CN101115764B - New macrolides - Google Patents
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- CN101115764B CN101115764B CN2006800040125A CN200680004012A CN101115764B CN 101115764 B CN101115764 B CN 101115764B CN 2006800040125 A CN2006800040125 A CN 2006800040125A CN 200680004012 A CN200680004012 A CN 200680004012A CN 101115764 B CN101115764 B CN 101115764B
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- 0 C*O[C@@]1[C@](O[C@]([C@](C)[C@@]([C@@](C)C(OC[C@](C)([C@](*)(C2*)C(C)C([C@](C)C3)=O)OC2=O)=O)O[C@@](C[C@@]2(C)OC)O[C@@](C)[C@@]2O*)[C@]3(C)OC)O[C@](C)C[C@@]1*(C)C Chemical compound C*O[C@@]1[C@](O[C@]([C@](C)[C@@]([C@@](C)C(OC[C@](C)([C@](*)(C2*)C(C)C([C@](C)C3)=O)OC2=O)=O)O[C@@](C[C@@]2(C)OC)O[C@@](C)[C@@]2O*)[C@]3(C)OC)O[C@](C)C[C@@]1*(C)C 0.000 description 1
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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 relates to new antibiotic macrolide compounds of the general formula (I): with improved activity, to medicaments comprising such antibiotics, and to the use of such antibiotics for the treatment of infectious diseases, inflammatory diseases and human diseases or disorders which can be ameliorated by inhibition human phospdiesterases.
Description
The present invention relates to new active macrolide antibiotics, comprise the purposes that this type of antibiotic medicine and this type of microbiotic are used to treat infection and inflammatory diseases with raising.
Macrolide is one type of effective and safe microbiotic.Macrolide antibiotics wherein commonly used is an Oxacyclotetradecane,erythromycin deriv, and s-generation Macrocyclolactone lactone kind medicine is clarithromycin and Azythromycin.The 3-ketone macrolide antibiotics that is known as ketolide recently is developed, and the bacterium of such microbiotic antagonism macrolide antibiotic has the activity of raising.
Have with the ketolide compound of macrolide ring condensed lactone ring five membered and in following document, address: WO02/16380, WO03/072588, WO02/50091, WO02/50092, WO03/024986 and US2004/0038915.Have with macrolide ring condensed lactone ring five membered and the macrolides compound that is connected to the cladinose of macrolide ring and in WO03/042228 and WO03/004509, address to some extent.Yet, different in the replacement type of the cladinose described in the WO03/042228 with the replacement type of the compound described in this paper, and in the compound described in the WO03/004509, do not have sulphur atom to be connected to lactone ring five membered.
In addition, existing report points out that macrolides compound has anti-inflammatory activity, and recently people have also had raising (Journal ofAntimicrobial Chemotherapy for example to the interest of the treatment potential research of this anti-inflammatory activity; 1998; 41, Suppl.B, 37-46).
The invention provides the ester of cleavable in new macrolide antibiotic compounds and their pharmaceutically-acceptable acid addition or the body of following general formula I of biological property with raising:
Wherein:
R1 is residue-Y-X-Q;
Y is S, SO or SO
2
X is key or has 9 straight chain group that are selected from C, N, O and/or S atom at the most, and wherein 2 atoms can be N at the most, and an atom can be O or S, and a carbon atom can be CO group form, and a sulphur atom can be SO
2Group form and two adjacent C atoms can with-CH=CH-or-C ≡ C-form exists;
Q is hydrogen, alkyl, heterocyclic radical or aryl;
*Be represented as (R) or (S) chiral centre of form, promptly comprise non-enantiomer mixture and isolating stereoisomer form.
The compound of preceding text definition is new and has the anti-microbial activity to resisting gram-positive bacteria and part Gram-negative bacteria.Therefore; They can be used as the medicine of resisting gram-positive pathogenic agent; For example staphylococcus, suis, streptococcus pneumoniae and propionibacterium and some gram negative strains; For example hemophilus influenzae (H.influenzae) and the infection that can treat and prevent the susceptible biology to cause as the mankind or beasts medicine comprise the infection that those cause the biology of Oxacyclotetradecane,erythromycin deriv, clindamycin and tetracycline resistant.
Except having anti-microbial property, above-claimed cpd also has the potential anti-inflammatory, therefore can treat or preventing inflammation as the mankind or beasts medicine.
The term " alkyl " that here uses mean have 1-12 carbon atom, the preferred saturated hydrocarbyl group of straight or branched of 1-6 carbon atom.This type of group is for example methyl, ethyl, n-propyl, sec.-propyl, the tertiary butyl, amyl group, hexyl etc.This type of alkyl group can be further be selected from following substituting group and replaces by one or more: for example, lower alkoxy is like C
1-C
4Alkoxyl group is such as methoxyl group, oxyethyl group, propoxy-or positive fourth oxo group; C
3-C
7Cycloalkyloxy or C
3-C
7Naphthenic base-C
1-G
4Alkoxyl group, like cyclopentyloxy, cyclopropyl methoxy for group; Like the defined halogen of preceding text; The substituted alkyl of halogen, for example difluoromethyl, trifluoromethyl or three chloroethyls; Cyanic acid; Nitro; Amino; Alkylamino; Dialkyl amido; Alkylthio; Sulfydryl; Hydroxyl; Formamyl; Carboxylic group; Oxo group; Or like the aryl or the heterocyclic radical of hereinafter definition.Substituting group can be identical or differs from one another.
Term " halogen " means fluorine, chlorine, bromine or iodine.
Term " aryl " means to have one or more and is preferably 6 yuan aromatic kernel and has the aromatic group of 6-14 carbon atom.Instance is phenyl, naphthyl, anthryl and phenanthryl particularly.These groups can further be selected from following substituting group by 1,2,3,4 or 5 and replace: for example, and like the defined alkyl of preceding text; Lower alkoxy, for example C
1-C
4Alkoxyl group is such as methoxyl group, oxyethyl group, propoxy-or positive fourth oxo group; C
3-C
7Cycloalkyloxy or C
3-C
7Naphthenic base-C
1-C
4Alkoxyl group, like cyclopentyloxy, cyclopropyl methoxy for group; Like the defined halogen of preceding text; The substituted alkyl of halogen, for example difluoromethyl, trifluoromethyl or three chloroethyls; Cyanic acid; Nitro; Amino; Alkylamino; Dialkyl amido; Alkylthio; Sulfydryl; Hydroxyl; Formamyl; Carboxyl; Oxo group; Or the aryl or the heterocyclic radical of definition here, can be for unsubstituted or replaced by the substituting group except aryl or heterocyclic radical of one or more preceding text definition.Substituting group can be identical or differs from one another.When more than one substituting group was connected to aromatic yl group, these substituting groups can be identical or differ from one another, and this also is contained in the scope of the invention.For example dimethoxy-phenyl means two methoxyl groups replacements based on 2,3-position, 2, and 4-position, 2,5-position, 2,6-position, 3,4-position, 3,5-position and 3, the 6-position is connected to phenyl ring.
The instance of substituted aryl rings is right-methoxyl group-phenyl, 3; 4-dimethoxy-phenyl, 3-cyclopentyloxy-4-methoxyl group-phenyl, 3-cyclopropyl methyl oxygen base-4-difluoromethyl oxygen base-phenyl, right-dimethylamino-phenyl, right-cyanic acid-phenyl, 5-(dimethylamino)-1-naphthyl, 2; 4-Dimethoxyphenyl, 2 '-methoxyl group-1; 1-xenyl, 3,4-3,5-dimethylphenyl and 1,4-difluorophenyl.
The term " heterocyclic radical " that here uses means first (monocycle or dicyclo) the heterocycle ring system of undersaturated or saturated unsubstituted or substituted 5-to 10-, and this heterocycle ring system comprises the heteroatoms that at least one is selected from oxygen, nitrogen and/or sulphur.Examples of heterocyclic substituents include, but are not limited to, groups such as the following: piperidinyl, morpholinyl group, a 2 - pyridyl, 3 - pyridyl, 4 - pyridyl, pyrrolidinyl, piperazinyl, 1H-pyrazol- -1 - yl, 1H-imidazol-1 - yl, 1H-imidazol-2 - yl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazinyl, thiazolyl, thiadiazolyl, oxadiazolyl pyrazolyl, triazolyl, e.g. 1H-[1,2,4] - triazol-1 - yl, 1H-tetrazolyl, 2H-tetrazolyl; thienyl, furyl group (2 - or 3-furanyl - furanyl), 1H-azepine, Leather tetrahydro - thienyl, 3H-1, 2,3 - oxathiazole group, 1,2,3 - oxadiazolyl, 1,2,5 - oxa dithiolane cyclopentenyl (oxadithiolyl), isoxazolyl, isothiazolyl, 4H-1, 2,4 - triazine oxadiazolyl, 1,2,5 - oxathiazine group, 1,2,3,5 - evil thiadiazine, 1,3,4 - thiadiazole diazepin leather group, 1,2,5,6 - evil triaza
group, 1,6,3,4 - dioxa-dithiol heptanyl (dioxadithiopanyl), oxazolidinyl, tetrahydrothienyl, etc., or a fused heterocyclic ring system, for example, quinolinyl, such as quinolin-8 - yl, quinolin-5 - yl, quinolin-2 - yl , quinolin-6 - yl, quinolin-3 - yl, isoquinolinyl (6 - isoquinolinyl), quinazolinyl, 1H-benzotriazolyl, 1H-imidazo [4,5 - c] pyridinyl, 5H-imidazo [4,5-c] pyridinyl, 1H-imidazo [4,5-b] pyridin-1 - yl, 3H-imidazo [4,5-b] pyridin - 3 -, 1,2,3,4 - tetrahydro - quinolyl, 1,2,3,4 - tetrahydro - isoquinolinyl, thieno [2,3-b] pyridyl, benzothiazolyl group (e.g., 2 - benzothiazolyl), 1H-benzimidazolyl, 1H-indolyl, 1,2,3,4 - tetrahydro - quinolyl, purine base, e.g. 9H-purin-9 - yl 6 - amino-9H-purin-9 - yl, 2,6 - diamino-9H-purin-9 - yl, 1H-purin-6 - yl, 1H-2, 3 - dihydro-indol-1 - yl , 2,1,3 - benzo-oxadiazol-5 - yl, 2,1,3 - benzoxadiazol-4 - yl, 1,3 - benzodioxol-penten-5 - yl 6 - quinoxalinyl 2 - benzo [b] thiophen-3 - yl, 3,4 - dihydro-1H-2-oxo - quinoline-6 - groups.
The heterocyclic radical group can further be replaced by one or more substituting groups.This type of substituting group comprises, for example, and like the defined alkyl group of preceding text; Lower alkoxy, for example C
1-C
4Alkoxyl group is such as methoxyl group, oxyethyl group, propoxy-or positive fourth oxo group; C
3-C
7Cycloalkyloxy or C
3-C
7Naphthenic base-C
1-C
4Alkoxyl group, like cyclopentyloxy, cyclopropyl methoxy for group; Like the defined halogen of preceding text; The substituted alkyl group of halogen, for example trifluoromethyl, three chloroethyls; Nitro; Amino; Alkylamino; Dialkyl amido; Alkylthio; Sulfydryl; Hydroxyl; Formamyl; Carboxyl; Oxo group; Or, can be unsubstituted or mentioned above do not replaced for the substituting group of aryl or heterocyclic radical by one or more like defined aryl of preceding text or heterocyclic radical.If be connected to the heterocyclic radical group more than a substituting group, these substituting groups can be identical or differ from one another so, and this also is contained in the scope of the invention.For example the lutidine base means two methyl substituents and all can be connected to pyridyl in the possible position of chemistry.For example two methyl substituents can be connected to the 2-pyridyl in following positions: 3, and 4-position, 4,5-position, 5,6-position, 3,5-position, 3,6-position and 4,6-position.Two methyl substituents can be connected to the 3-pyridyl in following positions: 2, and 4-position, 2,5-position, 2,6-position, 4,5-position, 4,6-position and 5,6-position.Two methyl substituents all can be connected to the 4-pyridyl in following positions: 2, and 3-position, 2,5-position, 2,6-position and 3,5-position.
Substituted heterocyclic radical examples of groups is 5-(2-pyridyl) thiophene-2-base, 2,4,6-trimethoxy-3-pyridyl, 5-methyl-3-isoxazolyl, 5-cyanopyridine-2-base; 6-(1H-imidazoles-1-yl)-3-pyridyl, 6-(1H-pyrazol-1-yl)-3-pyridyl, 6-bromo-2-methyl-quinazoline-4-base.
The substituting group of preferred especially heterocyclic radical group is: alkyl, alkoxyl group, oxo, amino, alkylamino, dialkyl amido or aryl, wherein alkyl, alkoxyl group and aryl such as preceding text define.
Preferred substituted heterocyclic instance is: 1H-pyrimidine-2; 4-diketone-1-base, 1H, 3H-pyrimidine-2,4-diketone-5-methyl isophthalic acid-Ji, 1H-pyrimidine-4-amino-2-ketone-1-base, 6-be amino-9H-purine-9-base, 6-dimethylamino-9H-purine-9-base, 2; 6-diamino--9H-purine-9-base, 6-be amino-8-[(3-pyridylmethyl) amino]-9H-purine-9-base, 4-phenyl-1H-pyrazol-1-yl, 3-(pyridin-3-yl)-1H-pyrazol-1-yl, 3-(pyridin-4-yl)-1H-pyrazol-1-yl, 3-(pyridin-3-yl)-1H-imidazoles-1-base, basic, the 3-(pyridin-3-yl)-1H-[1 of 3-(pyridin-4-yl)-1H-imidazoles-1-; 2,4] triazol-1-yl, 3-(pyridin-4-yl)-1H-[1,2; 4] triazol-1-yl and 2-oxo-1; 2,3,4-tetrahydrochysene-quinoline-6-base.
In combination " heterocyclic radical alkyl " and " aralkyl ", " heterocyclic radical ", " virtue " (aryl) and " alkyl " have definition mentioned above.
In particular of the present invention, Q can be for hydrogen or like defined alkyl of preceding text or following formula group
For phenyl ring or contain 2 to (x-1) individual carbon atom and 1-3 heteroatomic x unit's saturated or unsaturated heterocycle aliphatic series ring or heteroaromatic rings that is selected from nitrogen, oxygen and sulphur, wherein x is 5 or 6, and R2 and R3 independently are selected from hydrogen; Alkyl like the preceding text definition; Lower alkoxy, for example C
1-C
4Alkoxyl group is such as methoxyl group, oxyethyl group, propoxy-or n-butoxy; C
3-C
7Cycloalkyloxy or C
3-C
7Naphthenic base-C
1-C
4Alkoxyl group is like cyclopentyloxy, cyclo propyl methoxy; Like the defined halogen of preceding text; The substituted alkyl group of halogen, for example difluoromethyl, trifluoromethyl or three chloroethyls; Cyanic acid; Nitro; Amino; Alkylamino; Dialkyl amido; Alkylthio; Sulfydryl; Hydroxyl; Formamyl; Carboxylic group; Oxo group; Or as the aryl or the heterocyclic radical of definition here, can for unsubstituted or by the definition of one or more preceding text be that the substituting group of aryl or heterocyclic radical replaces, or all be positioned at ring as substituent R 2 and R3
Adjacent carbon atom on the time; These two substituting groups can with said adjacent carbon atom form 5-6 unit aromatics or contain 2 to (x-1) individual carbon atom and wherein 1-3 for being selected from the heteroatomic x saturated or unsaturated heterocycle aliphatic series of unit or the heteroaromatic rings of nitrogen, oxygen and sulphur; Wherein x is 5 or 6;, wherein residue Q can have the substituting group that defines among 1-4 R2 and the R3.
Preferred especially group Q is for for example:
Symbol X represents key; Be " not existing ", or for having at the most 9 atoms and as the spacer of the straight chain group that defines of preceding text.Straight chain group with 9 atoms at the most can also other Wasserstoffatoms so that the C atom is saturated for methylene radical or make the N atom saturated for amino.Preferred this spacer comprises 2-5 atom.
Preferred radicals X is:
(CH
2)
n, (CH
2)
mOCH
2, (CH
2)
2NCH
3(CH
2)
2, CH
2CH
2NH and (CH
2)
pCOW, wherein n and p are 1-3, m is that 0-3 and W do not exist or for O or NH.
Preferred especially radicals X is ethyl and propyl group.
Preferred group Y is:
S, SO
2S particularly.
Y and X are combined as:
When Y=S, X is ethyl, propyl group, CH
2CO, CH
2COCH
2, CH
2CONR, CH
2CONRCH
2, CH
2CONRCH
2CH
2, CH
2CH
2CONR, CH
2CH
2CONRCH
2, CH
2CH
2NR, CH
2CH
2NRCO, CH
2CH
2NRSO
2, CH
2CH
2NRCOO, CH
2CH
2OCH
2, CH
2SO
2NR, CH
2SO
2NRCH
2, CH
2CH
2OCONR, CH
2CH=CH or CH
2C ≡ C; R in the wherein above-mentioned expression is hydrogen or methyl.
Preferred radicals R 1 is:
Also preferred following groups R1
Two chiral centres for * in the general formula I representes preferably are configured as 3S, 4R.
Preferred formula I compound such as 1 of following table are listed;
Formula I:
Table 1:
Special preferred embodiment 1,4,11,13 and 16 compound.
If desired, can formula I compound be converted into pharmaceutically-acceptable acid addition.The formation of salt can adopt method known to those skilled in the art to carry out under room temperature.This not only comprises inorganic acid salt, also comprises organic acid salt.The instance of this type of salt has hydrochloride, hydrobromate, vitriol, nitrate salt, Citrate trianion, acetate, trifluoroacetate, PHENRAMINE MALEATE, SUMATRIPTAN SUCCINATE, mesylate, right-tosylate etc.
In addition, compound can be converted into the ester of cleavable in the body, for example 2 of sugar moieties '-ester of oh group, this type of ester is for example acetic ester, valeryl ester, tartrate, maleic acid ester, succinate etc.These esters can prepare according to methods known in the art, for example through with suitable anhydride reaction.
The compounds of this invention can be as antibiotic and anti-inflammatory treatment medicine with the ester of their pharmaceutically-acceptable acid addition or the interior cleavable of their bodies.For example streptococcus aureus (Staphylococcusaureus) and streptococcus pneumoniae (Streptococcuspneumoniae) have the excellent antibiotic activity to formula I compound to some pathogenic bacteria.Therefore they can be as the medicine of treatment infection, the infection that is particularly caused by staphylococcus, for example septicemia, skin and soft tissue infection; The degree of depth that the implantation of wound, operation or foreign matter causes infects; Endocarditis; Pneumonia; Sacroiliitis; Bursitis and osteomyelitis; Or by the microbial infection of hammer, for example septicemia, skin and soft tissue infection; The degree of depth that the implantation of wound, operation or foreign matter causes infects; Endocarditis; The tonsilla pharyngitis; Pneumonia; Bronchopneumonia; Bronchitis; Otitis; Sinusitis and scarlet fever.
In addition, formula I compound has the excellent antibiotic activity to for example propionibacterium acnes strain of some bacterium (Propionibacteriumacnes) and propionibacterium granulosum (Propionibacterium granulosum).Therefore they can be as the medicine of treatment acne.
In addition; Formula I compound can be as the medicine of the bacterial infection of treatment, and said bacterium has the for example susceptible strain of moraxelle catarrhalis (Moraxella catarrhalis), hemophilus (Haemophilus spp.), neisseria (Neisseria spp.), legionella (Legionella spp.), Mycoplasma (Mycoplasmaspp.), molten urea urea substance (Ureaplasma urealyticum), Dermacentroxenus (Rickettsia spp.), Bartonella (Bartonella spp.), coxiella burnetii genus (Coxiella burnetti chlamydiaspp), chlamydiaceae (Chlamydia spp.) or Mycobacterium (Mycobacterium spp.), Nocardia (Nocardia spp.) and Niu Shi actinomyces (Actinomyces spp.).
Formula I compound is except having anti-microbial activity; Also has anti-inflammatory activity; Therefore they can be used to treat following disease, and for example DPB, capsule property fibering become disease, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel, acne erythematosa, sacroiliitis and acne.The compounds of this invention also can be used to treat psoriatic.
Neutrophil leucocyte is the principal element of inflammatory process.Neutrophil leucocyte is transferred to inflammation part, can activation and the toxic substance that discharges, comprise for example Pancreatopeptidase E of proteolytic ferment.Neutrophil leucocyte is replied begins to be by the cell surface receptor mediation of chemoattractant, and these chemoattractants comprise bacterial product, platelet activation factor, leukotrienes B4 and interleukin 8.Pancreatopeptidase E is activatory neutrophil leucocyte excretory primary product and also suffers the main arch-criminal of destructive for tissue in the inflammatory diseases.Several kinds of biological assays that suppress to carry out based on the Pancreatopeptidase E excretory are set forth to some extent in document and are used to monitor anti-inflammatory product (Johansson; S.;
, U., Luijendik T.; Backlund; A., Claeson P., Bohlin L. (2002) J.Nat.Prod.65:32-41).Shown in hereinafter embodiment (embodiment 35), this test is used to show that The compounds of this invention is active to the granulocytic adjusting of neutrality.Neutrophil leucocyte can come activation through adding bacterial product N-formylmethionyl base-leucyl-phenylalanine (fMLP) and cytochalasin B (a kind of secretion yield stimulant).The secretory volume of Pancreatopeptidase E is by the reaction assay of Pancreatopeptidase E and chromophoric substrate succinyl--alanyl-alanyl-valyl-N-methyl-p-nitroaniline (SAAVNA), and this reaction has produced the 4-N-methyl-p-nitroaniline behind the elastin enzymatic lysis.Assaying reaction absorbs and changes in the 405nm place.
The MIC value of non-anerobes can adopt CAMHB (BBL) through the meat soup microdilution; Obtain (National Committee for Clinical Laboratory Standards according to the NCCLS guide; Methodsfor dilution antimicrobial susceptibilitytests for bacteria thatgrow aerobically, 5
ThEd.Approved standard M7-A6.NCCLS, Wayne, Pennsylvania, 2003).Medicine is dissolved in DMSO, is incorporated in then in 96 microwell plates; The concentration of DMSO in measuring the hole is no more than 2% (v/v).When cultivating streptococcus pneumoniae, (Sigma cat.no.H-1270) replenishes CAMHB to replace cracking horse blood with 5% (v/v) horse serum; When cultivating hemophilus influenzae, and employing 5% (v/v) Fildes reinforcement (BBL, cat.no.220810) supernatant replaces hemophilus detection substratum and additive to replenish (Pankuch GA; Hoellman DB, Lin G, Baj aksouzian S; Jacobs MR, Appelbaum PC.Activityof HMR3647compared to those of five agents against Haemophilus influenzae andMoraxella catarrhalis by MIC determination and time-Kill assay。Antimicrob.Agents Chemother.1998Nov；42(11)：3032-4)。Active as shown in table 3 below with minimum inhibition concentration (MICs) (μ g/ml) expression, the mikrobe that is used to test is as shown in table 2 below.
MIC value to propionibacterium can adopt WCB (AnaerobeBroth MIC through broth microdilution antifungal susceptibility test; Difco) obtain (National Committee for ClinicalLaboratory Standards.Methods for anti-microbial susceptibility testing ofanaerobic bacteria, 5 according to the NCCLS guide
ThEd.; Approved standard.NCCLS publication no.M11-A5.NCCLS, Wayne, Pennsylvania, 2001).Microtiter plate is inserted 7-LGENbox anaerobism culturing bottle (BioM é rieux; Cat.no.96128); This is bottled have anaerobism atmosphere maker (BioM é rieux, cat.no.96124) with dry type anaerobism indicator (Dry AnaerobicIndicator Strip) (BBL, cat.no.271051).Under these conditions, reach behind the 2.5h<0.1% O
2Concentration, Da Dao > behind the 24h; 15% CO
2Concentration.In 35-37 ℃, read MIC value (table 3) after cultivating 48h.
Table 2:
| Mikrobe | Code |
| Streptococcus aureus (Staphylococcus aureus) ATCC29213 | A |
| Streptococcus aureus 1086 | B |
| Intestinal bacteria (Escherichiacoli) 25922 | C |
[0064]
| Streptococcus pneumoniae (Streptococcus pneumoniae) 1/1 | D |
| Streptococcus pneumoniae SL199T | E |
| Streptococcus pneumoniae Tupelo | F |
| Hemophilus influenzae (Haemophilus influenzae) 12214 | G |
| Hemophilus influenzae QK50 | H |
| Propionibacterium acnes (Propionibacterium acnes) EG7NS | I |
| Propionibacterium acnes SW101T | K |
Table 3:
Ex. embodiment
Nd=does not confirm
(cf. is Lipworth B.J. for example also to have found The compounds of this invention the human phosphatase diesterase (PDEs), the particularly PDE3 that participate in inflammatory process and PDE4 to be had significant inhibitions activity; Lancet (2005) 365; P.167 or Giembycz M.A..Curr.Opin.Pharmacol. (2005); 5, p.238).This sets forth among embodiment 36 and 37 hereinafter, and this also is the description of the first time to macrolide derivatives such as erythromycin derivatives.The use of this type of macrolide derivatives compound; Particularly The compounds of this invention is used to treat human diseases and disorder also is the further aspect of the present invention, and said disease and disorder (comprising inflammatory diseases mentioned above) can improve or alleviate through suppressing human phosphatase diesterase, particularly phosphodiesterase 3 and 4.
The compounds of this invention can be used as medicine.They have good oral absorption character.Therefore the other embodiment of the present invention is the medicine that comprises the ester of cleavable in formula I compound, their pharmaceutically-acceptable acid addition or their bodies; Said medicine can be used for treatment and prophylaxis against infection diseases; For example, with the pharmaceutical dosage forms of intestines (oral) administration.Product of the present invention can be with following form administration, for example, and oral administration, for example tablet, film-coated tablet, sweet tablet tablet, hard and soft capsule, solution, emulsion or form of suspension; Per rectum administration, for example suppository form; Administered parenterally, for example injection form; Nose administration; Through sucking; Percutaneous dosing; Or local, topical for example, preferred compound are through the part or oral administration.
The ordinary method preparation that the medicinal compsns that comprises these compounds can adopt those skilled in the art to be familiar with; For example with acceptable solid or liquid carrier material in composition and suitable nontoxic, inertia, the treatment; And if necessary, comprising also that the medicine auxiliary is mixed together processes formulation.
Be appreciated that compound finally is made into suitable to can be taken orally, administered parenterally or topical drug delivery composition.The present composition can comprise the auxiliary that is used to produce pharmaceutical prepn as the various routines of optional ingredients.Therefore, for example, when this preparation of compositions is required oral dosage form, can adopt weighting agent, for example Microcrystalline Cellulose, calcium phosphate or lactose as optional component; Disintegrating agent, for example starch, Sodium Croscarmellose or cross-linked polyvinylpyrrolidone; And lubricant, for example talcum powder, Magnesium Stearate, calcium stearate etc.Yet, being appreciated that fully cited optional component only is exemplary here, the present invention is not confined to use these compositions.This type of auxiliary that other is known in the art also can be used for embodiment of the present invention.
Suitable examples of such carriers material not only comprises inorganic carrier material, and comprises the organic carrier material.Therefore, can adopt for example lactose, W-Gum or their verivate, talcum powder, Triple Pressed Stearic Acid or its salt for tablet, film-coated tablet, sweet tablet tablet and hard capsule.For soft capsule, appropriate carriers is for for example, vegetables oil, wax, fat and semisolid and liquid polyol (character that depends on activeconstituents).The suitable solution and the carrier substance of syrup preparation be for for example, water, alcohols, polyvalent alcohol, sucrose, Nulomoline and glucose.The carrier substance of suitable suppository is for for example, natural oil or winterized stearin, wax, fat and semiliquid or liquid polyol.
Be appreciated that the salt, buffer reagent, seed dressing agent and the inhibitor that also comprise sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings, adjusting osmotic pressure as the medicine auxiliary usually.
The ester of cleavable can be used for administered parenterally in formula I compound and their acid salt or their bodies, for this reason, preferably they is processed freeze-drying or dry powder injection formulations, and with for example water or isobaric conventional salts solution dilution of conventional liq.
The ester of cleavable can be used for topical in formula I compound and their acid salt or their bodies, for this reason, preferably they is processed ointment, creme or gel preparation.
Be prevention and treatment Mammals (mankind and non-human) infection and/or inflammatory diseases; Per daily dose is generally about 10mg to about 2000mg; Particularly about 50mg is to about 1000mg; It will be understood by those skilled in the art that dosage also depends on the kind of the disease that mammiferous age, himself situation and institute prevent or treat.Per daily dose can also can be divided into several dosage gradation administrations with the single dose administration.Average single dose is about 100mg, 250mg, 500mg and 1000mg.
The reactions step that is obtained formula I end product by compound known can be according to shown in hereinafter flow process 1-3, carrying out.
Flow process 1
The compounds of this invention can adopt clarithromycin to prepare.R wherein
P1And R
P2For the preparation of formula II, III and the IV compound of H, ethanoyl, benzoyl-or any other suitable hydroxy-protective group can be carried out (flow process 1) according to method well known in the art.For obtaining wherein R
P1And R
P2Like the defined formula II compound of preceding text, can be through deriving from 2 ' of commercial clarithromycin-with 4 with suitable acid anhydrides or acyl chloride reaction "-oh group protects in order or simultaneously, and this reaction can be carried out according to the said method of following document; for example, Baker etc., J.Org.Chem.1988; 53,2340-2345 and Kashimura etc., J.Antibiotics; 2001,54,664-678.Subsequently, can formula II compound be converted into formula IV compound to be similar to the said method of following document: Baker etc., J.Org.Chem.1988,53,2340-2345.
Through in chlorinated solvent (for example methylene dichloride), handling, with 12 oh group esterification of formula IV compound with 2-chloracetic acid, DCC and DMAP or 2-chloracetic acid acid anhydride, pyridine, DMAP.Then in the presence of alkali (for example DBU), midbody V handled obtaining formula VI compound with suitable nucleophilic reagent R1H, wherein R1, R in acetone
P1And R
P2Such as preceding text definition.According to the character of R1, formula VI compound also can be through making formula IV compound and suitable carboxylic acid (R1CH
2COOH), DCC and DMAP react the synthetic formula VI compound that obtains in chlorinated solvent (for example methylene dichloride).Formula VI compound with alkali metal base (for example NaH or potassium tert.-butoxide or LDA), is handled in aprotic solvent (for example DMF or THF) and obtained formula VII compound, be the non-enantiomer mixture (flow process 1) of various ratios.
To wherein R1, R
P1And R
P2As the defined formula VII compound of preceding text in 2 '-position uses the methyl alcohol deprotection, this reacts on TR and carries out through 2-5 days for 20 ℃-60 ℃, obtains formula VIII compound (flow process 2).This compound is handled 3-12 hour (J.Antibiotics, 2001,54 (8) with DBU, in the methyl alcohol that refluxes; 664) or with guanidine/Guanidinium nitrate, at ethanol/methylene (TetrahedronLetters1997; 38 (9), 1627) handle in or handle or handle, preferably with DBU, processing 5-7 hour in the methyl alcohol of backflow with the carbinol mixture of MeONa with salt of wormwood, in methyl alcohol; With with 4 "-the oh group deprotection, obtain formula VIII compound.
Perhaps, with formula VII compound in 2 '-position and 4 "-position deprotection simultaneously, this reaction employing is mentioned above about 4 "-one of the method for oh group deprotection carries out, and obtains formula I compound (flow process 2).
Flow process 2
When R1 is S-R
P3And R
P3For sulfur protecting group group like benzyl, 4-methoxy-benzyl, 3, when 4-dimethoxy-benzyl or 4-nitro-benzyl, preferably the 4-methoxy-benzyl can be converted into disulfide derivatives IX with midbody VIIa, wherein R in the presence of molecular sieve
P1And R
P2Such as preceding text definition, and R
P4Be for example 3-nitro-2-pyridyl or methyl, this method is similar to the described method of WO03/072588.
With formula IX compound with reductive agent for example trialkyl phosphine (preferred tributylphosphine) or triaryl phosphine (triphenylphosphine); At solvent (for example aqueous acetone solution, the N aqueous solution, the dioxane aqueous solution or tetrahydrofuran aqueous solution; The preferred N aqueous solution) in; Handled 1 minute-1 hour, preferred 15 minutes down in 0 ℃-60 ℃ (being preferable over room temperature), obtain compounds X.With compounds X, preferably do not separate, directly in identical solvent systems; With formula Q-X-Lg compound treatment, in formula Q-X-Lg, Q and X such as preceding definition; And Lg is a leavings group; For example chlorine, bromine, iodine, methylsulfonyl oxygen base, ptoluene-sulfonyl oxygen base, trifyl oxygen base perhaps are vinyl groups under X represents the situation of carbonyl or alkylsulfonyl group, obtain formula VII compound.This reaction is preferably at alkali alkaline carbonate or supercarbonate (salt of wormwood for example for example; Cesium carbonate or sodium hydrogencarbonate) or organic bases (for example triethylamine, N-ethyl n, N-diisopropylamine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene or l; 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene; Preferred 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene) exist down, carry out in temperature 0 ℃-50 ℃ (being preferable over 20 ℃).The iodide salt that preferably in reaction mixture, adds catalytic amount, preferred Soiodin.
Work as R1=S-R
P3The time
Flow process 3
The following example is used for further setting forth the present invention, but is not used in restriction scope of the present invention.
Essential Terms: MS mass spectrum (A) Micromass Waters ZQ system, adopt Masslynx software and (B) adopt the Q-Tof-Ultima (Waters AG) that Waters Cap-LC is housed to measure.For accurately measuring, can use nano lock mass ESI source.Accurately mass spectrum is represented with 4 tens digits.The HPLC purifying of end product can adopt following system: post: YMCODS-AQ, 120A.5 μ m, 50 * 20mm; Pre-column: YMC ODS-AQ, 120A, 5 μ m, 10 * 20mm; Flow velocity: 30ml/min; Injection: 500 μ l; Monitoring: ELSD; Mobile phase A: water+0.1%HCOOH; Mobile phase B: acetonitrile; Gradient: linearity, from 10 to 95% acetonitriles, 4min.Abbreviation: HPLC is a high performance liquid chromatography; DMSO is a DMSO 99.8MIN.; DBU is the diazabicyclo undecane; DCM is a methylene dichloride; DIPEA is diisopropylethylamine (a HuenigShi alkali); DMF is a N; THF is a THF; DCC is a NSC 57182; DMAP is a 4-dimethylaminopyridine; EDCHCl is N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride; MCPBA is a m-chloro peroxybenzoic acid; KotBu is a tert-butyl potassium; MS is a mass spectrum; NMR is a nucleus magnetic resonance; ISP is an IP ionspray.
Embodiment 1
Preparation (3S, 3aR, 4R, 6R, 8R; 9R, 10S, 11S, 12R, 15R; 15aS)-and 3-[[2-[6-amino-9H-purine-9-yl] ethyl] sulfo-]-11-[[2,6-dideoxy-3-C-methyl-3-O-methyl-[α]-L-examines (ribo)-pyranohexose base (hexopyranosyl)] oxygen base]-15-ethyl decahydro-8-methoxyl group-4,6,8,10; 12,15a-hexamethyl-9-[[3,4,6-three deoxies-3-(dimethylamino)-β-D-wood-pyranohexose base] oxygen base]-2H-furo [2.3-c] oxa-ring 14 alkynes (oxacyclotetradecin)-2,5; 13 (3H, 6H)-triketone (I-1), formula I compound, wherein R1 is [2-[6-amino-9H-purine-9-yl] ethyl] sulfo-.
A] preparation 2 ', 4 " two-O-ethanoyl-6-O-erythromycin A (II-I) (formula II compound, wherein R
P1And R
P2Be ethanoyl)
Disposable adding 11ml (117mmol) diacetyl oxide in the 50mlDCM solution of 25g (33.4mmol) clarithromycin and 1.63g (13.4mmol) DMAP stirs 20h with mixture under room temperature.Reaction mixture is inclined to capacity 0.2N NaOH, obtain pH value 8-9, then extraction.With the organic layer water and the brine wash that merge, through MgSO
4Dry also reduction vaporization.The bullion product obtains 24.3g (87%) clear crystal from the hot ethyl acetate crystallization.MS(ISP)：832.5[MH]
+。
B] preparation 2 ', 4 " two-O-ethanoyl-6-O-erythromycin A, 11,12 carbonic ethers (III-1) (formula III compound, wherein R
P1And R
P2Be ethanoyl)
In-45 ℃, ar gas environment; With 24.3g (29.2mmol) 2 '; 4 " two-O-ethanoyl-6-O-erythromycin A is dissolved in 500ml THF, and with 15 minutes, the tetrahydrofuran solution (29.2mmol) that is added dropwise to two (trimethyl silyl) ammonification sodium of 29.2ml1M was handled.Behind the 20min,, add 16.24g (100.1mmol) carbonyl dimidazoles for 3 parts with 5 minutes branches in-45 ℃.In-45 ℃ of stirred reaction mixture 30min, be warmed to 0 ℃ with 15 minutes then, and placed 2.5 hours in 0 ℃.
With reaction mixture with saturated NaHCO
3The aqueous solution and water (1:1) are handled and with ethyl acetate extraction 2 times.The organic layer that merges obtains 23.57g (94%) colorless solid with 10% ammonia soln, brine wash 2 times through dried over sodium sulfate and reduction vaporization.MS(ISP)：858.6[MH]
+。
C] preparation 2 ', 4 " two-O-ethanoyl-10,11-two dehydrogenations-6-O-erythromycin A (IV-I) (formula IV compound, wherein R
P1And R
P2Be ethanoyl)
" two-O-ethanoyl-6-O-erythromycin A, 11,12 carbonic ethers and 10.25ml (68.7mmol) DBU heats 1.5h, is cooled to room temperature and inclines to 0.5M NaH under reflux temperature, will to be dissolved in the 23.5g (27.47mmol) 2 ' of 500ml toluene, 4
2PO
4The aqueous solution.Water layer is with ethyl acetate extraction 2 times.The organic extraction that merges is used 0.5M NaH
2PO
4, brine wash, through Na
2SO
4Dry and concentrated 18.43g (86%) colorless solid that obtains.MS(ISP)：814.5[MH]
+。
D] preparation 10,11-two dehydrogenations-11-deoxy-6-O-erythromycin A, 2 ', 4 " diacetate esters-12-(chloracetic acid ester) is (formula V compound, wherein R (V-I)
P1And R
P2Be ethanoyl)
With 2 hours; Under nitrogen to 64.0g (78.6mmol) 2 ' '; 4 " two-O-ethanoyl-10 is added dropwise to the 250ml dichloromethane solution of 26.9g chloracetic acid acid anhydride (157.3mmol) in the 600ml dichloromethane solution of 11-two dehydrogenations-6-O-erythromycin A, 3.84g (31.4mmol) 4-dimethylaminopyridine and 12.5g pyridine.In stirring at room solution 3.5 hours.Reaction mixture is inclined to 0.2N NaOH, obtain the pH value for 8-9 and with dichloromethane extraction 2 times.With the organic layer that merges in order with water washing 1 time, use 0.5N NaH
2PO
4Wash 2 times, water washs 1 time and with brine wash 2 times, through Na again
2SO
4Dry and evaporation obtains the bullion product.Sherwood oil is added to the bullion product, obtain target compound (57.5g, 82%), be filbert solid in stirring at room mixture 3 hours and filtration.MS(ISP)：890.3[M]
+。
E] preparation formula VI compound, wherein R1 is [2-[6-amino-9H-purine-9-yl] ethyl] sulfo-, and R
P1And R
P2Be ethanoyl) (VI-I)
Under argon gas; 9.79g (10.99mmol) embodiment 1 step D compound is dissolved in 370ml acetone and 1.73ml DBU (11.54mmol), and (6-amino-9H-purine)-1-sulfur alcohol (12.4mmol) (WO0216380) to add 82.4mg Soiodin (0.55mmol) and 2.43g.Under room temperature, argon gas, stirred reaction mixture spends the night.Evaporating solvent also is dissolved in DCM with residue.Organic layer is used 5%NaHCO
3, brine wash, through Na
2SO
4Dry also vacuum-evaporation.The bullion product is through flash chromatography on silica gel purifying (DCM:MeOH:NH
398:2:0.01 → 90:10:0.01) obtain the filbert foam of 6.85g (59.4%).MS(ISP)：1050.4[MH]
+；526.4[MH
2]
++)。
F] preparation formula VII compound, wherein R1 is [2-[6-amino-9H-purine-9-yl] ethyl] sulfo-, and R
P1And R
P2Be ethanoyl) (VII-I)
Under argon gas, 6.89g (6.57mmol) embodiment 1 step e compound is dissolved in 40mlDMF and cools off with ice bath.Add 0.37g sodium hydride (55-65%; 8.54mmol), in 0-5 ℃, mixture was stirred 4 hours.Add KH then
2PO
40.5N the aqueous solution, mixture is with extracted with diethyl ether 2 times.The organic layer that merges is used 150ml NaHCO
35% aqueous solution and 150ml brine wash 2 times are through Na
2SO
4Dry and vacuum-evaporation obtains 7.05g bullion product.MS(ISP)：1050.3[MH]
+；526.2[MH
2]
++)。
G] preparation I compound, wherein R1 is [2-[6-amino-9H-purine-9-yl] ethyl] sulfo-) (I-1)
7.0g (6.5mmol) embodiment 1 step F compound bullion is dissolved in 200ml methyl alcohol, adds 4.99ml (33.4mmol) DBU.Under argon gas, will be mixed and heated to and reflux 7 hours.Solvent evaporated under reduced pressure also is dissolved in DCM with residue.Organic layer is used NaHCO
35% aqueous solution and brine wash are through Na
2SO
4Dry also vacuum-evaporation.The bullion product is through flash chromatography on silica gel purifying (DCM:MeOH:NH
395:5:0.01 → 85:15:0.01) obtain 4.50g (69.9%) target compound, be colorless solid, single diastereomer.MS(ISP)：966.3[MH]
+.1H-NMR(CDCl
3)：0.85(t，3H)，1.11(d，3H)，1.13-1.27(m，15H)，1.29(d，3H)，1.45(s，3H)，1.47(s，3H)，1.51-1.95(m，8H)，2.29(s，6H)，2.29-2.48(m，5H)，2.58(s，1H)，2.59-2.68(m，1H)，2.82-2.89(m，1H)，3.01-3.10(m，2H)，3.06(s，3H)，3.11-3.23(m，2H)，3.32(s，3H)，3.46-3.54(m，2H)，3.57-3.65(m，1H)，3.68(d，1H)，3.75(d，1H)，3.97-4.02(m，1H)，4.42-4.58(m，3H)，4.67-4.75(m，1H)，4.85(d，1H)，5.37(dd，1H)，5.74(s，br，2H)，8.28(s，1H)，8.33(s，1H)。
Embodiment 2
Preparation I compound, wherein R1 is [2-[[3H-imidazo [4.5-b] pyridin-3-yl] methoxyl group] ethyl] sulfo-(I-2).
A] preparation acetate 2-[(3H-imidazo [4.5-b] pyridin-3-yl) methoxyl group]-ethyl ester
In the 20mlDMF solution that places 1.0g (8.39mmol) 3H-imidazo [4, the 5-b] pyridine under 0 ℃, argon gas, add 0.94g (8.39mmol) uncle-butanols potassium.Solution is warmed to room temperature, after 1 hour, uses half a hour, be added dropwise to the 5ml DMF solution of 1.74g (8.8mmol) (2-acetoxyethoxy) MB.Stirred reaction mixture is 20 hours under room temperature, inclines then to the 75ml frozen water.With mixture with 50ml ethyl acetate extraction 2 times.The organic layer water and the brine wash that merge are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product obtains the required product of 0.81g (41%) through flash chromatography purifying (silica gel, gradient DCM, DCM/MeOH95/5 and 9/1).MS(ISP)：236.2[MH]
+
B] preparation 2-[(3H-imidazo [4,5-b] pyridin-3-yl) methoxyl group]-ethanol
0.79g (3.36mmol) acetate 2-(3H-imidazo [4,5-b] pyridin-3-yl methoxyl group)-ethyl ester is dissolved in 10ml methyl alcohol, adds 10mg (1.85mmol) sodium methylate.In stirring at room mixture 3 hours.Orange mixture obtains 0.64g (99%) bullion product through vacuum concentration.MS(EI)：193.2，163.2，148.2，133.2。
C] preparation 3-(2-chloro-ethoxyl methyl)-3H-imidazo [4,5-b] pyridine
Use 10min, in the 10ml pyridine suspension-s that places 0.63g (3.26mmol) 2-(3H-imidazo [4,5-b] pyridin-3-yl methoxyl group)-ethanol and 1.71g (6.52mmol) triphenyl phosphine under the argon gas, be added dropwise to 0.32ml (3.32mmol) CC
14Under room temperature, suspension-s was stirred 18 hours and vacuum concentration.The bullion product is through flash chromatography purifying (silica gel, gradient DCM → DCM/MeOH9/1), and grind with ether and to obtain the 0.7g brown solid.MS(ISP)：212.1[MH]
+。
D] preparation thioacetic acid S-[2-(3H-imidazo [4,5-b] pyridin-3-yl methoxyl group)-ethyl] ester
The 15ml acetone suspension-s of 0.7g (3.3mmol) 3-(2-chloro-ethoxyl methyl)-3H-imidazo [4,5-b] pyridine and 378mg (3.3mmol) thioacetic acid potassium is heated to backflow 12 hours.With the orange suspension vacuum concentration.The bullion product obtains the required product MS of 380mg (46%) (ISP): 252.1 [MH] through flash chromatography purifying (silica gel, the DCM of gradient 0-10% methyl alcohol)
+ 1H-NMR (CDCl
3): 2.28 (s, 3H), 3.05 (t, 2H), 3.69 (t, 2H), 5.72 (s, 2H), 7.27 (m, IH), 8.09 (dd, IH), 8.20 (s, IH), 8.43 (dd, IH).
E] 2-(imidazo [4,5-b] pyridin-3-yl methoxyl group)-sulfur alcohol
370mg (1.47mmol) thioacetic acid S-[2-(3H-imidazo [4,5-b] pyridin-3-yl methoxyl group)-ethyl] ester is dissolved in the 10ml degassing methyl alcohol that places under the argon gas.In solution, charged into ammonia 5 minutes, interior temperature rise to 40 ℃.With the solution stirring that obtains 60 minutes and concentrated, obtain required product in room temperature in 60 ℃ of vacuum-dryings.MS(ISP)：210.2[MH]
+
According to embodiment 1 step e-G, can prepare target compound I-2 from 2-(imidazo [4,5-b] pyridin-3-yl methoxyl group)-sulfur alcohol and V-I.MS(ESI)：978.5238。
Embodiment 3
Preparation I compound, wherein R1 is [3-[quinoline-6-yl] propyl group] sulfo-(I-3) A] preparation 6-(3-chloro-propyl group)-quinoline
With 0.52g (2.77mmol) 3-quinoline-6-base-third-1-alcohol be dissolved in the 5.5ml THIONYL CHLORIDE 97 and be heated to 70 ℃ 50 minutes.Add entry and sodium hydrogen carbonate solution, mixture is with DCM extraction 3 times.The organic layer that merges is used brine wash, through MgSO
4Dry and vacuum concentration obtains 0.41g (72%) brown oil.MS(ISP)：206.2[MH]
+
B] preparation thioacetic acid S-(3-quinoline-6-base-propyl group) ester
The 8ml acetone soln of 0.41g (2.0mmol) 6-(3-chloro-propyl group)-quinoline and 287mg (2.5mmol) thioacetic acid potassium is heated to backflow 8 hours.Vacuum concentrated mixture.The bullion product obtains 353mg (71%) darkorange oily matter through flash chromatography purifying (silica gel, the DCM of gradient 0-2% methyl alcohol).MS(ISP)：246.3[MH]
+
C] preparation 3-quinoline-6-base-propane-1-mercaptan
Under argon gas, 450mg (1.83mmol) thioacetic acid S-(3-quinoline-6-base-propyl group) ester is dissolved in the 15ml degassing methyl alcohol.In solution, charged into ammonia 5 minutes, temperature rise to 40 ℃ in making.The solution that obtains in stirring at room 60 minutes concentrates and in 60 ℃ of vacuum-dryings, obtains the required product of 288mg (77%).MS(ISP)：204.1[MH]
+；
1H-NMR(CDCl
3)：1.40(t，1H)，2.00-2.08(m，2H)，2.58(q，2H)，2.94(t，2H)，7.35-7.40(m，1H)，7.55-7.60(m，2H)，8.01-8.12(m，2H)，8.86-8.88(m，IH)。
According to embodiment 1 step e-G, can prepare target compound I-3 from 3-quinoline-6-base-propane-1-mercaptan and V-1.MS(ESI)：972.5388。
Embodiment 4
Preparation (3S, 3aR, 4R, 6R, 8R, 9R; 10S, 11S, 12R, 15R, 15aS)-11-[[2; 6-dideoxy base-3-C-methyl-3-O-methyl-α-1-nuclear-pyranohexose base] the oxygen base]-15-ethyl decahydro-8-methoxyl group-4,6,8,10,12; 15a-hexamethyl-3-[[2-[3H-imidazo [4,5-b] pyridin-3-yl] ethyl] sulfo-]-9-[[3,4,6-three-deoxy-3-(dimethylamino)-β-D-wood (xylo)-pyranohexose base] oxygen base]-2H-furo [2.3-c] oxa-ring 14 alkynes-2,5; 13 (3H, 6H)-triketone (I-4), formula I compound, wherein R1 is [2-[3H-imidazo [4,5-b] pyridin-3-yl] ethyl] sulfo-.
A] preparation 3-(2-chloro ethyl)-3H-imidazo [4,5-b] pyridine
Under argon gas, 6.5g (54.56mmol) 3H-imidazo [4,5-b] pyridine is dissolved among the 100mlDMF, and in ice bath, is cooled to 0 ℃.Add 4.6g (109.1mmol) sodium hydride, in stirring at room mixture 1 hour.Use 1 hour then, add the 30ml DMF solution of 9ml (109.1mmol) 1-bromo-2-monochloroethane, and in stirring at room solution 20 hours.Brown solution is inclined to frozen water and with ethyl acetate extraction 3 times.Merge organic layer, use brine wash, through Na
2SO
4Dry and vacuum-evaporation obtains yellow oil.Oil and the hot heptane of 50ml are stirred 3 times.Pour out heptane, merging component and evaporation obtain the 2.08g light yellow crystal.MS(ISP)：182.2[MH]
+；
1H-NMR(CDCl
3)：3.99(t，2H)，4.66(t，2H).7.28-7.32(m，IH)，8.11-8.17(m，2H)，8.40-8.42(m，IH)。
B] preparation formula VIIa compound, wherein R
P3Be (4-p-methoxy-phenyl) methyl, R
P1Be ethanoyl and R
P2Be hydrogen (VIIa-4)
2.0g (2.16mmol) compound I-10 is dissolved in 50ml DCM, adds 0.22ml (2.4mmol) diacetyl oxide.In stirring at room mixture 48 hours.Solution is used NaHCO
3(5%) aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration obtains the filbert foam of 2.17g.The bullion product can directly be used for next step without being further purified.MS(ISP)：967.3[MH]
+。
C] preparation formula IX compound, wherein R
P4Be methyl, R
P1Be ethanoyl and R
P2Be hydrogen (IX-4)
2.17g (2.25mmol) embodiment 4 step B products are dissolved in 50ml DCM, add molecular sieve.880mg (4.49mmol) dimethyl-(methylthio group) Tetrafluoroboric acid sulfonium is added in the mixture, and in stirring at room 5 hours.Filter reaction mixture is also used 20ml NaHCO
3(5%) aqueous solution and brine wash are 2 times, through Na
2SO
4Drying is filtered and vacuum concentration, obtains the filbert foam of 1.62g.The bullion product can not purifiedly directly be used for next step.MS(ISP)：893.1[MH]
+。
D] preparation formula VII compound, wherein R1 is [2-[3H-imidazo [4,5-b] pyridin-3-yl] ethyl] sulfo-, R
P1Be ethanoyl and R
P2Be hydrogen (VII-4)
Be dissolved in to 0.60g (0.07mmol) embodiment 4 step C products and add 1 17 μ l (0.07mmol) the tributylphosphine aqueous solution in the solution of 1ml DMF, and under room temperature, mixture is stirred 30min.And then in solution, add 12.2mg (0.07mmol) 3-(2-chloro ethyl)-3H-imidazo [4,5-b] pyridine, 10 μ l DBU (0.07mmol) and part Soiodins.Stirred reaction mixture 4 hours and vacuum concentration under room temperature, residue is dissolved in DCM.Organic layer is used NaHCO
3(3%) aqueous solution and brine wash are through Na
2SO
4Drying, filtration and vacuum concentration are to obtaining the 150mg yellow oil.The bullion product can not purifiedly directly be used for next step MS (ISP): 992.3 ([MH]
+497.1 ([MH
2]
++).
E] preparation I compound, wherein R1 is [2-[3H-imidazo [4,5-b] pyridin-3-yl] ethyl] sulfo-(I-4)
The bullion product (150mg) of embodiment 4 step D is dissolved in 3ml methyl alcohol, and under room temperature, stirred 72 hours.With the reaction mixture vacuum concentration, residue obtains the required product of 22.2mg (35%) through the HPLC purifying, is white solid, single diastereomer then.MS(ISP)：950.1([MH]
+；476.0([MH
2]
++)。
1H-NMR(CDCl
3)：0.85(t，3H)，1.1(d，3H)，1.14-1.22(m，9H)，1.23(d，3H)，1.25(d，3H)，1.29(d，3H)，1.46(s，3H)，1.48(s，3H)，1.52-1.59(m，2H)，1.65-1.71(m，1H)，1.75-1.95(m，3H)，2.20-2.35(m，2H)，2.3(s，6H)，2.40-2.48(m，1H)，2.59(d，1H)，2.62-2.70(m，1H)，2.81-2.90(m，1H)，2.99-3.11(m，2H)，3.08(s，3H)，3.17-3.26(m.2FI)，3.32(s，3H)，3.45-3.53(m，2H)，3.63-3.71(m，2H)，3.75(d，1H)，3.95-4.02(m，1H)，4.45(d，1H)，4.52(d，IH)，4.58-4.66(m，1H)，4.80-4.88(m，H)，5.38(dd，1H)，7.22(dd.1H)，8.05(dd，1H)，8.36(dd，1H)，8.57(s，1H)。
Embodiment 5
A] preparation 6-(3-hydroxypropyl)-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone
To 4.0g (27mmol) furo [3,4-b] pyridine-5, add the 7ml chloroformic solution of 2.03g (27mmol) 3-aminopropanol in the 10ml chloroform suspension-s of 7-diketone, with mixture heating up to refluxing 30 minutes.Then solvent is slowly evaporated, mixture is heated to 150-160 ℃ gradually, and keep vacuum simultaneously.After two hours, mixture is cooled to room temperature, (silica gel, ETHYLE ACETATE/MeOH15:1), obtain the required product of 3.9g (70%) is white powder to brown bullion product through the flash chromatography purifying.
1H-NMR(CDCl
3)：1.89-1.95(m，2H)，2.25(s，br，IH)，3.64-3.68(m，2H)，3.90-3.96(m，2H)，7.60-7.66(m，IH)，8.14-8.20(m，IH)，8.93-8.99(m，IH)。
B] preparation 6-(3-bromopropyl)-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone
In the 10ml acetonitrile solution of 0.813g (3.94mmol) 6-(3-hydroxypropyl)-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone, be added dropwise to 0.854g (3.15mmol) PBr
3, and with mixture heating up to refluxing 2 hours.Add residue with the mixture vacuum concentration and with 6ml cold water.Leach throw out,, obtain the required product of 0.71g (71%), be pale yellow powder with cold water washing and vacuum-drying.
1H-NMR(DMSO)：2.10-2.23(m，2H)，3.52-3.63(m，2H)，3.70-3.82(m，2H)，7.72-7.81(m，IH)，8.22-8.33(m，1H)，8.91-9.00(m，1H)。
According to embodiment 4 step D-E, from 6-(3-bromopropyl)-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone and IX-4 (formula IX compound, wherein R
P1Be ethanoyl, R
P2Be hydrogen and R
P4For methyl prepares target compound 1-5.MS(ESI)：991.5051。
Embodiment 6
Preparation I compound, wherein R1 is [2-[(2-pyridylmethyl) amino]-2-oxoethyl] sulfo-(1-6)
A] preparation 2-chloro-N-pyridine-2-ylmethyl-ethanamide
In 0 ℃, in the 10ml acetone soln of 0.5g (4.6mmol) 2-(amino methyl) pyridine, add 1.27g (9.2mmol) salt of wormwood and 0.57g (5.1mmol) 2-chloro-acetyl chloride.In 0 ℃, stirred reaction mixture to raw material reaction finishes, and inclines to frozen water then.With mixture with ethyl acetate extraction 2 times.The organic layer that merges is used NaHCO
3(saturated) aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product can directly be used for next step.MS(ISP)：185.21([MH]
+。
B] preparation formula VII compound, wherein R1 is [2-[(2-pyridylmethyl) amino]-2-oxoethyl] sulfo-, R
P1Be ethanoyl and R
P2Be hydrogen (VII-6)
Be dissolved in the aqueous solution that adds 1 27.7 μ l (0.11mmol) tributylphosphine in the solution of 10ml DMF to 0.50g (0.06mmol) embodiment 4 step C products, in stirring at room mixture 3 hours.The Soiodin that in solution, adds 10.3mg (0.06mmol) 2-chloro-N-pyridine-2-ylmethyl-ethanamide, 8.4 μ l DBU (0.06mmol) and the catalytic amount that are dissolved in 1ml DMF then.In stirring at room reactant 4 hours, and vacuum concentration, residue is dissolved in DCM.Organic layer is through NaHCO
3(5%) aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product is through chromatography purification (silica gel, DCM:MeOH:NH
398:2:0.01) obtain the required product of 36mg.MS(ISP)：995.31([MH]
+。
C] preparation I compound, wherein R1 is [2-[(2-pyridylmethyl) amino]-2-oxoethyl] sulfo-
34mg (0.03mmol) compound VI I-6 is dissolved in 10ml methyl alcohol and in stirring at room 3 days.Vacuum concentrated mixture and with residue through the HPLC purifying, obtain the required product of 16mg (49%), be white solid, single diastereomer.MS(ESI)：951.5101。
Embodiment 7
Preparation I compound, wherein R1 is [3-[6-amino-9H-purine-9-yl] propyl group] alkylsulfonyl (1-7)
In 0 ℃, in the 2ml DCM solution of 67mg (0.07mmol) I-16 (formula I compound, wherein R1 is [3-[6-amino-9H-purine-9-yl] propyl group] sulfo-), add 40mg (0.48mmol) sodium hydrogencarbonate and 59mg (0.24mmol) mCPBA.Mixed 2 hours and stirred the mixture 3 hours in 5-10 ℃ in 0 ℃, add 5ml metabisulfite solution (10%), and in room temperature restir 1 hour.Add NaHCO
3The aqueous solution, and with mixture with DCM extraction 2 times.The organic layer that merges is used NaHCO
3(5%) aqueous solution and brine wash are 2 times, through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product obtains the required product of 8mg through the HPLC purifying, is single diastereomer.MS(ISP)：1012.4([MH]
+；507.1([MH
2]
++)
Embodiment 8
Preparation I compound, wherein R1 is [2-[(3-pyridyl carbonyl) amino] ethyl] sulfo-(1-8) A] preparation formula VII compound, wherein R1 is (2-amino-ethyl) sulfo-, R
P1And R
P2Be benzoyl-(VII-8)
(wherein R1 is [2-[[(1,1-dimethyl-oxyethyl group) carbonyl] amino] ethyl] sulfo-and R to 1.0g (0.87mmol) formula VII compound in remaining in-10 ℃, argon atmospher
P1And R
P2Be benzoyl-) add 1.51ml (12.9mmol) 2 among (WO03072588) the 50ml DCM, 6-lutidine and 1.56ml (8.65mmol) trimethyl silyl-fluoroform sulphonate stirs mixture 2 hours in-10-0 ℃.Solution is inclined to K
2CO
3(5%) aqueous solution separates each layer.Separate organic layer, through Na
2SO
4Drying is filtered and vacuum concentration.In 0 ℃, residue is dissolved in 20ml THF, add THF (1M) solution of 1.3ml tetrabutyl ammonium fluoride.The mixture that obtains is warmed to room temperature.After 24 hours, vacuum concentrated mixture, residue is dissolved in DCM, with saturated NaHCO
3The aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product can not purifiedly be used for next step.
B] preparation formula VII compound, wherein R1 is [2-[(3-pyridyl carbonyl) amino] ethyl] sulfo-, R
P1And R
P2Be benzoyl-
Under room temperature, with the 10ml THF solution stirring of 11.5mg (0.09mmol) nicotinic acid, 46.6mg (0.09mmol) 1-benzo-triazolyl oxygen base tripyrrole alkane subbase phosphine hexafluorophosphate and 43.8 μ l (0.26mmol) N-ethyl-diisopropylamines 15 minutes.The 5ml THF of 90mg (0.09mmol) embodiment 8 steps A products is added mixture, spend weekend in the stirring at room reaction mixture.Vacuum concentrated mixture, residue is dissolved in DCM, uses NaHCO
3(5%) aqueous solution and brine wash are 2 times, through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product is through flash chromatography purifying (silica gel, first post: DCM:MeOH98:2, second post DCM: acetone 9:1) obtain the required product of 77mg (77%), be amorphous solid.MS(ISP)：581.6([MH
2]
++)。
C] preparation I compound, wherein R1 is [2-[(3-pyridyl carbonyl) amino] ethyl] sulfo-(I-8)
With 5 days, the 10ml methanol solution of 77mg (0.07mmol) embodiment 8 step B products and 49 μ l (0.33mmol) DBU is heated to 75 ℃.Vacuum concentrated mixture, bullion product obtain the required product of 16mg (25%) through the HPLC purifying, are white solid, single diastereomer.MS(ISP)：953.3([MH]
+；477.6([MH
2]
++)。
Embodiment 9
Preparation I compound, wherein R1 is [2-[(1H-purine-6-yl) amino] ethyl] sulphur (I-9)
A] formula I compound, wherein R1 is [2-[[(1,1-dimethyl-oxyethyl group) carbonyl] amino] ethyl] sulfo-
With 5 days, (wherein R1 was [2-[[(1,1-dimethyl-oxyethyl group) carbonyl] amino] ethyl] sulfo-and R with 0.5g (0.43mmol) formula VII compound
P1And R
P2Be benzoyl-) (WO03072588) and the 10ml methanol solution of 0.32ml (2.16mmol) DBU be heated to backflow.Vacuum concentrated mixture, residue is dissolved in DCM, uses NaHCO
3(5%) aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product directly is used for next step.MS(ISP)：948.5([MH]
+)。
B] preparation I compound, wherein R1 is (2-amino-ethyl) sulfo-
According to the said method of embodiment 8 steps A, required product derives from the product of embodiment 9 steps A.The bullion product can not purifiedly be used for next step.
C] preparation I compound, wherein R1 is [2-[(1H-purine-6-yl) amino] ethyl] sulfo-(I-9)
In the 15ml acetonitrile solution of 350mg embodiment 9 step B bullion products, add 69 μ l triethylamines and 70mg6-chloropurine.With 4 days, will be mixed and heated to backflow.Vacuum concentrated mixture, residue is dissolved in DCM, uses NaHCO
3(5%) aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product obtains required product through the HPLC purifying, is single diastereomer.MS(ISP)：966.6([MH]
+；484.1([MH
2]
++)。
The method preparation that listed product can embodiment mentioned above in the table 4:
Table 4:
| Embodiment | R1 | Method preparation according to following embodiment | MS |
| 10 | [(4-p-methoxy-phenyl) methyl] sulfo- | 1 | 925.48 |
| 11 | [2-(2,6-diamino--9H-purine-9-yl) ethyl] sulfo- | 1 | 979.5351 |
| 12 | [3-(3H-imidazo [4.5-b] pyridin-3-yl) propyl group] sulfo- | 1 | 962.5254 |
| 13 | [2-(4-amino-pyrazolo [3,4-d] pyrimidine-1-yl) propyl group] sulfo- | 1 | 964.5141 |
| 14 | 3-[[[2-(6-amino-9H-purine-9-yl) ethyl] methylamino] ethyl] sulfo- | 1 | 1021.5794 |
| 15 | [3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl) propyl group] sulfo- | 4 | 990.5087 |
| 16 | [3-(6-amino-9H-purine-9-yl) propyl group] sulfo- | 4 | 978.5341 |
| 17 | [2-[3-(3-pyridine)-1H-pyrazol-1-yl] ethyl] sulfo- | 4 | 974.5292 |
| 18 | [2-(1H-1,2,4-triazol-1-yl) ethyl] sulfo- | 4 | 898.4956 |
| 19 | [2-(1H-benzoglyoxaline-1-yl) ethyl] sulfo- | 4 | 949.5 |
| 20 | [2-(9H-purine-9-yl) ethyl] sulfo- | 4 | 951.4 |
| 21 | [2-(5-methyl-2,4-1H-pyrimidine dione-1-yl) ethyl] sulfo- | 4 | 957.4 |
| 22 | [2-(3,4-3,5-dimethylphenyl-amino)-2-oxoethyl] sulfo- | 6 | 964.5283 |
| 23 | [2-(2,4 difluorobenzene base-amino)-2-oxoethyl] sulfo- | 6 | 972.4841 |
| 24 | [2-(3-methoxyl group-4-methoxycarbonyl-phenyl amino)-2-oxoethyl] sulfo- | 6 | 1024.5165 |
| 25 | [2-(quinoline-8-base is amino)-2-oxoethyl] sulfo- | 6 | 987.518 |
| 26 | [2-[4-(diethylamino)-phenyl]-2-oxoethyl] sulfo- | 4 | 992.5646 |
| 27 | [2-(2, the 4-3,5-dimethylphenyl)-2-oxoethyl] sulfo- | 4 | 981.507 |
| 28 | [2-(benzo [b] thiene-3-yl-)-2-oxoethyl] sulphur | 4 | 977.4685 |
| 29 | [2-(benzo [1,3] dioxole-5-yl)-2-oxoethyl] sulfo- | 4 | 965.479 |
| 30 | [2-[[(2-EL-970-3-yl) carbonyl] amino] ethyl] sulfo- | 8 | 966.5189 |
| 31 | [2-[[3,4-dimethoxy benzoyl-] amino] ethyl] sulfo- | 8 | 1010.5401 |
Embodiment 32
Preparation I compound, wherein R1 is [2-[6-amino-8-[(3-pyridylmethyl) amino]-9H-purine-9-yl] ethyl] sulfo-(I-32)
A] preparation 6-amino-8-bromo-9-(2-hydroxyethyl)-9H-purine
200ml0.5MCH to 10g (55.8mmol) 6-amino-9-(2-hydroxyethyl)-9H-purine
3COONa/CH
3Add the 4ml bromine in the solution of COOH damping fluid (pH4).In stirring at room reaction mixture 8 hours.Sediment separate out obtains the required product of 6.13g (43%) with water washing and from alcohol crystal.
B] preparation 6-amino-9-(2-hydroxyethyl)-8-[(3-pyridylmethyl) amino]-9H-purine
Under argon gas, with the mixture heating up to 150 of 0.387g (1.5mmol) 6-amino-8-bromo-9-(2-hydroxyethyl)-9H-purine and 0.4563-picolyl amine (4.2mmol) ℃.After reaction is accomplished (～5 hours), with the reaction mixture dilute with water, the product deposition.Sediment separate out, water and ether washing obtain the required product of 0.372g (87%).
B] preparation 6-amino-9-(2-chloro ethyl)-8-[(3-pyridylmethyl) amino]-9H-purine
In 50 ℃, stir the mixture of 350mg (1.22mmol) 6-amino-9-(2-hydroxyethyl)-8-[(3-pyridyl-methyl) amino]-9H-purine and 2ml THIONYL CHLORIDE 97.Reaction accomplish the back (～3h), vacuum concentrated mixture, dilute with water subsequently, using ammoniacal liquor adjusting pH is 7.Sediment separate out, water, ETHYLE ACETATE and ether washing obtain the required product of 197mg (53%).
1H-NMR(DMSO)：8.62(s，IH)，8.44(d，IH)，7.92(s，IH)，7.80(d，IH)，7.38(t，1H)，7.33(m，1H，NH)，6.32(s，2H，NH
2)，4.60(d，2H)，4.34(t，2H)，3.92(t，2H)。
Target compound I-32 can be from 6-amino-9-(2-chloro ethyl)-8-[(3-pyridyl-methyl) amino]-9H-purine and IX-4 (formula IX compound, wherein R
P1Be ethanoyl, R
P2Be hydrogen and R
P4Be methyl), prepare according to embodiment 4 step D-E methods.MS(ESI)：1070.5701。
Embodiment 33
Preparation I compound, wherein R1 is [2-[(3-cyclopentyloxy-4-p-methoxy-phenyl) amino] ethyl] sulfo-(I-33)
A] preparation (2-chloro ethyl) (3-cyclopentyloxy-4-p-methoxy-phenyl) amine
In the 100ml methanol solution of 2.15g (10.4mmol) 3-cyclopentyloxy-4-anisidine (J.Org.Chem.2005,70,1050), add 2.0g (14.1mmol) chloro acetaldehyde solution (55% water), 3.9g (62.6mmol) NaBH
3CN and 0.5ml acetate.Spend the night in 15 ℃ of stirred reaction mixtures, subsequently evaporating solvent.Residue is dissolved in the 120ml methylene dichloride, and organic layer is used brine wash, through Na
2SO
4Drying, vacuum-evaporation.The bullion product obtains the required product of 1.78g (63.5%) through silica gel column chromatography purifying (hexane: ETHYLE ACETATE 100:1 is 15:1 then), is yellow oil.
1H-NMR(DMSO)：6.70(d，1H).6.28(s，1H)，6.06(d，1H)，5.43(m，IH)，4.69(m，IH)，3.68(m，2H)，3.60(m，3H)，3.32(m，2H)，1.83(m，2H)，1.69(m，4H)，1.55(m， 2H)。
According to embodiment 4 step D-E, from (2-chloro ethyl) (3-cyclopentyloxy-4-p-methoxy-phenyl) amine and IX-4 (formula IX compound, wherein R
P1Be ethanoyl, R
P2Be hydrogen and R
P4Be methyl) preparation target compound I-33.
Embodiment 34
Preparation I compound, wherein R1 is [2-[(4-pyridylmethyl) amino] ethyl] sulfo-(I-34) B] preparation formula VII compound, wherein R1 is [2-[(4-pyridylmethyl) amino] ethyl] sulfo-, R
P1And R
P2Be benzoyl-
In the 3ml methanol solution of 163mg (0.15mmol) embodiment 8 steps A products, add 0.0146ml (0.15mmol) 4-pyridylaldehyde, 0.0442ml acetate and 7.8mg NaBH
3CN.In room temperature the mixture stirred overnight is also diluted with 30ml ETHYLE ACETATE subsequently.Organic layer is with saturated NaHCO
3The aqueous solution and brine wash are through Na
2SO
4Drying is filtered and vacuum concentration.The bullion product is through flash chromatography on silica gel purifying (DCM:MeOH:NH
3100:0:0.01 → 96:4:0.01) obtain required product, be white solid.
According to embodiment 8 step C, prepare target compound I-34 from embodiment 34 steps A products.MS(ESI)：937.5300。
Embodiment 35
The adjusting that neutrophil elastase generates
The Histopaque post comes and centrifugal collection granulocyte separates human neutrophil leucocyte through the heparinization whole blood is splined on.The activity of The compounds of this invention (formula I compound) (being called test-compound hereinafter) can be through with test-compound (50 μ M) solution and cytochalasin B (5mg/L) and about 10 in the standard phosphate buffered saline buffer that comprises 2.5% (w/v) bovine serum albumin and 0.8mM SAAVNA
6Individual neutrophil leucocyte mixes to be measured.The reaction mixture TV is 0.8mL, and the concentration that provides is the final concentration in mixture.In 37 ℃/5%CO
2The middle cultivation after 10 minutes makes the reaction beginning through adding fMLP (0.1 μ M), in 37 ℃/5%CO
2Middle incubation mixture 30 minutes is measured absorption in 405nm then.Replicate(determination) derives from the neutrophil leucocyte preparation of the blood of 3 different donors.All sample standard deviations are measured with a-type double.Result's active inhibition with the % neutrophil leucocyte in following table 5 is represented.
Table 5:
| Test compound | Average activity suppresses (%) |
| Embodiment 1 | 19±0.6 |
| Embodiment 4 | 31±2.4 |
| Embodiment 11 | 20±0.97 |
| Oxacyclotetradecane,erythromycin deriv | 5±0.30 |
| Clindamicin | 4±0.07 |
| Tsiklomitsin | -17±0.30 |
Embodiment 36
The inhibition of phosphodiesterase 3 (PDE3)
From human thrombocyte separate phosphodiesterase 3 (Weishaar, R.E., Burrows, S.D., Kobylarz, D.C, Quade, M.M. and Evans, D.B. (1986), Biochem.Pharmacol., 35.:787).Test-compound, reference compound or water (contrast) adding is comprised 40mM Tris-HCl (pH7.8), 3mM MgCl
2, 1mM DTT, 0.01%BSA, 200mMNH
4Cl, 0.1 μ M cAMP and 0.1 μ Ci [
3H] in the damping fluid of cAMP.
Subsequently, add enzyme (final amount depends on separating effect) and begin reaction, in 30 ℃, incubation mixture 30min.For the substrate blank determination, in reaction mixture, do not add enzyme.Behind the incubation,, after this add the SPA strain through heating culture plate to 60 ℃ 3min termination reaction.In 22 ℃ jolt 20min after, adopt scintillometer (Topcount, Packard) measure [
3H] amount of 5 ' AMP.The data that obtain are used to calculate IC
50Value, the IC that obtains
50Be worth as shown in table 6.
Table 6:
| Test compound | IC 50(PDE3)(μM) |
| Embodiment 1 | 0.32 |
| Embodiment 4 | 1.90 |
| Embodiment 11 | 0.23 |
| Oxacyclotetradecane,erythromycin deriv | >;10 |
Embodiment 37
The inhibition of phosphodiesterase 4 (TDE4)
From human monocyte's (U-937 cell) separate phosphodiesterase 4 (Torphy, T.J., Zhou, H.L. and Cieslinski, L.B. (1992), J.Pharmacol.Exp.Ther., 263:1195).
Test-compound, reference compound or water (contrast) adding is comprised 40mM Tris-HCl (pH7.8), 3mM MgCl
2, 1mM DTT, 0.01%BSA, 200mM NH
4Cl, 1 μ M cAMP and 0.1 μ Ci [
3H] in the damping fluid of cAMP.
Subsequently, add enzyme (final amount depends on separating effect) and begin reaction, in 30 ℃, incubation mixture 30min.When carrying out the substrate blank determination, do not add enzyme in the reaction mixture.Behind the incubation,, after this add the SPA strain through heating culture plate to 60 ℃ 3min termination reaction.In 22 ℃ jolt 20min after, adopt scintillometer (Topcount, Packard) measure [
3H] amount of 5 ' AMP.The data that obtain are used to calculate IC
50Value, the IC that obtains
50Be worth as shown in table 7.
Table 7:
| Test compound | IC 50(PDE4)(μM) |
| Embodiment 1 | 0.71 |
| Embodiment 4 | 5.80 |
| Embodiment 11 | 0.23 |
| Oxacyclotetradecane,erythromycin deriv | >;10 |
Embodiment A
Ointment (w/o) with following composition can adopt ordinary method production:
| Active substance | 1.0g |
| The emulsification Stearyl alcohol | 9.0g |
| Whiteruss | 10.5g |
| Vaseline | 10.5g |
| Water | 69.0g |
Embodiment B
Ointment (w/o) with following composition can adopt ordinary method production:
| Active substance | 1.0g |
[0223]
| Wool wax alcohol | 3.0g |
| Stearyl alcohol | 0.25g |
| Vaseline | 46.75g |
| Water | 49.0g |
Embodiment C
Ethanol system gel with following composition can adopt method production well-known to those skilled in the art:
| Active substance | 1.0g |
| Butylated Hydroxytoluene | 0.02g |
| Hydroxypropylcellulose | 2.0g |
| Ethanol 99.5% | 96.98g |
Claims (20)
1. the macrolide antibiotic compound of general formula I:
Wherein
R1 is selected from:
2. the compound of claim 1, wherein R1 is selected from following groups:
3. the compound of claim 1, wherein R1 is selected from following groups:
4. the compound of claim 1, wherein R1 is selected from following radicals:
5. the compound of claim 1, wherein R1 is a following radicals:
6. the compound of claim 1, wherein R1 is a following radicals:
7. the compound of claim 1, wherein R1 is a following radicals:
8. the compound of claim 1, wherein R1 is a following radicals:
9. the compound of claim 1, wherein R1 is a following radicals:
10. medicine, this pharmaceutical pack contain right and require among the 1-9 each compound and pharmaceutically acceptable carrier.
11. the medicine of claim 10, this medicine are used to prevent or treat the pathologic conditions that relates to infection.
12. be used to prevent or treat the medicine of the claim 11 of inflammatory diseases.
13. comprise the medicine of the compound of claim 4, this medicine is used to treat can be through suppressing the disease that human phosphatase diesterase 3 and/or human phosphatase diesterase 4 improve.
14. the compound of claim 1 or 2 is used for preventing and treating the purposes of the medicine of infection in production.
15. the compound of claim 1 or 2 is used for preventing and treating the purposes of the medicine of inflammatory diseases in production.
16. the compound of claim 4 is used for treating the purposes of medicine that can be through suppressing disorder that the human phosphatase diesterase improves or disease in production.
17. the purposes of claim 16, wherein said human phosphatase diesterase are human phosphodiesterase 4 and/or human phosphatase diesterase 3.
18. the compound of claim 1 or 2 is used for treating the purposes of the medicine of acne in production.
19. the method for the formula I compound of production claim 1 or 2, this method comprises:
A) with the clarithromycin of known method with following formula:
Be converted into formula IV compound:
R wherein
P1And R
P2Be respectively hydroxy-protective group,
B) with known method said formula IV compound is converted into formula VI compound:
Wherein R1 such as claim 1 definition or be formula-S-R
P3Group, R wherein
P3Be sulfur protecting group group, and R
P1And R
P2Have above-mentioned definition,
C) make said formula VI compound in aprotic solvent, obtain formula VII compound with the alkali metal base reaction:
Wherein R1, R
P1And R
P2Have above-mentioned definition, and
Simultaneously or remove hydroxy-protective group R in order
P1And R
P2, form formula I compound,
Prerequisite be when R1 be S-R
P3The time, removing hydroxy-protective group R
P1And R
P2Before, formula VII compound is converted into the disulfide derivatives of formula IX in the presence of molecular sieve:
R wherein
P4Be C
1-C
4Alkyl, or 3-nitro-2-pyridyl are handled with reductive agent this compound in solvent, obtain formula X compound:
R wherein
P1And R
P2Have above-mentioned definition, make the compound reaction of this compound and formula Q-X-Lg then, wherein Q-X-is selected from following group:
Lg is selected from chlorine, bromine, iodine, methylsulfonyl oxygen base, ptoluene-sulfonyl oxygen base or trifyl oxygen base, obtains formula VII compound, wherein R1 such as claim 1 definition.
20. the method for claim 19, wherein R
P4Be methyl or 3-nitro-2-pyridyl, reductive agent is trialkyl phosphine or triaryl phosphine, and said solvent is aqueous acetone solution, DMF, dioxane or THF solution.
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| EP05002664 | 2005-02-09 | ||
| EP05011419.8 | 2005-05-26 | ||
| EP05011419 | 2005-05-26 | ||
| PCT/CH2006/000083 WO2006084410A1 (en) | 2005-02-09 | 2006-02-08 | New macrolides |
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| TW200946109A (en) * | 2008-05-09 | 2009-11-16 | Enanta Pharm Inc | Anti-bacterial activity of 9-hydroxy derivatives 6, 11-bicyclolides |
| FR2995605B1 (en) * | 2012-09-18 | 2014-09-19 | Sanofi Sa | MACROLIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003072588A1 (en) * | 2002-02-28 | 2003-09-04 | Basilea Pharmaceutica Ag | Macrolides with antibacterial activity |
| CN1464880A (en) * | 2000-08-22 | 2003-12-31 | 巴斯利尔药物股份公司 | New macrolides with antibacterial activity |
| CN1492874A (en) * | 2000-12-21 | 2004-04-28 | Macrolide antibiotics |
-
2006
- 2006-02-08 CN CN2006800040125A patent/CN101115764B/en not_active Expired - Fee Related
-
2007
- 2007-08-23 ZA ZA200707143A patent/ZA200707143B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1464880A (en) * | 2000-08-22 | 2003-12-31 | 巴斯利尔药物股份公司 | New macrolides with antibacterial activity |
| CN1492874A (en) * | 2000-12-21 | 2004-04-28 | Macrolide antibiotics | |
| WO2003072588A1 (en) * | 2002-02-28 | 2003-09-04 | Basilea Pharmaceutica Ag | Macrolides with antibacterial activity |
Non-Patent Citations (2)
| Title |
|---|
| Gorrini M. et al.Inhibition of human neutrophil elastase by erythromycinandflurithromycin, two macrolide antibiotics.American Journal of Respiratory Cell and Molecular Biology25 4.2001,25(4),492-499. * |
| GorriniM.etal.Inhibitionofhumanneutrophilelastasebyerythromycinandflurithromycin two macrolide antibiotics.American Journal of Respiratory Cell and Molecular Biology25 4.2001 |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200707143B (en) | 2008-07-30 |
| CN101115764A (en) | 2008-01-30 |
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