CN105218427A - Contain two amidine analog derivatives of two amidino groups indoles benzene and its preparation method and application - Google Patents
Contain two amidine analog derivatives of two amidino groups indoles benzene and its preparation method and application Download PDFInfo
- Publication number
- CN105218427A CN105218427A CN201410310157.4A CN201410310157A CN105218427A CN 105218427 A CN105218427 A CN 105218427A CN 201410310157 A CN201410310157 A CN 201410310157A CN 105218427 A CN105218427 A CN 105218427A
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- CN
- China
- Prior art keywords
- indoles
- benzene
- base
- amidino groups
- nitrae
- Prior art date
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 229940126136 compound 5i Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- 229960003263 cyclopentamine Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006101 laboratory sample Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- JBLLRCOZJMVOAE-HSQYWUDLSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1h-indole-2-carboxamide Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)C=1NC=2C=CC=C(C=2C=1)OC)C(=O)C=1SC2=CC=CC=C2N=1)[C@@H]1CCNC1=O JBLLRCOZJMVOAE-HSQYWUDLSA-N 0.000 description 1
- YKQOSKADJPQZHB-RGYSVOEGSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(6r,9s,12r,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydr Chemical compound CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)C([C@@H](C)O)NC(=O)[C@@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O YKQOSKADJPQZHB-RGYSVOEGSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a kind of two amidine analog derivatives containing two amidino groups indoles benzene and its preparation method and application.This two amidines analog derivative has the structure of following formula [1], R
1and R
2independently selected from the C being substituted or being unsubstituted
1-12straight chained alkyl, C
3-12branched-chain alkyl or C
3-12cycloalkyl; Or R
1and R
2the 3-6 ring being substituted or being unsubstituted is formed with the N being connected them; R
3independently selected from hydrogen, halogen, low-grade halogenated alkyl, lower alkoxy, amino or rudimentary substituted amido.Two amidine analog derivative and the pharmacologically acceptable salts thereof containing two amidino groups indoles benzene provided by the invention, have the activity of antimicrobial agent, especially have the activity of strong resisting gram-positive and negative resistant organism.
Description
Technical field
The invention belongs to medical art, relate to a class and contain two amidine analog derivatives of two amidino groups indoles benzene and its preparation method and application.
Background technology
In recent years, because the unreasonable use of antibacterials and multi-drug resistant bacteria are in the increase of hospital inner propagation, make bacterial resistance sexual development rapid, infect with community cultule by the microbial hospitals of resistance such as methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), multidrug resistant Acinetobacter bauamnnii (MDR-AB) and multidrug resistant tubercule bacillus (MDRMT), the health and lives safety of patient and resident in serious threat.To antimicrobial agent, particularly resist multidrug resistant Gram-negative bacteria become 21 century world-wide medical circle common faced by one of the biggest problem.The discovery speed of novel antibacterials is correspondingly far from catching up with the tempo of resistant organism, and within nearly 20 years, the listing new drug for Gram-positive resistant organism only has two kinds-daptomycin and linezolid, and the medicine not for multidrug resistant gram-negative bacteria goes on the market.The clinical drug combination to multidrug resistant negative microbial infections many employings Multiple Classes of Antibiotics is treated, and this can bring the danger of crossing drug resistant undoubtedly.
NDM-1 is a kind of super drug resistance gene, current part Gram-negative resistant organism is with this drug resistance gene, this gene encodes synthesizes a kind of enzyme, make all beta-Lactam antibiotics almost lose effect completely, comprise carbapenem antibiotics meropenem and the imipenum of latest generation.Now, except Tigecycline and Totazina, this bacterium with NDM-1 gene pasts medical help, and with it some patients, even also occurs the bacterial strain to these two kinds of medicine resistances.In addition, research finds, the gene of coding NDM-1 enzyme does not exist only in the genome of bacterium nucleoid, also appear at (a kind of cyclic DNA easily occurring to exchange between bacterium) on the plasmid of bacterium, this makes this gene to propagate between different strains easily, the transferability of this drug resistant gene makes to obtain resistance to the bacterium of antibiotic sensitive, if superpose with other resistance, will greatly increase the difficulty of antibacterial therapy.More alarming is be with the bacterium of NDM-1 gene extensively to exist in community environment.And along with abuse of antibiotics, Fast-propagation goes out super resistant organism to these band NDM-1 bacteriums not having under competitive pressure, once disseminate in the whole world, the mankind will face incorrigible condition.
As can be seen here, research and develop the novel medicine with the strong anti-gram resistant organism of new texture type or novel mechanism, the medicine particularly with anti-band NDM-1 gene resistant organism activity is very urgent, significant.
Summary of the invention
The invention provides a kind of two amidine analog derivative and pharmacologically acceptable salts thereof containing two amidino groups indoles benzene, it has the activity of antimicrobial agent.
The present invention also provides a kind of above-mentioned containing two two amidine analog derivatives of amidino groups indoles benzene and the preparation method of pharmacologically acceptable salt thereof, and synthetic route is simple, and cost is lower.
Present invention also offers the above-mentioned two amidine analog derivatives containing two amidino groups indoles benzene and drug salts can prepare the application in antibacterials, there is the activity of strong resisting gram-positive and negative resistant organism, in anti-Gram-negative NDM-1 resistant organism, more have the effect of its uniqueness.
The present invention also provides a kind of antibacterial combination, comprise the above-mentioned two amidine analog derivatives containing two amidino groups indoles benzene and can drug salts as activeconstituents.
One aspect of the present invention provides a kind of two amidine analog derivatives containing two amidino groups indoles benzene or its pharmacologically acceptable salt, and it has the structure of formula [1]:
Wherein,
R
1and R
2independently selected from the C being substituted or being unsubstituted
1-12straight chained alkyl, C
3-12branched-chain alkyl or C
3-12cycloalkyl; Or R
1and R
2the 3-6 ring being substituted or being unsubstituted is formed with the N being connected them; R
3independently selected from hydrogen, halogen, low-grade halogenated alkyl, lower alkoxy, amino or rudimentary substituted amido.
Wherein, " low-grade halogenated alkyl " refers to that carbonatoms is the haloalkyl of 1-6, and " lower alkoxy " refers to that carbonatoms is the alkoxyl group of 1-6, as methoxyl group, oxyethyl groups etc., " rudimentary substituted amido " refers to that carbonatoms is the substituted amido of 1-6, and substituting group is such as halogen, hydroxyl etc.
According to the two amidine analog derivatives containing two amidino groups indoles benzene provided by the invention or its pharmacologically acceptable salt, R
1and R
2independently selected from the C being substituted or being unsubstituted
1-6straight chained alkyl, C
3-6branched-chain alkyl or C
3 -6cycloalkyl.
C
1-6straight chained alkyl include, for example methyl, ethyl, propyl group, allyl group, normal-butyl, n-pentyl, n-hexyl, n-heptyl etc.;
C
3-6branched-chain alkyl include, for example sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, isohexyl etc.;
C
3-6cycloalkyl include, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
According to two amidine analog derivatives provided by the invention or its pharmacologically acceptable salt, R
1and R
2independently selected from the C replaced through oxy radical or sulfur-containing group
3-12straight chained alkyl, C
3-12branched-chain alkyl or C
3-12cycloalkyl.Described oxy radical is selected from hydroxyl, aldehyde radical, carboxyl, methoxyl group etc., described sulfur-containing group selected from mercapto, sulfonic group etc.
According to two amidine compounds provided by the invention or its pharmacologically acceptable salt, R
1, R
2can be connected their atom N and other heteroatomss except described atom N form 3-6 ring.As R
1and R
2form in the 3-6 ring that is substituted or is unsubstituted with the N being connected them and at least also there is O or S.In one embodiment of the invention, R
1, R
2morpholine ring can be formed with the atom N and O atom being connected them.
According to two amidine compounds provided by the invention or its pharmacologically acceptable salt, R
1and R
2forming with the N being connected them the 3-6 ring being substituted or being unsubstituted can comprise as shown in the formula the group represented by [2]-[8]:
As the example of indefiniteness, the two amidine analog derivatives containing two amidino groups indoles benzene provided by the invention can such as:
Isosorbide-5-Nitrae-bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N ', N '-diethyl base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-ethyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-propyl group amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-sec.-propyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-cyclopropyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-heterocycle butyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-cyclopentyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-morpholinyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-4-methylpiperazine base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-4-tetramethyleneimine 1-phenylpiperidines base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-2,5-pyrrolin base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-1,2,3,6-tetrahydro pyridyl amidino groups) indoles-2-base] benzene
The pharmacologically acceptable salt with the two amidine analog derivatives containing two amidino groups indoles benzene of formula [1] structure provided by the invention, for the product of salt-forming reaction occurs for this two amidines analog derivative and acid.Described acid can be the acid of pharmacy field routine, can be mineral acid, such as hydrochloric acid, Hydrogen bromide or sulfuric acid etc.; Or be organic acid, such as acetic acid, lactic acid, succsinic acid, fumaric acid, toxilic acid, citric acid, phenylformic acid, methylsulfonic acid or para Toluic Acid etc.
Another aspect of the present invention provides above-mentioned containing two two amidine analog derivatives of amidino groups indoles benzene or the preparation method of its pharmacologically acceptable salt, comprises the following steps:
That 4-methyl-3-nitro benzyl cyanide and terephthalaldehyde react generation 4,4'-under weak base condition is two-[2-nitro-4-cyanostyrene base)] benzene;
In the presence of a reducing agent, two for 4,4'--[2-nitro-4-cyanostyrene base)] phenyl ringization is generated Isosorbide-5-Nitrae-bis--(6-itrile group indoles-2-base) benzene;
By 1,4-pair-(6-itrile group indoles-2-base) benzene carries out acidification, and reacts with the secondary amine R1R2NH of setting, generates the two amidine analog derivatives containing two amidino groups indoles benzene with formula [1] structure, namely corresponding pharmacologically acceptable salt is obtained, wherein R through salt-forming reaction
1and R
2as aforementioned definitions.
Concrete building-up process can be described below:
In said synthesis route,
Process a:4-methyl-3-nitro benzyl cyanide (compound 1) and 2,4-terephthal aldehyde (compound 2) as reactant in the solvent of such as tetramethylene sulfone, reacting by heating under weak basic condition, obtain 4,4'-two-[2-nitro-4-cyanostyrene base)] benzene (compound 3); The compound of weak basic condition can be provided such as to can be piperidines, reactant can be heated to such as 130-160 DEG C.
Process b: compound 3 cyclisation obtained by process a, such as, reflux in triethyl-phosphite, after raw material reaction is complete, cooling, adds water filtration, obtains 4,4 '-bis--[2-(6-itrile group indyl)] benzene (compound 4).
Process c and d: compound 4 first through acidification, such as, can adopt hydrochloric acid etc., at about 50 DEG C reacting by heating 3-5d, further by the product of gained after acidifying and secondary amine (R
1r
2nH) carry out reacting until reactant reaction is complete, such as 10-30h, two indole rings generate two amidine derivatives simultaneously, and obtain the two amidine analog derivatives with following formula (1) structure, wherein R1 and R2 is as aforementioned definitions.According to design needs, namely obtain corresponding pharmacologically acceptable salt through salt-forming reaction further.
Radicals R in formula [1]
1r
2n-) concrete example can be as shown in table 1:
Table 1
In table 1, compound name is called:
5a:1,4-pair-[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene;
5b:1,4-pair-[6-(N '-methyl-N '-ethyl amidino groups) indoles-2-base] benzene;
5c:1,4-pair-[6-(N '-heterocycle butyl amidino groups) indoles-2-base] benzene;
5d:1,4-pair-[6-(N '-cyclopentyl amidino groups) indoles-2-base] benzene;
5e:1,4-pair-[6-(N '-morpholinyl amidino groups) indoles-2-base] benzene;
5f:1,4-pair-[6-(N '-4-methylpiperazine base amidino groups) indoles-2-base] benzene;
5g:1,4-pair-[6-(N '-4-tetramethyleneimine 1-phenylpiperidines base amidino groups) indoles-2-base] benzene;
5h:1,4-pair-[6-(N '-2,5-pyrrolin base amidino groups) indoles-2-base] benzene;
5i:1,4-pair-[6-(N '-1,2,3,6-tetrahydro pyridyl amidino groups) indoles-2-base] benzene;
The fluoro-Isosorbide-5-Nitrae of 6a:2--bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene.
The present inventor is through research and experiment, the a series of two amidine analog derivatives containing two amidino groups indoles benzene of design and synthesis, and be surprised to find, when the side chain of two amidino groups is replaced by secondary amine, compound has obvious anti-microbial activity to Gram-negative and positive resistant organism, particularly shows amazing anti-microbial activity to Gram-negative NDM-1 resistant organism, and the MIC as compound 5a reaches 4 μ g/ml, activity is better than clinical application meropenem, levofloxacin and Faropenem, suitable with Tigecycline.Compound 5a also has good anti-microbial activity to the klebsiella pneumoniae of Nosocomial infection, enteroaerogen and Acinetobacter bauamnnii, and its activity is better than contrast medicine meropenem and Faropenem, suitable with levofloxacin.
The present invention also provides a kind of above-mentioned two amidine analog derivatives containing two amidino groups indoles benzene or the application of its pharmacologically acceptable salt in preparation antibacterials.
Above-mentioned antibacterials are the medicine of resisting gram-positive bacteria and against gram-negative bacteria.
The present invention also provides a kind of antibacterial combination, and it comprises above-mentioned two amidine analog derivatives or its pharmacologically acceptable salt containing two amidino groups indoles benzene as antibiotic effective ingredient, also comprises acceptable excipient substance in pharmaceutics.
The mixture of the above-mentioned two amidine analog derivatives containing two amidino groups indoles benzene or its pharmacologically acceptable salt itself or itself and pharmaceutically acceptable vehicle, thinner etc. can be made the form of tablet, capsule, granule, powder or syrup.Above-mentioned preparation is prepared by conventional pharmaceutical method.
Excipient substance can be used in the material in conventional pharmaceutical method.The example of available excipient substance comprises vehicle (such as carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder, starch derivative is W-Gum, potato starch, dextrin and carboxymethyl starch such as, derivatived cellulose is as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine, gum arabic, dextran, silicate derivative is as Neusilin US2, phosphate derivative is as calcium carbonate, sulfate-derivatives is as calcium sulfate etc.), tackiness agent (such as gelatin, polyvinylpyrrolidone and polyoxyethylene glycol), (such as derivatived cellulose is as Xylo-Mucine for disintegrating agent, polyvinylpyrrolidone), lubricant (such as talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (such as conventional sweeting agent, acidic flavoring agent and spices etc.), thinner and injection liquid solvent (such as water.Ethanol and glycerine etc.).
The enforcement of the present invention program, at least has following advantage:
1, two amidine analog derivative and the pharmacologically acceptable salts thereof containing two amidino groups indoles benzene provided by the invention, good activity is shown in antimicrobial agent, there is the antibiotic effect of wide spectrum, especially there is the activity of strong resisting gram-positive and negative resistant organism, and in anti-Gram-negative NDM-1 resistant organism, more have the effect of its uniqueness, for development of new antibacterials provide possibility;
2, provided by the invention containing two two amidine analog derivatives of amidino groups indoles benzene and the preparation method of pharmacologically acceptable salt thereof, synthetic route is simple, and cost is lower, is beneficial to industrializing implementation.
Embodiment
More fully the present invention is described referring to the embodiment of the present invention.But the present invention can embody in many different forms, should not be construed as the embodiment being limited to and stating herein.
Embodiment 1
Prepare Isosorbide-5-Nitrae-bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene (5a)
1) preparation of Isosorbide-5-Nitrae-bis--(6-itrile group indoles-2-base) benzene (compound 4)
The 4-methyl-3-nitro benzyl cyanide (5.0g through pulverizing is added in 100mL round-bottomed flask, 31.0mmol, compound 1), terephthalaldehyde (2.0g, 15.5mmol, compound 2), tetramethylene sulfone (10.0mL, as solvent) and piperidines (1.0g, 15.8mmol), connect reflux condensing tube, and use nitrogen protection, heat at 150 DEG C, stirring reaction 2h, be cooled to room temperature, then 50mL methylene dichloride is added, continue stirring dispersion in 30 minutes and be settled out product, product is filtered and uses dichloromethane rinse, by gained solid drying, 5.1g orange/yellow solid compound 3 is obtained after weighing, yield is 78% as calculated.
Above-mentioned orange/yellow solid compound 3 is joined in 250mL round-bottomed flask; add 50mL triethyl-phosphite, reflux two days later under nitrogen protection, stops heating; the solid suspended in reaction process becomes glassy yellow from orange-yellow; add methylene dichloride 25mL after cooling, continue stirring 30 minutes, product is filtered and uses dichloromethane rinse; 2.9g solid is obtained after drying; i.e. Isosorbide-5-Nitrae-bis--(6-itrile group indoles-2-base) benzene (compound 4), yield is 67% as calculated.
2) preparation of Isosorbide-5-Nitrae-bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene (compound 5a)
Obtained above 1 is added in the withstand voltage reaction flask of 300mL, 4-pair-(6-itrile group indoles-2-base) benzene (200mg, 0.56mmol), add absolute ethanol (150mL), stirring reaction liquid, be cooled to-5 DEG C, pass into HCl gas to saturated rear sealing, reaction solution is heated to 50 DEG C of reactions four days.Careful open bottle cover, solvent is removed in underpressure distillation, obtains dark green solid 295mg, i.e. Isosorbide-5-Nitrae-bis--{ 6-[oxyethyl group (imino-) methyl] indoles-2-base } benzene.
Above-mentioned dark green solid (0.29g is added in 50mL round-bottomed flask, 0.56mmol), methyl alcohol (20mL) and N, N dimethylamine (0.36mL, 5.6mmol), 40 DEG C of reacting by heating are spent the night (about 10h), till raw material reaction completely.Solvent is removed in underpressure distillation, product is used a small amount of dissolve with methanol, by HL-20 glucose gel-purified, ethanol elution, obtains Tan solid 175mg, and namely 1,4-pair-[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene (5a), yield is 60% as calculated.
In embodiment 1 preparation compound 5a, utilize by proton nmr spectra (
1hNMR) and high resolution mass spectrum (HRMS) characterize as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 3.09 (6H, s, 2CH
3), 3.27 (6H, s, 2CH
3), 7.19 (2H, s, indoles-H), 7.21 (2H, d, J=8.0, indoles-H), 7.66 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 8.10 (4H, s, Ph-H), 8.87 (2H, s, 2NH), 9.26 (2H, s, 2NH), 12.30 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
28H
29N
6(M+H)
+449.2448；found,449.2443.
Embodiment 2
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-ethyl amidino groups) indoles-2-base] benzene (5b)
In embodiment 1, by N, N dimethylamine replaces to N-methylethyl amine, and all the other conditions are identical with embodiment 1, obtains Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-ethyl amidino groups) indoles-2-base] benzene (5b).
In embodiment 2 preparation compound 5b can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 1.15 (6H, t, J=4.0,2CH
3), 3.24 (6H, s, 2CH
3), 3.36 (4H, m, 2CH
2), 7.16 (2H, d, J=8.0, indoles-H), 7.19 (2H, s, indoles-H), 7.66 (2H, s, indoles-H), 7.78 (2H, d, J=8.0, indoles-H), 8.93 (2H, s, 2NH), 9.30 (2H, s, 2NH), 12.39 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
30H
33N
6(M+H)
+477.2761；found,477.2758.
Embodiment 3
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-heterocycle butyl amidino groups) indoles-2-base] benzene (5c)
In embodiment 1, by N, N dimethylamine replaces to N-heterocycle butylamine, and at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtains Isosorbide-5-Nitrae-bis--[6-(N-(cyclobutyl amidino groups) indoles-2-base] benzene (5c).
In embodiment 3 preparation compound 5c can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 2.38 (4H, m, 2CH
2), 4.37 (8H, m, 4CH
2), 7.09 (2H, d, J=8.0, indoles-H), 7.16 (2H, s, indoles-H), 7.57 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 8.09 (4H, s, Ph-H), 8.66 (2He, s, 2NH), 9.23 (2H, s, 2NH), 12.33 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
30H
29N
6(M+H)
+473.2448；found,473.2445.
Embodiment 4
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-cyclopentyl amidino groups) indoles-2-base] benzene (5d)
In embodiment 1, by N, N dimethylamine replaces to cyclopentamine, and at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtains Isosorbide-5-Nitrae-bis--[6-(N '-cyclopentyl amidino groups) indoles-2-base] benzene (5d).
In embodiment 4 preparation compound 5d can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 1.87 (4H, m, 2CH
2), 2.10 (4H, m, 2CH
2), 3.52 (4H, t, J=4.0,2CH
2), 3.62 (4H, t, J=4.0,2CH
2), 7.18 (2H, s, indoles-H), 7.26 (2H, d, J=8.0, indoles-H), 7.71 (2H, s, indoles-H), 7.80 (2H, d, J=8.0, indoles-H), 8.80 (2H, brs, 4NH), 9.23 (2H, s, 2NH), 12.33 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
32H
33N
6(M+H)
+501.2761；found,501.2756.
Embodiment 5
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-morpholinyl amidino groups) indoles-2-base] benzene (5e)
In embodiment 1, by N, N dimethylamine replaces to morpholine, and at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtains Isosorbide-5-Nitrae-bis--[6-(N '-morpholinyl amidino groups) indoles-2-base] benzene (5e).
In embodiment 5 preparation compound 5e can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 3.03 (4H, m, 2CH
2), 3.76 (12H, m, 6CH
2) 7.02 (2H, s, indoles-H), 7.19 (2H, s, indoles-H), 7.20 (2H, d, J=8.0, indoles-H), 7.72 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 9,25 (6H, brs, 6NH), 12.48 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
32H
33N
6O
2(M+H)
+533.2660；found,533.2653.
Embodiment 6
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-4-methylpiperazine base amidino groups) indoles-2-base] benzene (5f)
In embodiment 1, by N, N dimethylamine replaces to 4-methylpiperazine, and at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtains Isosorbide-5-Nitrae-bis--[6-(N '-4-methylpiperazine base amidino groups) indoles-2-base] benzene (5f).
In embodiment 6 preparation compound 5f can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 2.26 (6H, s, 2CH
3), 2.51 (8H, m, 4CH
2), 3.66 (8H, m, 4CH
2), 7.19 (4H, m, indoles-H), 7.68 (2H, s, indoles-H), 7.77 (2H, d, J=8.0, indoles-H), 8.10 (4H, s, benzene-H), 9,45 (6H, brs, 6NH), 12.37 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
34H
38N
8(M+H)
+558.3219；found,558.3210.
Embodiment 7
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-4-tetramethyleneimine 1-phenylpiperidines base amidino groups) indoles-2-base] benzene (5g)
In embodiment 1, by N, N dimethylamine replaces to 4-tetramethyleneimine 1-phenylpiperidines, at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtain Isosorbide-5-Nitrae-bis--[6-(N '-4-tetramethyleneimine 1-phenylpiperidines base amidino groups) indoles-2-base] benzene (5g).
In embodiment 7 preparation compound 5g can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 1.74 (8H, m, 4CH
2), 1.91 (4H, m, 2CH
2), 2.09 (4H, m, 2CH
2), 2.53 (8H, m, 4CH
2), 3.32 (2H, m, 2CH), 3.46 (2H, m, 2CH), 3.64 (2H, m, 2CH), 4.14 (2H, m, 2CH), 7.19 (2H, s, indoles-H), 7.21 (2H, s, indoles-H), 7.68 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 8.10 (4H, s, benzene-H), 9.15 (3H, brs, 3NH), 9.37 (3H, brs, 3NH), 12.35 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
42H
50N
8(M+H)
+666.4158；found,666.4160.
Embodiment 8
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-2,5-pyrrolin base amidino groups) indoles-2-base] benzene (5h)
In embodiment 1, by N, N dimethylamine replaces to 2,5-pyrrolin, at 40 DEG C of reacting by heating 24h, all the other conditions are identical with embodiment 1, obtain Isosorbide-5-Nitrae-bis--[6-(N '-2,5-pyrrolin base amidino groups) indoles-2-base] benzene (5h).
In embodiment 8 preparation compound 5h can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 4.29 (4H, s, 2CH
2), 4.45 (4H, s, 2CH
2), 5.93 (2H, m, CH=CH), 6.08 (2H, m, CH=CH), 7.17 (2H, m, indoles-H), 7.30 (2H, m, indoles-H), 7.73 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 8.11 (4H, s, benzene-H), 8.98 (2H, m, 2NH), 9.47 (2H, m, 2NH), 12.37 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
34H
32N
6(M+H)
+496.2375；found,496.2377.
Embodiment 9
Prepare Isosorbide-5-Nitrae-bis--[6-(N '-1,2,3,6-tetrahydro pyridyl amidino groups) indoles-2-base] benzene (5i)
In embodiment 1, by N, N dimethylamine replaces to 1, and 2,3,6-tetrahydropyridine, at 40 DEG C of reacting by heating 24h, other condition is identical with embodiment 1, obtains 1,4-pair-[6-(N '-1,2,3,6-tetrahydro pyridyl amidino groups) indoles-2-base] benzene (5i).
In embodiment 9 preparation compound 5i can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 2.27 (4H, m, 2CH
2), 3.52 (4H, m, 2CH
2), 4.02 (2H, m, CH
2), 4.22 (2H, m, CH
2), 5.88 (4H, m, CH=CH), 7.19 (2H, m, indoles-H), 7.21 (2H, m, indoles-H), 7.71 (2H, s, indoles-H), 7.76 (2H, d, J=8.0, indoles-H), 8.12 (4H, s, benzene-H), 9,48 (4H, m, 4NH), 12.51 (2H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
34H
32N
6(M+H)
+524.2688；found,524.2680.
Embodiment 10
The fluoro-Isosorbide-5-Nitrae of preparation 2--bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene (6a)
In embodiment 1 first step, two phenyl aldehydes are replaced to 2-fluoro-Isosorbide-5-Nitrae-two phenyl aldehyde, all the other conditions are identical with embodiment 1, obtain the fluoro-Isosorbide-5-Nitrae of 2--bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene (6a).
In embodiment 10 preparation compound 6a can pass through proton nmr spectra (
1hNMR) and its structure of high resolution mass spectrum (HRMS) testing authentication, result is as follows:
1hNMR (DMSO-d
6, 400MHz, δ ppm) and 3.07 (6H, m, 2CH
3), 3.27 (6H, m, 2CH
3), 7.20 (2H, m, indoles-H), 7.31 (1H, s, indoles-H), 7.40 (1H, s, indoles-H), 7.70 (2H, m, indoles-H), 7.80 (t, J=8.0, indoles-H), 8.25 (d, J=8.0, benzene-H) 8.50 (d, J=8.0, benzene-H), 8.95 (2H, m, 2NH), 9.29 (2H, m, 2NH), 9.34 (1H, m, benzene-H), 12.38 (1H, s, indoles-NH), 12.72 (1H, s, indoles-NH);
HRMS(ESI)m/zcalcdforC
28H
28FN
6(M+H)
+467.2354；found,467.2350.
Antibacterial experiment
Compound 5a-5i and 6a prepared by embodiment 1-10 carries out following antibacterial experiment.
1, reagent and material
Compound 5a-5i and 6a prepared by laboratory sample: embodiment 1-10.
Substratum:
1) MH nutrient agar (MuellerHintonAgar), purchased from Nat'l Pharmaceutical & Biological Products Control Institute;
2) MH meat soup (MuellerHintonBroth) substratum; Purchased from Nat'l Pharmaceutical & Biological Products Control Institute;
3) brain heart infusion (BrainHeartInfusion) substratum, U.S. company BD product;
Positive control: levofloxacin (Levofloxacin), purchased from Nat'l Pharmaceutical & Biological Products Control Institute;
Experimental bacteria: the standard bacteria that 34 strain laboratories are preserved and clinical isolates;
Quality Control bacterium: select streptococcus aureus ATCC29213, enterococcus faecalis ATCC29212, escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853.
2, experimental technique: with reference to U.S. clinical and laboratory standards institute (CLSI) standard, adopts plate doubling dilution and Denlay multi-point inoculator to carry out drug sensitive experiment.
1) experimental bacteria MH meat soup or brain heart infusion are carried out Zengjing Granule, medicine DMSO dissolves, and after then using MH broth dilution to desired concn, is added in plate respectively by appropriate above-mentioned experimental bacteria after Zengjing Granule and the medicine DMSO after dissolving;
2), after being melted by MH nutrient agar, be quantitatively injected into the interior mixing of plate of above-mentioned drug containing DMSO and experimental bacteria, in plate, the final concentration of sample is respectively 128,64 ... 0.06,0.03 μ g/mL;
3) inoculation experiments bacterium (inoculum size is 104cfu/ point) after culture medium solidifying, observations cultivate 18h under the constant temperature of 35 DEG C after, the concentration that in the plate of asepsis growth, contained drug is minimum is minimum inhibitory concentration (MinimalInhibitoryConcentration, MIC).
3, experimental result
Above-mentioned antibacterial experiment result as shown in Table 3-5.Wherein, table 3 is the anti-microbial activity testing data of compound 5a-5i and 6a resisting gram-positive bacteria and negative bacterium.Table 4 is the antibacterial activity in vitro experimental data of compound 5a to band NDM-1 bacterium.Table 5 is the antibacterial activity in vitro experimental data of compound 5a to Nosocomial infection bacterium.
Table 3
(before continuous table)
Can be found out by table 3, compound 5a-5i and 6a has obvious fungistatic effect for the bacterial strain of above-mentioned gram-positive microorganism and negative bacterium, especially for bacterial strains such as staphylococcus aureus 12-33, enterococcus faecalis 09-9, faecium ATCC700221, faecium 12-1, faecium 12-3, Klebsiella Pneumoniae ATCCBAA-2146, have stronger fungistatic effect, successful is better than existing antibacterials levofloxacin.
As mentioned before, current part Gram-negative resistant organism, with NDM-1 drug resistance gene, can make existing antibiotic almost lose effect completely, comprises carbapenem antibiotics meropenem and the imipenum of latest generation.For compound 5a, carry out Antimicrobial test to the bacterial strain with NDM-1 genes encoding, result is as shown in table 4.Can find out that compound 5a all has stronger bacteriostatic activity to all test strain with NDM-1 drug resistance gene, its antibacterial effect is obviously better than vancomycin, Linezolid, meropenem, Faropenem and levofloxacin in existing antibacterials.
Table 4
Below for compound 5a, Antimicrobial test is carried out to the Nosocomial infection bacterium occurred in the bacterial strain with NDM-1 genes encoding, result is as shown in table 5, can find out that compound 5a has stronger bacteriostatic activity equally to all test strain, its antibacterial effect is obviously better than vancomycin, Linezolid, meropenem, Faropenem and levofloxacin in existing antibacterials.
Table 5
Last it is noted that above each embodiment is only in order to illustrate technical scheme of the present invention, be not intended to limit; Although with reference to foregoing embodiments to invention has been detailed description, those of ordinary skill in the art is to be understood that: it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein some or all of technical characteristic; And these amendments or replacement, do not make the essence of appropriate technical solution depart from the scope of various embodiments of the present invention technical scheme.
Claims (11)
1., containing two amidine analog derivatives or its pharmacologically acceptable salt of two amidino groups indoles benzene, it has the structure of formula [1]:
Wherein,
R
1and R
2independently selected from the C being substituted or being unsubstituted
1-12straight chained alkyl, C
3-12branched-chain alkyl or C
3-12cycloalkyl; Or R
1and R
2the 3-6 ring being substituted or being unsubstituted is formed with the N being connected them; R
3independently selected from hydrogen, halogen, low-grade halogenated alkyl, lower alkoxy, amino or rudimentary substituted amido.
2. the two amidine analog derivatives containing two amidino groups indoles benzene according to claim 1 or its pharmacologically acceptable salt, wherein, R
1and R
2independently selected from the C being substituted or being unsubstituted
1-6straight chained alkyl, C
3-6branched-chain alkyl or C
3-6cycloalkyl.
3. two amidine analog derivatives according to claim 1 or its pharmacologically acceptable salt, wherein, R
1and R
2independently selected from the C replaced through oxy radical or sulfur-containing group
3-12straight chained alkyl, C
3-12branched-chain alkyl or C
3-12cycloalkyl.
4. two amidine compounds according to claim 1 or its pharmacologically acceptable salt, wherein, R
1and R
2form in the 3-6 ring that is substituted or is unsubstituted with the N being connected them and at least also there is O or S.
5. two amidine analog derivatives according to claim 4 or its pharmacologically acceptable salt, wherein, R
1and R
2forming with the N being connected them the 3-6 ring being substituted or being unsubstituted comprises as shown in the formula the group represented by [2]-[8]:
。
6. two amidine analog derivatives according to any one of claim 1-5 or its pharmacologically acceptable salt, comprising:
Isosorbide-5-Nitrae-bis--[6-(N ', N '-dimethyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N ', N '-diethyl base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-ethyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-propyl group amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-sec.-propyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-methyl-N '-cyclopropyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-heterocycle butyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-cyclopentyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-morpholinyl amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-4-methylpiperazine base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-4-tetramethyleneimine 1-phenylpiperidines base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-2,5-pyrrolin base amidino groups) indoles-2-base] benzene
Isosorbide-5-Nitrae-bis--[6-(N '-1,2,3,6-tetrahydro pyridyl amidino groups) indoles-2-base] benzene.
7. described in any one of claim 1-6 containing two two amidine compounds of amidino groups indoles benzene or the preparation method of its pharmacologically acceptable salt, comprise the following steps:
That 4-methyl-3-nitro benzyl cyanide and terephthalaldehyde react generation 4,4'-under weak base condition is two-[2-nitro-4-cyanostyrene base)] benzene;
In the presence of a reducing agent, make 4,4'-two-[2-nitro-4-cyanostyrene base)] phenyl ringization generates Isosorbide-5-Nitrae-bis--(6-itrile group indoles-2-base) benzene;
Acidification is carried out to Isosorbide-5-Nitrae-bis--(6-itrile group indoles-2-base) benzene, and with setting secondary amine R
1r
2nH reacts, and generates the two amidine analog derivatives containing two amidino groups indoles benzene or its pharmacologically acceptable salt with formula [1] structure.
8. method according to claim 7, wherein, described reductive agent is triethyl-phosphite.
9. the two amidine analog derivatives containing two amidino groups indoles benzene described in any one of claim 1-6 or the application of its pharmacologically acceptable salt in preparation antibacterials.
10. application according to claim 9, described antibacterials are the medicine of resisting gram-positive bacteria and against gram-negative bacteria.
11. 1 kinds of antibacterial combinations, it comprises as the two amidine analog derivatives containing two amidino groups indoles benzene described in any one of claim 1-6 of antibiotic effective ingredient or its pharmacologically acceptable salt, also comprises acceptable excipient substance in pharmaceutics.
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| CN201410310157.4A CN105218427B (en) | 2014-07-01 | 2014-07-01 | Two amidine analog derivatives containing double amidino groups indoles benzene and its preparation method and application |
| PCT/CN2015/082642 WO2016000587A1 (en) | 2014-07-01 | 2015-06-29 | Bisamidine derivative containing bis(amidino) indole benzene and preparation method and use thereof |
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| KR101822761B1 (en) | 2016-03-23 | 2018-01-29 | 아주대학교산학협력단 | New compounds or pharmaceutically acceptable salt thereof selective for amyloid-β plaque and method for imaging amyloid-β plaque in vivo using the same |
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| Title |
|---|
| JOHN D. WILLIAMS，等: "Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: Synthesis and SAR of novel analogs of MBX 1066 and MBX 1090", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| LAIXING HUA，等: "Synthesis and structure–activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| MICHAEL R. JACOBSA，等: "Novel bis-indole agents active against multidrug-resistantAcinetobacter baumannii", 《DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE》 * |
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| CN111362834A (en) * | 2020-02-26 | 2020-07-03 | 湖南大学 | Antibacterial amidine oligomer with drug resistance and preparation method and application thereof |
| CN111362834B (en) * | 2020-02-26 | 2021-04-02 | 湖南大学 | Antibacterial amidine oligomer with drug resistance and preparation method and application thereof |
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| CN105218427B (en) | 2018-05-25 |
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