CN105646370A - Antimicrobial compounds and methods of making and using same - Google Patents

Antimicrobial compounds and methods of making and using same Download PDF

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Publication number
CN105646370A
CN105646370A CN201610065325.7A CN201610065325A CN105646370A CN 105646370 A CN105646370 A CN 105646370A CN 201610065325 A CN201610065325 A CN 201610065325A CN 105646370 A CN105646370 A CN 105646370A
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E.M.杜菲
A.巴塔查吉
H.奥多德
M.德维托
Y.杜
S.西尼什塔
Y.唐
B.T.温伯利
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Melinta Subsidiary Corp
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Rib X Pharmaceuticals Inc
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Abstract

Provided are antimicrobial compounds and methods of making and using the same. The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.

Description

Antimicrobe compound and its preparation and application
Related application
The divisional application of to be the denomination of invention on October 15th, 2010 be " Antimicrobe compound and its preparation and application " PCT/US2010/052928 application for a patent for invention that the application is international filing date, original application enter National Phase in China obtain national applications number be 201080057306.0 and its require U.S. Provisional Patent Application 61/252, 478 (applications on October 16th, 2009), U.S. Provisional Patent Application 61/314, 287 (application on March 16th, 2010) and U.S. Provisional Patent Application 61/358, the priority of 201 (applications on June 24th, 2010). the content of above-mentioned application is fully incorporated to herein in the way of quoting as proof.
The field of the invention
The present invention broadly relates to Antimicrobe compound field and preparation and the method using them. These compounds can be effectively used for treatment, the microorganism of prevention humans and animals is infected and it is dangerous to reduce it.
Background
Owing to being found that penicillin in nineteen twenties and being found that streptomycin in nineteen forties, so, there are many noval chemical compounds to be found or have been used as antibiotic medicament by specific design. People once thought, can completely control by means of this therapeutic agent or eliminate infectious disease. But, owing to having the cell of resistance or the bacterial strain of microorganism to continue to evolve effective therapeutic agent at present, so, this viewpoint is challenged. The almost every kind of antibiotic medicament developed used clinically has eventually encountered problem antibiotic-resistant bacteria occur. Such as, the resistant strain of gram-positive bacteria has been defined, for instance the staphylococcus of methicillin-resistant, the enterococcus of penicillin-fast streptococcus and anti-vancocin. Infected patient can be caused serious consequences or even fatal result by antibiotic-resistant bacteria. Referring to, for instance, Lowry, F.D. " AntimicrobialResistance:TheExampleofStaphylococcusaureus, " J.Clin.Invest., vol.111, no.9, pp.1265-1273 (2003); And Gold, H.S. and Moellering, R.C., Jr., " Antimicrobial-DrugResistance, " N.Engl.J.Med., vol.335, pp.1445-53 (1996).
In decades, it has been found that with the principal focal point that the new antibacterial of research and development has become as many drugmakers. While it is true, recent years, existing many drugmakers exit from this research field and Field of Drug Discovery. Exiting due to this, the antibiotic that only minimal amount is new comes into the market. Lack new antibiotic especially uneasy, particularly when the resistance of Current Therapy is all improved by antibacterial in hospital and community environment.
In the process finding new antibiotic medicament, research worker has tested combination or the connection of the various piece of antibiotic molecule, in order to is formed multi-functional or mixes type compound. Other research worker has manufactured experimently the derivant of known Antibiotics, for instance, Ketek (telithromycin), it is sold with trade (brand) name Ketek, is the derivant of erythromycin.But, the success of these methods is restricted.
The approach forming new Antimicrobe compound is designing modulators, for instance, the inhibitor of bacterial ribosome function. By regulating or suppress bacterial ribosome function, this antimicrobial compound can hinder main process, for instance RNA translation and protein synthesis, thus provides anti-microbial effect. It is true that more known Antibiotique compositions, for instance erythromycin, clindamycin and Linezolid (linezolid), be combined with ribosome.
In order to find and develop new antimicrobial, the present invention uses Structure-ba sed drug design approach. In order to design the Antimicrobe compound with specific chemical structures, ribosome binding characteristic and antimicrobial acivity of new kind, this approach originates in ribosomal high-resolution X ray crystal. This drug discovery approach based on structure: Franceschi described in publication below, F.andDuffy, E.M., " Structure-baseddrugdesignmeetstheribosome ", BiochemicalPharmacology, vol.71, pp.1016-1025 (2006).
Based on this Structure-ba sed drug design approach, the present invention describes the Antimicrobe compound of the new chemical species that the antibacterial that can be used for treating humans and animals infects. Without being bound by theory, it is believed that these compounds suppress bacterial ribosome function by being combined with ribosome. By utilizing these ribosome binding sites, the Antimicrobe compound of the present invention can provide the activity better activity than existing antimicrobial compound, especially for the resistant strain of antibacterial.
In order to find and develop new antimicrobial, the present invention uses Structure-ba sed drug design approach. In order to design the Antimicrobe compound with specific chemical structures, ribosome binding characteristic and target antimicrobial acivity of New raxa, this approach originates in ribosomal high-resolution X ray crystal. This drug discovery approach based on structure: Franceschi described in publication below, F.andDuffy, E.M., " Structure-baseddrugdesignmeetstheribosome ", BiochemicalPharmacology, vol.71, pp.1016-1025 (2006).
Therefore, present invention accomplishes the needs of the important development of the new antimicrobial providing active for Drug resistance malignant bacteria organism, especially antimicrobial.
The present invention summarizes
The present invention broadly relates to Antimicrobe compound field and preparation and the method using them. These compounds can be effectively used for treatment, the microorganism of prevention humans and animals is infected and it is dangerous to reduce it. Present invention also offers the officinal salt of these compounds, ester, N-oxide and prodrug.
The invention provides the compound with having structure:
WhereinIt is chosen from following chemical part:
,,
,, or
,
Wherein V is independently selected from-CR4a-or-N-,
W is O, NR1, NOR1Or S, or W=is selected from the combination of HO-and H-being both connected with identical carbon atoms, or (the C being both connected with identical carbon atoms1-8Alkyl) combination of O-and H-;
X---Y represents singly-bound or double bond, works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---When Y is double bond, X is N, Y is carbon atom,
Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or ,-G-H-J is selected from:
,
Wherein each H and J selects independently,
C-B-A-,-D-E-F and-G-H-J are chemical groups, wherein
A, D and G independently selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Thiazolinyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6-, (g)-S (O)p-, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)-OC (O) O-, (l)-C (O) NR6-, (m)-NR6CO-,(n)-NR6C(O)NR6-, (o)-C (=NR6)-, (p)-C (=NR6)O-,(q)-OC(=NR6)-, (r)-C (=NR6)NR6-, (s)-NR6C(=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6-, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)-NR6(CNR6)NR6-, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t-, (dd) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur,
(ee) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(ff)-(CR6R6)t-,
Wherein (dd) or (ee) is optionally by one or more R5Group replaces;
B, E and H independently selected from:
(a) singly-bound,
B () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
C () 3-14 unit is saturated, unsaturated or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group replaces;
(d)-(C1-8Alkyl)-, (e)-(C2-8Thiazolinyl)-, (f)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-C (=NR6)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t-,
C, F and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3(j)-NO2, (k)-NR6(CR6R6)tR8, (l)-OR8, (m)-S (O)p(CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (o)-OC (O) (CR6R6)tR8, (p)-SC (O) (CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (r)-NR6C(O)(CR6R6)tR8, (s)-C (O) NR6(CR6R6)tR8, (t)-C (=NR6)(CR6R6)tR8, (u)-C (=NNR6R6)(CR6R6)tR8, (v)-C (=NNR6C(O)R6)(CR6R6)tR8, (w)-C (=NOR8)(CR6R6)tR8, (x)-NR6C(O)O(CR6R6)tR8, (y)-OC (O) NR6(CR6R6)tR8, (z)-NR6C(O)NR6(CR6R6)tR8, (aa)-NR6S(O)p(CR6R6)tR8, (bb)-S (O)pNR6(CR6R6)tR8, (cc)-NR6S(O)pNR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH3, (ii)-S (O)pR8, (jj)-NC (O) R8, (kk)-NR6C(NR6)NR6R8, (ll) C1-8Alkyl, (mm) C2-8Thiazolinyl, (nn) C2-8Alkynyl, (oo) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur, and (pp) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, (qq)-(CR6R6)tNR6(CR6R6)tR8, (rr)-N [(CR6R6)tR8][C=O(CR6R6)tR8], (ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8], (tt)-(CR6R6)tNR6(C=O)(CR6R6)tR8, (uu)-haloalkyl, (vv)-C (O) (CR6)[(CR6R6)tR8]R8, (ww)-(CR6R6)tC(O)NR8R8, (xx)-(CR6R6)tC(O)O(CR6R6)tR8, (yy)-NR6C(O)CR8R8R8, (zz)-N [(CR6R6)tR8]C(O)R8(aaa)-S (O)pNR8R8;
Wherein (ll) to (pp) is optionally by one or more R7Group replaces;
R5It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;Or, two R5Group combines, and forms carbocyclic ring,
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Replace;
R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;
Wherein (b) to (e) is optionally by one to multiple R8Replace;
R7It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (y)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (z)-(CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6, (cc)-NR6C(O)R6(dd)-C (=NR6)NR6R6;
Wherein (m) to (q) and (x) to (y) is optionally by one or more R9Replace;
R8It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R9, (k)-OR9, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), r () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, s ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (t)-haloalkyl, (u)-C (O) (CR6R6)tR9, (v)-SR6, (w)-OC (O) (CR6R6)tR9, (x)-NR6C(O)NR6R9, (y)-NR6C(O)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6)NR6R6, (bb)-C (=NR9)NR6R6, (cc)-S (O)pR9, (dd)-(CR6R6)tC(O)NR6R9, (ee)-(CR6R6)tOR9(ff)-(CR6R6)tNR6R9;
Wherein (m) to (s) is optionally by one to multiple R9Replace;
R9It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R10;
Wherein (n) to (r) and (z) to (aa) is optionally by one or more R10Replace;
R10It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R6;
Optionally, wherein-D-E-F or-G-H-J one of both is absent from (such as, group-D-E-F or group-G-H-J represents hydrogen), but-D-E-F and both-G-H-J can not be absent from simultaneously;
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, tautomer or prodrug.
It addition, the method that the invention provides synthesis above-claimed cpd. After synthesis, it is possible to one or more this compound of therapeutically effective amount and pharmaceutically suitable carrier are made into preparation, as antimicrobial especially antibacterial, are used for giving human or animal. In certain embodiments, the compound of the present invention can be effectively used for treatment, prophylaxis of microbial infects or reduces that it is dangerous, or for prepare can treat, prophylaxis of microbial infects or reduces the medicine of its danger. Correspondingly, in order to provide this compound of effective dose, this compound or preparation can be given by following approach to human or animal: oral, parenteral, ear, eyes, nose or topic route.
With reference to following detailed description and claims, it is possible to be more fully understood from the above and other aspects and embodiments of the present invention.
The detailed description of the present invention
The invention provides the chemical families that can serve as antimicrobial, be more specifically used as antibacterial.
The present invention includes the officinal salt of compound described herein, ester, tautomer, N-oxide and prodrug.
Compounds described herein can have asymmetric center. The compounds of this invention of the atom containing Asymmetrical substitute can be separated with optically active or racemic form. In this field, it is well-known for how preparing optically active form, for instance, racemic form is split, or synthesizes with the initiation material of optically active. Many geometric isomers of alkene, C=N double bond etc. can also be present in compounds described herein, and all this stable isomers are included in the invention. This document describes the cis and trans geometric isomer of the compounds of this invention, and can separate with the form of mixtures of isomer or independent isomeric form. All chiralitys of structure, diastereomeric, raceme and geometrical isomerism form are object forms, unless specifically indicated that specific spatial chemistry or isomeric form. For the part that all methods preparing the compounds of this invention and the intermediate wherein prepared are the present invention. It is additionally considered that all tautomers of compound that are indicated or that describe are the parts of the present invention. Additionally, present invention additionally comprises the metabolite of compound described herein.
Present invention additionally comprises all isotopes being present in the atom among the compounds of this invention. Isotope includes having same atoms ordinal number but different those atoms of mass number. As Typical examples (but not limited to), the isotope of hydrogen includes tritium and deuterium. The isotope of carbon includes C-13 and C-14.
As any variable (such as, R6) when occurring more than once in any ingredient or formula of compound, its definition when occurring every time with its in office what it occurs time definition unrelated. Thus, for instance, if showing that group is by one or more R6Group replaces, then R6When occurring every time independently selected from R6Definition. Equally, substituent group and/or variable can combine, but condition is: this combination can produce stable compound within the scope of the atom common fare indicated.
Display represents that the chemical constitution of the dotted line of chemical bond exists with showing this key option. Such as, it is close to the dotted line that solid line singly-bound draws and shows that this key can be singly-bound, it is also possible to be double bond.
When connect the key table of substituent group be shown as intersect with the key being connected in ring two atoms time, then this substituent group can with on ring any atomic linkage.When listing substituent group, without show this substituent group remainder with the compound of given chemical formula be bonded via atom when, this substituent group can via any atomic linkage in this substituent group. Substituent group and/or variable can combine, but condition is: this combination can produce stable compound.
When having nitrogen-atoms in the compounds of this invention, if appropriate, by processing with oxidant (such as, MCPBA and/or hydrogen peroxide), these nitrogen-atoms can be changed into N-oxide. Thus, it is believed that nitrogen-atoms that is shown and that require includes shown nitrogen and its N-oxide (N �� O) derivant (depending on the circumstances).
The method developing antiproliferative and the anti-infective improved is to provide the regulator (such as inhibitor) of ribosome function.
Ribosome is ribonucleoprotein, and it is present in prokaryote and eukaryote. Ribosome is responsible for the organelle of protein synthesis. During gene expression, ribosome by messenger RNA coding hereditary information be translated in albumen (Garrett et al. (2000) " TheRibosome:Structure; Function; AntibioticsandCellularInteractions; " AmericanSocietyforMicrobiology, Washington, D.C.).
Ribosome includes two non-equivalent ribonucleoprotein subunits. The size of bigger subunit (also known as " large ribosomal subunit ") is about the twice of less subunit (also known as " little ribosomal subunit "). Little ribosomal subunit is in conjunction with messenger RNA (mRNA), and mediates the interaction between mRNA and transfer RNA (tRNA) anticodon (it determines the fidelity of translation). Large ribosomal subunit catalysis peptide bond is formed, i.e. the peptide acyl of protein synthesis-transferring enzyme reaction, and includes the different tRNA binding site of at least three (be called aminoacyl, peptide acyl and exit site). Aminoacyl site or aminoacyl site receive the aminoacyl-tRNA introduced, and its aminoacid can be supplied to the peptide chain of growth by it. Additionally, the A interval of aminoacyl site is important. Peptide acyl-tRNA complex is received in peptidyl site or P position, i.e. have its amino acid whose tRNA, and it is the part increasing peptide chain. After deacylated tRNA provides its aminoacid to the polypeptide chain increased, exit position or E-position and receive deacylated tRNA.
1. definition
" isomerism " refers to have same molecular formula but compounds different in the bonding order or their steric arrangement of character or their atom. Isomers different in their steric arrangement is called " stereoisomer ". It not that the stereoisomer of mirror image is called " diastereomer " each other, be that the stereoisomer of non-overlapped mirror image is called " enantiomer " each other, or be sometimes referred to as optical isomer. The carbon atom of the substituent group bonding different from four is called " chiral centre ".
" chiral isomer " refers to the compound with at least one chiral centre. It has two opposite-handed enantiomeric forms, and can exist with the form of mixtures of individual enantiomers or enantiomer. Mixture containing the opposite-handed individual enantiomers form of equivalent is called " racemic mixture ". The compound with more than one chiral centre has 2n-1Individual enantiomer pair, wherein n is chiral centre number. The compound with more than one chiral centre can exist with mixture (being called " the non-enantiomer mixture ") form of independent diastereomer or diastereomer.When there is a chiral centre, stereoisomer can pass through the absolute configuration (R or S) of this chiral centre and characterize. Absolute configuration refers to the spatial arrangements mode of the substituent group being connected with chiral centre. With consider in the substituent group that is connected of chiral centre be according to the Cahn-Ingold-Prelog sequence rule of Cahn, Ingold and Prelog sort (Cahn et al., Angew.Chem.Inter.Edit.1966,5,385; Errata511; Cahn et al., Angew.Chem.1966,78,413; CahnandIngold, J.Chem.Soc.1951 (London), 612; Cahn et al., Experientia1956,12,81; Cahn, J., Chem.Educ.1964,41,116).
" geometric isomer " refers to that its existence is the diastereomer owing to there is interrupted rotation around double bond. The title of these configurations distinguishes these configurations, cis and trans or Z and E by prefixes cis and trans or Z and E and represents homonymy or the offside (according to Cahn-Ingold-Prelog rule) of group double bond in the molecule.
Further, structure discussed herein and other compound include its all of reversion (atropic) isomer. " reversion isomer " is the stereoisomeric forms that the spatial arrangements of the atom of two isomers is different. The existence of reversion isomer is because, by hindering the rotation of macoradical around center key to cause resistance rotation effect. This reversion isomer typically exists with mixture form, but, due to the development of recent chromatographic technique, it is already possible to separate the mixture of two reversion isomers when selected.
" tautomer " refers to the compound that structure is dramatically different in atomic arrangement, but it is to be easy to and the existence of quick equilibrium form. Should be appreciated that, it is possible to the compound of the present invention is described as different tautomers. Being also to be understood that when compound has tautomeric form, all of tautomeric form is within the scope of the invention, and the name of this compound is not excluded for any tautomeric form.
Can there is tautomeric form in some compounds of the present invention, these tautomeric forms are also included within the scope of the invention.
The compound of the present invention, salt and prodrug can some tautomeric forms exist, including its enol and imines form, and ketone and enamine form and geometric isomer and mixture. All this tautomeric forms are included in the scope of the present invention. In the solution, tautomer exists with the mixture form of one group of tautomer. In solid form, generally a kind of tautomer is preponderated. Even if being likely to only describe a kind of tautomer, but the present invention including all tautomers of the compounds of this invention.
Tautomer is the one in two or more constitutional isomers, and they exist evenly, and is easily transformed into another kind of isomeric form from a kind of isomeric form. This reaction causes that the form of hydrogen atom migrates, simultaneously with the conversion of adjacent conjugated double bond. It may happen that in the solution of tautomerization, it is possible to reach the chemical equilibrium of tautomer. The definite ratio of tautomer depends on some factors, including temperature, solvent and pH value. The concept of the tautomer mutually converted by tautomerization is referred to as tautomerism.
In the middle of the various types of possible tautomerism, generally can observe two kinds of patterns. In ketoenol tautomerization, the movement of electronics and hydrogen atom occurs simultaneously.Glucose demonstrates ring-chain tautomerism phenomenon. It is owing to the aldehyde radical (-CHO) in sugar chain molecule reacts with a hydroxyl (-OH) in same molecular, obtains the result of ring (ring-type) form.
Tautomerization can by following material catalysis: alkali: 1. deprotonation; 2. form delocalization anion (such as enolate); 3. the protonation of the diverse location of anion; Acid: 1. protonation; 2. form delocalization cation; 3. near the deprotonation of cationic diverse location.
Common tautomerism is to being: keto-enol, amide-nitrile, lactams-lactim, the amide in heterocycle-imidic acid tautomerism (such as, in core base guanine, thymus pyrimidine and cytosine), amine-ene amine and enamine-enamine. For illustrative purposes, the present invention is not limited to this embodiment to an embodiment below:
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Term " crystal polymorph " or " polymorph " or " crystal form " refer to crystal structure, in such an embodiment, compound (or its salt or solvate) can with different crystal packing arrangements form crystallizations, and all of crystal all has identical elementary composition. Different crystal form is generally of different X-ray diffractogram, infrared spectrum, fusing point, density hardness, crystal form, optical activity and electrical property, stability and dissolubility. Recrystallization solvent, crystalline rate, storage temperature and other factors can cause that a kind of crystal habit is preponderated. The crystal polymorph of compound can be prepared by crystallization at different conditions.
Terms used herein " replacement " refers to that any one or more hydrogen on specified atom (usually carbon, oxygen or nitrogen-atoms) are selected from and specifies the group of group to replace, condition is: less than the common fare of specified atom, and this replacement produces stable compound. When substituent group is ketone group (that is ,=O), then 2 hydrogen on this atom are replaced. Ring double bond used herein is the double bond formed between two adjacent cyclic atom (such as, C=C, C=N, N=N etc.).
Terms used herein " anomeric carbon " refers to the acetal carbon of glucosides.
Terms used herein " glucosides " is cyclic acetal.
Terms used herein " alkyl " includes having concrete carbon number purpose side chain and straight chain saturated fat hydrocarbyl group. Such as, C1-6Alkyl includes C1��C2��C3��C4��C5And C6Alkyl. Some examples of alkyl are including, but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, sec-amyl, n-hexyl, n-heptyl and n-octyl.
" thiazolinyl " used herein includes straight or branched configuration and the hydrocarbon chain of one or more unsaturated carbon-carbon bond, and unsaturated carbon-carbon bond may reside in any point of safes along chain, for instance vinyl and acrylic. Such as, C2-6Thiazolinyl includes C2��C3��C4��C5And C6Thiazolinyl.
" alkynyl " used herein includes straight or branched configuration and the hydrocarbon chain of one or more carbon-to-carbon triple bonds, and carbon-to-carbon triple bond may reside in any point of safes along chain, for instance acetenyl and propinyl. Such as, C2-6Alkynyl includes C2��C3��C4��C5And C6Alkynyl.
Additionally, " alkyl ", " thiazolinyl " and " alkynyl " includes radical moieties, i.e. have two junction points, an example in the present invention is when D is selected from these chemical groups time. The non-limitative example of this moieties (double-basis) is-CH2CH2-, i.e. by the C of each terminal carbon Yu the remainder covalent bonding of molecule2Alkyl. ALkyl diradicals is also known as " alkylidene " atomic group. Thiazolinyl double-basis is also known as " alkenylene " atomic group. Alkynyl double-basis is also known as " alkynylene " atomic group.
Terms used herein " cycloalkyl " includes saturated rings group, for instance cyclopropyl, cyclobutyl or cyclopenta.C3-8Cycloalkyl includes C3��C4��C5��C6��C7And C8Cycloalkyl.
" counter ion " used herein refers to the positively charged or electronegative kind that the ions binding with opposite charges exists. The non-limitative example of counter ion is the ion providing balance to the electric charge on organic compound. The non-limitative example of counter ion includes: chloride ion, bromide ion, hydroxyl, acetate, sulfate radical and ammonium.
" halogen " used herein or " halo " refer to fluorine, chlorine, bromine and iodine substituent group.
" haloalkyl " used herein include having specific number carbon atom, by the side chain of one or more halogen substiuted and straight chain saturated fat hydrocarbyl group (such as ,-CvFw, wherein v=1 to 3, w=1 is to (2v+1)). The example of haloalkyl is including, but not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.
" alkoxyl " used herein refer to that connected by oxo bridge, there is the abovementioned alkyl specifying number carbon atom. C1-6Alkoxyl includes C1��C2��C3��C4��C5And C6Alkoxyl. C1-6Alkoxyl includes C1��C2��C3��C4��C5��C6��C7And C8Alkoxyl. The example of alkoxyl including, but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, second amoxy, positive heptan oxygen base and n-octyloxy.
" alkylthio group " used herein refer to that connected by sulphur bridge, there is the abovementioned alkyl specifying number carbon atom. C1-6Alkylthio group includes C1��C2��C3��C4��C5And C6Alkylthio group. C1-6Alkylthio group includes C1��C2��C3��C4��C5��C6��C7And C8Alkylthio group.
Unless otherwise mentioned, otherwise, " carbocyclic ring " used herein or " carbocyclic ring " refers to any 3,4,5,6,7,8,9,10,11 or 12 yuan of stable monocycles, dicyclo or three rings, and any of can be saturated, unsaturated (including partially and fully unsaturated) or aromatic carbocyclic. The example of this carbocyclic ring is including, but not limited to cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl, cycloheptenyl, adamantyl, ring octyl group, cyclo-octene base, cyclo-octadiene base, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] dicyclo decane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetralyl. As it has been described above, bridged ring is also included within the definition of carbocyclic ring (such as, [2.2.2] bicyclooctane). When one or more carbon atoms connect two non-conterminous carbon atoms, bridged ring occurs. Preferred bridge is one or two carbon atoms. It will be noted that bridge always makes monocycle be converted into three rings. When ring is bridged ring, the substituent group of cited ring can also be present on bridge. Also include the ring (such as naphthyl and tetralyl) and the volution that condense.
Unless otherwise mentioned, otherwise, terms used herein " heterocycle " refers to stable 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 yuan of monocycles, dicyclo or three rings, it is saturated, unsaturated (including partially and fully unsaturated) or aromatic heterocycle, it is made up of carbon atom and one or more ring hetero atom, such as, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 hetero atom, hetero atom is independently selected from nitrogen, oxygen and sulfur, and including any dicyclo or three cyclic groups, in this dicyclo or three cyclic groups, any heterocycle as defined above and second ring are (such as, phenyl ring) condense or connect. nitrogen and sulfur heteroatom can optional oxidized (that is, N �� O and S (O)p, wherein p=1 or 2).When nitrogen-atoms includes in ring, according to whether it is connected with the double bond in ring, it can being both N, can also being NH (if that is, needing to keep three quantivalences of nitrogen-atoms, then there is hydrogen). Nitrogen-atoms can be replace or unsubstituted (that is, N or NR, wherein R is H or other defined substituent group). Heterocycle side base with it can be connected on any hetero atom that can produce rock-steady structure or carbon atom. If the compound obtained is stable compound, then heterocycle described herein can be replaced on carbon or nitrogen. Assorted nuclear nitrogen can be optionally quaternized. Bridged ring is additionally included in the definition of heterocycle. When connecting two non-conterminous carbon or nitrogen-atoms when one or more atoms (that is, C, O, N or S), bridged ring occurs. Preferred bridge is including, but not limited to a carbon atom, two carbon atoms, a nitrogen-atoms, two nitrogen-atoms and carbon-to-nitrogen group. When ring is bridged ring, the substituent group of cited ring can also be present on bridge. Also include volution and fused rings.
Terms used herein " aromatic heterocycle " or " heteroaryl " refer to stable 5,6,7,8,9,10,11 or 12 yuan monocycle or Bicyclic ring, it is made up of carbon atom and one or more hetero atom, such as, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 hetero atom, hetero atom is independently selected from nitrogen, oxygen and sulfur. When bicyclic heterocycle aromatic rings, two rings being only required, a ring is aromatic rings (such as, 2,3-indoline), but two rings can also be all aromatic rings (such as, quinoline). Second ring can also is that defined the condensing or bridge ring of heterocycle above. Nitrogen-atoms can be replace or unsubstituted (that is, N or NR, wherein R is H or another defined substituent group). Nitrogen and sulfur heteroatom can optional oxidized (that is, N �� O and S (O)p, wherein p=1 or 2). In some compound, S in aromatic heterocycle and the sum of O atom are less than 1.
The example of heterocycle is including, but not limited to acridinyl, azabicyclo caprylyl (azabicyclooctanonyl), azetidinyl, azocine base, benzimidazolyl, benzofuranyl, benzimidazole thiophanate furyl, benzothienyl, benzoxazolyl group, benzothiazole quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazole radical, benzo isoxazole base, benzisothiazole base, benzimidazoline base, benzodioxole group (benzodioxoly), benzodiazole base, carbazyl, 4aH-carbazyl, carbolinyl, chromanyl, chromenyl, scold Lin Ji, suberyl, decahydroquinolyl, dihydrobenzo two English base, 2H, 6H-1, 5, 2-dithiazine base, dihydrofuran also [2, 3-b] oxolane, furyl, furazanyl, imidazolidinyl, imidazolidinyl imines, imidazolinyl, imidazole radicals, imidazoline ketone group, 1H-indazolyl, indole thiazolinyl, indolinyl, indenes piperazine base, indyl, 3H-indyl, isatin base (isatinoyl), isobenzofuran-base, isochroman base, iso indazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazole base, methylenedioxyphenyl base, methylbenzotrazole base, methylfuran base, methylimidazolyl, methylthiazol base, morpholinyl, naphthyridinyl, octahydro isoquinolyl, di azoly, 1, 2, 3-di azoly, 1, 2, 4-di azoly, 1, 2, 5-di azoly, 1, 3, 4-di azoly, oxazolidinyl, oxazolidine ketone group, azoles base, hydroxyindole base, phenanthridinyl, luxuriant and rich with fragrance quinoline base, phenazinyl, phenothiazinyl, phenoxanthein base (phenoxathinyl), phenazinyl, phthalazinyl, piperazinyl, piperazine ketone group (piperazinonyl), piperidyl, piperidone base (piperidonyl), 4-piperidone base, piperonyl, pteridine radicals, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido azoles base, pyridine-imidazole base, pyridothiazole base, pyridine radicals, pyriconyl (pyridinonyl), pyridine radicals (pyridyl), pyrimidine radicals, pyrrolidone-base (pyrroldionyl), pyrrolidinyl, pyrrolidone-base (pyrrolidinonyl), pyrrolinyl, 2H-pyrrole radicals, pyrrole radicals, quinazolyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1, 2, 5-thiadiazine base, 1, 2, 3-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 1, 2, 5-thiadiazolyl group, 1, 3, 4-thiadiazolyl group, thianthrene group, thiazolyl, thienyl, thieno thiazolyl, thieno azoles base, Thienoimidazole base, thienyl, tetrahydro-1,4-thiazine base dioxide (thiomorpholinyldioxidyl), triazine radical, triazolopyrimidinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl andTon base.
Terms used herein " pharmaceutically acceptable " refers to: within the scope of reliable medical judgment, being suitable for the contact tissue of patient but do not have excessive toxicity, zest, allergy or other problem or those compounds of complication, raw material, compositions and/or dosage form, itself and rational benefit/hazard ratio match.
" officinal salt " used herein refers to the derivant of disclosed compound, and wherein parent compound is changed by producing its acid or basic salt. the example of officinal salt is including, but not limited to the inorganic or acylate of alkaline residue (such as amine), the alkali metal of acidic residues (such as carboxylic acid) or organic salt, etc.. officinal salt includes conventional non-toxic salts or the quaternary ammonium salt of parent compound, for instance, nontoxic inorganic or organic acid the salt formed. such as, this conventional non-toxic salts is including, but not limited to derived from selected from following those salt of inorganic and organic acid: Aspirin, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, two carbonic acid, carbonic acid, citric acid, edetic acid, ethionic acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycol acid, glycollyl arsanilic acid (glycollyarsanilic), hexyl resorcin acid (hexylresorcinic), hydrabamic, hydrobromic acid, hydrochloric acid, hydriodate, hydroxymaleic acid, carbonaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, LOMAR PWA EINECS 246-676-2 (napsylic), nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propanoic acid, salicylic acid, stearic acid, secondary acetic acid (subacetic), succinic acid, sulfamic acid, sulfanilic acid, sulphuric acid, tannic acid, tartaric acid and toluenesulfonic acid.
Conventional chemical processes can be utilized, by the officinal salt of the parent compound synthesis present invention containing alkalescence or acidic moiety. Generally, this salt can be made by: in water or organic solvent, or in both mixture, the suitable alkali of the free acid of these compounds or alkali form and stoichiometric or acid reaction; Generally, it is preferred to non-aqueous media, for instance, ether, ethyl acetate, ethanol, isopropanol or acetonitrile. The detail list of acceptable acid addition salts can obtain in following: Remington'sPharmaceuticalSciences, 18thed., MackPublishingCompany, Easton, PA, USA, p.1445 (1990).
Due to known precursors medicine can improve medicine many desirable quality (such as, dissolubility, bioavailability, preparation, etc.), so, it is possible to prodrug form deliver the present invention compound. Thus, the present invention includes the prodrug of advocated compound, delivers its method and containing its compositions. " prodrug " includes any covalently bound carrier, and when giving mammalian subject by this prodrug, it discharges the active parent drug of the present invention in vivo. Prepare the prodrug of the present invention by modifying the functional group being present in compound, method used can make this be modified in routine operation or internal fracture obtains parent compound. Prodrug includes the compounds of this invention that the hydroxyl of the compounds of this invention, amino or sulfydryl are combined with any group, and when giving the prodrug of the mammalian subject present invention, this group ruptures, and forms free hydroxyl group, free amine group or free sulfhydryl groups respectively.The example of prodrug is including, but not limited to: the acetas of the alkohol and amine functional group in the compounds of this invention or salt, formic acid esters or salt and benzoate or salt derivative.
" stable compound " used herein and " rock-steady structure " refer to fully firm compound, it is possible to stand and separate from reactant mixture to effective purity, and can be formulated as effective therapeutic agent.
Terms used herein " patient " refers to and is likely to carry out to perform the operation or human or animal (when animal, the be more typically mammal) patient of invasive medical procedures. It is believed that this patient or experimenter need to reduce the dangerous method of the infection caused due to operation process or invasive method, or the method preventing the infection caused due to operation process or invasive method. It is also believed that this patient or experimenter need the prevention at peri-operation period.
Terms used herein " treatment " refers to cure or improve the therapeutic intervention infected and provide.
Terms used herein " prevention " refers to completely or almost completely to terminate infecting occur, for instance, when patient or experimenter tend to infect or be among risk of infection. Prevention can also include suppressing to infect, the development namely prevented infections.
Terms used herein " reduces danger " and refers to the probability or probability that reduce infection appearance, for instance, when patient or experimenter tend to infect or be among risk of infection.
" unsaturated " used herein refers to the compound (such as, at least one multiple bond) with at least one degree of unsaturation, and includes partially and fully unsaturated compound.
Terms used herein " effective dose " refers to the quantity of the compositions of the compounds of this invention or the compounds of this invention when being administered effective alone or in combination as antimicrobial. Such as, effective dose refers to and is present in the compound amounts accepted in the compositions of patient or experimenter, preparation or medical apparatus, it is enough to cause biological activity, such as, anti-infection activity, for instance, antimicrobial acivity, antibacterial activity, Antifungal action, antiviral activity or Antiparasitic Activity.
Term " prevention effective dose " refers to the effective dose of the compounds of this invention given, and this effective dose is for preventing infection owing to operation process or invasive medical procedures cause or to reduce it dangerous.
It is further appreciated by, statement " hydrogen bond receptor-hydrogen bond receptor-hydrogen-bond donor " and " hydrogen bond receptor-hydrogen bond receptor-hydrogen bond receptor " refers to the relative orientation of hydrogen bond receptor and donor, do not imply that this group of restriction is directly linked together, because other atom or atomic group can be included between this group.
In this specification, singulative also includes plural number, unless clearly dictated otherwise in context. Unless otherwise defined, otherwise, all technology used herein and scientific term have the identical meanings that those skilled in the art are generally understood that. When contradiction, it is as the criterion with this specification. " mammal " used herein refers to people and non-human patients.
Terms used herein " therapeutically effective amount " refers to the compositions quantity of the compounds of this invention being supplied to receiver or the compounds of this invention, this quantity is enough to cause biological activity, such as, antimicrobial acivity, Antifungal action, antiviral activity, Antiparasitic Activity, anti diarrhea activity and/or antiproliferative activity. Preferably, the combination of compound is synergistic combination.When the effect of compound that combination gives is more than the additive effect of the compound individually given with single medicine type, for instance, ChouandTalalay, Adv.EnzymeRegul.vol.22, the synergism described by pp.27-55 (1984) occurs. Generally, under the suboptimum concentration of compound, it will most apparent from performance synergism. Synergism can reduce cytotoxicity, improves antiproliferative and/or anti-infection effect or some other beneficial effect (compared with one-component) of combination.
Terms used herein " RNA micro-spiral (microhelix) binding site " refers to kernel function (ribofunctional) position of the large ribosomal subunit occupied by the micro-spiral of RNA of formula III. RNA micro-thread joint locator qualification at least some of E-site or overlapping with E-position.
Terms used herein " aminoacyl site " refers to that just participating in peptide at aminoacyl tRNA molecules combines its occupied kernel function position before formation is reacted.
Terms used herein " E-position " refers to that participating in peptide at deacylated tRNA combines its occupied kernel function position after formation is reacted.
Terms used herein " P-position " refers to the kernel function position when peptidyl tRNA participates in peptide bond composition reaction, occupied by peptide acyl-tRNA.
Terms used herein " A-interval " refers to that the amino acid moiety at peptidyl transferase core alanyl t-RNA is incorporated into aminoacyl site part therein, or refers to that the oxazolidone ring of Linezolid (linezolid) is incorporated into aminoacyl site part therein.
When using and mention ribosome or ribosomal subunit herein, term " part " or " part for three dimensional structure " can be regarded as the part referring to ribosome or ribosomal subunit's three dimensional structure, including CHARGE DISTRIBUTION and hydrophilic/hydrophobic characteristic, by at least three, more preferably at three to ten, and most preferably at least ten amino acid residue and/or ribosome or ribosomal subunit nucleotide residue constitute. The residue constituting this part can be, such as, i (), based on the continuous residue of the primary sequence of such as ribosomal RNA or ribosomal protein, (ii) constitutes the residue of the continuous part of ribosome or ribosomal subunit's three dimensional structure or (c) its combination. When using herein and mention the micro-spiral of RNA, term " part " or " part for three dimensional structure " can be regarded as the part referring to the micro-helix three-dimensional structure of RNA, including CHARGE DISTRIBUTION and hydrophilic/hydrophobic characteristic, by least three of one or more parent nucleus residues of formula III, more preferably at three to ten atomic buildings. Constitute the atom of this part it may be that such as, the inaccessible atom of solvent that (i) RNA micro-spiral parent nucleus is embedded in, the accessible atom of solvent of the micro-spiral of (ii) RNA, or (iii) its combination.
All percentage ratio used herein and ratio, unless otherwise stated, be by weight.
Run through this description, when compositions is to have, to include, or comprise specific component when describing, or when method is to have, include or to comprise specific method step and describe, refer to that the compositions of the present invention is also substantially made up of the component enumerated, or formed by enumerating component, and the method for the present invention is also substantially made up of the processing step enumerated, or be made up of processing step. Further, it should be appreciated that the order of step or the order right and wrong of some operation of carrying out are substantial, as long as the present invention remains exercisable.Additionally, two or more steps or operation can carry out simultaneously.
2. the compound of the present invention
On the one hand, the present invention relates to the compound with having structure:
WhereinIt is chosen from following chemical part:
,,
,, or
,
Wherein V is independently selected from-CR4a-or-N-,
W is O, NR1, NOR1Or S, or W=is selected from the combination of HO-and H-being both connected with identical carbon atoms, or (the C being both connected with identical carbon atoms1-8Alkyl) combination of O-and H-;
X---Y represents singly-bound or double bond, works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---When Y is double bond, X is N, Y is carbon atom,
Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, whereinComprise hydrogen-bond donor part or other hydrogen bond receptor part further.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, whereinIt it is the chemical part comprising at least two hydrogen bond receptor part and at least one hydrogen-bond donor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein hydrogen bond receptor part and hydrogen-bond donor are partially in following direction:
Hydrogen bond receptor-hydrogen bond receptor-hydrogen-bond donor.
The term that uses above " be in ... direction " do not refer to that hydrogen-bond donor or acceptor portion must be directly linked together because can there is other atom or atomic group in the middle of hydrogen-bond donor or acceptor portion.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein hydrogen bond receptor part is each other within 5 scopes, and hydrogen-bond donor part is within 5 scopes of hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein hydrogen bond receptor part is each other within 3 scopes, and hydrogen-bond donor part is within 3 scopes of hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein hydrogen bond receptor is partly comprised within circulus, and wherein said circulus is single ring architecture or the multiring structure condensed.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, whereinIt it is the chemical part comprising at least three hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein hydrogen bond receptor is partially in following direction:
Hydrogen bond receptor-hydrogen bond receptor-hydrogen bond receptor.
The term that uses above " be in ... direction " do not refer to that hydrogen-bond donor or acceptor portion must be directly linked together because can there is other atom or atomic group between hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein each hydrogen bond receptor part is within about 5 scopes of at least one other hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein each hydrogen bond receptor part is within about 3 scopes of at least one other hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, at least two of which hydrogen bond receptor is partly comprised within circulus, and wherein said circulus is single ring architecture or the multiring structure condensed.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein said hydrogen bond receptor part is independently selected from carbonyl, thiocarbonyl, imine group, the imine group that alkyl replaces, sulfoxide radicals, sulfone group, oximido group, the oximido group that alkyl replaces, hydrazone groups, the hydrazone groups that monoalkyl or dialkyl group replace, oxygen ether (-O-) group, sulfide (also known as sulfide group (-S-)), hydroxyl, alkoxyl, amino, the amino of monoalkyl or dialkyl group replacement and nitro.
In some embodiments, the present invention relates to compound, its officinal salt, ester, tautomer or prodrug, wherein said hydrogen-bond donor part is selected from hydroxyl, mercapto, amino and mono-substituted amino.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
W is O, NR1, NOR1Or S, or W=is selected from the combination of HO-and H-being both connected with identical carbon atoms, or (the C being both connected with identical carbon atoms1-8Alkyl) combination of O-and H-;
X---Y represents singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---When Y is double bond, X is N, Y is carbon atom,
Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein W is O, NR1, NOR1Or S.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
Wherein Z is selected from O, NR4Or S (O)n;
R4Selected from H and C1-6Alkyl,
With
N is 0,1 and 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
Wherein R4Selected from hydrogen and C1-6Alkyl.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein R4It is H.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise cytosine or isocytosine moieties or derivatives thereof.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
,,
,, or
,
Wherein V is independently selected from-CR4a-or-N-,
W is O, NR1, NOR1Or S, or W=is selected from the combination of HO-and H-being connected with identical carbon atoms, or (the C being all connected with identical carbon atoms1-8Alkyl) combination of both O-and H-;
X---Y represents singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---When Y is double bond, X is N, Y is carbon atom,
Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
,,
,, or
,
Wherein V is independently selected from-CR4a-or-N-,
Wherein Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4;
R4Selected from H or C1-8Alkyl,
R4aSelected from H or C1-8Alkyl,
With
N is 0,1 or 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein
Comprise having structure part
,,
,, or
,
Wherein V is independently selected from-CR4a-or-N-,
Wherein R4Selected from H or C1-8Alkyl,
R4aSelected from H or C1-8Alkyl.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or prodrug, wherein R4It is H.
In some embodiments, the present invention relates to the compound of following formula:
(I),(II),
(III),(IV), or
(V),
Wherein V is independently selected from-CR4a-or-N-,
W is O, NR1, NOR1Or S, or W=is selected from the combination of HO-and H-being both connected with identical carbon atoms, or (the C being both connected with identical carbon atoms1-8Alkyl) combination of O-and H-;
X---Y represents singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---When Y is double bond, X is N, Y is carbon atom,
Z is selected from O, NR4, S (O)n, NR4CO, CONR4Or NR4CONR4,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or ,-G-H-J is selected from:
,
Wherein each H and J selects independently,
C-B-A-,-D-E-F and-G-H-J are chemical groups, wherein
A, D and G independently selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Thiazolinyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6-, (g)-S (O)p-, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)-OC (O) O-, (l)-C (O) NR6-, (m)-NR6CO-,(n)-NR6C(O)NR6-, (o)-C (=NR6)-, (p)-C (=NR6)O-,(q)-OC(=NR6)-, (r)-C (=NR6)NR6-, (s)-NR6C(=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6-, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)-NR6(CNR6)NR6-, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t-, (dd) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur,
(ee) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(ff)-(CR6R6)t-,
Wherein (dd) or (ee) is optionally by one or more R5Group replaces;
B, E and H independently selected from:
(a) singly-bound,
B () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
C () 3-14 unit is saturated, unsaturated or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group replaces;
(d)-(C1-8Alkyl)-, (e)-(C2-8Thiazolinyl)-, (f)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-C (=NR6)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t-,
C, F and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3(j)-NO2, (k)-NR6(CR6R6)tR8, (l)-OR8, (m)-S (O)p(CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (o)-OC (O) (CR6R6)tR8, (p)-SC (O) (CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (r)-NR6C(O)(CR6R6)tR8, (s)-C (O) NR6(CR6R6)tR8, (t)-C (=NR6)(CR6R6)tR8, (u)-C (=NNR6R6)(CR6R6)tR8, (v)-C (=NNR6C(O)R6)(CR6R6)tR8, (w)-C (=NOR8)(CR6R6)tR8, (x)-NR6C(O)O(CR6R6)tR8, (y)-OC (O) NR6(CR6R6)tR8, (z)-NR6C(O)NR6(CR6R6)tR8, (aa)-NR6S(O)p(CR6R6)tR8, (bb)-S (O)pNR6(CR6R6)tR8, (cc)-NR6S(O)pNR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH3, (ii)-S (O)pR8, (jj)-NC (O) R8, (kk)-NR6C(NR6)NR6R8, (ll) C1-8Alkyl, (mm) C2-8Thiazolinyl, (nn) C2-8Alkynyl, (oo) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur, and (pp) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, (qq)-(CR6R6)tNR6(CR6R6)tR8, (rr)-N [(CR6R6)tR8][C=O(CR6R6)tR8], (ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8], (tt)-(CR6R6)tNR6(C=O)(CR6R6)tR8, (uu)-haloalkyl, (vv)-C (O) (CR6)[(CR6R6)tR8]R8, (ww)-(CR6R6)tC(O)NR8R8, (xx)-(CR6R6)tC(O)O(CR6R6)tR8, (yy)-NR6C(O)CR8R8R8, (zz)-N [(CR6R6)tR8]C(O)R8(aaa)-S (O)pNR8R8;
Wherein (ll) to (pp) is optionally by one or more R7Group replaces;
R5It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic; Or, two R5Group combines, and forms carbocyclic ring,
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Replace;
R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;
Wherein (b) to (e) is optionally by one to multiple R8Replace;
R7It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (y)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (z)-(CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6, (cc)-NR6C(O)R6(dd)-C (=NR6)NR6R6;
Wherein (m) to (q) and (x) to (y) is optionally by one or more R9Replace;
R8It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R9, (k)-OR9, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), r () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, s ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (t)-haloalkyl, (u)-C (O) (CR6R6)tR9, (v)-SR6, (w)-OC (O) (CR6R6)tR9, (x)-NR6C(O)NR6R9, (y)-NR6C(O)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6)NR6R6, (bb)-C (=NR9)NR6R6, (cc)-S (O)pR9, (dd)-(CR6R6)tC(O)NR6R9, (ee)-(CR6R6)tOR9(ff)-(CR6R6)tNR6R9;
Wherein (m) to (s) is optionally by one to multiple R9Replace;
R9It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R10;
Wherein (n) to (r) and (z) to (aa) is optionally by one or more R10Replace;
R10It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R6;
Optionally, wherein-D-E-F or-G-H-J one of both is absent from (such as, group-D-E-F or group-G-H-J represents hydrogen), but-D-E-F and both-G-H-J can not be absent from simultaneously;
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein
A is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein B is selected from: (a)-(C1-8Alkyl)-, (b)-(C2-8Thiazolinyl)-, (c)-(C2-8Alkynyl)-and (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-C (=NR6)-,-S (O)pNR6-and-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group replaces, and
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-C8Alkyl)-R5Group replaces.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein C is selected from: (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein
A is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 4-7 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 4-7 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group replaces.
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein A is selected from: azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl and tetrahydro pyridyl (piperidenyl);
Any one of the A wherein just mentioned above is optionally by one or more R5Group replaces;
Or, A is singly-bound.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein B is selected from: (a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group replaces, and/or
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group replaces;
Or, B is singly-bound.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein C is selected from: (a) NH2, and (b)-NHC (=NH) NH2��
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein G is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound;
Wherein (a) or (b) is optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein G is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 4-7 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 4-7 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound;
Wherein (a) or (b) is optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein G is selected from azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl, tetrahydro pyridyl (piperidenyl) and singly-bound.
In some embodiments, the present invention relates to the compound of following formula:
(I),
Wherein C-B-A-,-D-E-F ,-G-H-J, V, W, X, Y and Z as defined above, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(II),
Wherein C-B-A-,-D-E-F ,-G-H-J, V, W, X, Y and Z are defined in formula (II), or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(III),
Wherein C-B-A-,-D-E-F ,-G-H-J, V, W, X, Y and Z as above facial (III) in defined, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(IV),
Wherein C-B-A-,-D-E-F ,-G-H-J, V, W, X, Y and Z as above facial (IV) in defined, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(V),
Wherein C-B-A-,-D-E-F ,-G-H-J, V, W, X, Y and Z are defined in formula (V), or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound with Formulas I a, IIa, IIIa, IVa or Va:
(Ia),(IIa),
(IIIa),(IVa), or
(Va),
Or its officinal salt, ester, tautomer or prodrug, wherein variable such as Formulas I, II, defined in III, IV and V.
In some embodiments, the present invention relates to the compound of following formula:
(Ia)
Wherein C-B-A-,-D-E-F ,-G-H-J and Z are defined in formula (I); Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(IIa),
Wherein C-B-A-,-D-E-F and-G-H-J are defined in formula (II), or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(IIIa),
Wherein C-B-A-,-D-E-F and-G-H-J as above facial (III) in defined, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(IVa),
Wherein C-B-A-,-D-E-F and-G-H-J as above facial (IV) in defined, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(Va),
Wherein C-B-A-,-D-E-F and-G-H-J are defined in formula (V), or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound according to Formulas I, II, III, IV or V with formula (Ia), wherein Z is-NR4CONR4-, C-B-A-,-D-E-F and-G-H-J is defined in formula (I); Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
(Ib),
Wherein C-B-A-, D-E-F and-G-H-J are defined in formula (I); Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:Wherein
A is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group replaces;
B is selected from: (a)-(C1-8Alkyl)-, (b)-(C2-8Thiazolinyl)-, (c)-(C2-8Alkynyl)-and (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-C (=NR6)-,-S (O)pNR6-and-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group replaces, and/or
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-C8Alkyl)-R5Group replaces; With
C is selected from: (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen;
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:, wherein
A is selected from: azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl and tetrahydro pyridyl (piperidenyl);
Any one of the A wherein just mentioned above is optionally by one or more R5Group replaces;
Or, A is singly-bound;
B is selected from: (a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group replaces, and/or
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group replaces;
Or, B is singly-bound;
C is selected from: (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen;
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:, wherein C-B-A-is selected from:
Hydrogen,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:
Wherein G is selected from
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound;
Wherein (a) or (b) is optionally by one or more R5Group replaces,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to and comprise R5The compound according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, wherein R5It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NH2, (k)-OR6, (l)-NHC (=NH) NH2, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (r)-haloalkyl, (s) alkylthio group, t () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic; Or, two R5Group combines, and forms carbocyclic ring or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to and comprise R6The compound according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, IVa or Va, wherein R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:,
Wherein G is selected from azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl, tetrahydro pyridyl (piperidenyl) and singly-bound; Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:, wherein-G-H-J is selected from hydrogen,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:,
Wherein-G-H-J is selected from
Hydrogen,
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the compound of following formula:,
Wherein-G-H-J is selected from:
Or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to containing R5Compound, wherein R5It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NH2, (k)-OR6, (l)-NHC (=NH) NH2, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic; Or, two R5Group combines, and forms carbocyclic ring or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to containing R6Compound, wherein R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein group-D-E-F represents hydrogen.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein when W exists, W is O, NR1, NOR1Or S.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein work as X---When Y exists, it is double bond, and X is N, Y is carbon atom.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein work as R4aWhen existing, it is H.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein when Z exists, it is NR4��
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, wherein R4It is H.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, it is combined with ribosome.
In some embodiments, the present invention relates to according to Formulas I, the compound or pharmaceutically acceptable salt thereof of II, III, IV, V, Ia, IIa, IIIa, IVa or Va, ester, tautomer or prodrug, it is combined with ribosome, and wherein ribosome is bacterial ribosome.
In some embodiments, the present invention relates to according to the compound or pharmaceutically acceptable salt thereof of any one compound, ester, tautomer or prodrug in table 1.
In some embodiments, the present invention relates to the pharmaceutical composition comprising the compounds of this invention or its officinal salt, ester, tautomer or prodrug and pharmaceutically suitable carrier.
In some embodiments, the present invention relates to treatment, the morbid state preventing human or animal or the method reducing its danger, the method includes: need the compounds of this invention or its officinal salt, ester, tautomer or the prodrug of its human or animal's effective dose.
In some embodiments, the present invention relates to the method that the microorganism for the treatment of human or animal is infected, the method includes: give the compounds of this invention or its officinal salt, ester, tautomer or the prodrug of described human or animal's effective dose.
In some embodiments, the present invention relates to the compounds of this invention or its officinal salt, ester, tautomer or the prodrug purposes in preparing medicine, this medicine infects for the microorganism treating human or animal.
In some embodiments, the method that the present invention relates to treatment, prevent the microorganism of human or animal to infect or reduce its danger, the method includes: give the compounds of this invention or its officinal salt, ester, tautomer or the prodrug of human or animal's effective dose, or the compounds of this invention or its officinal salt, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prophylaxis of microbial infects or it is dangerous to reduce it
Wherein microorganism is infected and is selected from:
Skin infection, Gram positive infections, Gram-negative infects, Nosocomial Pneumonia, community acquired pneumonia, pneumonia after viral infection, Nosocomial Pneumonia/Ventilator Associated Pneumonia, respiratory tract infection, such as chronic respiratory tract infection (CRTI), acute pelvic infects, concurrent skin and skin structure infection, Skin and soft tissue infection (SSTI), including not concurrent Skin and soft tissue infection (uSSTI) and concurrent Skin and soft tissue infection, abdominal infection, infect in concurrent abdomen, urinary tract infection, bacteremia, septicemia, endocarditis, chamber shunt infection, contacts blood sexuality contaminates, meningitis, surgical prophylaxis, peritoneal infection, infection of bone, the infection of joint, the S. aureus infection of methicillin-resistant, the enterococcus of anti-vancocin infects, the organism of anti-Linezolid (linezolid) infects, infection due to Bacillus anthracis, soil draws hot Francisella to infect, Yersinia pestis infection and pulmonary tuberculosis.
In some embodiments, the present invention relates to method or purposes, in the method or purposes, the compounds of this invention or its officinal salt, ester, tautomer or prodrug are given by ear, eye, nose, oral, parenteral, local or intravenous.
In some embodiments, the present invention relates to treatment, the method infecting or reducing its danger in the concurrent abdomen of prevention human or animal, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent in concurrent abdomen, to infect or reduce its danger,
Infect in wherein concurrent abdomen selected from polymicrobic infection, such as, due to the following abscess caused: escherichia coli (Escherichiacoli), fusiform bacilarmature (Clostridiumclostridioforme), Eubacterium lentum (Eubacteriumlentum), Peptostreptococcus (Peptostreptococcusspp.), bacteroides fragilis (Bacteroidesfragilis), bacteroides disiens (Bacteroidesdistasonis), bacteroides ovatus (Bacteroidesovatus), bacteroides thetaiotaomicron (Bacteroidesthetaiotaomicron), bacteroides uniformis (Bacteroidesuniformis), streptococcus anginosus (Streptococcusanginosus), Streptococcus constellatus (Streptococcusconstellatus), enterococcus faecalis (Enterococcusfaecalis), proteus mirabilis (Proteusmirabilis) or bacillus perfringens (Clostridiumperfringens).
In some embodiments, the present invention relates to treatment, the prevention concurrent skin of human or animal and skin structure infection or the method reducing its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent concurrent skin and skin structure infection or reduce its danger,
Wherein concurrent skin and skin structure infection contaminate (not having osteomyelitis) selected from due to the following diabetic feel caused: staphylococcus aureus (Staphylococcusaureus) (methicillin-susceptible and Drug resistance separator), streptococcus agalactiae (Streptococcusagalactiae), micrococcus scarlatinae (Streptococcuspyogenes), escherichia coli (Escherichiacoli), Klebsiella pneumoniae (Klebsiellapneumoniae), proteus mirabilis (Proteusmirabilis), bacteroides fragilis (Bacteroidesfragilis), Peptostreptococcus (Peptostreptococcusspecies), do not understand sugar rufous Zymomonas mobilis (Porphyromonasasaccharolytica) or two tunnel bacteroids (Prevotellabivia).
In some embodiments, the present invention relates to treatment, the community acquired pneumonia preventing human or animal or the method reducing its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent community acquired pneumonia or reduce its danger,
Wherein community acquired pneumonia causes due to streptococcus pneumoniae (Streptococcuspneumoniae) (penicillin sensitivity and Drug resistance separator) (including with the bacteremic situation of concurrency), hemophilus influenza (Haemophilusinfluenzae) (including beta-lactam enzyme positive separator), Moraxella catarrhalis (Moraxellacatarrhalis) or atypical antibacterial such as mycoplasm hyopneumoniae (Mycoplasmaspp.).
In some embodiments, the present invention relates to treatment, the concurrent urinary tract infection preventing human or animal or the method reducing its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent concurrent urinary tract infection or reduce its danger,
Wherein concurrent urinary tract infection is selected from the pyelonephritis caused due to escherichia coli (Escherichiacoli), concurrent bacteremia or Klebsiella pneumoniae (Klebsiellapneumoniae).
In some embodiments, the present invention relates to treatment, the method that the acute pelvic of prevention human or animal infects or reduces its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevention acute pelvic infects or reduces its danger,
Wherein acute pelvic infects and (includes Endomyometritis in puerperal, septic abortion and postoperative gynecological infection) it is due to streptococcus agalactiae (Streptococcusagalactiae), escherichia coli (Escherichiacoli), bacteroides fragilis (Bacteroidesfragilis), do not understand sugar rufous Zymomonas mobilis (Porphyromonasasaccharolytica), Peptostreptococcus (Peptostreptococcusspp.) or what two tunnel bacteroids (Prevotellabivia) were caused.
In some embodiments, the present invention relates to treatment, Nosocomial Pneumonia/the Ventilator Associated Pneumonia preventing human or animal or the method reducing its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent Nosocomial Pneumonia/Ventilator Associated Pneumonia or reduce its danger,
Wherein Nosocomial Pneumonia/Ventilator Associated Pneumonia is due to streptococcus pneumoniae (Streptococcuspneumoniae) (penicillin sensitivity and Drug resistance separator), staphylococcus aureus (Staphylococcusaureus) (methicillin-susceptible and Drug resistance separator), Klebsiella pneumoniae (Klebsiellapneumoniae), bacillus pyocyaneus (Pseudomonasaeruginosa), acinetobacter (Acinetobacterspp.), stenotrophomonas maltophilia (Stenotrophomonasmaltophilia), hemophilus influenza (Haemophilusinfluenzae) (includes beta-lactam enzyme positive separator) or what legionella pneumophilia (Legionellapneumophilia) caused.
In some embodiments, the present invention relates to treatment, the method that the microorganism relevant to aerobic and facultative gram positive microbes of prevention humans and animals is infected and reduced its danger, the method includes: give humans and animals effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent the microorganism relevant to aerobic and facultative gram positive microbes to infect or reduce its danger,
Wherein aerobic and facultative gram positive microbes is selected from:
Staphylococcus aureus (Staphylococcusaureus) (methicillin-susceptible and Drug resistance separator), streptococcus pneumoniae (Streptococcuspneumoniae) (penicillin sensitivity and Drug resistance separator), enterococcus (Enterococcusspp.) (vancomycin sensitive and Drug resistance separator), streptococcus agalactiae (Streptococcusagalactiae), micrococcus scarlatinae (Streptococcuspyogenes) or staphylococcus epidermidis (Staphylococcusepidermidis) (methicillin-susceptible and Drug resistance separator).
In some embodiments, the present invention relates to treatment, the method that the microorganism relevant to aerobic and facultative Gram-negative microorgansims of prevention humans and animals is infected or reduced its danger, the method includes: give humans and animals effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent the microorganism relevant to aerobic and facultative Gram-negative microorgansims to infect or reduce its danger,
Wherein aerobic and facultative Gram-negative microorgansims is selected from:
Escherichia coli (Escherichiacoli) (include ESBL and the KPC separator produced), hemophilus influenza (Haemophilusinfluenzae) (includes beta-lactam enzyme positive separator), Klebsiella pneumoniae (Klebsiellapneumoniae) (includes ESBL and the KPC separator produced), citrobacter freundii (Citrobacterfreundii), clostridium perfringen (Enterobacteraerogenes), enterobacter cloacae (Enterobactercloacae), rub root (family name) bacterium (Morganellamorganii), serratia marcescens (Serratiamarcescens), bacillus pyocyaneus (Pseudomonasaeruginosa), Acinetobacter bauamnnii (Acinetobacterbaumanni), Moraxella catarrhalis (Moraxellacatarrhalis), proteus mirabilis (Proteusmirabilis), Ke Shi citric acid bacillus (Citrobacterkoseri), Hemophilus parainfluenzae (Haemophilusparainfluenzae), klebsiella oxytoca (Klebsiellaoxytoca) (includes ESBL and the KPC separator produced), proteus vulgaris (Proteusvulgaris), providencia rettgeri (Providenciarettgeri) or providencia stuartii (Providenciastuartii).
In some embodiments, the present invention relates to treatment, the method that the microorganism relevant to anaerobe of prevention human or animal is infected or reduced its danger, the method includes: give human or animal's effective dose according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or prodrug, or relate to according to Formulas I, II, III, IV, V, Ia, IIa, IIIa, the compound or pharmaceutically acceptable salt thereof of IVa or Va, ester, tautomer or the prodrug purposes in preparing medicine, this medicine is used for treating, prevent relevant to anaerobe to obtain microorganism and infect or to reduce it dangerous,
Wherein this anaerobe is selected from: bacteroides fragilis (Bacteroidesfragilis), bacteroides disiens (Bacteroidesdistasonis), bacteroides ovatus (Bacteroidesovatus), bacteroides thetaiotaomicron (Bacteroidesthetaiotaomicron), bacteroides uniformis (Bacteroidesuniformis), fusiform bacilarmature (Clostridiumclostridioforme), Eubacterium lentum (Eubacteriumlentum), peptostreptococcus (Peptostreptococcusspecies), do not understand sugar rufous Zymomonas mobilis (Porphyromonasasaccharolytica), two tunnel bacteroids (Prevotellabivia), deformity bacterium (Bacteroidesvulgates), bacillus perfringens (Clostridiumperfringens) or Fusobacterium (Fusobacteriumspp.).
In some embodiments, the method that the present invention relates to synthesis the compounds of this invention or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the medical treatment device containing the compounds of this invention or its officinal salt, ester, tautomer or prodrug.
In some embodiments, the present invention relates to the medical treatment device containing the compounds of this invention, wherein this device is support.
3. the synthesis of the compounds of this invention
The preparation method that the invention provides the compounds of this invention. Following reaction scheme 1b-5b briefly describes the exemplary approach of synthesis the compounds of this invention. Chemistry describes in detail and is provided in embodiment more specifically.
Reaction scheme 1b-cytosine
Reaction scheme 2b-iso-cytosine
Reaction scheme 3b-ring has the cytosine of the 3rd N
Reaction scheme 4b-ring does not have the cytosine of second double bond
Reaction scheme 5b-ring does not have the iso-cytosine of second double bond
4. the sign of the compounds of this invention
Designed by said method, select and/or optimized compound, once preparation, it is possible to use various tests well known by persons skilled in the art characterize, so that it is determined that whether this compound has biological activity. For example, it is possible to characterize molecule with routine test, including, but not limited to test as described below, so that it is determined that whether they have the activity of expectation, combine activity and/or binding specificity.
Additionally, high flux screening can be used for the analysis accelerating to use this test. Therefore, it can screen rapidly the activity of molecule described herein, for instance, anticancer, antibacterium, antifungal, parasiticide or antiviral agent. Equally, technology known in the art is used, it is possible to how test compound interacts with ribosome or ribosomal subunit, and/or, the regulator (such as, it is suppressed that agent) how to synthesize effectively as albumen. The conventional method carrying out high flux screening describes in such as Devlin (1998) HighThroughputScreening, MarcelDekker and United States Patent (USP) 5,763,263.High throughput test can use one or more different tests technology, includes but not limited to those technology as described below.
(1) surface combination research
Various binding tests can be effectively used for new the having of screening and combine active molecule. A kind of method includes surface plasma resonance technology (SPR), and it can be used for evaluating the molecule that the makes people interested binding ability for ribosome, ribosomal subunit or its fragment.
SPR method carrys out the interaction between the two or more macromole of the real time measure by producing quantum-mechanical surface plasma. A kind of device (BIAcoreBiosensorRTM, it is obtained from PharmaciaBiosensor, Piscataway, N.J.) provide heterogeneous light focused beam acts to the interface between gold film (providing with disposable biological sensor " dummy slider " form) and the surge chamber that can be regulated by user. Thick for 100nm " hydrogel " (being made up of carboxymethylated glucosan, it provides covalency to fix the substrate of the analyte making people interested) is affixed on gold film. When the free electron cloud of the light focused on gold film interacts, plasma resonance strengthens. The reflection light obtained sends in the wavelength of this resonance in the best and exhausts to light spectrality. By the polychromatic light of reflection being separated into its composition wavelength (by means of prism) and measuring the frequency exhausted, BIAcore forms optical interface, and it accurately reports the characteristic of the surface plasma resonance formed. When according to when being designed above, plasma resonance (with the spectrum thus exhausted) is to the mass-sensitive (it corresponds roughly to the thickness of hydrogel) in evanescent field. If interact to an ingredient be fixed in hydrogel, and by surge chamber provide interaction participant (partner), then can in evanescent field quality accumulation and by exhaust spectrometric it plasma resonance corresponding effect based on carry out the interaction between two ingredients of the real time measure. This system can quickly and delicately the real time measure intermolecular interaction, it is not necessary to any one component of labelling.
(2) fluorescence polarization
Fluorescence polarization (FP) is the determination techniques that can be readily used for protein-protein, protein ligand or RNA-ligand interaction, thus the IC of the association reaction obtained between two molecules50Value and Kd. In this technology, make a molecule and fluorophore conjugated that people is interested. This is usually less molecule in this system (in this case, be interested compound). The sample mixture containing ligand-probe conjugate and ribosome, ribosomal subunit or its fragment is excited with orthogonal polarized light. Light is absorbed by fluorescence probe group, and launches after the short time again. Measure the degree of polarization launching light. The polarization launching light depends on some factors, but most significantly depends on the viscosity of solution and the apparent molecular weight of fluorogen. Under suitable control, the degree of polarization change launching light is solely dependent upon the apparent molecular weight change of fluorogen, and next it depend on whether probe-ligand conjugate keeps free state in the solution or be combined with receptor. Binding tests based on FP has many important benefits, including: measure IC50 value and Kd when correct homogeneous equilibrium, analyze speed and suitable automatization and the ability shielded in cloudy suspension and color solution.
(3) albumen synthesis
Except being characterized by above-mentioned biochemical test, it is also possible to characterize compound interested with regulator (such as, the protein synthesis inhibitor) form of ribosome or the functional activity of ribosomal subunit.
In addition, more specific albumen synthesis inhibition test can be carried out as follows: give the ribosome preparation of whole organism, tissue, organ, organelle, cell, cell or subcellular fraction extract or purification, and by measuring the inhibition constant (IC of such as its suppression albumen synthesis50Value) observe its pharmacology and rejection. In order to study albumen synthesizing activity, it is possible to carry out3H leucine or35The merging of S methionine or similar experiment. Under the existence making molecule that people is interested, albumen synthesis quantity or speed in cell change, it was shown that this molecule is the regulator of albumen synthesis. If the speed of albumen synthesis or quantity reduce, it was shown that this molecule is protein synthesis inhibitor.
(4) anti-microbial test and other evaluation
Furthermore, it is possible to test antiproliferative or the infection performance of this compound under cellular level. Such as, if targeting organism is microorganism, then can by containing compound or cultivate this microorganism in there is no the culture medium of compound and test the activity of compound interested. Growth inhibited can represent that this molecule can serve as protein synthesis inhibitor. More specifically, the activity of compound bacteria resistance pathogen interested can suppress the growth of determined human pathogen bacterial strain to prove by this compound. For this purpose, it is possible to assemble strains (panel) so that it is including various targeting pathogenic species, some of them include the Resistance Mechanism characterized. The use of this organism group can measure structure-activity relation, not only considers usefulness and pedigree, and is conceived to avoid resistance mechanism.
According to TheClinicalandLaboratoryStandardsInstitute [CLSI; TheNationalCommitteeforClinicalLaboratoryStandards (NCCLS) originally] scheme listed, utilize micro-dilution process to measure minimum inhibitory concentration (MICs), final volume is 100 microlitre typically. Referring to CLSI: Methodsfordilutionantimicrobialsusceptibilitytestsforbac teriathatgrowaerobically; Standard-the five editions of approval. Wayne, PA: NCCLS; 2000. Conventional method disclosed in CLSI, it is also possible to carry out this test in microtiter plates. Referring to CLSI.MethodsforDilutionAntimicrobialSusceptibilityTestsf orBacteriaThatGrowAerobically; Standard-the seven editions of approval. CLSIDocumentM7-A7 [ISBN1-56238-587-9] CLSI, 940WestValleyRoad, Suite1400, WaynePennsylvania19087-1898USA, 2006).
Can in various internal mammals be tested, for instance, mice or rat peritoneum inflammation infection model, skin and soft tissue model (being commonly referred to a strand model) or murine pneumonia model, evaluate antimicrobial and other pharmaceutical properties of compound further. Also have septicemia well known by persons skilled in the art or organ infection's model. These effect models can serve as a part for evaluation methodology, and can serve as the guidance of potential effect in people. Terminal can be different to the reduction of fatality rate because of bacterial load. For the terminal of the latter, typically by PD50Value represents result, or represents with the drug dose protecting 50% animal to avoid death.
In order to evaluate class medicine (drug-like) performance of compound further, it is also possible to use recombinant people enzyme system or more complicated system (such as, people's hepatomicrosome) to measure cytochrome P 450 enzymes and the suppression of second phase metabolic enzyme activity.Further, it is also possible to evaluate compound with the matrix form of these metabolic enzymatic activitys. These activity can be effectively used for measuring compound and cause drug-drug interactions or form the potentiality of metabolite (it retains antimicrobial acivity or does not have useful antimicrobial acivity).
In order to evaluate the potentiality of compound oral bioavailability, it is also possible to carry out dissolubility and Caco-2 test. The latter is derived from the cell line of people's epithelium, uses it to measure ingestion of medicines and passing through through Caco-2 cell monolayer (generally cultivating in the hole equipped with 24 hole microwell plates of 1 micron membranes). Can measuring the free drug concentration on the Basolateral face of monolayer, assessment can pass the medication amount of intestinal monolayer. Require suitable control, in order to ensure the integrity of monolayer and the compactness of gap connection. Use this identical system, it is possible to evaluate the outflow of P-glycoprotein mediation. P-glycoprotein is in being formed the pump of the cell teleblem of polarized monolayer. This pump can eliminate the activity or Passive intake that stride across Caco-2 cell membrane, causes less medicine traverse enteric epithelium layer. These results are generally combined use with solubility test, and known the two factor can promote oral bioavailability rate in mammal. Use conventional medicine dynamic experiment, animal measures oral bioavailability rate, in people, finally measure oral bioavailability rate, thus measure absolute oral bioavailability rate.
Result of the test can be also used for setting up model, this model can aid forecasting to the contributive physical-chemical parameters of class pharmaceutical properties. When determining this model, it is possible to simplify experimental technique, increase the dependence to model prediction simultaneously.
5. preparation and administration
The compound of the present invention can be effectively used for prevention or treats various people or the disease of other animal (including mammal and nonmammalian), including, for instance, antibacterial infects, fungal infection, viral infection, diarrhoea, parasitic disease and cancer. Once confirm, it is contemplated that the bioactive molecule of the present invention can be incorporated in any suitable carrier before the use. Intended recipient and targeting organism are depended in the use of the dosage of bioactive molecule, mode of administration and suitable carrier. The preparation used according to for animals of the compounds of this invention and people's medical treatment typically comprises this compound and is combined with pharmaceutically suitable carrier.
In the compatibility with other component of preparation, carrier should be acceptable, and its receiver is safe from harm. In this respect, pharmaceutically suitable carrier include any and all solvent matched with administering mode, disperse medium, coating, antibacterium and antifungal, etc. blend absorption delay reagent etc. This medium and reagent for pharmaceutically active substances are known in the art. Any conventional media or reagent, unless they are incompatible with reactive compound, otherwise, they may be used in compositions. Auxiliary reactive compound (according to the present invention confirm or design, and/or reactive compound known in the art) can also be incorporated in compositions. Preparation can provide with dosage unit form suitably, and the well-known any method of pharmacy/microbiological art can be utilized to prepare. Generally, be made by some preparations: make compound and liquid-carrier or solid carrier in small, broken bits or in combination with, then, if it is necessary, making formed product is target formulation.
The pharmaceutical composition of the present invention should be prepared, so that it is with desired for administration approach fit. The example of route of administration includes being administered orally, ear, eyes, nose or parenteral, for instance, intravenous administration, intradermal administration, inhalation, transdermal administration (locally), transmucosal administration and rectally.Solution or suspensoid for parenteral, Intradermal or subcutaneous application can include following component: the solvent of aseptic diluent, for instance water for injection, saline solution, expressed oi, Polyethylene Glycol, glycerol, propylene glycol or other synthesis; Antibacterial, for instance benzyl alcohol or methyl parahydroxybenzoate; Antioxidant, for instance ascorbic acid or sodium sulfite; Chelating agen, for instance ethylenediaminetetraacetic acid; Buffer agent, for instance acetate, citrate or phosphate, and regulate the reagent of tension force, for instance sodium chloride or glucose. Acid or alkali can be used to regulate pH value, for instance with hydrochloric acid or sodium hydroxide.
The well-known any method of drug world can be utilized to prepare useful oral and parenteral administration solution, for instance, the method in following is described: Remington'sPharmaceuticalSciences, (Gennaro, A., ed.), MackPub., (1990). The preparation of parenteral could be included for the glycocholate of buccal administration, the methoxysalicylate for rectally or the citric acid for vagina administration. Parenteral administration can be loaded in bottle, disposable syringe or the multidose phial being made up of glass or plastics. Suppository for rectally can also be made by: by medicine and non-irritating excipient (such as cocoa butter, other glyceride, or other compositions, they are at room temperature solids, are liquid under body temperature) mixing. Preparation can also include, for instance, polyglycols, for instance Polyethylene Glycol, vegetable oil and hydrogenated naphthalene. Preparation for being directly administered can include glycerol and other full-bodied compositions. Parenteral vehicles for other potentially useful of these medicines includes ethylene-vinyl acetate copolymer granule, osmotic pumps, implantable infusion system and liposome. Preparation for inhalation can include such as lactose (as excipient), it can be maybe the aqueous solution containing such as laureth9, glycocholate and dexycholate, or the oil solution with the administration of nasal drop form, or the gel that intranasal uses. Enema,retention can be also used for rectal delivery.
The invention formulation being suitable for oral administration can be following form: discrete unit, for instance capsule, gelatine capsule, pouch, tablet, lozenge or lozenge, each the medicine containing predetermined quantity; Powder or particulate composition; Solution in liquid, aqueous or on-aqueous liquid or suspensoid; Or oil in water emulsion or water in oil emulsion. Medicine can also be given injecting (bolus), unguentum or paste form. Tablet can be prepared by suppressing together with one or more auxiliary agent or mould medicine. Compressed tablet can be made by: in suitable machinery, is extruded by the medicine (such as powder or granule) of free-flowing form, optional and binding agent, lubricant, inert diluent, surfactant or dispersant. Molded tablet can be made by: in suitable mechanical, by the mixture of the powdered drug moistening by inert liquid diluent and suitable carrier molding.
Orally administered composition generally comprises inert diluent or edible carrier. Oral disposition therapeutic administratp, reactive compound can be combined with excipient. Using the Orally administered composition (as mouthwash) prepared of liquid-carrier to include compound in a liquid carrier, orally use, rustle (swished), and expectoration or swallow. The binding agent of compatible pharmaceutical and/or the adjuvant substance part as compositions can be comprised.Tablet, pill, capsule, lozenge etc. can comprise the compound of any following component or similarity: binding agent, for instance microcrystalline Cellulose, gum tragacanth or gelatin; Excipient, for instance starch or lactose, disintegrating agent, for instance alginic acid, Primogel or corn starch; Lubricant, for instance magnesium stearate or Sterotes; Fluidizer, for instance silica sol; Sweeting agent, for instance sucrose or saccharin; Or flavoring agent, for instance Mentha arvensis L. syn.M.haplocalyxBrig (peppermint), methyl salicylate or orange flavor.
The pharmaceutical composition being suitable for injection use includes aseptic aqueous solution (water miscible) or dispersion and sterile powder (extemporaneous preparation of aseptic injectable solution agent or dispersion). For intravenous administration, suitable carrier includes normal saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS) (PBS). Producing with under preservation condition, it should be stable, and should preserve when the contamination of antimicrobial such as antibacterial and fungus. Carrier can be solvent or disperse medium, including, for instance water, ethanol, polyhydric alcohol (such as, glycerol, propylene glycol and liquid macrogol, etc.) and its suitable mixture. By utilizing coating (such as lecithin), in the case of a dispersion, by keeping the particle diameter of required dispersion, by utilizing surfactant, it is possible to keep suitable mobility. In many cases it is preferred to comprise isotonic reagent in the composition, for instance, sugar, polyhydric alcohol, for instance mannitol, Sorbitol, or sodium chloride. By comprising the reagent of delayed absorption in the composition, for instance, aluminum monostearate and gelatin, it is possible to make injectable composition extend and absorb.
Aseptic injectable solution agent can be made by: in a suitable solvent, the compositions of the reactive compound of requirement with above-named a kind of component or component is combined, and is then filtered sterilizing as required. Generally, preparing dispersion by being attached to by reactive compound in sterile excipient, sterile excipient comprises basic dispersion medium and above-named other required component. When being used for the sterile powder preparing aseptic injectable solution agent, preparation method includes vacuum drying and lyophilizing, obtains the active component powder plus any additional object component (being obtained from previous sterilefiltered solutions).
The preparation being suitable for intra-articular administration can be the sterile aqueous form of medicine, and medicine can be microcrystalline form, for instance, moisture microcrystalline suspension form. Liposomal formulation or biodegradable polymer system also may be used to provide medicine to intraarticular and eyes.
The preparation (including eye therapy) being suitable for topical includes liquid or semi-liquid preparations, for instance, liniment, lotion, gel, application (applicants), oil-in-water or water in oil emulsion, for instance ointment, ointment or paste; Or solution or suspensoid, for instance drop. The preparation administering locally to skin surface can be made by: is disperseed together with Dermatology acceptable carrier by medicine, for instance lotion, ointment, ointment or soap. In order to position application and suppress to depart from, it is particularly useful that the carrier of film or layer can be formed on skin. In order to administer locally to internal tissue surfaces, medicament can be dispersed in liquid tissue adhesive, or known enhancing is in other material of tissue surface adsorptivity.Such as, in order to favorably, it is possible to use hydroxypropyl cellulose or Fibrinogen/thrombin solution. Or, it is possible to use tissue-coating solution, for instance, containing the preparation of pectin.
For anapnotherapy, it is possible to use the powder inhalation (self-propelled preparation or spray agent) of aerosol apparatus, nebulizer or ejector distribution. This preparation could be for the fine powder form stemming from powder inhalation device of pulmonary administration or self-propelled powder-dispensing formulations. When self-propelled solution and spray agent, there is the valve of target spray characteristic (namely by selecting, the spray with target grain size can be produced) or by combining the active component of the suspended powder form controlling particle diameter, it is possible to obtain effect. For inhalation, it is also possible to deliver compound with aerosol injection form from the pressure vessel comprising proper emission agent (such as, gas, for instance carbon dioxide) or allotter or nebulizer.
It is administered systemically and can also utilize mucosa or transdermal methods. For saturating mucosa or transdermal administration, use is suitable for the penetrating agent of the barrier to penetrate in the formulation. This penetrating agent is commonly known in this area, for transmucosal administration, including, for instance, detersive and cholate. Transmucosal administration can be sprayed into by use nose or suppository completes. For transdermal administration, reactive compound is typically formulated as ointment commonly known in the art, ointment, gel or ointment.
Can be prevented from compound quickly from health discharge carrier prepare reactive compound, for instance controlled release preparation, including implant and micro-encapsulated delivery system. Polymer biodegradable, biocompatible can be used, for instance ethane-acetic acid ethyenyl ester, polyanhydride, polyglycolic acid, collagen, poe and polylactic acid. The method preparing this preparation it will be apparent to those skilled in the art that. Liposome suspension is also used as pharmaceutically suitable carrier. These can be prepared according to method known to those skilled in the art, for instance, the method described in US Patent No. 4,522,811.
In order to easily be administered the uniformity with dosage, it is possible to the oral or parenteral compositions of preparation dosage unit form. Dosage unit form refers to the physical dispersion unit of the suitable unit dose as treated patient; Reactive compound that each unit contains predetermined quantity, that be computed being suitable to generation objective response, and be combined with required pharmaceutical carrier. The standard of the dosage unit form of the present invention is determined by the restriction (and directly depending on them) that the reactive compound field that this treatment of the specific characteristic of reactive compound and the concrete therapeutic effect to reach and preparation is individual is intrinsic. Furthermore, it is possible to be administered by injecting the periodic injections of (bolus), outside reservoir (such as, the bag of intravenous) maybe can be used to be continued medication by intravenous, intramuscular or Intraperitoneal medication.
If requiring to adhere on tissue surface, compositions can include the medicine being dispersed in fibrinogen-thrombin compositions or other bioadhesive polymer. It is then possible to compound is coated with, sprays or be applied on target tissue surface. Or, it is possible to compounding pharmaceutical, for ear, eyes, nose, parenteral or be orally administered to people or other mammal, such as, give therapeutically effective amount, for instance, it is possible to provide suitable concn medicine thus causing the quantity of target effect to target tissue within a period of time.
If reactive compound is used as a part for implantation method, it is possible to before remove tissue or organ from donor, provide this reactive compound for the living tissue to transplant or organ.This compound can be supplied to donor host. Or, or additionally, once organ or living tissue remove from donor, it is possible to organ or living tissue are placed in the preservation solution containing this reactive compound. For all situations, use any method and formulation described herein and/or known in the art, destination organization can be directly given by this reactive compound, can to this reactive compound of tissue injection or this reactive compound can systematically be provided, such as, by ear, eyes, nose, oral and parenteral administration method. If medicine includes part tissue or organ preserves (preservation) solution, it can be advantageous to use any commercially available preservation solution. Such as, useful solution known in the art includes Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and Lactated Ringer's solution.
Medical treatment device is used the compounds of this invention, this device and contact tissue, thus compound directly can be given to tissue site. The example of medical treatment device is support, and it contains or is coated with the compound of one or more present invention.
For example, it is possible to reactive compound is applied on the support of vascular lesions sites. Support can be prepared by the well-known any method of pharmaceutical field. Referring to, for instance, Fattori, R. and Piva, T., " DrugElutingStentsinVascularIntervention, " Lancet, 2003,361,247-249; Morice, M.C., " ANewEraintheTreatmentofCoronaryDisease " EuropeanHeartJournal, 2003,24,209-211; And Toutouzas, K. et al., " Sirolimus-ElutingStents:AReviewofExperimentalandClinical Findings, " Z.Kardiol., 2002,91 (3), 49-57. With rustless steel or other biocompatible intermetallic composite coating support, maybe can make with biocompatible polymer. Reactive compound can be combined with rack surface, in the polymeric material that to be embedded on support coated, and discharge from which, or the carrier being coated or covering support is wrapped up, and by its release. Support can be used for giving the single or multiple reactive compound of tissue near this support.
Method described herein can be confirmed or the reactive compound of design gives individuality, in order to treatment disease (prevention or treatment). Combine with this treatment, it may be considered that pharmacogenomics (that is, the research to the relation between foreign compound or medicine response in individual genotype and individuality). By the ratio between dosage and the blood drug level of change active pharmacological agent, the metabolism difference for the treatment of can cause serious toxicity or Endodontic failure. Thus, doctor or clinicist can be used in the knowledge that obtains in relevant pharmacogenomics research, it is determined whether give dosage and/or the therapeutic scheme of medicine and this Drug therapy of design.
In treating or resist the application that mammiferous antibacterial infects, can passing through ear, eye, nose, oral, parenteral and/or administer locally to compound or its pharmaceutical composition, the dosage given should obtain and keep the active component concentration (quantity) of antimicrobial effectiveness or blood level or the level of organizing in carrying out the animal treated. Generally, the effective dose of active component is in the scope of about 0.1 to about 100mg/kg body weight/day, and more preferably about 1.0 to about 50mg/kg body weight/day.Administration quantity is possibly also on following variables: such as, the disease treated or the type of indication and degree, the general health of concrete patient, the Relative biological effect of the compound delivered, the preparation of medicine, the excipient existed in preparation and type, and route of administration. Being also to be understood that to obtain target blood level or tissue level rapidly, initial dosages can exceed above-mentioned higher level, or predose less than optimal dose, and during treating, can gradually step up daily dose as the case may be. If necessary, daily dose may be divided into multiple dosage, for instance, twice daily to four times.
In people and other mammal, it has been found that various morbid states or disease are suddenlyd change caused by nonsense mutation or ambiguity or mediated by them. these sudden changes cause by negatively affecting such as albumen synthesis, folding, transport and/or function or mediated disease state or disease. think and suddenlyd change, by nonsense or ambiguity, the disease caused or the example of morbid state or disease that disease accounts for obvious percentage ratio includes: hemophilia (factor �� gene), neurofibroma (NF1 and NF2 gene), retinitis pigmentosa (people's USH2A gene), bullous dermatoses, such as prurigo sample epidermolysis bullosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCA1 and BRCA2 gene), duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair gene, main in MLH1 and MSH2) and lysosomal storage disease, such as Neimann-Pick disease (ASM gene). referring to SandersCR, MyersJK.Disease-relatedmisassemblyofmembraneproteins.Ann uRevBiophysBiomolStruct.2004, 33:25-51, NationalCenterforBiotechnologyInformation (U.S.)GenesanddiseaseBethesda,MD:NCBI,NLMID:101138560; With Rask ��, Istv �� n; Downes, CSGenes inmedicine:molecularbiologyandhumangeneticdisorders1sted.London;NewYork:Chapman&Hall,1995.NLMID:9502404. The compound of the present invention can be used for treating or prevent the mammiferous morbid state being caused by this nonsense or ambiguity sudden change or being mediated, this treatment or prevention need the compound of the present invention of its mammal effective dose, thus suppressing to relate to this nonsense of morbid state or ambiguity sudden change.
6. embodiment
BrukerAvance300 or Avance500 spectrogrph obtains nuclear magnetic resonance, NMR (NMR) spectrum, or uses GE-Nicolet300 spectrogrph in some cases. Popular response solvent is high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, obtains from manufacturer with anhydrous form, unless otherwise mentioned. " chromatograph " or " silica gel purification " refers to the flash column chromatography using silica gel (EMMerck, SilicaGel60,230-400 order), unless otherwise mentioned.
The known chemical conversion of concrete condition being suitable for inquiring into can be used to prepare the compound of the present invention.
Some the abbreviation definition used in the experimental detail of embodiment synthesis below are as follows: h or hr=hour; Min=minute; Mol=mole; Mmol=mM; M=molar concentration; ��M=micro-molar concentration; G=gram; Mg=microgram; Rt=room temperature; L=liter; ML=milliliter; Et2O=diethyl ether; THF=oxolane; DMSO=dimethyl sulfoxide; EtOAc=ethyl acetate; Et3N=triethylamine; I-Pr2NEt or DIPEA=diisopropylethylamine; CH2Cl2=dichloromethane; CHCl3=chloroform;CDCl3=Deuterated chloroform; CCl4=carbon tetrachloride; MeOH=methanol; CD3OD=deuterated methanol; EtOH=ethanol; DMF=dimethylformamide; BOC=tertbutyloxycarbonyl; CBZ=benzyloxycarbonyl group; TBS=t-butyldimethylsilyl; TBSCl=tert-butyldimethylsilyl chloride; TFA=trifluoroacetic acid; DBU=diazabicylo endecatylene; TBDPSCl=tert-butyl diphenyl chlorosilane; Hunig's alkali=N, N-diisopropylethylamine; DMAP=4-dimethyl aminopyridine; CuI=Copper diiodide (I); MsCl=mesyl chloride; NaN3=Hydrazoic acid,sodium salt; Na2SO4=sodium sulfate; NaHCO3=sodium bicarbonate; NaOH=sodium hydroxide; MgSO4=magnesium sulfate; K2CO3=potassium carbonate; KOH=potassium hydroxide; NH4OH=ammonium hydroxide; NH4Cl=ammonium chloride; SiO2=silicon dioxide; Pd-C=palladium/carbon; Pd (dppf) Cl2=dichloro [1,1'-bis-(diphenylphosphino) ferrocene] palladium (II).
It is listed in table 1 according to the illustrative compounds of present invention synthesis. Runic or empty key table show the specific spatial chemistry of chiral centre, and corrugated key specifies substituent group can be any one orientation or this compound is its mixture. Will also be appreciated that to save space, the chemical constitution of some compounds is divided into two parts, and the key table that two each free wavy lines of junction point intersect shows. Referring to, for instance compound 1345, it is classified as two parts and draws:
But corresponding with following complete chemical constitution:
��
Can prepare, prepare and deliver the compound of the present invention with salt, ester and prodrug form. For convenience, concrete salt, ester or prodrug form are not indicated when generally showing compound.
The compound of the present invention is shown in Table 1. If appropriate, it is provided that LCMS (liquid chromatography mass) data. When there is no data, " NA " represent. LCMS data use conventional m/z, with [M+H]+Form provide, except situation about showing in another manner.
Table 1
In further embodiment, the compound of the present invention does not include the compound with having structure:��
Use synthesising chemical technology well known to those skilled in the art, it is possible to the compound of the preparation present invention.
The synthesis of embodiment 1-iso-cytosine
[4-(2-amino-4-oxo-1,4-dilzydro-pyrimidine-5-base)-benzyl]-(3-t-butoxycarbonyl amino-propyl group)-carbamate:
Guanidine carbonate (278mg, 3.30mmol) and Feldalat NM (in methanol (0.5M, 6.6mL, 3.3mmol)) it is separately added in EtOH (12mL) solution of acrylate (1.43g, 3.00mmol). This mixture is heated to 90 DEG C, and stirs overnight. This reactant mixture is cooled to room temperature, leaches the solid of formation, and filtrate is concentrated. Use purification by flash chromatography crude product, use 0-20%2NNH3/MeOH:CH2Cl2Gradient solvent system, obtain target product white solid (1.95mmol, 65%). [M+23]=496.2.
3-[tertbutyloxycarbonyl-4-{4-oxo-2-[3-(2-trifluoromethoxy-phenyl)-urea groups]-1,4-dilzydro-pyrimidine-5-base }-benzyl)-amino]-propyl group }-carbamate:
To iso-cytosine derivant (0.913g, dimethylformamide (10mL) solution 1.93mmol) adds 2-(trifluoromethoxy) phenyl isocyanate (0.30mL, 2.2mmol), and by this reaction at room temperature stir two hours. Concentrate this reactant mixture. Use purification by flash chromatography crude product, use 0-20%2NNH3/MeOH:CH2Cl2Gradient solvent system, separate targets product as white solid (1.60mmol, 83%).[M+1]=577.1.
1-(5-{4-[(3-Amino-propylamino)-methyl]-phenyl }-4-oxo-1,4-dilzydro-pyrimidine-2-base)-3-(2-trifluoromethoxy-phenyl)-urea:
Urea derivative (1.07g, 1.58mmol) is suspended in dichloromethane (50mL), and is added thereto to trifluoroacetic acid (20mL). This reaction is at room temperature stirred one hour. Evaporating volatile matter, the product of separation is limpid oil (1.32gxTFA salt). [M+1]=477.1.
Guanidine derivatives:
To unhindered amina (1) (0.661g, dimethylformamide (10mL) solution 0.811mmol) is separately added into triethylamine (0.901mL, 6.45mmol) and N, double; two (benzyloxycarbonyl group)-1H-pyrazoles-1-carbonamidine (2) of N'-, and this reaction is at room temperature stirred overnight. In this mixture, add two dimethyl dicarbonate butyl esters (0.201g, 0.921mmol), water (5mL) and oxolane (5mL), and at room temperature stir 2 hours. By the dilution in EtOAc (100mL) of this reactant mixture, wash with saturated brine (2x50mL), and organic layer is dried (MgSO4), filter, concentration. Use purification by flash chromatography crude product, use 0-7%2NNH3/MeOH:CH2Cl2Gradient solvent system, separate targets product (3) limpid oil (0.35mmol, 43%). [M+1]=719.3.
Final analog:
By guanidine analog (3) (0.291g, 0.351mmol) at CH2Cl2(10mL) in, dilution, is added thereto to trifluoroacetic acid (3mL), and this reaction is at room temperature stirred one hour. Evaporate volatile matter, crude product is dissolved in water (10mL) and 1.0NHCl (5mL), then concentrates. Residue is re-dissolved in water (10mL), filters, then freezing and lyophilizing, the HCl salt (4) (0.184g) of separate targets product. [M+1]=519.1;1HNMR(D20):��7.80-7.77(m,2H),7.60(s,1H),7.40-7.13(m,4H),7.09(m,2H),6.94(s,1H),4.08(s,2H),3.18-3.14(m,2H),3.03-3.01(m,2H),1.92-1.82(m,2H).
Embodiment 2-antimicrobial acivity
The antimicrobial acivity of inspection the compounds of this invention. These data are provided in table 2. Operate this compound for coli strain ATCC25922, use the micro-dilution test of standard, measure minimum inhibitory concentration (MICs). Data are provided, wherein "+" representing that this compound has the MIC value of 16 micrograms/ml or less, "-" represents that this compound has the MIC value more than 16 micrograms/ml. " N/A " refers to and cannot obtain data. Those skilled in the art are able to recognize that, it is possible to evaluate compound for other bacterial organism, and the data for colibacillary activity provided are illustrative data, are not intended to limit the scope. According to the usefulness activity that hope is collected, it is possible to the compound of the present invention is resisted other microorganism a large amount of and is measured. Additionally, "+", "-" and " N/A " statement and the boundary value of 16 micrograms/ml selected also be illustrative, be not intended to restriction the scope of the present invention. Such as, "-" does not indicate that compound does not necessarily have activity or an application, but its for the MIC value of prescribed microorganism more than 16 micrograms/ml.
Table 2
In conjunction with list of references
For all purposes, the complete disclosure of each patent documentation mentioned above and scientific paper is incorporated herein in the way of quoting as proof.
Equivalent
Without departing from the spirit or essential characteristics of the present invention, it is possible to express the present invention in other specific forms. It is intended, therefore, that the embodiment above is all illustrative embodiment in every respect, rather than restriction invention as described herein. Thus, the scope of the present invention is shown by appended claims, rather than is shown by description above, and all changes in the implication of equivalent and scope of claim all include wherein.

Claims (26)

1. there is the compound of following formula:
Wherein Z is selected from S (O)n, NR4CO and NR4CONR4, wherein R4Selected from hydrogen and C1-8Alkyl, and n is 0,1 or 2;
Or, wherein-G-H-J is
Wherein each H and J selects independently,
C-B-A-,-D-E-F and-G-H-J are chemical groups, wherein
A is selected from:
(b)-(C1-8Alkyl)-, (c)-(C2-8Thiazolinyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6-, (g)-S (O)p-, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)-OC (O) O-, (m)-NR6CO-, (n)-NR6C(O)NR6-, (o)-C (=NR6)-, (p)-C (=NR6) O-, (q)-OC (=NR6)-, (r)-C (=NR6)NR6-, (s)-NR6C (=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6-, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)-NR6(CNR6)NR6-, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t-, (dd), containing one or more heteroatomic 6,7,8,9,10,11 or 12 yuan of saturated, unsaturated or aromatic heterocycles, hetero atom is selected from nitrogen, oxygen and sulfur,
(ee) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(ff)-(CR6R6)t-,
Wherein (dd) or (ee) is optionally by one or more R5Group replaces;
G is selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Thiazolinyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6-, (g)-S (O)p-, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)-OC (O) O-, (l)-C (O) NR6-, (m)-NR6CO-, (n)-NR6C(O)NR6-, (o)-C (=NR6)-, (p)-C (=NR6) O-, (q)-OC (=NR6)-, (r)-C (=NR6)NR6-, (s)-NR6C (=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6-, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)-NR6(CNR6)NR6-, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t-, (dd) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur,
(ee) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(ff)-(CR6R6)t-,
Wherein (dd) or (ee) is optionally by one or more R5Group replaces;
D is selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Thiazolinyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6-, (g)-S (O)p-, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)-OC (O) O-, (l)-C (O) NR6-, (m)-NR6CO-, (n)-NR6C(O)NR6-, (o)-C (=NR6)-, (p)-C (=NR6) O-, (q)-OC (=NR6)-, (r)-C (=NR6)NR6-, (s)-NR6C (=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6-, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)-NR6(CNR6)NR6-, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t-;
B is selected from:
B () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
C () 3-14 unit is saturated, unsaturated or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group replaces;
(d)-(C2-8Alkyl)-, (e)-(C2-8Thiazolinyl)-, (f)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-C (=NR6)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t-,
H is selected from:
(a) singly-bound,
B () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
C () 3-14 unit is saturated, unsaturated or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group replaces;
(d)-(C1-8Alkyl)-, (e)-(C2-8Thiazolinyl)-, (f)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-(C=O)-,-C (=NR6)-,-S (O)pNR6-,-NR6S(O)p-and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t-,
C and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3(j)-NO2, (k)-NR6(CR6R6)tR8, (l)-OR8, (m)-S (O)p(CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (o)-OC (O) (CR6R6)tR8, (p)-SC (O) (CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (r)-NR6C(O)(CR6R6)tR8, (s)-C (O) NR6(CR6R6)tR8, (t)-C (=NR6)(CR6R6)tR8, (u)-C (=NNR6R6)(CR6R6)tR8, (v)-C (=NNR6C(O)R6)(CR6R6)tR8, (w)-C (=NOR8)(CR6R6)tR8, (x)-NR6C(O)O(CR6R6)tR8, (y)-OC (O) NR6(CR6R6)tR8, (z)-NR6C(O)NR6(CR6R6)tR8, (aa)-NR6S(O)p(CR6R6)tR8, (bb)-S (O)pNR6(CR6R6)tR8, (cc)-NR6S(O)pNR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH3, (ii)-S (O)pR8, (jj)-NC (O) R8, (kk)-NR6C(NR6)NR6R8, (ll) C1-8Alkyl, (mm) C2-8Thiazolinyl, (nn) C2-8Alkynyl, (oo) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, and hetero atom is selected from nitrogen, oxygen and sulfur, and (pp) 3-14 unit is saturated, unsaturated or aromatic carbocyclic, (qq)-(CR6R6)tNR6(CR6R6)tR8, (rr)-N [(CR6R6)tR8] [C=O (CR6R6)tR8], (ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8], (tt)-(CR6R6)tNR6(C=O) (CR6R6)tR8, (uu)-haloalkyl, (vv)-C (O) (CR6)[(CR6R6)tR8]R8, (ww)-(CR6R6)tC(O)NR8R8, (xx)-(CR6R6)tC(O)O(CR6R6)tR8, (yy)-NR6C(O)CR8R8R8, (zz)-N [(CR6R6)tR8]C(O)R8(aaa)-S (O)pNR8R8;
Wherein (ll) to (pp) is optionally by one or more R7Group replaces;
R5It is selected from: (a) oxygen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;Or, two R5Group combines, and forms carbocyclic ring,
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Replace;
R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;
Wherein (b) to (e) is optionally by one or more R8Replace;
R7It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (y)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (z)-(CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6, (cc)-NR6C(O)R6(dd)-C (=NR6)NR6R6;
Wherein (m) to (q) and (x) to (y) is optionally by one or more R9Replace;
R8It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R9, (k)-OR9, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), r () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, s ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (t)-haloalkyl, (u)-C (O) (CR6R6)tR9, (v)-SR6, (w)-OC (O) (CR6R6)tR9, (x)-NR6C(O)NR6R9, (y)-NR6C(O)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6)NR6R6, (bb)-C (=NR9)NR6R6, (cc)-S (O)pR9, (dd)-(CR6R6)tC(O)NR6R9, (ee)-(CR6R6)tOR9(ff)-(CR6R6)tNR6R9;
Wherein (m) to (s) is optionally by one or more R9Replace;
E is singly-bound;
F is hydrogen or halogen;
R9It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R10;
Wherein (n) to (r) and (z) to (aa) is optionally by one or more R10Replace;
R10It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)-C1-8Thiazolinyl, (p)-C1-8Alkynyl, q () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, r ()-3-14 unit is saturated, unsaturated or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd)-ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R6;
P is 0,1 or 2, and
T is 1,2 or 3,
Or its officinal salt or tautomer.
2. according to the compound of claim 1:
Wherein Z is selected from-NR4CO-and-NR4CONR4-; Or its officinal salt or tautomer.
3., according to the compound of claim 2, wherein Z is-NR4CONR4-; Or its officinal salt or tautomer.
4. according to the compound of claim 3,
Wherein Z is-NHCONH-; Or its officinal salt or tautomer.
5. according to the compound of claim 4, wherein
A is selected from
A (), containing one or more heteroatomic 6,7,8,9,10,11 or 12 yuan of saturated, unsaturated or aromatic heterocycles, hetero atom is selected from nitrogen, oxygen and sulfur, and
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic,
Wherein (a) or (b) is optionally by one or more R5Group replaces;
B is selected from: (a)-(C2-8Alkyl)-, (b)-(C2-8Thiazolinyl)-, and (c)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-C (=NR6)-,-S (O)pNR6-and-NR6S(O)pNR6-,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group replaces, and
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-C8Alkyl)-R5Group replaces, and
C is selected from: (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen;
Or its officinal salt or tautomer.
6. according to the compound of claim 5, wherein
A is selected from: azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, tetrahydro pyridyl, and piperidyl;
Any one of the A wherein just mentioned above is optionally by one or more R5Group replaces;
B is: (a)-(C2-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally selected from following group replacement :-O-,-S (O)p-,-NR6-,-S (O)pNR6-and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group replaces, and
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group replaces; Further,
C is selected from: (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen;
Or its officinal salt or tautomer.
7., according to the compound of claim 6, wherein C-B-A-is selected from:
Or its officinal salt or tautomer.
8., according to the compound of claim 4, wherein G is selected from:
A () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic 3-14 units, hetero atom is selected from nitrogen, oxygen and sulfur,
B () 3-14 unit is saturated, unsaturated or aromatic carbocyclic, and
(c) singly-bound;
Wherein (a) or (b) is optionally by one or more R5Group replaces,
Or its officinal salt or tautomer.
9. according to the compound of claim 5, wherein R5It is selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i)-NO2, (j)-NH2, (k)-OR6, (l)-NHC (=NH) NH2, (m)-C1-8Alkyl, (n)-C1-8Thiazolinyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more heteroatomic 3-14 units selected from nitrogen, oxygen and sulfur saturated, unsaturated or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 unit saturated, unsaturated or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, and (u)-3-14 unit is saturated, unsaturated or aromatic carbocyclic;Or, two R5Group combines, and forms carbocyclic ring or its officinal salt or tautomer.
10. according to the compound of claim 5, wherein R6It is selected from: (a) hydrogen, (b)-C1-8Alkyl, or, it is alternatively that, two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, d () be saturated, unsaturated or aromatic heterocycle containing one or more heteroatomic-3-14 units selected from nitrogen, oxygen and sulfur, (e)-3-14 unit is saturated, unsaturated or aromatic carbocyclic, or its officinal salt or tautomer.
11. according to the compound of claim 8, wherein G is selected from: azepan base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl and singly-bound; Or its officinal salt or tautomer.
12. according to the compound of claim 11, wherein-G-H-J is selected from: hydrogen,
Or its officinal salt or tautomer.
13. according to the compound of claim 12, wherein each-G-H-J is selected from:
Hydrogen,
Wherein R5As defined in claim 10,
Or its officinal salt or tautomer.
14. the compound of any one according to claim 1 to 13, it is combined with ribosome.
15. according to the compound of claim 14, wherein ribosome is bacterial ribosome.
16. compound, it is selected from
Or its officinal salt or tautomer.
17. pharmaceutical composition, comprise the compound or pharmaceutically acceptable salt thereof of any one according to claim 1-16 or tautomer and pharmaceutically suitable carrier.
18. the compound or pharmaceutically acceptable salt thereof of any one according to claim 1-16 of therapeutically effective amount or tautomer purposes in preparing medicine, this medicine infects for the microorganism treating, preventing human or animal or reduces its danger.
19. the compound or pharmaceutically acceptable salt thereof of any one according to claim 1-16 of therapeutically effective amount or tautomer purposes in preparing medicine, this medicine infects for the microorganism treating, preventing human or animal or reduces its danger, and wherein microorganism is infected and is selected from:
Skin infection, Gram positive infections, Gram-negative infects, Nosocomial Pneumonia, community acquired pneumonia, pneumonia after viral infection, Nosocomial Pneumonia/Ventilator Associated Pneumonia, respiratory tract infection, acute pelvic infects, concurrent skin and skin structure infection, Skin and soft tissue infection (SSTI), abdominal infection, infect in concurrent abdomen, urinary tract infection, bacteremia, septicemia, endocarditis, chamber shunt infection, contacts blood sexuality contaminates, meningitis, surgical prophylaxis, peritoneal infection, infection of bone, the infection of joint, the S. aureus infection of methicillin-resistant, the enterococcus of anti-vancocin infects, the organism of anti-Linezolid (linezolid) infects, infection due to Bacillus anthracis, soil draws hot Francisella to infect, Yersinia pestis infection and pulmonary tuberculosis.
20. according to the purposes of claim 18 or 19, wherein said medicine is formulated as and is given by ear, eye, nose, oral, parenteral, local or intravenous.
21. according to the purposes of claim 19, wherein said skin infection is hospital's skin infection.
22. according to the purposes of claim 19, wherein said respiratory tract infection is chronic respiratory tract infection (CRTI).
23. according to the purposes of claim 19, wherein said Skin and soft tissue infection (SSTI) is not concurrent Skin and soft tissue infection (uSSTI) or concurrent Skin and soft tissue infection.
24. according to the synthetic method of the compound or pharmaceutically acceptable salt thereof of any one of claim 1-16 or tautomer, wherein-D-E-F is hydrogen, and Z is NH-CO.
25. contain the compound or pharmaceutically acceptable salt thereof of any one according to claim 1-16 or the medical treatment device of tautomer.
26. according to the medical treatment device of claim 25, wherein this device is support.
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