CN1863801A - Imidazopyridine substituted tropane derivatives with ccr5 receptor antagonist activity for the treatment of HIV and inflammation - Google Patents
Imidazopyridine substituted tropane derivatives with ccr5 receptor antagonist activity for the treatment of HIV and inflammation Download PDFInfo
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- CN1863801A CN1863801A CNA2004800286836A CN200480028683A CN1863801A CN 1863801 A CN1863801 A CN 1863801A CN A2004800286836 A CNA2004800286836 A CN A2004800286836A CN 200480028683 A CN200480028683 A CN 200480028683A CN 1863801 A CN1863801 A CN 1863801A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present invention provides compounds of formula (I) wherein R<1> and R<2> are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory
Description
The present invention relates to tropane derivatives, its method for making, contain the composition of this tropane derivatives and their purposes.
More particularly, the present invention relates to the purposes of 8-azabicyclic [3.2.1] Octane derivatives on the multiple disease of treatment, described disease comprises the disease that relates to adjusting (especially antagonism) chemokine receptor CCR 5.Therefore, compound of the present invention can be used for treating HIV, the retroviral infection of for example HIV-1, and genetic correlation (and the acquired immune deficiency syndrome (AIDS) that is caused, AIDS), and inflammatory diseases.
Term " chemokine " is the abbreviation of " chemotactic cytokine ".Chemokine comprises the protein of extended familys, and they have common important structure feature and have the leukocytic ability of attraction.Chemokine is as leukocytic chemokine, plays requisite effect in the process that attracts white corpuscle each tissue to the body, and this process all is necessary for inflammation and health to the response of infecting.Because chemokine and acceptor thereof are the physiopathology maincenters of inflammation and infectious diseases, the active medicament that therefore can regulate (preferred antagonism) chemokine and acceptor thereof is applicable to the therapeutic treatment of described inflammation and infectious diseases.
Chemokine receptor CCR 5 is even more important to the treatment of inflammation and infectious diseases.CCR5 is the acceptor of chemokine, particularly the macrophage inflammatory protein (MIP) of called after MIP-α and MIP-β and regulate and by the acceptor of normal T cell expressing and excretory protein (RANTES) via activation.
Now, the contriver finds a compounds, and it is potent and tool optionally conditioning agent, the especially antagonist of CCR5 acceptor.
According to first kind of aspect of the present invention, provide formula (I) compound as follows:
Or its pharmaceutically useful salt, solvate or derivative, wherein:
R
1Be C
1-C
6Alkyl; And
R
2Be C
1-C
6Alkyl or C
3-C
7Cycloalkyl, wherein alkyl is optional by CF
3Replace.
Term " alkyl " comprises straight chain and branched group as the part of group or group.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Term " C
3-C
7Cycloalkyl " representative ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.
In one embodiment, R
1Be C
1-C
4Alkyl.
In another embodiment, R
1It is methyl.
In another embodiment, R
2Be optional by CF
3The C that replaces
1-C
4Alkyl.
In another embodiment, R
2Be cyclopropyl or cyclobutyl.
In another embodiment, R
2Be methyl, ethyl or sec.-propyl.
Be understandable that whole combinations of embodiment of the present invention mentioned above have been contained in the present invention, as long as it meets the definition of formula (I) compound.
Compound of the present invention comprise formula (I) compound and pharmaceutically useful salt, solvate or derivative (wherein derivative comprise mixture, prodrug, through isotope-labeled compound, and their salt and solvate).In another embodiment, compound of the present invention is formula (I) compound and pharmaceutically useful salt and solvate, particularly formula (I) compound thereof.Will be understood that above-mentioned The compounds of this invention comprises its polymorphic form and isomer.
The pharmaceutically useful salt of formula (I) compound comprises its acid salt and alkali salt.
Suitable acid salt is formed by the acids that forms non-toxic salt.Example comprises acetate; aspartate; benzoate; benzene sulfonate; supercarbonate; hydrosulfate; borate; bromide; camsilate; carbonate; muriate; Citrate trianion; ethanedisulphonate; esilate; formate; fumarate; glucoheptose salt; gluconate; glucuronate; hexafluorophosphate; hydroxy benzoyl benzoate (hibenzate); hydrobromate; hydrochloride; hydriodate; iodide; isethionate; lactic acid salt; malate; maleate; malonate; mesylate; metilsulfate; naphthoate; the 2-naphthalenesulfonate; nicotinate; nitrate; Orotate; oxalate; palmitate; embonate; phosphate/phosphor acid monohydric salt/dihydrogen phosphate; saccharate; stearate; succinate; vitriol; Tartaric acid salt; tosylate and trifluoroacetate.
Suitable alkali salt is formed by the bases that forms non-toxic salt.Example comprises aluminium salt, arginic acid salt, benzyl star salt (benzathine), calcium salt, choline salt, diethyl amine salt, diethanolamine salt (diolamine), glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt (olamine), sylvite, sodium salt, tromethane salt and zinc salt.
For the summary of suitable salt, referring to " Handbook ofPharmaceutical Salts:Properties, Selection, and Use " (Wiley-VCH, Weinheim, Germany, 2002) that Stahl and Wermuth showed.
The pharmacologically acceptable salt of formula (I) compound can be by one or more the method preparation in following three kinds of methods:
(i) make formula (I) compound and required acid-respons;
(ii) from the suitable precursor of formula (I) compound, remove acid or alkali labile protecting group, or use required acid to make suitable cyclic precursor (for example lactone or lactan) open loop;
(iii) with suitable acid-respons or utilize suitable ion exchange column, a kind of salt of formula (I) compound is converted into another kind of salt.
Above-mentioned three kinds of methods are carried out in solution usually.Salt can be settled out from solution, filters collection or evaporating solvent and is collected.The degree of ionization of this salt is in complete ionization to hardly between the ionization.
Can there be not two kinds of solvation forms and solvation form in The compounds of this invention.Term used herein " solvate " is used for a kind of like this complex molecule of explanation, and it comprises compound of the present invention and one or more pharmaceutically useful solvent molecule, for example ethanol.When this solvent is water, use term " hydrate ".
Mixture comprises inclusion compound, that is, medicine-host molecule inclusion body mixture, different with above-mentioned solvate is that medicine and host molecule in this inclusion body mixture are stoichiometry or nonstoichiometry.Mixture also comprises the mixture of the medicine that contains two or more organic and/or inorganic component, and wherein said component can be stoichiometry or nonstoichiometry.The mixture of gained can be Ionized, partial ionization or nonionicization.For the summary of this class mixture, referring to the J.Pharm.Sci. that Haleblian showed, 64 (8), 1269-1288 (in August, 1975).
Compound of the present invention has the ability that crystallization goes out more than one forms, promptly is called the feature of heteromorphism, and this class polymorphic form all includes within the scope of the invention.When response temperature or pressure or the two change, heteromorphism can take place usually, also can cause heteromorphism owing to the variation of crystallisation process.Polymorphic form can be distinguished according to various physical features, utilizes X-ray diffraction figure, solubility behavior and the fusing point of compound to distinguish polymorphic form usually.
Some derivative of formula (I) compound itself has extremely low or parmacodynamics-less activity, in being applied to body or during body surface, can being converted into and having required active formula (I) compound, for example utilizes hydrolytic rupture.This analog derivative is called " prodrug ".The further data that prodrug is used can be with reference to following document: " Pro-drugs as Novel Delivery Systems ", the 14th volume, ACS Symposium Series (T.Higuchi and W.Stella); And " Bioreversible Carriers in Drug Design ", Pergamon press, 1987 (E.B.Roche edits, American Pharmaceutical Association).
For example, adopt some group of the known conducts of those skilled in the art " prodrug group ", " Design of Prodrugs " (Elsevier that for example H.Bundgaard showed, 1985) disclosed group in, the suitable functional group that exists in displaced type (I) compound can prepare prodrug of the present invention.
(NHR, wherein R ≠ H), therefore prodrug example of the present invention comprises its acid amides, for example with (C because formula (I) compound contains secondary amino group functional group
1-C
10) alkyloyl displacement hydrogen atom produces.
Other displacement examples of groups of above-mentioned example and the example of other prodrug type of the present invention can be referring to above-mentioned documents.
In addition, some formula (I) compound itself can be used as the prodrug of other formula (I) compound.
The metabolite that also comprises formula (I) compound within the scope of the invention promptly, is used the compound that forms in vivo behind this medicine.The part example of metabolite of the present invention comprises:
(i) when formula (I) when compound contains methyl, its metabolite is hydroxymethyl derivative (CH
3→-CH
2OH);
(ii) when formula (I) compound contained uncle's amino, its metabolite was secondary amino group derivative (NR
1R
2→-NHR
1Or-NHR
2);
(iii) when formula (I) when compound contains secondary amino group, its metabolite is primary amino derivative (NHR
1→-NH
2);
(iv) when formula (I) when compound contains phenyl, its metabolite be phenol derivatives (Ph →-PhOH);
(v) when formula (I) when compound contains amido, its metabolite is carboxylic acid derivative (CONH
2→ COOH).
Formula (I) compound can contain one or more other unsymmetrical carbon, so there is two or more steric isomer.The tropane ring of formula (I) compound can carry out imidazoles with introversive (endo-) or export-oriented (exo-) configuration and replace, so may obtain cis/trans (Z/E) isomer how much.For example, when compound contains ketone group, tautomerism can take place.Know by inference thus, the simplification compound can present more than one isomery.
Whole steric isomers of formula (I) compound all include within the scope of the present invention, comprise all optically active isomers, geometrical isomer and tautomeric form, and the compound that presents at least a isomery, and the mixture of one or more these forms.Also comprise acid salt or alkali salt in the scope of the present invention, wherein counter ion have optically active (for example D-lactate or L-Methionin), or racemic (for example DL-tartrate or DL-arginine).
Preferred tropane ring carries out imidazoles with endo-configuration and replaces.
Can utilize routine techniques well known to those skilled in the art to separate introversion/export-oriented isomer, for example chromatography and Steppecd crystallization.
The routine techniques of the indivedual enantiomers of preparation/separation comprises that carrying out chirality by suitable optically active precursor synthesizes, and perhaps racemoid (the perhaps racemoid of salt or derivative) is split, and for example uses chirality high pressure lipuid chromatography (HPLC) (HPLC).
Perhaps, racemoid (or racemize precursor) can react with suitable activity of optically active compounds (for example alcohol); Perhaps, when formula (I) compound contains acidic-group or basic group, make this racemoid with such as the acid or the alkali reaction of tartrate or 1-phenyl-ethyl amine.The diastereo-isomerism mixture of gained can utilize chromatography and/or Steppecd crystallization to separate, and utilizes method well known to those skilled in the art, and one of this diastereomer or both are converted into corresponding pure enantiomer.
Utilize chromatography, HPLC normally, on asymmetric resin, carry out, moving phase is by hydrocarbon, normally heptane or hexane are formed, wherein contain 0 to 50%, common 2 to 20% Virahols and 0 to 5% alkylamine, 0.1% diethylamine normally, can make the chipal compounds of the present invention (or its chiral precurser) that is rich in the enantiomerism form.Concentrate eluant obtains being rich in the mixture of enantiomerism form.
The mixture of steric isomer can utilize routine techniques well known by persons skilled in the art to be separated, for example, and referring to " Stereochemistry of Organic Compounds " (Wiley publishes, New York, 1994) that E.L.Eliel showed.
The present invention comprises that also all are pharmaceutically useful through isotope-labeled formula (I) compound, and one of them or more than one atom are replaced into has the same atoms preface but atomic mass or total mass number and natural common atomic mass or the different atom of total mass number.
The suitable isotopic example that mixes The compounds of this invention comprises the isotropic substance of following atom: hydrogen atom, for example
2H reaches
3H; Carbon atom, for example
11C,
13C reaches
14C; The chlorine atom, for example
36Cl; Fluorine atom, for example
18F; The iodine atom,
123I reaches
125I; Nitrogen-atoms, for example
13N reaches
15N; Sauerstoffatom, for example
15O,
17O reaches
18O; Phosphorus atom, for example
32P; And sulphur atom, for example
35S.
Some for example mixes those of radioactive isotope through isotope-labeled formula (I) compound, is applicable to the tissue distribution research of medicine and/or substrate.With regard to mixing easness and existing detection means, the radioactive isotope tritium (promptly
3H) with carbon-14 (promptly
14C) be specially adapted to this purpose.
With heavier isotropic substance (deuterium for example, promptly
2H) replace, can provide because bigger some that produces of metabolic stability treated advantage, for example, transformation period increase or dosage demand reduce in the body, so in some cases, and the heavier isotropic substance of preferred employing.
With the positron radiation isotropic substance (for example
11C,
18F,
15O reaches
13N) replace, can be used for the occupation rate that positron emission computerized tomography (PET) research detects the substrate acceptor.
Usually can utilize ordinary method well known by persons skilled in the art, or by being similar to the hereinafter method described in the embodiment and preparation example, adopt the suitable unmarked reagent through the original use of isotope-labeled reagent replacement, preparation is through isotope-labeled formula (I) compound.
Acceptable solvent thing of the present invention comprises those that are used for wherein that the crystalline solvent replaced by isotropic substance, for example D
2O, d
6-acetone, d
6-DMSO.
Preferred formula (I) compound comprises the compound of embodiment 1-8, and pharmaceutically useful salt, solvate or derivative.
In general method for making and schema, follow following condition: unless otherwise, R
1And R
2As above definition; Z is OH or carboxylic acid activating group, for example chlorine or 1H-imidazoles-1-base; EsGp is that ester forms group, for example C
1-6Alkyl; Pg is an amino protecting group, for example boc; ArLg is the leaving group that is suitable for the aromatics nucleophilic substitution, for example " the Advanced OrganicChemistry " that shown of Jerry March (the 4th edition, Wiley Interscience, 1992, the 652nd page, be incorporated herein by reference) middle those disclosed, F, Cl, Br, OMe or OEt are for example arranged; Boc is a tertbutyloxycarbonyl; DMF is N, dinethylformamide; DCM is a methylene dichloride; THF is a tetrahydrofuran (THF); Lg is suitable for the leaving group that aliphatic nucleophilic replaces, and for example those disclosed among the Jerry March (source is the same, the 352nd page, is incorporated herein by reference) comprises Cl, Br, I and sulfonic acid esters (for example tosylate, methanesulfonates and triflate); WSCDI is 1-(3-dimethyl amine propyl group)-3-ethyl-carbodiimide hydrochloride; DCC is N, the N-dicyclohexylcarbodiimide; HOAT is 1-hydroxyl-7-azepine benzotriazole; HOBt is the I-hydroxybenzotriazole hydrate; HBTU is O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate.
According to first kind of method for making (A), the preparation of formula (I) compound is under carboxylic acid/amine coupling condition in routine, to make formula (II) compound
React with formula (III) compound
This coupled reaction is carried out under the described condition of schema 1 step (i) easily hereinafter.
According to second kind of method for making (B), the preparation of formula (I) compound is under carboxylic acid/amine coupling condition in routine, to make formula (XVI) compound
React with the formula V compound.
This coupled reaction is carried out under the described condition of schema 1a step (i) easily hereinafter.
According to the third method for making (C), the preparation of formula (I) compound is under normal condition, utilizes the amine of formula (XX),
Make the aldehyde of formula (XIX) be reduced amination.
This reductive amination process carries out under the described condition of schema 1 step (g) easily hereinafter.
According to the 4th kind of method for making (D), the preparation of formula (I) compound is under normal condition, utilizes the amine of formula (XX), makes the nitrile of formula (XXI) be reduced amination.
This reductive amination process carries out under the described condition of schema 1 step (g) easily hereinafter.
According to the 5th kind of method for making (E), the preparation of formula (I) compound is under conventional alkylation conditions, utilizes formula (XXII) compound,
The amine that makes formula (XX) is by alkylation.Under following condition, can carry out this alkylated reaction easily: in The suitable solvent such as haloalkane (for example DCM), alcohol (for example ethanol) or ether (for example THF), carry out; Optional have the alkali such as amine (for example triethylamine or N-ethyl-N, N-Diisopropylamine) to exist; And temperature is that envrionment temperature is to elevated temperature (for example reflux temperature).
According to another kind of method for making (F), the preparation of formula (I) compound is under the conventional reduction condition, and the alkene acid amides that makes formula (XXIII) is by asymmetric reduction.
Under following condition, can carry out this asymmetric reduction reaction easily: have transition metal (for example Rh, Ru, Pd, Pt, Ir or Ti) (for example 0.001-0.1 molar equivalent); Chiral ligand, for example BINAP (2, two (diphenyl phosphine)-1 of 2-, 1 '-dinaphthalene), tol-BINAP (2, two (the two pairs of toluene phosphino-s)-1 of 2-, 1 '-dinaphthalene), Du-PHOS (1,2-two (2, the 5-dimethyl
Basic (phospholano)) benzene) or Penn-Phos (P, P '-1,2-penylene two (introversion-2,5-dimethyl-7-phospha two ring [2,2,1] heptane)) (for example 0.001-0.2 molar equivalent); Hydrogen atom donor, for example hydrogen molecule, phenyl silane, 2-propyl alcohol or ammonium formiate; In solvent, carry out such as alcohol (for example methyl alcohol, ethanol or 2-propyl alcohol), nitrile (for example acetonitrile), ester (for example ethyl acetate), ether (for example THF) or toluene; Temperature be 0 ℃ to reflux temperature; And choose wantonly under rising pressure.
According to another kind of method for making (G), the preparation of formula (I) compound is under normal condition, and the amine of formula (II) or its metal-salt (being the deprotonation type) react with the ester of formula (XXIV).
R
1CO
2EsGp (XXIV) can carry out above-mentioned reaction easily under following condition: have excessive alkali, such as amine (for example triethylamine or N-ethyl-N, N-Diisopropylamine); Optional catalyzer; In The suitable solvent such as haloalkane (for example DCM), ether (for example THF), ester (for example ethyl acetate) or toluene; Have or anhydrous existence as solubility promoter.Perhaps, this is reflected under the existence of enzyme-catalyzer, carries out in The suitable solvent such as haloalkane (for example DCM), ether (for example THF), ester (for example ethyl acetate) or toluene, have or anhydrous existence as solubility promoter.
This paper encloses schema subsequently, and it further specifies the general method of preparation formula (I) compound and relevant intermediate thereof.
Those skilled in the art it will be appreciated that some operation of the preparation of (I) compound of formula in the schema and relevant intermediate thereof may not be suitable for some possible substituting group.
Those skilled in the art more can understand, and have necessity or wish that employing differs from the described order of schema and transforms, and perhaps accommodation are carried out in one or more conversion reaction, to obtain required formula (I) compound.
Those skilled in the art also can understand, and shown in hereinafter schema, in synthetic arbitrary stage of formula (I) compound, have necessity or wish the intramolecular one or more sensitive group of protection, to avoid undesirable side reaction.Particularly, be necessary or wish that protection is amino.The employed protecting group of preparation formula (I) compound can be used in a usual manner.For example; " the Protective Groups in OrganicSynthesis " that is shown referring to Theodora W.Green and Peter G.M.Wuts; (the 3rd edition; John Wiley and Sons; 1999); the 7th chapter 494-653 page or leaf (" amino protection ") particularly, the document is incorporated herein by reference, and the document has also been described the method for removing this class group.
Amido protecting group boc, carbobenzoxy-(Cbz), methoxycarbonyl, benzyl and ethanoyl are specially adapted to the preparation of formula (I) compound and relevant intermediate thereof.
Schema 1
Specifically with reference to schema 1, wherein the conversion reaction of Miao Shuing can be reached according to the following step:
(a) utilize the amine of formula (XIV) to replace leaving group on the nitropyridine of formula (XV), this reaction is carried out under following condition easily: have the alkali such as amine (for example triethylamine or N-ethyl-N, N-Diisopropylamine) or alkaline carbonate (for example yellow soda ash or salt of wormwood); In solvent as alcohol (for example methyl alcohol or ethanol), nitrile (for example acetonitrile) or acid amides (for example DMF) in; And temperature is that envrionment temperature is to elevated temperature (for example about at the most 120 ℃).
(b) amino-nitropyridine with formula (XIII) is reduced and the original position cyclisation, but the imidazopyridine of preparation formula (XII), this reaction is carried out under following condition easily: the existence of reductive agent (for example iron powder) is arranged, in solvent, carry out, and temperature is that envrionment temperature arrives about at the most 120 ℃ such as carboxylic acid (for example acetate).By adding acetic anhydride and under elevated temperature (for example about 140 ℃), can carrying out the cyclization of intermediate amino-aminopyridine easily.
(c) pass through catalytic hydrogenation, can carry out of the reduction of the imidazopyridine of formula (XII) easily to the imidazo piperidines of formula (XI), wherein catalytic hydrogenation suitable catalyzer, for example transition-metal catalyst as platinum (platinum oxide) or palladium (for example palladium hydroxide or palladium carbon) catalyzer in the presence of, carry out in the solvent such as alcohol (for example methyl alcohol or ethanol) or carboxylic acid (for example acetate), temperature is that envrionment temperature is to elevated temperature (for example about at the most 80 ℃); Pressure is rising pressure, for example 150 to 500kPa hydrogen (for example 400kPa hydrogen).
(d) by reacting, make the imidazo piperidines of formula (XI) protected with alkyl chloroformate (for example methyl-chloroformate).This reaction adopts alkali, for example amine (for example triethylamine or N-ethyl-N, N-Diisopropylamine) to carry out under room temperature easily in the solvent such as haloalkane (for example DCM) or ether (for example THF).
(e) step (c) and another kind (d) are chosen as, with alkyl chloroformate (for example methyl-chloroformate) and amine alkali (for example triethylamine or N-ethyl-N, the N-Diisopropylamine) imidazopyridine of processing formula (XII) makes the season intermediate, and it is reduced under normal condition.Can in the presence of solvent, methyl-chloroformate be added in the imidazopyridine of formula (XII) easily in envrionment temperature such as ether (for example THF) or haloalkane (for example DCM), make the season intermediate, (for example about-70 ℃) interpolation alkali metal halide (for example lithium borohydride) makes it reduction under the cooling condition subsequently.Pass through catalytic hydrogenation, the intermediate that makes is further reduced, wherein catalytic hydrogenation is carried out in the solvent such as alcohol (as methyl alcohol or ethanol) or carboxylic acid (for example acetate) in the presence of as palladium catalyst (for example palladium hydroxide or palladium carbon) at suitable catalyzer, for example transition-metal catalyst, and temperature is that envrionment temperature is to elevated temperature (for example about at the most 80 ℃).
(f) when protecting group is ethanoyl protecting group or similar group; the alkali of utilization such as alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) or handle down in elevated temperature such as 60-100 ℃ such as the acid of mineral acid (for example HCl) can be removed this protecting group easily.
(g) by fit the aldehyde reduction amination of formula (IX), preparation formula (VII) compound with the amine of formula (VIII).This reaction easily in the presence of such as the acid of organic acid (for example acetate), in solvent such as ether (for example THF) or haloalkane (for example DCM), adopt alkalimetal hydride reductive agent such as sodium triacetoxy borohydride, sodium cyanoborohydride or sodium borohydride under envrionment temperature, to carry out.
(h) when the protection of step (d) provides by methoxycarbonyl, by with alkali such as alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) such as aqueous alcohols (H for example
2The O/ propan-2-ol) handles down in elevated temperature (for example 100 ℃) in the solvent, can remove methoxycarbonyl easily.
(i) acid/amine coupled reaction can followingly easily be carried out: the amine of employing formula (VI) and the chloride of acid of formula V; Excessive sour recipient, for example triethylamine or N-ethyl-N, N-Diisopropylamine; Solvent such as haloalkane (for example DCM) or ether (for example THF); In envrionment temperature.
Perhaps, acid/amine coupled reaction can followingly be carried out: adopt the acid of the reagent activatory formula V of quilt such as WSCDI or DCC and HOBT or HOAt; Excessive sour recipient, for example triethylamine or N-ethyl-N, N-Diisopropylamine; Solvent such as haloalkane (for example DCM) or ether (for example THF); And envrionment temperature.
(j) when protecting group is the boc protecting group; in the presence of acid, for example mineral acid (for example anhydrous HCl) or trifluoroacetic acid; in suitable solvent such as ester (for example ethyl acetate), haloalkane (for example DCM) or ether (for example THF), in 0 ℃ to envrionment temperature, remove this protecting group easily.
(k) under the described condition of above-mentioned steps (i), the acid or the chloride of acid of the amine of use formula (II) and formula (III) carry out acid/amine coupled reaction easily.
Those skilled in the art it will be understood that for required formula (I) compound is provided, and can carry out one or more conversion reaction to be different from schema 1 described order, perhaps can be in addition flexible.
In a kind of alternative of schema 1, carry out step (h) to (k) with different order, preparation formula (I) compound is shown in following schema 1a.
Schema 1a
Formula (XX) compound has the structure of the formula of being similar to (I) compound or its relevant intermediate, can prepare according to similar approach.
Formula (III), (V), (IX), (XV), (XIX), (XXI), (XXII) and compound (XXIII) are compound known, perhaps can utilize the conventional chemical method to prepare; For example, referring to WO01/90106 (especially 5-19 page or leaf), the document is incorporated herein by reference.
Formula (I) compound salt pharmaceutically useful with it, solvate and derivative are useful because they for animal, comprise that the people has pharmacologically active.More specifically, they can be used for treating the disorder that relates to adjusting CCR5 acceptor.Interested especially disease type comprise HIV, with retroviral infection, AIDS and the inflammatory diseases of HIV genetic correlation.
Compound of the present invention can be used for treating respiratory disease, comprises adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, wind-puff, rhinitis and chronic sinusitis.
Other medicable disease be by the T cell that in Different Organs, transports cause, invasion and attack or be associated with any alternate manner those.Can expect that compound of the present invention can be used for treating this class disease, the illness set up of the relation of (but being not limited to) and CCR5 or CCR5 chemokine especially, more especially (but being not limited to): multiple sclerosis; Sacroiliitis, for example rheumatoid arthritis, spondyloarthropathy, urarthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis; And transplant rejection, especially but be not limited to the solid organ transplantation thing, for example heart, lung, liver, kidney and pancreas transplantation thing (for example allograft of kidney and lungs).The disease of the similarity relation of other foundation and CCR5 or CCR5 chemokine includes but not limited to: inflammatory bowel comprises Crohn disease and ulcerative colitis; Endometriosis; Type i diabetes; Ephrosis, for example renal glomerular disease (for example glomerulonephritis); Fibrosis, for example fibrosis of liver, lung and kidney; Chronic pancreatitis; Inflammatory lung disease; Encephalitis, for example HIV encephalitis; Chronic heart failure; Ischemic heart disease; Psoriasis; Apoplexy; Obesity; Central nervous system (CNS) disease, for example AIDS dependency dementia and Alzheimer; Anemia; Restenosis; Atherosclerotic plaque; Atopic dermatitis; Chronic pancreatitis; Cancer, for example non-Hodgkin lymphoma, Kaposi sarcoma, melanoma and mammary cancer; Pain, for example nociceptive pain and neuropathic pain (for example peripheral nerve pain); And by the stress reaction of performing the operation, infect, damaging or other traumatic injury produced.
Relate to the infectious diseases of regulating the CCR5 acceptor and comprise infection acute and chronic HBV (HBV) and hepatitis C virus (HCV); Glandular plague, septicemic plague and pneumonic plague; Poxvirus infection, for example smallpox; Toxoplasma infects; Mycobacterial infections; Trypanosome is infected as chagas disease; Pneumonia; And cryptosporidiosis.
About chemokine and Chemokine Receptors blocker can applicable recent summary, referring to Cascieri, M.A. with Springer, M.S. " the The chemokine/chemokinereceptor family:potential and progress for therapeutic intervention " that is shown, Curr.Opin.Chem.Biol., 4 (4), 420-7 (in August, 2000).
Therefore, another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or the derivative as medicine.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, is used for the treatment of to relate to the disease of regulating the CCR5 acceptor.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, be used for the treatment of HIV, with retroviral infection, AIDS or the inflammatory diseases of HIV genetic correlation.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, be used for the treatment of respiratory disease, comprise adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, wind-puff, rhinitis or chronic sinusitis.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, is used for the treatment of multiple sclerosis, rheumatoid arthritis or transplant rejection.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, is used for the treatment of inflammatory bowel; Endometriosis; Type i diabetes; Ephrosis; Fibrosis; Chronic pancreatitis; Inflammatory lung disease; Encephalitis; Chronic heart failure; Ischemic heart disease; Psoriasis; Apoplexy; Obesity; Central nervous system (CNS) disease; Anemia; Restenosis; Atherosclerotic plaque; Atopic dermatitis; Chronic pancreatitis; Cancer; Pain; And by the stress reaction of performing the operation, infect, damaging or other traumatic injury produced.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or derivative, is used for the treatment of HBV, HCV, the plague, poxvirus infection, toxoplasmosis, mycobacterial infections, trypanosome infection, pneumonia or cryptosporidiosis.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically useful salt, solvate or the derivative purposes in the preparation medicine, and this medicine is used for the treatment of and relates to the disease of regulating the CCR5 acceptor.
Another aspect of the present invention provides the method for the treatment of mammiferous disease, and wherein said disease relates to regulates the CCR5 acceptor, and this method comprises formula (I) compound or its pharmaceutically useful salt, solvate or this Mammals of derivatives for treatment with significant quantity.
Compound of the present invention can be used with crystalline or amorphous products.For example, they can be by obtaining with solid-state embolus, meal or diaphragm thing form such as methods such as precipitation, crystallization, lyophilize, spraying drying or evaporation dryings.Can use microwave or radio-frequency seasoning and reach this purpose.
Compound of the present invention can be used separately, perhaps with one or more The compounds of this invention combined administrations or with one or more other medicines combined administrations (perhaps their any combination).Generally speaking, these compounds are used with the dosage form that contains one or more pharmaceutically acceptable vehicle.Term " vehicle " is used to illustrate any composition except that The compounds of this invention.The selection of vehicle is depended on such as concrete method of application, vehicle to a great extent to factors such as the influence of solubleness and stability and formulation character.
Pharmaceutical composition that is suitable for transmitting The compounds of this invention and preparation method thereof will be apparent to those skilled in the art.This based composition and preparation method thereof can be referring to for example " Remington ' sPharmaceutical Sciences ", the 19th edition (Mack publishing company, 1995).
But compound dosage forms for oral administration of the present invention.Dosage forms for oral administration can comprise swallows, and compound enters gi tract thus; Perhaps can adopt to contain clothes or sublingual administration, compound directly enters blood flow by the oral cavity thus.
The preparation of suitable dosage forms for oral administration comprises solid preparation such as tablet, contains particle, the capsule of liquid or powder, lozenge (comprise the filling liquid person), masticatory, many particles and nanoparticle, gel, solid solution, liposome, film (comprising mucomembranous adhesion agent), ball system (ovules), sprays and liquid preparation.
Liquid preparation comprises suspensoid, solution, syrup and elixir.This class preparation can be used as the weighting material of soft or hard capsule, and it comprises carrier usually, for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil and one or more emulsifying agent and/or suspension agent.Liquid preparation also can prepare solid (for example from sachet) reconstruct.
Compound of the present invention also can be used for quick dissolving, rapidly disintegrating dosage form, for example those disclosed in Liang and Chen " Expert Opinion in Therapeutic Patents " (11 (6), 981-986,2001).
For tablet, according to dosage, medicine can account for 0.1 weight % to 80 weight % of this formulation, more generally is 1 weight % to 60 weight %, for example 5 weight % to 50 weight %.Except that medicine, tablet contains disintegrating agent usually.The example of disintegrating agent comprises hydroxypropylcellulose, starch, pregelatinized Starch and the sodium alginate that primojel, Xylo-Mucine, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpolypyrrolidone, polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low alkyl group replace.Generally speaking, disintegrating agent accounts for 0.1 weight % to 25 weight % of this formulation, more generally is 0.5 weight % to 20 weight %, for example 1 weight % to 15 weight %.
Tackiness agent is commonly used to make tablet formulation to have sticking property.Suitable tackiness agent comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic colloidal substance, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet also can contain thinner, for example lactose (monohydrate, spray-dried monohydrate, lactose hydrous etc.), N.F,USP MANNITOL, Xylitol, dextrose, sucrose, sorbyl alcohol, Microcrystalline Cellulose, starch, lime carbonate and dicalcium phosphate dihydrate.
Also optional tensio-active agent, for example Sulfuric acid,monododecyl ester, sodium salt and the Polysorbate 80 of comprising of tablet; And glidant, for example silicon-dioxide and talcum powder.When containing these materials, 0.2 weight % to 5 weight % of surfactant comprise tablet; Glidant accounts for 0.2 weight % to 1 weight % of tablet.
Tablet also contains lubricant, for example mixture of Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate and Magnesium Stearate and Sulfuric acid,monododecyl ester, sodium salt usually.Lubricant accounts for 0.25 weight % to 10 weight % of tablet usually, preferred 0.5 weight % to 3 weight %.
Other possible composition comprises antioxidant, person's toner, correctives, sanitas and odor mask.
The tablet of example contain about at the most 80% medicine, about 10 weight % to about 90 weight % tackiness agents, about 0 weight % to about 85 weight % thinners, about 1 weight % to about 10 weight % disintegrating agents and about 0.25 weight % to about 10 weight % lubricants.
Tablet mixture directly compressible or utilize the cylinder compressing tablet.Perhaps, the part of tablet mixture or mixture can be carried out wet method, dry method or melt granulation, melting and solidification or be extruded before compressing tablet.Final preparation can comprise one or more layers, can be dressing or dressing not; Even can be wrapped in the capsule.
Being formulated in of tablet has discussion in the following document that H.Lieberman and L.Lachman show: " Pharmaceutical Dosage Forms:Tablets ", the 1st volume, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).
The solid preparation of dosage forms for oral administration can be mixed with quick-release and/or discharge the form that changes.Discharge the preparation that changes and comprise that postponing release, slowly-releasing, pulse release, controlled release, target release and program discharges (programmed release).
The release that is applicable to the object of the invention changes preparation at United States Patent (USP) 6,106, description is arranged in 864.Other appropriate drug release tech, for example high-energy dispersion agent and infiltration and coated granule see people such as Verma " Pharmaceutical Technology On-line " for details, and 25 (2), 1-14 (2001).Described among the WO00/35298 and utilized Chewing gum to reach controlled release.
Compound of the present invention also can directly be applied in blood flow, muscle or the intracorporeal organ.Being suitable for the mode that gi tract use outward comprises: in intravenously, intra-arterial, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, encephalic, intramuscular and subcutaneous.Be suitable for the device that gi tract use outward and comprise syringe needle (comprising micro-needle) syringe, needleless injector and perfusion device.
Parenteral formulations is the aqueous solution normally, it can contain vehicle such as salt, carbohydrate and slow-action agent (preferred pH is 3 to 9), but for some usefulness, preferably they are mixed with the non-aqueous solution of sterilization, perhaps are mixed with the dried forms that uses with suitable solvent (as the pyrogen-free water of sterilizing).
The preparation of parenteral formulations under sterilising conditions for example utilizes freeze-drying, can adopt standard pharmaceutical technology well known to those skilled in the art easily to finish.
Use the appropriate formulations technology, for example add solubilizing agent, can be increased in the solvability of The compounds of this invention used in the outer solution of preparation gi tract.
The preparation of using outside gi tract can be mixed with quick-release and/or discharge the form that changes.The preparation that discharge to change comprises and postpones to discharge, continuously release, pulse release, controlled release, target discharges and program discharges.Compound of the present invention can be mixed with solid, semisolid or thixotropic fluid, uses as the implantation bank that the compound that change is provided discharges.This class examples of formulations comprises coating support and PGLA microballoon.
Compound of the present invention also can be locally applied to skin or mucous membrane, that is, and and through skin or transdermal administration.The exemplary formulations that is used for this purpose comprises gel, hydrogel, lotion, solution, creme, ointment, dusting, dressing (dressing), foam, film, transdermal patches, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical carriers comprises alcohol, water, mineral oil, white oil, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Can add penetration enhancer, for example referring to the J.Pharm.Sci. of Finnin and Morgan, 88 (10), 955-958 (in October, 1999).
The alternate manner of topical application comprises by electroporation, iontophoresis, sound and penetrates method (phonophoresis), ultrasonic method (sonophoresis) and micro-syringe needle or the needle-less (Powderject for example that penetrates
TM, Bioject
TMDeng) injection transmission medicine.
The preparation of topical application can be mixed with quick-release and/or discharge the form that changes.Discharge the preparation that changes and comprise that postponing release, slowly-releasing, pulse release, controlled release, target release and program discharges.
But compound of the present invention is also in the intranasal or utilize inhalation to use, usually the self-desiccation powder inhalator is (independent for example to use with the drying composite form of lactose with dry powdered form since, perhaps as the blending ingredients particle, for example use with phosphatide such as phosphatidylcholine blended form) use, perhaps conduct is from pressurizing vessel, pump, atomizer, the spraying gun (preferably adopt electrohydrodynamic and produce the spraying gun of mist) or the aerosol spray of frost making equipment (nebuliser) are used, use or do not use suitable propellent, for example 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane.For intranasal administration, this powder can contain bioadhesive polymer, for example chitosan or cyclodextrin.
Pressurizing vessel, pump, atomizer, spraying gun or frost making equipment comprise the solution or the suspension of The compounds of this invention, its for example comprise ethanol (optional aqueous ethanolic solution) or other be suitable for disperseing, solubilize compound or prolong the replacement reagent of its release; Propellent as solvent; And optional tensio-active agent, for example take off sorbitol olein, oleic acid or lact-acid oligomer.
Use before dried powder or the mixed suspension preparation, with the medicament production micronize to the size (usually less than 5 microns) that is suitable for transmitting through sucking.This can finish by the breaking method of any suitable, for example spiral air flow pulverizer, fluidized bed air flow crusher, the treatment with supercritical fluid that can form nanoparticle, high pressure homogenizing or spraying drying.
The capsule that uses in sucker or the insufflator (for example being made by gelatin or HPMC), bubble-cap and cartridge case can be mixed with the form of the powdered mixture that contains following composition: compound of the present invention, suitable powder matrix (for example lactose or starch) and performance modifier (for example+/-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be the form of anhydrous or monohydrate, the preferred latter.Other suitable vehicle comprises dextran, glucose, maltose, sorbyl alcohol, Xylitol, fructose, sucrose and trehalose.
Be suitable for the The compounds of this invention that the pharmaceutical solutions that adopts electrohydrodynamic to produce the spraying gun of mist contains every spray 1 μ g to 20mg, the ejection volume is 1 μ l to 100 μ l.Exemplary formulations can contain compound of the present invention, propylene glycol, aqua sterilisa, ethanol and sodium-chlor.Can be used to replace the replace solvents of propylene glycol to comprise glycerine and polyoxyethylene glycol.
Suitable correctives (for example mentha camphor and left-handed mentha camphor) or sweeting agent (for example asccharin or soluble saccharin) can be added into the preparation of the present invention that is used for through suction/intranasal administration.
Can adopt for example poly-(DL-lactic acid-oxyacetic acid) altogether (PGLA) to be mixed with quick-release and/or discharge the form that changes through the preparation of suction/intranasal administration.Discharge the preparation that changes and comprise that postponing release, slowly-releasing, pulse release, controlled release, target release and program discharges.
When being dry powder inhaler and aerosol, dose unit is by the valve decision that transmits dosing.Dose unit of the present invention is usually designed to uses dosing or " emitted dose " that contains 1 μ g to 10mg The compounds of this invention.Every day, total dose was generally 1 μ g to 200mg, can use with single dose, or more frequent separate doses as one day was used.
But compound per rectum of the present invention or vaginal application are for example used with the form of suppository, vaginal suppository or enema.Theobroma oil is conventional suppository base, but can use other various selectable matrix as one sees fit.
The preparation of per rectum/vaginal application is mixed with quick-release and/or discharges the form that changes.Discharge the preparation that changes and comprise that postponing release, slowly-releasing, pulse release, controlled release, target release and program discharges.
Compound of the present invention also can directly be applied to eye or ear, usually with waits open, pH in the sterile saline of adjusting the micronize suspension or the drops form of solution use.Be suitable for eye or other preparation of using of ear comprises ointment, biodegradable implants (for example absorbable gel sponge, collagen) and not biodegradable implant (for example siloxanes), wafer, eyeglass and particulate or vesica system, for example nonionic surfactant vesicle (niosomes) or liposome.Polymkeric substance, for example cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulosic polymer such as Vltra tears, Natvosol or methylcellulose gum, perhaps mixed polysaccharide polymkeric substance such as gelling gum (gelan gum) can and be used with sanitas such as benzalkonium chloride.This class preparation also can utilize the iontophoresis transhipment.
The preparation of using through eye/ear can be mixed with quick-release and/or discharge the form that changes.Discharge the preparation that changes and comprise that postponing release, slowly-releasing, pulse release, controlled release, target release or program discharges.
In order to improve solvability, dissolution rate, taste masking, bioavailability and/or the stability that The compounds of this invention is used for aforementioned any one method of application, they can with soluble macromole entity (for example cyclodextrin and appropriate derivative thereof or contain the polymkeric substance of polyoxyethylene glycol) combination.
For example, have been found that the drug-cyclodextrin mixture can be used for most of formulations and route of administration usually.Can use and comprise and the non-mixture that comprises.As with a kind of optional mode of the direct complexing of medicine, cyclodextrin can be used as supplementary additive, that is, as carrier, thinner or solubility promoter.Be most commonly used to this purpose be α-, β-and γ-Huan Hujing, its example can be referring to International Patent Application WO 91/11172, WO 94/02518 and WO 98/55148.
Owing to may wish with The compounds of this invention and other therapeutical agent combined administration, for example in order to treat concrete disease or illness, be suitable for kit form that composition uses jointly also within the scope of the invention so two or more pharmaceutical composition (one of them kind contains compound of the present invention) is combined into easily.
Therefore, medicine box of the present invention comprises two or more separated drug composition, wherein at least a formula of the present invention (I) compound or its pharmaceutically useful salt, solvate or the derivative of containing, and comprise the instrument that holds described composition respectively, for example container, the bottle that separates or cellular-type aluminium foil packing.The example of this class medicine box is the Blister Package that is usually used in package troche, capsule etc.
Medicine box of the present invention is particularly suitable for using different dosage form, for example, and the outer formulation of per os formulation and gi tract; Be used for using independent composition at interval with different dosing; Or be used for independent composition dosage escalation separately.In order to help conformability, medicine box generally includes medication guide, and so-called " memory is auxiliary " may be provided.
If desire to be applied to about 65 to 70kg the patient of body weight, total dose every day of The compounds of this invention is generally 1 to 10,000mg, for example 10 to 1,000mg, for example 25 to 500mg, and this depends on patient's mode of administration, age, illness and body weight certainly, in any case and will make final decision by the doctor.Every day, total dose can be used with single or separate doses.
Therefore, another aspect of the present invention provides as the pharmaceutical composition of giving a definition, and it contains formula (I) compound or its pharmaceutically useful salt, solvate or derivative, and one or more pharmaceutically useful vehicle, diluent or carrier.
Compare with compound of the prior art, formula (I) compound and pharmaceutically useful salt, solvate and derivative have following advantage: selectivity is higher, it is faster to begin effect, more potent, absorb better, more stable, more ability metabolism, " food effect " reduces, and improved safety perhaps has other character of more wanting (for example solvability or water absorbability).
Especially The compounds of this invention reduces the inhibition of HERG potassium channel is active.The prolongation (QT prolongation) of having determined the myocardial action potential time length is owing to due to the effect of HERG potassium channel (Expert Opinion of Pharmacotherapy, 2, the 947-973 pages or leaves, 2000).Known QT prolongs the fatal arrhythmia that might produce torsade de pointes (TdP).By providing the inhibition activity that shows the HERG potassium channel further to reduce and having quite or the compound of the pharmacokinetics of improving, the invention provides such compound, it is that a kind of effectively CCR5 antagonist and cardiac safety are further improved in treatment.
Formula (I) compound and pharmaceutically useful salt, solvate and derivative can be used separately, perhaps as the part of combination treatment.Therefore, within the scope of the invention, contained such embodiment: except compound of the present invention, also use one or more other therapeutical agents jointly, and the composition that also comprises described one or more other therapeutical agents.This multiple medicines object space case is commonly referred to combination treatment, can be used for treating and preventing to relate to by infection mediation or that relevant with it any disease or illness, particularly human immunodeficiency virus (HIV) causes of CCR5 Chemokine Receptors regulating effect.The patient of needs treatments or be among the patient of ill danger, use such combination treatment to treat and prevent human immunodeficiency virus (HIV) and relevant pathogenic retroviral infection and breed especially appropriate.What document was known already is that this class retrovirus cause of disease physical efficiency is developing into the virus strain that any monotherapy that has given described patient is had resistance in the short period relatively.The recommended therapy of HIV is the medicinal composition therapy that is called " high reactivity antiretroviral therapy " or HAART.The HIV medicine of HAART combination more than three kinds or three kinds.Therefore, methods of treatment of the present invention and pharmaceutical composition can use compound of the present invention with the form of monotherapy, but can also use described method and composition with the form of combination treatment, wherein one or more compound of the present invention and one or more other therapeutical agent (example as will be detailed later those) combination and using jointly.
In another embodiment of the present invention, combination of the present invention comprises the treatment that use formula (I) compound or its pharmaceutically useful salt, solvate or derivative and one or more other therapeutical agent carry out, wherein said other therapeutical agent is selected from: hiv protease inhibitor (PIs) includes but not limited to Indinavir, ritonavir, Saquinavir, viracept see nelfinaivr, rltonavir, amprenavir, Reyataz R (atazanavir), tipranavir, AG1859 and TMC114; Non-nucleoside reverse transcriptase inhibitor (NNRTIs), include but not limited to nevirapine, Delavirdine, capravirine, efavirenz, 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazoles-4-yl] the oxygen base } m-dicyanobenzene or its pharmaceutically useful salt, solvate or derivative, 5-{[3-cyclopropyl-1-(2-hydroxyethyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] the oxygen base } m-dicyanobenzene or its pharmaceutically useful salt, solvate or derivative, GW-8248, GW-5634 and TMC125; Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) includes but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, Abacavir, adefovir dipivoxil, tynofovir, emtricitabine and Aovudine; Other CCR5 antagonist, include but not limited to N-{ (1S)-3-[3-(3-sec.-propyl-5-methyl-4H-1,2,4-triazole-4-yl)-extroversion-8-azabicyclic [3.2.1] suffering-8-yl]-the 1-phenyl propyl }-4,4-difluoro cyclohexane carboxamide or its pharmaceutically useful salt, solvate or derivative, in the 1-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate or its pharmaceutically useful salt, solvate or derivative, in the 3-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-5-methyl-formiate or its pharmaceutically useful salt, solvate or derivative, in the 1-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-ethyl formate or its pharmaceutically useful salt, solvate or derivative, Sch D, ONO4128, GW873140, AMD-887 and CMPD-167; Suppress gp120 and the interactional medicament of CD4, include but not limited to BMS806, BMS-488043,5-{ (1S)-2-[(2R)-4-benzoyl-2-methyl-piperazine-1-yl]-1-methyl-2-oxo-oxyethyl group }-4-methoxyl group-pyridine-2-formic acid methane amide, and 4-{ (1S)-2[(2R)-4-benzoyl-2-methyl-piperazine-1-yl]-1-methyl-2-oxo-oxyethyl group }-3-methoxyl group-N-methyl-benzamide; Other suppresses HIV and enters the medicament of target cell, includes but not limited to enfuviritide, T1249, PRO 542 and PRO 140; Integrase inhibitor comprises but does not sink into L-870,810; And RNaseH inhibitor.
Within the scope of the invention, also comprise the combination of formula (I) compound or its pharmaceutically useful salt, solvate or derivative and one or more other therapeutical agent, described other therapeutical agent is independently selected from: antiblastic, for example hydroxyurea; Immunomodulator, the granular leukocyte macrophage colony stimulating growth factor (for example Sargramostim) for example, tachykinin receptor conditioning agent (for example NK1 antagonist), and various forms of Interferon, rabbit or interferon derivative; Other chemokine receptor agonists/antagonist, for example CXCR4 antagonist (for example AMD-070); Suppress, destroy or reduce the medicament of virus transcription or rna replicon in essence, for example tat (trans-activating factor) or nef (negative regulatory factor) inhibitor; Suppress in essence, destroy or reduce one or more the medicament of proteinic translation (including but not limited to one or more downward modulation of proteinic protein expressions or antagonisms) except that reversed transcriptive enzyme, for example Tat or Nef by expressing viral; The medicament of influence (especially downward modulation) CCR5 expression of receptor; Lure the chemokine of CCR5 acceptor internalization into, for example MIP-1 α, MIP-1 β, RANTES and derivative thereof; And suppress virus infection or improve the illness of individuality of infected by HIV or other medicament of result through different mechanisms.
The medicament of influence (especially downward modulation) CCR5 expression of receptor comprises: immunosuppressor, and calcineurin inhibitors for example is as tacrolimus and ciclosporin A; Class is because of alcohols; The medicament of signal is produced or sent to the interference cell factor, Janus kinases (JAK) inhibitor for example, as the JAK-3 inhibitor, comprise 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-amino]-piperidines-1-yl }-3-oxo-propionitrile and pharmaceutically useful salt, solvate or derivative; Cytokine antibodies for example suppresses the antibody of interleukin-2 (IL-2) acceptor, comprises basiliximab and daclizumab; And interference cell activation or the medicament of cell cycle, for example rapamycin.
Within the scope of the invention, also comprise the combination of formula (I) compound or its pharmaceutically useful salt, solvate or derivative and one or more other therapeutical agent, described other therapeutical agent reduces the metabolic rate of The compounds of this invention, and patient's medicine contact is increased.Increase the medicine contact by this way and be called strengthening action (boosting).Strengthening action has following benefit: the effect or the minimizing that increase The compounds of this invention reach the effect required dosage identical with non-reinforcement dosage.The metabolism of The compounds of this invention comprises: the oxidising process of being undertaken by P450 (CYP450) enzyme, especially CYP3A4, and the association reaction that is undertaken by UDP glucuronyl transferase and sulfurylase (sulphating enzyme).Therefore, increase in the medicament of patient to the contact of The compounds of this invention can be used for, comprising can be as those of the inhibitor of at least a Cytochrome P450 (CYP450) enzyme isoform.Can be included but not limited to CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4 by the CYP450 isoform of useful inhibition.The suitable medicament that can be used for suppressing CYP3A4 includes but not limited to ritonavir, Saquinavir or KETOKONAZOL.
It will be understood by those skilled in the art that aforesaid medicinal composition therapy can comprise two or more the compound with identical or different mechanism of action.Therefore, only as an illustration, combination can comprise the combination of compound of the present invention and following medicament: one or more NRTIs; One or more NRTIs and PI; One or more NRTIs and other CCR5 antagonist; PI; PI and NNRTI; NNRTI; By that analogy.
Except the requirement of therapeutic efficiency (it is essential that this makes that the therapeutical agent of use except that The compounds of this invention becomes), other reason forces or gives a energetical recommendation and use the combination of The compounds of this invention and other therapeutical agent in addition, is for example treating directly cause or indirect associated disease or the illness of disease basic or that potential CCR5 Chemokine Receptors is regulated or illness.For example, disease of regulating when basic CCR5 Chemokine Receptors or illness are that HIV infects and during propagation, are necessary or are to wish treatment hepatitis C virus (HCV), hepatitis B virus (HBV), human papillomavirus (HPV), opportunistic infection (comprising bacterium and fungi infestation), vegetation and other is because the illness due to the patient's that treats the immune deficiency state at least.For example in order to provide immunostimulation or treatment to follow the initial stage and the phase of foundation (fundamental) HIV to infect pain and the inflammation that occurs, other therapeutical agent can use with compound of the present invention.
Therefore, be used for also comprising: the interferons, Peg-Intron (for example glycol interferon alpha-2a and glycol interferon alpha-2b), lamivudine, ribavirin and the emtricitabine that are used for the treatment of hepatitis with the therapeutical agent of formula (I) compound or its pharmaceutically useful salt, solvate or derivative combination; Anti-mycotic agent, for example fluconazole, fosfluconazole, itraconazole and voriconazole; Antiseptic-germicide, for example Azithromycin and clarithromycin; The interferons, daunorubicin, Zorubicin and the taxol that are used for the treatment of AIDS dependency Kaposi sarcoma; And cidofovir, cidofovir, phosphine formic acid, ganciclovir and the valganciclovir of treatment cytomegalovirus (CMV) retinitis.
Be applicable to that other combination of the present invention comprises the combination of formula (I) compound or its pharmaceutically useful salt, solvate or derivative and following medicament: CCR1 antagonist (for example BX-471); Beta-2 adrenoceptor agonist, for example Salmeterol; Reflunomide agonist, for example fluticasone propionate; LTD4 antagonist, for example Singulair; Muscarine antagonist, for example tiotropium bromide; PDE4 inhibitor, for example cilomilast or roflumilast; Cox 2 inhibitor, for example celecoxib, valdecoxib or rofecoxib; Alpha-2-delta ligand, for example gabapentin or Pregabalin; Beta-interferon, for example REBIF; TNF receptor modulators such as TNF-alpha inhibitor (for example adalimumab), HMG CoA reductase inhibitor such as statin compound, for example atorvastatin; Or immunosuppressor, for example ciclosporin (cyclosporin) or Macrolide such as tacrolimus.
In aforesaid combination, with regard to formulation, formula (I) compound or its pharmaceutically useful salt, solvate or derivative and other therapeutical agent can be used respectively or combine with one another and use; With regard to time of application, can simultaneously or use successively.Therefore, a kind of component medicament can be before using another component medicament, simultaneously or use afterwards.
Therefore, another aspect of the present invention provides pharmaceutical composition, and it comprises formula (I) compound or its pharmaceutically useful salt, solvate or derivative, and one or more other therapeutical agents.
Be appreciated that the mentioned treatment of this paper comprises healing property, the property alleviated or preventative treatment.
By the following example and preparation, further specify the present invention, wherein use abbreviation:
H=hour;
Min=minute;
LRMS=low resolution mass spectrum;
The HRMS=high resolution mass spec;
The APCI+=atmospheric pressure chemical ionization;
ESI+=electricity mist ionization method;
The NMR=nucleus magnetic resonance;
The tlc=tlc;
The Me=methyl.
Embodiment 1
In N-{ (1S)-3-[3-to-(5-ethanoyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
Under the room temperature, with Acetyl Chloride 98Min. (18 μ l, 0.26mmol) add in amine N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } (94mg 0.21mmol) in the stirred solution in methylene dichloride (5ml), adds N to ethanamide subsequently, the N-diisopropylethylamine (45 μ l, 0.26mmol).After 15 hours,, make it then by the post that is separated with methylene dichloride (5ml) and water (5ml) diluted reaction mixture.In solution, feed nitrogen gas stream organic constituent is concentrated, use Mega Bond Elut
Flash(1 0g, Varian) purifying gained mixture are used methylene dichloride: methyl alcohol: (95: 5: 0.5, wash-out by volume) made the title compound (80mg, 79%) of white foam shape to strong aqua to the Si post.
LRMS (electric mist method): m/z[M+Na
+] 504, [MH
+] 482
Measured value C, 63.35; H, 7.32; N, 13.59.C
27H
36N
5FO
2.0.5CH
2Cl
2Calculated value C, 63.03; H, 7.12; N, 13.36.
[α]
D-21.7 ° (2.12mg/ml MeOH solution)
Embodiment 2-3
These embodiment prepare according to the foregoing description 1 described method, wherein use in N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide and corresponding formula V compound.LRMS all adopts electric mist ionization method.
Embodiment 2
Embodiment 3
LRMS:m/z[MH
+] 508 measured value C, 66.53; H, 7.59; N, 13.23.C
29H
38FN
5O
2.0.1 H
2O calculated value C, 66.26; H, 7.67; N, 13.32%.[α]
D-20.5 ° (2.38 mg/ml MeOH solution)
Embodiment 4
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
With triethylamine (7.0ml, 50.0mmol) add in N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } (19.9g is 45.3mmol) in the stirred solution in tetrahydrofuran (THF) (500ml) for ethanamide, drip subsequently isobutyryl chloride (5.3ml, 50.mmol).After 1 hour, drip second part of isobutyryl chloride (0.5ml, 5.0mmol).0.5 after hour, make reaction mixture be concentrated into about 300ml, add ethyl acetate (200ml).With 10%K
2CO
3The aqueous solution (200ml; Weight/volume) washing reaction mixture.Water phase separated extracts with ethyl acetate (100ml).Organic constituent is merged, with salt solution (100ml) washing, dry (MgSO
4), concentrate, up to obtaining to be ready beginning to form the mobile oil of foamy.Resistates is dissolved in the ethyl acetate (100ml), is heated to 90 ℃.(0.5ml) adds in this hot solution with water, makes mixture slowly cool to room temperature.Filter the collecting precipitation thing, with ethyl acetate (50ml) washing, drying under reduced pressure makes the title compound (20.9g, 90%) of white solid state.
LRMS：m/z[MH
+]510
1H NMR (400MHz, CD
3OD): δ: 7.29-7.35 (1H, m), 7.1 2-7.14 (1H, m), 7.05-7.07 (1H, m), 6.92-6.97 (1H, m), 5.13-5.17 (1H, m), 4.52-4.63 (1H, m), 4.43-4.44 (2H, m), 3.78-3.89 (2H, m), 3.31-3.40 (2H, m), 2.90-3.06 (1H, m), 2.77-2.84and 2.69-2.75 (2H, 2 * m), 2.39-2.51 (2H, m), 2.36 and 2.35 (3H, 2 * s), 2.20-2.30 (2H, m), 2.03-2.13 (2H, m), 1.95 (3H, s), 1.84-1.90 (2H, m), 1.55-1.65 (4H, m), 1.08-1.11 and 1.04-1.06 (6H, 2 * m). rotational isomer.
Measured value C, 66.94; H, 7.92; N, 13.47.C
29H
40FN
5O
2.0.5 H
2O.
Calculated value C, 67.16; H, 7.97; N, 13.50.
[α]
D-23.4 ° (1.64mg/ml MeOH solution)
Embodiment 5-7
These embodiment prepare according to the foregoing description 1 described method, wherein use in N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide and corresponding formula V compound.Except embodiment 6 used Atmospheric PressureChemical lonization, other LRMS all adopted electric mist method.
Embodiment 5
Embodiment 6
Embodiment 7
The NMR data of embodiment 5
In N-{ (1S)-3-[3-to-(2-methyl-5-propionyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
1H NMR (400MHz, CD
3OD): δ: 7.31-7.37 (1H, m), 7.14-7.16 (1H, d), 7.06-7.10 (1H, m), 6.94-6.99 (1H, m), 5.14-5.21 (1H, m), 4.56-4.63 (1H, m), 4.40 and 4.45 (2H, 2 * s), 3.81-3.89 (1H, m), 3.75-3.80 (1H, m), 3.33-3.41 (2H, m), 2.78-2.86 (1H, m), 2.70-2.76 (1H, m), 2.40-2.54 (4H, m), 2.37 and 2.38 (3H, 2 * s), 2.23-2.30 (2H, m), 2.07-2.14 (2H, m), 1.98 (3H, s), 1.86-1.93 (2H, m), 1.57-1.67 (4H, m), 1.07-1.17 (3H, m). rotational isomer.
Embodiment 8
In N-{ (1S)-3-[3-to-(2-methyl-5-(3,3,3-three fluoro-propionyls)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (65mg, 1.71mmol) and triethylamine (47 μ l, 3.41mmol) add 3,3, (15 μ l are 1.71mmol) in the stirred solution in methylene dichloride (2ml) for the 3-trifluoroacetic acid, add subsequently in amine N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } and ethanamide (50mg, 1.14mmol).Make reaction mixture in 30 ℃ of heating 15 hours, concentrate, utilize preparation HPLC purifying [PhenomenexC by in solution, feeding nitrogen gas stream
1815 * 10 centimetres, 10 microns posts, 20ml/ minute flow velocity, 225nm detects wavelength, and eluent gradient is that (the A:0.1% diethylamine is in water for 95: 5 to 5: 95 A: B; B:MeCN)], make gelationus title compound (20mg).
LRMS (electric mist method): 550[MH
+]
HRMS (electric mist method).Measured value 550.2800.C
28H
36N
5F
4O
2(MH
+), calculated value 550.2800.
Embodiment 9
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide. fumarate
In N-{ under reflux state (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4; 5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide (300mg; 0.59mmol) drip fumaric acid (68mg, 0.59mmol) solution in hot ethanol (2ml) in the solution in tetrahydrofuran (THF) (2ml).After 48 hours, add tetrahydrofuran (THF) (2ml), after 48 hours, crystallization is collected in filtration again, and is air-dry with tetrahydrofuran (THF) (2ml) washing, makes the title compound (110mg, 30%) of white powder.
Measured value C, 62.04; H, 7.26; N, 10.70.C
33H
44FN
5O
6.0.75H
2O
Calculated value C, 62.00; H, 7.17; N, 10.96.
Embodiment 10
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
With in N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } (264.4g 0.60mol) adds propan-2-ol (2.67 liters) to ethanamide, adds salt of wormwood (92.7g then, 0.67mol), make products therefrom be cooled to 15 ℃.Go through then and added isobutyryl chloride in 10 minutes (97.8g 0.91mol), keeps and is lower than 25 ℃ temperature, stirs after 10 minutes, finishes reaction.Be incorporated in the salt of wormwood (267.2g) in the water (2.40 liters) subsequently, separately the two-phase of gained.With ethyl acetate (2.67 liters) aqueous layer extracted, wash the organic phase that is merged, vacuum concentration then with saturated sodium-chloride water solution (1.32 liters) and water (800ml).With ethyl acetate (1.07 liters) dilution resistates, vacuum concentration once more.Repeat above-mentioned dilution once more and enrichment step and handle the resistates of gained, reach 1.07 liters up to cumulative volume with acetic acid ethyl ester.Be cooled to 0-5 ℃, stirred 2 hours, filter, with (2 * 130ml) washings of ice-cold ethyl acetate.Make solid product dry in 50 ℃ of vacuum drying ovens then, make title compound (269.8g, 0.53mol, 88.0%).
Embodiment 11
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide. fumarate
With in N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4; 5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } (554.0g 1.08mol) adds propan-2-ol (13.85 liters) to ethanamide, adds fumaric acid (126.2g then; 1.09mol), products therefrom is warmed to reflux and stirred 20 minutes.Under this temperature; filter this solution of clarification; vacuum concentration then; in according to initiator N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } to calculate solvent volume be 4ml/g to ethanamide.Make it be cooled to 0-5 ℃, stirred 2 hours, filter and with (2 * 550ml) washings of ice-cold propan-2-ol.Make solid product dry in 50 ℃ of vacuum drying ovens then, make title compound (495.9g, 0.79mol, 72.9%).
Embodiment 12
Method according to the fumarate of above-mentioned preparation embodiment 9; in preparation N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4; 5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } (the D)-tartrate of ethanamide; wherein use in N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide and D-tartrate.The PXRD peak data is provided in hereinafter.
Preparation example 1
8-benzyl-8-azabicyclic [3.2.1] suffering-3-ketone
With 2, (50g, 378mmol) (0.025N, the 160ml) solution in were cooled to 16 hours in 0 ℃ the 5-dimethoxy-tetrahydrofuran in hydrochloric acid.Add aniline hydrochloride (65g, 453mmol), the oxo propanedioic acid (55g, 377mmol) and sodium acetate aqueous solution (300ml, 0.69M), reactant was in stirring at room 1 hour.Mixture was heated 90 minutes in addition in 50 ℃, and ice bath cooling then uses the 2N sodium hydroxide solution to alkalize to pH12.Layering is with ethyl acetate washing water (3 * 300ml).The organic extract that is merged washes with water, dry (MgSO
4), filter and reduction vaporization.Decompression is (126 °/3mmHg), distill residual brown oil make the solid-state title compound of canescence (37.81g) down.
LRMS：m/z 216.3(MH
+)。
Preparation example 2
3-oxo-8-azabicyclic [3.2.1] octane-8-t-butyl formate
Hydrogen-pressure at room temperature and 269kPa is down, make 8-benzyl-8-azabicyclic [3.2.1] octane-3-ketone (15.0g, 69.7mmol), tert-Butyl dicarbonate (18.2g, 83.4mmol) and (20% w/w, 3.0g) mixture in ethyl acetate (165ml) stirred 4 hours to drape over one's shoulders the charcoal of palladium hydroxide.Make this mixture pass through Arbocel
Filter removal of solvent under reduced pressure.By silica gel column chromatography purifying resistates, use hexane: the gradient of ether (100: 0 to 50: 50), make title compound (16.2g), be water white oil, leave standstill crystallization.
1H NMR(400MHz，CDCl
3)：δ：1.48(9H，s)，1.60-1.68(2H，m)，2.00-2.11(2H，m)，2.26-2.34(2H，m)，2.48-2.82(2H，m)，4.35-4.58(2H，m)ppm。
Preparation example 3
3-(benzylamino)-introversion-8-azabicyclic [3.2.1] octane-8-t-butyl formate
Under the room temperature, make 3-oxo-8-azabicyclic [3.2.1] octane-8-t-butyl formate (10.0g, 44.4mmol), benzylamine (4.85ml, 49.7mmol) and sodium triacetoxy borohydride (14.11g, 66.6mmol) solution in Glacial acetic acid: (1: 9 volume/volume 290ml) stirred 16 hours in the mixture methylene dichloride.Solvent evaporated under reduced pressure is dissolved in resistates in the ethyl acetate (200ml), with saturated aqueous sodium carbonate (50ml) and water (50ml) washing.Make this organic solution drying (MgSO
4), filter and reduction vaporization.Utilize silica gel column chromatography purifying resistates, use methylene dichloride: methyl alcohol: the elutriant of strong aqua (98: 2: 0.25) makes the title compound (7.00g) of white solid state.
1H NMR(400MHz，CDCl
3)：δ：1.42-1.48(11H，m)，1.52-1.61(2H，m)，1.85-2.19(5H，m)，2.95-3.03(1H，m)，3.74(2H，s)，4.03-4.23(2H，m)，7.20-7.26(1H，m)，7.26-7.32(4H，m)ppm。
Preparation example 4
In the 3-to-amino-8-azabicyclic [3.2.1] octane-8-t-butyl formate
Make 3-(benzylamino)-introversion-8-azabicyclic [3.2.1] octane-8-t-butyl formate (7.00g, 22.1mmol), ammonium formiate (7.00g, 111mmol) with carbon (20% w/w of draping over one's shoulders palladium hydroxide, 0.7g) mixture in ethanol (200ml) is in 50 ℃ of heating, stop to disengage up to gas.Make the refrigerative mixture pass through Arbocel
Filter reduction vaporization filtrate.Utilize silica gel column chromatography purifying resistates, wherein use methylene dichloride: methyl alcohol: the gradient of strong aqua (98: 2: 0.25 to 95: 5: 0.5) makes the title compound (4.70g) of colorless oil.
LRMS：m/z 227.2(MH
+)
Preparation example 5
In the 3-to-[(3-nitro-4-pyridyl) amino]-8-azabicyclic [3.2.1] octane-8-t-butyl formate
With 3-amino-introversion-8-azabicyclic [3.2.1] octane-8-t-butyl formate (3.0g, 13.2mmol), 4-oxyethyl group-3-nitropyridine. hydrochloride (2.7g, 13.2mmol) and N-ethyl-N, N-Diisopropylamine (1.89g, 14.6mmol) be dissolved in the 1-Methyl-2-Pyrrolidone (5ml), in 120 ℃ of heating 18 hours.With ethyl acetate (150ml) dilution refrigerative reaction mixture, make water (3 * 50ml), saturated sodium bicarbonate aqueous solution (50ml) and salt solution (30ml) washing.Make organic layer drying (MgSO
4), solvent removed by evaporation at reduced pressure.With diethyl ether development resistates and filtration, make yellow solid-state title compound (1.5g).
LRMS：m/z 349(MH
+)
Preparation example 6
In the 1-to-(8-ethanoyl-8-azabicyclic [3.2.1] oct-3-yl)-2-methyl isophthalic acid H-imidazo [4,5-c] pyridine
With in the 3-to-[(3-nitro-4-pyridyl) amino]-8-azabicyclic [3.2.1] octane-8-t-butyl formate (4.40g, 12.6mmol) and iron powder (2.11g 37.8mmol) is dissolved in the Glacial acetic acid (50ml), with mixture in 60 ℃ of heating 2 hours.Add acetic anhydride (8ml) then, make mixture, make the refrigerative reaction mixture pass through Arbocel in 140 ℃ of heating 18 hours
Pad filters, removal of solvent under reduced pressure.Resistates is distributed between methylene dichloride (200ml) and water (200ml), and using the 2N aqueous sodium hydroxide solution to regulate mixture pH is 9.Make mixture pass through Arbocel once more
Pad filters, and separates organic phase.Use methylene dichloride (100ml) aqueous layer extracted, make the organic extract drying (MgSO that is merged
4).Solvent evaporated under reduced pressure with ethyl acetate development resistates, is filtered and dry (MgSO
4), make the title compound (3.27g) of white solid state.
LRMS：m/z 285(MH
+)。
Preparation example 7
In the 1-to-(8-ethanoyl-8-azabicyclic [3.2.1] oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine
With bromotoluene (1.78g; 10.4mmol) add in the 1-to-(8-ethanoyl-8-azabicyclic [3.2.1] oct-3-yl)-2-methyl isophthalic acid H-imidazo [4; 5-c] (2.47g, 8.7mmol) in the solution in ethanol (20ml), mixture was in stirring at room 48 hours for pyridine.This reaction mixture is cooled to-70 ℃ then, in ten minutes, drip sodium borohydride (0.33g, 8.7mmol).In-70 ℃ go through 1 hour after, make reaction mixture be warmed to-40 ℃, and then be cooled to-70 ℃ and add once more sodium borohydride (0.33g, 8.7mmol).In-70 ℃ go through 1 hour again after, add entry (10ml) and make reaction mixture be warmed to room temperature.Reduction vaporization ethanol uses methylene dichloride (3 * 25ml) extraction water-based resistatess.Make the organic extract drying (MgSO that is merged
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use ethyl acetate: methyl alcohol: the solvent gradient of diethylamine (by volume, be converted into 98: 2: 2 at 100: 0: 2, be converted into 95: 5: 2 then) wash-out.Evaporation contains the fraction of product, makes the title compound (2.23g) of white foam shape.
LRMS：m/z 379(MH
+)
Preparation example 8
In the 1-to-(8-azabicyclic [3.2.1] oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine
With in the 1-to-(8-ethanoyl-8-azabicyclic [3.2.1] oct-3-yl)-5-benzyl-2-methyl-4,5,6, (2.23g 5.89mmol) is dissolved in 6N aqueous hydrochloric acid (30ml), reflux 18 hours to 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine.By adding the 2N aqueous sodium hydroxide solution, it is 10 that cooled reaction mixture is regulated pH, uses dichloromethane extraction (2 * 50ml).Make the organic extract drying (MgSO that is merged
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use methylene dichloride: methyl alcohol: the solvent gradient of diethylamine (being converted into 93: 7: 1 in 100: 0: 0.5 by volume) wash-out.Evaporation contains the fraction of product, makes the title compound (1.47g) of white foam shape.
LRMS (electric mist method): m/z[M+H]
+337.
Preparation example 9
1-(S)-1-(3-fluorophenyl)-3-oxopropyl t-butyl carbamate
With diisobutyl aluminium hydride (1M dichloromethane solution, 39ml, 39mmol) be cooled to-78 ℃, drop to (3S)-3-[(tertbutyloxycarbonyl of-78 ℃ then) amino]-3-(3-fluorophenyl) methyl propionate (WO0039125, the 60th page, preparation example 12) (5.4g is 18.2mmol) in the solution in methylene dichloride (100ml).Make reactant in-78 ℃ of stirrings 30 minutes, add methyl alcohol (50ml is chilled to-78 ℃ in advance) then.Reactant was stirred 30 minutes, add 2N hydrochloric acid (250ml) then.Make this biphase mixture be warmed to room temperature, layering makes organic layer drying (MgSO
4), filter and reduction vaporization, make title compound (4.8g), for clarifying colourless oil.
LRMS：m/z 268.1(MH
+)
Preparation example 10
(1S)-3-[3-in to-(5-benzyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester
Under room temperature and nitrogen, with acetic acid (0.39g, 6.4mmol) add in the 1-to-(8-azabicyclic [3.2.1] oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine (2.16g, 6.4mmol) with (1S)-(2.06g 7.7mmol) is dissolved in the stirred solution in the methylene dichloride (25ml) 1-(3-fluorophenyl)-3-oxopropyl t-butyl carbamate.(1.63g 7.7mmol), places reactant 2 hours in room temperature to add sodium triacetoxy borohydride then.Reaction mixture is distributed between saturated sodium bicarbonate aqueous solution (50ml) and methylene dichloride (50ml).Remove organic phase, water washs with methylene dichloride (50ml).Make the organic phase drying (MgSO that is merged
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use methylene dichloride: methyl alcohol: the solvent gradient of strong aqua (being converted into 96: 4: 0.4 in 99: 1: 0.1 by volume) wash-out.Evaporation contains the fraction of product, makes the title compound (2.56g) of white foam shape.
LRMS (electric mist method): m/z[M+H]
+588
Preparation example 11
(1S)-3-[3-in to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester
With in (1S)-3-[3-to-(5-benzyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester (2.55g, 4.34mmol), ammonium formiate (2.73g, 43.4mmol) and carbon (20% w/w, 0.25g) mixture heating up to 60 in ethanol (35ml) ℃ of draping over one's shoulders palladium hydroxide.(0.63g 10.1mmol), continues at 60 ℃ and heated 2 hours in addition to add other ammonium formiate after 1 hour.Make the refrigerative reaction mixture pass through Arbocel then
Filter reduction vaporization filtrate.Resistates is distributed between methylene dichloride (100ml) and saturated sodium bicarbonate aqueous solution (50ml), separate organic phase and wash with water (30ml).Make organic layer drying (MgSO
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use methylene dichloride: methyl alcohol: the solvent gradient of strong aqua (by volume, being converted into 93: 7: 1 at 99: 1: 0.1) wash-out makes the title compound (1.50g) of white foam shape.
LRMS (electric mist method): m/z[M+H]
+498.
Preparation example 12
In the 1-to-(8-{ (3S)-3-[(tertbutyloxycarbonyl) amino]-3-(3-fluorophenyl) propyl group-8-azabicyclic [3.2.1] oct-3-yl)-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate
Under room temperature and nitrogen, with methyl chlorocarbonate (0.167g, 1.76mmol) add in (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-(0.80g is 1.60mmol) in the solution in methylene dichloride (10ml) for 1-(3-fluorophenyl) the propyl carbamic acid tert-butyl ester.Make reactant in stirring at room 1.5 hours, wash with saturated sodium bicarbonate aqueous solution (10ml) then.Separate organic phase, once more with dichloromethane extraction water (2 * 10ml).Make the dichloromethane extract drying (MgSO that is merged
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use methylene dichloride: methyl alcohol: the solvent mixture of strong aqua (being converted into 93: 7: 1 at 99: 1: 0.1) wash-out makes the title compound (0.84g) of white foam shape.
LRMS (electric mist method): m/z[M+H]
+556
Preparation example 13
In the 1-to-8-[(3S)-3-amino-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate. tri hydrochloride
In 0 ℃, hydrogen chloride gas is fed in the 1-to-(8-{ (3S)-3-[(tertbutyloxycarbonyl) amino]-3-(3-fluorophenyl) propyl group }-8-azabicyclic [3.2.1] oct-3-yl)-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] and pyridine-5-methyl-formiate (0.83g, 1.50mmol) in the solution in methylene dichloride (15ml), saturated up to this solution.Make reaction mixture be warmed to room temperature then, stirred 1 hour.Solvent evaporated under reduced pressure is suspended in the methylene dichloride (10ml) resistates.Repeat this operation three times, make the title compound (0.82g) of white solid state.
LRMS (electric mist method): m/z[M+H]
+456.
Preparation example 14
In the 1-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate
Under nitrogen and room temperature, with Acetyl Chloride 98Min. (0.062g, 0.79mmol) add in the 1-to-8-[(3S)-3-amino-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate. tri hydrochloride (0.409g, 0.72mmol) and triethylamine (0.33g 3.25mmol) is dissolved in the solution in the methylene dichloride (10ml), and reaction mixture was stirred 2 hours.This solution is with water (10ml), 1N sodium hydroxide solution (10ml) and salt solution (10ml) washing then.Separate organic phase, dry (MgSO
4), solvent evaporated under reduced pressure.Utilize quick silica gel column chromatography purifying resistates, it is to use methylene dichloride: methyl alcohol: the solvent gradient of strong aqua (by volume is converted into 97: 3: 0.3 at 99: 1: 0.1) wash-out.Evaporation contains the fraction of product, makes the title compound (0.24g) of white foam shape.
LRMS (electric mist method): m/z[M+H]
+498.
Preparation example 15
In N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
In 1-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate (13.27g, 26.7mmol) add 2M aqueous sodium hydroxide solution (120ml) in the stirred solution in propan-2-ol (80ml), made the mixture reflux 48 hours.After being cooled to room temperature, (2 * 200ml) extract this mixture with ethyl acetate.Make the organic constituent that is merged with salt solution (150ml) washing, dry (MgSO
4), concentrating under reduced pressure.Utilize flash column chromatography purification of crude product mixtures, it is to use methylene dichloride: methyl alcohol: and strong aqua (90: 10: 1, be converted into 80: 201 then, wash-out by volume) makes the title compound (8.54g, 73%) of white foam shape.
LRMS (Atmospheric PressureChemical lonization): m/z[MH
+] 440.
Preparation example 16
In N-{ (1S)-3-[3-to-(2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
With in the 1-to-8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclic [3.2.1] oct-3-yl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-5-methyl-formiate. (L)-tartrate (WO03/084954, embodiment 46) (898g 1.39mol) adds in methylene dichloride (4.5 liters) and the water (4.5 liters).(10M 450ml), stirred the gained mixture 15 minutes to add aqueous sodium hydroxide solution then.Separate two-phase, with other methylene dichloride (2.25 liters) aqueous layer extracted.Concentrate the organic phase that is merged then, the oil of gained is dissolved in the propan-2-ol (4.5 liters).(2M, 13.9mol), makes this two-phase mixture reflux 65 hours by 6.93 liters to add aqueous sodium hydroxide solution then.After being cooled to room temperature, separate phase, with ethyl acetate (4.5 liters) aqueous layer extracted.The organic phase of using saturated sodium-chloride water solution (4.5 liters) washing to be merged then, vacuum concentration.With ethyl acetate (9 liters) dilution resistates, vacuum concentration once more.At last, add other ethyl acetate (4.5 liters), make the gained soup compound, filter, with ice-cold ethyl acetate washing (2 * 450ml) in 0-5 ℃ of stirring 1 hour.Make solid product dry in 40 ℃ of vacuum drying ovens then, make title compound (547.2g, 1.24mol, 89.8%).The LRMS data of this title compound are identical with the title compound of preparation example 15.
Biological data
Formula (I) compound and the active ability of pharmaceutically useful salt, solvate and derivatives modulate che mokine receptors thereof are confirmed by methods known in the art, for example adopt J.Leukoc.Biol. according to people such as Combadiere, 60, the CCR5 binding analysis that the operation described in the 147-52 (1996) is carried out; And/or adopt as the described intracellular Ca2+ mobilization of same author analytical method.The clone of expressing the acceptor of studying comprises those of natural expression this receptor, PM-1 for example, and the perhaps peripheral blood lymphocyte (PBL) of IL-2 stimulation, perhaps through engineering approaches is with the cell of express recombinant acceptor, for example CHO, 300.19, L1.2 or HEK-293.
When the CCR5 binding analysis method that adopts people's (ibid) such as Combadiere is tested, the IC of the compound of embodiment 4
50Value is 7.5nM (MIP-1 α), 7.3nM (MIP-1 β) and 6.7nM (RANTES).
When the CCR5 binding analysis method that adopts people such as Combadiere is tested, the IC of the compound of embodiment 5
50Value is 2.7nM (MIP-1 α), 2.4nM (MIP-1 β) and 1.9nM (RANTES).
When the intracellular Ca2+ mobilization analytical method that adopts people's (ibid) such as Combadiere was tested, all the compound of embodiment was IC
50Value is lower than the potent antagonist of 100nM (MIP-1 β).
Adopt gp160 inductive cell-cytogamy analytical method (to be used for the IC that test compounds merges anti-HIV-1
50Value), further confirm the pharmacologically active of formula (I) compound and pharmaceutically useful salt, solvate and derivative.Gp160 inductive cell-cytogamy analytical method is used HeLa P4 clone and CHO-Tat10 clone.
HeLa P4 expression of cell lines CCR5 and CD4, and by the transfection of HIV-1LTR-beta-galactosidase gene.The substratum of cultivating this clone is eagle ' the s substratum (D-MEM) (not containing L-glutaminate) of Dulbecco improvement, and it contains 10% foetal calf serum (FCS), 2mM L-glutaminate penicillin/streptomycin (Pen/Strep); 100U/ml penicillin+10mg/ml Streptomycin sulphate) and 1 μ g/ml puromycin.
Chinese hamster ovary celI system is the clone that the Tat (transcribing trans-activator) that is derived from CHO JRR17.1 clone expresses, and this CHO JRR17.1 clone is by pTat puro plasmid transfection.The substratum of cultivating this clone is the rich medium RPMI1640 that is used for mammalian cell cultures (not containing L-glutaminate) that is developed by Roswell Park MemorialInstitute at first, and it contains 10%FCS, 2mM L-glutaminate, 0.5mg/ml hygromycin B and 12 μ g/ml puromycins.CHO JRR177.1 expression of cell lines gp160 (JRFL) is owing to it can merge the clone that is selected with CCR5/CD4 express cell system.
In case cytogamy, the HIV-1 long terminal repeat (LTR) that exists in the Tat that exists in the Chinese hamster ovary celI energy trans-activation HeLa cell causes the expression of beta-galactosidase enzymes.Adopt Fluor Ace then
TMBeta-galactosidase enzymes is reported the expression of sub-assay kit (Bio-Rad, catalog number (Cat.No.) 170-3150) mensuration.This test kit is to adopt 4-methyl umbelliferone galactopyranoside (MUG) to measure the QFT that beta-galactosidase enzymes is expressed as substrate.The beta-galactosidase enzymes hydrolysis fluorescin substrate that becomes second nature, release place fluorescence molecule 4-methyl umbelliferone (4MU).Measure the fluorescence intensity of 4-methyl umbelliferone then on photofluorometer, excitation wavelength is 360nm, and emission wavelength is 460nm.
The compound that suppresses cytogamy causes signal weakening, along with solubilising in suitable solvent and the dilution in substratum, uses the dose-response curve of every kind of compound to calculate IC
50Value.
According to aforesaid method, the IC of all embodiment compounds of the present invention
50Value all is lower than 10nM.The IC of the compound of embodiment 1 and embodiment 5
50Value is respectively 130 and 120pM.
Powder x-ray diffraction (PXRD) data
PXRD figure is all gathered 2-55 ° of 2-θ angular region, 0.02 ° of step-length by Bruker D5000 powdery diffractometry device.Sample rotation uses simultaneously that (filterable copper K-α 1X-ray (wavelength=1.5046 dusts) the irradiation sample of λ=0.15405nm), wherein graphite monochromator is furnished with in the X-x ray tube of 40kV/40mA operation through graphite monochromator.Before and after every batch sample image data, with standard quartz sample calibration diffractometer.
The main peak of embodiment 10,11 and 12 PXRD figure (2-θ angular unit for °) is illustrated in following table.
In table 1:N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group the PXRD peak data of ethanamide
| Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) |
| 8.1 | 90.5 | 17.0 | 49.6 | 24.1 | 35.8 |
| 9.0 | 20.9 | 17.8 | 80.7 | 24.8 | 29.5 |
| 9.8 | 12.8 | 18.3 | 67.4 | 25.4 | 38.0 |
| 10.7 | 89.1 | 18.6 | 43.6 | 25.6 | 34.6 |
| 11.3 | 39.8 | 18.9 | 48.3 | 26.2 | 43.0 |
| 12.3 | 100.0 | 19.9 | 39.2 | 27.0 | 21.3 |
| 13.1 | 24.2 | 20.5 | 48.3 | 27.9 | 28.6 |
| 14.1 | 67.3 | 21.0 | 43.8 | 28.9 | 25.5 |
| 14.5 | 19.4 | 21.5 | 50.4 | 29.4 | 24.6 |
| 15.8 | 55.4 | 22.5 | 51.4 | 30.0 | 21.7 |
| 16.3 | 49.9 | 23.1 | 46.1 | 35.9 | 18.9 |
| 16.6 | 48.5 | 23.3 | 54.9 |
In table 2:N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide. the PXRD peak data of fumarate
| Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) |
| 6.7 | 38.6 | 19.1 | 18.2 | 25.0 | 12.9 |
| 10.0 | 34.1 | 19.6 | 77.8 | 25.5 | 10.1 |
| 10.2 | 17.7 | 20.1 | 10.2 | 26.7 | 17.6 |
| 10.4 | 36.2 | 20.6 | 65.2 | 28.3 | 24.1 |
| 10.9 | 16.2 | 20.8 | 23.4 | 28.6 | 13.6 |
| 12.8 | 13.1 | 21.1 | 42.3 | 29.0 | 10.1 |
| 13.6 | 10.1 | 22.2 | 20.2 | 29.7 | 19.0 |
| 16.7 | 100.0 | 22.6 | 24.1 | 30.0 | 12.8 |
| 17.0 | 16.1 | 22.9 | 37.0 | 31.0 | 11.0 |
| 17.6 | 32.0 | 23.4 | 12.3 | 33.0 | 15.2 |
| 18.2 | 31.1 | 24.8 | 14.3 | 34.6 | 13.2 |
| 18.4 | 77.8 |
In table 3:N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide. (D)-the PXRD peak data of tartrate
| Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) |
| 5.0 | 12.5 | 16.6 | 42.4 | 28.0 | 21.2 |
| 6.9 | 59.6 | 17.1 | 100.0 | 29.1 | 25.7 |
| 9.0 | 17.1 | 18.0 | 65.1 | 29.7 | 21.6 |
| 9.2 | 10.9 | 18.5 | 50.0 | 30.9 | 17.2 |
| 10.0 | 14.6 | 19.0 | 27.1 | 32.1 | 21.0 |
| 10.4 | 17.3 | 19.5 | 23.9 | ||
| 11.0 | 15.1 | 20.0 | 31.5 | ||
| 12.4 | 14.5 | 20.8 | 30.6 | ||
| 13.6 | 12.5 | 21.2 | 42.2 | ||
| 14.4 | 13.7 | 21.4 | 39.0 | ||
| 14.8 | 10.1 | 22.5 | 41.6 | ||
| 16.4 | 41.3 | 25.0 | 15.8 |
At in N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide. the PXRD figure simulation (comprising 2-θ angle, d spacing and relative intensity) of fumarate is by single crystal structure, the employing Accelrys Materials Studio of this compound
TM" Reflex Powder Diffraction " module (2.2 editions) calculate and get.Relevant analog parameter is:
Wavelength=1.540562 dusts (Cu K α)
Polarization factor=0.5
Pseudo-Voigt figure (U=0.01, V=-0.001, W=0.002)
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide. the main peak of the simulated PXRD figure of fumarate (2-θ angular unit for °) is shown in table 4.
In table 4:N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4; 5; 6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide. the simulated PXRD peak data of fumarate
| Angle (° 2-θ) | Intensity (%) | Angle (° 2-θ) | Intensity (%) |
| 6.7 | 59.4 | 19.6 | 98.3 |
| 10.0 | 64.5 | 20.6 | 56.8 |
| 10.5 | 67.7 | 21.1 | 45.1 |
| 11.0 | 28.8 | 22.2 | 13.8 |
| 12.8 | 12.7 | 22.5 | 16.1 |
| 13.6 | 17.0 | 22.9 | 39.1 |
| 16.7 | 93.8 | 23.4 | 10.0 |
| 17.0 | 19.6 | 26.8 | 11.2 |
| 17.7 | 32.3 | 28.3 | 15.5 |
| 18.2 | 30.0 | 28.6 | 10.8 |
| 18.5 | 100.0 | 29.7 | 14.1 |
| 19.1 | 15.4 | 30.0 | 11.6 |
Dsc (DSC) data
All DSC gather by Perkin Elmer PYRIS Diamond DSC, and this apparatus preparation has automatic sampler and stream of nitrogen gas.Sample is placed in the 50 μ l aluminium dishes of porose and lid, by 10 ℃ to 300 ℃ heating, speed is 20 ℃/minute.
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide
Sample is heavy: 3.016mg
Endotherm(ic)peak: 118 ℃-fusion
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide. fumarate
Sample is heavy: 2.905mg
Endotherm(ic)peak: 219 ℃-fusion
The heat absorption incident betides 228 ℃
The heat release incident betides 246 ℃
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide. (D)-tartrate
Sample is heavy: 2.979mg
Endotherm(ic)peak: 217 ℃-fusion
Claims (19)
1. formula (I) compound or its pharmaceutically useful salt, solvate or derivative,
Wherein:
R
1Be C
1-C
6Alkyl; And
R
2Be C
1-C
6Alkyl or C
3-C
7Cycloalkyl, wherein this alkyl is optional by CF
3Replace.
2. as the desired compound of claim 1, wherein R
1Be C
1-C
4Alkyl.
3. as claim 1 or 2 desired compound, wherein R
1It is methyl.
4. as each desired compound, wherein R in the claim 1 to 3
2Be optional by CF
3The C that replaces
1-C
4Alkyl.
5. as each desired compound, wherein R in the above-mentioned claim
2Be methyl, ethyl or sec.-propyl.
6. as each desired compound, wherein R in the claim 1 to 3
2Be cyclopropyl or cyclobutyl.
7. as the desired compound of claim 1, it is selected from:
In N-{ (1S)-3-[3-to-(5-ethanoyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(5-tetramethylene carbonyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(5-cyclopropane carbonyl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(2-methyl-5-propionyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(5-butyryl radicals-2-methyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(2-methyl-5-(2,2-dimethyl-propionyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
In N-{ (1S)-3-[3-to-(2-methyl-5-(3,3,3-three fluoro-propionyls)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclic [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group ethanamide;
And their pharmaceutically useful salt, solvate or derivative.
8. pharmaceutical composition contains in the aforesaid right requirement each formula (I) compound or its pharmaceutically useful salt, solvate or derivative and one or more pharmaceutically useful vehicle, diluent or carrier.
9. the pharmaceutical composition of claim 8 contains one or more other therapeutical agent.
10. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 are used as medicine.
11. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 are used for the treatment of and relate to the disease of regulating the CCR5 acceptor.
12. the compound of claim 11, wherein this disease be the human immunodeficiency virus infection, with retroviral infection, acquired immune deficiency syndrome (AIDS) or the inflammatory diseases of human immunodeficiency virus's genetic correlation.
13. the compound of claim 11, wherein this disease is multiple sclerosis, rheumatoid arthritis or transplant rejection.
14. the compound of claim 11, wherein this disease is an inflammatory bowel; Endometriosis; Type i diabetes; Ephrosis; Fibrosis; Chronic pancreatitis; Inflammatory lung disease; Encephalitis; Chronic heart failure; Ischemic heart disease; Psoriasis; Apoplexy; Obesity; Central nervous system disease; Anemia; Restenosis; Atherosclerotic plaque; Atopic dermatitis; Chronic pancreatitis; Cancer; Pain; Or by the stress reaction of performing the operation, infect, damaging or other traumatic injury produced.
15. the compound of claim 11, wherein this disease is hepatitis b virus infected, infection with hepatitis C virus, the plague, poxvirus infection, toxoplasmosis, mycobacterial infections, trypanosome infection, pneumonia or cryptosporidiosis.
16. each formula (I) compound or its pharmaceutically useful salt, solvate or derivative are used for the treatment of purposes in the medicine that wherein relates to the disease of regulating the CCR5 acceptor in preparation in the claim 1 to 7.
17. treatment suffers from the mammiferous method that wherein relates to the disease of regulating the CCR5 acceptor, this method comprises each formula (I) compound or its pharmaceutically useful salt, solvate or derivative in the claim 1 to 7 of this administration significant quantity.
18. each formula (I) compound or the method for its pharmaceutically useful salt, solvate or derivative in the preparation claim 1 to 7, this method comprises the following steps:
(A) under the carboxylic acid/amine coupling condition of routine, make formula (II) compound
React with formula (III) compound
(B) under the carboxylic acid/amine coupling condition of routine, make formula (XVI) compound
React with the formula V compound
(C) under normal condition, utilize the amine of formula (XX),
Make the aldehyde of formula (XIX) be reduced amination,
(D) under normal condition, utilize the amine of formula (XX), make the nitrile of formula (XXI) be reduced amination,
(E) under conventional alkylation conditions, utilize formula (XXII) compound,
The amine that makes formula (XX) is by alkylation;
(F) under the conventional reduction condition, the alkene acid amides that makes formula (XXIII) is by asymmetric reduction,
Perhaps
(G) under normal condition, the amine of formula (II) or its metal-salt (being the deprotonation type) react with the ester of formula (XXIV),
R
1CO
2EsGP (XXIV)
R wherein
1And R
2Define as claim 1 Chinese style (I) compound, Lg is the leaving group that is suitable for the aliphatics nucleophilic substitution, and EsGp is that ester forms group.
19. formula (II), (IV), (VI), (VII), (XVI), (XVII), (XVIII), (XX) or compound (XXIII).
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|---|---|---|---|---|
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2003
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910168B (en) * | 2007-10-25 | 2014-07-30 | 埃克塞利希斯股份有限公司 | Tropane compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100526313C (en) | 2009-08-12 |
| ZA200602096B (en) | 2007-05-30 |
| UA84714C2 (en) | 2008-11-25 |
| GB0323236D0 (en) | 2003-11-05 |
| GT200400203A (en) | 2005-04-18 |
| CN101632664A (en) | 2010-01-27 |
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