CN103709102B - Containing whorled pleuromulins microbiotic - Google Patents

Containing whorled pleuromulins microbiotic Download PDF

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CN103709102B
CN103709102B CN201310452247.2A CN201310452247A CN103709102B CN 103709102 B CN103709102 B CN 103709102B CN 201310452247 A CN201310452247 A CN 201310452247A CN 103709102 B CN103709102 B CN 103709102B
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amino
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CN103709102A (en
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张蕙
王爱臣
孙亮
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to shown in logical formula I containing whorled pleuromulins microbiotic, its pharmacy acceptable salt, its prodrug, its solvate or its steric isomer, wherein R 1, m, A and X definition define with the specification above; The invention still further relates to the preparation method of these compounds, the pharmaceutical composition containing these compounds and pharmaceutical preparation, and these compounds are preparing the application treated and/or prevented in the medicine of the disease caused by microorganism.

Description

Spiro-containing pleuromutilin antibiotics
1. Field of the invention
The invention belongs to the technical field of medicines, and relates to a pleuromutilin antibiotic containing a spiro ring, a pharmaceutically acceptable salt, a prodrug, a solvate, a deuteron or a stereoisomer thereof, a preparation method of the compounds, a pharmaceutical composition and a pharmaceutical preparation containing the compounds, and application of the compounds in preparing medicines for treating and/or preventing diseases caused by microorganisms.
2. Background of the invention
Pleuromutilin antibiotics (Pleurothelin antibiotics) are diterpene antibiotics, which are fused by five-membered ring, six-membered ring and eight-membered ring to form a 5-6-8 tricyclic diterpene structure, and are separated from two basidiomycetes (basidiomycetes species), Pleurotus mutilis (Pleurothelius) and P.paseckerianus in 1951.
Pleuromutilin antibiotics exert antibacterial activity by inhibiting bacterial protein synthesis, and based on the unique action mechanism, cross drug resistance is not found clinically at present, and excellent clinical application characteristics are shown. However, few studies to date have found that veterinary drug Tiamulin (Tiamulin) is used to treat swine dysentery, swine epidemic pneumonia and chronic respiratory disease in poultry, and Retapamulin (Retapamulin) is successfully applied as an ointment to human skin pustular dermatitis infection.
In addition, other pleuromutilin derivatives are still under investigation, and as disclosed in patents EP1972618, WO0222580 and the like, pleuromutilin compounds are used as antibacterial agents.
Based on the current clinical needs, researches and developments of pleuromutilin antibiotic medicines which have good antibacterial activity and stable metabolism and are used for treating human skin soft tissue infection and pneumonia infection are urgently needed.
3. Summary of the invention
In order to meet clinical requirements, the invention provides pleuromutilin antibiotic medicaments which have good antibacterial activity and less metabolic elimination and are used for treating human skin soft tissue infection and pneumonia infection, and the specific technical scheme is as follows:
a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
wherein R is1Is hydrogen, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radicalRadical, halo C1-6Alkoxy radical, C1-6Alkylthio, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyl, sulfonic acid, sulfonyl C1-6Alkyl, sulfonamide C1-6Alkyl, aminosulfonyl, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, aminosulfonyl C1-6Alkyl radical, C1-6Alkylaminocarbonyl, di (C)1-6Alkyl) carbamoyl, carbamoyl C1-6Alkyl, 3-14 membered cycloalkyl, 6-14 membered aryl C1-6Alkyl, 3-14 membered heterocyclic group C1-6An alkyl group, a carboxyl group,
or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R5A substituted 3-14 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
a is unsubstituted or substituted by 1 to 6R6Substituted 5-14 membered spirocyclic group wherein said R is6Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkyl amino formyl group,
x is-O-, -S-, -SO2-、-COO-、NR7、CONR7-NHCONH-or a bond;
R7is hydrogen or C1-6An alkyl group;
m and n are 0, 1,2,3 or 4.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein R is1Is hydrogen, C1-6Alkyl, or a group of the formula:
R2and R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R5A substituted 3-14 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-to 14-membered cycloalkyl or 3-to 14-membered heterocyclyl,
a is unsubstituted or substituted by 1 to 3R6Substituted 6-11 membered spirocyclic group, wherein said R6Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
m and n are each independently 0, 1 or 2.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein,
R1is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R4Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R4Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R5A substituted 3-6 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl, amino, and amino,Carbamoyl radical C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
a is unsubstituted or substituted by 1-2R6Substituted 7-9 membered spirocyclic group wherein said R6Selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
m is 0 or 1; n is 0, 1 or 2.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein,
R1is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R4Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiathiopheneThiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, a benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R4、R5independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted 7-9 membered spirocyclic group wherein said R6Selected from hydrogen, fluoro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
m is 0 or 1; n is 0, 1 or 2.
The compound represented by the general formula (i), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof is more preferably:
wherein,
R1is hydrogen, methyl, ethyl, or a group of the formula
R2And R3Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, methylmercapto, methylamino, ethylamino, methyl ethyl,
(3) Unsubstituted or substituted by R4Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R4、R5independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted by Wherein said R6Selected from hydrogen, fluoro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino;
m is 0 or 1; n is 0, 1 or 2.
The other technical scheme of the invention is as follows: a compound represented by the general formula (II), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
wherein R is1Is hydrogen, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkylthio, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyl, sulfonic acid, sulfonyl C1-6Alkyl, sulfonamide C1-6Alkyl, aminosulfonyl, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, aminosulfonyl C1-6Alkyl radical, C1-6Alkylaminocarbonyl, di (C)1-6Alkyl) carbamoyl, carbamoyl C1-6Alkyl, 3-14 membered cycloalkyl, 6-14 membered aryl C1-6Alkyl, 3-14 membered heterocyclic group C1-6An alkyl group, a carboxyl group,
or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R5A substituted 3-14 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
a is unsubstituted or substituted by 1 to 6R6Substituted 5-14 membered spirocyclic group wherein said R is6Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkyl amino formyl group,
R7is hydrogen or C1-6An alkyl group; m and n are 0, 1,2,3 or 4.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein R is1Is hydrogen, C1-6Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R4Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R5A substituted 3-14 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-to 14-membered cycloalkyl or 3-to 14-membered heterocyclyl,
a is unsubstituted or substituted by 1 to 3R6Substituted 6-11 membered spirocyclic group, wherein said R6Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
m and n are each independently 0, 1 or 2.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein R is1Is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R4Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R4Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R5A substituted 3-6 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
a is unsubstituted or substituted by 1-2R6Substituted 7-9 membered spirocyclic group wherein said R6Selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
m is 0 or 1; n is 0, 1 or 2.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein R is1Is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R4Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R4、R5independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted 7-9 membered spirocyclic group wherein said R6Selected from hydrogen, fluorine, methyl, trifluoromethyl, hydroxyl, hydroxymethyl and aminoMethylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
m is 0 or 1; n is 0, 1 or 2.
The compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof is more preferably:
wherein R is1Is hydrogen, methyl, ethyl, or a group of the formula
R2And R3Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, methylmercapto, methylamino, ethylamino, methyl ethyl,
(3) Unsubstituted or substituted by R4Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R4、R5independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted by Wherein said R6Selected from hydrogen, fluoro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino;
m is 0 or 1; n is 0, 1 or 2.
Detailed Description
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. Fluorine atom and chlorine atom are preferred.
The term "halo" as used herein means that any atom in the group which can be substituted is substituted by halogen, and can be perhalogenated, i.e., the halogen atom is substituted at all positions in the group which can be substituted.
Said "C" of the present invention1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. Preferably C1-3An alkyl group. Said "C" of the present invention1-3Alkyl "refers to the above examples containing 1 to 3 carbon atoms.
Said "C" of the present invention2-6The "alkenyl group" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and having a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl, 3-methyl group-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2-methyl-3-pentenyl, 3-methyl-1-pentenyl, 2-methyl-2-hexenyl, 2, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 2-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1,1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-methyl-2-butenyl, 2-methyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-ethyl-1-butenyl, 1, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-6Alkynyl "means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having a triple bond, such as ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, etc, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4Pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-6Alkoxy "means" C1-6Alkyl "a group bonded to another structure through an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 1-methylpropyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropyloxy and 1-ethyl-2-methylpropyloxy. The term "C1-3The "alkoxy group" refers to a specific example containing 1 to 3 carbon atoms among the above examples.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "a group attached to another structure through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
Said "C" of the present invention1-6Alkoxycarbonyl "is the term" C1-6Alkoxy "a group bonded to another structure through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.
The "3-to 14-membered cycloalkyl group" as referred to herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes a 3-to 8-membered monocyclic cycloalkyl group, a 6-to 14-membered carbocyclic fused cycloalkyl group, a 7-to 12-membered carbocyclic bridged cyclic group and a 5-to 14-membered carbocyclic spiro cyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-8Cycloalkyl group "," C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the following examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like;
the 6-14-membered carbocyclic fused ring group means a 6-14-membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, and includes a 6-14-membered saturated fused ring group and a 6-14-membered partially saturated fused ring group. 6-to 12-membered fused ring group, 6-to 10-membered fused ring group are preferred. 6-14 membered saturated fused cycloalkyl, meaning that the fused ring group is a fully saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl and the like. A 6-14 membered partially saturated fused cycloalkyl group, meaning that at least one ring in the fused ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentalenyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9, 10-decahydrophenanthryl and the like;
5-14 membered carbocyclic bridged ring groups are structures containing 5-14 carbon atoms formed by any two rings sharing two atoms not directly connected, and "5-14 membered bridged ring" includes 5-14 membered saturated bridged ring groups, 5-14 membered partially saturated bridged ring groups. 5-14 membered saturated bridged ring group, preferably 6-10 membered saturated bridged ring group, including but not limited to bicyclo [2.1.1] hexanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.1] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [4.3.1] nonanyl, 4-azabicyclo [5.3.1] decanyl and the like. 7-12 membered partially saturated bridged ring group means a cyclic group in which at least one ring in the bridged ring is unsaturated, preferably 6-10 membered partially saturated bridged ring group, and specific examples include, but are not limited to, bicyclo [2.2.1] hept-5-enyl, bicyclo [3.2.1] oct-6-enyl, bicyclo [4.3.1] non-5-enyl, biscyclopentadienyl and the like;
5-14 membered carbocyclic spiro ring groups are a class of 5-14 membered carbocyclic fused ring structures formed by at least two rings sharing an atom. 5-14 membered saturated spiro ring group means that all rings in the spiro ring group are saturated cyclic groups, specific examples include but are not limited to:and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 5-14 membered partially saturated spiro ring group means a cyclic group in which at least one ring of the spiro ring group is unsaturated, and specific examples include, but are not limited to: in the shape of an iso-ringA group formed by substituting an optionally substitutable hydrogen atom with a structure, and the like. Preferred are 7-to 10-membered spiro ring groups, including "7-to 10-membered saturated spiro ring groups" and "7-to 10-membered unsaturated spiro ring groups".
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "a group attached to another structure through an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.
The "6-14 membered aryl" in the present invention means a cyclic aromatic group having 6-14 membered carbon atoms as ring atoms, and includes 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. The 6-8 membered monocyclic aryl group means an all unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. Preferably 6-to 10-membered aryl, more preferably benzene or a benzo 3-to 8-membered saturated monocyclic cycloalkyl, a benzo 3-to 8-membered partially saturated monocyclic cycloalkyl. The term "6-to 10-membered aryl" refers to a specific example of the above-mentioned "aryl" having 6 to 10 ring atoms.
The "5-to 14-membered heteroaryl" includes one or more heteroatoms in addition to carbon atoms in the ring, including but not limited to oxygen, nitrogen, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Including 5-8 membered monocyclic heteroaryl and 8-14 membered fused heterocyclic aryl. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl, oxadiazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, isooxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; 8-14 membered fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b ] pyridyl, purinyl, acridinyl, xanthenyl, and the like.
The term "3-14 membered heterocyclic group" as used herein means a 3-14 membered cyclic group containing one or more heteroatoms, wherein the "heteroatom" means N, S, O, SO and/or SO2And the like. Including saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO23-8 membered heteromonocyclic group and 5-14 membered heteromonocyclic group of the hetero atom of (a). Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. 5-14 membered diheterocyclyl includes saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferred is a 3-to 8-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 3-to 8-membered heteromonocyclic group. More preferred is a 5-8-membered, 5-7-membered, 5-6-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 5-8-membered, 5-7-membered, 5-6-membered heteromonocyclic group.
3-8 membered heteromonocyclic group means a monocyclic heterocyclic group containing 3 to 8 ring atoms (wherein at least one hetero atom is contained), and includes 3-8 membered unsaturated heteromonocyclic group, 3-8 membered partially saturated heteromonocyclic group, 3-8 membered saturated heteromonocyclic group. Preference is given to 5-7-membered unsaturated heteromonocyclic groups, 5-7-membered partially saturated heteromonocyclic groups, 5-7-membered saturated heteromonocyclic groups. 3-8 membered unsaturated Monoheterocyclyl, which means an aromatic heteroatom-containing cyclic group, specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, oxacycloheptatrienyl, oxa-yl, oxacycloheptatrienyl, and the like, Thiepinatrienyl, azepinatrienyl, 1, 3-diazacycloheptatrienyl, azepintetraenyl, and the like. 3-8 membered partially saturated monoheterocyclyl means a cyclic group containing a double bond, a heteroatom, and specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, and the like. 3-8 membered saturated monoheterocyclyl, refers to heteroatom-containing cyclic groups that are all saturated bonds, specific examples include, but are not limited to: aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
Said has 1-4 selected from N, S, O and/or SO2Is a fused, spiro or bridged ring of a heteroatom, in particular a fused, spiro or bridged ring in which one of the carbon atoms not shared by it is N, S, O and/or SO2The heteroatom(s) in place of the 6-to 14-membered heterocyclic group, 5-to 14-membered spiroheterocyclic group, 5-to 14-membered bridged heterocyclic group formed.
The 6-to 14-membered heterocyclic group means a heterocyclic ring structure having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two adjacent atoms to each other, and includes a 6-to 14-membered unsaturated heterocyclic group, a 6-to 14-membered partially saturated heterocyclic group, and a 6-to 10-membered saturated heterocyclic group. 6-14 membered unsaturated heterocyclo means that all rings are unsaturated fused ring structures such as structures formed by benzo 3-8 membered unsaturated heteromonocyclic group, structures formed by 3-8 membered unsaturated heteromonocyclic group and 3-8 membered unsaturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: benzofuranyl, benzisofuranylBenzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenanthridinyl, phenanthridin,And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. The 6-14 membered partially saturated and heterocyclic group means a condensed ring structure containing at least one partially saturated ring, such as a structure formed by a benzo 3-8 membered partially saturated heteromonocyclic group, a structure formed by a 3-8 membered partially saturated heteromonocyclic group and a 3-8 membered partially saturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: 1, 3-dihydrobenzofuranyl, benzo [ d ]][1.3]Dioxolyl, isoindolinyl, chromanyl, 1,2,3, 4-tetrahydropyrrolo [3,4-c ]]Pyrrole, pyrrole, And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 6-to 10-membered saturated and heterocyclic group means a fused ring structure in which all rings are saturated, such as a structure formed by a 3-to 8-membered saturated heteromonocyclic group and a 3-to 8-membered saturated heteromonocyclic group, and specific examples include, but are not limited to: cyclobutane tetrahydropyrrole, cyclopentane tetrahydropyrrole, azetidine imidazolidine radical,And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The 5-14 membered bridged heterocyclic group means a bridged ring structure formed by 5 to 14 ring atoms (containing at least one hetero atom therein). "5-14 membered bridged heterocyclic group" includes 5-14 membered saturated bridged heterocyclic group, 5-14 membered partially saturated bridged heterocyclic group.
5-14 membered saturated bridged heterocyclyl, meaning all of the bridged heterocyclylsThe rings are saturated cyclic groups, preferably 7-8 membered saturated bridged heterocyclic groups, specific examples include, but are not limited to: and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-14 membered partially saturated bridged heterocyclyl means that there is a cyclic group in the bridged heterocyclyl in which at least one ring is unsaturated, preferably 7-8 membered partially saturated bridged heterocyclyl, specific examples include, but are not limited to:and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-14 membered spiroheterocyclyl means a spirocyclic structure formed by 5-14 ring atoms containing at least one heteroatom. The 5-14 membered spiroheterocyclic group includes a 5-14 membered saturated spiroheterocyclic group, a 5-14 membered partially saturated spiroheterocyclic group.
5-14 membered saturated spiroheterocyclyl, meaning that all rings in the spiroheterocyclyl are saturated cyclic groups, specific examples include, but are not limited to: and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-14 membered partially saturated spiroheterocyclic group, meaning that at least one ring of said spiroheterocyclic group is unsaturatedSpecific examples include, but are not limited to:and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The terms 3-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group mean specific examples in which the number of ring atoms in the above-mentioned "3-14 membered heterocyclic group" is 3-8, 5-7, 5-6 membered.
In the present invention, the term "3-14-membered cyclic group" means a 3-14-membered saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group containing a heteroatom selected from N, O and S, and includes a 3-6-membered cyclic group, a 3-14-membered cycloalkyl group, a 6-14-membered aryl group, a 5-14-membered aryl group and a 3-14-membered heterocyclic group, wherein:
"3-6 membered cyclic group" includes, but is not limited to, for example, the following groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine, azetidine, 1, 2-diazacyclobutene, pyrrole, 4, 5-dihydropyrrole, 2, 5-dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, 1,2, 4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1, 2-dithiocyclobutene, furan, 4, 5-dihydrofuran, 2, 5-dihydrofuran, thiophene, 2, 5-dihydrothiophene, 4, 5-dihydrothiophene, 1, 2-dithiole, 1, 3-dithiole, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiine, 1, 4-oxathiahexadiene, oxazole, 4, 5-dihydrooxazole, 2, 3-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, 2, 3-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, benzene ring, pyridine group and the like.
The 5-14 membered spiro ring group refers to a 5-14 membered fused ring structure formed by at least two rings sharing one atom. Including the 5-to 14-membered carbocyclic spiro ring group described above and the compound having 1 to 4 substituents selected from N, S, O and/or SO2The heteroatom of (5) to (14) membered spiroheterocyclyl. Specific examples include, but are not limited to: and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. A "6-to 11-membered spiro ring group" is preferable, and a "7-to 9-membered spiro ring group" is more preferable.
"6-to 11-membered spirocyclic group" and "7-to 9-membered spirocyclic group" refer to specific examples in which the number of ring atoms in the "5-to 14-membered spirocyclic group" is 6-to 11-and 7-to 9-membered.
The term "1 to 3" as used herein means 1,2 or 3.
Particularly preferred compounds include:
a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof.
In one embodiment, the present invention provides a process for the preparation of the above-described compounds of the present invention.
In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above.
In one embodiment, the present invention provides a method for treating and/or preventing a disease caused by a microorganism using the above-described compound of the present invention.
In one embodiment, the present invention provides the use of a compound of the invention as described above for the preparation of a medicament for the treatment and/or prevention of a disease caused by a microorganism.
The above compounds of the present invention can be synthesized using the methods described in the schemes below and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods below.
The reaction equation is as follows:
the reaction steps are as follows:
step 1: dissolving raw materials 1 and 2, inorganic base (such as NaOH, KOH, etc.) water solution and phase transfer catalyst (such as triethyl benzyl ammonium chloride) in organic solvent (such as DMF, dioxane, THF), heating under nitrogen protection for reaction, concentrating, adding water, extracting with organic solvent, drying, concentrating, and separating with silica gel column to obtain intermediate 1.
Step 2: intermediate 1, starting material 3, HATU and DIEA are dissolved in an organic solvent (e.g., DCM, THF) and reacted to completion at room temperature. Or dissolving the intermediate 1 in methanol, adding the raw material 3 in ice water bath, reacting for 1-2h, adding a reducing agent (such as sodium triacetoxyborohydride), reacting at room temperature, adding water, extracting with an organic solvent, drying, concentrating, and separating with a silica gel column to obtain the compound of formula 1.
The raw materials 1 and 2 in the above reaction equation are prepared by converting easily available raw materials through simple functional groups. R in the above reaction equation1M, X, A are as defined above.
The compounds of the present invention include compounds in any form, such as free forms, salt forms, solvate forms, and salt and solvate forms.
According to another aspect, the present invention provides a compound of the invention in the form of a salt and/or solvate.
The salts preferably include pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are also included, for example, for purposes of preparation, isolation, purification.
Salts of the compounds of the present invention include base or acid addition salts. Pharmaceutically acceptable base salts include ammonium salts such as the tri ylammonium salt, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases including primary, secondary and tertiary amines such as isopropylamine, diethylamine, ethanolamine, tri amine, dicyclohexylamine and N-methyl-D-glucamine, preferably the sodium salt.
The acid addition salts may be pharmaceutically or non-pharmaceutically acceptable salts. When a non-pharmaceutically acceptable salt, it can be used to isolate and purify the compound of the invention or an intermediate thereof, and then converted into a pharmaceutically acceptable salt or a free base. Pharmaceutically acceptable acid addition salts include those described in journal of pharmaceutical sciences (j.pharm.sci), 1977, 66, 1-19. Such as hydrogen fumarate (hydrogen fumarate), fumaric acid, tartaric acid, ethane-1, 2-disulfonic acid, maleic acid, naphthalene-1, 5-sulfonic acid, acetic acid, maleic acid, succinic acid, salicylic acid, azelaic acid, 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid, hydrochloric acid, deuterochloric acid (deuterochloric aid); hydrochloric acid is preferred.
"pharmaceutically acceptable salts" of the compounds of the present invention refers to base addition salts or acid addition salts of the compounds of the present invention with pharmaceutically acceptable, non-toxic bases or acids, including organic acid salts, inorganic acid salts, organic base salts, inorganic base salts. The organic acid salt includes formate, acetate, propionate, benzenesulfonate, benzoate, p-toluenesulfonate, 2, 3-dihydroxysuccinate, camphorsulfonate, citrate, methanesulfonate, ethanesulfonate, propanesulfonate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, succinate, tartrate and the like, and benzoate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, tartrate are particularly preferable. The inorganic acid salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate and the like, and the hydrochloride, hydrobromide, sulfate, phosphate are particularly preferable. Organic base salts include amine salts, including salts with primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins, and may be selected from salts with the following organic bases: such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The inorganic base salt includes salts with ammonia, alkali metals and alkaline earth metals, such as ammonium salts and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, copper, ferrous, manganese and manganous salts, with ammonium salts and sodium, potassium, calcium and magnesium salts being particularly preferred.
The compounds of the invention in free form can be converted to the corresponding compounds in salt form and vice versa. The compounds of the invention in free form or in salt form and/or solvate form can be converted into the corresponding compounds in non-solvate form, in free form or in salt form; and vice versa.
The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount (stoichiometric amount) of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. When the solvent is water, the term "hydrate" is used.
The structures described herein also include compounds in which one or more isotopically enriched atoms are present. For example, structures having the invention but including replacement of hydrogen by deuterium or tritium or enrichment of carbon13C or14Carbon-substituted compounds of C are within the scope of the present invention.
The use of prodrugs, such as esters, of the compounds to which the invention relates is also part of the invention. By "prodrug" is meant a compound which can be converted in vivo by metabolic means (e.g., by hydrolysis, reduction or oxidation) to a compound of formula (I). For example, ester prodrugs of compounds of formula (I) may be converted in vivo to the parent molecule by hydrolysis. Examples of ester prodrugs are those described in f.j.leinweber, Drug metab.res, 1987, 18, 379. As used herein, reference to the meaning of the compounds of formula (I) also includes prodrug forms.
The compounds of the present invention may exist as isomers and mixtures thereof, such as optical isomers, diastereomers, cis/trans conformers. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers (enatiomers) or diastereomers and mixtures thereof, e.g., racemates or diastereomeric mixtures. Any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration.
The compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The present invention includes all stereoisomeric forms of these compounds.
The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified.
The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. Each tautomer and mixtures thereof are included in the compounds of the invention.
The configuration of the substituent attached to the asymmetric carbon atom of the tiamulin-tricycles (tricyclus) is preferably the same as the configuration of the natural pleuromutilins.
The isomer mixtures can be separated as desired, for example, in analogy to conventional methods, to give the pure isomers. The present invention includes compounds of the present invention in any isomeric form and any isomeric mixture thereof. The present invention also includes tautomers of the compounds of the present invention, as long as tautomers can exist.
The compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals.
For example, the compounds of the present invention exhibit antimicrobial activity, such as the following: against gram-positive bacteria, for example coagulase-positive Staphylococci (Staphylocci) such as Staphylococcus aureus (Staphyloccus aureus), coagulase-negative Staphylococci such as Staphylococcus epidermidis (Staphyloccus epidermidis), Staphylococcus haemolyticus (Staphyloccus haemolyticus), and Streptococcus (Streptococcus) such as Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus agalactiae (Streptococcus agalactiae), Streptococcus pneumoniae (Streptococcus pneumoniae), Enterococci (Enterococci) such as Enterococcus faecalis (Enterococcus faecalis), and Listeria monocytogenes (Listeria monocytogenes); and anti-gram-negative bacteria such as Moraxella (Moraxella) such as Moraxella catarrhalis (Moraxella catarrhalis), Haemophilus such as Haemophilus influenzae (Haemophilus influenzae), Legionella such as Legionella pneumophila and Legionella (Legionella pneumochysiella), Neissiaceae such as Neisseria gonorrhoeae (Neisseria gonorrhoeae), and anti-mycoplasmas (Mycoplasma), Chlamydia (Chlamydia), and obligate anaerobes such as Bacteroides fragilis (Bacteroides fragilis), Clostridium difficile (Clostridium difficile), Clostridium (Fusobacterium spp.) and Propionibacterium (Propionibacterium spp.).
The compounds of the invention are therefore suitable for the treatment and prophylaxis of diseases which are mediated by microorganisms, for example bacteria. Diseases that can be treated also include, for example, Helicobacter (Helicobacter pylori) mediated diseases and Mycobacterium tuberculosis (Mycobacterium tuberculosis) mediated diseases. Diseases that can be treated also include inflammatory diseases in general, where the inflammation, including acne for example, is mediated by microorganisms.
In another aspect, the present invention provides a compound of the invention for use as a medicament, preferably as an antimicrobial such as an antibiotic and e.g. an anti-hypoxic medicament.
In another aspect, the invention provides a compound of the invention for use in the treatment of acne.
In a further aspect, the present invention provides a compound of the invention for use in the preparation of a medicament for the treatment of a disease mediated by a microorganism such as a bacterium, for example:
diseases mediated by bacteria, for example selected from staphylococci, streptococci, enterococci;
diseases mediated by bacteria, for example selected from the group consisting of moraxella, haemophilus, legionella, neisseriaceae;
diseases mediated by helicobacter;
diseases mediated by mycobacterium tuberculosis; such as diseases mediated by mycoplasma, chlamydia and obligate anaerobes.
In a further aspect, the present invention provides a method of treating a disease mediated by a microorganism, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g., in the form of a pharmaceutical composition.
In a further aspect, the present invention provides a method for treating acne comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, e.g. in the form of a pharmaceutical composition.
Treatment includes both treatment and prevention.
For antimicrobial and acne treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and pharmacokinetic data of the compound of the invention employed, the host individual, the mode of administration, and the nature and severity of the condition being treated. In general, however, in order to achieve satisfactory results in most mammals, e.g. humans, a recommended daily dose is from about 0.5mg to 3g of a compound of the invention, suitably administered, e.g. in divided doses up to four times a day.
The compounds of the invention may be administered, for example, in the form of coated or uncoated tablets, capsules, injectable solutions or suspensions, for example in the form of ampoules, vials, emulsions, gels, pastes, inhalation powders, foams, tinctures, lipsticks, drops, sprays, or in the form of suppositories, for example in a form analogous to that of macrocyclic lactones, for example erythromycin, such as clarithromycin and azithromycin, by any conventional route, for example enterally, including, for example, nasal, buccal, rectal, oral administration; parenteral administration, including, for example, intravenous, intramuscular, subcutaneous administration; or topical administration, including, for example, transdermal, intranasal, intratracheal administration.
The compounds of the invention may be administered in the following forms: in the form of a pharmaceutically acceptable salt, for example an acid addition salt or a base addition salt such as a metal salt; or administered in free form; optionally in the form of a solvate. The compounds of the invention in salt form exhibit the same degree of activity as the compounds of the invention in free form, optionally in solvate form.
According to the present invention, the compounds of the present invention may be used in pharmaceutical therapy, either alone or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include, for example, other antibiotics and anti-inflammatory agents, and if the compounds of the present invention are used to treat acne, other pharmaceutical agents include additional drugs effective against acne.
Said combination comprises a fixed combination wherein the two or more pharmaceutically active agents are in the same formulation; kits in which two or more pharmaceutically active ingredients are sold in separate formulations and in the same package, e.g., with instructions for co-administration; and free combinations, wherein the pharmaceutically active agents are packaged separately, but instructions for simultaneous or sequential administration are given.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form and/or solvate form; and at least one pharmaceutically acceptable excipient, such as a carrier or diluent, including, for example, fillers, binders, disintegrants, flow regulators, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating osmotic pressure and/or buffering agents.
In another aspect, the invention provides a pharmaceutical composition according to the invention, further comprising another pharmaceutically active agent.
The pharmaceutical compositions may be manufactured, for example, in a manner similar to conventional methods, e.g., by mixing, granulating, coating, dissolving or lyophilizing processes. The unit dosage form may contain, for example, from about 0.5mg to about 2000mg, such as from 10mg to about 500mg, of the active ingredient.
The compounds of the invention are also suitable for use as veterinary, e.g. veterinary active compounds, e.g. for the prevention and treatment of microbial, e.g. bacterial, diseases in animals, e.g. poultry, pigs and cattle; and dilution liquids such as are used in artificial insemination and egg soaking techniques.
In another aspect, the present invention provides a compound of the invention for use as a veterinary drug.
In a further aspect, the present invention provides a compound of the invention for use in the preparation of a veterinary composition for use as a veterinary drug.
In another aspect, the present invention provides a veterinary method of prevention and treatment of microbial, e.g. bacterial, diseases, which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g. in the form of a veterinary composition.
The present invention also provides a method of treating a microbial infection in an animal, particularly a human and domestic mammal, comprising administering to a patient in need of treatment a compound of the present invention, or a pharmaceutically acceptable salt or derivative or solvate thereof, or a composition of the present invention.
The invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament for the treatment of a microbial infection.
In another aspect, the present invention also provides a use of the compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deutero-compound thereof, or a stereoisomer thereof in the preparation of a medicament for treating and/or preventing a disease caused by a microorganism.
In a further aspect, the present invention also provides a method for the treatment and/or prevention of a disease caused by microorganisms, which comprises administering a compound of the general formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the present invention to a mammal, such as a human, in need of such treatment or prevention.
The invention also provides a pharmaceutical preparation, such as oral preparation, injection, inhalation, nasal preparation, ophthalmic preparation, percutaneous absorption preparation, rectal administration preparation, ointment or gel, containing the compound of the general formula (I), pharmaceutically acceptable salt thereof, prodrug thereof, solvate thereof, deuteron or stereoisomer thereof. In another aspect, the pharmaceutical formulation of the present invention is in a spray form starting from nasal administration. The spray is an aqueous spray.
The invention also provides the use of a compound of formula (I) of the invention, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron or a stereoisomer thereof, in the manufacture of a medicament suitable for nasal administration to reduce or eliminate nasal infection by pathogenic organisms.
The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt, a prodrug, a solvate, a deutero-isomer or a stereoisomer thereof, for the manufacture of a medicament suitable for nasal administration for the prevention of recurrent otitis media or recurrent acute bacterial sinusitis.
The invention also provides the application of the compound of the general formula (I), the pharmaceutically acceptable salt, the prodrug, the solvate, the deuteron or the stereoisomer thereof in preparing the medicine for treating skin and soft tissue infection and acne.
Experiments prove that the pleuromutilin antibiotic compound containing spiro rings has good antibacterial activity and can be used for treating and/or preventing diseases caused by microorganisms.
The beneficial effects of the compounds of the present invention are further illustrated below by antibacterial activity experiments, but this should not be understood as meaning that the compounds of the present invention have only the following beneficial effects.
Experimental examples in vitro antibacterial Activity of the Compounds of the invention
Test strains: the following clinical isolates were purchased at public institutions.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), streptococcus pneumoniae, viridans streptococcus, and the like.
And (3) testing the sample: the chemical names and preparation methods of some compounds of the invention are shown in the preparation examples of each compound. Linezolid, commercially available.
The experimental method comprises the following steps: agar Dilution method, see National Committee for Clinical Laboratory standards, 2006.methods for Dilution of analytical chemistry Tests for bacterial That Grow Aerobically, Approved Standard- -Seventh Edition M7-A7Vol26, No.2, 2006. MIC represents the minimum inhibitory concentration.
Experimental results and conclusions:
TABLE 1 antibacterial Activity of some of the compounds of the invention
TABLE 2 antibacterial Activity of some of the compounds of the invention
TABLE 3 antibacterial Activity of some of the Compounds of the invention
TABLE 4 antibacterial Activity of some of the Compounds of the invention
TABLE 5 antibacterial Activity of some of the Compounds of the invention
TABLE 6 antibacterial Activity of some of the Compounds of the invention
In addition, MIC of Compound 4 of the present invention for MRSA90(. mu.g/mL) was 0.125.
The experimental results show that the compound has better antibacterial activity on gram-positive strains and fastidious strains, and has better clinical application potential.
4. Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The generic name "tiamulin" refers to the IUPAC systematic name (1S,2R,3S,4S,6R,7R,8R,14R) -3, 6-dihydroxy-2, 4,7, 14-tetramethyl-4-vinyl-tricyclo [5.4.3.0 ]1,8]Tetradecan-9-one. In the examples, the pleuromutilin derivatives were numbered using a tiamulin numbering system similar to that described in H.Berner (Berner, H.; Schulz, G.; Schneider H.tetrahedron 1982,36, 1807-1811.).
Example 14-O- (p-toluenesulfonylacetyl) tiamulin (intermediate M1)Preparation of
Tiamulin (SM1,37.8g,0.1mol) was dissolved in 60ml of dichloromethane, and triethylamine (15.15g,0.15mol) was added under nitrogen protection. After stirring for 30 min, the temperature was reduced to-15 ℃ and a solution of TosCl (13.75g,0.12mol) in dichloromethane was added dropwise. The mixture was stirred for 2 hours and 1.15L of water was added slowly. The organic phase was separated, dried and spin dried to give intermediate M1(44g, 96%).
With reference to the above preparation method, the following compounds can also be prepared:
example 114-O- (7-methyl-7-azaspiro [3.5]]) Preparation of nonan-2-yl) methylmercapto) tiamulin (Compound 1)
(1) Preparation of tert-butyl 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate
2- (hydroxymethyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (SM2,5.10g,0.02mol) and triethylamine (3.03g,0.03mol) were added to 100mL of dichloromethane, cooled to 0 deg.C, MsCl (4.58g,0.04mol) was added dropwise, stirred vigorously for 2h, water was added and stirred for 15 minutes, the organic phase was separated, dried and spun dry to give the product, tert-butyl 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate (5.02g, 75%).
(2) Preparation of tert-butyl 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylate
Adding 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (3.3g,0.1mol) into 50mL DMF, heating to 50 ℃, adding AcSK (2.56g), heating to 95 ℃, stirring for 2 hours, adding ethyl acetate and water into the reaction compound, removing the water phase, and purifying by organic phase drying and column chromatography to obtain 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (2.2g, 71%).
(3) Preparation of S- (7-methyl-7-azaspiro [3.5] nonan-2-yl) methyl acetyl thioester
Tert-butyl 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylate (3.1g,0.01mol) was dissolved in formic acid (20ml), formaldehyde (10ml) was added, and the solution was stirred for 3 hours while warming to 100 ℃. Cooling to room temperature, adjusting pH to 7, washing with water and ethyl acetate, separating the organic phase, drying and spin-drying to obtain S- (7-methyl-7-azaspiro [3.5] nonan-2-yl) methyl acetyl sulfide (1.2g, 55%).
(4) Preparation of 7-methyl-7-aza [3.5] nonan-2-yl) methylmercapto
S- (7-methyl-7-azaspiro [3.5] nonan-2-yl) methyl acetyl thioester (2.7g,1mmol) was dissolved in methanol (34ml), NaOMe (0.11g,2mmol) was added, stirring was carried out for 4 hours, hydrochloric acid was added to adjust the pH to 2.6-3, extraction was carried out with t-butyl methyl ether, drying and spin-drying to give 7-methyl-7-aza [3.5] nonan-2-yl) methyl mercapto group (1.7g, 98%).
(5) Preparation of 14-O- (7-methyl-7-azaspiro [3,5]) nonan-2-yl) methylmercapto) tiamulin (Compound 1)
7-methyl-7-aza [3.5] nonan-2-yl) methylmercapto (4.56g,10mmol) was dissolved in 100mL tetrahydrofuran, 1N NaOH (10mL) and benzyltributylammonium chloride (1.2g) were added, the mixture was stirred at 15 deg.C for 20 hours with (7-methyl-7-aza [3.5] nonan-2-yl) methylmercapto (0.36g,2mmol) added, the mixture was stirred at room temperature, a mixture of water and ethyl acetate was added, the organic phase was separated, dried to give the product (84mg,8%).
Mass spectrum (M/e):546(M + H)+
1H NMR(400MHz,CDCl3,ppm):6.49(m,1H),5.75(m,1H),5.36(m,1H),5.18(m,1H),3.35(m,1H),3.10(s,2H),2.66(m,2H),2.32(m,4H),2.22(m,4H),2.10(m,2H),1.95(m,2H),1.78(m,1H),1.65(m,7H),1.46(m,7H),1.36(m,2H),1.27(m,1H),1.18(m,3H),1.12(m,1H),0.88(m,5H),0.75(m,3H).
Example 214O- (6-azaspiro [2.5 ]]) Preparation of octane-2-yl) methylmercapto) tiamulin (Compound 2)
(1) Preparation of intermediate 657801
2-SM (25mg,0.1mmol) was dissolved in 10mL THF at-1Adding BH at 5 DEG C3THF (2M,2ml), warmed to room temperature, was stirred for 24 h. The reaction mixture was concentrated under reduced pressure, and then purified by column chromatography to obtain 657801(24mg, 98%).
(2) Preparation of intermediate 657802
657801(62mg,0.26mmol) and TEA (37mg,0.36mmol) were dissolved in anhydrous DCM and cooled to 00MsCl (36mg,0.31mmol) was added dropwise with stirring. The reaction was carried out for 2h, and TLC showed that the starting material had reacted completely. After adding water, stirring was continued for 10 min. Saturated NaHCO is used for reaction liquid3Washing with the solution to separate the organic phase, and adding anhydrous Na2SO4Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain the product (70mg, 95%).
(3) Preparation of intermediate 657803
657802(32mg,0.1mmol) and AcSK (45mg,0.4mmol) were added to MeCN (5ml), and the reaction was stirred at 70 ℃ for 2 h. Column chromatography gave the product (15mg, 30%).
(4) Preparation of intermediate 657804
657803(0.5g,1mmol) was dissolved in 34ml of methanol under an inert atmosphere and K was added over a period of at least 15min2CO3(0.65g,1.2mmol) of the solution. After the reaction was complete, the pH was adjusted to 7.0. The reaction was concentrated in vacuo to give crude 657804(1.1g, 100%). Used in the next step without further purification.
(5) Preparation of intermediate 657805
629101(2.01g,4.4mmol) was dissolved in THF (20ml) and 1N NaOH (10ml) and benzyltributylammonium chloride (1.4g) were added. The reaction solution was cooled to 15 ℃ and 657804(0.52g,2mmol) was added dropwise. The two-phase reaction mixture was stirred at 20 ℃ for 1 hour. After the reaction was complete, the organic phase was separated, dried and concentrated to give 657805(200mg, 13%).
(6) Preparation of Compound 2
657805(0.3g,0.5mmol) was dissolved in 6ml DCM, 2ml TFA was added, the reaction was stirred for 2h, concentrated under reduced pressure, and purified by column chromatography to give the trifluoroacetate salt of compound 2 (60mg, 50%).
Mass spectrum (M/e):518(M + H)+.
1H NMR(400MHz,MeOD,ppm):6.33(m,1H),5.75(m,1H),5.15-5.19(m,2H),3.51(m,1H),3.34(m,1H),3.26(m,1H),3.21(m,4H),2.83(m,1H),2.65(m,1H),2.33(m,2H),2.17(m,2H), 1.86(m,2H),1.65(m,6H),1.45(m,4H),1.35(m,4H),1.16(m,4H),1.06(m,1H),0.93(m,3H),0.74(m,3H),0.35(m,1H).
Example 314O- ((7-azaspiro [ 3.5)]) Preparation of nonan-2-yl) methylmercapto) tiamulin (Compound 3)
(1) Preparation of intermediate 659701
Sodium borohydride (1.4g, 24.9 mmol) was slowly added to 3-SM (2 g, 8.3 mmol) in THF (100mL) at room temperature, the temperature was raised to 65 ℃ for reflux reaction for 3h, 100mL of water was added after the reaction was completed, after quenching, extraction with DCM (15 mL. times.3) was performed, and the organic phase was dried to afford intermediate 659701(1g, 50%).
(2) Preparation of intermediate 659702
To intermediate 659701(0.5g,2mol) in DCM (20mL) was added TEA (0.4g, 4mol) under ice-bath and MsCl (0.27 g, 2.4 mmol) was slowly added dropwise. TLC monitoring after the reaction was complete, DCM/H2O extraction, organic phase drying and spin drying to obtain the target compound intermediate 659702(0.52g, 82%).
(3) Preparation of intermediate 659703
To intermediate 659702(0.52g,1.6mmol) in acetonitrile (30mL) was added potassium thioacetate (0.22g, 1.9mmol) and the temperature was raised to reflux. After the reaction was completed, column chromatography was used for separation and purification to obtain intermediate 659703(0.45g, 91%).
(4) Preparation of intermediate 659704
Room temperature N2To intermediate 659703(0.45g,1.5mmol) in methanol (20mL) was added sodium methoxide (0.16g, 3mmol) with protection and the reaction was carried out for 3 h. After the reaction was complete, the solution was adjusted to pH 6 with dilute hydrochloric acid, filtered with suction and the filtrate was spin dried to give intermediate 659704(0.33g, 83%).
(5) Preparation of intermediate 659705
To intermediate 659704(0.5g,1.2mmol) in THF (20mL) at room temperature was added benzyltriethylammonium chloride (0.27 g, 2.4 mmol), NaOH (0.24g, 6mmol) in 1N aqueous solution, and compound 5(0.33g,1.2mmol) was added. After TLC monitoring the reaction was complete, column chromatography was used for isolation and purification to afford intermediate 659705(0.63g, 85%).
(6) Preparation of Compound 3
Trifluoroacetic acid (2mL) was added to DCM (20mL) of compound 7(0.63g,1mmol) at room temperature and reacted for 3 h. After completion of the reaction, the solvent was distilled off, and 10mL of ether was added to crystallize, whereby Compound 3(0.6g,86%) was obtained.
The molecular formula is as follows: c30H47NO4S molecular weight: 517.3
1H-NMR (400MHz, CDCl3, its trifluoroacetate salt,ppm):9.10(br s,2H),6.53(m,1H),5.74(d,1H),5.33(d,1H),5.20(d,1H),3.55(m,1H),3.37(d,1H),3.02-3.10(m,6H),2.30–2.35(m,3H),2.12(m,2H),2.06-2.10(m,2H),1.65-2.08(m,13H),1.23-1.39(m,7H),1.13(m,1H),0.89(d,3H),0.72(d,3H).
EXAMPLE 4 preparation of Compound 4
(1) Preparation of intermediate 4-1
Room temperature N2Under protection, t-BuOK (4.68g,0.04mol) was added to a solution of methyltriphenylphosphonium bromide (10g,0.04mmol) in 1, 4-dioxane (200mL) and the temperature was raised to 40 ℃ for reaction for 1.5 h. The temperature was lowered to 10 ℃ and a solution of Compound 4-1 (7.35 g,0.03mol) in 1, 4-dioxane (50mL) was added dropwise and the reaction was carried out for 7 h. After the reaction, the solvent was evaporated, 150mL of petroleum ether was added, and the mixture was filtered under suction, and the filtrate was spin-dried to obtain the objective compound 4-2(5.68g, 80%).
(2) Preparation of intermediate 4-3
To a THF solution (150mL) of compound 4-2(5.68g, 0.024mol) at 0 deg.C was slowly added borane dimethylsulfide tetrahydrofuran solution (2M,10mL), after 5H of reaction, an aqueous solution (20mL) of NaOH (0.96 g, 0.024mol) was added under ice bath, and H was added2O2(0.97 g, 0.029 mol), after completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. times.3), and the organic phase was washed with saturated brine (50mL), dried and spin-dried to obtain the objective compound 4-3(3g, 49%).
(3) Preparation of intermediate 4-4
TEA (2.36g, 23.4mol) was added to compound 4-3(3g,11.7mmol) in DCM (100mL) under ice-bath and MsCl (1.5g, 12.87 mmol) was slowly added dropwise. TLC monitoring after the reaction was complete, DCM/H2O extraction, organic phase drying and spin drying to obtain the target compound 4-4(2.5g, 64.2%).
(4) Preparation of intermediates 4 to 5
To compound 4-4(2.5g,7.5mmol) in acetonitrile (100mL) was added potassium thioacetate (1.28g, 11.25mmol) and the temperature was raised to reflux. After the reaction, column chromatography was performed to isolate and purify the target compound 4-5(2.24g, 95.4%).
(5) Preparation of intermediates 4 to 6
To compound 4-5(2.24g,7.1mmol) in DCM (100mL) was added trifluoroacetic acid (5mL) and reacted at room temperature for 3 h. After completion of the reaction, the solvent was evaporated to dryness, and 20mL of ether was added thereto to crystallize, whereby the objective compound 4-6(1.86g,80.1%) was obtained.
(6) Preparation of intermediates 4 to 7
To compound 4-6(1.86g,5.7mmol) in DCM (50mL) was added TEA (1.51g, 15mmol), HATU (4.3 g, 11.4 mmol) at room temperature and reacted overnight at room temperature. After the reaction is finished, column chromatography separation and purification are carried out to obtain the target compound 4-7(1.96g,83.5%)
(7) Preparation of intermediates 4 to 8
Room temperature N2Sodium methoxide (0.38g, 7mmol) was added to compound 4-7(1.96g,4.7mmol) in methanol (100mL) under protection and the reaction was carried out for 3 h. After the reaction is finished, the pH value of the solution is adjusted to 6 by using dilute hydrochloric acid, the solution is filtered, and the filtrate is dried in a spinning mode to obtain 4-8(1.5g,83.1 percent) of the target compound
(8) Preparation of intermediates 4 to 9
To compound 4-8(2.2g,4.68mmol) in THF (100mL) at room temperature was added benzyltriethylammonium chloride (1.32 g,4.68mmol), NaOH (0.78g, 19.5mmol) in 1N aqueous solution, and compound M2(1.5g,3.9mmol) was added. After TLC monitoring reaction, column chromatography separation and purification are carried out to obtain the target compound 4-9(2.8g,99%)
(9) Preparation of Compound 4
Trifluoroacetic acid (2mL) was added to the compound 4-9(1g,1.4mmol) in DCM (50mL) at room temperature and reacted for 3 h. After completion of the reaction, the solvent was distilled off, and 10mL of diethyl ether was added thereto to crystallize it, whereby Compound 4(0.873g,83.7%)
The molecular formula is as follows: c36H58N2O5S molecular weight: 630.4
1H-NMR(400MHz,CDCl3The compound of the compound, the trifluoroacetic acid salt,ppm):8.30(br s,2H),6.49(m,1H),5.75(d,1H),5.33(d,1H),5.19(d,1H),4.25(m,1H),3.60(m,1H),3.50(m,2H),3.20-3.47(m,4H),3.11(s,2H),2.68(d,2H),2.45(m,1H),2.35(m,1H),2.18(m,2H),2.02-2.13(m,6H),1.51-1.80(m,12H),1.25-1.46(m,7H),1.18(d,3H),1.09(d,3H),0.89(d,3H),0.74(d,3H).
example 514-O- (S- (2-methyl-3, 3-dimethylpropionyl- (7-azaspiro [3,5]]) Preparation of nonan-2-yl) thio) tiamulin (Compound 5)
(1) Preparation of tert-butyl 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate
2- (hydroxymethyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (5-1,5.10g,0.02mol) and triethylamine (3.03g,0.03mol) were added to 100mL of dichloromethane, cooled to 0 deg.C, MsCl (4.58g,0.04mol) was added dropwise, stirred vigorously for 2h, water was added and stirred for 15 minutes, the organic phase was separated, dried and spun dry to give the product, tert-butyl 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate (5.02g, 75%).
(2) Preparation of tert-butyl 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylate
Adding 2- ((methylsulfonyloxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (3.3g,0.1mol) into 50mL DMF, heating to 50 ℃, adding AcSK (2.56g), heating to 95 ℃, stirring for 2 hours, adding ethyl acetate and water into the reaction compound, removing the water phase, and purifying by organic phase drying and column chromatography to obtain 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (2.2g, 71%).
(3) Preparation of S- (7-methyl-7-azaspiro [3.5] nonan-2-yl) methyl acetyl thioester
Tert-butyl 2- (acetylmercaptomethyl) -7-azaspiro [3.5] nonane-7-carboxylate (3.1g,0.01mol) was dissolved in formic acid (20ml), formaldehyde (10ml) was added, and the solution was stirred for 3 hours while warming to 100 ℃. Cooling to room temperature, adjusting pH to 7, washing with water and ethyl acetate, separating the organic phase, drying and spin-drying to obtain S- (7-methyl-7-azaspiro [3.5] nonan-2-yl) methyl acetyl sulfide (1.2g, 55%).
(4) Preparation of 14-O- (S- (2-methyl-3, 3-dimethylpropionyl- (7-azaspiro [3,5]) nonan-2-yl) thio) tiamulin
22-O-methylsulfonyl tiamulin (M2, 4.56g,10mmol) was dissolved in 100mL tetrahydrofuran, 1N NaOH (10mL) and benzyltributylammonium chloride (1.2g) were added, the mixture was stirred at 15 deg.C for 20 hours at room temperature with addition of (7-methyl-7-aza [3.5] nonan-2-yl) methylmercapto (0.36g,2mmol), the organic phase was separated and dried to give the product (84mg,8%).
The molecular formula is as follows: c35H56N2O5S molecular weight: 616.4
1H-NMR (400MHz, CDCl3, its trifluoroacetate salt,ppm):8.20(br s,2H),6.50(m,1H),5.76(d,1H),5.34(d,1H),5.20(d,1H),4.26(m,1H),3.52-3.60(m,2H),3.20-3.50(m,4H),3.11(s,2H),2.20-2.40(m,6H),2.12(m,4H),1.76-1.82(m,4H),1.50-1.70(m,10H),1.21-1.46(m,6H),1.18(d,3H),1.09(d,3H),0.89(d,3H),0.74(d,3H).
example 614-O- ((2R) -2-amino-2-cyclopropyl-acetyl- (7-azaspiro [3, 5)]) Preparation of nonan-2-yl) thio) tiamulin (Compound 6)
(1) Preparation of 14-O- ((N-Boc-7-azaspiro [3,5]) nonan-2-yl) thio) tiamulin
22-O-methylsulfonyl tiamulin (5.88g,12.9mmol), N-Boc-5-mercapto 7-azaspiro [3,5] nonane (3.3g,12.9mmol), aqueous NaOH (1N,51.6mL) and triethylbenzyl ammonium chloride (275mg, 1.29mmol) were dissolved in 100mL MTBE and reacted overnight at 90 ℃ under nitrogen, after concentration, water was added, extraction with ethyl acetate was performed, drying and after concentration, separation on a silica gel column (petroleum ether: ethyl acetate = 10: 1) gave 3.7g of product in 46% yield.
(2) Preparation of 14-O- ((7-azaspiro [3,5] nonan-2-yl) thio) tiamulin trifluoroacetate
14-O- ((N-Boc-7-azaspiro [3,5] nonan-2-yl) thio) tiamulin (3.7g, 6.0mmol) was dissolved in 20mL DCM, 5mL trifluoroacetic acid was added, reaction was carried out at room temperature for 1h and then concentrated to give an oil, which was used in the next reaction without purification.
(3) Preparation of 14-O- ((2R) -N-Boc-2-amino-2-cyclopropyl-acetyl- (7-azaspiro [3,5]) nonan-2-yl) thio) tiamulin
The product of the previous step (500mg,0.79mmol), (R) -N-Boc-cyclopropylglycine (220mg, 0.95mmol), HATU (450mg, 1.2mmol) and DIEA (203mg,1.58mmol) were dissolved in 20mL DCM and reacted at room temperature for 2h, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give the product which was used in the next step without purification.
(4) Preparation of 14-O- ((2R) -2-amino-2-cyclopropyl-acetyl- (7-azaspiro [3,5]) nonan-2-yl) thio) tiamulin
Dissolving the product of the last step in 20mL of dichloromethane, adding 5mL of trifluoroacetic acid, reacting at room temperature for 2h, evaporating the solvent to dryness, adding water, adjusting pH with sodium bicarbonate to =9, extracting with dichloromethane, drying, concentrating, and separating with a silica gel column (dichloromethane: methanol = 50: 1) to obtain 100mg of the product, wherein the yield of the two steps is 19%.
The molecular formula is as follows: c35H54N2O5S molecular weight: 614.4 Mass Spectrometry (m/e): 614.8(M +1)
1H-NMR(400MHz,CDCl3,ppm):6.53-6.46(q,J=11Hz,1H),5.75(d,J=8.4Hz,1H),5.33(d,J=11Hz,1H),5.23(d,J=16Hz,1H),3.56-3.49(m,3H),3.40-3.36(m,5H),3.10(s,2H),2.36-2.20(m,6H),2.12-2.06(m,3H),1.79-1.75(m,3H),1.51-1.63(m,13H),1.24(m,5H),0.89(d,3H),0.72(d,3H),0.51(m,2H),0.33(m,2H).
With reference to the above preparation method, the following compounds can also be prepared:
example 714-O- ((2R) -2-amino-3, 3-dimethyl-butyryl- (7-azaspiro [3,5]]) Preparation of nonan-2-yl) thio) tiamulin (Compound 7)
The molecular formula is as follows: c36H58N2O5S molecular weight: 630.9 Mass Spectrometry (m/e): 631.1(M +1)
1H-NMR(400MHz,CDCl3,ppm)6.44-6.51(m,1H),5.73(d,1H),5.30-5.33(m,1H),5.19(d1H),3.30-3.64(m,7H),3.09(s,2H),2.04-2.34(m,7H),1.78(s,8H),1.53-1.69(m,3H),1.45(s,4H),1.21-1.38(m,4H),1.08-1.13(m,4H),0.95(m,9H),0.87(d,3H),0.72(d,3H).
Example 814-O- ((2R) -2-amino-3-hydroxy-propionyl- (7-azaspiro [3, 5)]) Preparation of nonan-2-yl) thio) tiamulin (Compound 8)
The molecular formula is as follows: c33H52N2O6S molecular weight: 604.8 Mass Spectrometry (m/e): 605.0(M +1)
1H-NMR(400MHz,CDCl3,ppm):6.44-6.53(m,1H),5.74(d,1H),5.30-5.33(m,1H),5.20(d1H),3.93(br,1H),3.70(m,1H),3.30-3.55(m,7H),3.11(s,2H),2.36(m,3H),1.65-1.82(m,4H),1.53-1.70(m,8H),1.45(s,4H),1.13-1.39(m,12H),0.88(d,3H),0.73(d,3H).
.Example 914-O- ((2R) -2, 3-diaminopropionyl- (7-azaspiro [3,5]]) Preparation of nonan-2-yl) thio) tiamulin (Compound 9)
The molecular formula is as follows: c33H53N3O5S molecular weight: 603.4 Mass Spectrometry (m/e): 604.4(M +1)
1H-NMR(400MHz,CDCl3,ppm):6.49(q,1H),5.75(d,1H),5.33(d,1H),5.20(d,1H),3.36-3.67(m,7H),3.10(s,2H),2.61-2.92(m,2H),2.20-2.34(m,5H),2.06-2.08(m,2H),1.76-1.80(m,3H),1.51-1.63(m,12H),1.46(s,3H),1.25-1.39(m,4H),1.18(s,3H),0.88(d,3H),0.73(d,3H).
Example 1014-O- ((2R) -prolyl- (7-azaspiro [3,5]]) Preparation of nonan-2-yl) thio) tiamulin (Compound 10)
The molecular formula is as follows: c35H54N2O5S molecular weight: 614.8 Mass Spectrometry (m/e): 614.8 (M)+)
1H-NMR(400MHz,CDCl3,ppm):6.44-6.51(m,1H),5.73(d,1H),5.30-5.33(m,1H),5.19(d1H),4.24(m,1H),3.07-3.57(m,9H),2.19-2.35(m,6H),2.04-2.10(m,2H),1.92-1.97(m,1H),1.60-1.81(m,16H),1.09-1.48(m,9H),0.87(d,3H),0.72(d,3H).
Example 1114-O- ((2R,4S) -4-Hydroxyprolyl- (7-azaspiro [3,5]]) Preparation of nonan-2-yl) thio) tiamulin (Compound 11)
The molecular formula is as follows: c35H54N2O6S molecular weight: 630.4 Mass Spectrometry (m/e): 631.4(M +1)
1H-NMR(400MHz,CDCl3,ppm):6.55(m,1H),5.75(t,1H),5.33(d,1H),5.22(d,1H),5.18(d,1H),4.5(s,1H),4.45(m,1H),3.5(m,3H),3.4(m,4H),3.1(m,3H),2.1-2.4(m,7H),2.1(m,2H),1.8-1.9(m,4H),1.5-1.7(m,8H),1.58(t,3H),1.2-1.3(m,4H),1.15(s,3H),0.88(d,3H),0.74(m,3H).
Example 1214-O- ((2R) -2-amino-2- (4-fluorophenyl) acetyl- (7-azaspiro [3, 5)]) Preparation of nonan-2-yl) thio) tiamulin (Compound 12)
The molecular formula is as follows: c38H53FN2O5S molecular weight: 668.9 Mass Spectrometry (m/e): 668.7
1H NMR(CDCl3,400MHz,ppm):7.25(t,2H),7.01(m,2H),6.44(m,1H),5.71(d,1H),5.25-5.29(m,1H),5.18(d,1H),4.70(s,1H),3.54-3.69(m,1H),3.37-3.50(m,2H),3.34(d,1H),3.09-3.24(m,2H),3.05(s,1H),1.5-2.34(m,22H),1.42(s,6H),1.14(s,3H),0.86(d,3H),0.69(d,3H).
Example 1314-O- ((7-azaspiro [3, 5)]) Preparation of nonan-2-hydroxy-2-yl) methylthio) tiamulin (Compound 13)
The molecular formula is as follows: c31H49NO5S molecular weight: 547.3 Mass Spectrometry (m/e): 548.4(M +1)
1H-NMR(400MHz,CDCl3,ppm):0.70-0.75(m,3H),0.85-0.90(m,3H),1.10-1.20(m,4H),1.30-1.40(m,2H),1.40-1.60(m,7H),1.60-1.70(m,4H),1.70-1.80(m,1H),1.85-1.95(m,4H),2.05-2.15(m,3H),2.15-2.30(m,2H),2.30-2.48(m,3H),2.70-2.80(m,4H),2.83(s,2H),3.25(s,2H),3.35-3.40(m,1H),5.20(d,1H),5.35(s,1H),5.75(d,1H),6.43-6.53(m,1H)。

Claims (7)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
R1is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R4Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R4Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R2And R3Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R5A substituted 3-6 membered cyclic group,
R4、R5independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
a is unsubstituted or substituted by 1-2R6Substituted byWherein said R6Selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
x is-S-;
m is 0 or 1;
n is 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof:
wherein,
R1is hydrogen, C1-4Alkyl, or a group of the formula
R2And R3Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R4Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-bisHydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R4、R5independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted byWherein said R6Selected from hydrogen, fluoro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
x is-S-;
m is 0 or 1;
n is 0, 1 or 2.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof:
wherein,
R1is hydrogen, methyl, ethyl, or a group of the formula
R2And R3Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R4Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, methylmercapto, methylamino, ethylamino、
(3) Unsubstituted or substituted by R4Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R2And R3Taken together with the C atom to which they are attached to form an unsubstituted or substituted R5Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R4、R5independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
a is unsubstituted or substituted by 1-2R6Substituted byWherein said R6Selected from hydrogen, fluoro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino;
x is-S-;
m is 0 or 1;
n is 0, 1 or 2.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
5. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, together with a further pharmaceutically active ingredient.
7. Use of a compound according to claims 1-4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of a disease caused by a microorganism.
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CN104803926B (en) * 2015-03-25 2017-05-03 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
CN105399684A (en) * 2015-11-03 2016-03-16 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin compound, preparation method of pleuromutilin compound, polymorphism and preparation method of polymorphism
CN109195608B (en) * 2016-03-02 2021-05-11 比尔及梅琳达盖茨基金会 Boron-containing small molecules

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102210812A (en) * 2011-06-09 2011-10-12 山西新源华康化工股份有限公司 Compound Retapamulin medicinal membrane agent and preparation method thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027790A1 (en) * 1998-11-11 2000-05-18 Smithkline Beecham P.L.C. Mutilin compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102210812A (en) * 2011-06-09 2011-10-12 山西新源华康化工股份有限公司 Compound Retapamulin medicinal membrane agent and preparation method thereof

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