CN106083994B

CN106083994B - Substituted oxazolidinone water-soluble derivatives and uses thereof

Info

Publication number: CN106083994B
Application number: CN201610438425.XA
Authority: CN
Inventors: 不公告发明人
Original assignee: Nanjing Major Biotechnology Co Ltd
Current assignee: Nanjing Major Biotechnology Co Ltd
Priority date: 2016-04-18
Filing date: 2016-06-17
Publication date: 2019-12-06
Anticipated expiration: 2036-06-17
Also published as: CN106083994A

Description

Substituted oxazolidinone water-soluble derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicinal chemistry, and relates to an oxazolidinone derivative, in particular to a substituted oxazolidinone water-soluble derivative or pharmaceutically acceptable acid salt thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparation of medicines for preventing or treating bacterial infection.

Background

Novel oxazolidinone derivative antibacterial agents are disclosed in patent CN 200480037612.2, and additionally the us FDA has approved tedizolid phosphate (tedizolid phosphate) for the treatment of bacterial (human and animal pathogens including gram positive bacteria such as staphylococci, enterococci and streptococci, anaerobic microorganisms such as bacteroides and clostridia, and acid-resistant microorganisms such as mycobacterium tuberculosis, mycobacterium avium) infections, which is a phosphate prodrug of tedizolid, which is hydrolyzed by in vivo phosphatase to produce tedizolid action.

The tedizolid is poor in water solubility due to the structural characteristics of the compound, the tedizolid is not easy to prepare into a solution for intravenous administration, although the solubility of the compound can be improved by preparing the tedizolid into phosphate, the tedizolid phosphate cannot be clinically mixed with a solution containing divalent ions (calcium ions and magnesium ions) due to the existence of phosphate, and in addition, the saturation of phosphatase in vivo can be caused by taking the medicine more than a specific dose orally, and the bioavailability is reduced.

There is a need for antimicrobial agents with enhanced solubility and activity for the treatment of bacterial infections including infections with human and animal pathogens including gram positive bacteria such as staphylococci, enterococci and streptococci, anaerobic microorganisms such as bacteroides and clostridia and acid-fast microorganisms such as mycobacterium tuberculosis, mycobacterium avium, and the like, while having favorable physical forms, suitable physicochemical properties to produce formulations that are more convenient for route of administration, more stable in efficacy, and safer for clinical use without incompatibility.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to overcome the defects of the prior art and provide a novel substituted oxazolidinone water-soluble derivative for preparing a medicament for preventing or treating bacterial infectious diseases; the substituted oxazolidinone water-soluble derivative has the characteristics of good water solubility, rapid conversion into active ingredients in vivo, more convenient administration route, more stable curative effect, no incompatibility in clinical use and higher safety.

The second object of the present invention is to provide a process for the preparation of the above-mentioned water-soluble derivatives of substituted oxazolidinones.

It is a third object of the present invention to provide a pharmaceutical composition comprising the above-mentioned water-soluble derivative of substituted oxazolidinone.

A fourth object of the present invention is to provide the use of a water-soluble derivative of a substituted oxazolidinone as defined above, or a pharmaceutical composition, for the manufacture of a medicament for the prevention or treatment of bacterial infections in a host, including a warm-blooded animal, especially a human.

The technical scheme is as follows: a compound of formula I, or a pharmaceutically acceptable acid salt thereof, as described herein:

Wherein: r1 is a dipeptide acyl or polypeptide acyl group wherein at least one amino acid acyl group is formed from a natural amino acid; the compound is selected from one of the following compounds, or pharmaceutically acceptable acid salt thereof:

The derivatives provided by the invention comprise optical isomers of the compounds in the formula I.

The derivatives of the present invention include compounds of formula I or pharmaceutically acceptable acid salts thereof, including but not limited to the salts of the compounds with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.

The "amino acid acyl group" in the present invention refers to a group (NH2-R-C (═ O) -) formed by the amino acid (NH2-R-C (═ O) -OH) in which the carboxyl group is deficient in — OH. The amino acids referred to herein include 20 natural amino acids, for example: alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (gin), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His) and the like, and also include various unnatural amino acids.

In a second aspect, the present invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable acid salt thereof, which is a water-soluble derivative of the above-mentioned substituted oxazolidinones, comprising the steps of:

Referring to the synthesis of patent application 200480037612.2, the compound of formula II, which is also commercially available, is synthesized first using the corresponding starting materials.

Reacting the compound of formula II with the compound of formula III under the condition of a condensing agent or reacting the compound of formula II with the compound of formula IV, and then removing an amino protecting group to obtain the compound of formula I:

Wherein R3 is carbobenzoxy to protect the amino terminal, and the corresponding protecting group of the side chain with the corresponding protecting group on the amino acid side chain can be trityl, tert-butyloxycarbonyl, carbobenzoxy, fluorenylmethyloxycarbonyl, etc., when the compound of formula III is used as the synthesis raw material in the preparation reaction, the condensing agent can be Carbonyldiimidazole (CDI), N, N ' -Diisopropylcarbodiimide (DIC), N, N ' -Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride (EDC. HCl), O- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), and the corresponding catalyst such as N can be added in the reaction, n-dimethylamino pyridine and an acid-binding agent, wherein a Cbz group is a benzyloxycarbonyl protecting group for protecting amino.

As a preferred embodiment, the present invention provides a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, which comprises dissolving a compound of formula II or a salt thereof in an organic solvent, adding a base in portions while cooling, then reacting with a compound of formula IV, and removing the Cbz protecting group by catalytic hydrogenation to give a compound of formula I; or reacting the compound of formula III with a condensing agent, then with an organic solvent for the compound of formula II or a salt thereof, adding a base, and then removing the Cbz protecting group by catalytic hydrogenation to give the compound of formula I, which can be further purified by conventional methods such as recrystallization, column chromatography, etc., if necessary. Here, the base may be an inorganic base or an organic base, and may be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or N, N-diisopropylethylamine, etc. Salifying the compound of the formula I with an organic solvent solution or an aqueous solution of an acid according to a ratio to obtain a salt of the compound of the formula I.

In particular, for compounds of the present invention in which the amino acid side chain has additional reactive functional groups, the side chain protected amino acid is used as the starting material, and a deprotection step is added after the condensation reaction.

In a third aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a water-soluble derivative of a substituted oxazolidinone, a compound of formula I, or a pharmaceutically acceptable acid salt thereof, which may further comprise a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition can also be combined with other active ingredients to form a combined composition or a composition with synergistic effect. The pharmaceutical composition can be administered by intravenous injection, by injection into tissue, intraperitoneal administration, oral administration or intranasal administration. The pharmaceutical composition may have a form selected from the group consisting of a solution, a dispersion, a suspension, a powder, a capsule, a tablet, a pill, an extended release capsule, an extended release tablet, and an extended release pill. The administration dosage of the pharmaceutical composition is 5-5000 mg/day.

In a fourth aspect, the present invention provides the use of a water-soluble derivative of a substituted oxazolidinone as defined above, such as a compound of formula I, or a pharmaceutically acceptable acid salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a bacterial infection in a host, including a warm-blooded animal, especially a human; wherein the bacteria are selected from gram positive bacteria such as staphylococci, enterococci or streptococci; anaerobic microorganisms such as bacteroides or clostridia; acid-resistant microorganisms such as Mycobacterium tuberculosis or Mycobacterium avium.

Has the advantages that: compared with the prior art, the novel substituted oxazolidinone water-soluble derivative has the characteristics of remarkable antibacterial infection activity, high bioavailability, very good water solubility (easy injection administration), convenient preparation, more stable curative effect, no incompatibility in clinical use, higher safety and the like.

Detailed Description

The technical solution of the present invention is described in detail by the following specific examples, and it is obvious to those skilled in the art that the embodiments of the present invention can be modified based on the prior art under the teaching of the present invention, and still fall into the protection scope of the present invention.

The sources of the compound starting materials used in the examples are: all reagents were purchased from reagent companies, and the compound of formula II was synthesized using the corresponding starting materials according to the method of chinese patent application 200480037612.2, and the compound of formula II was also purchased from reagent companies.

NMR data were collected and processed by a Bruker AV-300 NMR spectrometer.

Example 1: synthesis of MJ20824

(1) Synthesis of intermediate M24

Cbz-Lys (Cbz) -Pro-OH (S24,512mg,1mmol) is dissolved by 3ml of N, N-Dimethylformamide (DMF), the temperature is reduced to-5 ℃, DIC (63.1mg,0.5mmol) is added under stirring, the reaction is carried out for 30min at room temperature, the temperature is further reduced to-5 ℃, 2ml of DMF solution of II (185mg,0.5mmol) and catalytic amount of 4-Dimethylaminopyridine (DMAP) are sequentially added, the reaction is carried out for 4h at room temperature, after the reaction is finished, 15ml of water is poured, the mixture is extracted for 3 times by 15ml of ethyl acetate, organic layers are combined, anhydrous sodium sulfate is dried, the solvent is dried in a rotary manner to obtain yellow solid, and the yellow solid is separated by silica gel column chromatography to obtain 229mg of white-like powder (M24), and the yield is 53. MS (m/z): 864.3[ M +1] +.

(2) synthesis of MJ20824

M24(216mg,0.25mmol) was dissolved in 3ml of methanol, 5% Pd/C200 mg was added, reaction was carried out under hydrogen for 30min, after completion of the reaction, Pd/C was filtered off, the solvent was spun off from the filtrate, and separation was carried out by silica gel column chromatography to obtain 64mg of white powder (MJ20824), with a yield of 43.2%. MS (m/z): 596.3[ M +1] +; 1H-NMR (DMSO-d6) delta: 1.41-1.95(m,10H),2.16-2.28(m,2H),2.61-2.91(m,2H),3.41-3.53(m,1H),3.69-3.82(m,1H),3.88-3.98(m,1H),4.08-4.21(m,1H),4.23-4.32(m,1H),4.33-4.45(m,1H),4.47-4.55(s,3H),4.95-5.06(m,1H),7.49-7.58(d,1H),7.65-7.74(d,1H),7.75-7.84(m,1H),7.99-8.16(m,3H),8.17-8.27(m,2H),8.28-8.43(m,3H),8.91-8.99(s, 1H).

Example 2: synthesis of MJ20801

Referring to the synthesis of MJ20824, the difference is that Cbz-Gly-Pro-OH and II are selected as starting materials, and MJ20801 is obtained through condensation and deprotection. MS (m/z): 525.2[ M +1] +.

Example 3: synthesis of MJ20802

Reference is made to the synthesis of MJ20824, except that Cbz-Ala-Pro-OH and II are selected as starting materials, and finally MJ20802 is obtained through condensation and deprotection. MS (m/z): 539.2[ M +1] +.

Example 4: synthesis of MJ20803

Referring to the synthesis of MJ20824, the difference is that Cbz-Val-Pro-OH and II are selected as starting materials, and MJ20803 is obtained through condensation and deprotection. MS (m/z): 567.2[ M +1] +.

Example 5: synthesis of MJ20804

Referring to the synthesis of MJ20824, the difference is that Cbz-Gly-Ala-OH and II are selected as starting materials, and MJ20804 is finally obtained through condensation and deprotection. MS (m/z): 499.2[ M +1] +.

Example 6: synthesis of MJ20805

Reference is made to the synthesis of MJ20824, except that Cbz-Ala-Ala-OH and II are used as starting materials, which are condensed and deprotected to finally obtain MJ 20805. MS (m/z): 513.2[ M +1] +.

Example 7: synthesis of MJ20806

Referring to the synthesis of MJ20824, the difference is that Cbz-Val-Ala-OH and II are selected as starting materials, and MJ20806 is obtained through condensation and deprotection. MS (m/z): 541.2[ M +1] +.

Example 8: synthesis of MJ20807

Reference is made to the synthesis of MJ20824, except that Cbz-Leu-Ala-OH and II are used as starting materials, which are condensed and deprotected to finally obtain MJ 20807. MS (m/z): 555.2[ M +1] +.

Example 9: synthesis of MJ20808

Reference is made to the synthesis of MJ20824, which differs in that Cbz-Ile-Ala-OH and II are selected as starting materials, and finally MJ20808 is obtained through condensation and deprotection. MS (m/z): 555.2[ M +1] +.

Example 10: synthesis of MJ20809

reference is made to the synthesis of MJ20824, except that Cbz-Phe-Ala-OH and II are used as starting materials, which are condensed and deprotected to finally obtain MJ 20809. MS (m/z): 589.2[ M +1] +.

Example 11: synthesis of MJ20810

Referring to the synthesis of MJ20824, the difference is that Cbz-Trp (Boc) -Ala-OH and II are selected as starting materials, and the MJ20810 is finally obtained through condensation, removal of tert-butoxycarbonyl protection by hydrogen chloride, and removal of benzyloxycarbonyl protection by catalytic hydrogenation. MS (m/z): 628.2[ M +1] +.

Example 12: synthesis of MJ20811

Referring to the synthesis of MJ20824, the difference is that Cbz-Tyr (tBu) -Ala-OH and II are selected as starting materials, and MJ20811 is finally obtained through condensation, tert-butyl protection removal by hydrogen chloride, and debenzyloxy carbonyl protection removal by catalytic hydrogenation. MS (m/z): 605.2[ M +1] +.

Example 13: synthesis of MJ20812

Referring to the synthesis of MJ20824, the difference is that Cbz-Asn-Ala-OH and II are selected as starting materials, and MJ20812 is finally obtained through condensation and deprotection. MS (m/z): 556.2[ M +1] +.

example 14: synthesis of MJ20813

referring to the synthesis of MJ20824, the difference is that Cbz-Asp (OBzl) -Ala-OH and II are selected as starting materials, and are subjected to condensation and catalytic hydrogenation to remove carbobenzoxy protection, and MJ20813 is finally obtained. MS (m/z): 557.2[ M +1] +.

Example 15: synthesis of MJ20814

Referring to the synthesis of MJ20824, the difference is that Cbz-Glu (OBzl) -Ala-OH and II are selected as starting materials, and the protection of carbobenzoxy is removed through condensation and catalytic hydrogenation, and MJ20814 is finally obtained. MS (m/z): 571.2[ M +1] +.

Example 16: synthesis of MJ20815

Reference is made to the synthesis of MJ20824, except that Cbz-Gln-Ala-OH and II are used as starting materials, and MJ20815 is obtained by condensation and deprotection. MS (m/z): 570.2[ M +1] +.

Example 17: synthesis of MJ20816

Referring to the synthesis of MJ20824, the difference is that Cbz-Met-Ala-OH and II are selected as starting materials, and MJ20816 is finally obtained through condensation and Raney Ni catalytic hydrogenation debenzyloxy carbonyl protection. MS (m/z): 573.2[ M +1] +.

example 18: synthesis of MJ20817

Referring to the synthesis of MJ20824, the difference is that Cbz-Lys (Cbz) -Ala-OH and II are selected as starting materials, and MJ20817 is finally obtained through condensation and catalytic hydrogenation to remove the protection of carbobenzoxy. MS (m/z): 570.3[ M +1] +.

Example 19: synthesis of MJ20818

Referring to the synthesis of MJ20824, the difference is that Cbz-Ser (tBu) -Ala-OH and II are selected as starting materials, and MJ20818 is obtained finally through condensation, tert-butyl protection removal by hydrogen chloride, and debenzyloxy carbonyl protection removal by catalytic hydrogenation. MS (m/z): 529.2[ M +1] +.

example 20: synthesis of MJ20819

Referring to the synthesis of MJ20824, the difference is that Cbz-Thr (tBu) -Ala-OH and II are selected as starting materials, and MJ20819 is finally obtained through condensation, tert-butyl protection removal by hydrogen chloride, and debenzyloxy carbonyl protection removal by catalytic hydrogenation. MS (m/z): 543.2[ M +1] +.

Example 21: synthesis of MJ20820

Referring to the synthesis of MJ20824, the difference is that Cbz-Cys (Trt) -Ala-OH and II are selected as starting materials, and the MJ20820 is finally obtained through condensation, trityl protection removal by hydrogen chloride, and benzyloxycarbonyl protection removal by Raney Ni catalytic hydrogenation. MS (m/z): 545.2[ M +1] +.

Example 22: synthesis of MJ20821

Reference is made to the synthesis of MJ20824, except that Cbz-Pro-Ala-OH and II are selected as starting materials, and finally MJ20821 is obtained by condensation and deprotection. MS (m/z): 539.2[ M +1] +.

Example 23: synthesis of MJ20822

Referring to the synthesis of MJ20824, the difference is that Cbz-His (Trt) -Ala-OH and II are selected as starting materials, and the MJ20822 is finally obtained through condensation, trityl protection removal by hydrogen chloride, and debenzyloxy carbonyl protection removal by catalytic hydrogenation. MS (m/z): 579.2[ M +1] +.

Example 24: synthesis of MJ20823

Referring to the synthesis of MJ20824, the difference is that Cbz-Arg (Boc)2-Ala-OH and II are selected as starting materials, and the MJ20823 is finally obtained through condensation, removal of tert-butoxycarbonyl protection by hydrogen chloride, and removal of benzyloxycarbonyl protection by catalytic hydrogenation. MS (m/z): 598.3[ M +1] +.

Example 25: synthesis of MJ20825

Referring to the synthesis of MJ20824, the difference is that Cbz-Ser (tBu) -Pro-OH and II are selected as starting materials, and MJ20825 is obtained finally through condensation, tert-butyl protection removal by hydrogen chloride, and debenzyloxy carbonyl protection removal by catalytic hydrogenation. MS (m/z): 555.2[ M +1] +.

example 26: synthesis of MJ20826

Reference is made to the synthesis of MJ20824, which differs in that Cbz-Ala-Gly-OH and II are selected as starting materials, and finally MJ20826 is obtained through condensation and deprotection. MS (m/z): 499.2[ M +1] +.

Example 27: synthesis of MJ20827

referring to the synthesis of MJ20824, the difference is that Cbz-Val-Gly-OH and II are selected as starting materials, and MJ20827 is obtained through condensation and deprotection. MS (m/z): 527.2[ M +1] +.

Example 28: synthesis of MJ20828

Referring to the synthesis of MJ20824, the difference is that Cbz-Gly-Gly-OH and II are selected as starting materials, and are subjected to condensation and deprotection to finally obtain MJ 20828. MS (m/z): 485.2[ M +1] +.

Example 29: preparation of the hydrochloride salt of the Compound of formula I

Dissolving the compound in a mixed solvent of methanol and ethyl acetate, dropwise adding an ethyl acetate solution of hydrogen chloride, removing part of the solvent by spinning, replacing the solvent by using the mixed solvent of ethyl acetate and petroleum ether, and performing rotary evaporation for 3 times, wherein the solid is washed for 3 times by using the mixed solvent of ethyl acetate and petroleum ether, so that hydrochloride of the compound MJ20801-MJ20828 is obtained.

Example 30: test for solubility of Compounds

The product is taken, ground into fine powder and operated according to the solubility of the two examples in the 2010 version of the Chinese pharmacopoeia. Accurately weighing a proper amount of a sample, adding water, placing in a water bath at 25 ℃, shaking for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes, and if no visible particles are considered to be dissolved, the dissolution experiment result is shown in table 1;

TABLE 1 results of dissolution test of the compounds

Sample (I)	Solubility (%)
		Tidilazoli	<0.008％
MJ20801-MJ 20803 (hydrochloride)	>3.8％
		MJ 20804-MJ 20823 (hydrochloride)	>3.1％
MJ 20824-MJ 20825 (hydrochloride)	>3.3％
		MJ20826 MJ20828 (hydrochloride)	>3.7％

The above results show that the compound (hydrochloride) of the present invention has a water solubility more than 310 times higher than that of tedizolid.

The tedizolid is white powder with low water solubility, the medicine for injection administration needs good solubility, and the hydrochloride of the compound has good water solubility, so that the preparation is convenient.

Example 31: biotransformation assay of Compounds of formula I in human plasma

The compounds of the invention need to be converted in vivo to compounds of formula II for pharmaceutical action, so the degree of in vivo biotransformation is directly related to the potency. Dissolving a test compound by using methanol to prepare a solution with the concentration of 10mg/ml, taking 3ul, adding the solution into 300ul of plasma, incubating for 2 hours at 37 ℃, taking 100ul of incubated plasma, adding 900ul of methanol, vortexing for 3min, centrifuging for 3min at 10000 rpm, feeding 20ul of supernate, analyzing by using high performance liquid chromatography, and calculating the conversion rate by using an area normalization method, namely the peak area of the compound shown in the formula II/(the peak area of the compound shown in the formula II + the peak area of the compound shown in the invention). The results are shown in table 2:

TABLE 2 human plasma incubation conversion for 1 hour

Compound (I)	MJ20801-20803	MJ20804-20823	MJ20824-20825	MJ20826-20828
					Conversion rate	96％	About 65 percent	97％	About 58 percent

Example 32: compatibility testing of Compounds of formula I with solutions containing divalent cations

Tedizolid phosphate group: 20 mg of tedizolid phosphate is precisely weighed and placed in a 1.5ml plastic centrifuge tube, 0.4 ml of purified water is added, sodium hydroxide solution (about 14 drops; 44.41mg of sodium hydroxide is dissolved in 10ml of purified water) is dropwise added as little as possible to assist dissolution, and the tedizolid phosphate stock solution is completely dissolved. Taking 8ml of compound sodium chloride injection (ringer's solution) and placing the compound sodium chloride injection into a 10ml centrifuge tube, dripping 2 drops of tedizolid phosphate stock solution, standing, observing and then centrifuging.

Blank group: 0.4 ml of purified water was added to an empty 1.5ml centrifuge tube, and 15 drops of sodium hydroxide solution (44.41mg of sodium hydroxide dissolved in 10ml of purified water) were added dropwise to form a blank stock solution. Taking 8ml of compound sodium chloride injection (ringer's solution) and placing the compound sodium chloride injection into a 10ml centrifuge tube, dripping 2 drops of blank stock solution, standing, observing and then centrifuging.

Test groups: 30 mg of hydrochloride of the compound MJ20801-MJ20828 is weighed and placed in a 1.5ml plastic centrifuge tube, and the centrifuge tube is dissolved by 0.4 ml of purified water to form a stock solution after complete dissolution. And (3) putting 8ml of compound sodium chloride injection (ringer's solution) into a 10ml centrifuge tube, dropwise adding 2 drops of the stock solution, standing, observing and centrifuging. The results are shown in Table 3:

TABLE 3 compatibility test of the Compounds with calcium ions

Compound (I)	Tedizolid phosphate group	Blank group	Test group MJ20801-20828
				Phenomenon of standing	White turbidity	Clarification	Clarification
after centrifugation	Bottom white precipitate	No precipitation	No precipitation

Phosphate radical can form precipitation with bivalent metal ions (such as calcium ions and magnesium ions), so the clinically used tedizolid phosphate injection cannot be used together with injection (ringer's solution and the like) containing bivalent metal ions, the compound does not react with the bivalent metal ions, and the compound has no incompatibility with the ringer's solution during use.

Example 33: pharmaceutical compositions formulated with the compounds of the invention or their pharmaceutically acceptable acid salts as active ingredients

the pharmaceutical composition comprises hydrochloride of the compound, mannitol and water for injection; the specific formula is as follows: weighing 150g of mannitol, adding 4000ml of water for injection, stirring and dissolving to obtain a 3.75% mannitol solution. 300g of hydrochloride of the compound of the present invention was weighed and added to 4000ml of the above 3.75% mannitol solution, followed by stirring and dissolution. Filtering with 0.22 μm filter membrane, packaging into penicillin bottles (4 ml/bottle), freeze drying, and sealing with gland.

Example 34: tests for combating bacterial infections with the Compounds of the invention

The test is carried out by adopting a trace broth dilution method, the compound of the invention is dissolved by deionized water to prepare a solution about 1mg/mL, and then a proper amount of solution is removed and diluted by the deionized water. The MIC of the compound is determined on a 96-well bacterial culture plate, linezolid solution is used as a positive control, deionized water is used as a blank control, the test compound is repeated for 1 time, corresponding sample solution and diluted clinical separation methicillin-resistant staphylococcus aureus (MRSA) suspension (1 multiplied by 107CFU/mL) are added into each well, the wells are tightly covered, the wells are placed in a shaking table at the temperature of 37 ℃ at 160r/min, 20 mu L of thiazole blue (MTT, 4mg/mL) is added into each well after 24 hours of culture and is shaken evenly without color change, and the minimum reagent concentration in each well is the MIC of the test compound to the test strain. The minimum inhibitory concentration of the compounds of the invention against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was determined in this way. The results are shown in Table 4:

TABLE 4 minimal inhibitory concentrations of the compounds of the invention against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA)

As can be seen from the data in Table 4, the drug provided by the invention has a good inhibition effect on methicillin-resistant staphylococcus aureus under a low concentration condition when used for carrying out a bacteriostasis test on methicillin-resistant staphylococcus aureus, so that the product provided by the invention has a good effect on resisting bacterial infection.

As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable acid salt thereof:

Wherein:

R1 is a dipeptide acyl or polypeptide acyl group wherein at least one amino acid acyl group is formed from a natural amino acid, said compound selected from the group of structures:

。

2. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable acid salt thereof.

3. The use of a compound of formula I, or a pharmaceutically acceptable acid salt thereof, as claimed in claim 1, or a pharmaceutical composition as claimed in claim 2, in the manufacture of a medicament for the prophylaxis or treatment of bacterial infections in warm-blooded animals.

4. Use according to claim 3, characterized in that: the bacteria are selected from gram-positive bacteria, anaerobic microorganisms or acid-resistant microorganisms.