The content of the invention
Only summarize some aspects of the present 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 overall.Work as the disclosure of the specification
With citation it is variant when, be defined by the disclosure of the specification.
The invention provides the compound that a class has orexin receptor antagonistic activity, and in particular to 7-naphthyridine derivatives, and
Its pharmaceutical composition.The compounds of this invention shows good antagonistic activity to orexin receptor, with preferable drug effect, medicine generation
Property and/or toxicological characteristics, the compound and pharmaceutical composition can be used for preventing or treat related to orexin receptor
Disease.
On the one hand, the present invention relates to a kind of compound, its compound shown in the compound or formula (I) shown in formula (I)
Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein, L, R1、R2、R3、R4, m, n, t and k there is implication described in the invention.
In some embodiments, L is-C (R9R10- C)-, (=O)-,-C (=S)-or-S (=O)q-;Wherein, R9、R10
There is implication described in the invention with q.
In some embodiments, each R1And R4It independently is H, D, F, Cl, Br, CN, C1-6Alkyl, C1-6Haloalkyl ,-
OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7、C3-12
Carbocylic radical, 3-12 former molecular heterocyclic radicals, C6-10Aryl or 5-10 former molecular heteroaryls;
Wherein, R1And R4Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally
By one or more R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R1And R4It independently is H, D, F, Cl, Br, CN, methyl, ethyl, propyl group, butyl, three
Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-
SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle,
Azelidinyl, aziridinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, benzene
Base, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals;
Wherein, R1And R4Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoros
Ethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base,
Tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrrole
Oxazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R2It independently is H, D, F, Cl, Br, NO2、CN、C1-4Alkyl, C1-4Haloalkyl ,-
OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7、C3-8Carbon
Ring group, 3-8 former molecular heterocyclic radicals, C6-10Aryl or 5-10 former molecular heteroaryls;
Wherein, R2Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally by one
Individual or multiple R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R2It independently is H, D, F, Cl, Br, NO2, CN, methyl, ethyl, propyl group, butyl, three
Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-
SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azacyclo-
Butyl, aziridinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrroles
Base, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals;
Wherein, R2Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second
Base, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base, thiophane
Base, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazoles
Base, triazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R3It independently is H, D, F, Cl, Br, NO2、CN、C1-4Alkyl, C1-4Haloalkyl ,-
OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7、C3-8Carbon
Ring group, 3-8 former molecular heterocyclic radicals, C6-10Aryl or 5-10 former molecular heteroaryls;
Wherein, R3Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally by one
Individual or multiple R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R3It independently is H, D, F, Cl, Br, NO2, CN, methyl, ethyl, propyl group, butyl, three
Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR5、-NR6R7,-C (=O) NR6R7,-C (=O) R8、-
SR5,-S (=O)qR8,-S (=O)qOR5,-S (=O)qNR6R7, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle,
Azelidinyl, aziridinyl, tetrahydrofuran base, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furan
Mutter base, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals;
Wherein, R3Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second
Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base, pyrrole
Cough up alkyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, three
Oxazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R11Replaced;
Wherein, R5、R6、R7、R8、R11There is implication described in the invention with q.
In some embodiments, each R5It independently is H, C1-4Alkyl, C1-4Haloalkyl ,-(CR9R10)pC (=O)
NR6R7、-(CR9R10)pC (=O) R8、-(CR9R10)pC (=O) OR5a、-(CR9R10)pS (=O)qR8、-(CR9R10)pS (=O)qOR5a、-(CR9R10)pS (=O)qNR6R7、C3-8Carbocylic radical, (C3-6Carbocylic radical)-(C1-4Alkylidene)-, 3-8 it is former molecular
Heterocyclic radical, (3-6 former molecular heterocyclic radicals)-(C1-4Alkylidene)-, C6-10Aryl, (C6-10Aryl)-(C1-4Alkylidene)-,
5-6 former molecular heteroaryls or (5-6 former molecular heteroaryls)-(C1-4Alkylidene)-;
Wherein, R5Described in alkyl, haloalkyl, carbocylic radical, carbocylic radical alkylidene, heterocyclic radical, heterocycloalkylene,
Aryl, aryl alkylene, heteroaryl and heteroarylalkylenyl are individually optionally by one or more R11Replaced;
Wherein, R6、R7、R8、R9、R10、R5a, p and q there is implication described in the invention.
In some embodiments, each R5Independently be H, methyl, ethyl, propyl group, butyl, trifluoromethyl, difluoromethyl,
1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-(CR9R10)pC (=O) NR6R7、-(CR9R10)pC (=O) R8、-(CR9R10)pC (=
O)OR5a、-(CR9R10)pS (=O)qR8、-(CR9R10)pS (=O)qOR5a、-(CR9R10)pS (=O)qNR6R7, cyclopropyl, ring penta
Base, cyclobutyl, cyclohexyl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinylmethyl, piperidyl second
Base, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl or pyridyl-ethyl group;
Wherein, R5Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second
Base, cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinyl
Methyl, piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl and pyridine radicals
Ethyl is individually optionally by one or more R11Replaced;
Wherein, R6、R7、R8、R9、R10、R5a, p and q there is implication described in the invention.
In some embodiments, each R5aIt independently is H, C1-4Alkyl, C1-4Haloalkyl, C3-8Carbocylic radical, 3-8 original
Molecular heterocyclic radical, C6-10Aryl or 5-10 former molecular heteroaryls;Wherein, R5Described in alkyl, haloalkyl,
Carbocylic radical, heterocyclic radical, aryl and heteroaryl are individually optionally by one or more R11Replaced;R11With described in the invention
Implication.
In some embodiments, each R5aIndependently be H, methyl, ethyl, propyl group, butyl, trifluoromethyl, difluoromethyl,
1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, pyrrolidines
Base, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals or pyrimidine radicals;Wherein, R5aDescribed in methyl, ethyl, propyl group, fourth
Base, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azacyclo-
Butyl, pyrrolidinyl, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals and pyrimidine radicals are individually optionally one or more
R11Replaced;R11With implication described in the invention.
In some embodiments, each R6And R7It independently is H, C1-4Alkyl, C3-8Carbocylic radical, (C3-6Carbocylic radical)-(C1-4
Alkylidene)-, 3-8 former molecular heterocyclic radicals, (3-6 former molecular heterocyclic radicals)-(C1-4Alkylidene)-, C6-10Aryl,
(C6-10Aryl)-(C1-4Alkylidene)-, 5-6 former molecular heteroaryls or (5-6 former molecular heteroaryls)-(C1-4It is sub-
Alkyl)-;
Wherein, R6And R7Described in alkyl, haloalkyl, carbocylic radical, carbocylic radical alkylidene, heterocyclic radical, heterocyclic radical alkylene
Base, aryl, aryl alkylene, heteroaryl and heteroarylalkylenyl are individually optionally by one or more R11Replaced;R11Have
Implication described in the invention.
In some embodiments, each R6And R7Independently be H, methyl, ethyl, propyl group, butyl, cyclopropyl, cyclopenta,
Cyclobutyl, cyclohexyl, Cvclopropvlmethvl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinylmethyl,
Piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl or pyridyl-ethyl group.
In some embodiments, each R8It independently is H, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, C1-4Halo
Alkyl, C1-4Halogenated alkoxy, C1-4Haloalkylamino, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C6-10Aryl or
5-10 former molecular heteroaryls;
Wherein, R8Described in alkyl, haloalkyl, alkoxy, alkyl amino, halogenated alkoxy, haloalkylamino,
Carbocylic radical, heterocyclic radical, aryl and heteroaryl are individually optionally by one or more R11Replaced;R11With described in the invention
Implication.
In some embodiments, each R8It independently is H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino or three
Methyl fluoride.
In some embodiments, each R9And R10It independently is H, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, C1-4
Haloalkyl, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C6-10Aryl or 5-10 former molecular heteroaryls;
Wherein, R9And R10Described in alkyl, haloalkyl, alkoxy, alkyl amino, carbocylic radical, heterocyclic radical, aryl and
Heteroaryl is individually optionally by one or more R11Replaced;R11With implication described in the invention.
In some embodiments, each R9And R10Independently be H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino,
Trifluoromethyl, cyclopropyl, cyclopenta, cyclohexyl, the ethyl group of ring third, pyrrolidinyl, piperidyl, phenyl, pyrrole radicals or pyridine radicals.
In some embodiments, k is 0,1,2,3,4,5,6,7,8,9 or 10.
In some embodiments, t is 0,1,2,3,4 or 5.
In some embodiments, n is 0,1,2,3 or 4.
In some embodiments, m is 0,1 or 2.
In some embodiments, each p independently is 1,2,3 or 4.
In some embodiments, each q independently is 1 or 2.
In some embodiments, each R11It independently is H, D, F, Cl, Br, NO2, CN, hydroxyl, amino, C1-4Alkyl, C1-4
Haloalkyl, C1-4Alkoxy, C1-4Alkyl amino, C1-4Halogenated alkoxy, C1-4Haloalkylamino, the C of amino substitution1-4Alkane
Base, the C of hydroxyl substitution1-4Alkyl, the C of cyano group substitution1-4Alkyl, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C6-10Virtue
Base or 5-10 former molecular heteroaryls.
In some embodiments, each R11It independently is H, D, F, Cl, Br, NO2, CN, hydroxyl, amino, methyl, ethyl,
Propyl group, butyl, trifluoromethyl, methoxyl group, methylamino, dimethylamino, trifluoromethoxy, amino methyl, hydroxymethyl, ring
Propyl group, cyclohexyl, piperidyl, morpholinyl, phenyl, pyrrole radicals or pyridine radicals.
On the other hand, the present invention relates to the structure of one of:
Or its solid is different
Structure body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes compound of the present invention;Wherein, it is described
Pharmaceutical composition further includes at least one of pharmaceutically acceptable excipient, carrier, adjuvant and solvent.
In some embodiments, pharmaceutical composition of the present invention is further comprising in other preventions or treatment
The medicine of pivot nervous system nerve and psychiatric disorders and disease, described other preventions or treatment central nervous system god
Medicine through property and psychiatric disorders and disease is antidepressant, anxiolytic drugs, the salts medicine as mood stabilizers
Thing, antipsychotics, atypical antipsychotic drug, antiepileptic, anti-parkinson class medicine, hypnotic sedative agent
Thing, antihistamine drug, GABA receptor stimulating agents and/or GABA reuptaking inhibitor classes medicine, it is used as MAOI
Medicine, the medicine as melatonin receptors activator and the medicine as orexin receptor antagonists or their any group
Close.
In other embodiments, other preventions of the present invention or treatment central nervous system nerve and essence
Godhead obstacle and the medicine of disease are amitriptyline, desipramine, Mirtazapine, Bupropion, Reboxetine, Prozac, bent azoles
Ketone, Sertraline, Duloxetine, Fluvoxamine, Milnacipran, left-handed Milnacipran, desmethylvenlafaxine, vilazodone, Wen La
Method is pungent, Dapoxetine hydrochloride, Nefazodone, femoxetine, chlorimipramine, Citalopram, escitalopram, Paxil, carbonic acid
Lithium, buspirone, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, Perospirone, Clozapine, modafinil,
Mecamylamine, Cabergoline, adamantane, imipramine, Pramipexole, thyroxine, dextromethorphan, quinindium, naltrexone,
Samidorphan, buprenorphine, melatonin, alprazolam, Pipamperone, dimension replace smooth, perphenazine, midazolam, a triazole
Logical sequence, estazolam, diazepam, Flurazepam, nitrazepam, Clonazepam, Temazepam, Flunitrazepam, Oxazepam, zolpidem,
Zaleplon, zopiclone, eszopiclone, English general grand, Tiagabine, Gaboxadol, clomipramine, doxepin, hydration chlorine
Aldehyde, haloperole, chlorpromazine, carbamazepine, fenazil, Lorazepam, hydroxyzine, aspirin, diphenhydramine, chlorpheniramine, bromine
For azoles logical sequence, Ramelteon, Te Simeiertong, agomelatine, mianserin, method Mack Xi Ting, nabilone, doxepin plus bar
Spray fourth, librium, suvorexant, Xuezang Guben 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 is prepared,
The medicine is used to preventing, treat or mitigating the disease related to orexin receptor.
In one embodiment, the disease related to orexin receptor be sleep-disorder, depression, anxiety disorder, probably
Flurried disease, obsession, 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, Parkinson's disease, dyskinesia, feeding desorder, head
Bitterly, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease
Disease, endocrine relevant disease or hypertension.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine is prepared,
The medicine is used for antagonism orexin receptor.
On the other hand, the method for preparation, separation and the purifying of the compound included the present invention relates to formula (I).
Biological results show that the compound that the present invention is provided can be as preferable orexin receptor antagonists.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
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.
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 enclosed.This
Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim
In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material
The practice present invention.The present invention is not limited to method of the present invention and material.In the document combined, patent and similar material
One or more or contradict in the case of (include but is not limited to defined in term, term application, institutes different from the application
Technology of description, etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments
Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity,
It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
There is obvious conflict unless otherwise indicated or in context, 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 or situation that then describe can with but not necessarily occur, and this is retouched
State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.
Term " optionally by ... replace ", can exchange with term " unsubstituted or by ... replace " and use, i.e.,
The structure or group are unsubstituted or replaced by one or more substituents of the present invention, wherein the substitution meaning
Taste the rational position for occurring that any chemical valence allows in given structure or group.Substituent of the present invention includes,
But it is not limited to D, F, Cl, Br, I ,-N3、-CN、-NO2、-OH、-SH、-NH2, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,
Alkylthio group, alkylamino, carbocylic radical, heterocyclic radical, aryl, heteroaryl, carbocylic radical alkylidene, heterocycloalkylene, aryl alkylene,
Heteroarylalkylenyl, etc..
In general, term is " substituted " to represent that institute is specifically replaced to one or more of structure or group hydrogen atom
Base is replaced.Unless otherwise indicated, a substituent can be replaced each commutable rational position in group.
When one or more specific substituents that more than one position can be selected from given structural formula are replaced, then substituent
It can be replaced with identical or different each rational position in structural formula.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise
Content.
In each several part of this specification, the substituent that the present invention discloses compound is disclosed according to radical species or scope.It is special
Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term
“C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this
Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do
The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl "
The alkylidene group or arylene group of connection.
Term " D " represents D-atom.
Term " hetero atom " represents oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulphur (S) and phosphorus
(P) form of any oxidation state;The form of primary, secondary, tertiary amine and quaternary ammonium salt;Or the shape that the hydrogen in heterocycle on nitrogen-atoms is substituted
Formula, for example, N (as the N in 3,4- dihydro-2 h-pyrrole bases), NH (as the NH in pyrrolidinyl) or the NR (pyrroles replaced as N-
NR in alkyl).
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine
(I)。
Terminology used in the present invention " alkyl " or " alkyl group ", are represented containing 1-20 carbon atom, the straight chain of saturation or
Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention
Substitution.In some embodiments, alkyl group contains 1-6 carbon atom;In other embodiments, alkyl group contains
1-4 carbon atom;Also in some embodiments, alkyl group contains 1-3 carbon atom.The example of alkyl group is included, but
It is not limited to, methyl, ethyl, propyl group (including n-propyl and isopropyl), butyl (including normal-butyl, isobutyl group, sec-butyl and uncle
Butyl), etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has
Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In some implementations
In scheme, alkoxy base contains 1-6 carbon atom;In other embodiments, alkoxy base contains 1-4 carbon original
Son;In other embodiment, alkoxy base contains 1-3 carbon atom.The example of alkoxy base includes, but does not limit
In methoxyl group, ethyoxyl, propoxyl group, butoxy, etc..The alkoxy base can be optionally by one or more hairs
The substituent of bright description is replaced.
Term " haloalkyl " represents that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has
Implication as described in the present invention, such example is included, but is not limited to ,-CF3、-CF2CF3、-CH2CF2CHF2Deng.At some
In embodiment, " haloalkyl " is the C of lower level1-4Haloalkyl the, wherein " C1-4Haloalkyl " replaces comprising fluorine
C1-4Alkyl, the C of chlorine substitution1-4Alkyl, the C of bromine substitution1-4Alkyl, the C of iodine substitution1-4Alkyl, etc..The haloalkyl is optional
Ground is replaced by one or more substituents described in the invention.
Term " halogenated alkoxy " represents that alkoxy base is replaced by one or more halogen atoms, wherein alkoxy base
Group has implication as described in the present invention, and such example is included, but is not limited to ,-OCF3、-OCF2CF3、-OCH2CF2CHF2
Deng.The halogenated alkoxy is optionally replaced by one or more substituents described in the invention.
Term " alkyl of amino substitution ", " alkyl of hydroxyl substitution " and " alkyl of cyano group substitution " represents alkyl group quilt
One or more amino, hydroxyl or cyano group are replaced, and wherein alkyl group has implication as described in the present invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base
Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, represent containing 3-12 ring carbon atom, it is monovalent or
Monocyclic, the bicyclic or three-ring system of multivalence, its middle ring can be fully saturated or comprising one or more degrees of unsaturation, but
One armaticity ring can not all have.In some embodiments, carbocylic radical group contains 3-8 ring carbon atom;In other realities
Apply in scheme, carbocylic radical group contains 3-6 ring carbon atom.
Term " cycloalkyl " represents that, containing 3-12 ring carbon atom, the saturation of monovalent or multivalence is monocyclic, bicyclic or tricyclic
System.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, represent comprising 3-12 annular atom, monovalent or many
The monocyclic, bicyclic or tricyclic system of valency, wherein the member ring systems include at least one hetero atom, the hetero atom has such as this hair
Bright described implication, heterocycle can be fully saturated or comprising one or more degrees of unsaturation, but an armaticity ring is not
Can have.In some embodiments, heterocyclyl groups contain 3-8 annular atom;In other embodiments, heterocyclyl groups
Contain 3-6 annular atom.
Term " aryl " is represented containing 6-14 annular atom or 6-10 annular atom or 6 annular atoms, monovalent or many
The monocyclic, bicyclic or tricyclic carbocyclic ring system of valency, wherein at least one ring is aromatic.Aromatic yl group is usual, but necessarily
Ground is connected by the armaticity ring of aromatic yl group with parent molecule.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring "
Change and use.The example of aromatic yl group can include phenyl, naphthyl, anthryl, etc..The aromatic yl group is optionally by one or many
Individual substituent described in the invention is replaced.
Term " heteroaryl " represents individual containing 5-14 annular atom or 5-10 annular atom or 5-9 annular atom or 5-6
Annular atom, 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 usual, but the unnecessarily armaticity ring by heteroaryl groups and mother
Body molecule is connected.Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl
Group is optionally replaced by one or more substituents described in the invention.
The descriptions such as " 3-8 former molecular heterocyclic radicals ", " 5-10 former molecular heteroaryls " represent composition ring structure
Annular atom number, wherein, described annular atom includes the hetero atoms such as carbon atom and N, O, S, P, and the species of atom is depended on
The species of the specific group formed.For example, " 3-8 former molecular heterocycles " refers to by 3-7 former molecular heterocyclic radicals,
Wherein, the heterocyclic radical includes at least one hetero atom.When the ring structure is by specific substituent group, the atom of substituent
Number is not included in the number of described annular atom.
Term " carbocylic radical alkylidene ", " heterocycloalkylene ", " aryl alkylene ", " heteroarylalkylenyl " expression " carbon
Ring group ", " heterocyclic radical ", " aryl ", " heteroaryl " are connected by " alkylidene " with the remainder of molecule, wherein, described " carbon
Ring group ", " heterocyclic radical ", " aryl ", " heteroaryl " and " alkylidene " have implication described in the invention.
As described in the present invention, substituent R is connected to the member ring systems formed on the ring at center by a key and represents substitution
Base R any on ring can may replace or any rational position is replaced.For example, formula a represent it is any on ring A or ring B can
Position that can be substituted can be replaced by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the whole text in the present invention
" each ... and ... independently be ", " ... and ... be each independently " and " ... with ... separately for " can exchange, and refer to institute
It is separate and be independent of each other between each option of description;Also illustrate that the specifically chosen scope of each option (that is, after " being " in description
The option content in face) it is independent of each other.For example, " each R1、R2And R3It independently is " " R can be described as1For ", " R2For ", " R3
For ", represent R1、R2And R3It is separate, and R1、R2And R3Each expressed specific item can be the same or different.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group
Compound.It is different that stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometry
Structure body (cis/trans) isomers, atropisomer, etc..
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and
Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,
Inc,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 is rotated.When describing optically active compound, represent molecule on one using prefix D and L or R and S
Individual or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are to be used to linearly polarized light caused by appointed compound revolve
The symbol turned, wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for (+) or d compound.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 referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or three-dimensional special
When different in nature, such case may occur in which.
The mixture of any stereoisomer of gained 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 end-product or intermediate can be passed through into those skilled in the art with known method
Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production
Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping
Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, 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:APractical
Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,
2007)。
Term " dynamic isomer " or " tautomeric form " refer to that (low can be built by low energy with different-energy
Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), it can reach
The chemical balance of dynamic isomer.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 that is carried out by proton migration, such as keto-enol isomerization and
Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to such some compounds, raw material, composition and/or formulation, and they are cured rationally
Learn judge in the range of, it is adaptable to patient tissue contacts without excessive toxicity, excitant, allergy or with rational profit
The symmetrical other problemses of benefit/Hazard ratio and complication, and effective for given application.
Term " prodrug " used in the present invention, the chemical combination shown in formula (I) can be converted into vivo by representing a compound
Thing.Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.
Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class, fat as pro-drug in existing invention
Fat race (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.For example, in the present invention
One compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms
It is being obtained through the di on parent including phosphate, such as these phosphate compounds.It is complete on pro-drug
Discussion may be referred to documents below:Higuchi et al.,Pro-drugs as Novel Delivery Systems,
Vol.14,A.C.S.Symposium Series;Roche et al.,ed.,Bioreversible Carriers in Drug
Design,American Pharmaceutical Association and Pergamon Press,1987;Rautio et
al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,
2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,
J.Med.Chem., this is incorporated herein by reference in 2008,51,2328-2345, every document.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art
Adopt and experimentally characterized as stating.Such product can be by passing through oxidation, reduction, water to drug compound
Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound
Metabolite, including the compound of the present invention is fully contacted to the metabolite produced by a period of time with mammal.
" 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 art on, such as document:S.M.Berge et al.,describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, 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 described on books document
Other method such as ion-exchange 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 acids
Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid
Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta
Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through appropriate alkali
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 quaternary ammonium salt that the compound of group is formed.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..It is appropriate, nontoxic that pharmaceutically acceptable salt further comprises
Ammonium, quaternary ammonium salt and gegenions formation amine cation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid
Compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed
Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, monoethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When the solvent is water, term " hydrate " can be used.In some embodiments, a chemical combination of the present invention
Thing molecule can be combined with a hydrone, such as monohydrate;In other embodiments, a compounds of this invention
Molecule can be combined with more than one hydrone, such as dihydrate;In other embodiment, a present inventionization
Adduct molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention is protected
Leave the biological effectiveness of the compound of nonhydrated form.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to trigger individual
Thing or medicinal response (for example reduce or inhibitory enzyme or protein active, or improve symptom, alleviate illness, slow down or postpone disease
Disease development, or prevention disease etc.) the compounds of this invention amount.
The compound of the present invention
Unless otherwise mentioned, all suitable isotope changes of compound of the 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) can exist with different tautomeric forms, and all these dynamic isomers
It 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.Can be by an elevated temperature using normal
With oxidant (such as hydrogen peroxide), in the presence of having sour (such as acetic acid), corresponding nitrogen-containing basic material, Huo Zhetong are aoxidized
Cross with crossing acid reaction in suitable solvent, such as reacted in dichloromethane, ethyl acetate or methyl acetate with peracetic acid, or
Reacted in chloroform or dichloromethane with 3- chloroperoxybenzoic acids, prepare the nitrogen oxides of the compounds of this invention.
In addition, when the compound formation hydrate or solvate of the present invention, they are also included within the scope of the present invention
It is interior.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within the model of the present invention
In enclosing.
Compound shown in formula (I) can exist in a salt form.In some embodiments, the salt refers to pharmaceutically may be used
The salt of receiving.The pharmaceutically acceptable salt of the present invention can be with conventional chemical processes by parent compound, alkalescence or acidity portion
Divide to synthesize.In general, such salt can be by making the free acid form of these compounds and the suitable alkali of stoichiometry
(such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate) reacts, or by making the free alkali of these compounds
It is prepared by the suitable acid reaction of form and stoichiometry.Such reaction is generally in water or organic solvent or the mixing of the two
Carried out in thing.Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol
Or acetonitrile.In 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(Wiley-
VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
The compounds of this invention is alkaline, therefore is generally possible to form pharmaceutically acceptable by using suitable acid treatment
Acid-addition salts.Suitable acid includes pharmaceutically acceptable inorganic acid and pharmaceutically acceptable organic acid.Representational 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, it is 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- hydroxyls
Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..
Any structural formula that the present invention is provided is also intended to expression these compounds not by the form of isotope enrichment and same
The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or many
Individual 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
Include the isotope of 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 is radio isotope, such as3H、14C and18F those compounds, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for metabolism research (to use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread
Single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.18The compound of F enrichments to PET or
It is especially desirable for SPECT researchs.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art
Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement
Carry out used unmarked reagent to prepare.
On the other hand, the present invention relates to the intermediate for preparing compound shown in formula (I).
On the other hand, the present invention relates to the method for the preparation of compound shown in formula (I), separation and purifying.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
A kind of pharmaceutical composition of present invention offer, including compound shown in compound shown in formula (I) or formula (I) are three-dimensional different
Structure body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.The medicine group
Compound is further comprising at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, others treatment
And/or prevention composition.
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 " means related to form of administration or pharmaceutical composition uniformity used in the present invention
Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into
Split-phase is held, and the interaction of effect of the compounds of this invention can be substantially reduced during avoiding that patient is administered and can cause not being 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 formulation.In addition, can be according to them in group
Specific function in compound selects pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature
Some pharmaceutically acceptable excipient.The some pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected
Agent.It may be selected to help to carry when patient is administered or transport the compounds of this invention from an organ of body or partly to body
Another organ or partial some pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is some pharmaceutically
Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient:Diluent, filler, adhesive,
Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify
Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably
Agent, surfactant and buffer.One skilled in the art will recognize that, some pharmaceutically acceptable excipient can be provided not
Only a kind of function, and provide alternative function, this depends in preparation having in how much excipient and preparation which be present
Other a little excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention
Pharmaceutically acceptable excipient.Additionally, there are resource 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
Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any undesirable life
Thing is acted on, or with interaction occurs for any other composition in harmful way and pharmaceutically acceptable composition and with the present invention
Outside the incompatible any commonly employed carrier of compound, pay close attention to its application and belong to the scope of the present invention.
The compounds of this invention is usually formulated as the formulation for being suitable for that patient is administered by required approach.For example, formulation
It is suitable for the formulation of following method of administration including those:(1) it is administered orally, such as tablet, capsule, caplet agent, pill, lozenge
Agent, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet;(2) parenteral, such as it is sterile
Solution, supensoid agent and redissolution powder;(3) cutaneous penetration, such as transdermal patch tablet;(4) rectally, such as suppository;(5) inhale
Enter, for example aerosol, solution and dry powder doses;(6) local administration, such as cream, ointment, lotion, solution, paste
Agent, spray, foaming agent and gel.
It will also be appreciated that some compounds of the present invention can exist and for treating in a free form, or it is if suitable
When can exist and for treating in the form of its pharmaceutically acceptable derivates.Some of pharmaceutically acceptable derivative are non-
Restricted embodiment includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or patient in need is given
Can directly or indirectly be provided during medicine compound of the present invention or its metabolite or residue any other adduct or
Derivative.
In some embodiments, the compounds of this invention can be configured to peroral dosage form.In other embodiments, originally
Invention compound can be configured to inhalant dosage form.In other embodiments, the compounds of this invention can be configured to intranasal to
Pharmaceutically dosage form.In other embodiment, the compounds of this invention can be configured to transdermal administration.Also in some embodiments
In, the compounds of this invention can be configured to Topical dosage forms.
The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or
Enteric coatel tablets, sugar-coat or Film coated tablets are provided.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines
The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat
Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat is surrounded
Piece, it can be beneficial to cover taste beastly or smell and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble
The compressed tablets of thin layer or the film covering of material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose
Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple
Tabletting is to pass through compressed tablets prepared by more than one press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind for individually or with the present invention being described in powder, crystallization or granular active component
Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit
Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.
The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl
Element, starch or calcium alginate is tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section
Fill in another section, therefore enclose active component completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell,
It is plastified by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include the pre- preventing microorganism life of preservative
It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This
Inventing the liquid provided, semi-solid and solid dosage forms can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in
Solution and supensoid agent 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;Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted
Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention is provided 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 which liquid is thoroughly dispersed in another liquid in pellet form,
It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and
Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used
Two (low alkyl group) acetals of the acetal of receiving, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal;With with one or many
The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense
The aqueous solution of sugared such as sucrose, and preservative can also be included.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.
The pharmaceutical composition that the present invention is provided can be configured to be suitable to any formulation to patient's inhalation, such as dry powder
Agent, aerosol, supensoid agent or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared
Into suitable for formulation of the dry powder doses to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention
It can be configured to be suitable to the formulation by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual
Compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes are obtained comprising fine powdered
Shape agent.The pharmaceutically acceptable excipient dawn known to those skilled in the art of dry powder doses is especially suitable for use as, it includes breast
Sugar, starch, mannitol and single-, two- and polysaccharide.Fine powder can be prepared for example, by micronizing and grinding.It is general next
Say, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed
Amount) define.
Discontinuous paster agent can be prepared into by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient
It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as
General description in Pharmaceutical Research, 3 (6), 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis,
Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can use water or oil
Matrix, and suitable thickener and/or gel and/or solvent are configured.Such matrix can 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.Used according to medium property
Thickener and gel 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 combined with as the soluble polymer of target medicine carrier.Such polymer bag
Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or
The oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can be with realizing medicine
The class Biodegradable polymeric that is used in control release is combined, for example, PLA, poly-epsilon-caprolactone, poly butyric,
Poe, polyacetals, poly- dihydropyran, crosslinking or the amphiphilic block copolymer of polybutylcyanoacrylate and hydrogel.
The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete
Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest
In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention is provided can be configured to any formulation suitable for parenteral, 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 formulation can according to known to the technical staff in pharmaceutical science field conventional method preparing (referring to
Remington:The Science and Practice of Pharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and
Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life
The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and scattered
Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent
And inert gas.
The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins
Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped
In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro-
Biological agent.All parenteral administrations all must be sterile, as known in the art with practice.
The pharmaceutical composition that the present invention is provided can with will not to damage other active components of expected therapeutic action common
Prepare, or the material co-formulation with the expected effect of supplement.
In some embodiments, treatment method of the invention includes the sheet that safe and effective amount is given to patient in need
Invention compound or the pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention is included by suffering in need
Person 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 some embodiments, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by appointing
What suitable method of administration is administered, including Formulations for systemic administration and local is administered.Formulations for systemic administration includes being administered orally, parenteral given
Medicine, cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular
With hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and intranasal administration.
In some embodiments, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be administered orally.
In other embodiments, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.Also
Have in some embodiments, the compounds of this invention or can be intranasal administration comprising the compounds of this invention.
In some embodiments, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be disposable
Administration, or according to dosage regimen, at the appointed time in section, in different time interval administrations several times.For example, daily administration
Once, twice, three times or four times.In one embodiment, it is administered once a day.In other embodiment, daily administration
Twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention
Or the appropriate dosage regimen of the pharmaceutical composition comprising the compounds of this invention depends on the pharmacokinetic property of the compound, example
As absorbed, being distributed and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including chemical combination of the present invention
The appropriate dosage regimen of the pharmaceutical composition of thing, including implement the duration of the program, it depends on treated disease, quilt
Treat the order of severity, the age of patient under consideration and the health of disease, the medical history of patient under consideration, while the property of therapy
The factor in the range of technical staff's knowledge and experience such as matter, desired therapeutic effect.Such technical staff should also be understood that
Reaction for individual patient to dosage regimen, or when passage individual patient needs change over time, in order to be sufficiently accurate it may be desired to adjust matters
Dosage regimen.
The compounds of this invention can simultaneously, or before it or afterwards be administered with one or more other therapeutic agents.This hair
Bright compound can be respectively administered with other therapeutic agents by identical or different method of administration, or therewith with pharmaceutical composition
Form is administered.
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 medicament, benzene phenodiazines
Leather, barbiturate, 5HT-2 antagonists etc. are used in combination, for example: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 handkerchief
Bright, Clonazepam, Domperidone, Decacil, cloretate, Clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine
Aldehyde willow amine, double valproic acids, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west
Dissolve, Flurazepam, Fluvoxamine, fluoxetine, fosazepam, glutethimide, Halazepam, hydroxyzine, imipramine, lithium, chlorine hydroxyl go first
Stable, Lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles
Logical sequence, Buddhist nun's method oxazolone, Nisobamate, intrazepam, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, amobarbital, piperazine
Even up, perphenazine, nardil, phenobarbital, prazepam, fenazil, propofol, protriptyline, quazepam, auspicious chlorine
West is dissolved, rolipram, quinalbarbitone, Sertraline, Suproclone, Temazepam, thioridazine, Tracazolate, anti-phenyl ring third
Amine, Trazodone, triazole benzene phenodiazine, Trepipam, 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 is 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 patient is administered, the functional derivatives of the compounds of this invention can be finally discharged in vivo.This hair is given with prodrug forms
During bright compound, those skilled in the art can implement one kind in following manner and more than:(a) the internal action of compound is changed
Time;(b) the internal acting duration of compound is changed;(c) the internal conveying or distribution of compound are changed;(d) modification
The internal solubility of compound;And (e) overcomes the side effect or other difficult points that compound faced.For preparing the typical of prodrug
Functional derivatives, comprising in vivo chemically or enzyme the variant of compound that cracks of mode.Comprising prepare phosphate,
Acid amides, ester, monothioester, these variants of carbonate and carbaminate are well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound and pharmaceutical composition of the present invention are as orexin receptor antagonists, to preventing or treating and appetite
The related disease of plain acceptor is effective, available for the medicine for preparing antagonism orexin receptor.
The disease related to orexin receptor may be selected from all types of sleep-disorder, all types of psychiatry, god
Learned through disease and neurodegeneration obstacle, all types of pressure correlation syndromes, all types of habituation (especially psychotropic activity thing
The use of matter, abuse, seek and recover), 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 some embodiments, the disease related to orexin receptor comprising sleep-disorder, depression, anxiety disorder, probably
Flurried disease, obsession, 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, Parkinson's disease, dyskinesia, feeding desorder, head
Bitterly, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease
Disease, endocrine relevant disease or hypertension.
In some embodiments, the disease related to orexin receptor may be selected from sleep-disorder, and it includes all types
Insomnia, Narcolepsy's myodystony related to other hyper somnolence diseases, parasomnia, sleep, not peaceful
When leg syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome are with sleep
Phase retardation or in advance syndrome or the related insomnia of mental illness, etc..
In some embodiments, the disease related to orexin receptor may be selected from psychiatry, neurology and nerve
Degenerative disorder, it includes depression, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious god
Through disease, mood disorder, panic attack obstacle, posttraumatic stress disorder, sex dysfunction, mental disease, Parkinson's disease, dementia or
Mental retardation, etc..
In some embodiments, the disease related to orexin receptor may be selected from cognition dysfunction, and it is included in just
It is normal, health, young, adult's or old crowd in transient episodes or chronic seizures all types of attentions,
Learning and memory function reduction, or the transient episodes or slow in mental disease, neuropathy, angiocarpy and disease of immune system patient
Property breaking-out all types of attentions, learning and memory function reduction, etc..
It should be appreciated that in some environmental conditions such as such as pressure or fear, (wherein, pressure may have society source such as
Social pressures or with physiological sources such as physical stress, including the pressure produced by fear) promote or accelerate it is any as previously described
Illness or disease in the case of, compound of the invention is particularly useful to the illness or disease for the treatment of the regulation of these environment
's.
The compound and pharmaceutical composition of the present invention applies also for veterinary treatment and doted in addition to beneficial to human treatment
Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.
This, compound of the invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
Usually, compound of the invention can be prepared by method described in the invention, unless there are further
Explanation, the wherein definition of substituent compound as shown in formula (I).Following reaction scheme and embodiment are used to further illustrate
Illustrate present disclosure.
Those skilled in the art will realize that:Chemical reaction described in the invention can be for suitably preparing perhaps
Other compounds of many present invention, and be considered as preparing other methods of compound of the invention in model of the invention
Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except 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 applied to the preparation of other compounds of the invention.
The embodiments described below, unless otherwise indicated, all temperature are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou
Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao
Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride
With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N-
Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below
Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance
Determined by Bruker Avance400 nuclear magnetic resonance spectrometers or the nuclear magnetic resonance spectrometers of Bruker Avance III HD 600,
With CDC13,d6-DMSO,CD3OD or d6- acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform
(7.26ppm) is used as reference standard.When there is multiplet, following abbreviation will be used:S (singlet, unimodal), d
(doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd
(doublet of doublets, double doublet), dt (doublet of triplets, double triplets), ddd (doublet
Of doublet of doublets, in pairs doublet), ddt (doublet of doublet of triplets, in pairs three
Weight peak), dddd (doublet of doublet of doublet of doublets, in pairs double doublet).Coupling constant,
Represented with hertz (Hz).
The condition of Algorithm (MS) data determination is:Agilent 6120Quadrupole HPLC-MS (pillars
Model:Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase:5%-95% (contains
The CH of 0.1% formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in))), detected in 210/254nm with UV, with electron spray electricity
From pattern (ESI).
The characteristic manner of compound purity is:The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or
The preparative high performance liquid chromatographies of Calesep Pump 250 (Pre-HPLC) (pillar model:NOVASEP, 50/80mm, DAC),
210nm/254nm is detected with UV.
Synthetic schemes
Following synthetic schemes describes the step of preparation present invention discloses compound:
The synthetic schemes of intermediate
Midbody compound (3) can be prepared by following process, wherein, R1、R2, n and m there is the present invention to be retouched
The implication stated.
Substituted benzoic acid (1) and the triazole (1a) of substitution are in [Cu] catalyst (such as cuprous iodide), appropriate part
Under (such as trans-N, N'- dimethyl -1,2- cyclohexanediamine) and appropriate alkali (such as cesium carbonate) effect, in reaction under heating condition
Obtain compound (2).Compound (2) obtains compound (3) in a heated condition with chlorinating agent (such as thionyl chloride).
Synthetic schemes 1
Target compound (8) can be prepared by following process, wherein, R1、R2、R3、R4, n, t, k and m have this
The described implication of invention.
Substituted or non-substituted 1,6- naphthyridines -5 (6H) -one (4) obtains compound (5) through chlorination, and compound (5) is entered
One step is reacted in a heated condition with compound (6) obtains compound (7).Compound (7) is with midbody compound (3) in alkali
Target compound (8) is directly reacted in the presence of (such as triethylamine).
Synthetic schemes 2
Target compound (14), (15) and (16) can be prepared by following process, wherein, R1、R2、R4, n, k and m
With implication described in the invention.
The oxidized reaction of compound (5) obtains compound (9), and compound (9) obtains compound through lactamization reaction
(10), compound (10) is reacted with bromoacetate (11) in the presence of alkali (such as potassium carbonate) obtains compound (12), chemical combination
Thing (12) further reacts in a heated condition with compound (6) obtains compound (13).Compound (13) and intermediate compound
Directly reaction obtains target compound (14) to thing (3) in the presence of alkali (such as triethylamine).Compound (14) is in alkali (such as carbonic acid
Caesium) in the presence of hydrolysis obtain target compound (15).Compound (15) occurs ammonolysis reaction and obtains target compound (16).