxyl substitution1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) or-C (=O)-(C1-4Alkylamino)；
R6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynes Base, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylthio group, C1-4Alkylamino, C1-4The alkane that hydroxyl replaces Base ,-C (=O)-(C1-4Alkyl) ,-C (=O)-(C1-4Alkoxy) or-C (=O)-(C1-4Alkylamino).
5. compound according to claim 1 or 2, wherein R1For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、- OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3、-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2；
R2For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl Base, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、-CH2CF3、-CF2CF3, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、- CH2OH ,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
6. compound according to claim 1 or 2, wherein R3、R4、R5And RxBe each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl, vinyl, acetenyl ,- CHF2、-CF3、-CH2CHF2、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、- OCF3、-OCH2CHF2、-OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2；
R6For H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl Base, vinyl, acetenyl ,-CHF2、-CF3、-CH2CHF2、-CH2CF3、-CF2CF3, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCF2CF3, methyl mercapto, ethylmercapto group ,-NHCH3、-N(CH3)2、- CH2OH ,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) NHCH3Or-C (=O) N (CH3)2。
7. compound according to claim 1 or 2 for the compound with one of following structure or has one of following It is the stereoisomer of the compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable Salt or prodrug,
8. a kind of pharmaceutical composition, it includes compounds described in claim 1-7 any one；
Described pharmaceutical composition optionally includes pharmaceutically acceptable carrier, excipient, adjuvant or their any combination.
9. compound described in claim 1-7 any one or pharmaceutical composition according to any one of claims 8 are in medicine preparation Purposes, the drug is for preventing, treating or mitigate disease relevant to orexin receptor.
10. purposes according to claim 9, wherein the disease relevant to orexin receptor is sleep disturbance, depression It is disease, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, terrified Break out obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic Depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, Feeding desorder, headache, migraine, pain, disease of digestive system, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, Immune correlated disease, endocrine related disease or hypertension.
CN201711468833.0A 2017-12-29 2017-12-29 Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof Pending CN109988171A (en)

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