WO2014101294A1 - 糖肽类化合物或其药用盐及其制备方法、以及药物组合物和用途 - Google Patents
糖肽类化合物或其药用盐及其制备方法、以及药物组合物和用途 Download PDFInfo
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- WO2014101294A1 WO2014101294A1 PCT/CN2013/001647 CN2013001647W WO2014101294A1 WO 2014101294 A1 WO2014101294 A1 WO 2014101294A1 CN 2013001647 W CN2013001647 W CN 2013001647W WO 2014101294 A1 WO2014101294 A1 WO 2014101294A1
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- acceptable salt
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- -1 Glycopeptide compound Chemical class 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 108010015899 Glycopeptides Proteins 0.000 title claims abstract description 13
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- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
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- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 5
- KKFGZKBFBZYLJH-UHFFFAOYSA-N N-ethyl-N-propan-2-ylpropan-2-amine hydrazine Chemical compound C(C)(C)N(CC)C(C)C.NN KKFGZKBFBZYLJH-UHFFFAOYSA-N 0.000 claims description 5
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
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- 208000015181 infectious disease Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 3
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 150000001298 alcohols Chemical class 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 claims 1
- 238000000338 in vitro Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
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- 239000002904 solvent Substances 0.000 description 6
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
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- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 2
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- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
- C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/19—Antibiotic
Definitions
- Glycopeptide compound or medicinal salt thereof preparation method thereof, and pharmaceutical composition and use thereof
- the invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a novel novel glycopeptide derivative with Mannich side chain, a preparation method thereof, a pharmaceutical composition and use thereof. Background technique
- Glycopeptide antibiotics are the drug of choice for clinical treatment of methicillin-resistcint Staphylococcus aureus (MRSA) infection.
- MRSA methicillin-resistcint Staphylococcus aureus
- the empirical treatment of glycopeptide antibiotics as M RSA has led to the development of bacterial resistance, such as the reduced sensitivity of MRSA to vancomycin, which will pose a serious threat to clinical anti-infective treatment, therefore, looking for New glycopeptide antibiotics that are effective against drug-resistant strains are imminent.
- Chinese Patent 200910053906.9 reports a novel glycopeptide compound LYV07ww01 which has antibacterial activity and is novel in that the four-position hydroxyl group of the six amino acid glycosyl group of the peptide skeleton is an upright bond.
- Chinese Patent No. 201110070597.3 reported based compound LYV07ww01 of three amino acid residues ⁇ ', ⁇ ⁇ ⁇ 6 trisubstituted Derivatives and antibacterial activity.
- the present invention synthesizes a series of derivatives based on the resorcinol group of the 7-amino acid residue of the N 4 -monodecyl compound, and a series of derivatives are synthesized and their antibacterial activity is determined.
- the glycopeptide compound or a pharmaceutically acceptable salt thereof preferably has a hydroxyl group at the four positions of the six amino acid sugar group of the peptide skeleton as an upright bond.
- the glycopeptide compound or a pharmaceutically acceptable salt thereof preferably, the monosubstituted benzyl group is 2-bromobenzyl, 3-bromophenyl, 4-bromobenzyl, 4-isopropyl Base benzyl, or 4-methoxybenzyl.
- Another object of the present invention is to provide a process for the preparation of the above compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof.
- the compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof described in the present invention can be obtained by the following synthetic route:
- the resorcinol structure of the 7-amino acid residue of the compound (III) is synthesized by the Mannich reaction (I) or a pharmaceutically acceptable salt thereof, and the specific methods include the following:
- the reaction is carried out at 0 ° C to 35 ° C to give a compound of the formula (I). among them, ! ⁇ is 11, n-decyl, or a monosubstituted benzyl substituted by halogen, methoxy, isopropyl; R 2 is H, fluorenylmethoxycarbonyl, or n-decyl; R 3 is H or n- Sulfhydryl; N R4R 5 is diethylamino, n-butylamino, morpholinyl, or phosphomethyleneamino.
- the molar ratio of formaldehyde to compound (III) is 1:1 to 5:1, and the molar ratio of amine to compound (III) is 1:1 to 7:1, hydrazine, hydrazine-diisopropylethylamine and The molar ratio of the compound (III) is from 0:1 to 15:1. More preferably, the molar ratio of formaldehyde to compound (III) is 1:1 to 1.2:1, and the molar ratio of amine to compound (III) is 1.1:1, hydrazine, hydrazine-diisopropylethylamine and compound (III) The molar ratio is 14:1.
- the monosubstituted benzyl group is 2-bromobenzyl, 3-bromophenyl, 4-bromobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl.
- the organic solvent is selected from one or more of C 4 4 alcohol, acetonitrile, and water, and the temperature is 15 ° C to 25 ° C.
- the alcohol of d ⁇ C 4 is methanol, ethanol, propanol, butanol or n-butanol.
- the compound (IV) is reacted with formaldehyde, an amine R 5 , N,N-diisopropylethylamine in an organic solvent at a temperature of from 0 Torr to 35 ° C to form a compound of the formula (II). among them, ! ⁇ is 11 or n-decyl, or oxime halogen, methoxy, isopropyl substituted monosubstituted benzyl; NR4R 5 is diethylamino, n-butylamino, morpholinyl, or phosphonic acid methylene amino .
- the molar ratio of formaldehyde to compound (IV) is 1:1 to 10:1, and the molar ratio of amine to compound (IV) is 1:1 to 6:1, N,N-diisopropylethylamine and The molar ratio of the compound (IV) is from 0:1 to 14:1.
- the molar ratio of formaldehyde to compound (IV) is from 3:1 to 6:1, and the molar ratio of amine to compound (IV) is 1.2:1, N,N-diisopropylethylamine and compound (IV) The molar ratio is 14:1.
- the monosubstituted benzyl group is 2-bromobenzyl, 3-bromophenyl, 4-bromobenzyl, 4-isopropylbenzyl, or 4-methoxybenzyl.
- the alcohol of d ⁇ C 4 is methanol, ethanol, propanol, butanol or n-butanol.
- a further object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the above glycopeptide derivative or a pharmaceutically acceptable salt thereof (or a pharmaceutically acceptable salt thereof) and pharmaceutically acceptable a.
- the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier such as a diluent, an excipient (such as water), a binder (such as a cellulose derivative, gelatin, polyvinylpyrrolidone, etc.). ), fillers (such as starch, etc.), cracking agents (such as calcium carbonate, sodium bicarbonate).
- other adjuvants such as flavoring agents and sweeteners may be added to the composition.
- the pharmaceutical composition of the present invention can be administered to a patient in need of treatment by intravenous injection, subcutaneous injection or oral administration.
- oral administration it can be prepared into a conventional solid preparation such as a tablet, a powder or a capsule; for injection, it can be prepared as an injection.
- the various dosage forms of the pharmaceutical composition of the present invention can be prepared by a conventional method in the medical field, wherein the active ingredient is contained in an amount of from 0.1% to 99.5% by weight.
- the compound of the present invention has a weight content of 0.1 to 99.5%, preferably a content of 0.5 to 90%.
- the general dosage of the above pharmaceutical composition applied to a patient in need of treatment can be referred to the existing dosage of vancomycin and norvancomycin.
- an adult may be 0.1 to 2.0 g/d, which may vary depending on the age and condition of the patient.
- the compound of the present invention can be salted in a conventional manner, for example, into a hydrochloride.
- Still another object of the present invention is to provide the use of the above compounds for the preparation of a medicament for the prevention of bacterial infection.
- the beneficial effects of the present invention are that the derivative of the compound of the formula (I) or ( ⁇ ) of the present invention has a good antibacterial action.
- the reaction solution was adjusted to neutral with 20% TFA in an ice water bath, and an appropriate amount of acetonitrile was added thereto.
- the obtained precipitate was suction filtered, and the filter cake was washed several times with acetonitrile, purified by preparative HPLC using an aqueous solution containing 0.1% HCOOH and methanol.
- the mobile phase the obtained components are evaporated to methanol under reduced pressure, adjusted to pH 6-7 with a saturated aqueous solution of NaHCO 3 , and separated from a gel column, and water is used as a mobile phase.
- the obtained components are evaporated under reduced pressure and dried in vacuo to give a solid. UOmg, yield 42.2%. (See Table 1)
- the desired fraction was concentrated to a concentration of about 20 ml under reduced pressure.
- the mixture was adjusted to pH 6 to 7 with a saturated sodium hydrogen carbonate solution, and then extracted with an equal volume of n-butanol.
- the organic layer was separated, washed with water (10 ml ⁇ 2), and evaporated.
- the residue was added to dichloromethane and stirred overnight, filtered, and then dried and evaporated (See Table 1)
- the synthesis method of the compounds ⁇ 7 and ⁇ 8 is the same as that of the method of the embodiment 10 except that different compounds ( ⁇ ) are respectively selected, wherein R 2 and R 3 are hydrogen, respectively, 4-bromobenzyl group, 4-methoxybenzyl group. base. (see table
- the detection wavelengths were 240 nm and 280 nm.
- the organic solvent was removed under reduced pressure, and the mixture was adjusted to pH 6 to 7 with saturated sodium hydrogen carbonate, extracted with n-butanol, washed with water, and evaporated to dryness under reduced pressure.
- the yield referred to in the present invention means a molar yield.
- Drugs Dissolve first in DMSO, dilute to the appropriate concentration with sterile water, and then dilute in sequence. Determination method: The minimum inhibitory concentration (MIC value) was determined by agar double dilution method according to the CSSI 2008 edition standard.
- VSE clinical isolate MEFA 0039
- PISP Streptococcus pneumoniae
- the positive control drug is vancomycin hydrochloride.
- the activity of the series I compounds is generally superior to the series II compounds.
- the series I compounds were more or less effective against vancomycin than vancomycin; the activity against S. pneumonia was superior to vancomycin.
- the activity of Compound 19 and Compound I 14 against Streptococcus pneumoniae is more than 4 times that of vancomycin, which is worthy of further modification and pharmacological activity studies.
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Abstract
本发明提供了如通式(I)或(II)所示的糖肽类化合物或其药用盐及其制备方法,药物组合物和用途。本发明的糖肽类化合物具有体外抗菌活性。
Description
糖肽类化合物或其药用盐及其制备方法、 以及药物组合物和用途
技术领域
本发明属于药物化学合成技术领域, 具体地说涉及一类新颖的带有 Mannich 侧链的新型糖肽类衍生物及其制备方法以及药物组合物和用途。 背景技术
糖肽类抗生素是临床治疗耐甲氧西林金黄色葡萄球菌 ( methicillin-resistcint Staphylococcus aureus, MRSA )感染的首选药物。然而, 以糖肽类抗生素作为 M RSA的经验治疗导致了细菌耐药性的发展, 例如 MRSA对万古霉素的敏感性有 所下降, 这将对临床抗感染治疗产生严重威胁, 因此, 寻找能够对耐药菌株有效 的新型糖肽类抗生素迫在眉睫。
中国专利 200910053906.9报道了一个新型糖肽类化合物 LYV07ww01,具有 抗菌活性, 其新颖性在于其肽骨架六位氨基酸糖基的四位羟基为直立键。
中国专利 201110070597.3报道了基于化合物 LYV07ww01的三个氨基酸残基 Ν',Ν^Ν6上三取代衍生物的合成及其抗菌活性。
中国专利 201110070599.2报道了基于化合物 LYV07wwO 1氨基酸残基上的单 取代衍生物的合成及抗菌活性。 研究发现, N4-垸基化合物活性最好, N1,^4-二垸 基化合物次之, N1^,^6-三烷基化合物没有明显活性。 发明内容
本发明基于 N4-单垸基化合物的 7-氨基酸残基的间苯二酚位进一歩发生 Ma nnich反应, 合成一系列衍生物并测定其抗菌活性。
本发明的一个目的是为了提供通式 (I ) 或 (II ) 的各种系列的糖肽类衍生 物或其药用盐:
其中:
为11、 癸垸基、 或 ώ卤素、 甲氧基、 异丙基取代的单取代苄基; 为11、 笏甲氧羰基、 或正癸垸基;
为 Η或正癸垸基;
Ν 为二乙氨基、 正丁胺基、 吗啉基、 或膦酸亚甲基氨基。
根据本发明, 所述的糖肽类化合物或其药用盐较佳的是,其肽骨架六位氨基 酸糖基的四位羟基为直立键。
根据本发明, 所述的糖肽类化合物或其药用盐较佳的是, 所述单取代苄基为 2-溴苄基、 3-溴苯基、 4-溴苄基、 4-异丙基苄基、 或 4-甲氧基苄基。
本发明的另一目的是为了提供上述通式(I)或(II)化合物或其药用盐的制 备方法。 本发明中所述的通式(I)或(II)化合物或其药用盐可由下列合成路线 制得:
A、 通式 (I ) 化合物的合成:
化合物 (III) 的 7-氨基酸残基的间苯二酚结构发生 Mannich反应合成化合 (I) 或其药用盐具体方法包括如下:
H
N
将化合物 (m) 与甲醛、 R5、 Ν,Ν-二异丙基乙胺在有机溶剂和温度为
0°C~35°C中反应, 生成通式 (I)化合物。 其中, !^为11、 正癸烷基、 或由卤素、 甲氧基、 异丙基取代的单取代苄基; R2为 H、 笏甲氧羰基、 或正癸垸基; R3为 H或正癸垸基; N R4R5为二乙氨基、 正丁胺基、 吗啉基、 或膦酸亚甲基氨基。
优选地, 甲醛与化合物 (III) 的摩尔比为 1 :1~5:1, 胺与化合物 (III ) 的摩 尔比为 1 :1〜7:1, Ν,Ν-二异丙基乙胺与化合物 (III) 的摩尔比为 0:1~15:1。 更优 选地, 甲醛与化合物(III) 的摩尔比为 1 :1~1.2:1, 胺与化合物(III ) 的摩尔比为 1.1 :1, Ν,Ν-二异丙基乙胺与化合物 (III) 的摩尔比为 14:1。
优选地, 所述单取代苄基为 2-溴苄基、 3-溴苯基、 4-溴苄基、 4-异丙基苄基、 4-甲氧基苄基。
优选地, 所述有机溶剂选自 C €4的醇、 乙腈、 水中的一种或多种, 所述温 度为 15°C~25°C。 d~C4的醇为甲醇、 乙醇、 丙醇、 丁醇、 正丁醇。
更优选地, 所述有机溶剂为乙腈: 水 =1 :1。
化合物(III)的合成方法参见中国专利申请 201110070599.2 禾 B 2011100705
Β、 通式 (II)化合物的合成:
化合物 (IV ) 经 Mannich反应合成化合物 (II ) 或其药用盐具体方法包括如
H
N
将化合物 (IV ) 与甲醛、 胺类 R5、 N,N-二异丙基乙胺在有机溶剂和温 度为 0ΐ〜 35°C中反应, 生成通式 (II ) 化合物。 其中, !^是 11或正癸垸基、 或 ώ卤素、 甲氧基、 异丙基取代的单取代苄基; NR4R5是二乙氨基、 正丁胺基、 吗 啉基、 或膦酸亚甲基氨基。
优选地, 甲醛与化合物 (IV) 的摩尔比为 1 :1~10:1, 胺与化合物(IV ) 的摩 尔比为 1 :1~6:1, N,N-二异丙基乙胺与化合物 (IV) 的摩尔比为 0:1〜14:1。 更优
选地, 甲醛与化合物 (IV ) 的摩尔比为 3:1~6:1, 胺与化合物 (IV) 的摩尔比为 1.2:1 , N,N-二异丙基乙胺与化合物 ( IV ) 的摩尔比为 14:1。
优选地, 所述单取代苄基为 2-溴苄基、 3-溴苯基、 4-溴苄基、 4-异丙基苄基、 或 4-甲氧基苄基。
优选地, 所述有机溶剂选自 C 4的醇、 乙腈、 水中的一种或多种, 所述温 度为 15°C~25°C。 更优选地, 所述有机溶剂为乙腈: 水 =1 :1。 d~C4的醇为甲醇、 乙醇、 丙醇、 丁醇、 正丁醇。
化合物 (IV) 的合成方法参见中国专利 201110070598.8。
本发明的再一目的是提供一类药物组合物, 该药物组合物包含治疗有效量 的上述糖肽类衍生物或其在药学上可接受的盐(或其药用盐)和药学上可接受的 载体。 本发明中, 所述的药学上可接受的载体是指药学领域常规的药物载体, 如 稀释剂, 赋形剂 (如水等), 粘合剂 (如纤维素衍生物、 明胶、 聚乙烯吡咯烷酮 等), 填充剂 (如淀粉等), 崩裂剂 (如碳酸钙、 碳酸氢钠)。 另外, 还可以在组 合物中加入其他辅助剂, 如香味剂和甜味剂等。
本发明的药物组合物, 可以通过静脉注射、 皮下注射或口服的形式施加于 需要治疗的患者。用于口服时, 可将其制备成常规的固体制剂如片剂、 粉剂或胶 囊等; 用于注射时, 可将其制备成注射液。本发明的药物组合物的各种剂型可以 采用医学领域常规的方法进行制备, 其中活性成分的含量为 0.1%~99.5% (重量 比)。制剂中,本发明的化合物的重量含量为 0.1〜99.5%,优选的含量为 0.5~90%。
上述药物组合物施加于需要治疗的患者的一般剂量可以参照万古霉素和去 甲万古霉素的现有剂量, 例如成人可以为 0.1~2.0g/d, 具体可根据患者的年龄和 病情等变化。 本发明的化合物可以按常规方法成盐, 例如制成盐酸盐。
本发明的又一个目的是提供上述化合物在制备抗细菌感染的药物中的用途。 本发明的有益效果在于本发明的如通式(I)或(Π )化合物的衍生物具有良好的 抗菌作用。 具体实施方式
为了进一歩阐明本发明, 下面给出一系列实施例。 需要指出的是, 这些实施 例完全是例证性的。 给出这些实施例的目的是为了充分明示本发明的意义和内
容, 但并不因此将本发明限制在所述的实施例范围之中。 实施例 1
化合物 I ,的合成
冰水浴 (0°C ) 下, 将氨基甲垸膦酸 (140mg, 1.26mmol) 溶解在 3ml的水 中,再加入 DIEA(0.2ml, 1.26mmol)和 3ml乙腈。加入 37%甲醛的水溶液( 15μ1, 0.18mmol ) , 15min 后加入化合物 (III ) ( Ri=H, R2=H, R3=H, 参见中国专利 CN 101928331 A) 300mg (0.18mmol)禾 B DIEA (0.2ml, 1.26mmol )。 室温 25 °C 反应 3h后停止反应。冰水浴下用 20%TFA将反应液调节至中性, 并加入适量乙 腈, 得到的沉淀抽滤, 滤饼用乙腈洗涤数次, 用制备型 HPLC 纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相, 所获得的组分减压蒸去甲醇, 用饱和 NaHC03水溶液调 pH6-7, 凝胶柱分离, 水作为流动相, 所获得的组分减压蒸去 水, 真空干燥, 得固体 UOmg, 产率为 42.2%。 (参见表 1 )
化 合 物 I 1 : 'H-NMR(400MHz, DMSO-d6+D20) 6(ppm): 7.80(1 H), 7.67-7.60(2H), 7.40(2H), 7.15-6.98(4H), 6.50(2H), 5.61-5.39(6H), 5.27-5.24(2H), 5.06(1 H), 4.44-4.41 (3 H), 4.30(2H), 4.07-4.06(2H), 3.77-3.59(6H), 3.41(3H), 2.97-2.94(2H), 2.64-2.58(2H), 2.42(3H), 2.30-2.21(2H), 2.00(2H), 1.71-1.60(5H), 1.35-1.33(10H), 0.91 (6H). 实施例 2
化合物 1 2的合成
室温 20°C下往 100ml茄形瓶中加入甲醇 10ml, 再加入 lmmol/ml吗啉溶液 (0.23ml, 0.23mmol ) 以及 DIEA (0.1ml, 0.63mmol) 搅匀, 然后加入 lmmol/ml 甲醛溶液 (0.21ml, 0.21mmol),加毕搅拌 15min。投入化合物(III ) (R,=H, R2=H, R3=H,参见中国专利 CN 101928331 A) 300mg (0.18mmol) 以及 DIEA ( 0.1ml, 0.63mmol), 加毕于室温搅拌 3h。 搅拌下往里加入 70ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然后用制备型 HPLC 纯化, 采用含 0.1%HCOOH 的水溶液和甲醇作为流动相, 梯度洗脱, 检测波长为 240nm 和 280nm, 流速 22ml/min。 将所需流分减压浓缩至约 20ml, 用饱和碳酸氢钠溶液
调 pH至 6〜7, 加入等体积正丁醇萃取, 分出有机层, 用水 (10mlx2) 洗涤, 减 压蒸干溶剂,残余物加入二氯甲垸搅拌过夜,过滤, 45°C干燥,得化合物 I 2 30mg (游离碱, 白色粉末状固体), 收率 9.3%。 (参见表 1 )
化合物 1 2: lH-NMR(400MHz, DMSO-d6+D20) S(ppm): 7.90-8.31 (2H), 7.54-7.80 (2H),7.35-7.11 (4H), 7.12 (2H), 6.75 (2H), 6.47 (1H), 5.68-5.55 (2H), 5.45-4.98 (5H), 4.74 (2H), 4.65-4.43(3H), 3.76 (2H), 3.64 (4H), 3.45 (2H), 3.00 -3.50 (6H), 2.33 (5H), 2.02-1.46 (5H), 1.28-1.02 (10H), 0.94-0.79 (6H). 实施例 3
化合物 1 3的合成
室温 25°C下往 50ml茄形瓶中加入正丁醇 10ml, 再加入 lmmol/ml正丁胺 溶液 (0.12ml, 1.2mmol) 和 lmmol/ml甲醛溶液 ( 0.25ml, l.Ommol ), 加毕搅拌 15min。投入化合物 (III )
R2=H, R3=H, 参见中国专利 CN 101928331 A) 320mg (0.2mmol), 加毕于室温 15-25°C搅拌 3h。 搅拌下往里加入 70ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然后用制备型 HPLC纯 化, 采用含 0.1%HCOOH 的水溶液和甲醇作为流动相, 梯度洗脱, 检测波长为 240nm和 280nm, 流速 22ml/min。 将所需流分减压浓缩至约 20ml, 用饱和碳酸 氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水 (10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲垸搅拌过夜, 过滤, 45°C干燥, 得化合 物 I 335mg, 收率 9.8%。 (参见表 1 )
化合物 I 3: lH-NMR(400MHz, DMSO-d6+D20) 5(ppm): 7.90-8.31 (2H), 7.54-7.80 (2H),7.35-7.11 (4H), 7.12 (2H), 6.75 (2H), 6.47 (1H), 5.68-5.55 (2H), 5.45-4.98 (5H), 4.74 (2H), 4.65-4.43(3H), 3.76 (2H), 3.64 (4H), 3.45 (2H), 3.00 -3.50 (6H), 2.33 (5H), 2.02-1.46 (5H), 1.28-1.02 (10H), 0.94-0.79 (6H). 实施例 4
化合物 I 4的合成
室温 25°C下, 将正丁胺 (14.1μ1, 0.14mmol ) 溶解在 3ml 的水中, 再加入 DIEA (0.35ml, 2.10mmol )和 3ml乙腈。 然后用移液枪加入 37%甲醛的水溶液
( 10.5μ1, 0.14mmol), 15min后加入化合物(III ) (R,=正癸垸基, R2=正癸垸基, R3=IH癸垸基, 合成方法参见中国专利 201110070599.2 ) 300mg (0.14mmol), 并 置于 30°C油浴中。 23h30min后停止反应, 用 3mol/L HC1将反应液调节至中性, 并加入适量丙酮,得到的沉淀抽滤,滤饼用丙酮洗涤数次,用制备型 HPLC纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相,所获得的组分减压蒸去甲醇, 用饱和 NaHC03水溶液调 pH6-7, 凝胶柱分离, 水作为流动相, 所获得的组分减 压蒸去水, 真空千燥, 得固体 I 4 152mg, 产率为 51.9%。 (参见表 1 )
化合物 I 4: 1H-NMR(400MHz, DMSO-d6+D20) S(ppm): 9.57(1H), 8.38(1H), 8.15(1H), 7.90-7.84(2H), 7.65-7.13(8H), 6.85-6.73(4H), 6.52(1H), 6.38(2H), 5.92(1H), 5.73(1H), 5.57(1H), 5.40-5.18(7H),4.95(lH), 4.80-4.31(l lH), 3.94-3.08(31H), 2.97(3H), 2.27-2.16(6H), 2.00(1 H), 1.69-1.07(71H),0.87-0.86(18H). 实施例 5
化合物 I 5的合成
室温 35°C下往 100ml茄形瓶中加入水(5ml)和乙腈(5ml),再加入 lmmol/ml 吗啉溶液 (0.25ml, 0.25mmol) 以及 DIEA (0.26ml, 1.61mmol) 搅匀, 然后加入 lmmol/ml甲醛溶液(0.27ml, 0.27mmol),加毕搅拌 15min。投入化合物(IΠ)(R1=2- 溴苄基, R2=H, R3=H, 合成参见中国专利 201110070598.8 ) 500mg (0.23mmol) 以及 DIEA ( 0.26ml, 1.61mmol), 加毕于室温搅拌 3h。 搅拌下往里加入 70ml丙 酮,析出白色不溶物,抽滤,滤饼用丙酮洗涤,得白色固体,然后用制备型 HPLC 纯化, 采用含 0.1%HCOOH 的水溶液和甲醇作为流动相, 梯度洗脱, 检测波长 为 240nm和 280nm, 流速 22ml/min。 将所需流分减压浓缩至约 20ml, 用饱和碳 酸氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水(10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲烷搅拌过夜, 过滤, 45°C干燥, 得化合 物 I s 30mg (游离碱, 褐色粉末状固体), 收率 10.0%。 (参见表 1 )
化合物 1 5: 'H-NMR(400MHz, DMSO-d6+D20) S(ppm): 7.82 (2H), 7.65-7.11 (7H), 6.77 (2H), 6.51-6.47 (1H), 6.32 (2H), 5.61-5.59 (2H), 5.32 (3H), 5.18-5.12 (2H), 4.94 (1H), 4.87 (1H), 4.72-4.60 (3H), 4.48-4.09 (7H), 3.65-2.85 (9H), 2.33-2.00 (6H), 1.93 (2H), 1.77-1.40 (9H), 1.39-1.12 (11H), 1.05-1.03 (6H), 0.96-0.80 (6H).
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制备型 HPLC纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相, 梯度洗 脱,检测波长为 240nm和 280nm,流速 22ml/min。将所需流分减压浓缩至约 20ml, 用饱和碳酸氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水 ( 10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲垸搅拌过夜, 过滤, 45°C 干燥, 得化合物 I 7 27mg (游离碱, 白色粉末状固体), 收率 7.0%。 (参见表 1 ) 化合物 1 7: 'H-NMR(400MHz, DMSO-d6+D20) S(ppm): 7.91 (1H), 7.79-7.11 (9H), 6.86-6.76 (3H), 6.49 (1H), 6.32 (1H), 5.52 (2H), 5.31-5.11 (3H), 5.20-5.00 (3H), 4.94 (IH), 4.85 (IH), 4.74-4.48 (4H), 4.34-4.10 (7H), 3.60-2.70 (9H), 2.33 (5H), 2.02-1.93 (2H), 1.77-1.60 (5H), 1.38 (5H), 1.20 (10H), 1.03 (5H), 0.85-0.80 (9H). 化合物 i„、 1 14与方法实施例 7相同, 只是分别选用不同的化合物(m), 其中, 、 是 fi, 分别是 4-溴苄基、 4-异丙基苄基。 (参见表 1 )
化合物 I U : 'H-NMR(400MHz, DMSO-d6+D20) 6(ppm): 7.90-7.85 (2H), 7.38-7.23 (4H), 7.23-7.13 (3H), 6.76-6.69 (3H), 6.50 (IH), 6.33-6.31 (2H), 5.66 (IH), 5.55 (IH), 5.38-5.19 (5H), 4.84-4.73 (2H), 4.68-4.21 (7H), 3.30-2.94 (8H), 2.33-2.01 (5H), 2.00 (2H), 1.96-1.44 (9H), 1.21 (19H), 1.04-0.88 (6H), 0.88-0.82 (9H).
化合物 I ": 'H-NMR(400MHz, DMSO-d6+D20) S(ppm): 7.89-7.80 (2H), 7.59 (IH), 7.40 (2H), 7.17-7.10 (4H), 6.78 (2H), 6.48 (IH), 6.32 (IH), 5.54 (IH), 5.34-5.19 (3H), 5.13-5.00 (2H), 4.95 (1H), 4.86 (IH), 4.75 (2H), 4.47-4.10 (4H), 3.50-3.00 (9H), 2.28 (5H), 1.94 (2H), 1.74-1.53 (4H), 1.39-1.37 (5H), 1.34-1.12 (16H), 0.85-0.81 (9H). 实施例 8
化合物 I 15的合成
室温 22°C下往 100ml茄形瓶中加入水(5ml )和乙腈(5ml),再加入 lmmol/ml 正丁胺溶液(0.22ml, 0.22mmol ) 以及 DIEA ( 0.2ml, 1.26mmol )搅匀, 然后加入 lmmol/ml 甲醛溶液 ( 0.22ml, 0.22mmol ), 加毕搅拌 15min。 投入化合物 ( III ) (Ri=H, R2=Fmoc -, R3=H,合成参见中国专利 201110070598.8 )400mg, 0.20mmol
以及 DIEA (0.2ml, 1.26mmol),加毕于室温搅拌 3h。搅拌下往里加入 70ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然后用制备型 HPLC纯 化, 采用含 0.1%HCOOH 的水溶液和甲醇作为流动相, 梯度洗脱, 检测波长为 240nm和 280nm, 流速 22ml/min。 将所需流分减压浓缩至约 20ml, 用饱和碳酸 氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水 (10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲烷搅拌过夜, 过滤, 45Ό干燥, 得化合 物 I 15 30mg (游离碱, 白色粉末状固体), 收率 10.0%。 (参见表 1 )
MS (ESI): I 15分子式为 CwH^ChNnC^, 计算分子量为 1897。 质谱中有 m/z 1898.31 (M+H), m/z 1920.28 (M+Na)。 m/z 1899 (M+2), 1900 (M+2+H), 1901 (M+4) 是同位素峰。 化合物 I 16的合成与方法实施例 8相同,只是分别选用吗啉溶液代替正丁胺 溶液, 合成底物和方法相同。 (参见表 1 )
化合物 I 16:
MS (ESI): 1 16分子式为
计算分子量为 1897。 质谱中有 m/z 1912.34(M+H), m/z 1935.31 (M+Na)0m/z 1913.32CM+2 ), 1914.30CM+2+H), 1915.31 (M+4) 是同位素峰。 实施例 9
化合物 II ,的合成
冰水浴 0 °C下往 50ml茄形瓶中加入水( 3 ml )和乙腈( 3ml ),再加入 1 mmol/ml 正丁胺溶液 (0.12ml, 1.2mmol) 和 1 mmol/ml甲醛溶液 ( 0.25ml, l.Ommol), 加 毕搅拌 15min。投入化合物( III X R,=H, R2=H, R3=H,参见中国专利 CN 101928331 A) 320mg (0.2mmol), 加毕, 撤除冰水浴, 于室温 15-25°C搅拌 3h。 搅拌下往 里加入 70ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然 后用制备型 HPLC纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相, 梯 度洗脱, 检测波长为 240nm和 280nm, 流速 22ml/min。 将所需流分减压浓缩至 约 20tnl, 用饱和碳酸氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机 层, 用水 (10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲垸搅拌过夜, 过
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化合物 Π 7、 Π 8的合成方法与方法实施例 10相同, 只是分别选用不同的化 合物(ΠΙ), 其中, R2、 R3是氢, 分别是 4-溴苄基、 4-甲氧基苄基。 (参见表
2 )
化合物 II 7: 'H-NMR(400MHz, DMSO-d6+D20) S(ppm): 789 (2H), 7.57 (2H), 7.54-7.50 (3H), 7.26-7.11 (3H), 6.77-6.67 (2H), 6.55 (IH), 5.73 (IH), 5.63 (IH), 5.52 (IH), 5.38-5.11 (5H), 4.86 (IH), 4.72-4.52 (2H), 4.38 (IH), 4.36 (IH), 4.33 (IH), 4.23-4.04 (4H), 3.25-2.67 (7H), 2.34-2.01 (5H), 1.86 (2H), 1.77-1.35 (9H), 1.22 (7H), 1.20-1.00 (8H), 0.89-0.83 (6H).
化合物 II 8: 1H-NMR(400MHz, DMSO-d6+D20) 6(ppm): 7.90 (2H), 7.59 (2H), 7.36-7.27 (2H), 7.22-7.14 (4H), 6.85-6.68 (4H), 6.56 (1H), 6.34 (IH), 5.74 (1H), 5.65 (IH), 5.55 (IH), 5.40-5.11 (5H), 4.87-4.74 (4H), 4.63 (IH), 4.50 (IH), 4.42 (IH), 4.35 (2H), 4.25-3.75 (4H), 3.65-3.10 (9H), 2.40-2.02 (5H), 1.94-1.60 (5H), 1.50-1.21 (12H), 1.00 (6H), 0.99-0.84 (6H). 实施例 11
化合物 II 4的合成
室温 25 °C下往 100ml 茄形瓶中加入甲醇 (5ml ) 和乙醇 (5ml ), 再加入 lmmol/ml二乙胺溶液(0.23ml, 0.23mmol )以及 DIEA ( 0.26ml, 1.61mmol )搅匀, 然后加入 lmmol/ml甲醛溶液 (0.69ml, 0.69mmol ) , 加毕搅拌 15min。 投入化合 物(III ) (Ri=2-溴苄基, R2=H, R3=H,合成参见中国专利 201110070598.8 ) 500mg, 0.23mmol 以及 DIEA ( 0.26ml, 1.61mmol ) , 加毕于室温搅拌 3h。 搅拌下往里加 入 70 ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然后用 制备型 HPLC纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相, 梯度洗 脱,检测波长为 240nm和 280nm,流速 22ml/min。将所需流分减压浓缩至约 20ml, 用饱和碳酸氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水 ( 10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲垸搅拌过夜, 过滤, 45 Ό 干燥, 得化合物 II 4 40mg (游离碱, 白色粉末状固体), 收率 10.0%。(参见表 2 ) 化合物 II 4: 'H-NMR(400MHz, DMSO-d6+D20) 6(ppm): 7.87-7.60 (2H), 7.54-7.11 (6H), 7.12 (2H), 6.75 (2H), 6.50 (1H), 5.68-5.50 (2H), 5.33-5.00 (5H), 4.84-4.62 (4H), 4.47-4.06 (6H), 3.70-3.35 (8H), 3.25-2.84 (4H), 2.33 (5H), 2.02-1.46
(5H), 1.38-1.02 (18H), 0.86-0.80 (9H). 实施例 12
化合物 II 3的合成
于 35°C下往 100ml茄形瓶中加入水(5ml )和乙腈(5ml), 再加入 lmmol/ml 正丁胺溶液 (0.28ml, 0.28mmol) 以及 DIEA ( 0.22ml, 1.38mmol ) 搅匀, 然后加 入 lmmol/ml甲醛溶液 ( 1.38ml, 1.38mmol), 加毕搅拌 15min。 投入化合物 (III )
( Ri=2-溴苄基, R2=H, R3=H , 合成参见中国专利 201110070598.8 ) 500mg, 0.23mmol 以及 DIEA (0.22ml, 1.38mmol) , 加毕于室温搅拌 3h。 搅拌下往里加 入 70ml丙酮, 析出白色不溶物, 抽滤, 滤饼用丙酮洗涤, 得白色固体, 然后用 制备型 HPLC纯化, 采用含 0.1%HCOOH的水溶液和甲醇作为流动相, 梯度洗 脱,检测波长为 240nm和 280nm,流速 22ml/min。将所需流分减压浓缩至约 20ml, 用饱和碳酸氢钠溶液调 pH至 6~7, 加入等体积正丁醇萃取, 分出有机层, 用水
( 10mlx2 ) 洗涤, 减压蒸干溶剂, 残余物加入二氯甲垸搅拌过夜, 过滤, 45°C 干燥, 得化合物 n3 40mg (游离碱, 白色粉末状固体), 收率 10.5%。 (参见表 2 ) 'H-NMR(400MHz, DMSO-d6+D20) 5(ppm): 7.88-7.83 (2H), 7.59-7.12 (9H), 6.78 (2H), 6.70-6.53 (2H), 5.73-5.54 (3H), 5.38-5.12 (6H), 4.94-4.63 (5H), 4.49-4.05 (8H), 3.44-2.84 (6H), 2.34 (5H), 2.13-1.68 (3H), 1.61-1.43 (6H), 1.38-1.22 (6H), 1.05-1.04 (7H), 0.99-0.88 (6H).. 化合物 II 5的合成方法与方法实施例 12相同, 只是分别选用不同的化合物 (m), 其中, 是3-溴苄基, R2是氢, R3是氢。 (参见表 2 )
化 合物 II5:1H-NMR(400MHz, DMSO-d6+D20) 6(ppm):7.87-7.60 (2H), 7.54-7.11 (6H), 7.12 (2H), 6.75 (2H), 6.50 (1H), 5.68-5.50 (2H), 5.33-5.00 (5H), 4.84-4.62 (4H), 4.47-4.06 (6H), 3.70-3.35 (8H), 3.25-2.84 (4H), 2.33 (5H), 2.02-1.46 (5H), 1.38-1.02 (18H), 0.86-0.80 (9H). 实施例 13
化合物 II 6的合成
邈 7鹭三 Vd丄
^I^S ^^-N'N vaia 〇。οε~〇。θζ^ ^ ^ ^軍暴;^ ^非^
•(Η9) 980 '(ΗΠ) Ori-ΟΠ '(Η8)
'(Η01) Z^Z-Q Z \) 9Γ£-00 '(HI/) £^ "99 '(Ht) 6/. "00"5 XUZ) SI'S H ) ie-S-09"S '(HI) 6 9 '(Hi) 96 S '(H3) 8 9 '(HZ) 06·9_00·乙 '(Ht^) 0 '(HI/) '(Η3) 6 L-i^L : (t"dd)g (0¾+9P_OSWa 'zHW00t7)¾WN-H,:6 II
(H9) 88Ό '(H91) Wl-.9'1
'(Ηζ) 58Ί '(Η9) 00· _0 · '(Ηζ) 0A'3" 8'3 '(HS) ΟΓΕ^Γε '(HS) 06 1z '(Η£) 6t7 -00"S '(Ht 90-ζ-ί£-ς '(Η3) 'S-S-'S '(HI) £'9 '(Hi) Z£'9 XUZ) 69·9_9Ζ/9 '(HZ.) ZYL-L^L \m) 68",:(uidd)9 (o¾+9P"OSWa 'ZHWOO^WN-H,:9 II ^ ^
91
Lt9l00/£l0ZSiD/lDd ΜΖΐΟΐ/ ΟΖ OAV
MIC 最低抑菌浓度 通式( I )或(II ) 的某些实例化合物的相关数据见表 1和表 2。
实施例 1~13中, 制备型 HPLC纯化条件: 色谱柱 Sepax BR-C18 21.2x 100 mm (5μπι) , 梯度洗脱, 流动相组成如下:
IS-8.81
(Z+Vi)
vzz- 3(¾¾)N- ∑II Ι9·"8Ι
(H+W) 9¾UN 66H6 WD-u-HN- H 'II Z.9'8891
ro=3
isa Ή
( II) ^li ^m^ ' ^inar:^ ' ^ , :¾
8【
丽 OZ OAV
Br
1856.47
II 4 26
-CH2^ -N(C2H5)2 C86H104BrCl2NnO -64a
(M+H)
Br
1856.70 li s -CH2^ -NH-1 -C4H9 C86H,04BrCl2N11O26 -53b
(M+H)
Br
1893.15
II 6 C86Hio2BrCl2Nn027 -32b
(M+Na)
1878.62
II 7 -N(C2H5)2 C86H104BrCl2NnO26 -51b
(M+Na)
1808.64
I" -N(C2H5)2 C87Hi07Cl2NnO27 -18a
(M+H)
1834.70
II 9 C89Hi09Cl2NnO27 -34b
(M+H) 注: a以水为溶剂, b以 DMF为溶剂, e以甲醇为溶剂 效果实施例
本发明部分目标化合物的体外抗菌活性试验结果如下:
1、 试验方法:
药物: 先用 DMSO溶解, 再用无菌水稀释成合适浓度, 然后依次对倍稀释。 测定方法: 参照 CSSI 2008年版标准, 采用琼脂二倍稀释法, 测定最低抑菌 浓度 (MIC值)。
2、 试验菌株:
屎肠球菌(VSE临床分离株: MEFA 0039);肺炎链球菌(PISP: ATCC 49619)。
3、 阳性对照药为盐酸万古霉素。
部分化合物的 MIC值见表 3。
表 3部分化合物的 MIC ( μ^πιΐ)
化合物 肠球菌 肺炎链球菌 盐酸万古霉素 0.25 0.125
Ι ι 0.5 0.125
I 2 0.5 0.063
I 3 0.5 0.25
>8 >8
0.25 0.125
ι 6 1 0.25
I T 1 0.5
0.25 0.063
I 9 0.25 0.031
I 10 2 0.25
I n 1 0.25
I 12 2 1
I 13 1 0.25
1 .4 0.5 0.031
II , 0.25 0.125
II 2 2 0.5
II 3 2 0.25
II 4 2 0.25
I" 1 0.25
II 6 2 0.25
II 7 1 0.25 li s 1 0.25
II 9 1 0.25
从表 3可以看出, 系列 I化合物的活性普遍优于系列 II化合物。与阳性对照 万古霉素相比, 系列 I化合物对肠球菌的活性与万古霉素相当或弱于万古霉素; 对肺炎链球菌的活性优于万古霉素。 其中, 化合物 1 9和化合物 I 14对肺炎链球 菌的活性是万古霉素的 4倍以上, 值得进一歩的修饰和药理活性研究。
需要说明的是,上述发明内容及具体实施方式意在证明本发明所提供技术方 案的实际应用, 不应解释为对本发明保护范围的限定。本领域技术人员在本发明 的精神和原理内, 当可作各种修改、 等同替换、 或改进。 本发明的保护范围以所 附权利要求书为准。
Claims
权 利 要 求 书 、
22 为11、 正癸垸基、 或 ώ卤素、 甲氧基、 异丙基取代的单取代苄基; 为11、 芴甲氧羰基、 或正癸烷基;
R3为 Η或正癸烷基;
NR4R5为二乙胺基、 正丁胺基、 吗啉基、 或膦酸亚甲基胺基。
2、 如权利要求 1所述的糖肽类化合物或其药用盐, 其中, 所述单取代苄基 为 2-溴苄基、 3-溴苯基、 4-溴苄基、 4-异丙基苄基、 或 4-甲氧基苄基。
3、 如权利要求 1所述的糖肽类化合物或其药用盐, 其中, 其肽骨架六位氨 基酸糖基的四位羟基为直立键。
一N : E
!^为!^、 正癸垸基、 或 ώ卤素、 甲氧基、 异丙基取代的单取代苄基; 为11、 芴甲氧幾基、 正癸垸基;
为!^、 正癸垸基;
NR4R5为二乙胺基、 正丁胺基、 吗啉基、 膦酸亚甲基胺基。
5、 如权利要求 4所述的方法, 其中, 甲醛与化合物 (III) 的摩尔比为 1:1~ 5:1, 胺与化合物 (III) 的摩尔比为 1:1〜7:1, N,N-二异丙基乙胺与化合物 (III) 的摩尔比为 0:1~15:1。
6、 如权利要求 5所述的方法, 其中, 甲醛与化合物 (III) 的摩尔比为 1:1〜 1.2:1, 胺与化合物 (III) 的摩尔比为 1.1:1, N,N-二异丙基乙胺与化合物 (III) 的摩尔比为 14:1。
7、 如权利要求 4所述的方法, 其中, 所述单取代苄基为 2-溴苄基、 3-溴苯 基、 4-溴苄基、 4-异丙基苄基、 4-甲氧基苄基。
8、 如权利要求 4所述的方法, 其中, 所述有机溶剂选自 C^CA的醇、 乙腈、 水中的一种或多种, 所述温度为 15°C~25°C。
9、 如权利要求 8所述的方法, 其中, 所述有机溶剂为乙腈: 水 =1:1。
10、 一种制备如权利要求 1〜3任一所述的通式 (II) 化合物或其药用盐的方 法, :
H
N
将化合物 (IV) 与甲醛、 胺类 Rs、 Ν,Ν-二异丙基乙胺在有机溶剂和温 度为 0Χ〜 35Ό中反应, 生成通式 (II) 化合物; 其中,
是11、 正癸垸基、 或由卤素、 甲氧基、 异丙基取代的单取代苄基; Ν 是二乙氨基、 正丁氨基、 吗琳基、 膦酸亚甲基氨基。
11、 如权利要求 10 所述的方法, 其中, 甲醛与化合物 (IV ) 的摩尔比为 1 :1-10:1 , 胺与化合物 (IV) 的摩尔比为 1:1~6: 1,, N,N-二异丙基乙胺与化合物
(IV) 的摩尔比为 0:卜 14:1。
12、 如权利要求 11 所述的方法, 其中, 甲醛与化合物 (IV ) 的摩尔比为 3:1~6:1,,胺与化合物(IV)的摩尔比为 1.2:1, N,N-二异丙基乙胺与化合物(IV) 的摩尔比为 14:1。
13、 如权利要求 10所述的方法, 其中, 所述单取代苄基为 2-溴苄基、 3-溴 苯基、 4-溴苄基、 4-异丙基苄基、 4-甲氧基苄基。
14、 如权利要求 10所述的方法, 其中, 所述有机溶剂选自 d~C4的醇、 乙 腈、 水中的一种或多种, 所述温度为 15°C~25°C。
15、 如权利要求 14所述的方法, 其中, 所述有机溶剂为乙腈: 水 =1 :1。
16、一种药物组合物,包括治疗有效量的权利要求 1~3中任一所述的糖肽类 化合物或其药用盐、 以及药学上可接受的载体。
17、如权利要求 16所述的药物组合物,其中,所述药物组合物包含 0.1~99.5 重量%所述糖肽类化合物或其药用盐,优选为 0.5~90重量%所述糖肽类化合物或 其药用盐。
18、一种在制备用于抗细菌感染如权利要求 1~3任一所述的化合物或其药用 盐或如权利要求 16~17任一所述的药物组合物的药物中的应用。
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