CN100457756C - Imidazo-pyrimidines and triazolo-pyrimidines: benzodiazepine receptor ligands - Google Patents
Imidazo-pyrimidines and triazolo-pyrimidines: benzodiazepine receptor ligands Download PDFInfo
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- CN100457756C CN100457756C CNB2004800213799A CN200480021379A CN100457756C CN 100457756 C CN100457756 C CN 100457756C CN B2004800213799 A CNB2004800213799 A CN B2004800213799A CN 200480021379 A CN200480021379 A CN 200480021379A CN 100457756 C CN100457756 C CN 100457756C
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- imidazoles
- pyrimidine
- triazolo
- pyridine
- fluoro
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Compounds of Formula (I) are provided, as are methods for their preparation. The variables Z1, Z2, Z3, R4, R5, R6, R7, R8 and Ar in the above formula are defined herein. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).
Description
Technical field
Relate generally to of the present invention has the imidazoles miazines and the triazolo pyrimidine class of useful medicinal properties.The present invention is pharmaceutical compositions and the purposes of these compounds in treatment central nervous system (CNS) disease about comprising these compounds further.
Background technology
This GABA
AThe super family of acceptor is one type a acceptor, by this receptor, makes main inhibitory nerve mediator γ-An Jidingsuan (GABA) generation effect.GABA widely, but unequal ground is distributed in the mammiferous brain, its be by be called GABA
AThe protein complex of acceptor is used for regulating its many effects, and this effect can cause the change of chlorine conductivity and film polarized action.Many medicines comprise antianxity and calm: benzodiazepine (benzodiazepine), also in conjunction with acceptor so far.GABA
AAcceptor comprises chloride channel, opens when this chloride channel reacts GABA, makes chlorine enter cell.Then the hyperpolarizing action by cell membrane potential makes neural activity slack-off.
GABA
AAcceptor is made up of five protein subunits.Many these GABA have been cloned
AThe cDNA of receptor subunits and determined its primary structure.Though these subunits have the basic function district (basic motif) of 4 transmembrane spirane structures jointly, it is to have enough sequence differences it is divided into several cohorts.So far, at least six kinds of α, three kinds of β, three kinds of γ, a kind of ε, a kind of δ and two kinds of ρ subunits have been identified.Natural GABA
AAcceptor is made up of two alpha subunits, two β subunits and a γ subunit typically.Various evidences (for example information distribution, genome location and biochemical research result) show that the acceptor of main natural generation is combined as α
1β
2γ
2, α
2β
3γ
2, α
3β
3γ
2, and α
5β
3γ
2
GABA
AGABA binding site in the acceptor (each receptor complex has two) is that the amino acid by α and β subunit is formed.α in each acceptor forms a: benzodiazepine site with the amino acid of γ subunit, and: benzodiazepine is to represent its medicinal activity in herein.In addition, this GABA
AAcceptor also comprises other multiple medications and carries out interactive site.These sites comprise steroid binding site, picrotoxin (picrotoxin) site and veronal (barbiturate) site.GABA
AThe: benzodiazepine site of acceptor is the site of a uniqueness on receptor complex, and to carry out interactive site not overlapping with other multiple medications or GABA.
In typical allosteric (allosteric) mechanism, when being bonded to the: benzodiazepine site, medicine can change the affinity of GABA acceptor to GABA.Known: benzodiazepine and can strengthen GABA and open GABA
AThe related drugs of the ability of receptor channel is agonist or part agonist (deciding according to GABA enhanced degree).The medicine of other kind, for example β-Ka Lin (derivative of β-carboline), can occupy same loci and negative regulation GABA effect be called as reverse agonist (inverse agonist).Therefore these can occupy same loci and to not tool or adiaphorous compound agonist capable of blocking or the reverse agonist effect substantially of GABA activity, therefore be called as GABA
AReceptor antagonist.
Before confirmed that the important destructurization that medicine causes in the: benzodiazepine site, the activity distribution of different receptor subtypes had become concentrated pharmacy and found the zone.Known agonist in: benzodiazepine site effect can represent anxiety, calmness, spasmolytic and soporific function, then manifests anxiety, cognitively strengthens and cause spasm (proconvulsant) effect in the compound of the reverse agonist effect in this site.
: benzodiazepine has secular pharmaceutical application, so these compounds can represent many side effects that do not need.Therefore, need other can regulate GABA in this area
AReceptor activation effect and/or active therapeutical agent.The present invention can satisfy this demand, and other relevant advantage is provided.
Summary of the invention
The invention provides imidazoles miazines and the triazolo pyrimidine compounds of formula I:
And the pharmaceutically acceptable salt class of this compounds, in the formula:
Z
1Be nitrogen or CR
1Z
2Be nitrogen or CR
2Z
3Be nitrogen or CR
3And Z
1, Z
2And Z
3In at least one (but being no more than two) be nitrogen;
R
1, R
2, R
3And R
4Be independently to be selected from separately:
(a) hydrogen, halogen, nitro and cyano group; And
(b) following formula group:
In the formula:
L is bond or C
1-C
8Alkylene;
G is bond, N (R
B) (that is,
), O, C (=O) (that is,
), C (=O) O (that is,
), C (=O) N (R
B) (that is,
), N (R
B) C (=O) (that is,
), S (O)
m(that is ,-S-,
), CH
2C (=O), S (O)
mN (R
B) (that is,
) or N (R
B) S (O)
m(that is,
);
Wherein m is 0,1 or 2; And
R
AWith each R
BBe independently to be selected from respectively:
(i) hydrogen; And
(ii) C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, (C
3-C
8Cycloalkyl) C
0-C
4Alkyl, (3 to 7 yuan of Heterocyclylalkyls) C
0-C
4Alkyl, (C
6-C
10Aryl) C
0-C
2Alkyl and (5 to 10 yuan of heteroaryls) C
0-C
2Alkyl, its each optionally be substituted naturally, and be preferably by 0 to 4 and independently be selected from halogen, hydroxyl, nitro, cyano group, amino, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, list-and two (C
1-C
4Alkyl) amino, C
1-C
4Alkylhalide group and C
1-C
4The substituting group of halogen alkoxyl group replaces;
R
5For:
(a) hydrogen, halogen or cyano group; Or
(b) C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
1-C
4Alkoxyl group or list-or two-(C
1-C
4Alkyl) amino, its each optionally be substituted naturally, and be preferably by 0 to 5 and be independently selected from halogen, hydroxyl, nitro, cyano group, amino, C respectively
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
3-C
8Cycloalkyl, phenyl, phenyl C
1-C
4The substituting group of alkoxyl group and 5-or 6-unit heteroaryl replaces;
R
6And R
7Be independent respectively be hydrogen, methyl, ethyl or halogen;
R
8Represent 0,1 or 2 and independently be selected from halogen, hydroxyl, nitro, cyano group, amino, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, list-and two (C
1-C
4Alkyl) amino, C
3-C
7Cycloalkyl, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group; And
Ar represents phenyl, naphthyl or 5-to 10-unit heteroaryl, its each optionally be substituted naturally, and be preferably by 0 to 4 and independently be selected from halogen, hydroxyl, nitro, cyano group, amino, C
1-C
8Alkyl, C
1-C
8Thiazolinyl, C
1-C
8Alkynyl, C
1-C
8Alkoxyl group, (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, (C
3-C
7Cycloalkyl) C
1-C
4Alkoxyl group, C
1-C
8Alkyl oxide, C
1-C
8Alkane ketone (alkanone), C
1-C
8Alkyloyl, (3-to 7-unit Heterocyclylalkyl) C
0-C
4Alkyl, C
1-C
8Alkylhalide group, C
1-C
8Halogen alkoxyl group, oxo base, C
1-C
8Hydroxyalkyl, C
1-C
8Aminoalkyl group and list-and two-(C
1-C
8Alkyl) amino C
0-C
8The substituting group of alkyl replaces.
In some aspects, these compounds provided herein are GABA
AReceptor modulators, it can regulate GABA
AReceptor activation effect and/or GABA
AThe signal conduction that acceptor is regulated.These GABA
AReceptor modulators is preferably high-affinity and/or highly selective GABA
AReceptors ligand and be as GABA
AAcceptor, for example human GABA
AThe agonist of acceptor, reverse agonist or antagonist.So, it can be used for treating various CNS diseases.
On the other hand, the invention provides pharmaceutical compositions, it is to comprise that above-mentioned one or more compound or its salt class and pharmacy can accept the combination of supporting agent, thinner or vehicle.Pharmaceutical formulations through packing also is provided, and it is to comprise being loaded on the above-mentioned pharmaceutical compositions in the container and how using this constituent treatment patient to make it avoid the specification sheets of CNS disease (for example anxiety, melancholy, somnopathy, the not enough disease of absorbed power, schizophrenia or cognitive disorder such as short term memory loss or Ah's Mohs lose intelligence).
In others, the present invention further provides the treatment patient and make it avoid the method for CNS disease (for example anxiety, melancholy, somnopathy, the not enough disease of absorbed power, schizophrenia or cognitive disorder), comprise that the patient to this treatment of needs throws the above-claimed cpd that gives the treatment significant quantity.The present invention also provides the method for the short-term memory that improves patient, comprises that the patient to this treatment of needs throws the above-claimed cpd that gives the treatment significant quantity.With compounds for treating provided herein suffer from the mankind of specific CNS disease, companion animals (pet) or livestock animals through raising and train also is contained among the present invention.
In another independent aspects, the invention provides the method for the effect of strengthening other CNS active compound.These methods comprise throws formula I compound or its salt and common other CNS active compound that gives the treatment significant quantity of throwing that gives the treatment significant quantity to patient.
The invention still further relates to the compound conduct location GABA in sample (for example tissue slice) that utilizes formula I
AThe probe of acceptor.In certain specific embodiments, GABA
AAcceptor is to utilize automatic radioautography to detect.In addition, the invention provides whether there is GABA in the confirmatory sample
AThe method of acceptor comprises the following steps: that (a) is in allowing above-mentioned compound and GABA
AUnder the condition of receptors bind, sample is contacted with above-mentioned compound; (b) remove not and GABA
AThe compound of receptors bind and (c) detect and GABA
AThe compound of receptors bind.
On the other hand, the invention provides the method for preparation compound disclosed herein, comprise its middle product.
Should understand these and other aspect of the present invention by the reference following detailed description.
Embodiment
As above-mentioned, the invention provides imidazoles miazines and the triazolo pyrimidine compounds of formula I, comprise imidazo [1,5-c] miazines, imidazo [1,2-c] miazines, [1,2,4] triazolo [4,3-c] miazines and [1,2,4] triazolo [1,5-c] miazines.Some preferred compounds is bonded to GABA
AAcceptor is preferably and has high sensitive; Better is that these compounds can further provide the regulating effect useful to brain function.Be not subject to the particular theory of any operation, think these compounds and GABA
AInteraction between the: benzodiazepine site of acceptor can make these compounds generations effect pharmaceutically.These compounds can use in external or body, to measure GABA in all cases
AThe position of acceptor or GABA
AThe activity of acceptor is regulated.
Chemical is described and proper noun
Compound provided herein generally is to name with standardized denomination.For compound, should be appreciated that (unless otherwise specified) all optical isomeric compounds and composition thereof all are contained in the present invention with asymmetric center.All chiralitys (mirror image and non-mirror image) and racemization form, and structural rotamerism form also is contained in the present invention, unless name especially specific stereochemistry or isomeric form.The rotamerism thing of the two keys of olefines and C=N etc. also can be contained in the compound as herein described, and all these stable isomers is to be contained in the present invention.The present invention also comprises cis and trans rotamerism thing, and form of mixtures or isolating isomer form that it can isomer are separated.This paper also one or more atom in the inclusion compound by isotropic substance (that is having the same atoms preface but the atom of different mass number) substituent.Generally speaking, but non-limiting, the isotropic substance of hydrogen comprises tritium and deuterium, and the isotropic substance of carbon comprises
11C,
13C and
14C.
Utilize the specific compound of the general formula explanation that comprises variable symbol herein.Unless otherwise specified, otherwise each variable symbol in the formula and other variable symbol are to define independently, and any variable symbol more than occurring surpassing once in formula, and it is to define independently when occurring at every turn.Therefore, for example, as if being described as of a group through 0 to 2 R
*Replace, then this group can be unsubstituted or at most through two R
*Group replaces, and R
*Be to be independently selected from the R that is defined when occurring at every turn
*In addition, when the combination that should understand substituting group and/or variable symbol only can betide this combination and can produce stable compound (that is, can through separating, identify and can testing its bioactive compound).
" pharmacologically acceptable salts " is the acid or the base salt forms of compound, the salt form of this compound can be suitable for contacting with the tissue of the mankind or animal, and do not have excessive toxicity or carinogenicity, and be preferably and do not have pungency, anaphylaxis or other problem or a complication.These salts comprise for example inorganic and organic acid salt of amine of alkaline residue, and the acidic residues for example alkalescence or the organic salt of carboxylic acid.Specific pharmacy salt comprises, but non-being limited to, the salt of acid, for example spirit of salt, phosphoric acid, Hydrogen bromide, oxysuccinic acid, hydroxyethanoic acid, FUMARIC ACID TECH GRADE, sulfuric acid, thionamic acid, Sulphanilic Acid, formic acid, toluenesulphonic acids, methylsulphonic acid, Phenylsulfonic acid, ethane disulfonic acid (ethane disulfonic), the 2-hydroxyethylsulfonic acid, nitric acid, phenylformic acid, the 2-acetoxy-benzoic acid, citric acid, tartrate, lactic acid, stearic acid, Whitfield's ointment, L-glutamic acid, xitix, pamoic acid (pamoic), succsinic acid, FUMARIC ACID TECH GRADE, maleic acid, propionic acid, hydroxy-maleic acid, hydroiodic acid HI, phenylacetic acid, alkanoic acid is acetate for example, HOOC-(CH
2)
n-COOH wherein n is 0 to 4, etc.Similarly, pharmacy can be accepted positively charged ion and comprise, but non-sodium, potassium, calcium, aluminium, lithium and the ammonium of being limited to.Those skilled in the art should understand which other pharmaceutically acceptable salt class of the compound that this paper provides comprises and list in Lei Shi pharmacy complete works (Remington ' s Pharmaceutical Sciences), 17th ed., Mack PublishingCompany, Easton, PA, the p.1418 part in (1985).Generally speaking, acceptable acid of pharmacy or alkali salt can be synthetic via any chemical process of knowing by the former compound that contains alkalescence or acidic moiety.In brief, these salts can via with the free acid of these compounds or alkali form and stoichiometric suitable alkali or acid in water or organic solvent, perhaps in both mixtures, react and prepared; Usually, to use non-aqueous media, for example ether, vinyl acetic monomer, ethanol, Virahol or acetonitrile are for preferable.
Each compound that should be appreciated that formula I is passable, but does not need, and is modulated into hydrate, solvate or non--covalent complex.In addition, its various crystallization shapes and polymorph (polymorphs) also are contained in the category of the present invention.This paper also provides formula I the prodrug of compound." prodrug " is a kind of compound, its may and not in full conformity with compound that this paper provided in structural demand, give to patient but throw, it is modified in body, and production I compound, or the compound of other chemical formula provided herein.For example, prodrug can be the acylated derivatives of compound provided herein.Prodrug comprises the compound that hydroxyl, amine or sulfhedryl (sulfhydryl) combine with any group, when it offers medicine to the Mammals recipient, then is cut off and forms free hydroxyl, amino or sulfhedryl respectively.The example of prodrug comprises, but non-being limited to, and this paper provides the derivative of alcohol in the compound and amine functional group's acetate (ester), formate (ester) and benzoate (ester).The prodrug of the compound that this paper provided can prepare by modifying the functional group who exists in this compound, and this modification can produce former compound through cut-out in body.
" substituting group " used herein speech is meant the molecular moiety of the atom of covalency bond to the perceptual interesting molecule.For example, " ring substituents " can be covalency bond part of an atom (being preferably carbon or nitrogen-atoms member) to the ring, such as halogen, alkyl, alkylhalide group or other substituting group discussed in this article." metalepsy " speech is meant the hydrogen atom in the molecular structure is replaced with above-mentioned substituting group, and it does not surpass the valence mumber of this specified atom, and this metalepsy can produce chemically stable compound (that is, can through separating, identify and can testing its bioactive compound).When substituting group be the oxo base (that is ,=O) time, then two hydrogen on this atom are to be substituted.When aromatic series part when the oxo base replaces, then this aromatic ring is to replace through the unsaturated ring of corresponding part.For example the pyridyl that replaces through the oxo base is a pyridone.
" optionally be substituted " speech and be meant that a group can be unsubstituted or on one or more any available site, typically be 1,2,3,4 or 5 sites, replace with one or more suitable substituting group disclosed herein.Metalepsy optionally also shows that with " replacing with 0 to X substituting group " vocabulary wherein X is substituent maximum number.
The employed dash ("-") that is not arranged in two words or symbol is meant substituent attachment point.For example ,-CONH
2Be to connect by carbon atom.
As used herein, " alkyl " is to comprise side chain and straight chain representative examples of saturated aliphatic alkyl; Name, these groups have specified carbonatoms herein.Therefore, C used herein
1-C
6Alkyl one speech is meant the alkyl with 1 to 6 carbon atom." C
0-C
4Alkyl " be meant a bond or C
1-C
4Alkyl.Alkyl comprises and has 1 to 8 carbon atom (C
1-C
8Alkyl), 1 to 6 carbon atom (C
1-C
6Alkyl) and 1 to 4 carbon atom (C
1-C
4Alkyl) group, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, second butyl, tributyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl and 3-methyl amyl.In certain specific embodiments, preferable alkyl is methyl, ethyl, propyl group, butyl and 3-amyl group." aminoalkyl group " be meant alkyl that this paper defines through one or more-NH
2Substituting group replaces." hydroxyalkyl " be meant alkyl that this paper defines through one or more-the OH substituting group replaces.
" thiazolinyl " is meant the straight or branched hydrocarbon chain that comprises one or more carbon-to-carbon double bond, for example vinyl and propenyl.Thiazolinyl comprises C
2-C
8Thiazolinyl, C
2-C
6Thiazolinyl and C
2-C
4Thiazolinyl (it is to have 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively), for example vinyl, allyl group or pseudoallyl.
" alkynyl " is meant the straight or branched hydrocarbon chain that comprises one or more carbon-to-carbon triple bond.Alkynyl comprises C
2-C
8Alkynyl, C
2-C
6Alkynyl and C
2-C
4Alkynyl, it is to have 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively.Alkynyl comprises, for example, and ethynyl and proyl.
As used herein, " alkoxyl group " is meant abovementioned alkyl, the alkenyl or alkynyl that connects by oxo bridge.Alkoxyl group comprises C
1-C
6Alkoxyl group and C
1-C
4Alkoxyl group, it is to have 1 to 6 or 1 to 4 carbon atom respectively.Specific alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, second butoxy, the 3rd butoxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methyl pentyloxy.Similarly, " alkylthio " is meant abovementioned alkyl, the alkenyl or alkynyl that connects by sulphur bridge.
" cycloalkyl " is saturated or the cyclic group of fractional saturation, wherein all ring memberses are carbon, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, bornyl, adamantyl, decahydro-naphthyl, octahydro-indenyl and arbitrary aforesaid fractional saturation variation thing, for example cyclohexenyl.These groups typically comprise 3 to about 10 ring carbon atoms; In certain specific embodiments, these groups have 3 to 7 ring carbon atoms (that is, C
3-C
7Cycloalkyl).If be substituted, then any available ring carbon atom through bond to any specified substituting group.
Term " (cycloalkyl) alkyl ", " cycloalkyl " and " alkyl " are as above to define, and its attachment point is to be positioned at alkyl.Some these group is (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, wherein this cycloalkyl is by direct key or C
1-C
4Alkyl connects.Term comprises, for example, and cyclopropyl methyl, cyclohexyl methyl and cyclohexyl ethyl.Similarly, " (C
3-C
7Cycloalkyl) C
1-C
4Alkoxyl group " be meant and pass through C
1-C
4The C that alkoxyl group connects
3-C
7Cycloalkyl.
" alkyloyl " speech be meant by the carbonyl bridge joint the attached above-mentioned alkyl group that defines.Alkyloyl comprises C
2-C
8Alkyloyl, C
2-C
6Alkyloyl and C
2-C
4Alkyloyl, it is to have 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively." C
1Alkyloyl " be meant-(C=O)-and H, its (and C
2-C
8Alkyloyl) be to be contained in term " C
1-C
8Alkyloyl " in.Ethanoyl is C
2Alkyloyl.
This paper employed " oxo base " speech is meant ketone group (C=O).The oxo base is the substituting group of non-aromatic ring, and it can produce-CH
2-to-C (=O)-conversion.Should understand oxo base substituting group is caused meeting destruction aromaticity (aromaticity) on the aromatic ring.
" alkane ketone " is ketone group, and wherein carbon atom is to arrange with the straight or branched alkyl." C
3-C
8Alkane ketone ", " C
3-C
6Alkane ketone " and " C
3-C
4Alkane ketone " be the alkane ketone that refers to have 3 to 8,6 or 4 carbon atoms respectively.For example, C
3The alkane ketone group has structure-CH
2-C (=O)-CH
3
Similarly, " alkyl oxide " is meant the straight or branched ether substituting group that connects through C-C.Alkyl ether groups comprises C
2-C
8Alkyl oxide, C
2-C
6Alkyl oxide and C
2-C
4Alkyl oxide, it is to have 2 to 8,6 or 4 carbon atoms respectively.For example, C
2Alkyl ether groups has structural formula-CH
2-O-CH
3
" alkoxy carbonyl " speech be meant the alkoxyl group that connects through carbonyl (that is, have general structural formula-C (=O)-group of O-alkyl).Alkoxycarbonyl groups comprises C
2-C
8, C
2-C
6And C
2-C
4Alkoxycarbonyl groups, it is to have 2 to 8,6 or 4 carbon atoms respectively." C
1Alkoxy carbonyl " be meant-(C=O)-and OH, it is to be contained in " C
1-C
8Alkoxy carbonyl " in the speech.These groups also can be described as alkyl carboxylic acid foundation group.For example, methyl carboxylic acids root (methylcarboxylate) be meant-(C=O)-O-CH
3And ethyl carboxylic acid root (ethylcarboxylate) be meant-(C=O)-O-CH
2CH
3
" formamido group (carboxamido) " speech be meant acid amides (amide) group (that is ,-(C=O) NH
2).
" alkylamino " be meant have general structural formula-NH-alkyl or-secondary or the tertiary amine substituting group of N (alkyl) (alkyl), wherein each alkyl can be identical or different.These groups comprise, for example, single-and two-(C
1-C
6Alkyl) amino, wherein each alkyl can be identical or different and can be comprised 1 to 6 carbon atom, and for example single-and two-(C
1-C
4Alkyl) amino.Alkyl amino alkyl be meant the alkylamino group that connects by alkyl (that is, have general structural formula-alkyl-NH-alkyl or-group of alkyl-N (alkyl) (alkyl)).These groups comprise, for example, single-and two-(C
1-C
8Alkyl) amino C
1-C
8Alkyl, wherein each alkyl can be identical or different." single-or two-(C
1-C
8Alkyl) amino C
0-C
8Alkyl " be meant by direct key or C
1-C
8The list that alkyl connects-or two-(C
1-C
8Alkyl) amino.Under classify representational alkyl amino alkyl group as:
" halogen " speech is meant fluorine, chlorine, bromine, reaches iodine." alkylhalide group " is through 1 or branched-chain or straight-chain alkyl (for example, " C that replaces of a plurality of halogen atom
1-C
8Alkylhalide group " have 1 to 8 carbon atom; " C
1-C
2Alkylhalide group " have 1 to 2 carbon atom).The example of alkylhalide group comprises, but non-being limited to, single-, two-or three-methyl fluoride; Single-, two-or three-chloromethyl; Single-, two-, three-, four-or five-fluoro ethyl; And single-, two-, three-, four-or five-chloroethyl.Typical alkylhalide group is trifluoromethyl and difluoromethyl." halogen alkoxyl group " speech is meant by oxo bridge and connects and through attached above-mentioned alkylhalide group." C
1-C
8The halogen alkoxyl group " have 1 to 8 carbon atom.
As used herein, " aryl " speech is meant only carbonaceous aromatic group in the aromatic ring.These aromatic groups can be further through carbon or non-carbon atom or group replacement.Typical aryl comprises the ring of 1 to 3 isolating, condensed, spiral shell or side joint, and this ring has 6 to about 18 annular atomses, does not have heteroatoms in its ring members.Preferable aryl is 6-to a 12-unit group, for example phenyl, naphthyl (comprising 1-naphthyl and 2-naphthyl), and xenyl.Aralkyl is the aryl that connects by alkyl; Aralkoxy is the aryl that partly connects by alkoxyl group.For example, phenyl C
1-C
2Alkoxyl group is meant benzyloxy or benzene oxyethyl group (also being styroyl oxygen base (phenethyloxy)).
That speech such as " heterocycle " or " heterocyclic radical " is meant is saturated, part unsaturation or aromatic group, and it has 1 or 2 ring, and each ring contains 3 to 8 atoms, and at least one ring contains 1 to 4 independent respectively heteroatoms (that is, oxygen, sulphur or nitrogen) through selecting.Heterocycle can pass through any ring hetero atom or the attached stable structure that produces of carbon atom, and if the compound of gained is stable, then can replace on carbon and/or nitrogen-atoms.Any nitrogen and/or sulfur heteroatom can be optionally through oxidations, and any nitrogen can be optionally through level Fourization (quaternized).
Some heterocycle is " heteroaryl " (that is comprise that at least one has 1 to 4 heteroatomic aromatic ring, other annular atoms is a carbon), for example 5-to 7-unit's monocycle base and 7-to 10-unit bicyclic group.When the sum of S in the heteroaryl and O atom surpassed 1, these heteroatomss can be not adjacent one another are; The sum of S and O atom is preferably and is not more than 1,2 or 3 in the heteroaryl, is more preferred to be not more than 1 or 2 and best for being not more than 1.The example of heteroaryl comprises pyridyl, indyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolyl, pyrryl, pyrazolyl and 5,6,7,8-tetrahydroisoquinoline.Bicyclic heteroaryl except aromatic ring, can, but non-needs contain saturated ring (for example, tetrahydric quinoline group or tetrahydro isoquinolyl)." 5-or 6-unit heteroaryl " is the bicyclic heteroaryl with 5 or 6 ring memberses.
Other heterocycle mentioned herein is " Heterocyclylalkyl " (that is, the heterocycle of saturated or fractional saturation).Heterocyclylalkyl has 3 to about 8 annular atomses, is typically 3 to 7 (or 5 to 7) annular atomses.The example of Heterocyclylalkyl comprises morpholinyl, piperazinyl and pyrrolidyl.(3-to 6-unit Heterocyclylalkyl) C
0-C
4Alkyl is the Heterocyclylalkyl with 3 to 6 ring memberses, and it is by direct key or C
1-C
4Alkyl connects.The example of Heterocyclylalkyl comprises morpholinyl, piperazinyl and pyrrolidyl.
" GABA
AAcceptor " reach speech such as ": benzodiazepine receptors " and be meant a kind of protein complex, it is can be incorporated into GABA with detecting and regulate chlorine conduction and film polarized action with dose-dependently.Generally with the GABA of the Mammals (especially people or rat) that comprises nature-generation
AReceptor subunits is preferable, though subunit can be modified, prerequisite is to limit any modification all can't suppress the ability (that is this receptor to GABA at least kept 50% binding affinity) of this receptor in conjunction with GABA in fact.Can utilize standard part binding analysis method assessment candidate GABA provided herein
AAcceptor is to the binding affinity of GABA.Should understand that various GABA are arranged
AReceptor subtype is at " GABA
AAcceptor " category in.These hypotypes comprise, but the non-α that is limited to
2β
3γ
2, α
3β
3γ
2, α
5β
3γ
2And α
1β
2γ
2Receptor subtype.GABA
AAcceptor can be obtained by multiple source, for example by the cortex prepared product of rat or by the human GABA that can show through the clone
AThe cell of acceptor.Utilize standard technique can prepare specific hypotype (for example as described herein) easily via the mRNA introducing host cell of the subunit that codified is required.
GABA
A" agonist " of acceptor is a kind of GABA of enhancing
AThe active compound of GABA on the acceptor.Agonist also can, but non-needs strengthen GABA to GABA
AThe combination of acceptor.Compound is as GABA
AThe ability of agonist can utilize electric Physiological Analysis method to measure, for example the analytical method that provided of embodiment 7.
GABA
A" the reverse agonist " of acceptor is a kind of GABA of reduction
AThe active compound of GABA on the acceptor.Reverse agonist also can, but non-needs suppress GABA to GABA
AThe combination of acceptor.Through GABA-inductive GABA
AThe minimizing of receptor active can be measured by electric Physiological Analysis method, for example the analytical method that provided of embodiment 7.
The employed GABA of this paper
A" antagonist " of acceptor is a kind of GABA of occupying
AThe compound in the: benzodiazepine site of acceptor, but to GABA
AThe activity of GABA there is no detectable influence on the acceptor.These compounds can suppress the effect of agonist or reverse agonist.GABA
AThe activity of receptor antagonist can be in conjunction with suitable GABA
AReceptor binding assay method and measuring, the analytical method that provided of this paper embodiment 6 for example, and utilize the appropriate functional analytical method and measure, for example electric Physiological Analysis method that provided of this paper embodiment 7.
" GABA
AReceptor modulators " be meant any GABA of can be used as
AThe compound of receptor agonists, reverse agonist or antagonist.In some specific embodiment, these instrumentalities are in standard GABA
ACan represent affinity costant (Ki) in the acceptor radioligand-binding assay, or in electric Physiological Analysis, can represent EC less than 1 micro-molar concentration less than 1 micro-molar concentration
50In other specific embodiment, GABA
AReceptor modulators can represent less than the affinity costant of 500nM, 200nM, 100nM, 50nM, 25nM, 10nM or 5nM or EC
50
If at GABA
AKi on the acceptor is less than 1 micro-molar concentration, and is preferable during less than 100 nanomole concentration or less than 10 nanomole concentration, then claims GABA
AReceptor modulators has " high-affinity ".Embodiment 6 herein provides and can measure GABA
AThe representative analytical method of Ki on the acceptor.Should be appreciated that Ki is the hypotype that depends on the employed acceptor of this analytical method.In other words, the high-affinity compound can be " hypotype-specificity " (that is compound is more than at least 10 times of Ki to another kind of hypotype to the Ki of a certain hypotype).If at the few a kind of GABA of u
AWhen Ki met above-mentioned any one on the receptor subtype, then these compounds were to GABA
AAcceptor has high-affinity.
If GABA
AReceptor modulators and at least a GABA
AThe hypotype combination of acceptor, and its Ki is lower than this GABA
AReceptor modulators and other film-bind receptor (that is, non-GABA
A) at least 10 times of bonded Ki, be preferably at least 100 times, then claim this GABA
AReceptor modulators has " highly selective ".Especially, the compound that manifests highly selective should be GABA the Ki of following acceptor
AMore than at least 10 times of the Ki of acceptor: thrombotonin (serotonin), Dopamine HCL (dopamine), galanin (galanin), VR1, C5a, MCH, NPY, CRF, bradykinin (bradykinin) and tachykinin (tackykinin).Can utilize standard then, for example use the commercially available membrane receptor binding analysis method that gets (for example, available from MDS PHARMASERVICES, Toronto, Canada and CEREP, Redmond, the binding analysis of WA), measure the Ki of compound other acceptors in conjunction with analytical method.
" CNS disease " is that patient's central nervous system is to GABA
AThe disease of acceptor conditioned reaction or illness.These diseases (for example comprise anxiety disorder, Phobias, obsession, agoraphobia, social phobia, specific fear disease, spirit depressing, adjustment disorder, separation anxiety disorder, the cyclothymia disfunction, and generalized anxiety disorder), stress disorders (for example, stress disorders after the wound, acute stress disorders of anticipatory anxiety and acute stress disorders), dysthymia disorders (for example, dysthymia disorders, the atypia dysthymia disorders, the depressive period of manic depressions and manic depressions), somnopathy (for example, primary insomnia, daily rhythmicity sleep disease, dyskoimesis NOS, Parasomnias, comprise nightmare disease, night terror, by melancholy, the somnopathy that anxiety and/or other mental illness cause, and the somnopathy of medicine initiation), cognitive disorder (for example, cognitive impairment, mild cognitive impairment (mild cognitiveimpairment, MCI), age related cognitive decline (age-related cognitive decline, ARCD), schizophrenia, traumatic brain injury, Down syndrome, neurodegenerative disorders is Ah's Mohs disease and Parkinson's disease for example, and apoplexy), the dementia that AIDS-follows, with melancholy, the dementia that anxiety or psychosis are followed, aprosexia disease (for example, aprosexia disease and aprosexia/Attention Deficit Hyperactivity Disorder), spasm (for example, epilepsy),: benzodiazepine excessive and drug habit and alcohol dependence.
" CNS medicament " be used for the treatment of prevent the CNS disease or be used for healthy patient with bring out or prolong the sleep any medicine.The CNS medicament comprises, for example: GABA
AReceptor modulators, serotonin receptor (for example, 5-HT
1A) agonist and antagonist and selective serotonin reuptake inhibithors (SSRIs); Neural plain (neurokinin) receptor antagonist; Adrenocortical hormone releasing hormone acceptor (CRF
1) antagonist; The Melatonin receptor agonists; The nicotine agonist; Muscarine (muscarinic) agent; Acetylcholinesterase depressant and Dopamine Receptors agonist.
" treatment significant quantity " (or dosage) is to offer medicine to the patient to cause the amount (for example, the symptom of one or more CNS disease is reduced or sleep is produced desired effect) of obvious benefit to patient.Usually this tittle or dosage can make compound concentration in the celiolymph in utilizing embodiment 6 described assays, are enough in vitro inhibition GABA
AReceptors ligand and GABA
AReceptors bind.Should be appreciated that the treatment significant quantity of compound is to depend on to use which kind of compound, and other CNS medicament of giving of any common throwing.
" patient " is meant any individuality with the compounds for treating that this paper was provided.Patient comprises the mankind, and other vertebrates for example companion animals and domestic animal.Patient may suffer from the CNS disease, or may not suffer from these illnesss (that is treatment can be prophylactic treatment or causes the treatment of sleeping property).
Imidazoles miazines and triazolo pyrimidine class
As above-mentioned, the invention provides the compound (it has above-mentioned variation thing) of formula I, and the pharmaceutically acceptable salt class of these compounds.
In some compound provided herein, R
8Represent that 0 substituting group or 1 are selected from halogen, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group.
In some compound of formula I, Ar independently is selected from halogen, hydroxyl, amino, cyano group, C respectively through 0,1,2 or 3 again
1-C
4Alkyl, C
1-C
4Alkoxyl group, list-and two-C
1-C
4Alkylamino, C
2-C
4Alkyloyl, (C
3-C
7Cycloalkyl) C
0-C
2Alkyl, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.
In certain specific embodiments, Ar is phenyl, pyridyl, thiazolyl, thienyl, pyridazinyl or pyrimidyl, and it is 0 to 4 the above-mentioned substituting group replacement of respectively hanging oneself, or independently is selected from chlorine, fluorine, hydroxyl, cyano group, amino, C respectively through 0 to 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylamino, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.Representational Ar group (for example comprises phenyl, pyridyl, pyridine-2-yl), thiazolyl (for example, 1, the 3-thiazol-2-yl), thienyl (for example, thiophene-2-yl) or pyridazinyl (for example, pyridazine-3-yl), it is respectively to hang oneself 0 to 3 independently to be selected from chlorine, fluorine, hydroxyl, cyano group, amino, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, list-or two-(C
1-C
2) alkylamino, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group replaces; Being preferably it respectively hangs oneself 0 to 3 and independently is selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.For example, the Ar group comprises, but non-being limited to, 2,6-two fluoro-phenyl, 2,5-two fluoro-phenyl, 5-fluoro-2-methyl-phenyl, pyridine-2-base, 3-fluoro-pyridine-2-base, 3-cyano group-pyridine-2-base, 3-trifluoromethyl-pyridine-2-base, 3-hydroxyl-pyridine-2-base, 3-methoxyl group-pyridine-2-base, 6-fluoro-pyridine-2-base, 6-cyano group-pyridine-2-base, 6-trifluoromethyl-pyridine-2-base, 6-hydroxyl-pyridine-2-base and 6-methoxyl group-pyridine-2-base.
In specific compound, R
1, R
2, R
3And R
4Be independently to be selected from respectively:
(a) hydrogen, halogen or cyano group; And
(b) following formula group:
In the formula
(i) L is a bond;
(ii) G is bond, NH, N (R
B), O, C (=O) O or C (=O); And
(iii) R
AWith R
BBe independently to be selected from (1) hydrogen and (2) C respectively
1-C
6Alkyl, C
2-C
6Thiazolinyl, (C
3-C
7Cycloalkyl) C
0-C
2Alkyl, (3 to 7 yuan of Heterocyclylalkyls) C
0-C
2Alkyl, phenyl, thienyl, pyridyl, pyrimidyl, thiazolyl, and pyrazinyl, it is respectively to hang oneself 0 to 4 independently to be selected from hydroxyl, halogen, cyano group, amino, C respectively
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group replaces.
For example, in specific compound, R
1, R
2, R
3, and R
4Be independently to be selected from respectively: hydrogen, hydroxyl, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
2-C
6Alkyl oxide, C
3-C
7Cycloalkyl, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
6Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl.Representational R
1And R
4Group comprises hydrogen, methyl and ethyl.Representational R
2Group comprises hydrogen, cyano group, formamido group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Carbalkoxy, C
2-C
4Alkyl oxide, C
3-C
7Cycloalkyl, C
1-C
2Hydroxyalkyl, methyl fluoride, difluoromethyl, trifluoromethyl, phenyl and pyridyl.
In the specific compound of formula I, R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, C
3-C
8Cycloalkyl, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces.Representational R
5Group comprises ethyl, propyl group, butyl, oxyethyl group and methoxyl methyl.
In certain specific embodiments, R
6And R
7Be all hydrogen.
The specific compound of formula I further meets formula II, wherein Z
1Be nitrogen, Z
2Be CR
2And Z
3Be CR
3:
These changes wait in the compound R at some
2And R
3Be independently to be selected from hydrogen, cyano group, formamido group, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, trifluoromethyl, phenyl, pyridyl, methyl carboxylic acids root and ethyl carboxylic acid root.In other these compounds:
R
2And R
3Be independently to be selected from hydrogen, hydroxyl, halogen, cyano group, formamido group, C respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
4Alkoxyl group, list-or two-C
1-C
4Alkylamino, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, C
3-C
8Cycloalkyl, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be independently to be selected from hydrogen, methyl, ethyl or halogen respectively;
R
8Represent 0 or 1 to be selected from halogen, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group; With and/or
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
The compound of some formula I further meets formula III, wherein Z
1And Z
3Be nitrogen, and Z
2Be CR
2:
These changes wait in the compound R at some
2Be to be selected from hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
4Alkyl oxide, C
1-C
2Hydroxyalkyl, methyl fluoride, difluoromethyl, trifluoromethyl, phenyl and pyridyl.In other these compounds:
R
2Be to be selected from hydrogen, hydroxyl, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, C
3-C
8Cycloalkyl, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be independent respectively be hydrogen, methyl, ethyl or halogen;
R
8Represent 0 or 1 to be selected from halogen, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group; And/or
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
The specific compound of formula I further meets formula IV, wherein Z
1Be CR
1, Z
2Be CR
2And Z
3Be CR
3:
In some these compound, R
3Be hydrogen or methyl.In other these compounds:
R
1Be hydrogen, halogen or C
1-C
6Alkyl;
R
3Be to be selected from hydrogen, hydroxyl, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, C
3-C
8Cycloalkyl, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be independent respectively be hydrogen, methyl, ethyl or halogen;
R
8Represent 0 or 1 to be selected from halogen, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group; And/or
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
The specific compound of formula I also meets formula V, wherein Z
1And Z
2Be nitrogen, and Z
3Be CR
3:
In some these compound, R
3Be hydrogen, cyano group, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
6Alkylhalide group, C
1-C
6Alkyloyl, pyridyl or formamido group.In other these compounds:
R
3Be to be selected from hydrogen, hydroxyl, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, C
3-C
8Cycloalkyl, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be independent respectively be hydrogen, methyl, ethyl or halogen;
R
8Represent 0 or 1 to be selected from halogen, C
1-C
2Alkyl and C
1-C
2The substituting group of alkoxyl group; And/or
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
Compound provided herein can change (adjusting) part and GABA
AThe combination of acceptor, and this change can utilize the outer receptor binding assay method of standard body to detect." the GABA of this paper
AThe receptors ligand binding analysis " be meant the outer receptor binding assay method of standard body that embodiment 6 provided.In brief, the analytical test that can be at war with wherein is with GABA
AThe acceptor prepared product with through mark (for example,
3H) part (for example, flumazenil (flumazenil)), and the test compound of un-marked is cultivated.And with can after testing and can regulate part and GABA
AThe cultivation results of the compound of receptors bind can cause with respect to not with the amount of compound bonded mark, with GABA
AThe amount of acceptor prepared product bonded mark reduces or increases.Preferably, these compounds are to GABA
AAcceptor can represent less than 1 micro-molar concentration, is more preferred from the Ki less than 500nM, 100nM, 20nM or 10nM.Be used to carry out external bonded GABA
AAcceptor can be obtained by multiple source, for example derives from the cortex prepared product of rat or derives from the human GABA that can show through the clone
AThe cell of acceptor.
In certain specific embodiments, preferable compound has suitable pharmacy characteristic, comprise oral administration biaavailability (as, its sublethal dose or be preferably the acceptable oral dosage of pharmacy, be preferably less than 2 grams, be more preferred from be less than or equal to 1 the gram or 200 milligrams, can provide a kind of detectable interaction in vitro), hypotoxicity (preferable compound is to be that tool is not toxic when it offers medicine to the receptor with the treatment significant quantity), (preferable compound is for when it offers medicine to the receptor with the treatment significant quantity few side effects, the side effect and the placebo that are produced are suitable), low serum protein keying action, and have the suitable transformation period in external and body that (preferable compound can represent and allows the Q.I.D. dispensing in body, be preferably the T.I.D. dispensing, be more preferred from the transformation period of B.I.D. dispensing, and best for offeing medicine once every day).Compound is distributed to specific position in body activity also must satisfactory (for example, the compound that is used for the treatment of the CNS disease be preferably penetrable blood-brain barrier person, and is good with the compounds for treating peripheral nerve disease of using low brain concentration typically).
Can use the routine analytical method of being known in this technology with these characteristics of assessing compound and the optimizing compound that identifies suitable specific end use.For example, the analytical method that is used to predict bioavailability comprises by the transporting of human small intestine cells individual layer, for example the Caco-2 cell monolayer.The blood-brain barrier penetration power of compound can be predicted by the brain concentration of the compound of the laboratory animal after administration (for example, intravenously administrable) among the mankind.The serum protein keying action can be predicted by the albumin bound analytical method, for example by people such as Oravcov á in the described analytical method of (1996) Journal ofChromatography B 677:1-27.The compound transformation period is to be inversely proportional to the frequency that needs administration.Compound can be predicted by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26:1120-27 described microsome transformation period analytical method in the external transformation period.
As above-mentioned, the preferred compounds that this paper provided is atoxic.Usually, should understand this paper employed " non-toxicity " speech with relative meaning, it is meant anyly can throw the material that gives to Mammals (being preferably the mankind) through united States food and drug administration (FDA) approval, or meets the restricted condition of having set up and may can throw the material that gives to Mammals (being preferably the mankind) through united States food and drug administration (FDA) approval.In addition, throw with minimum treatment significant quantity when it and give or suppress GABA to be enough to make
AReceptors ligand and GABA
AAcceptor is when external bonded concentration and cells contacting, and splendid non-toxic chemical can meet one or more following restricted condition usually: (1) can not suppress the manufacturing of cell ATP basically; (2) can not prolong heart QT significantly at interval; (3) can not cause the liver enlargement basically; Or (4) can not cause liver enzyme to disengage basically.
As used herein, the compound that can not suppress the manufacturing of cell ATP basically is meant in the test of embodiment 8, can not make the ATP concentration of cell reduce compound greater than 50%.Preferably, the ATP concentration of handling through embodiment 8 that cell represented is at least 80% of ATP concentration measured in the undressed cell.Better compound is that those work as the EC of compound concentrations for this compound
50Or IC
50At least 10 times, 100 times or 1000 times the time, can not suppress the ATP producer of cell basically.
The compound that can not prolong heart QT interval significantly is meant works as this compound can produce the EC that is equivalent to compound
50Or IC
50The dosage of serum-concentration throw when giving to cavy, minipig or dog, can not cause statistically evident heart QT prolongation (judging) at interval by electrocardiogram(ECG.In some preferred embodiment, when non-oral way or oral administration are given, can not cause statistically evident heart QT prolongation at interval with 0.01,0.05,0.1,0.5,1,5,10,40 or 50 milligram/kilogram dosage." on the statistics significantly " is meant the canonical parameter formula analytical method of utilizing statistics to go up significance (for example t check (student ' s T test)) measure the result by compared with the control, if p<0.1 degree or be more preferred from p<0.05 degree and then have significance.
The compound of the liver enlargement that can not cause basically is meant, if every day is can produce the EC that is equivalent to compound
50Or IC
50The dosage of serum-concentration handle the Nie tooth class (for example mouse or rat) 5 to 10 days of experiment usefulness, its result is not more than 100% of corresponding control group for liver to the increase ratio of weight ratio.In the specific embodiment of Yu Gengjia, these dosage can not cause 75% or 50% liver enlargement greater than corresponding control group.If use non-Nie tooth Mammals (for example, dog), then these dosage should not cause liver to the increasing amount of weight ratio greater than 50% of corresponding unprocessed control group, be preferably and be not more than 25%, and be more preferred from and be not more than 10%.Preferable dosage comprises in non-oral or per os mode and offers medicine 0.01,0.05,0.1,0.5,1,5,10,40 or 50 milligram/kilogram in these analytical methods.
Similarly, can not promote compound that liver enzyme is disengaged to be meant when can produce the EC that is equivalent to compound basically
50Or IC
50The dosage of serum-concentration throw when giving, can not improve experiment and reach more than 3 times (are preferably and are no more than 2 times) that surpass pseudo-processing control group with ALT, LDH or the AST serum-concentration of Nie tooth class animal.In the better specific embodiment, these dosage can not make the serum-concentration of these materials be increased to greater than 75% or 50% of corresponding control group.Perhaps, if in external liver cell analytical method, compound does not promote the release (concentration by the external substratum that contacts or cultivate with liver cell or other these solution is learnt) of liver enzyme basically, that is to be equivalent to the EC of compound
50Or IC
50The dosage of concentration handle after, not detecting any of these liver enzyme in substratum, burst size above base value concentration, this base value concentration are arranged is the concentration of these liver enzyme in the corresponding pseudo-substratum of handling control cells.In the specific embodiment of Yu Gengjia, when these compounds are EC with compound
50Or IC
50Twice, five times and be preferably ten times concentration and handle after, not detecting these liver enzyme in substratum has any burst size that surpasses base value concentration.
In other specific embodiment, specific preferable compound in concentration quite at the EC of compound
50Or IC
50Shi Buhui suppresses or induced microparticle somatocyte cytochrome p 450 enzymic activity, for example CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity.
Specific preferable compound in concentration quite at the EC of compound
50Or IC
50The time, for non-body breaking property (clastogenic) or bring out mutagenicity (for example, utilize standard method of analysis to judge, as Chinese hamster ovary cell in-vitro micronucleus analytical method, mouse lymphoma analytical method, people's quasi-lymphocyte chromosome abnormalty analytical method, Nie tooth marrow micronucleus assay method, the contrary mutation analysis (Ames test) of salmonella etc.).In other specific embodiment, specific preferable compound can not cause that sister strand exchanges (sister chromatid exchange) (for example, in Chinese hamster ovary cell) when these concentration.
For the purpose that detects (following detailed discussion will be arranged), compound provided herein can be through isotopic labeling or radioactive rays mark.These compounds are identical with above-mentioned person, but in fact its one or more atom is replaced by atomic mass of finding with general nature circle or the different atom of total mass number.The isotopic example that can integrate with the compound that this paper provides comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and the isotropic substance of chlorine, for example,
2H,
3H,
11C,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F, and
36Cl.In addition, with heavy isotope (for example, deuterium, that is
2H) replacement can provide specific treatment advantage because of preferable metabolic stability, for example increases the transformation period or reduces the dosage demand, and therefore be fit to use under some situation.
As above-mentioned, different stereoisomeric forms in any ratio, for example racemic mixture and optical activity form, be contained in of the present invention.In certain specific embodiments, may need to obtain single mirror image isomerism thing (that is, optical activity form).The standard method for preparing single mirror image isomerism thing comprises the decomposition of asymmetric synthesis and racemic mixture.The decomposition of racemic mixture can for example be carried out crystallization via well-known process under decomposition agent exists, perhaps utilize the chromatography effect, for example chirality HPLC tubing string and finishing.
Pharmaceutical compositions
The present invention also provides the pharmaceutical compositions of being made up of at least a compound provided herein and at least a physiologically acceptable supporting agent or vehicle.These compounds can be used for the treatment needs and regulate GABA
AThe patient of acceptor (for example, suffer the patient of painful process, it can bring out certainly to lose memory and obtain an advantage, or those suffer anxiety, melancholy, somnopathy or cognitive disorder person).Pharmaceutical compositions can comprise, for example, water, damping fluid are (for example, neutral buffered saline solution or phosphoric acid buffer saline solution), ethanol, mineral oil, vegetables oil, dimethyl sulfoxide (DMSO), carbohydrate (for example glucose, seminose, sucrose or dextran), N.F,USP MANNITOL, protein, adjuvant, polypeptide or amino acid (for example, Padil), antioxidant, sequestrant (for example, EDTA or gsh) and/or sanitas.Preferable pharmaceutical compositions is to be modulated into the form that can supply human or other animal (for example, companion animals such as dog or cat) oral administration.If need, also can comprise other activeconstituents, for example other CNS-promoting agent.
Pharmaceutical compositions can be modulated into the form that is applicable to any medication administration method, comprises, for example, part, per os, intranasal, rectum or parenteral dosing mode.That the employed parenteral dosing mode of this paper comprises is subcutaneous, in the intracutaneous, blood vessel in (for example intravenously), intramuscular, spinal cord, the head, in the spinal cavity and intraperitoneal injection, and any similar injection or infusion techn.In certain specific embodiments, preferable with the composition that is applicable to oral form.These forms comprise, for example, and the pulvis of lozenge, tablet, rhombus lozenge, water-based or oily suspensions, dispersiveness or granula, emulsion, hard or soft capsule or syrup or elixir.In other specific embodiment, composition of the present invention can be modulated into freeze-dried (lyophilizate).
For likable and good to eat preparation is provided, the composition that oral administration is given can further comprise one or more composition, for example sweeting agent, seasonings, tinting material and preservatives.Lozenge contains and physiologically acceptable activeconstituents applicable to the mixed with excipients of making lozenge.These vehicle comprise; for example; inert diluent (for example; lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate), granulation or disintegrating agent (for example; W-Gum or Lalgine), binding agent (for example; starch, gelatin or gum arabic) and lubricant (for example, Magnesium Stearate, stearic acid or talcum).Lozenge can be uncoated or its coating be prolonged its disintegration in enteron aisle and sorption thereby the effect of long-time persistence is provided via known technology.For example, can adopt the material of time expand, for example glyceryl monostearate or bi-tristearin.
Formula of oral also can be the form of hard gelatin capsule, wherein this activeconstituents is (for example to mix with inert solid diluent, lime carbonate, calcium phosphate or kaolin), or be the form of soft gelatin capsule, wherein this activeconstituents is to mix (for example, peanut oil, liquid paraffin or sweet oil) with water or oily medium.
Waterborne suspension is applicable to that by active substance and one or more mixed with excipients of making waterborne suspension is formed.These vehicle comprise suspension agent (for example, Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic); And dispersion or wetting agent (for example, spontaneous phosphatide (as Yelkin TTS), alkylene oxide compound alkylene oxide) with the condensation product (as polyoxyethylene stearic acid ester) of lipid acid, the condensation product of ethylene oxide and long-chain fat alcohols is (as 17 oxyethane hexadecanols (heptadecaethyleneoxycetanol), ethylene oxide and condensation product (as octadecanoic acid ester of polyethylene glycol) derived from the part ester class of lipid acid and hexitol, or ethylene oxide and derived from the condensation product (as polyethylene sorbitanic monoleate) of the part ester class of lipid acid and hexitan.Waterborne suspension also can comprise one or more sanitas, and for example, ethyl, n-propyl be right-hydroxy-benzoic acid, one or more tinting material, one or more seasonings and/or one or more sweeting agent, for example sucrose or asccharin.
Oily suspensions can modulation forms in vegetables oil (for example, peanut oil, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (for example, whiteruss) via activeconstituents is suspended in.This oily suspensions can contain thickening material, as beeswax, paraffinum durum or hexadecanol.Can add one or more sweeting agent and/or seasonings so that good to eat oral preparations to be provided.These suspension can be preserved by adding antioxidant (for example xitix).
Be suitable for by add water be made into the dispersed pulvis of aqueous suspension liquid formulation and granula provide with dispersion or wetting agent, suspension agent and one or more preservative blends in activeconstituents.Suitable dispersion or wetting agent and suspension agent are persons as mentioned above.Also can contain other vehicle, for example sweeting agent, seasonings and tinting material.
The composition pharmaceutical compositions also can be the form of oil-in-water emulsion.This oil phase can be vegetables oil (for example, sweet oil or peanut oil) or mineral oil (for example, whiteruss) or its mixture.Suitable emulsifying agent (for example can be spontaneous natural gum, gum arabic or tragacanth), spontaneous phosphatide (for example, soybean, Yelkin TTS, and derived from the ester class or the part ester class of lipid acid and hexitol), acid anhydrides (for example, sorbitol monooleate anhydrates) and derived from the part ester class of lipid acid and hexitol and the condensation product of ethylene oxide (for example, Tween 80).This emulsion also can contain sweeting agent and/or seasonings.
Syrup or elixir can be modulated with sweeting agent, for example glycerine, propylene glycol, sorbyl alcohol or sucrose.These prescriptions also can contain one or more negative catalyst, sanitas, seasonings and/or tinting material.
Also the composition pharmaceutical compositions can be made water-based or the oleagenous suspension that aseptic injection is used.According to employed supporting agent and concentration, this compound can be suspended or is dissolved in the supporting agent.These compositions can form according to knowing technology utilization such as above-mentioned suitable dispersion, wetting agent and/or suspension agent allotment.In acceptable supporting agent and solvent, can adopt water, 1,3 butylene glycol, Ringer's solution (Ringer ' s solution) and etc. the sodium chloride solution opened.In addition, also can adopt aseptic, nonvolatile oil as solvent or suspension medium.Can adopt any bland nonvolatile oil for this purpose, comprise synthetic list-or two (acid) glyceryl ester.In addition, in the preparation of composition for injection, can use lipid acid,, and adjuvant can be dissolved in the supporting agent as local anesthetic, sanitas and/or buffer reagent as oleic acid.
Also the composition pharmaceutical compositions can be made the form (for example, being applicable to rectal administration) of suppository.These compositions can be via being prepared medicine and suitable nonirritating mixed with excipients, and this vehicle is solid down in normal temperature, but be liquid under the temperature of rectum, so can dissolve in rectum and discharge medicine.Appropriate excipients comprises, for example, and theobroma oil and polyoxyethylene glycol.
In order to offer medicine to inhuman animal, said composition also can make an addition in the feed or drinking-water of animal.Composition allocated in the feed of animal or drinking-water can comparatively conveniently make this animal composition an amount of along with diet absorbs.Also said composition can be modulated into pre-composition to make an addition in feed or the drinking-water.
The composition pharmaceutical compositions can be modulated into persistence release formulation (that is, can reach the prescription (for example capsule) of slow release compound effect after the dispensing).These prescriptions are prepared via the technology of knowing, and via for example, and per os, rectum or subcutaneous implantation or the mode that is implanted to the position of being desired are offerd medicine.Employed carrier is to have biological compatibility in these prescriptions, and also can have Biodegradable; Preferably, this prescription provides the release of the active compound of relative constant density.The content of compound is to decide according to the character of the illness of implantation site, rate of release and desired lasting time of releasing and desire treatment or prevention in the persistence release formulation.
As above-mentioned, compound provided herein generally is to be present in the pharmaceutical compositions with the treatment significant quantity.The dose concentration scope that composition provides with every day per kilogram of body weight from about 0.1 milligram to about 140 milligrams preferable (every day every human patient be about 0.5 milligram to about 7 the gram).The content of activeconstituents is to change according to host and specific types of administration that desire is treated, and wherein this activeconstituents can combine with the supporting agent material and produce single formulation.General dosage unit form be contain from about 1 milligram to about 500 milligrams activeconstituents.Yet the optimal dosage that should be appreciated that any given patient is to decide according to the various factors, comprises the activity of the specific compound that is adopted; Patient's age, body weight, healthy situation, sex and diet; The time and the approach of dispensing; Discharge rate; Any treatment of carrying out simultaneously, for example combination of medicine; And the type of the specified disease of desiring to treat and severity.Can utilize routine test and the program known in this technology to set up ideal dosage.
Pharmaceutical compositions can be packed and be used for the treatment of the CNS disease for example anxiety, depression, somnopathy, aprosexia disease or cognitive disorder such as short term memory loss or Ah's Mohs lose intelligence.Pharmaceutical formulations through packing comprises the container of the compound described herein of depositing at least a treatment significant quantity and illustrates that contained composition is the specification sheets (for example label) that is used for the treatment of the CNS disease.
Using method
In particular aspects, the invention provides the method that is used to suppress the CNS disease progression.In other words, methods of treatment provided herein can be used for treating the disease of existence, perhaps the outbreak that can be used to prevent, reduce severity or delay these diseases in the patient who does not detect the CNS disease.Being described in detail as follows of CNS disease, with and can utilize the criterion of having set up in this technology to be diagnosed and monitor.Perhaps, in addition, compound provided herein can be thrown give to healthy patients to improve its short-term memory power or to cause sleep.The patient who handles with above-mentioned medication and therapeutic modality comprises the mankind, through the companion animals (pet, for example dog) and the domestic animal of domestication.
The frequency of medication can become according to the specified disease of the compound that uses and desire treatment or prevention.Usually, in the treatment of numerous diseases, administrated method with four times a day or following be good.As for the treatment of sleeping peacefully, then be enough to suppress GABA can in celiolymph, can reach fast external
AReceptors ligand and GABA
AThe single dose of the concentration of receptors bind is good.Generally be the result of treatment of utilizing the analytical method monitoring patient who is fit to an illness for the treatment of or preventing, this analytical method is known to those skilled in the art to be known.
In preferable specific embodiment, be that compound provided herein is used for the treatment of the patient that this demand is arranged.Usually, these patients are formula I compound (or its pharmacy acceptable salt) treatments with the treatment significant quantity; Being preferably this consumption is one or more symptom that is enough to change the CNS disease.Can be used as α
2β
3γ
2And α
3β
3γ
2The compound of the agonist of receptor subtype is specially adapted to treat anxiety lack of proper care for example Phobias, obsession and generalized anxiety disorder; Stress disorders comprises stress disorders and acute stress disorders after the wound.Can be used as α
2β
3γ
2And α
3β
3γ
2The compound of the agonist of receptor subtype also is specially adapted to treat depressed dysthymia disorders or manic depressions, schizophrenia and somnopathy, and can be used for treating age related cognitive decline and Ah's Mohs disease.Can be used as α
5β
3γ
2Receptor subtype or α
1β
2γ
2And α
5β
3γ
2The compound of the reverse agonist of receptor subtype is specially adapted to treat cognitive disorder and comprises those by Down syndrome, the neurodegenerative disorders relevant dementia that causes of Ah's Mohs disease, Parkinson's disease and apoplexy for example.As α
5β
3γ
2The compound of the reverse agonist of receptor subtype can pass through hypermnesis, especially short-term memory, and is specially adapted to treat the cognitive disorder of remembering among the patient who damages; And can be used as α
5β
3γ
2The compound of the agonist of receptor subtype then is specially adapted to bring out the loss of memory.Can be used as α
1β
2γ
2The compound of the agonist of receptor subtype is specially adapted to treat for example epilepsy of somnopathy and spasm.The compound that can be used as the antagonist in: benzodiazepine site is to be applicable to the effect that reverse is caused because of excessive use: benzodiazepine and to be applicable to medicine habituation and alcohol dependence.
The CNS disease that can use compound provided herein and composition to be treated comprises:
Depressed, the depressed depressive period of the depressed dysthymia disorders of major depressive disorder (major depression), spirit depressing phobia, (dysthymicdisorder), atypia, manic depressions, manic depressions for example.
Anxiety disorder, for example generalized anxiety disorder (GAD), agoraphobia, Phobias+/-agoraphobia, social phobia, specific fear disease, wound after stress disorders, obsession (OCD), spirit depressing phobia, the acute stress disorders of adjustment disorder, separation anxiety disorder, anticipatory anxiety, adjustment disorder, the cyclothymia disfunction that cause by the interference of mood and anxiety.
Somnopathy, for example primary insomnia, daily rhythmicity sleep disease, dyskoimesis NOS, Parasomnias, the somnopathy that somnopathy that comprise nightmare disease, night terror, is caused by depression and/or anxiety or other mental illness and medicine cause.The representative symptom of medicable somnopathy comprises, for example, have difficulty in going to sleep, excessively clear-headed during night, too getting up early and clear-headed sensation do not rejuvenate.
Cognitive disorderFor example, the dementia followed of Ah's Mohs disease, Parkinson's disease, mild cognitive impairment (MCI), age related cognitive decline (ARCD), apoplexy, traumatic brain injury, AIDS, the dementia (comprising schizophrenia and paranoea) followed with depressed, anxiety or psychosis.
Aprosexia disease, for example, aprosexia disease (ADD) and absorbed power deficiency and Attention Deficit Hyperactivity Disorder (ADHD).
AphasisFor example, action type twitch (motor tic), dysarthria syllabaris spasmodica (clonicstuttering), speak not smooth (dysfluency), talk retardance (speech blockage), eat (dysarthria), Tourette syndrome (Tourette ' s syndrome) and logoklony (logospasm).
Compound provided herein and composition also can be used for improving patient's short-term memory (working memory).Preferable treatment significant quantity in order to the compound that improves short term memory loss is to be enough to cause in any standard test of short-term memory function statistics to go up the dosage that significantly improves, and this standard test comprises digital distance test (Forward Digit Span) forward and series is learnt study (serialrote learning) by heart.For example, these tests are to be designed for the ability that evaluating patient is recalled individual character or letter.Perhaps, can use more complete nervous physiology assessment with calibrating short-term memory function.Through the patient of treatment, it may be in order to improve short-term memory, but not necessarily need to be diagnosed as the person that has the memory impairment or think that this kind impairer might be taken place for it.
On the other hand, the invention provides the method for the effect (or result of treatment) that is used to strengthen other CNS medicament.These methods comprise uniting throws compound that this paper provided that gives the treatment significant quantity and other CNS medicament for the treatment of significant quantity.These other CNS medicaments comprise, but non-ly are limited to person what follows: be used for the anxiety aspect, serotonin receptor (for example, 5-HT
1A) agonist and antagonist; Be used for anxiety and depressed aspect, neural hormone receptor antagonists or adrenocortical hormone releasing hormone acceptor (CRF
1) antagonist; Be used for the somnopathy aspect, the Melatonin receptor agonists; And be used for neurodegenerative disorders, for example Ah's Mohs is sick dull-witted, is nicotine agonist, poisonous fungus alkaline agent, acetylcholinesterase depressant and Dopamine Receptors agonist.In particular specific embodiment, the invention provides the active method of antidepressive that strengthens selective serotonin reuptake inhibithors (SSRIs), this method is the common GABA that this paper provided that gives the treatment significant quantity that throws
AAgonist compound and SSRI.Throw when giving when compound and other CNS medicament are common, the treatment significant quantity of compound is compared to other CNS pharmaceutical treatment patient of independent use, be enough to cause in patient's Yu the symptom can detected change amount.
The present invention is also about suppressing the method for: benzodiazepine compound (that is, have the compound of: benzodiazepine ring structure), for example RO15-1788 or GABA) and GABA
AReceptors bind.These methods comprise makes performance GABA
AThe cell of acceptor contacts with compound provided herein, and wherein this compound concentrations is to use the 6 described analytical methods as embodiment, is enough in vitro inhibition GABA
AReceptors ligand is bonded to GABA
AThe concentration of acceptor.This method comprises, but non-being limited to suppressed: benzodiazepine compound and GABA in body
AReceptors bind (for example, is thrown the GABA that this paper provided that gives specified quantitative to patient
AReceptor modulators, and make this throwing amount of giving can cause the compound concentration in the celiolymph to be enough in vitro inhibition: benzodiazepine compound or GABA and GABA
AReceptors bind).In a specific embodiment, these methods are to be of value to the excessive: benzodiazepine medicine person of treatment picked-up.Be enough to suppress: benzodiazepine compound and GABA
AThe GABA of receptors bind
AThe amount of receptor modulators can be easily via embodiment 6 described GABA
AThe decision of receptor binding assay method.
On the other hand, the invention provides GABA as herein described
AThe various external purposes of receptor modulators.For example, these compounds can be used as and detect in sample (for example tissue slice) and location GABA
AThe probe of acceptor, in receptor active is analyzed as positive controls, in measuring candidate agent and GABA
AIn the ability of receptors bind as standard substance and reagent or in positron tomoscan (positron emission tomography, PET) image or single photon computed tomography (single photon emission computerized tomography, SPECT) in as radioactive tracer.These analytical methods can be used for identifying the GABA among the receptor alive
AAcceptor property.These compounds also can be in measuring and GABA
ADuring the ability of the potential drug of receptors bind as standard substance and reagent.
In detecting sample, whether there is GABA
AIn the method for acceptor, be to allow compound and GABA
AUnder the condition of receptors bind, sample is cultivated with compound provided herein.Detect then and GABA
AThe amount of the compound of receptors bind.For example, this compound can utilize that various to know technology (for example, as described herein, with the radioactive rays nuclear species, for example tritium carries out the radioactive rays mark) mark in addition, cultivate together with sample (it can be, for example, the culturing cell of preparation, tissue preparation thing or its fragment) then.Suitable incubation time can be decided by analyzing the combination degree that is taken place in for some time usually.After the cultivation, unconjugated compound is removed, and utilize any method that is applicable to the marker that is adopted to detect the bonded compound (for example, through the automatic radiography or the scintillation counting that compound was suitable for of radioactive rays mark; Spectroscopic analysis can be used for detecting luminophore and fluorescent group).As for control group, paired sample (matchedsample) is contacted with compound through the un-marked of the compound of radioactive rays mark and more amount.In kind remove through tagged compound and un-marked compound then, and detect through the bonded marker with unconjugated.If in test sample, detect, there is GABA in the expression sample than detectable more than control group
AAcceptor.The check and analysis method comprises the GABA in cultured cells or the tissue samples
AThe automatic radioautography of the acceptor of acceptor (receptor mapping) is can be according to Kuhar in Current Protocols in Pharmacology (1998) John Wiley ﹠amp; Sons, described the carrying out of 8.1.1 to 8.1.9 joint among the New York.
For example, compound provided herein can be used for detecting the GABA in the cell or tissue sample
AAcceptor.This can utilize before not and GABA
AThe paired cell or tissue sample of receptor modulators contact and finishing, wherein at least one are to be to organize sample in contrast as experiment sample and at least one.Experiment sample is via (the GABA in allowing RO15-1788 and cell and tissue samples
AUnder the condition of receptors bind) with sample with contact through the formula I of detectable label compound and prepare.Check sample is to prepare in the mode identical with experiment sample, and just it also contact with the compound of un-marked, should be greater than the concentration through the instrumentality of mark without volumetric molar concentration of the compound of sign.
Wash this experiment and control group sample then and remove the compound of unconjugated detectable label.The content of the compound of detectable label in the content of the compound of the detectable label of bonded that measurement is remaining and comparative experiments and the control group sample.Detected result shows the detectable that contains more amount through the check sample of experiment sample ratio through washing of washing, has GABA in the expression experiment sample
AAcceptor.
The GABA of employed detectable label in this step
AReceptor modulators can be through radioactive rays marker mark or directly or indirectly with the luminescent marking substance markers.When the section of this step using-system, and this marker is the radioactive rays markers, can use automatic radiography to detect this bonded tagged compound.
Compound provided herein also can be used in the various cell cultures of knowing and cell isolation method.For example, compound is connected to the surface, inside of tissue culture dish or other cell cultures upholder, to be used for fixing performance GABA
AThe cell of acceptor and in cultivating, screen, analyze and grow.This binding can utilize any suitable technology to carry out, for example above-mentioned method, and other standard technique.In external, compound can be used for helping cell identification and screening, can show GABA to select
AThe cell of acceptor.As above-mentioned, the compound that uses in these methods is preferably and is labeled.In a preferred embodiment, to be connected to the fluorescent sign, luciferin (fluorescein) for example, compound and cells contacting, (fluorescence activated cell sorting FACS) analyzes via fluorescent activatory cell screening method then.
In others, the invention provides and in external or body, regulate part and GABA
AThe method of receptors bind, it is included under the condition that is fit to part and receptors bind, with GABA
AThe GABA that this paper provided of acceptor and capacity
AThe receptor modulators contact.This GABA
AIn that acceptor can exist in solution, cultivate or the isolated cells prepared product or among patient Yu.This GABA
AAcceptor is preferably and is present in the mammiferous brain.Generally, the amount of the compound that contacts with acceptor should be enough in, for example in the embodiment 6 described binding analysis methods, in external adjusting part and GABA
AThe combination of acceptor.
This paper also provides and changes cell GABA
AThe method of the signaling activity of acceptor (especially chlorion conduction) is no matter this method is in external or body, under the condition that is fit to flumazenil and receptors bind, with GABA
AAcceptor contacts with the above-claimed cpd of capacity.This GABA
AIn that acceptor can exist in solution, cultivate or the isolated cells or in the cell membrane preparations or among patient Yu, and the amount of this compound is to be enough in external change GABA
AThe amount of the signaling activity of acceptor.In certain specific embodiments, the amount of the compound that contacts with acceptor or concentration should be enough in, for example in the embodiment 6 described binding analysis methods, in external adjusting flumazenil and GABA
AThe combination of acceptor.The electrophysiological change that the influence of signaling activity be can be used as cell utilizes standard technique to detect.This is enough to change GABA
AThe amount of the compound of the signaling activity of acceptor or concentration can be passed through GABA
AThe single conduction analytical method of acceptor as embodiment 7 described analytical methods, is measured.In body, can show GABA
AThe cell of acceptor is, but non-being limited to, neurocyte or brain cell.By contacting with the body fluid that contains compound (for example by with celiolymph), these cells can contact with the compound that one or more this paper is provided.In external, when there is down with after compound of the present invention contacts GABA in the cell in these cells in GABA
AThe change of the signaling activity of acceptor can show GABA certainly
ADetected change in the electric physiology of the cell of acceptor and deciding.
Can use intracellular recording method (intracellular recording) or diaphragm embedding system writing-method (patch-clamp recording) that the electrophysiological change of cell is given quantitatively.Give the animal of The compounds of this invention through throwing, the change that repeats in its behavior can be considered the cell of this animal, and (this cell can show GABA
AAcceptor) electric physiology changes.
The preparation of compound
Compound provided herein generally is to utilize the standard synthetic method to be prepared.Usually starting raw material can be buied by commercial source easily, for example Sigma-Aldrich Corp. (St.Louis, MO), perhaps as described herein the preparation.The exemplary steps that is applicable to preparation I compound is summarized in the following diagram, but category of the present invention or spirit should be limited to particular agent shown in the diagram and condition.It will be understood by a person skilled in the art that and to change this reagent or condition and also be included among the present invention for preparation other step that compound adopted.In some example,, must protect to have reactive functional moiety for reaching required conversion.Generally speaking, ripe people in organic synthesis technology all understands the group that needs protection, and the attached and condition that removes of these groups.Variable symbol in the following diagram is meant any group that meets the explanation of compound provided herein.
Following diagram and as follows together with the abbreviation of using among the embodiment:
The abbreviation of using
The Bu butyl
Bu
3The Sn tributyl tin
CDCl
3The deuterate chloroform
The CNBr cyanogen bromide
The δ chemical shift
The DCM methylene dichloride
The DME ethylene glycol dimethyl ether
DMF N, dinethylformamide
DPPF 1,1 '-two (diphenylphosphine) two luxuriant (network) iron
The EtOAc vinyl acetic monomer
EtOH ethanol
Eq. equivalent
HOAc acetic acid
HPLC high pressure liquid chromatography (HPLC) method
1H NMR proton nucleus magnetic resonance
The Hz hertz
LC/MS liquid chromatography (LC)/mass spectrum
MeOH methyl alcohol
The MS mass spectrum
M+1 quality+1
The NaOEt Sodium Ethoxide
The NMP 1-Methyl-2-Pyrrolidone
The n-BuLi n-Butyl Lithium
Palladium on the Pd/C C catalyst
Pd (PPh
3)
4Tetrakis triphenylphosphine palladium (0)
Pd (Ph
3P)
2Cl
2Two (triphenylphosphine) palladiums (II) of dichloro
Pd
2(dba)
3Three (dibenzenyl acetone) two palladiums (0)
Ph
3P (or PPh
3) triphenylphosphine
The Py pyridine
PTLC prepares the type thin layer chromatography
The THF tetrahydrofuran (THF)
The TLC thin layer chromatography
Reaction scheme
Intermediate product 6-chloropyrimidine compound 13 is to prepare from brooethyl or chloromethyl compound 5 and 9 as described in diagram 1.Ester 1 is to reach with excessive sodium methoxide processing in owing to MeOH with the condensation reaction of amidine 2.With POCl
3Handle 3 and can get chloro-pyrimidine 4, it can be with Br under 85 ℃, in HOAc
2Carry out bromination and convert brooethyl pyrimidine 5 to.Similarly, ethyl ester 10 can be handled and finish with the Sodium Ethoxide that is dissolved among the EtOH easily with the condensation reaction of oxalic acid diethyl ester 11.With the diester 6 of gained and suitable amidine 2 and excessive K
2CO
3Reaction under EtOH refluxes is to get pyrimidone 7 (pyrimidinone 7).With 7 transformations that convert 6-chloro-pyrimidine ester 8 to is with POCl under 85 ℃
3Handle and finish.Then with compound 8 via NaBH
4Reduction is converted to chloromethyl pyrimidine 9 with the thionyl chloride processing subsequently.Then bromide 5 or muriate 9 are reached K in DMF
2CO
3Following and imidazoles 12 reactions of excessive existence get compound 13.
Diagram 2 explanations are from the method for the compound of compound 13 synthesis types 17.In 70 ℃ of following DMF with 13 with NaN
3Handle a night and get corresponding 4-nitrine-pyrimidine compound 14, it can convert amino-pyrimidine 15 to via hydrogenization.At last, compound 15 and various α-bromines (chlorine) aldehydes or ketone 16 are reacted in DMF, and get desired imidazoles condensed pyrimidine compound 17.
The compound that replaces through 2-or 3-cyano group be as described in the diagram 3 from corresponding ester class preparation and get.Ester class 18 or 19 (making according to diagram 2) is handled in EtOH with excess of ammonia, aminate 20 and 21, its can via with excessive POCl
3In pyridine, stir and convert cyano compound 22 and 23 to.
Synthesizing of diagram 4 explanation [1,2,4] triazolo [1,5-c] miazines 27.With compound 13 with hydrazine handle intermediate product 24.The effect that converts compound 24 to compound 27 be in condition A to E down by intermediate product 25 (non-compound, 1,2,4-triazolo [4,3-c] miazines) through resetting and through the spit of fland if reset (Dimroth rearrangement) 26 and reach.According to R
2Character adopt various condition.Generally speaking, work as R
2During for not interrupted aliphatic group, be employing condition A; Work as R
2During for aryl, adopt condition B; And work as R
2During for interrupted aliphatic group, be to adopt condition C.[1,2,4] triazolo [1,5-c] miazines that employing condition D can replace through amino (27, R
2=NH
2), and [1,2,4] triazolo [1,5-c] miazines that when employing condition E, can replace through hydroxyl (27, R
2=OH).Under all these conditions, all need finish rearrangement reaction to obtain product 27 through resetting.If the demand as enumerating among the embodiment can further be handled the R in 27
2Group.
Be the product of synthetic non-rearrangement, adopt 1,2,4-triazolo [4,3-c] miazines 25 and relatively mild condition are carried out as diagram 5 described cyclic actions.Therefore, compound 25 is according to substituting group (R
3, R
4And R
5) the character and the availability of starting raw material prepared by 24 by various conditions (the condition A to C in the diagram 5).Generally speaking, be with excessive corresponding R with hydrazine class compound 24
3C (OR)
3Or solvent-free acid anhydrides (condition A and C) is handled.The scope of temperature of reaction is according to R
3, R
4And R
5Character from 50 ℃ to 100 ℃.In R
3Under the situation of=H, cyclic action is to carry out 5 to 10 minutes (condition B) with acetic acid diethoxy methyl esters and finish under room temperature.In order to form through 1,2 of difference replacement, the various conditions of 4-triazolo [4,3-c] miazines 25 are described in more detail in the following example.
Hydrazine class compound 24 enlarges through the described cyclization reagents of diagram 5 also can produce 1,2 after handling, 4-triazolo [1,5-c] miazines 27 (by the spit of fland if reset).Consistent (Brown and Nagamatsu (1977) Australian J.Chem.30:2515 with reported literature; Reach the document that Brown and Nagamatsu (1978) Australian J.Chem.31:2505 and this paper quote), 1,2,4-triazolo [4,3-c] miazines 25 is rearranged into 1,2,4-triazolo [1,5-c] effect of miazines 27 is to carry out via various conditions, comprises with acid or alkaline purification, and even with R
3C (OR)
3Enlarge and handle.In addition, as described in diagram 4, the condition of reaching transformation heats in carboxylic acid for (1); (2) handle hydrazine class compound 24 with aldehyde, then in acetic acid with bromine reaction; (3) with hydrazine class compound 24 with the acid anhydrides acidylate, then with POCl
3Handle; (4) hydrazine class compound 24 is heated with cyanogen bromide; And heat hydrazine class compound 24 in NMP (5) with urea.
Isomerized products 1,2,4-triazolo [4,3-c] miazines 25 and 1,2,4-triazolo [1,5-c] miazines 27 can be separated by PTLC or tubing string chromatography easily.As herein described 1,2,4-triazolo [4,3-c] miazines 25 has more polarity than its corresponding isomer 27.As herein described all 1,2,4-triazolo [4,3-c] miazines 25 also can be via it
1H NMR spectrum distinguishes from its isomer 27 easily.As herein described 1,2, the structure of 4-triazolo [4,3-c] miazines 25 is further via it being become its corresponding isomer 27 with 0.1N HCl treatment conversion under room temperature and confirming.
The synthetic method of diagram 6 explanation imidazoles condensed miazines 30.In Pd (Ph
3P)
2Cl
2Under the coupling condition, with intermediate product 13 and the coupling of tributyl tin vinyl ethyl group, then be hydrolyzed ketone 28.Ketone 28 is handled with methane amide and formic acid, then with POCl
3Carry out cyclic action and get compound 30.
Compound can utilize when synthetic and contain the precursor of at least one radio isotope atom and carry out radio-labeling.Each radio isotope (for example, is preferably carbon
14C), hydrogen (for example,
3H), sulphur (for example,
35S) or iodine (for example,
125I).Also can homogeneous phase-catalytic exchange gives catalytic preparation as being subjected to matter to carry out not with tritium gas by carrying out palladium-catalytic exchange in the acetic acid of tritiate, carry out acid-catalytic exchange or utilize this compound in the trifluoracetic acid of tritiate through tritium-labeled compound.In addition, optionally can make some precursor carry out following processing: to carry out the tritium gas reductive action of tritium-halogen exchange, unsaturated link(age) or the reductive action of use boron tritiate sodium with tritium gas.Preparation through radiolabeled compound can be carried out through radiolabeled probe compound easily via the customized especially synthetic of radio isotope supplier.
The following example that provides is the purpose that is used to explain orally and should not limit the present invention with it.Unless otherwise specified, all reagent and solvent are that the class of trade of standard and use need not be further purified.Starting raw material as herein described and intermediate product generally are to be prepared by the synthetic method that commercial source is buied, known by commercially available organic compound preparation or utilization.
[embodiment]
Starting raw material described in the following example and various intermediate product can be buied by commercial source, by commercially available organic compound preparation or utilize known synthetic method preparation.The representative embodiment that is applicable to the method for preparation intermediate product of the present invention also is presented below.
In the following example, the LC-MS condition that is used to describe this paper compound characteristic is:
1. analysis mode HPLC/MS instrument: the Pu (WatersCorporation of group that utilizes Waters 600 series, Milford, MA), Waters 996 diode arrays formula detectors (Diode ArrayDetector) and Gilson 215 self-actuated samplers (Gilson Inc, Middleton, WI), Micromass
LCT flight time formula EFI spills free spectrometry mass (time-of-flightelectrospray ionization mass analyzer) and analyzes.Utilize MassLynx
TM4.0 software is obtained data, and utilizes OpenLynx Global Server
TM, OpenLynx
TMAnd AutoLynx
TMHandle.
2. analysis mode HPLC condition: 4.6 * 50 millimeters, Chromolith
TMThe SpeedRODRP-18e tubing string (Merck KGaA, Darmstadt, Germany); 10 spectrum/seconds of UV, 220-340 millimicron summation; 6.0 milliliters of part clocks of flow velocity; Volume injected 1 microlitre;
Gradient condition-mobile phase A is 95% water, 5%MeOH and 0.05%TFA; Mobile phase B is 95%MeOH, 5% water and 0.025%TFA, and this gradient 0 to 0.5 minute was 10 to 100%B, kept 1.2 minutes in 100%B, again returning back to 10%B in 1.21 minutes, every injection-to-the infusion cycles time (inject-to-inject cycle time) is 2.15 minutes.
3. analysis mode MS condition: capillary voltage (capillary voltage) 3.5kV; Awl voltage (conevoltage) 30V; Desolvate and source temperature (desolvation and source temperature) is respectively 350 ℃ and 120 ℃; It is that to postpone (inter scan delay) be 0.05 minute for 0.22 second and scanning room that mass range 181 to 750 has sweep time.
Synthesizing of embodiment 1. imidazos [1,2-c] miazines
A.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine (106)
The preparation of step 1.5-propyl group-6-methyl-pyrimidin-4-one (100)
Under room temperature, NaOMe (1.30 gram, 24 mmoles) added to carbonamidine (formamidine) (12 mmole) in MeOH (75 milliliters) in stirred solution.Stirred this mixture 15 minutes.Add 2-ethanoyl-methyl valerate (10 mmole) and under room temperature, stir the mixture a night.Add acetic acid (0.72 gram, 12 mmoles) and move down and desolventize in vacuum.In resistates, add entry (30 milliliters) and extract with 2-butanone (3 * 30 milliliters).With the extract that merges with salt solution (40 milliliters) washing, dehydration (Na
2SO
4) and evaporation, getting yellow solid (100), it need not be further purified and promptly can be used for next step.
The preparation of step 2.5-propyl group-4-chloro-6-methyl-pyrimidine (101)
In 85 ℃ of heating 100 (10 mmole) and POCl
3The mixture of (25 milliliters) 4 hours.Move down in vacuum and to desolventize and in resistates, add EtOAc (30 milliliters) and water (30 milliliters).Add NaHCO carefully
3Up to the pH of water layer greater than 7.Extract with EtOAc (2 * 30 milliliters) with each layer separation and with water layer.With the extract that merges with salt solution (50 milliliters) washing, dehydration (Na
2SO
4) and evaporation.This resistates was with 6: 1 EtOAc: hexane carries out quick tubing string purification, so that the product that is faint yellow oily (101) to be provided.
The preparation of step 3.5-propyl group-6-brooethyl-4-chloro-pyrimidine (102)
Under 85 ℃ of heating with Br
2(1.28 gram, 8 mmoles) drop to 101 in HOAc (20 milliliters) in stirred solution.After the dropping, mixture was heated 1 hour down in 85 ℃.Move down in vacuum and to desolventize, and in resistates, add EtOAc (25 milliliters) and NaHCO
3(25 milliliters).With each layer separation and organic layer is first with Na
2S
2O
3Solution (saturated 15 milliliters) then washs with salt solution (20 milliliters).Make organic phase dehydration (Na
2SO
4) and evaporation.The quick tubing string of yellow oil utilization (6: 1 EtOAc, hexane) of gained is carried out purifying so that the product that is faint yellow solid (102) to be provided.
Step 4.6-chloro-4-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 5-propyl group-pyrimidine (103)
As U.S. patent application case 10/038, No. 069 embodiment 16 is described, preparation 6-fluoro-2-(1H-imidazoles-2-yl)-pyridine, the applying date of this application case is December 12 calendar year 2001 and open with No. 2003/0069257, U.S. on April 10th, 2003, and it is to examine data with three to integrate with this paper in the 31st page of synthetic method about this compound that is disclosed.Stirring 102 or 5-propyl group-6-chloromethyl-4-chloro-pyrimidine (being all 1 mmole), 6-fluoro-2-(1H-imidazoles-2-yl)-pyridine (163 milligrams, 1 mmole) and K under room temperature
2CO
3(552 milligrams, 4 mmoles) one night of mixture in DMF (6 milliliters).Move down in vacuum and to desolventize and in resistates, add EtOAc (10 milliliters) and water (10 milliliters).With each layer separation and with EtOAc (10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (10 milliliters) washing, dehydration (Na
2SO
4) and evaporation.Resistates is dissolved in CH with 5%
2Cl
2In MeOH carry out the PTLC centrifugation, can get the product (103) of white solid.
Step 5.6-nitrine-4-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 5-propyl group-pyrimidine (104)
With 103 (2.25 mmole) and NaN
3DMF (15 milliliters) solution of (731 milligrams, 11.25 mmoles) heats a night with 70 ℃ in the test tube of sealing.Vacuum moves down and desolventizes and add entry (10 milliliters) and EtOAc (10 milliliters) in resistates.With each layer separation and with EtOAc (2 * 10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (15 milliliters) washing, with Na
2SO
4Dehydration.Vacuum moves down and desolventizes, and the yellow oil of gained (104) need not be further purified and promptly can be used for next step.
Step 6.6-amino-4-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 5-propyl group-pyrimidine (105)
In solution, add Pd/C (10%, 10 milligram) in the MeOH of 104 (2 mmoles) (20 milliliters).H in 30psi
2Under stirred this mixture 4 hours.Remove this catalyzer and this filtrate of evaporation under vacuum via filtration.The faint yellow solid of gained (105) need not be further purified and promptly can be used for next step.
Step 7.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 8-propyl group-imidazo [1,2-c] pyrimidine (106)
105 (1.2 mmoles) and the solution of monochloroacetaldehyde (1 milliliter) in DMF (10 milliliters) are heated a night with 70 ℃ in the test tube of sealing.Vacuum moves down and desolventizes and add EtOAc (15 milliliters) and water (15 milliliters) in resistates.With each layer separation and with EtOAc (15 milliliters) aqueous layer extracted.The extract that merges is with salt solution (15 milliliters) washing, dehydration (Na
2SO
4) and evaporation.With resistates to be dissolved in CH
2Cl
2In 10%MeOH carry out the PTLC centrifugation, can get the title compound (106) of white solid.
1H-NMR(CDCl
3)δ:8.78(s,1H),8.11(dd,1H),7.83(q,1H),7.65(d,1H),7.56(d,1H),7.18(d,1H),7.15(d,1H),6.83(dd,1H),6.04(s,2H),3.07-3.13(m,2H),1.62-1.72(m,2H),0.99(t,3H).
B. other imidazo [1,2-c] miazines is synthetic
Compound shown in the table 1 is to synthesize by diagram 1 and 2 methods that provide and further illustrated by embodiment 1A.All compounds in the table 1 all can represent the Ki less than 1 micro-molar concentration in the part binding analysis method of embodiment 6, as compound 106 (above-mentioned) and 119,127 and 129 (following).
Table 1
C.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-methyl-8-propyl group-imidazo [1,2-c] pyrimidine (119)
The preparation of step 1.2-oxo base-3-propyl group-ethyl succinate (120)
Under room temperature, the mixture of Valeric acid ethylester (0.4 mole) with oxalic acid diethyl ester (compound 11 in the diagram 1) (73.1 grams, 0.5 mole) added in EtOH (250 milliliters) solution of NaOEt (32.7 grams, 0.48 mole).Under room temperature, stir this mixture 30 minutes and distill and remove EtOH.Then via this resistates of vacuum distilling purifying, so that clarification buttery product (120) to be provided.
The preparation of step 2.2-methyl-5-propyl group-6-hydroxyl-pyrimidine-4-carboxylic acid, ethyl ester (121)
Heat 120 (20 mmoles), acetamidine hydrochloride (40 mmole) and K down in 70 ℃
2CO
3(6.9 grams, 50 mmoles) one night of mixture in EtOH (50 milliliters).With solid filtering and with in the resistates water-soluble (30 milliliters).Add acetic acid pH is adjusted into 4.Then with mixture with CH
2Cl
2(4 * 50 milliliters) extract and the extract that merges are washed with salt solution (100 milliliters).With solution dehydrates (Na
2SO
4) and under vacuum, evaporate, getting faint yellow solid (121), it can be directly used in the next step.
The preparation of step 3.2-methyl-5-propyl group-6-chloro-pyrimidine-4-carboxylic acid, ethyl ester (122)
Heat 121 (10 mmole) and POCl down in 85 ℃
3The mixture of (25 milliliters) 4 hours.Vacuum moves down and desolventizes and add EtOAc (40 milliliters) and water (30 milliliters) in resistates.Add NaHCO carefully
3Up to the pH of water layer greater than 7.With each layer separation and with EtOAc (2 * 30 milliliters) aqueous layer extracted.The extract that merges is with salt solution (50 milliliters) washing, dehydration (Na
2SO
4) and evaporation.The quick tubing string of resistates utilization (3: 1 EtOAc, hexane) is carried out purifying so that the product that is faint yellow oily (122) to be provided.
The preparation of step 4.2-methyl-5-propyl group-4-chloromethyl-6-chloro-pyrimidine (123)
With NaBH
4(91 milligrams, 2.4 mmoles) add in MeOH (10 milliliters) solution of 122 (0.48 mmoles), are cooled to 0 ℃, then mixture are stirred a night under room temperature.Vacuum moves down and desolventizes and add entry (10 milliliters) and EtOAc (10 milliliters) in resistates.With each layer separation and with EtOAc (10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (20 milliliters) washing, dehydration (Na
2SO
4) and evaporation.Light color oily matter with gained is dissolved in CH then
2Cl
2In (5 milliliters) and add thionyl chloride (1 milliliter).This mixture was stirred under room temperature 4 hours.Remove solvent then.In resistates, add EtOAc (15 milliliters) and with NaHCO
3(15 milliliters) and salt solution (15 milliliters) washing, dehydration (Na then
2SO
4) and evaporation.The quick tubing string chromatography of resistates utilization is carried out purifying be the product (123) of being with yellow oily to provide.
Step 5.4-chloro-6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-methyl-5-propyl group-pyrimidine (124)
With 123 (1 mmoles), as 6-fluoro-2-(1H-imidazoles-2-the yl)-pyridine (163 milligrams, 1 mmole) and the K of above-mentioned preparation
2CO
3(552 milligrams, 4 mmoles) mixture in DMF (6 milliliters) stirs a night under room temperature.Vacuum moves down and desolventizes and add EtOAc (10 milliliters) and water (10 milliliters) in resistates.With each layer separation and with EtOAc (10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (10 milliliters) washing, dehydration (Na
2SO
4) and evaporation.With resistates to be dissolved in CH
2Cl
2In 5%MeOH carry out the PTLC centrifugation, can get the product (124) of white solid.
Step 6.4-nitrine-6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-methyl-5-propyl group-pyrimidine (125)
With 124 (2.25 mmole) and NaN
3(731 milligrams, 11.25 mmoles) solution in DMF (15 milliliters) heats a night with 70 ℃ in the test tube of sealing.Vacuum moves down and desolventizes and add entry (10 milliliters) and EtOAc (10 milliliters) in resistates.With each layer separation and with EtOAc (2 * 10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (15 milliliters) washing, with Na
2SO
4Dehydration.Vacuum moves down and desolventizes, and the yellow oil of gained (125) need not be further purified and promptly can be used for next step.
Step 7.4-amino-6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-methyl-5-propyl group-pyrimidine (126)
In 4-nitrine-6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-add Pd/C (10%, 10 milligram) in MeOH (20 milliliters) solution of 2-methyl-5-propyl group-pyrimidine (2 mmole) (125) and in the H of 30psi
2Under stirred this mixture 4 hours.Filtration removes this catalyzer and this filtrate of evaporation under vacuum.The faint yellow solid of gained (126) need not be further purified and promptly can be used for next step.
Step 8.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 5-methyl-8-propyl group-imidazo [1,2-c] pyrimidine (119)
126 (1.2 mmoles) and the solution of monochloroacetaldehyde (1 milliliter) in DMF (10 milliliters) are heated a night with 70 ℃ in the test tube of sealing.Vacuum moves down and desolventizes and add entry (15 milliliters) and EtOAc (15 milliliters) in resistates.With each layer separation and with EtOAc (15 milliliters) aqueous layer extracted.The extract that merges is with salt solution (15 milliliters) washing, dehydration (Na
2SO
4) and evaporation.With resistates to be dissolved in CH
2Cl
2In 10%MeOH carry out the PTLC centrifugation, can get the title compound (119) of white solid;
LC-MS,M+1?351.1;
1H-NMR(CDCl
3)δ:8.10(dd,1H),7.85(q,1H),7.66(d,1H),7.44(d,1H),7.20(d,1H),7.12(d,1H),6.86(dd,1H),6.02(s,2H),3.01-3.07(m,2H),2.69(s,3H),1.60-1.67(m,2H),0.94(t,3H).
D.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-2-nitrile (127) synthetic
Step 1.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 8-propyl group-imidazo [1,2-c] pyrimidine-2-carboxylic acid amide (128)
Under 0 ℃ with ammonia by being sealed in 7-[2-(the 6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl in the test tube through stirring]-8-propyl group-imidazo [1,2-c] pyrimidine-2-carboxylic acid, ethyl ester (110, above-mentioned) (1 mmole) is in the solution of EtOH (7 milliliters) 20 minutes.Heated 2 days down with the test tube sealing and in 90 ℃ then.Solvent evaporation and resistates (128) need be further purified be directly used in next step.
Step 2.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 8-propyl group-imidazo [1,2-c] pyrimidine-2-nitrile (127)
In pyridine (3 milliliters) solution of 128 (0.75 mmoles), add POCl
3(0.5 milliliter) also stirs one night of this mixture under room temperature.With solvent evaporation and resistates is to utilize PTLC (5%MeOH is in CH
2Cl
2) carry out purifying, get product (127);
LC-MS,M+1?362.1;
1H-NMR(CDCl
3)δ:8.77(s,1H),8.11(dd,1H),8.03(s,1H),7.82(q,1H),7.19(s,1H),7.18(s,1H),6.82(dd,1H),6.03(s,2H),3.11-3.17(m,2H),1.67-1.75(m,2H),1.01(t,3H).
E.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-3-nitrile (129)
This compound is as described in above-mentioned diagram 1 and 3 and further synthetic as the illustrated person of embodiment 1D.
LC-MS,M+1?362.1;
1H-NMR(CDCl
3)δ:8.95(s,1H),8.17(s,1H),8.14(dd,1H),7.83(q,1H),7.21(s,1H),7.20(s,1H),6.82(dd,1H),6.09(s,2H),3.17-3.22(m,2H),1.68-1.75(m,2H),1.01(t,3H).
Embodiment 2.[1,2,4] triazolo [1,5-c] miazines is synthetic
A.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (130)
The preparation of step 1.3-fluoro-2-(1H-imidazoles-2-yl)-pyridine
When synthetic as following prepared specific compound, be that (1H-imidazoles-2-yl)-pyridine as starting raw material (for example with 3-fluoro-2-, replace 6-fluoro-2-(1H-imidazoles-2-the yl)-pyridine in the above-mentioned steps): under-78 ℃ of nitrogen, (2.5M is in hexane, 86 milliliters with positive BuLi, 1.05 equivalent) drop to 3-fluorine pyridine (20 grams with time of 90 minutes, 0.206 mole) and N, N, N ', in ether (350 milliliters) solution of N '-Tetramethyl Ethylene Diamine (3.13 milliliters, 0.206 mole).Under this temperature, make the extra stirring of this mixture 3 hours.Add dry DMF (45 milliliters) down in uniform temp then.Mixture was risen again to one night of room temperature.Add entry (170 milliliters) and separate organic layer.Water layer is extracted with ether (3 * 200 milliliters), and then extract with vinyl acetic monomer (2 * 200 milliliters).Make the organic layer dehydration (MgSO-of merging
4) and move down in vacuum and to desolventize.With crude product with tubing string chromatography purification (hexane: ether 2: 1) obtain being the 3-fluoro-pyridine-2-formaldehyde of being with yellow oily.
Under 0 ℃, in MeOH (450 milliliters) solution of 3-fluoro-pyridine-2-formaldehyde (11.5 grams, 0.092 mole), add oxalic dialdehyde (40%w/w H
2O, 16.0 grams, 0.110 mole) and ammonium hydroxide (dense, 29 milliliters).Mixture was risen again to room temperature gradually with 18 hours time.Remove solvent.In resistates, add entry (100 milliliters), extract this mixture with methylene dichloride (5 * 150 milliliters) then.With the organic layer that merges with salt water washing (2 * 100 milliliters), through dehydration and remove solvent.Crude product with ether (200 milliliters) development, is obtained being solid 3-fluoro-2-(1H-imidazoles-2-yl)-pyridine.
Step 2.{6-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-propyl group-pyrimidine-4-yl }-preparation of hydrazine (131)
In the test tube of sealing, with 4-chloro-6-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-propyl group-pyrimidine (coming down to as described in embodiment 1, to prepare) (2.5 grams by 5-propyl group-6-brooethyl-4-chloro-pyrimidine and 3-fluoro-2-(1H-imidazoles-2-yl)-pyridine, 7.5 mmole) heat a night with 70 ℃ with the mixture of single hydrazine hydrate (1.37 grams, 27.4 mmoles) in EtOH (15 milliliters).Vacuum moves down and desolventizes and resistates is developed with vinyl acetic monomer and ether.Filter white solid (131), it need not be further purified and promptly can be used for next step.
Step 3.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (130)
In the test tube of sealing, acetic acid (25 milliliters) solution of (2.5 gram) is 110 ℃ of one nights of heating down with 131.Remove excessive acetic acid under the vacuum and in resistates, add NaHCO
3(aqueous solution) (50 milliliters) and methylene dichloride (150 milliliters).With the organic layer separation and with methylene dichloride (2 * 40 milliliters) aqueous layer extracted.With the organic layer dehydration (NaSO that merges
4) and remove solvent.Crude product (130) is to separate with tubing string chromatography (5%MeOH is in methylene dichloride);
LC-MS,M+1?352.1;
1H-NMR(CDCl
3)δ:9.03(s,1H),8.38(dt,1H),7.53(td,1H),7.31-7.25(m,1H),7.26(d,1H),7.20(d,1H),5.83(s,2H),2.93(t,2H),2.60(s,3H),1.70-1.58(m,2H),0.958(t,3H).
B. other [1,2,4] triazolo [1,5-c] miazines is synthetic
Compound shown in the table 2 is to provide and further synthetic by the illustrated method of embodiment 2A by diagram 1 and 4.All compounds in the table 2 all can represent the Ki less than 1 micro-molar concentration in the part binding analysis method of embodiment 6, as compound 130 (above-mentioned) and compound 155 to 158,167,171,173 to 177 and 186 to 189 (following).
Table 2
C.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-phenyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (155)
Make { 6-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-propyl group-pyrimidine-4-yl }-hydrazine (131) (60 milligrams, 0.18 mmole), the mixture of phenyl aldehyde (21 milligrams, 0.2 mmole) in EtOH refluxed 4 hours.Vacuum moves down and desolventizes.In resistates, add HOAc (2 milliliters) and then add bromine (0.3 mmole) lentamente.Mixture is stirred a night under room temperature.Vacuum move down desolventize and with resistates with NaHCO
3(aqueous solution) and DCM handle.Separate organic layer and with DCM (2 * 0 milliliters) aqueous layer extracted.With the organic layer dehydration (MgSO that merges
4), remove solvent, and make crude product with PTLC (10%MeOH is in DCM) purifying, get white solid;
1H-NMR(CDCl
3)δ:8.93(s,1H),8.44(dd,1H),7.78-7.88(m,2H),7.51-7.63(m,4H),7.22-7.36(m,3H),5.82(s,2H),3.05(q,2H),1.70-1.80(m,2H),1.02(t,3H).
D.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-sec.-propyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (156)
Isobutyric anhydride (0.5 milliliter) is added to 131 (45 milligrams) in the mixture of methylene dichloride (10 milliliters).Under room temperature, stirred the mixture 1 hour.Remove solvent to obtain resistates, LC-MS (M+1) 398.17.Resistates is dissolved in POCl
3(1 milliliter), and make this mixture in 85 ℃ of heating 1 hour.Remove excessive POCl
3Resistates is dissolved in methylene dichloride, and with saturated NaHCO
3Washing, dehydration, and, get title compound (156) via TLC (5%MeOH is in methylene dichloride) purifying.
1H?NMRδ(CDCl
3)1.02(t,3H,J=5.4Hz),1.43(d,6H,J=6.0Hz),1.71(p,2H,J=5.4Hz),2.93(m,2H),3.29(sep,1H,J=6.0Hz),5.57(s,2H),7.22-7.36(m,2H),7.70-7.82(m,2H),8.82(d,1H,J=3.3Hz),9.04(s,1H).LC-MS(M+1)380.17.
E.2-methyl fluoride-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (157)
In room temperature and N
2Down, with (0.2 milliliter of two (2-methoxy ethyl) amino sulphur trifluoride, 50% in THF) add 7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-base }-methyl alcohol (compound 223 is as following) (31 milligrams, 0.08 mmole) is in the solution of methylene dichloride (5 milliliters).Mixture was stirred two hours, and be poured into saturated NaHCO
3In (10 milliliters), work as CO
2The effect of shedding stop the back with dichloromethane extraction, dehydration (MgSO
4), filter and under vacuum, evaporate.PTLC via the 5%MeOH/ methylene dichloride gets pure products (157).
1H?NMR:0.98(3H,t,J=5.4Hz),1.67(2H,m),2.99(2H,m),5.69(2H,d,J=35.1Hz),5.88(2H,s),7.22(1H,s),7.22-7.31(2H,m),7.54(1H,t,J=6.0Hz),8.39(1H,s),9.13(1H,s).LCMS(M+1)370.20.
F.8-(2,2-two fluoro-ethyls)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidines (158)
The preparation of step 1.2-(2-benzyloxy-ethyl)-3-oxo base-methyl-butyrate (159)
Under 0 ℃, DME (10 milliliters) drips of solution of methyl acetoacetate (5.8 gram, 50 mmoles) is added NaH (2.0 grams, 60% in mineral oil) in the suspension of DME (50 milliliters).This solution was stirred under room temperature 30 minutes.Add a NaI (7.5 gram) and then add phenmethyl bromotrifluoromethane ether (10.75 grams, 50 mmoles).This mixture is stirred a night down in 70 to 80 ℃.After the solid that forms removed, remove solvent.Resistates is via the hexane of tubing string with 4: 1: the vinyl acetic monomer purifying gets colorless oil (159).
The preparation of step 2.5-(2-benzyloxy-ethyl)-6-methyl-pyrimidine-4-alcohol (160)
Under room temperature, NaOMe (2.75 gram, 50 mmoles) added to FORMAMIDINE ACETATE (formamidineacetate) (25 mmole) in MeOH (75 milliliters) in stirred solution.Stirred this mixture 15 minutes.Add 2-(2-benzyloxy-ethyl)-3-oxo base-methyl-butyrate (20 mmole) and under room temperature, stir the mixture a night.Add acetic acid (1.5 grams, 20 mmoles) and move down and desolventize in vacuum.In resistates, add entry (30 milliliters) and with 2-butanone (3 * 30 milliliters) extraction.With the extract that merges with salt solution (40 milliliters) washing, dehydration (Na
2SO
4) and evaporation, get yellow solid (160).
The preparation of step 3.5-(2-benzyloxy-ethyl)-4-chloro-6-methyl-pyrimidine (161)
In 100 ℃ of heating 160 (4.1 grams, 17 mmoles) and POCl
3The mixture of (10 milliliters) 3 hours.Move down in vacuum and to desolventize and in resistates, add EtOAc (30 milliliters) and water (30 milliliters).Add NaHCO carefully
3(aqueous solution) up to the pH of water layer greater than 7.Extract with EtOAc (2 * 30 milliliters) with each layer separation and with water layer.With the extract that merges with salt solution (50 milliliters) washing, dehydration (Na
2SO
4) and evaporating solvent.This resistates is with quick tubing string (EtOAc: hexane=1: 2) carry out purifying, the product that is faint yellow oily (161) is provided.
The preparation of step 4. acetic acid 2-(4-brooethyl-6-chloro-pyrimidine-5-yl)-ethyl ester (162) and 5-(2-benzyloxy-ethyl)-4-brooethyl-6-chloro-pyrimidine
Under 85 ℃ with Br
2(1.4 gram, 8 mmoles) drop to 5-(2-benzyloxy-ethyl)-4-chloro-6-methyl-pyrimidine (2.1 grams, 8 mmoles) in HOAc (20 milliliters) in stirred solution.After the dropping, mixture was additionally stirred 1 hour down in 85 ℃.Move down in vacuum and to desolventize and in resistates, add EtOAc (25 milliliters) and NaHCO
3(25 milliliters).Each layer separated, and organic layer is first with Na
2S
2O
3Solution (saturated 15 milliliters) then washs with salt solution (20 milliliters) again.Make organic phase dehydration (Na
2SO
4) and evaporating solvent.The yellow oil of gained is to utilize quick tubing string (EtOAc: hexane=6: 1) carry out purifying so that 5-(2-benzyloxy-ethyl)-4-brooethyl-6-chloro-pyrimidine and acetic acid 2-(4-brooethyl-6-chloro-pyrimidine-5-yl)-ethyl ester (162) that is faint yellow solid to be provided.
Step 5. acetic acid 2-{4-chloro-6-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-pyrimidine-5-yl }-preparation of ethyl ester (163)
Under room temperature, stir 162 (8.4 mmoles), 3-fluoro-2-(1H-imidazoles-2-yl)-pyridine (as above-mentioned) (1.38 grams, 8.4 mmoles) and K
2CO
3(1.17 grams, 8.4 mmoles) one night of mixture in DMF (6 milliliters).In mixture, add EtOAc (20 milliliters) and water (10 milliliters).With the organic layer separation and with EtOAc (3 * 10 milliliters) aqueous layer extracted.The extract that merges is with salt solution (10 milliliters) washing, dehydration (Na
2SO
4) and evaporating solvent.(5%MeOH is in CH with PTLC with resistates
2Cl
2) carry out centrifugation, can get the product (163) of white solid.
Step 6.2-{4-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-6-diazanyl-pyrimidine-5-yl }-preparation of ethanol (164)
163 (1.72 grams, 4.6 mmoles) and the mixture of single hydrazine hydrate (0.95 gram, 19 mmoles) in EtOH (20 milliliters) are heated a night with 70 ℃.Vacuum moves down and desolventizes and resistates is developed with vinyl acetic monomer and ether.Filter white solid product (164).
Step 7.2-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-preparation of ethanol (165)
Stir 164 down one night of suspension of acetic acid (15 mmole) in 100 ℃.Remove acetic acid under the vacuum and in resistates, add NaHCO
3(aqueous solution) (50 milliliters) and methylene dichloride (150 milliliters).Extract with methylene dichloride (2 * 40 milliliters) with the organic layer separation and with water layer.Make the organic layer dehydration (NaSO of merging
4) and remove solvent.Crude product and 10%HCl were stirred 1 hour.With mixture with saturated NaHCO
3Neutralization with dichloromethane extraction, is dewatered and is removed solvent.Crude product is separated with tubing string chromatography (5%MeOH is in methylene dichloride), must this product (165).
Step 8.{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-preparation of acetaldehyde (166)
Dai Si-Martin's's (Dess-Martin, 1.56 grams, 3.67 mmoles) methylene dichloride (8 milliliters) solution is added in methylene dichloride (10 milliliters) solution of 165 (1.3 grams, 3.67 mmoles).After two hours, should spare the phase reaction mixture and dilute with ether.Make mixture with 1.3M NaOH solution washing and dehydration (MgSO
4).Carry out TLC with the 5%MeOH/ methylene dichloride, get product 166.
Step 9.8-(2,2-two fluoro-ethyls)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-methyl-[1,2,4] triazolo [1,5-c] pyrimidines (158)
In 0 ℃ and N
2Two (2-methoxy ethyl) amino sulphur trifluorides (0.5 milliliter, 50% in THF) are added 166 (30 milligrams, 0.085 mmole) in the solution of methylene dichloride (5 milliliters) down.Make mixture be poured into saturated NaHCO in two hours then in 60 ℃ of heating
3(10 milliliters).Work as CO
2The effect of shedding stop after, with this mixture through being extracted to methylene dichloride, dehydration (MgSO
4), filter and under vacuum, evaporate.Carry out PTLC with the 5%MeOH/ methylene dichloride, get pure title product (158).
1H?NMR:2.59(3H,s),1.67(2H,m),3.72(2H,m),5.88(2H,s),6.25(1H,tt,J=42.3,3.3Hz),7.26-7.3(3H,m),7.543(1H,t,J=6.0Hz),8.35(1H,s),9.10(1H,s).LCMS(M+1)374.07.
G.2-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-niacin nitrile (167)
The preparation of step 1.7-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (168)
In the test tube of sealing, 4-chloro-6-methyl-5-propyl group-pyrimidine (101) (500 milligrams, 2.93 mmoles) and the mixture of single hydrazine hydrate (880 milligrams, 17.6 mmoles) in EtOH (15 milliliters) are heated a night down with 100 ℃.Add entry (15 milliliters) during cooling with solvent removal and in resistates.Filter out solid and with the washing of water (5 milliliters) and ether (10 milliliters).In the test tube of 110 ℃ of lower seals, solid is heated a night in acetic acid (10 milliliters) then.Remove excessive acetic acid under the vacuum.Resistates neutralizes with sodium bicarbonate aqueous solution, then with ethyl acetate extraction.The dehydration time shift desolventize product (168).
The preparation of step 2.7-brooethyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (169)
In the test tube of sealing, (168) (523 milligrams, 2.75 mmoles) and the mixture of bromine (1.12 grams, 7 mmoles) in acetic acid (15 milliliters) are heated a weekend with 100 ℃.Remove solvent and resistates is neutralized with sodium bicarbonate aqueous solution, and with ethyl acetate extraction.The dehydration time shift desolventizes, and (vinyl acetic monomer: hexane 1: 1) purifying gets product (169) with PTLC with crude product.
The preparation of step 3.2-(1H-imidazoles-2-yl)-niacin nitrile (170)
With 3-bromo-2-(1H-imidazoles-2-yl)-pyridine (come down to as people such as Clews Synthesis (2001): 1549 is described by 3-bromo-pyridine-2-nitrile preparation) (675 milligrams, 3 mmoles), zinc cyanide (223 milligrams, 1.9 mmoles), Pd
2(dba)
3(137 milligrams, 0.15 mmole), DPPF (160 milligrams, 0.3 mmole) and water (0.2 milliliter) in the mixture of DMF (15 milliliters) with argon gas degasification 15 minutes.Make this mixture in the test tube of sealing, heat a night then with 40 ℃.Remove solvent, add entry (30 milliliters) then with mixture with dichloromethane extraction.(MgSO during dehydration
4) remove solvent and with the solid of gained with ether washing (5 * 10 milliliters) product (170).
Step 4.2-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-preparation of niacin nitrile (167)
With 169 (56 milligrams, 0.22 mmole), 170 (42 milligrams, 0.25 mmole) and K
2CO
3(138 milligrams) mixture in DMF (4 milliliters) stirs a night under room temperature.Vacuum moves down and desolventizes.Add entry (10 milliliters) and with mixture with ethyl acetate extraction (3 * 25 milliliters).Make the organic layer dehydration of merging and remove solvent.Crude product gets solid title product (167) with PTLC (5%MeOH is in methylene dichloride) purifying.
1H?NMR?9.13(s,1H),8.64-8.66(m,1H),8.36(s,1H),8.07-8.10(m,1H),7.29-7.34(m,1H),7.32(s,1H),7.23(s,1H),5.94(s,2H),3.02-3.08(m,2H),1.66-1.74(m,2H),1.00(t,3H).
H.6-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-pyridine-2-nitrile (171)
The preparation of step 1.6-(1H-imidazoles-2-yl)-pyridine-2-nitrile (172)
Under 0 ℃, in (0.127 mole of 6-chloro-pyridine-2-formaldehyde; Come down to as people such as Vacher (1998), J.Med.Chem.41:5080 is described by the preparation of 2-chloro-6-methyl-pyridine) MeOH (620 milliliters) solution in add oxalic dialdehyde (40%w/w H
2O, 20 milliliters) and ammonium hydroxide (dense, 40 milliliters).Mixture was risen again to room temperature gradually with 18 hours time.Remove solvent.In resistates, add entry (125 milliliters) and extract this mixture with methylene dichloride (5 * 150 milliliters) then.With the organic layer that merges with salt water washing (2 * 100 milliliters), dewater and remove solvent.Crude product with ether (200 milliliters) development, must be solid 2-chloro-6-(1H-imidazoles-2-yl)-pyridine.
With 2-chloro-6-(1H-imidazoles-2-yl)-pyridine (800 milligrams, 4.45 mmoles), zinc cyanide (313 milligrams, 2.68 mmoles), Pd
2(dba)
3(122 milligrams, 0.133 mmole), DPPF (144 milligrams, 0.27 mmole) and water (0.1 milliliter) in the mixture of DMF (10 milliliters) with argon gas degasification 15 minutes.Make this mixture in the test tube of sealing, heat a whole night then with 40 ℃.Remove solvent, add entry (30 milliliters) then with mixture with dichloromethane extraction.(MgSO during dehydration
4) remove solvent.Carry out tubing string separate product (172).
Step 2.6-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-preparation of pyridine-2-nitrile (171)
With 169 (97 milligrams, 0.38 mmole), 172 (64 milligrams, 0.38 mmole) and K
2CO
3(160 milligrams) mixture in DMF (4 milliliters) stirs a night under room temperature.Vacuum moves down and desolventizes.Add entry (10 milliliters) and with mixture with ethyl acetate extraction (3 * 25 milliliters).Make the organic layer dehydration of merging and remove solvent.Crude product gets solid title product (171) with PTLC (5%MeOH is in methylene dichloride) purifying.
1H?NMR?9.12(s,1H),8.49(q,1H),8.36(s,1H),7.87(t,1H),7.56(q,1H),7.21(s,2H),6.11(s,2H),3.13-3.19(m,2H),1.71-1.79(m,2H),1.02(t,3H).
I.7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-Pyrrolizidine-1-base [1,2,4] triazolo [1,5-c] pyrimidines (173)
Step 1.7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-preparation of 8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-amine (174)
131 (2.46 grams, 7.52 mmoles), the solution of cyanogen bromide (879 milligrams, 8.3 mmoles) in EtOH (18 milliliters) were refluxed 4 hours.Vacuum moves down and desolventizes and make resistates in saturated NaHCO
3Layering between the aqueous solution (20 milliliters) and EtOAc (20 milliliters).With each layer separation and with EtOAc (2 * 30 milliliters) aqueous layer extracted.With the extract that merges with salt solution (15 milliliters) washing, dehydration (Na-
2SO
4) and evaporation.The solid of gained is washed with ether (10 milliliters), get faint yellow solid 174.
Step 2.2-bromo-7-[2-(3-fluorine pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 8-propyl group [1,2,4] triazolo [1,5-c] pyrimidines (175)
In the solution of HBr (48%, 8 milliliter), dropwise add NaNO in 174 (788 milligrams, 2.24 mmoles) that are cooled to 0 ℃
2(232 milligrams, 3.36 mmoles) are in the solution of water (2 milliliters).With mixture in 0 ℃ of CuBr (482 milligrams, 3.36 mmoles) that stirred 30 minutes and added 3 parts.Mixture is stirred in 0 ℃ rose again to room temperature in 2 hours in 30 minutes then.In solution, dropwise add dense NH
4OH is up to pH 〉=7.Then with EtOAc (3 * 15 milliliters) extraction mixture and with the extract that merges with salt solution (15 milliliters) washing, dehydration (Na-
2SO
4) and evaporation.The brown solid of gained is washed with ether (4 milliliters) and hexane (6 milliliters), get light brown solid 175.
Step 3.7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-preparation of 8-propyl group-2-Pyrrolizidine-1-base [1,2,4] triazolo [1,5-c] pyrimidines (173)
The mixture of 175 (77 milligrams, 0.185 mmole) with Pyrrolizidine (0.5 milliliter) stirred under room temperature 4 hours.Vacuum moves down and desolventizes and make resistates layering between water (5 milliliters) and EtOAc (5 milliliters).With each layer separation and with EtOAc (2 * 5 milliliters) aqueous layer extracted.With the extract that merges with salt solution (5 milliliters) washing, dehydration (Na-
2SO
4) and evaporation.(5%MeOH is in CH to make residual matter carry out the PTLC separation
2Cl
2), the title compound 173 of white solid.
H
1?NMR(δ,CDCl
3):8.84(s,1H),8.40(m,1H),7.51-7.56(m,1H),7.21-7.31(m,2H),7.18(s,1H),5.76(s,2H),3.53-3.57(m,4H),2.80-2.84(m,2H),1.99-2.02(m,4H),1.58-1.64(m,2H),0.93(t,3H).LC-MS(M+1),407.10.
J.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-isopropoxy-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidines (176)
Step 1.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-alcohol (177)
Under nitrogen, urea (1.60 grams, 26 mmoles) is added into 131 (3.27,10 mmoles) in the solution of anhydrous NMP (3.6 milliliters).With the mixture heating up to 160 of gained ℃ and stirred 6 hours.During cooling, reaction mixture is poured in the water (80 milliliters), pH is adjusted to 7, and extract this solution with methylene dichloride (50 * 4 milliliters) with hydrochloric acid.With organic solution with anhydrous sodium sulfate dehydration and concentrate oily crude product 177, it can be directly used in the reaction of next step.
Step 2.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 2-isopropoxy-8-propyl group-[1,2,4]-triazolo [1,5-c] pyrimidine (176)
In the DMF of compound 177 (10 milliliters) solution, add Anhydrous potassium carbonate (2 equivalent) and 2-iodopropane (2 equivalent).The mixture of gained is stirred a night down in 60 ℃.During cooling, reaction mixture is poured in the water (50 milliliters) and with this mixture of dichloromethane extraction, dewatered with sodium sulfate again.Organic solution is concentrated and get thickness oily product 176 with the PTLC purifying.LCMS(M+1)396.3。
K. other [1,2,4] triazolo [1,5-c] miazines is synthetic
Compound shown in the table 3 is that as described above method is synthetic.
Table 3
Embodiment 3.[1,2,4] triazolo [4,3-c] miazines is synthetic
A.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidines (186)
Under 110 ℃, the suspension of 131 (620 milligrams, 0.7 mmole) with acetic anhydride (2 milliliters) was stirred 1 hour.Add NaHCO
3(aqueous solution) (10 milliliters) and methylene dichloride (10 milliliters).With the organic layer separation and with methylene dichloride (2 * 10 milliliters) aqueous layer extracted.With the organic layer dehydration (NaSO that merges
4) and remove solvent.Crude product with PTLC (5% methyl alcohol is in methylene dichloride) separate product 186;
LC-MS,M+1352.18;
1H-NMR(CDCl
3)δ:8.59(s,1H),8.42(d,1H),7.54(t,1H),7.23-7.35(m,2H),7.21(s,1H),5.77(s,2H),2.98(t,2H),2.78(s,3H),1.62-1.74(m,2H),0.97(t,3H).
B.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidines (187)
The suspension of 131 (30 milligrams, 0.09 mmole) with acetic acid diethoxymethyl ester (1 milliliter) was stirred under room temperature 10 minutes.Add NaHCO
3(aqueous solution) (10 milliliters) and methylene dichloride (10 milliliters).With the organic layer separation and with methylene dichloride (2 * 10 milliliters) aqueous layer extracted.With the organic layer dehydration (NaSO that merges
4) and remove solvent.Crude product with PTLC (10% methyl alcohol is in methylene dichloride) separate product 187;
LC-MS,M+1?338.15;
1H-NMR(CDCl
3)δ:8.87(s,1H),8.83(s,1H),8.42(s,1H),7.54(t,1H),7.23-7.34(m,3H),5.79(s,2H),3.02(t,2H),1.66-1.76(m,2H),0.99(t,3H).
C.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-phenyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidines (188)
Under 110 ℃, the suspension of 131 (0.5 gram, 1.5 mmoles) with o-benzoic acid trimethyl (trimethylorthobenzioate) (2 milliliters) was stirred 2 hours.Add NaHCO
3(aqueous solution) (10 milliliters) and methylene dichloride (10 milliliters).With the organic layer separation and with methylene dichloride (2 * 10 milliliters) aqueous layer extracted.With the organic layer dehydration (NaSO that merges
4) and remove solvent.Crude product with PTLC (2: 1 acetone: vinyl acetic monomer) separate product 188;
LC-MS,M+1?414.15;
1H-NMR(CDCl
3)δ:8.93(s,1H),8.42(d,1H),7.79-7.81(m,2H),7.52-7.59(m,4H),7.23-7.34(m,3H),5.82(s,2H),3.06(t,2H),1.70-1.80(m,2H),1.02(t,3H).
D.3-difluoromethyl-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidines (189)
Under 50 ℃, the suspension of 131 (230 milligrams, 0.7 mmole) with difluoro acetic anhydride (2 milliliters) was stirred one hour.Add NaHCO
3(aqueous solution) (10 milliliters) and methylene dichloride (10 milliliters).With the organic layer separation and with methylene dichloride (2 * 10 milliliters) aqueous layer extracted.With the organic layer dehydration (NaSO that merges
4) and remove solvent.Crude product with PTLC (12: 1 vinyl acetic monomers: acetone) separate product 189;
LC-MS,M+1?388.13;
1H-NMR(CDCl
3)δ:8.95(s,1H),8.34(d,1H),7.51(t,1H),7.02-7.37(m,4H),5.81(s,2H),3.01(t,2H),1.62-1.73(m,2H),0.96(t,3H).
E.8-ethyl-7-[2-(3-trifluoromethyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidines (190) are that as described above method is synthetic.LC-MS(M+1)373.34。
F. other [1,2,4] triazolo [4,3-c] miazines is synthetic
Compound shown in the table 4 is a method as described above, and synthesizes as embodiment 3A to the D example person of institute.
Table 4
Synthesizing of embodiment 4. imidazos [1,5-c] miazines
A.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-1-methyl-8-propyl group-imidazo [1,5-c] pyrimidine (213)
Step 1.1-{6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-propyl group-pyrimidine-4-yl }-preparation of ethyl ketone (214)
In 4-chloro-6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-add tributyl tin EVE (0.27 gram) and Pd (Ph in toluene (30 milliliters) solution of 5-propyl group-pyrimidine (103) (0.168 gram)
3P)
2Cl
2(30 milligrams).This mixture is carried out degasification 10 minutes, heat a night in 110 ℃ then.Vacuum move down desolventize and crude product.LC-MS:(M+1)368.13。Above-mentioned crude product is dissolved in MeOH (15 milliliters).Add the HCl (10 milliliters) of 6N and under room temperature, stirred this mixture 3 hours.Remove solvent, with saturated NaHCO
3Neutralization, and with ethyl acetate extraction.With the organic layer dehydration that merges, remove solvent and crude product, it is carried out purifying with TLC (5%MeOH is in methylene dichloride) and product (214).
1H?NMRδ(CDCL
3)1.01(t,3H,J=7.5Hz),1.67(p,2H,J=7.2Hz),2.66(s,3H),2.94(t,2H,J=7.5Hz),6.05(s,2H),6.74(dd,1H,J=6.0,2.7Hz),7.10(s,1H),7.25(s,1H),7.83(q,1H,J=6.0Hz),8.13(d,1H,J=6.0Hz),8.90(s,1H).LC-MS:(M+1)340.14.
Step 2.N-(1-{6-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-propyl group-pyrimidine-4-yl }-ethyl)-preparation of methane amide (215)
(0.1 gram) and formic acid (0.1 milliliter) add in 2 milliliters the methane amide with 214 under in 160 to 180 ℃.Under 160-180 ℃, mixture was additionally heated 3 hours.Between heating period, add formic acid (0.2 milliliter) in addition.Mixture is cooled to room temperature and pours in the water (10 milliliters).With concentrated sodium hydroxide solution furnishing pH is at least 11 basic solution.With solution with ethyl acetate extraction.The organic layer that makes merging is with MgSO
4The dehydration, and remove solvent and crude product.Carry out PTLC (10%MeOH is in methylene dichloride) separate title product (215).
1H?NMRδ(CDCL
3)1.06(t,3H,J=7.5Hz),1.43(d,3H,J=5.1Hz),1.55-1.72(m,2H),2.72-2.80(m,1H),2.86-2.95(m,1H),5.52(p,1H,J=5.4Hz),5.81(d,1H,J=12.3Hz),6.08(d,1H,J=12.3Hz),6.73(dd,1H,J=6,2.1Hz)),6.99(d,1H,J=5.7Hz),7.12(d,1H,J=2.7Hz),7.23(d,1H,J=2.7Hz),7.78(q,1H,J=6.0Hz),8.12(dd,1H,J=6.0,2.1Hz),8.18(s,1H),8.79(s,1H).LC-MS:(M+1)369.13.
Step 3.7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-preparation of 1-methyl-8-propyl group-imidazo [1,5-c] pyrimidine (213)
With 215 (20 milligrams) and POCl
3The mixture reflux of (2 milliliters) 3 hours.Remove excessive POCl
3Add vinyl acetic monomer (10 milliliters), and with mixture with saturated NaHCO
3The washing of (5 milliliters), salt solution (5 milliliters), and with MgSO
4Dehydration.After making solvent evaporation, resistates is got title product (213) with PTLC (5%MeOH is in methylene dichloride) purifying.
1H?NMRδ(CDCL
3)0.99(t,3H,J=7.5Hz),1.55(p,2H,J=7.2Hz),2.62(s,3H),2.92(t,2H,J=7.5Hz),5.92(s,2H),6.87(dd,1H,J=8.1,3Hz),7.15(s,1H),7.22(s,1H),7.85(q,1H,J=8.1Hz),8.06(s,1H),8.14(d,1H,J=8.1Hz),8.57(s,1H).LC-MS:(M+1)351.12.
B.7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-1-methyl-8-propyl group-imidazo [1,5-c] pyrimidine (216)
1H?NMRδ(CDCl
3)0.94(t,3H,J=7.5Hz),1.48(p,2H,J=7.2Hz),2.58(s,3H),2.72(t,2H,J=7.5Hz),5.61(s,2H),7.18(d,1H,J=2.7Hz),7.20(s,1H),7.33(m,1H),7.55(t,1H,J=9.6Hz),8.05(s,1H),8.47(d,1H,J=4.5Hz),8.54(s,1H).LC-MS:(M+1)351.14.
Embodiment 5. other imidazopyrimidine class and triazolo pyrimidine classes
The compound shown in 5 and 6 of tabulating is down synthesized by above-mentioned diagram and the illustrated method of previous embodiment.In some example, be to adopt ripe other step that shifts in the functional group that this operator knew with the production compound.The asterisk on " Ki " hurdle represents that this compound can represent the Ki value less than 1 micro-molar concentration in the part binding analysis method that embodiment 6 provides.Above-claimed cpd 213 and 216 also represents the Ki value less than 1 micro-molar concentration.LCMS data of Xian Shiing herein are to represent as above-mentioned acquisition and with M+1.
Table 5
Table 6
Embodiment 6. part binding analysis methods
A. purified rat cortex film
Prepare purified rat cortex film according to step 1 or step 2:
Step 1: utilize POLYTRON clarifixator (setting 5 times 30 seconds) that refrigerated rat cortex is homogenized in the 50mM Tris 7.4 of ice (1 gram cortex/150 milliliter damping fluid).Suspension is poured in the centrifuge tube, and (48,000 * g) with 20, centrifugal 15 minutes of 000rpm in the SS34 rotor then.Remove supernatant liquor and with throw out with same buffer and centrifugal speed washed twice.Final throw out is placed the centrifuge tube of lid and be stored in-80 ℃.Before the use, will through the washing rat cortex film thaw and resuspending in ice 50mM Tris 7.4 (6.7 milligrams of refrigerated cortex weight/milliliter damping fluids) in.
Step 2: the cortex tissue of rat is downcut and in the buffer A (0.05M Tris HCl damping fluid, 4 ℃ of following pH are 7.4) of 25 volumetric quantitys (w/v), homogenize.To organize equal pledge in ice temperature (4 ℃) centrifugal 20 minutes down with 20,000 * g.Supernatant liquor is poured out, throw out is homogenized in the damping fluid of equal volume once more, and centrifugal with 20,000 * g once more.The supernatant liquor of this centrifugation step is poured out and throw out is stored in-20 ℃ of nights.Then throw out is thawed and resuspending in the buffer A (original weight/volume) of 25 volumetric quantitys, centrifugal and pour out supernatant liquor with 20,000 * g.This washing step is repeated once.At last with the buffer A of throw out resuspending in 50 volumetric quantitys.
B. radioligand-binding assay
Utilize originally by Thomas and the described binding analysis method of Tallman (J.Bio.Chem. (1981) 156:9838-9842, and J.Neurosci. (1983) 3:433-440) to confirm that compound provided herein is to GABA
AThe avidity in the: benzodiazepine site of acceptor.To analyze according to method 1 via the prepared film of step 1, and will analyze according to method 2 via the prepared film of step 2.
Method 1: the amount with 1.2 milligrams of film/holes is cultivated.To contain film suspension, 20 microlitres of 180 microlitres
3H-Ro15-1788 (
3The H-flumazenil, PerkinElmer Life Sciences, Boston, MA) and two increments these (cumulative volume body 202 microlitres) in the test compound of DMSO or contrast 1 of 2 microlitres cultivated 60 minutes down in 4 ℃.(CT) the undressed 102x258 millimeter filter paper pads on makes to cultivate and finishes for Tomtec filtration manifold, Hamden, and the 50mM Tris 7.4 of filter paper with ice washed three times to utilize quick filtration that sample is filtered menifold by Tomtec.Count with the filter paper season and with Wallac 1205 Betaplate liquid scintillation counters (Wallac 1205 Betaplate Liquid Scintillation Counter).Non-specificity is via inciting somebody to action in conjunction with (control group)
3H-RO15-1788 is with 10
-6The 4-oxo base-4,5,6 of M, 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid [4-(2-third amino-oxyethyl group)-phenyl]-acid amides is replaced and is measured.Calculate the inhibition per-cent of total specificity of each compound in conjunction with (total specificity combination=whole-non-specificity).
Method 2: contain the equal pledge of tissue of 100 microlitres in the culture, the radioligand (0.5nM of 100 microlitres
3H-RO15-1788, specific activity 80Ci/ mmole) and test compound or contrast (as follows), and it is with buffer A cumulative volume to be added to 500 microlitres.It is cultivated down in 4 ℃ filtered by Whatman GFB filter paper with separated free and through the bonded part in 30 minutes then fast.Filter paper is counted with fresh buffer A washed twice and with liquid scintillation counter.Non-specificity is via inciting somebody to action in conjunction with (control group)
3H-RO15-1788 is with stable (diazepam, Research Biochemicals International, Natick, MA) displacement and measuring of 10 μ M.Collect three parts of experimental datas, total specificity of it is average and computerized compound in conjunction with (total specificity in conjunction with=all-the non-specificity) inhibition per-cent.
Analyze A: the competition binding curve is from 10 by the test compound concentration range
-12M or 10
-11M to 10
-5Reaching 11 data measurement point (for example 7 points) among the M obtains.IC
50And (Hill coefficient is via SIGMAPLOT software (SPSS Inc., Chicago, assisting and determine IL) with these displacement bonded data nH) to analyse your coefficient.Utilize Cheng-Prusoff equation (Biochemical Pharmacology 22:3099-3108 (1973)) calculating K i:Ki=IC
50/ (1+[L]/Kd), IC wherein
50Determined IC by SIGMAPLOT
50For with maximum
3H-Ro15-1788 replaces to fall 1/2 o'clock compound concentration in conjunction with concentration, and [L] is used for this subject matter of mark
3The concentration of H-Ro15-1788, and Kd is
3H-Ro15-1788 in conjunction with separation constant, before be 1.0nM after measured.The preferable Ki value that compound represented of the present invention less than the Ki value that compound represented better among 100nM and the present invention less than 10nM.
Embodiment 7. electrophysiology
Following analysis is to be used to measure the characteristic whether compound of the present invention can change the electricity of cell, and whether can be used as GABA
AThe agonist in the: benzodiazepine site of acceptor, antagonist or reverse agonist.
Come down to according to White and Gurley (Neuro Report
6: 1313-1316,1995) described method and White, Gurley, Hartnett, Stirling and Gregory (Receptors andChannels
3: 1-5,1995) described method analyzes after revising.The record of electricity Physiological Experiment is to keep current potential via two electrode voltage strangulation technology in film to carry out under-the 70mV.Separate the ovum of Africa xenopus (Xenopus laevis) and inject respectively by enzyme with 4: 1: 4 the blended α of ratio institute, the β and the non-polyadenylation cRNA (non-polyadenylatedcRNA) of γ subunit.In the delivering of people such as White, the preferable α that is combined as in nine kinds of combinations of α, β and γ subunit
1β
2γ
2, α
2β
3γ
2, α
3β
3γ
2, and α
5β
3γ
2All cRNA of subunit are preferably human pure lines or are all the rat pure lines in each combination.Each subunit through the clone is illustrated in GENBANK, for example human α
1, GENBANK accession designation number X14766; Human α
2, GENBANK accession designation number A28100; Human α
3, GENBANK accession designation number A28102; Human α
5, GENBANK accession designation number A28104; Human β
2, GENBANK accession designation number M82919; Human β
3, GENBANK accession designation number Z20136; Human γ
2, GENBANK accession designation number X15376; Rat α
1, GENBANK accession designation number L08490; Rat α
2, GENBANK accession designation number L08491; Rat α
3, GENBANK accession designation number L08492; Rat α
5, GENBANK accession designation number L08494; Rat β
2, GENBANK accession designation number X15467; Rat β
3, GENBANK accession designation number X15468; And rat γ
2, GENBANK accession designation number L08497.For the combination of each subunit, when applying the GABA of 1 μ M, be that each insufficient information that constitutes subunit (constituent subunit) is introduced so that the electric current of amplitude greater than 10nA to be provided.The assessment compound in cause<when 10% maximum can cause the GABA electric current (for example, 1 μ M-9 μ M), to the concentration of GABA.In order to assess the relation of concentration/effect, each ovum is exposed under the concentration of compound (test compound) of desire assessment of increase.The effect of test compound is with the per-cent change calculations in the current amplitude: 100* ((Ic/I)-1), and wherein Ic is that to have current amplitude that viewed GABA down causes and I in test compound be the current amplitude that viewed GABA causes during in no test compound.
Test compound is decision after concentration/effect curves is finished to the specificity in: benzodiazepine site.In washing this ovum fully with after removing the test compound that is before applied, ovum is exposed under the GABA+1Mm RO15-1788, then be exposed to again under the GABA+1 μ M RO15-1788+ test compound.Because of adding the per-cent variation that compound caused is to calculate as above-mentioned mode.Do not exist down viewed current amplitude per-cent to change from 1 μ M RO15-1788 and deduct the viewed down any current amplitude per-cent variation of RO15-1788 existence.Via standard method these net value are used to calculate average effect and EC
50Value.In order to assess average effect and EC
50Value is with the concentration/effect data of cell on average and bring logistic equation formula (logistic equation) into.
Embodiment 8.MDCK oxicity analysis
This embodiment illustrates the kidney that utilizes Madin Darby dog, and (Madin Darby caninekidney, MDCK) the cytotoxicity analysis method of cell is with the toxicity of assessment compound.
(test compound of adding 1 microlitre makes the ultimate density of compound in this analytical method reach 10 micro-molar concentrations, 100 micro-molar concentrations or 200 micro-molar concentrations in each hole CT) for PACKARD, Meriden in the 96-of clear bottom porose disc.In the hole of control group, add the solvent that does not contain test compound.
With mdck cell, (U.S. bacterial classification center, Manassas VA), is stored under the sterile state ATCC numbering CCL-34 according to the product information list of ATCC.The mdck cell that covers with trypsin treatment, collecting cell and be 0.1 * 10 with the cell concn dilution with (37 ℃) substratum (VITACELLMinimum Essential Medium Eagle, ATCC catalogue #30-2003) of temperature
6Cells/ml.Except five holes (control group contains the not substratum of celliferous temperature of 100 microlitres), in each hole, add the diluted cell of 100 microlitres as the typical curve control group.Then porose disc is incubated at 37 ℃, 95%O
2, 5%CO
2Environment continued simultaneously to rock in following 2 hours.After the cultivation, in every hole, add the mammalian cell solvent soln of 50 microlitres, each hole is sealed with PACKARD TOPSEAL label, porose disc was rocked 2 minutes with the speed of about 700rpm.
With respect to untreated cell, toxigenous compound can make the production of ATP reduce.(Meriden, CT) ATP-LITE-M cold light ATP detects cover group, production code member 6016941, the production of measuring ATP in the treated and untreated mdck cell according to the indication of manufacturers generally to be to use PACKARD.With PACKARD ATP-LITE-M reagent and equilibrium at room temperature.In case balance, make through freeze the universe be subjected to matter solution reduce again in 5.5 milliliters be subjected to matter buffered soln (being contained in the cover group).ATP standardized solution through freezing the universe is reduced again in the mother solution (stock) of deionized water to obtain 10mM.As for five control group holes, be in each typical curve control group hole, add 10 microlitres through the PACKARD of a series of dilutions standard substance, and the ultimate density in each continuous hole is 200nM, 100nM, 50nM, 25nM and 12.5nM.In institute is porose, add PACKARD and be subjected to matter solution (50 microlitre), give capping then, porose disc is placed on the suitable wobbler again and rocked 2 minutes with the speed of 700rpm.The PACKARD label of white is attached to the bottom of each porose disc and utilizes tinfoil that the porose disc coating is made sample adaptation dark and placed the dark place 10 minutes.Utilize cold light counter (for example, PACKARDTOPCOUNT micropore dish flicker and cold light counter or TECAN SPECTRAFLUORPLUS) to measure cold light in 22 ℃ then, and calculate ATP concentration from typical curve.Relatively through the cell of test compound processing and the ATP concentration in the untreated cell.Cell through the preferable test compound of 10 μ M is handled shows that its ATP concentration is at least 80% of untreated cell, is preferably at least 90%.When using the test compound of 100 μ M, the shown ATP concentration of handling through preferable test compound of cell is at least 50% of the ATP concentration that detected in the untreated cell, is preferably at least 80%.
Claims (21)
1. the compound of a following formula:
Or its pharmacy acceptable salt, in the formula:
Z
1Be nitrogen or CR
1,
Z
2Be nitrogen or CR
2, and
Z
3Be nitrogen or CR
3, Z
1, Z
2And Z
3In at least one, but be no more than both for nitrogen;
R
1, R
2And R
3Be independently to be selected from respectively:
(a) hydrogen, halogen and cyano group; And
(b) following formula group:
In the formula:
L is bond or C
1-C
8Alkylidene group;
G is bond, N (R
B), O, C (=O), C (=O) O, C (=O) N (R
B) or N (R
B) C (=O); And
R
AWith each R
BBe independently to be selected from respectively:
(i) hydrogen; And
(ii) C
1-C
8Alkyl, (C
3-C
8Cycloalkyl) C
0-C
4Alkyl, (3 to 7 yuan of Heterocyclylalkyls) C
0-C
4Alkyl, (C
6-C
10Aryl) C
0-C
2Alkyl or (5 to 10 yuan of heteroaryls) C
0-C
2Alkyl, it is to replace with 0 to 4 substituting group that independently is selected from halogen and hydroxyl respectively separately;
R
4Be independently to be selected from hydrogen and C
1-C
8Alkyl;
R
5For:
C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group,, it is independently to be selected from halogen, hydroxyl, C respectively with 0 to 5 separately
1-C
4Alkoxyl group, phenyl and phenyl C
1-C
4The substituting group of alkoxyl group replaces;
R
6And R
7Be the independent respectively hydrogen that is;
R
8Represent 0,1 or 2 substituting group that independently is selected from halogen and hydrogen respectively; And
Ar represents phenyl, naphthyl or 5 to 10 yuan of heteroaryls, and it is independently to be selected from halogen, hydroxyl, cyano group, C respectively with 0 to 4 separately
1-C
8Alkyl, C
1-C
8Alkoxyl group and C
1-C
8The substituting group of alkylhalide group replaces.
2. compound as claimed in claim 1 or salt, wherein R
8Represent 0 or 1 substituting group that is selected from halogen.
3. compound as claimed in claim 1 or salt, wherein Ar represents phenyl, pyridyl, thiazolyl, thienyl or pyridazinyl, it is respectively to hang oneself 0 to 3 independently to be selected from chlorine, fluorine, hydroxyl, cyano group, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
2The substituting group of alkylhalide group replaces.
4. compound as claimed in claim 3 or salt, wherein Ar represents phenyl, pyridine-2-base, 1,3-thiazoles-2-base, thiophene-2-base or pyridazine-3-base, it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
5. compound as claimed in claim 3 or salt, wherein Ar represents 2,6-two fluoro-phenyl, 2,5-two fluoro-phenyl, 5-fluoro-2-methyl-phenyl, pyridine-2-base, 3-fluoro-pyridine-2-base, 3-cyano group-pyridine-2-base, 3-trifluoromethyl-pyridine-2-base, 3-hydroxyl-pyridine-2-base, 3-methoxyl group-pyridine-2-base, 6-fluoro-pyridine-2-base, 6-cyano group-pyridine-2-base, 6-trifluoromethyl-pyridine-2-base, 6-hydroxyl-pyridine-2-base or 6-methoxyl group-pyridine-2-base.
6. as the described compound of arbitrary claim or salt, wherein R in the claim 1 to 5
1, R
2, and R
3Be independently to be selected from respectively:
(a) hydrogen, halogen or cyano group; And
(b) following formula group:
In the formula:
(i) L is a bond;
(ii) G is bond, NH, N (R
B), O, C (=O) O or C (=O); And
(iii) R
AWith R
BBe independently to be selected from respectively: (1) hydrogen and (2) C
1-C
6Alkyl, (C
3-C
7Cycloalkyl) C
0-C
2Alkyl, (3 to 7 yuan of Heterocyclylalkyls) C
0-C
2Alkyl, phenyl, thienyl, pyridyl, pyrimidyl, thiazolyl, and pyridazinyl, it is the substituting group replacement of respectively hanging oneself 0 to 4 and independently being selected from hydroxyl and halogen respectively; And
R
4Be independently to be selected from hydrogen and C
1-C
8Alkyl.
7. as the described compound of arbitrary claim or salt, wherein Z in the claim 1 to 6
1And Z
3Be nitrogen and Z
2Be CR
2
8. compound as claimed in claim 7 or salt, wherein R
2Be to be selected from hydrogen, cyano group, formamido group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Carbalkoxy, C
2-C
4Alkyl oxide, C
3-C
7Cycloalkyl, C
1-C
2Hydroxyalkyl, methyl fluoride, difluoromethyl, trifluoromethyl, phenyl and pyridyl.
9. as the described compound of arbitrary claim or salt, wherein Z in the claim 1 to 6
1And Z
2Be nitrogen, Z
3Be CR
3
10. compound as claimed in claim 9 or salt, wherein R
3Be hydrogen, cyano group, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
6Alkylhalide group, pyridyl or formamido group.
11. as the described compound of arbitrary claim or salt, wherein R in the claim 1 to 10
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group,, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces.
12. compound as claimed in claim 11 or salt, wherein R
5Be ethyl, propyl group, butyl, oxyethyl group or methoxyl methyl.
13. compound as claimed in claim 1 or salt, wherein this compound has following structural:
In the formula:
R
2And R
3Be independently to be selected from hydrogen, halogen, cyano group, formamido group, C respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, list-and two-(C
1-C
4Alkyl) amino, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be the independent respectively hydrogen that is;
R
8Represent hydrogen; And
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
14. compound as claimed in claim 1 or salt, wherein this compound has following structural:
In the formula:
R
2Be to be selected from hydrogen, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be the independent respectively hydrogen that is;
R
8Represent 0 or 1 substituting group that is selected from halogen and hydrogen; And
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 to be independently selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
15. compound as claimed in claim 1 or salt, wherein this compound has following structural:
In the formula:
R
1Be hydrogen, halogen or C
1-C
6Alkyl;
R
3Be to be selected from hydrogen, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group,, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be the independent respectively hydrogen that is;
R
8Represent 0 or 1 substituting group that is selected from halogen and hydrogen; And
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
16. compound as claimed in claim 1 or salt, wherein this compound has following structural:
In the formula:
R
3Be to be selected from hydrogen, halogen, cyano group, formamido group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
2-C
6Alkyl oxide, C
1-C
4Hydroxyalkyl, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, C
1-C
4Carbalkoxy, phenyl and pyridyl;
R
4Be hydrogen or C
1-C
4Alkyl;
R
5Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl or C
1-C
4Alkoxyl group,, it is respectively to hang oneself 0 to 3 independently to be selected from halogen, hydroxyl, C respectively
1-C
2Alkoxyl group, phenyl and phenyl C
1-C
2The substituting group of alkoxyl group replaces;
R
6And R
7Be the independent respectively hydrogen that is;
R
8Represent 0 or 1 substituting group that is selected from halogen and hydrogen; And
Ar represents phenyl, 2-pyridyl, 1,3-thiazoles-2-base, 2-thienyl or 3-pyridazinyl, and it is respectively to hang oneself 0 to 3 independently to be selected from fluorine, chlorine, hydroxyl, C respectively
1-C
2Alkyl, C
1-C
2Alkylhalide group, cyano group and C
1-C
2The substituting group of alkoxyl group replaces.
17. a pharmaceutical compositions, it comprises as described compound of arbitrary claim or salt and physiologically acceptable supporting agent or vehicle in the claim 1 to 16.
18. pharmaceutical compositions as claimed in claim 17, wherein this pharmaceutical compositions is the paster that is deployed into injection liquid, sprays, breast frost, gel, pill, capsule, syrup or transdermal penetration.
19. the pharmaceutical formulations through packing, it comprises the pharmaceutical compositions of depositing in the container as claimed in claim 18 and uses the said composition treatment to suffer from the patient's of anxiety, depression, somnopathy, aprosexia disease, Ah's Mohs mistake intelligence or short term memory loss specification sheets.
20. compound as claimed in claim 1 or salt manufacturing be used for the treatment of be selected from anxiety, depression, somnopathy, aprosexia disease, Ah's Mohs lose intelligence, and the medicament of short term memory loss illness in purposes.
21. compound as claimed in claim 1 or salt, wherein this compound is:
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2,3-dimethyl-8-propyl group-imidazo [1,2-c] pyrimidine;
2-ethyl-7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-3-carboxylic acid, ethyl ester;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-2-carboxylic acid, ethyl ester;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-2-trifluoromethyl-imidazo [1,2-c] pyrimidine;
8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-imidazo [1,2-c] pyrimidine;
8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-2-trifluoromethyl-imidazo [1,2-c] pyrimidine;
7-[2-(2,6-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(2,6-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-propyl group-2-trifluoromethyl-imidazo [1,2-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[(pyridine-2-yl)-imidazoles-1-ylmethyl]-2-phenyl-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-methyl-8-propyl group-imidazo [1,2-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-2-formonitrile HCN; Or
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-imidazo [1,2-c] pyrimidine-3-formonitrile HCN;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
1-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-base }-ethanol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-2-trifluoromethyl-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methoxymethyl-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methoxymethyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-cyclobutyl-7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(6-methoxyl group-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
2-methyl-8-propyl group-7-(2-thiazol-2-yl-imidazoles-1-ylmethyl)-[1,2,4] triazolo [1,5-c] pyrimidine;
2-methyl-8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [1,5-c] pyrimidine;
6-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-pyridine-2-alcohol;
7-[2-(2,6-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
8-propyl group-7-(2-thiophene-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [1,5-c] pyrimidine;
2-methyl-8-propyl group-7-(2-pyridazine-3-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-ethyl-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-ethyl-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
8-ethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [1,5-c] pyrimidine;
8-ethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
2-ethyl-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-difluoromethyl-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-phenyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-sec.-propyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-methyl fluoride-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
8-(2,2-two fluoro-ethyls)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
2-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-the niacin nitrile;
6-[1-(8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-pyridine-2-formonitrile HCN;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-Pyrrolizidine-1-base [1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-isopropoxy-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2,5-dimethyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-ethyl-7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2,8-diethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-methoxymethyl-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
1-{7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-third-1-alcohol;
1-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-third-1-alcohol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-base }-methyl alcohol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-8-propenyl-[1,2,4] triazolo [1,5-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-2-pyridin-3-yl-[1,2,4] triazolo [1,5-c] pyrimidine;
8-(3-benzyloxy-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
8-(2-benzyloxy-ethyl)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
3-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-third-1-alcohol;
8-(2-fluoro-ethyl)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
8-(3-chloro-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
2-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine-8-yl }-ethanol;
8-(3-fluoro-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidine;
8-(3-fluoro-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [1,5-c] pyrimidine;
8-ethyl-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl } [1,2,4] triazolo [1,5-c] pyrimidine;
8-propyl group-7-[2-(6-trifluoromethyl-pyridine-2-yl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [1,5-c] pyrimidine;
2-{1-[8-(3-fluoro-propyl group)-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl]-1H-imidazoles-2-yl }-the niacin nitrile;
6-{1-[8-(3-fluoro-propyl group)-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl]-1H-imidazoles-2-yl }-pyridine-2-formonitrile HCN;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-carboxylic acid, ethyl ester;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-carboxylic acid amide;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine-2-formonitrile HCN;
7-[4-chloro-2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-{ methene amido-[1-(2-methyl-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-methylene radical }-penta-3-alkene nitrile;
1-[1-(8-oxyethyl group-2-methyl-[1,2,4] triazolo [1,5-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-2-fluoro-penta-butadienyl }-methylene radical-amine;
8-ethyl-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-2-methyl [1,2,4] triazolo [1,5-c] pyrimidine;
8-oxyethyl group-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl } [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-2-methoxyl group-8-propyl group-[1,2,4] triazolo [1,5-c] pyrimidine;
2-oxyethyl group-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-amine;
2-(7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-base) propan-2-ol;
2-(ethoxyl methyl)-7-{[2-(6-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-carboxylate methyl ester;
2-(7-{[2-(6-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-base) propan-2-ol;
6-(1-{[2-(methoxymethyl)-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidin-7-yl] methyl }-1H-imidazoles-2-yl) pyridine-2-formonitrile HCN;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-2-(tetrahydrofuran (THF)-2-yl) [1,2,4] triazolos [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-2-[(2,2, the 2-trifluoro ethoxy) methyl] [1,2,4] triazolo [1,5-c] pyrimidine;
2-chloro-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-2-(2,2, the 2-trifluoroethyl) [1,2,4] triazolos [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group-2-(1,3-thiazoles-2-yl) [1,2,4] triazolos [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-N, N, 8-tripropyl [1,2,4] triazolo [1,5-c] pyrimidine-2-amine;
6-(1-{[2-(ethoxyl methyl)-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidin-7-yl] methyl }-1H-imidazoles-2-yl) pyridine-2-formonitrile HCN;
2-(ethoxyl methyl)-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-the 8-propyl group) [1,2,4] triazolo [1,5-c] pyrimidine;
6-{1-[(2-methyl-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidin-7-yl) methyl]-1H-imidazoles-2-yl } pyridine-2-formonitrile HCN;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-2-(isopropoxy methyl)-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
6-(1-{[2-(isopropoxy methyl)-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidin-7-yl] methyl }-1H-imidazoles-2-yl) pyridine-2-formonitrile HCN;
The 2-[(cyclopentyloxy) methyl]-7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(5-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-2-methyl-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine;
3-{1-[(8-ethyl [1,2,4] triazolo [1,5-c] pyrimidin-7-yl) methyl]-1H-imidazoles-2-yl } cyanobenzene;
8-ethyl-7-{[2-(5-fluoro-2-p-methoxy-phenyl)-1H-imidazoles-1-yl] methyl } [1,2,4] triazolo [1,5-c] pyrimidine;
8-ethyl-7-{[2-(3-fluorophenyl)-1H-imidazoles-1-yl] methyl } [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(6-chloropyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-ethyl [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(2-chloro-phenyl-)-1H-imidazoles-1-yl] methyl }-8-ethyl [1,2,4] triazolo [1,5-c] pyrimidine;
7-{[2-(3-fluorine pyridine-2-yl)-1H-imidazoles-1-yl] methyl }-8-propyl group [1,2,4] triazolo [1,5-c] pyrimidine-2-carboxylic acid; Or
6-{1-[(8-ethyl [1,2,4] triazolo [1,5-c] pyrimidin-7-yl) methyl]-1H-imidazoles-2-yl } pyridine-2-formonitrile HCN;
8-ethyl-7-[2-(3-trifluoromethyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-phenyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
3-difluoromethyl-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
1-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidin-3-yl }-ethanol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-3-trifluoromethyl-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methoxyl group-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methoxymethyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
3-cyclobutyl-7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-3-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(6-methoxyl group-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
3-methyl-8-propyl group-7-(2-thiazol-2-yl-imidazoles-1-ylmethyl)-[1,2,4] triazolo [4,3-c] pyrimidine;
3-methyl-8-propyl group-7-(2-pyridine-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [4,3-c] pyrimidine;
6-[1-(8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-pyridine-2-alcohol;
7-[2-(2,6-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
8-propyl group-7-(2-thiophene-2-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [4,3-c] pyrimidine;
3-methyl-8-propyl group-7-(2-pyridazine-3-base-imidazoles-1-ylmethyl)-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-ethyl-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(2,5-two fluoro-phenyl)-imidazoles-1-ylmethyl]-8-ethyl-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine;
8-ethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidine;
8-ethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine;
3-ethyl-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3,5-dimethyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
3-ethyl-7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-5-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
3,8-diethyl-7-[2-(5-fluoro-2-methyl-phenyl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-methoxymethyl-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-sec.-propyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
1-{7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine-8-yl }-third-1-alcohol;
1-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine-8-yl }-third-1-alcohol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidin-3-yl }-methyl alcohol;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-8-propenyl-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-3-pyridin-3-yl-[1,2,4] triazolo [4,3-c] pyrimidine;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-methoxymethyl-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine;
3-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine-8-yl }-third-1-alcohol;
8-(2-fluoro-ethyl)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine;
2-{7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine-8-yl }-ethanol;
8-(3-fluoro-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-3-methyl-[1,2,4] triazolo [4,3-c] pyrimidine;
8-(3-fluoro-propyl group)-7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidine;
8-propyl group-7-[2-(6-trifluoromethyl-pyridine-2-yl)-imidazoles-1-ylmethyl]-[1,2,4] triazolo [4,3-c] pyrimidine;
2-{1-[8-(3-fluoro-propyl group)-[1,2,4] triazolo [4,3-c] pyrimidin-7-yl methyl]-1H-imidazoles-2-yl }-the niacin nitrile;
6-{1-[8-(3-fluoro-propyl group)-[1,2,4] triazolo [4,3-c] pyrimidin-7-yl methyl]-1H-imidazoles-2-yl }-pyridine-2-formonitrile HCN;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine-3-carboxylic acid, ethyl ester;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine-3-carboxylic acid amide;
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine-3-formonitrile HCN;
7-[4-chloro-2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidine;
2-{ methene amido-[1-(3-methyl-8-propyl group-[1,2,4] triazolo [4,3-c] pyrimidin-7-yl methyl)-1H-imidazoles-2-yl]-methylene radical }-penta-3-alkene nitrile;
7-[2-(6-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-1-methyl-8-propyl group-imidazo [1,5-c] pyrimidine or
7-[2-(3-fluoro-pyridine-2-yl)-imidazoles-1-ylmethyl]-1-methyl-8-propyl group-imidazo [1,5-c] pyrimidine.
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WO2001044249A1 (en) * | 1999-12-15 | 2001-06-21 | Merck Sharp & Dohme Limited | Triazolo-pyrimidine derivatives as ligands for gaba receptors |
WO2002002557A2 (en) * | 2000-06-30 | 2002-01-10 | Neurogen Corporation | 2-phenylimidazo[1,2-a]pyridine derivatives: a new class of gaba brain receptor ligands |
WO2002038569A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-pyrimidine derivatives as ligands for gaba receptors |
WO2002050062A2 (en) * | 2000-12-21 | 2002-06-27 | Neurogen Corporation | Benzimidazole and pyridylimidazole derivatives as ligands for gaba receptors |
WO2002076983A1 (en) * | 2001-03-23 | 2002-10-03 | Merck Sharp & Dohme Limited | Imidazo-pyrimidine derivatives as ligands for gaba receptors |
WO2003006471A1 (en) * | 2001-07-13 | 2003-01-23 | Neurogen Corporation | Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands |
WO2003048132A1 (en) * | 2001-11-28 | 2003-06-12 | Merck Sharp & Dohme Limited | Imidazopyridines, pyrimidines and triazines for enhancing cognition as gaba-a alpha 5 receptor subtype ligands |
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WO2001044249A1 (en) * | 1999-12-15 | 2001-06-21 | Merck Sharp & Dohme Limited | Triazolo-pyrimidine derivatives as ligands for gaba receptors |
WO2002002557A2 (en) * | 2000-06-30 | 2002-01-10 | Neurogen Corporation | 2-phenylimidazo[1,2-a]pyridine derivatives: a new class of gaba brain receptor ligands |
WO2002038569A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-pyrimidine derivatives as ligands for gaba receptors |
WO2002050062A2 (en) * | 2000-12-21 | 2002-06-27 | Neurogen Corporation | Benzimidazole and pyridylimidazole derivatives as ligands for gaba receptors |
WO2002076983A1 (en) * | 2001-03-23 | 2002-10-03 | Merck Sharp & Dohme Limited | Imidazo-pyrimidine derivatives as ligands for gaba receptors |
WO2003006471A1 (en) * | 2001-07-13 | 2003-01-23 | Neurogen Corporation | Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands |
WO2003048132A1 (en) * | 2001-11-28 | 2003-06-12 | Merck Sharp & Dohme Limited | Imidazopyridines, pyrimidines and triazines for enhancing cognition as gaba-a alpha 5 receptor subtype ligands |
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SI1648899T1 (en) | 2007-08-31 |
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