CN1894236B - Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication - Google Patents

Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication Download PDF

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CN1894236B
CN1894236B CN2004800372812A CN200480037281A CN1894236B CN 1894236 B CN1894236 B CN 1894236B CN 2004800372812 A CN2004800372812 A CN 2004800372812A CN 200480037281 A CN200480037281 A CN 200480037281A CN 1894236 B CN1894236 B CN 1894236B
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CN1894236A (en
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J·-F·邦凡蒂
K·J·L·安德里斯
F·E·扬森斯
F·M·索门
J·E·G·吉耶蒙特
J·F·A·拉克拉姆佩
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Janssen R&D Ireland ULC
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Abstract

The present invention concerns amino-benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein Q is Ar<1> or C1-6alkyl substituted with one or more substituents selected from trifluoromethyl, C3-7cycloalkyl, Ar<2>, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar<2>-oxy-, Ar<2>-thio-, Ar<2>(CH2)noxy, Ar<2>(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarbonyl, Ar<2>-carbonyl, C1-4alkoxycarbonyl, Ar<2>(CH2)ncarbonyl, aminocarbonyloxy, C1-4alkylcarbonyloxy, Ar<2>-carbonyloxy, Ar<2>(CH2)ncarbonyloxy, hydroxy-C2-4-alkyloxy, C1-4alkoxycarbonyl(CH2)noxy, mono- or di(C1-4alkyl)-aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(C1-4alkyl)aminosulfonyl, dioxolanyl optionally substituted with one or two C1-6alkyl radicals, and a heterocycle selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, thiazolidinyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, which each may optionally be substituted with oxo or C1-6alkyl; G is a direct bond or optionally substituted C1-10alkanediyl R<1> is Ar<1> or a monocyclic or bicyclic heterocycle; one of R<2a> and R<3a> is C1-6alkyl and the other one of R<2a> and R<3a> is hydrogen; in case R<2a> is different from hydrogen then R<2b> is hydrogen or C1-6alkyl, and R<3b> is hydrogen; in case R<3a> is different from hydrogen then R<3b> is hydrogen or C1-6alkyl, and R<2b> is hydrogen; Ar<1> is phenyl or substituted phenyl and Ar<2> is phenyl or substituted phenyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

Description

Amino-benzimidazoles derivatives as inhibitors of respiratiory syncytial virus replication
The present invention relates to have the amino-benzimidazoles derivatives of antiviral activity, particularly have respiratory syncytial virus (RSV) and duplicate the active amino-benzimidazoles derivatives of inhibition.Relate to their preparation in addition and comprise their composition, and they are as the application of medicine.
People RSV or respiratory syncytial virus are bigger ribonucleic acid virus, are the member of Paramyxoviridae Pneumovirinae (pneumoviridae) subfamily with ox RSV virus.People RSV is the reason of various respiratory tract disease in all age groups of the whole world.It is lower respiratory illness between infancy and childhood main diseases because of.In all babies, the baby who surpasses half met with RSV in its 1 year, and nearly all baby meets with RSV in its first two years.Infection in the young child can cause the injury of lung of lasting for years, and may promote forming chronic lung disease (chronic wheezing, asthma) in the life subsequently.(weight) flu takes place in children that the age is big slightly and adult when being everlasting rsv infection.When old age, susceptibility increases once more, and RSV has been involved in the repeatedly outbreak of pneumonia among the old man, causes significant mortality ratio.
Infecting specific subgroup (subgroup) virus can not prevent to be infected by the RSV isolate from identical subtribe in winter subsequently.Therefore, infecting again of RSV is common, although only have two hypotypes, A and B.
Have only three medicines to be approved for the antagonism rsv infection now.First is the nucleoside analogues 'Libaweilin ', and it is provided for the treatment by aerosol of the serious rsv infection of hospitalized child.Aerosol drug delivery approach, toxicity (teratogenecity danger), cost and highly unsettled effect have limited its application.Other two medicines, RespiGam And palivizumab, be polyclone and monoclonal antibody immunity stimulant, be used for prevention method.
Up to now, other effort of exploitation safety and effective RSV vaccine has all met with failure.Inactivated vaccine can not preventing disease, and disease is strengthened.Attempt life and weakened (life attenuated) vaccine, obtained limited success.Obviously, need medicine antagonism RSV effective, nontoxic and administration easily to duplicate.
Benzimidazoles and imidazopyridine as the RSV replication inhibitors are described in WO01/00611, WO 01/00612 and WO 01/00615 to some extent.
The present invention relates to the RSV replication inhibitors, it can be represented by formula (I):
Figure S04837281220060619D000021
Their prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and stereochemistry heterogeneous forms, wherein
Q is Ar 2, C 3-7Cycloalkyl or be selected from the C that following substituting group replaces independently of one another by one or more 1-6Alkyl: trifluoromethyl, C 3-7Cycloalkyl, Ar 2, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, Ar 2-oxygen base-, Ar 2-sulfenyl-, Ar 2(CH 2) nOxygen base, Ar 2(CH 2) nSulfenyl, hydroxycarbonyl group, aminocarboxyl, C 1-4Alkyl-carbonyl, Ar 2Carbonyl, C 1-4Alkoxy carbonyl, Ar 2(CH 2) nCarbonyl, aminocarboxyl oxygen base, C 1-4Alkyl-carbonyl oxygen base, Ar 2Ketonic oxygen base, Ar 2(CH 2) nKetonic oxygen base, hydroxyl C 2-4-alkyl oxy, C 1-4Alkoxy carbonyl (CH 2) nOxygen base, list-or two (C 1-4Alkyl) amino-carbonyl, list-or two (C 1-4Alkyl) aminocarboxyl oxygen base, amino-sulfonyl, list-or two (C 1-4Alkyl) amino-sulfonyl, optional by one or two C 1-6The dioxolane base that alkyl replaces and be selected from following heterocycle: pyrrolidyl, pyrryl, pyrrolin base, indyl, imidazolyl, triazolyl, piperidyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydro pyridyl, wherein each described heterocycle can be chosen wantonly by oxo or C 1-6Alkyl replaces;
G is a direct key or optional by one or more C that are independently selected from following substituting group replacement 1-10Alkane two bases: hydroxyl, C 1-6Alkyl oxy, Ar 1C 1-6Alkyl oxy, C 1-6Alkyl sulfenyl, Ar 1C 1-6Alkyl sulfenyl, HO (CH 2-CH 2-O) n-, C 1-6Alkyl oxy (CH 2-CH 2-O) n-and Ar 1C 1-6Alkyl oxy (CH 2-CH 2-O) n-;
R 1Be Ar 1Or be selected from following monocycle or bicyclic heterocycle: piperidyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, furyl, tetrahydrofuran base, thienyl, pyrryl, thiazolyl,
Figure 048372812_5
Azoles base, imidazolyl, isothiazolyl, pyrazolyl, different The azoles base, Di azoly, quinolyl, quinoxalinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo Azoles base, benzothiazolyl, pyridopyridine base, naphthyridinyl (naphthiridinyl), 1H-imidazo [4,5-b] pyridyl, 3H-imidazo [4,5-b] pyridyl, imidazo [1,2-a] pyridyl, 2,3-dihydro-1,4-two oxa-glutinous rehmannias be the group of [2,3-b] pyridyl and following formula also:
Figure S04837281220060619D000031
Wherein each described monocycle or bicyclic heterocycle can be chosen wantonly by 1 or be replaced by a plurality of as 2,3,4 or 5 substituting groups when possible, and described substituting group is independently selected from halo, hydroxyl, amino, cyano group, carboxyl, C 1-6Alkyl, C 1-6Alkyl oxy, C 1-6Alkyl sulfenyl, C 1-6Alkyl oxy C 1-6Alkyl, Ar 1, Ar 1C 1-6Alkyl, Ar 1C 1-6Alkyl oxy, hydroxyl C 1-6Alkyl, list-or two (C 1-6Alkyl) amino, single-or two (C 1-6Alkyl) amino C 1-6Alkyl, many halos C 1-6Alkyl, C 1-6Alkyl-carbonyl-amino, C 1-6Alkyl-SO 2-NR 4a-, Ar 1-SO 2-NR 4a-, C 1-6The alkyl oxy carbonyl ,-C (=O)-NR 4aR 4b, HO (CH 2-CH 2-O) n-, halo (CH 2-CH 2-O) n-, C 1-6Alkyl oxy (CH 2-CH 2-O) n-, Ar 1C 1-6Alkyl oxy (CH 2-CH 2-O) n-and single-or two (C 1-6Alkyl) amino (CH 2-CH 2-O) n-;
Each n is 1,2,3 or 4 independently;
R 2aAnd R 3aOne of be C 1-6Alkyl, R 2aAnd R 3aIn another be hydrogen;
Work as R 2aWhen being not hydrogen, R then 2bBe hydrogen or C 1-6Alkyl, and R 3bBe hydrogen;
Work as R 3aWhen being not hydrogen, R then 3bBe hydrogen or C 1-6Alkyl, and R 2bBe hydrogen; Or
R 2a, R 2b, R 3aAnd R 3bAll be hydrogen;
R 4aAnd R 4bCan be same to each other or different to each other, and be hydrogen or C independently of one another 1-6Alkyl; Or
R 4aAnd R 4bForm formula-(CH together 2) s-divalent group;
R 5Be hydrogen or C 1-6Alkyl;
M is 1 or 2;
P is 1 or 2;
S is 4 or 5;
Ar 1For phenyl or by one or more as the phenyl that 2,3 or 4 substituting groups replace, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl, hydroxyl C 1-6Alkyl, many halos C 1-6Alkyl and C 1-6Alkyl oxy;
Ar 2For phenyl or by one or more as the phenyl that 2,3 or 4 substituting groups replace, described substituting group is selected from halo, hydroxyl, amino, cyano group, C 1-6Alkyl, hydroxyl C 1-6Alkyl, many halos C 1-6Alkyl, amino C 1-6Alkyl, C 1-6Alkyl oxy, amino-sulfonyl, aminocarboxyl, hydroxycarbonyl group, C 1-4Alkyl-carbonyl, list-or two (C 1-4Alkyl) amino, single-or two (C 1-4Alkyl) aminocarboxyl, list-or two (C 1-4Alkyl)-amino-sulfonyl, list-or two (C 1-4Alkyl) amino C 1-6Alkyl and C 1-4Alkoxy carbonyl.
The present invention relates to the compound of formula (I) or its prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and stereochemistry heterogeneous forms are used for suppressing the medicine that RSV duplicates in production application.Perhaps, the present invention relates to suppress the method that the RSV in the warm-blooded animal duplicates, described method comprises the compound of the formula (I) of effective dosage, or its prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and stereochemistry heterogeneous forms.
In aspect in addition, the present invention relates to the compound of new formula (I) and the method for preparing these compounds.
The term that uses in this specification sheets and claim " prodrug " is meant the pharmacology acceptable derivates, and as ester and acid amides, the bioconversion product of the derivative that obtains is suc as formula the defined active medicine of (I) compound.The general Goodman of prodrug and reference (The Pharmacological Basis of Therapeutics, the 8th edition, the McGraw-Hill of Gilman of describing, Int., Ed 1992, " Biotransformation of Drugs ", 13-15 page or leaf) be merged in this paper.Prodrug is characterised in that to have good water-solubility and bioavailability, and easily is metabolised to activity inhibitor in vivo.
Term used in the definition as Q " is chosen the C that is replaced by one or more substituting groups wantonly 1-6Alkyl " or the definition as G in used term " the optional C that is replaced by one or more substituting groups 1-10Alkane two bases " refer to comprise do not have substituting group, have one, two or more substituent C respectively 1-6Alkyl or C 1-10Alkane two bases, for example do not have substituting group, have one, two, three, four, five or six substituting groups, particularly do not have substituting group, have one, two or three substituting groups, further, particularly do not have substituting group, have one or two substituting group.The upper limit of substituting group number determines that by number of hydrogen atoms that can be replaced and by substituent general aspects such as their volume these character make can determine the described upper limit by those skilled in the art.
As " wherein heterocycle can be chosen wantonly by oxo or C as described in each about the employed term of Q herein 1-6Alkyl replaces " refer to comprise by one or more, be independently selected from oxo and C as maximum 3 or maximum 2 1-6The substituting group of alkyl replaces or is independently selected from oxo and C by one 1-6The heterocycle that the substituting group of alkyl replaces.
Use as described above and hereinafter, as group or as many halos C 1-6" many halos C of the part of alkoxy base 1-6Alkyl " to be defined as be single-or C of replacing of many halos 1-6Alkyl, the particularly C that is replaced by maximum, two, three, four, five, six or a plurality of halo atom 1-6Alkyl, as have the methyl or the ethyl of one or more fluorine atoms, for example difluoromethyl, trifluoromethyl, trifluoroethyl.Also comprise perfluor C 1-6Alkyl, it is that wherein all hydrogen atom is all by the displaced C of fluorine atom 1-6Alkyl is as pentafluoroethyl group.Be connected in many halos C at the halogen atom that surpasses 1-4When alkyl defined interior alkyl, these halogen atoms can be identical or different.
R 1Definition in each monocycle or bicyclic heterocycle can choose wantonly by 1 or when may the time replaced as 2,3,4 or 5 substituting groups by a plurality of substituting groups.Particularly, described heterocycle can be chosen wantonly by maximum 4, maximum 3, maximum 2 substituting groups or maximum 1 substituting group and replace.
Each Ar 1Or Ar 2The phenyl that can be unsubstituted phenyl or replaced by one or more substituting groups, as by 5 or 4 substituting groups, perhaps preferably by maximum 3 substituting groups or maximum two substituting groups, or a substituting group replaces.
When on Sauerstoffatom or nitrogen-atoms, replacing, hydroxyl C 1-6Alkyl is preferably hydroxyl C 2-6Alkyl, wherein hydroxyl is separated by at least two carbon atoms with oxygen or nitrogen.
As used in this article, C 1-3Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 3 carbon atom, as methyl, ethyl, propyl group, 1-methylethyl etc.; C 1-4Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 4 carbon atom, as C 1-3Defined group of alkyl and butyl etc.; C 2-4Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 2 to 4 carbon atoms, as ethyl, propyl group, 1-methylethyl, butyl etc.; C 1-5Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 5 carbon atom, as C 1-4Defined group of alkyl and amyl group, 1-methyl butyl, 2-methyl butyl, 1-ethyl propyl etc.; C 1-6Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 6 carbon atom, as C 1-5Defined group of alkyl and hexyl, 2-methyl amyl, 3-methyl amyl etc.; C 1-9Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 9 carbon atom, as C 1-6Defined group of alkyl and heptyl, octyl group, nonyl, 2-methyl hexyl, 2-methylheptyl etc.; C 1-10Alkyl, as the part of group or group, being defined as is the saturated hydrocarbyl with straight or branched of 1 to 10 carbon atom, as C 1-9Defined group of alkyl and decyl, 2-methyl nonyl etc.
C 3-7Cycloalkyl is meant the general name of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
C 2-5It is to have the straight chain of 2 to 5 carbon atoms and a divalent saturated hydrocarbon base of side chain that alkane two bases are defined as, such as for example, and 1,2-second two bases, 1,3-glyceryl, 1,4-fourth two bases, 1,2-glyceryl, 2,3-fourth two bases, 1,5-penta 2 bases etc.; C 1-4It is to have the straight chain of 1 to 4 carbon atom and a divalent saturated hydrocarbon base of side chain that alkane two bases are defined as, such as for example, and methylene radical, 1,2-second two bases, 1,3-glyceryl, 1,4-fourth two bases etc.; C 1-6Alkane two bases comprise C1-4 alkane two base and have the higher homologue of 5 to 6 carbon atoms, such as for example, and 1,5-penta 2 bases, 1,6-dihexyl etc.; C 1-10Alkane two bases comprise C 1-6Alkane two base and have the higher homologue of 7 to 10 carbon atoms, such as for example, 1,7-base in heptan two, 1, hot two bases, 1 of 8-, 9-base in the ninth of the ten Heavenly Stems two, 1,10-base in the last of the ten Heavenly stems two etc.
As front herein using, term (=O) when being connected, form carbonyl moiety with carbon atom, when being connected, form the sulfoxide part with sulphur atom, and when two described terms are connected with a sulphur atom formation alkylsulfonyl part.Term (=N-OH) when being connected, form hydroxyl imines part with carbon atom.
The term halo is the general name of fluoro, chloro, bromo and iodo.
It is pointed out that group position on any molecular moiety that uses in the definition can be any position on the described part, as long as it is chemically stable.
Unless otherwise indicated, the group that uses in the definition of each variable comprises all possible isomer.For example, pyridyl comprises 2-pyridyl, 3-pyridyl and 4-pyridyl; Amyl group comprises 1-amyl group, 2-amyl group and 3-amyl group.
When any variable occurred surpassing one time in any formation, each definition was independently.
When using hereinafter, term " compound of formula (I) " or " compound of the present invention " or similar term comprise the compound of general formula (I), their prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and stereochemistry heterogeneous forms.The interested subgroup of the compound of formula (I) or any subgroup of described subgroup are N-oxide compound, salt and all stereoisomeric forms in any ratio of the compound of formula (I).
Should be appreciated that the compound of some formulas (I) can comprise one or more chiral centres and exist as stereochemistry heterogeneous forms.
As above-mentioned use, that term " stereochemistry heterogeneous forms " has defined is that the compound of formula (I) can have, by identical atom by identical bonding order in conjunction with but all possible compound with not interchangeable different three-dimensional structures.
Unless otherwise mentioned or show that the chemical name of compound comprises the mixture of all possible stereochemistry heterogeneous forms that described compound may have.Described mixture can comprise all diastereomers and/or the enantiomer of the base molecule structure of described compound.No matter all stereochemistry heterogeneous forms of compound of the present invention are pure form or the form that is mixed with each other, and all are included in the scope of the present invention.
It is to be substantially devoid of other enantiomorph of same base molecule structure of described compound or intermediate or the isomer of diastereomer form that the pure stereoisomeric forms in any ratio of compound of mentioning herein and intermediate is defined as.Particularly, term " steric isomer is pure " is meant that to have at least 80% steric isomer excessive (for example, minimum 90% a kind of isomer and maximum 10% another kind of possible isomer) to excessive (promptly up to 100% steric isomer, a kind of isomer of 100% and do not contain other isomer) compound or intermediate, more particularly, have 90% to maximum 100% excessive compound or the intermediate of steric isomer, more particularly for having 94% to maximum 100% excessive compound or the intermediate of steric isomer, be to have 97% to maximum 100% excessive compound or the intermediate of steric isomer the most especially.Term " enantiomer-pure " and " diastereomer is pure " should do same understanding, and that is still discussed is excessive excessive with diastereomer about the enantiomer of mixture respectively.
The pure stereoisomeric forms in any ratio of compound of the present invention and intermediate can obtain by adopting methods known in the art.For example, the selective freezing of the non-mapping salt that can form by enantiomorph and optically active acid or alkali is separated from one another with enantiomorph.The example of acid is tartrate, two (benzoyl) tartrate, two (toluyl) tartrate and camphorsulfonic acids.Perhaps, enantiomer can use chiral stationary phase to separate by chromatographic technique.Described pure stereochemistry heterogeneous forms also can be obtained from the corresponding pure stereochemistry heterogeneous forms of suitable starting raw material, and condition is that reaction is carried out in the stereospecificity mode.Preferably, if expect specific steric isomer, described compound will be synthetic by the stereospecificity preparation method.These methods advantageously adopt the starting raw material of enantiomer-pure.
The racemoid of the diastereomer of formula (I) can obtain respectively by ordinary method.The suitable physical separation method that can advantageously adopt is for example selective freezing and chromatography such as column chromatography.
For the intermediate that uses in the compound of some formulas (I), their prodrug, N-oxide compound, salt, solvate, quaternary ammonium or metal complex and its preparation, the absolute stereo chemical structure is not to use determination of experimental method.Those skilled in the art can use methods known in the art such as for example, and X-ray diffraction method is measured the absolute configuration of these compounds.
The present invention also is intended to comprise all isotropic substances of the atom that exists on the The compounds of this invention.But isotropic substance comprises those atoms with same atoms ordinal number different mass number.As general non-limitative example, the isotropic substance of hydrogen comprises tritium and deuterium.The isotropic substance of carbon comprises carbon-13 and carbon-14.
Use for treatment, the salt of the compound of formula (I) for counter ion wherein be pharmaceutically useful those.Yet, also can use the salt of non-medicinal bronsted lowry acids and bases bronsted lowry, for example in the preparation or purifying of pharmaceutically acceptable compound.All salt, no matter whether it is pharmaceutically useful, all comprises within the scope of the invention.
Aforesaid pharmaceutically useful bronsted lowry acids and bases bronsted lowry additive salt comprises the nontoxic bronsted lowry acids and bases bronsted lowry additive salt form with therapeutic activity that the compound of formula (I) can form.Pharmaceutically useful additive salt can be easily by obtaining with described suitable acid treatment alkali form.Suitable acid comprises for example mineral acid, as haloid acid example hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid, such as for example, acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid are (promptly, oxalic acid), propanedioic acid, succsinic acid are (promptly, Succinic Acid), toxilic acid, fumaric acid, oxysuccinic acid (that is hydroxy-butanedioic acid), tartrate, citric acid, methanesulfonic, ethane sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid, pamoic acid etc.
Reversibly, described salt form can become free alkali form by with suitable alkaline purification.
The compound that comprises the formula (I) of acid proton also can be by handling its nontoxic metal or the amine additive salt form of being converted into suitable organic bases and mineral alkali.Suitable base salt forms comprises for example ammonium salt; The salt of basic metal and alkaline earth salt such as lithium, sodium, potassium, magnesium, calcium etc.; With organic bases such as N, the salt of N '-dibenzyl-ethylenediamin, N-methyl D-glycosamine, Kazakhstan amine; With with the salt of amino acid such as for example arginine, Methionin etc.
Above the term additive salt of Shi Yonging also comprises the compound of formula (I) and the solvate that salt can form thereof.This solvate is for example hydrate, alcoholate etc.
As above to be defined as be basic nitrogen that the compound of formula (I) can through type (I) compound and suitable quaternizing agent such as for example reaction and the quaternary ammonium salt that forms between optional alkyl halide, aryl halide or the arylalkyl halogenide that replaces such as methyl iodide or the benzyl iodide to the term of Shi Yonging " quaternary ammonium ".Also can use other reactant, as trifluoromethanesulfonic acid alkyl ester, methylsulfonic acid alkyl ester and alkyl tosylate with good leavings group.Quaternary ammonium has positively charged nitrogen.Pharmaceutically useful counter ion comprise chlorion, bromide anion, iodide ion, trifluoracetic acid root and acetate moiety.Can make spent ion exchange resin introduce selected counter ion.
The N-oxide form of compound of the present invention comprises that one of them or several nitrogen-atoms are oxidized into the compound of the formula (I) of so-called N-oxide compound.
Should be appreciated that the compound of formula (I) can have the character with melts combine, chelating, formation complex compound, therefore can be used as metal complex or metallo-chelate and exist.This metallization derivative of the compound of formula (I) is also attempted to be included in the scope of the present invention.
The compound of some formulas (I) also can its tautomeric form exist.Though this form is not expressed in following formula, it attempts to be included in the scope of the present invention.
Any subgroup of the compound of the formula that this paper specifies (I) also comprises prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and the stereochemistry heterogeneous forms of the subgroup of this formula (I) compound.
One embodiment of the invention relate to the compound of formula (I-a):
Wherein, Q, R 5, G and R 1Definition as mentioned above or the specific descriptions in any subgroup of compound as herein described; With
R 2aBe C 1-6Alkyl;
R 2bBe hydrogen or C 1-6Alkyl.
Another embodiment of the invention relates to the compound of formula (I-b):
Figure S04837281220060619D000092
Wherein, Q, R 5, G and R 1Definition as mentioned above or the specific descriptions in any subgroup of compound as herein described; With
R 3aBe C 1-6Alkyl;
R 3bBe hydrogen or C 1-6Alkyl.
Another embodiment of the invention relates to the compound of formula (I-c):
Figure S04837281220060619D000101
Wherein, Q, R 5, G and R 1Definition as mentioned above or the specific descriptions in any subgroup of compound as herein described.
Should be appreciated that any other subgroup of the subgroup of compounds such as the formula of above-mentioned definition (I-a), (I-b) and definition herein also comprises any prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and the stereochemistry heterogeneous forms of these compounds.
The concrete subgroup of the compound of formula (I) is C for G wherein 1-10Alkane two bases, more specifically for G wherein any subgroup of the compound of the compound of those formulas described herein (I) of methylene radical or formula (I).
Other concrete subgroup of the compound of formula (I) is wherein to adopt any subgroup of the compound of the compound of those formulas described herein (I) of following restricted condition or formula (I):
(a) R 1Not Ar 1Or wherein
(b) R 1Be Ar 1Or monocyclic heterocycles, it is as specifying in the definition of the compound of formula (I) or its any subgroup.
The concrete subgroup of the compound of other formula (I) is wherein to adopt any subgroup of the compound of the compound of those formulas described herein (I) of following restricted condition or formula (I):
(c) R 1By 1 or 2 pyridyl that substituting group replaces, described substituting group is independently selected from halo, hydroxyl, amino, cyano group, carboxyl, C for optional 1-6Alkyl, C 1-6Alkyl oxy, C 1-6Alkyl sulfenyl, C 1-6Alkyl oxy C 1-6Alkyl, Ar 1, Ar 1C 1-6Alkyl, Ar 1C 1-6Alkyl oxy, hydroxyl C 1-6Alkyl, list-or two (C 1-6Alkyl) amino, single-or two (C 1-6Alkyl) amino-C 1-6Alkyl, many halos C 1-6Alkyl, C 1-6Alkyl-carbonyl-amino, C 1-6Alkyl-SO 2-NR 4a, Ar 1-SO 2-NR 4a, C 1-6The alkyl oxy carbonyl ,-C (=O)-NR 4aR 4b, HO (CH 2-CH 2-O) n-, halo (CH 2-CH 2-O) n-, C 1-6Alkyl oxy (CH 2-CH 2-O) n-, Ar 1C 1-6Alkyl oxy (CH 2-CH 2-O) n-and single-or two (C 1-6Alkyl) amino (CH 2-CH 2-O) n-; Or more specifically
(d) R 1Be the pyridyl that replaced by 1 or 2 substituting groups, described substituting group is independently selected from hydroxyl, C 1-6Alkyl, halo, C 1-6Alkyl oxy, Ar 1C 1-6Alkyl oxy and (C 1-6Alkyl oxy) C 1-6Alkyl oxy; Preferably wherein
(e) R 1Be the pyridyl that replaced by 1 or 2 substituting groups, described substituting group is independently selected from hydroxyl, C 1-6Alkyl, halo and C 1-6Alkyl oxy; Or wherein
(f) R 1Be the pyridyl that replaced by 1 or 2 substituting groups, described substituting group is independently selected from hydroxyl and C 1-6Alkyl; More preferably wherein
(g) R 1For by hydroxyl and C 1-6The pyridyl that alkyl replaces; Or more preferably wherein
(h) R 1For by hydroxyl and methyl substituted pyridyl; Or wherein
(i) R 1Be 3-hydroxyl-6-picoline-2-base.
Other embodiments comprise wherein any subgroup of the compound of the compound of those formulas (I) that adopt following restricted condition or formula (I):
(j) R 1Be Ar 1, quinolyl, benzimidazolyl-, following formula group
Figure S04837281220060619D000111
Pyrazinyl or pyridyl; Or wherein
(k) R 1Be Ar 1, quinolyl, benzimidazolyl-or wherein m be group, pyrazinyl or the pyridyl of 2 formula (c-4);
Wherein (j) and (k) in each group can choose wantonly by the substituting group that in the definition of formula (I) compound, specifies and replace, particularly pyridyl can be substituted according to the mode that specifies in above-mentioned (a) to (i).
Other embodiments comprise wherein any subgroup of the compound of the compound of those formulas (I) that adopt following restricted condition or formula (I):
(l) R 1Be Ar 1, quinolyl, benzimidazolyl-or wherein m be group, pyrazinyl or the pyridyl of 2 formula (c-4), wherein each of these groups all can be chosen wantonly by one, two or three groups and replace, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl, C 1-6Alkyl oxy, Ar 1C 1-6Alkyl oxy, (C 1-6Alkyl oxy) C 1-6Alkyl oxy; Or more specifically wherein
(m) R 1Be Ar 1, quinolyl, benzimidazolyl-or wherein m be group, pyrazinyl or the pyridyl of 2 formula (c-4), wherein each of these groups all can be chosen wantonly by one, two or three groups and replace, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl, C 1-6Alkyl oxy, benzyl oxygen base; Or more specifically wherein
(n) R 1By one, two or three phenyl that substituting group replaces, described substituting group is selected from halo, hydroxyl, C for optional 1-6Alkyl, C 1-6Alkyl oxy; Quinolyl; Wherein m is 2 group (c-4), and it is chosen wantonly and is selected from C by maximum two 1-6The group of alkyl replaces; Optional by C 1-6The benzimidazolyl-that alkyl replaces; The optional pyridyl that is replaced by one or two substituting group, described substituting group is selected from hydroxyl, halo, C 1-6Alkyl, benzyloxy and C 1-6Alkyl oxy; The optional pyrazinyl that is replaced by maximum three substituting groups, described substituting group is selected from C 1-6Alkyl; Or the replacement that in above-mentioned (a)-(i), specifies or optional substituted pyridyl; Or wherein
(o) R 1Be the optional phenyl that is replaced by one or two substituting group, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl, C 1-6Alkyl oxy; Or
(p) R 1Be quinolyl; Or
(q) R 1For m wherein is 2 group (c-4), it is optional to be selected from C by maximum two 1-6The group of alkyl replaces; Or
(r) R 1For choosing wantonly by C 1-6The benzimidazolyl-that alkyl replaces; The optional pyridyl that is replaced by one or two substituting group, described substituting group is selected from hydroxyl, halo, C 1-6Alkyl, benzyloxy and C 1-6Alkyl oxy; Or
(s) R 1Be selected from C for optional by maximum three 1-6The pyrazinyl that the group of alkyl replaces.
The arbitrary described subgroup of the subgroup of the compound of preferred formula (I) or the compound of formula (I) is direct key or methylene radical and R for G wherein 1As specifying in above-mentioned (a)-(s) those.Further preferably wherein G be direct key and R 1For group (c-4), particularly wherein m to be that 2 group (c-4), group (c-4) are optional be selected from C by maximum two 1-6Compound or any subgroup that the group of alkyl replaces in formula as herein described (I).Further preferably wherein or G be methylene radical and R 1As above-mentioned (a)-(s) definition but whether compound or any subgroup of the formula as herein described (I) of group (c-4).
Other embodiment comprises wherein R 5Any subgroup for the compound of the compound of the formula as herein described (I) of hydrogen or formula (I).
Other embodiment comprises any subgroup of the compound of the compound of those formulas as herein described (I) or formula (I), wherein:
(a) Q is Ar 2, C 3-7Cycloalkyl or the C that replaced by and two substituting groups 1-6Alkyl, described substituting group are selected from the substituting group of mentioning independently of one another in the definition of the compound of formula (I) or its any subgroup; Or particularly
(b) Q is Ar 2, C 3-7Cycloalkyl or the C that is replaced by a substituting group 1-6Alkyl, described substituting group are selected from the substituting group of mentioning in the definition of the compound of formula (I) or its any subgroup, and described C 1-6Alkyl is optional further to be replaced by a hydroxyl; Or
(c) Q is Ar 2, C 3-7Cycloalkyl or the optional C that is replaced by one or two substituting group 1-6Alkyl, described substituting group is selected from trifluoromethyl, Ar independently of one another 2, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, Ar 2-oxygen base-, Ar 5(CH 2) nOxygen base, hydroxyl-carbonyl, aminocarboxyl, C 1-4Alkyl-carbonyl, Ar 2Carbonyl, C 1-4Alkoxy carbonyl, C 1-4Alkyl-carbonyl oxygen base, hydroxyl-C 2-4-alkyl oxy, list-or two (C 1-4Alkyl) amino-carbonyl, optional by one or two C 1-6The dioxolane base that alkyl replaces and be selected from the heterocycle of pyrrolidyl, pyrryl, pyrrolin base, indyl, imidazolyl, triazolyl, piperidyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydro pyridyl, wherein each described heterocycle can be chosen wantonly by maximum two substituting groups and replace, and described substituting group is independently selected from oxo and C 1-6Alkyl; Or
(d) Q is Ar 2, C 3-7Cycloalkyl or the optional C that is replaced by a substituting group 1-6Alkyl, described substituting group is selected from trifluoromethyl, Ar 2, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, Ar 2-oxygen base-, Ar 2(CH 2) nOxygen base, hydroxycarbonyl group, aminocarboxyl, C 1-4Alkyl-carbonyl, Ar 2Carbonyl, C 1-4Alkoxy carbonyl, C 1-4Alkyl-carbonyl oxygen base, hydroxyl-C 2-4-alkyl oxy, list-or two (C 1-4Alkyl)-aminocarboxyl, optional by one or two C 1-6The dioxolane base that alkyl replaces and be selected from the heterocycle of pyrrolidyl, pyrryl, pyrrolin base, indyl, imidazolyl, triazolyl, piperidyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydro pyridyl, wherein each described heterocycle can be chosen wantonly by maximum two substituting groups and replace, and described substituting group is independently selected from oxo and C 1-6Alkyl and described C 1-6Alkyl is optional further to be replaced by a hydroxyl; Or
(e) Q is Ar 2, C 3-7Cycloalkyl or the optional C that is replaced by one or two substituting group 1-6Alkyl, described substituting group is selected from Ar independently of one another 2, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, aminocarboxyl, C 1-4Alkoxy carbonyl, hydroxyl-C 2-4-alkyl oxy, by two C 1-6The dioxolane base that alkyl replaces and be selected from the heterocycle of pyrrolidyl, indyl, imidazolyl, piperidyl, piperazinyl and pyridyl, wherein each described heterocycle can be chosen wantonly by maximum two substituting groups and replace, and described substituting group is independently selected from oxo and C 1-6Alkyl; Or
(f) Q is Ar 2, C 3-7Cycloalkyl or the optional C that is replaced by following group 1-6Alkyl: Ar 2, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, aminocarboxyl, C 1-4Alkoxy carbonyl, hydroxyl C 2-4-alkyl oxy, by two C 1-6The dioxolane base that alkyl replaces or be selected from the heterocycle of pyrrolidyl, indyl, imidazolyl, piperidyl, piperazinyl and pyridyl, wherein each described heterocycle can be chosen wantonly by maximum two substituting groups and replace, and described substituting group is independently selected from oxo and C 1-6Alkyl and described C 1-6Alkyl is optional further to be replaced by a hydroxyl; Or
(g) Q is Ar 2, C 3-7Cycloalkyl or the optional C that is replaced by following group 1-6Alkyl: Ar 2, one or two hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, aminocarboxyl, C 1-4Alkoxyl group-carbonyl, hydroxyl C 2-4-alkyl oxy, by two C 1-6The dioxolane base that alkyl replaces or be selected from the heterocycle of pyrrolidyl, indyl, imidazolyl, piperidyl, piperazinyl and pyridyl, wherein each described heterocycle can be chosen wantonly by two and be independently selected from oxo and C 1-6The substituting group of alkyl replaces; Or
(h) Q is the optional C that is replaced by following group 1-6Alkyl: Ar 2, one or two hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl sulfenyl, aminocarboxyl, C 1-4Alkoxy carbonyl or be selected from the heterocycle of pyrrolidyl, imidazolyl, piperidyl and piperazinyl, wherein each described heterocycle can be chosen wantonly by oxo or C 1-6Alkyl replaces or by oxo and C 1-6Alkyl replaces; Or
(i) Q is Ar 2
In the subgroup of mentioning in last paragraph, interested subgroup is Ar wherein 2For phenyl or by 1,2 or 3 substituting group or by those of 1 or 2 substituting groups or the phenyl that preferably replaced by a substituting group, substituting group is selected from halo, hydroxyl, amino, cyano group, hydroxyl C 1-6Alkyl, amino C 1-6Alkyl, C 1-6Alkyl oxy and amino-sulfonyl.In the subgroup of mentioning in last paragraph, interested subgroup in addition is Ar wherein 2For phenyl or by 1,2 or 3 substituting group or by those of 1 or 2 substituting groups or the phenyl that preferably replaced by a substituting group, substituting group is selected from amino, cyano group, hydroxyl C 1-6Alkyl, amino C 1-6Alkyl and amino-sulfonyl.
Particularly, Ar 1For phenyl or by 1,2,3 substituting group or the phenyl that replaced by 1,2 substituting group, described substituting group is selected from those that mention in the definition of the compound of formula (I) or its any subgroup.
Ar 2For phenyl or by 1,2,3 substituting group or the phenyl that replaced by 1,2 substituting group, described substituting group is selected from those that mention in the definition of the compound of formula (I) or its any subgroup.
In any subgroup of compound of the group of the compound of formula (I) or formula (I):
(a) Ar 1Be preferably phenyl or by maximum 3 substituting groups or by maximum 2 substituting groups or the phenyl that replaced by substituting group, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl, hydroxyl C 1-6Alkyl, trifluoromethyl and C 1-6Alkyl oxy;
(b) more preferably Ar 1For phenyl or by maximum 3 substituting groups or by maximum 2 substituting groups or the phenyl that replaced by substituting group, described substituting group is selected from halo, hydroxyl, C 1-6Alkyl and C 1-6Alkyl oxy;
(c) more preferably Ar 1For phenyl or by maximum 3 substituting groups or by maximum 2 substituting groups or the phenyl that replaced by substituting group, described substituting group is selected from halo and C 1-6Alkyl.
The concrete subgroup of the compound of other formula (I) is Ar wherein 2As Ar 1The compound of those formulas as herein described (I) of definition or any subgroup of the compound of formula (I).
The concrete subgroup of the compound of other formula (I) is R wherein 2aAnd R 3aOne of be C 1-6Alkyl, R 2aAnd R 3aIn another be hydrogen; Work as R 2aWhen being not hydrogen, R then 2bBe C 1-6Alkyl and R 3bBe hydrogen; Work as R 3aWhen being not hydrogen, R then 3bBe C 1-6Alkyl and R 2bAny subgroup for the compound of the compound of those formulas as herein described (I) of hydrogen or formula (I).
Preferred compound those compounds that to be table 1 enumerate in 3 more particularly are compound 1 to 11 and 25 to 28.
The compound of formula (I) or its any subgroup can be according to following reaction scheme preparations.
Figure S04837281220060619D000151
In these diagrams, Q, G, R 1, R 2a, R 2b, R 3a, R 3b, R 5Implication with definition of the above-mentioned compound that is used for formula (I) or its any subgroup.W is suitable leavings group, is preferably chlorine or bromine.These diagrammatic reactions can be usually at appropriate solvent such as ether such as THF; Halohydrocarbon such as methylene dichloride, CHCl 3Toluene; Carry out among polar aprotic solvent such as DMF, DMSO, the DMA etc.Can add the acid of alkali to discharge in the absorption reaction process.If expectation can add some catalyzer such as iodide salt (as KI).
The compound of formula (I) can transform each other by functional group as known in the art conversion reaction (be included in described below those).R wherein 5For the compound of the formula (I) of hydrogen can be converted into wherein R by the N-alkylated reaction 5Be not the compound of the formula (I) of hydrogen, this reaction can or (IV) be converted under the simulated condition of (I) at aforesaid (II) to be carried out.
Wherein Q is by C 1-4The C that alkoxy carbonyl replaces 1-6The compound of alkyl can be used for example LiAIH 4Be reduced to the wherein C of Q for being replaced by hydroxyl 1-6The corresponding compounds of alkyl.Identical starting raw material can react with amine, obtains corresponding amide.
Wherein Q is for having cyano group or cyano group C 1-5The compound of the formula of the Ar of alkyl substituent (I) can be used hydrogen reduction in the presence of suitable catalyzer such as Raney nickel, obtain corresponding benzylidene amino or amino C 1-6Alkyl substituent.
The many intermediates that are used for preparation formula (I) compound are the analogue of known compound or known compound, the improved method preparation of the means known in the art that it can be easy to get by those skilled in the art.The preparation of many intermediates provides in more detail following.Formula (II) and intermediate (IV) can prepare shown in following reaction scheme.
In first step, use urea with diaminobenzene (VI) cyclisation, preferably in appropriate solvent such as dimethylbenzene, carry out, obtain benzimidazolone (VII).The latter is converted into wherein that W is the benzimidazoles derivative (VIII) of the above-mentioned leavings group that specifies, especially, and by (VII) and suitable halide reagent such as POCl 3Reaction.In the N-alkylated reaction,, obtain intermediate (II) with the intermediate (VIII) and sulfonamide derivatives (IX) reaction that obtain.
Intermediate (VIII) can react with amine (XII) in a similar fashion, obtains intermediate (IV).Above-mentioned being reflected in the appropriate solvent carried out, if expectation is carried out in the presence of alkali.
The compound of formula (I) also can be converted into corresponding N-oxide form according to the method that is used for trivalent nitrogen is converted into its N-oxide form known in the art.Described N-oxidizing reaction can be usually undertaken by starting raw material that makes formula (I) and suitable organic or inorganic peroxide reactions.Suitable inorganic peroxide for example comprises hydrogen peroxide, basic metal or alkaline earth metal peroxide such as sodium peroxide, Potassium peroxide; Suitable organo-peroxide can comprise peroxy acid, such as for example, and benzoyl hydroperoxide such as 3-chloroperoxybenzoic acid that benzoyl hydroperoxide or halogen replace; Peroxide bond alkanoic acid such as Peracetic Acid, alkyl peroxide such as tertbutyl peroxide.Appropriate solvent be for example water, lower alcohol such as ethanol etc., hydrocarbon such as toluene, ketone such as 2-butanone, halohydrocarbon as methylene dichloride and as described in the mixture of solvent.
Can obtain the pure stereochemistry heterogeneous forms of the compound of formula (I) by methods known in the art.Diastereomer can separate with chromatographic technique such as counter-current distribution method, liquid phase chromatography etc. by physical method such as selective freezing.
The compound of the formula for preparing in aforesaid method (I) is generally the racemic mixture of enantiomer, can be according to method for splitting known in the art that it is separated from one another.Having the racemic formula of enough alkalescence or tart (I) compound can be by being converted into the form of corresponding non-mapping salt with suitable chiral acid or chiral base reaction.Subsequently described non-mapping salt form is separated,, and therefrom discharge enantiomer by alkali or acid for example by selective freezing or fractional crystallization.The alternative method of the enantiomeric form of separate type (I) compound relates to liquid phase chromatography, particularly uses the liquid phase chromatography of chiral stationary phase.Described pure stereochemistry heterogeneous forms also can derive from the corresponding suitably pure stereochemistry heterogeneous forms of starting raw material, and condition is that reaction is carried out in the stereospecificity mode.Preferably, if expect specific steric isomer, described compound is synthetic by the stereospecificity preparation method.These methods advantageously adopt the starting raw material of enantiomer-pure.
In aspect other, the present invention relates to medicinal compositions, it comprises compound and pharmaceutically acceptable carrier in any subgroup of compound of the compound of the formula as herein described (I) for the treatment of significant quantity or formula as herein described (I).Here, the treatment significant quantity for enough infected experimenter or be in the antagonism virus infection that prophylactically works among the experimenter under the infected danger, stable or reduce the amount of virus infection, particularly at the RSV virus infection.In aspect other, the present invention relates to prepare the method for medicinal compositions as herein described, it comprises the compound in any subgroup of the compound of the compound of formula as herein described (I) of pharmaceutically acceptable carrier and treatment significant quantity or formula as herein described (I) is closely mixed.
Therefore, compound of the present invention or its any subgroup can be formulated as the various medicament forms that are used for the administration purpose.As suitable composition, can mention all compositions that are generally used for being administered systemically.In order to prepare medicinal compositions of the present invention, with the specific compound as active ingredient of significant quantity (optional be additive salt form or metal complex form) be incorporated in the tight blended mixture of pharmaceutically acceptable carrier in, carrier can be taked various ways, decides according to the dosage form that administration is required.These medicinal compositionss can be suitable unit dosage as required, particularly are applicable to oral, rectum, through skin or non-enteron aisle drug administration by injection.For example, when the composition of preparation oral dosage form, in the situation of oral liquid such as suspension, syrup, elixir, emulsion and solution, can adopt any drug media commonly used, such as for example, water, glycol, oils, alcohol etc.; Or in the situation of powder, pill, capsule and tablet, use solid carrier such as starch, sugar, kaolin, lubricant, tackiness agent, disintegrating agent etc.Because tablet and the easy administration of capsule, tablet and capsule are best oral unit dosage form, in this case, obviously use the solid medicinal carrier.For non-enteron aisle composition, carrier generally includes sterilized water (comprising most sterilized water at least), also can comprise other component that for example helps solubleness.Can preparation example such as injection liquid, wherein carrier comprises the mixture of salt brine solution, glucose solution or salt solution and glucose solution.Also injectable suspensions can be prepared, in this case, suitable liquid vehicle, suspending agent etc. can be used.Also be included in the solid preparation that is converted into liquid preparation before being about to use.In being suitable for the composition of percutaneous dosing, optional penetration enhancers and/or the suitable wetting agent of comprising of carrier, their suitable additive combinations with any character optional and the trace ratio, described additive does not cause any significant deleterious effect to skin.
Compound of the present invention also can adopt oral in the art suction or be blown into the used method and formulation of administration by oral suction or be blown into administration.Therefore, usually, compound of the present invention can be used as the form of solution, suspension or dry powder to the lung administration, is preferably solution.Exploitation is used for by oral suction or is blown into the administration that any system of sending solution, suspension or dry powder all is suitable for The compounds of this invention.
Therefore, the present invention also provides and is adapted to pass through a mouthful medicinal compositions that sucks or be blown into administration, and it comprises compound and pharmaceutically acceptable carrier of formula (I).Preferably, compound of the present invention is by the solution mode administration with suction spraying or aerosolization dosage.
Particularly advantageous is that above-mentioned medicinal compositions is formulated as administration and the inhomogeneity unit dosage of being convenient to dosage.Be meant the discontinuous unit of the physics that is suitable as unitary dose at this used unit dosage, each unit comprises the active ingredient that produces the predetermined amount of required curative effect with the pharmaceutical carrier bonded plan of needs.The example of this unit dosage is tablet (comprising scored tablet or coating tablet), capsule, pill, flour bag, wafer, injectable solution or suspension etc. and the multiple agent type that separates thereof.
The compound of formula (I) shows antiviral properties.Can use the virus infection of Compounds and methods for of the present invention treatment to comprise those infection that cause by orthomyxovirus and paramyxovirus and particularly people and bovine respiratory syncytial virus (RSV).In addition, chemical compound lot of the present invention effectively resists the RSV mutant strain.In addition, chemical compound lot of the present invention shows favourable pharmacokinetic property and have more attractability aspect bioavailability, comprises acceptable transformation period, AUC and peak value, and does not have disadvantageous phenomenon, is detained as inadequate rapid onset and tissue.
The antiviral activity of the external anti-RSV of The compounds of this invention is tested in the test described in the experimental section of specification sheets, and it also can describe in viral underproduction test.In the body of The compounds of this invention the antiviral activity of anti-RSV can as people such as Wyde (AntiviralResearch (1998), 38,31-42) describe in the trial model of described use cotton mouse.
Because their antiviral properties, their anti-RSV character particularly, the compound of formula (I) or its any subgroup, their prodrug, N-oxide compound, additive salt, quaternary ammonium, metal complex and stereochemistry heterogeneous forms can be used for treating the individuality of experience virus infection, particularly experience the individuality of rsv infection, and be used for the prevention of these infection.Usually, compound of the present invention can be used for treating and has infected the virus warm-blooded animal of respiratory syncytial virus particularly.
Therefore, compound of the present invention or its any subgroup useful as drug.Described application as medicine or methods of treatment comprises systematically effective antagonism and the virus infection amount of the relevant patient's condition with rsv infection particularly of administration of experimenter that the experimenter of infective virus or susceptible viral are infected.
The invention still further relates to compound of the present invention or its any subgroup is used for the treatment of or the particularly application in the medicine of rsv infection of prophylaxis of viral infections in production.
The present invention relates in addition and treats by virus infection or be in by the method for the warm-blooded animal under the risk from viral infection, described infection is rsv infection particularly, and described method comprises the compound in any subgroup of compound of the compound of formula as herein described (I) of the antiviral significant quantity of administration or formula as herein described (I).
Usually, think that antiviral effective per daily dose arrives the 500mg/kg body weight for the 0.01mg/kg body weight, more preferably the 0.1mg/kg body weight is to the 50mg/kg body weight.Required dosage was divided into two, three, four or more a plurality of sub-doses in one day also be suitable with the appropriate intervals administration.Described sub-doses can be formulated as unit dosage, and for example the per unit formulation comprises 1 to 1000mg, more specifically is 5 to 200mg active ingredient.
The other medicines that definite dosage and frequency may be taken according to the degree of age of the severity of the patient's condition of the concrete patient's condition of the compound of the specific formula of using (I), treatment, treatment, particular patient, body weight, sex, illness and general physical condition and this individuality are decided, and these are well known to a person skilled in the art.In addition, apparent, can reduce or increase described effective per daily dose, decide according to treatment experimenter's reaction and/or according to the doctor's of the prescription of leaving The compounds of this invention evaluation.Therefore, the effective per daily dose scope of mentioning hereinbefore is that principle instructs.
In addition, can use the combination of compounds of another kind of antiviral agent and formula (I) as medicine.Therefore, the invention still further relates to comprise and in antiviral therapy, be used for simultaneously, separately or (I) compound of (a) formula that uses in order and (b) product of another kind of antiviral compound as combination preparation.Different medicines can be combined in the unitary agent with pharmaceutically acceptable carrier.For example, compound of the present invention can with the combination of interferon-beta or tumor necrosis factor-alpha, be used for the treatment of or prevent rsv infection.
Embodiment
Following examples are intended to illustrate the present invention rather than restriction the present invention.Term " compound 1 ", " compound 4 " that is used for these embodiment etc. is meant the same compound in the table.
Use following equipment to pass through the LC/MS authenticating compound:
LCT: with the electrospray ionization of positive power mode operation, scan mode from 100 to 900amu; Xterra MS C18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/min.Adopt two moving phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile), with 100%A keep 3 minutes, in 5 minutes to 100%B, 100%B keep 6 minutes, in 3 minutes to 100%A, and once more in 3 minutes gradient of 100%A balance operation).
ZQ: with the electrospray ionization of positive electricity and the operation of negative electricity (pulse) pattern, sweep limit is 100 to 1000amu; Xterra RP C18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/min.Adopt two moving phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile), with 100%A keep 3 minutes, in 5 minutes to 100%B, 100%B keep 6 minutes, in 3 minutes to 100%A, and once more in 3 minutes gradient condition of 100%A balance).
Embodiment 1: the preparation of dimethylbenzimidazole amine
Diagram A
Figure S04837281220060619D000211
The preparation of intermediate a-2:
With SOCl 2(14ml) be added drop-wise in 5 ℃ the solution of (3-benzyloxy-6-methyl-pyridine-2-yl)-methyl alcohol (0.0606mol).To react and at room temperature stir 3 hours.Solvent evaporated under reduced pressure.Resistates is dissolved in the ether.Throw out is filtered and drying, obtain the a-2 (98%, fusing point: 182 ℃) of 16.9g.
Intermediate a-4 preparation:
With 2-chloro-4,6-dimethyl-1H-benzoglyoxaline (0.083mol), a-2 (0.0913mol) and K 2CO 3(0.332mol) mixture in dimethyl formamide (100ml) at room temperature stirred 24 hours.Add H then 2O.Mixture CH 2Cl 2Extract three times.Organic layer is separated dry (MgSO 4), filter and 30 ℃ of following solvent evaporated under reduced pressure.Resistates is dissolved in CH 3The CN/ diisopropyl ether.Throw out is filtered and drying, obtain the a-4 (52%, fusing point: 155 ℃) of 16.8g.
The preparation of intermediate a-5:
The mixture of a-4 (0.0007mol) and 3-piperidines-1-base propyl group amine (0.003mol) was stirred 2 hours at 130 ℃.Resistates is from CH 3The CN crystallization.Throw out is filtered and drying, obtain [1-(3-benzyloxy-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-yl]-(3-piperidines-1-base propyl group)-amine (46%) of 0.174g.
The preparation of final compound a-6:
With [1-(3-benzyloxy-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-yl]-(3-piperidines-1-base propyl group)-amine (0.0003mol) and Pd/C (0.06g) at CH 3Diatomite filtration is passed through in the hydrogenation 1 hour under 3 bar pressures at room temperature of mixture among the OH (10ml) then.Filtrate is evaporated.Resistates is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=89/10/1; 10 μ m).Collect pure fraction and evaporating solvent.Resistates (0.084g) is from CH 3The CN crystallization.Throw out is filtered and drying, obtains the 2-[4 of 0.073g, 6-dimethyl-2-(3-piperidines-1-base-propyl group amino)-benzoglyoxaline-1-ylmethyl]-6-methyl-pyridine-3-alcohol (compound 1,51%, fusing point:＞260 ℃).
Embodiment 2: the preparation of the dimethylbenzimidazole amine that the dihydroxyl alkyl replaces
Diagram B
Figure S04837281220060619D000221
The preparation of intermediate b-3:
The mixture of b-1 (0.0014mol) and b-2 (0.0012mol) was stirred 3 hours at 130 ℃, stirred 2 hours at 160 ℃ then, cool to room temperature also is dissolved in CH 2Cl 2In.Organic layer 10%K 2CO 3Solution is washed, dry (MgSO 4), filtration and evaporating solvent are up to drying.Resistates is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=97/3/0.1).Collect pure fraction and evaporating solvent, obtain the intermediate b-3 (81%) of 0.55g.
The preparation of compound b-4:
With b-3 (0.0011mol) and Pd/C (0.18g) at CH 3Diatomite filtration is passed through in the hydrogenation 1 hour under 3 bar pressures of mixture among the OH (10ml) then.With diatomite CH 3The OH rinsing.Filtrate decompression is concentrated.Resistates (0.47g) is from CH 3The CN crystallization.Throw out is filtered and drying, obtains the 2-{2-[(2 of 0.27g, 2-dimethyl-[l, 3] dioxolane-4-ylmethyl)-amino]-4,6-dimethyl-benzoglyoxaline-1-ylmethyl }-6-methyl-pyridine-3-alcohol (compound 21,60%, fusing point: 225 ℃).
The preparation of final compound b-5:
With 2-{2-[(2,2-dimethyl-[1,3] dioxolane-4-ylmethyl)-and amino]-4,6-dimethyl-benzoglyoxaline-1-ylmethyl }-mixture of 6-methyl-pyridine-3-alcohol (0.0005mol) in 3N HCl solution (15ml) and tetrahydrofuran (THF) (15ml) stirred 4 hours.The reduction vaporization tetrahydrofuran (THF).With mixture K 2CO 3(powder) alkalization.With water layer K 2CO 3(powder) is saturated.Add CH 2Cl 2/ CH 3OH (90/10) solution.Separate organic layer, dry (MgSO 4), filter and evaporating solvent.Resistates (0.17g, 88%) is from CH 3The crystallization of CN/ diisopropyl ether.Throw out is filtered and drying.The 3-[1-of yield: 0.085g (3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino]-propane-1,2-glycol (compound 4, fusing point: 205 ℃).
Embodiment 3: the preparation of the dimethylbenzimidazole amine that hydroxyalkyl replaces
Diagram C
Figure S04837281220060619D000231
The preparation of intermediate c-3:
The mixture of c-2 (0.004mol) and c-1 (0.006mol) was stirred 12 hours at 130 ℃, be dissolved in CH then 2Cl 2In.With organic layer with 10% K 2CO 3Solution is washed, dry (MgSO 4), filtration and evaporating solvent are up to drying.Resistates (0.6g) is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=95/5/0.2; 10 μ m).Collect pure fraction and evaporating solvent, obtain the intermediate c-3 (38%) of 0.4g.
The preparation of compound c-5:
With c-3 (0.0015mol), c-4 (0.0016mol) and K 2CO 3(0.0052mol) mixture in dimethyl formamide (20ml) stirred 4 hours at 70 ℃.Evaporating solvent is up to drying.Resistates is dissolved in CH 2Cl 2In.With organic layer H 2O washes, dry (MgSO 4), filter and evaporating solvent.Resistates (0.81g) is by silica gel column chromatography purifying (elutriant: toluene/isopropanol/NH 4OH=90/10/0.5; 10 μ m). collect pure fraction and evaporating solvent.Resistates (0.12g) is from Virahol/CH 3The crystallization of CN/ diisopropyl ether.Throw out is filtered and drying, obtains the 3-[1-(3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4 of 0.12g, 6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino]-ethyl propionate (compound 12,21%, fusing point: 180 ℃).
The preparation of final compound c-6:
Under 5 ℃ at N 2Flow down LiAlH 4(0.0003mol) join 3-[1-(3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino in batches]-mixture of ethyl propionate (0.0001mol) in tetrahydrofuran (THF) (10ml) in.Mixture was stirred 1 hour at 5 ℃, at room temperature stirred then 3 hours.Add ethyl acetate and H 2O.The mixture ethyl acetate extraction.Separate organic layer, dry (MgSO 4), filtration and evaporating solvent are up to drying.From acetone/CH 3The crystallization of CN/ diisopropyl ether.Throw out is filtered and drying, obtains the 2-[2-(3-hydroxypropyl amino)-4 of 0.025g, 6-dimethyl-benzoglyoxaline-1-ylmethyl]-6-methyl-pyridine-3-alcohol (compound 7,73%, fusing point: 170 ℃).
Embodiment 4: the preparation of the dimethylbenzimidazole amine that amido alkyl replaces
Diagram D
Figure S04837281220060619D000241
With 3-[1-(3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino]-ethyl propionate (0.0001mol) is at NH 3Saturated CH 3Mixture in the OH solution (10ml) stirred 6 hours at 70 ℃.Evaporating solvent is up to drying.Resistates (0.05g) is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=88/12/1; 10 μ m).Collect pure fraction and evaporating solvent.Resistates (0.022g, 48%) is from acetone/CH 3The crystallization of CN/ diisopropyl ether.Throw out is filtered and drying, obtains the 3-[1-(3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4 of 0.014g, 6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino]-propionic acid amide d-2 (compound 8,30%, fusing point: 229 ℃).
Embodiment 5: the preparation of the dimethylbenzimidazole amine that aryl replaces
Diagram E
The preparation of intermediate e-3
The mixture of e-1 (0.0022mol) and e-2 (0.0023mol) was stirred 1 hour at 130 ℃, then cool to room temperature and be dissolved in CH 2Cl 2In.Throw out is filtered.The mother liquor layer is evaporated.Resistates (0.522g) is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=99/1/0.1 to 90/10/1; 5 μ m).Collect pure fraction and evaporating solvent, obtain the intermediate e-3 (62%) of 0.36g.
The preparation of Verbindung-5:
Prepare 4-[1-(3-hydroxyl-6-methyl-pyridine-2-ylmethyl)-4,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji amino to be similar to the described method of c-5]-benzonitrile (compound 20, fusing point:＞260 ℃).
The preparation of final compound e-6:
Raney nickel (0.2g) is joined e-5 (0.0001mol) at NH 3Saturated CH 3In the mixture in the OH solution (20ml).With mixture hydrogenation at room temperature 3 hours under 5 bar pressures, pass through diatomite filtration then.With diatomite H 2The O rinsing.Filtrate is evaporated up to drying.Resistates (0.07g) is by silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH/NH 4OH=85/15/1; 10 μ m).Collect pure fraction and evaporating solvent.Resistates (0.042g, 84%) is from acetone/CH 3The crystallization of CN/ diisopropyl ether.Throw out is filtered and drying, obtains the 2-[2-(4-amino methyl-phenyl amino)-4 of 0.022g, 6-dimethyl-benzoglyoxaline-1-ylmethyl]-6-methyl-pyridine-3-alcohol, e-6 (compound 9,44%, fusing point: 255 ℃).
Embodiment 6: the preparation of the dimethylbenzimidazole amine that aryl replaces
Diagram F
The preparation of intermediate f-3:
Prepare intermediate f-3 to be similar to the described method of intermediate e-3.
The preparation of intermediate f-5 and f-6:
To be similar to the mixture that the described method of c-5 prepares intermediate f-5 and f-6.
The preparation of intermediate f-7 and f-8:
Prepare compound f-7 and f-8 to be similar to the described method of e-6, obtain the fraction 1 (10%) of 0.18g and the fraction 2 (20%) of 0.36g.Fraction 1 is converted into acetate and from acetone/CH 3The crystallization of CN/ diisopropyl ether.Throw out filtered and dry, obtain 0.013g f-8 (7.5%, 1CH 3CO 2H, fusing point: 171 ℃).Be dissolved in fraction 2 among Virahol/HCl and be converted into hydrochloride.Throw out is filtered and drying.Resistates is from Virahol/diisopropyl ether crystallization.Throw out is filtered and drying, obtain the f-7 (compound 26,10.4%, 4HCl, fusing point: 213 ℃) of 0.021g.
Following form is enumerated to be similar to any the prepared compound of the present invention in the above-mentioned synthetic diagram.
Table 1
Figure S04837281220060619D000291
Table 2
Figure S04837281220060619D000292
Table 3
Embodiment 7: the active in-vitro screening of anti respiratory syncytial virus
Cytopathologic protection per-cent (antiviral activity or EC that the antagonism that is realized by test compound is caused by virus 50) and cytotoxicity (CC 50) all calculate from dose-response curve.The selectivity of antivirus action is by selectivity index (SI) expression, and it is by using CC 50(for the cell toxic amount of 50% cell) is divided by EC 50(for the antiviral activity of 50% cell) calculates.Enumerated the ownership of the compound of each preparation in the table of above-mentioned experimental section, the compound that belongs to active classification " A " has and equals or exceeds 6 pEC 50(be expressed as the EC of molal unit 50-the log value), the compound that belongs to active classification " B " has and is lower than 6 pEC 50
Use is based on tetrazolium The EC of automatic colorimetric test determination test compound 50And CC 50The EagleShi basic medium that is supplemented with 5%FCS (FLU 0%) and 20mM Hepes damping fluid that adds 180 μ l for flat 96 hole plastic microtiter.Subsequently, in triplicate hole, add the compound stoste (the final experimental concentration of 7.8x) of 45 μ l amount, to estimate them simultaneously to by the effect of the cell of virus infection and mimic infected cell.Use automatic control system directly in microtiter plate, to carry out five five times of dilutions.Undressed virus control and the contrast of HeLa cell are incorporated in each test.About 100 TCID that add 50 μ l amount in two row in triplex row 50Respiratory syncytial virus.The substratum that adds same amount to the third line is to measure the cytotoxicity of compound under the concentration identical with those concentration that are used to measure antiviral activity.After cultivating two hours, the suspension (4 * 10 of the HeLa cell of adding 50 μ l in institute is porose 5Individual cells/ml).With culture at 5%CO 2Cultivate down at 37 ℃ in the atmosphere.After infecting seven days, check cytotoxicity and antiviral activity with spectrophotometry.The MTT (3-(4,5-dimethylthiazole-2-yl)-2, the 5-phenylbenzene tetrazolium that in each hole of microtiter plate, add 25 μ l
Figure 048372812_10
Bromide).Plate was further cultivated 2 hours at 37 ℃, removed substratum from each hole then.Realize first by the Virahol that adds 100 μ l
Figure 048372812_11
(formazan) crystalline dissolving.Plate is being placed deck vibrator after last 10 minute, realizing first Crystalline dissolves fully.At last under two wavelength (540 and 690nm), reading absorbancy in the photometer (MultiskanMCC, Flow Laboratories) of eight channel computer-controls.Automatically the absorbancy from 540nm deducts the absorbancy of measuring at 690nm, to eliminate the influence of non-specific absorption.

Claims (9)

1. the compound of formula (I) expression:
Figure FA20184402200480037281201C00011
Or their additive salt, wherein
Q is by Ar 2, one or two hydroxyl, C 1-4Alkoxyl group, aminocarboxyl, C 1-4The C that alkoxy carbonyl replaces 1-6Alkyl;
G is a methylene radical;
R 1For by hydroxyl or C 1-6The pyridyl that alkyl replaces;
R 2aAnd R 3aOne of be C 1-6Alkyl, R 2aAnd R 3aIn another be hydrogen;
Work as R 2aWhen being not hydrogen, R then 2bBe hydrogen or C 1-6Alkyl, and R 3bBe hydrogen;
Work as R 3aWhen being not hydrogen, R then 3bBe hydrogen or C 1-6Alkyl, and R 2bBe hydrogen; Or
R 2a, R 2b, R 3aAnd R 3bAll be hydrogen;
R 5Be hydrogen;
Ar 2Be phenyl or the phenyl that replaced by 1 or 2 substituting group, described substituting group is selected from halogen, amino, cyano group, many halos C 1-6Alkyl, amino C 1-6Alkyl, C 1-6Alkyl oxy and amino-sulfonyl.
2. the compound of claim 1, wherein R 1For by the pyridyl of the replacement of hydroxyl and methyl.
3. the compound of claim 1, wherein R 1Be 3-hydroxyl-6-picoline-2-base.
4. each compound among the claim 1-3, the wherein C of Q for being replaced by one or two hydroxyl 1-6Alkyl.
5. each compound, wherein Ar among the claim 1-3 2Be phenyl or the phenyl that replaced by 1 or 2 substituting groups, described substituting group is selected from cyano group, hydroxyl C 1-6Alkyl and amino-sulfonyl.
6. each compound, wherein R among the claim 1-3 2aAnd R 3aOne of be C 1-6Alkyl, R 2aAnd R 3aIn another be hydrogen;
Work as R 2aWhen being not hydrogen, R then 2bBe C 1-6Alkyl, and R 3bBe hydrogen;
Work as R 3aWhen being not hydrogen, R then 3bBe C 1-6Alkyl, and R 2bBe hydrogen.
7. medicinal compositions, the compound that comprises in the claim 1 to 6 of pharmaceutically acceptable carrier and treatment significant quantity each is as active ingredient.
8. each compound is used for suppressing the application of the medicine that RSV duplicates in the claim 1 to 6 in production.
9. prepare the method for each compound in the claim 1 to 6, described method comprises
(a) intermediate of formula (II) and reagent (III) are reacted:
(b) intermediate of formula (IV) and reagent (V) are reacted:
Wherein Q, G, R 1, R 2a, R 2b, R 3a, R 3b, R 5As each definition in the claim 1 to 6;
W is a leavings group;
Randomly pass through with suitable alkali or acid treatment, the compound of the formula (I) that so obtains is converted into their pharmaceutically useful base addition salt or acid salt form, reversibly use described base addition salt of acid or alkaline purification or acid salt form, with the compound of the formula (I) that obtains free form.
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FR2731707A1 (en) * 1995-03-13 1996-09-20 Synthelabo Novel 2-imidazolyl alkylamino benzimidazole(s)
CN1358182A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors
CN1358180A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors
CN1358181A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2731707A1 (en) * 1995-03-13 1996-09-20 Synthelabo Novel 2-imidazolyl alkylamino benzimidazole(s)
CN1358182A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors
CN1358180A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors
CN1358181A (en) * 1999-06-28 2002-07-10 詹森药业有限公司 Respiratory syncytial virus replication inhibitors

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