WO2019037791A1 - 一种长效雷沙吉兰前药及其制备方法和用途 - Google Patents
一种长效雷沙吉兰前药及其制备方法和用途 Download PDFInfo
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- 0 CC(OC(*)(*)OC(N****)=O)=O Chemical compound CC(OC(*)(*)OC(N****)=O)=O 0.000 description 4
- RUOKEQAAGRXIBM-GFCCVEGCSA-N C#CCN[C@H]1c2ccccc2CC1 Chemical compound C#CCN[C@H]1c2ccccc2CC1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- APHISIIEGCLPPA-XSNSTOHYSA-N C=CN(C(CC1)c2c1cccc2)C(OCOC(CCCC[C@@H]([C@H]1N2)SCC1NC2=O)=O)=O Chemical compound C=CN(C(CC1)c2c1cccc2)C(OCOC(CCCC[C@@H]([C@H]1N2)SCC1NC2=O)=O)=O APHISIIEGCLPPA-XSNSTOHYSA-N 0.000 description 1
- VTOFKDMUXRUJQG-GFCCVEGCSA-N C=CN([C@H]1c2ccccc2CC1)C(OCCl)=O Chemical compound C=CN([C@H]1c2ccccc2CC1)C(OCCl)=O VTOFKDMUXRUJQG-GFCCVEGCSA-N 0.000 description 1
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- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the invention belongs to the field of medicinal chemistry, in particular to a long-acting rasagiline prodrug and a preparation method and use thereof.
- Parkinson's disease also known as tremor palsy
- tremor palsy is a common neurodegenerative disease characterized by progressive, multiple and insidious onset, mainly characterized by slowness of movement and muscle rigidity. Static tremors and unstable postures.
- PD has a very low incidence in the population before the age of 50, and the incidence is rapidly rising after the age of 60. It is estimated that there are more than 2 million PD patients in China, and the incidence rate of people over 65 years old is about 1.7%. As China gradually becomes aging, the number is increasing.
- the main pathological feature of PD is the death of dopaminergic neurons in the substantia nigra and the deterioration of the nigrostriatal pathway.
- PD drug therapy is mainly levodopa.
- levodopa With the increasing oral dose of levodopa in the treatment of Parkinson's disease, the medication time is gradually shortened, its efficacy has been weakened, and the incidence of adverse reactions such as switching phenomena, fluctuations in motor symptoms, and drug tolerance has also increased.
- Monoamine oxidase (MAO-B) in the brain is one of the key enzymes in the catabolism of dopamine. It also produces some free radicals during the catabolism of dopamine, causing oxidative stress to cause neuronal death.
- Rasagiline (English name rasagiline) is a second-generation monoamine oxidase inhibitor that blocks the breakdown of the neurotransmitter dopamine, and selegiline (first-generation monoamine oxidase inhibitors, including Sijinin, Mi Mi Pyridinium and Jinsiping) have a 5-10-fold stronger inhibitory effect, and have an improved effect on patients with long-term application of dopa preparations.
- selegiline first-generation monoamine oxidase inhibitors, including Sijinin, Mi Mi Pyridinium and Jinsiping
- the metabolite of rasagiline is an inactive non-amphetamine substance with little side effects.
- the drug has a certain symptom relief effect and there is more evidence to prove it. These drugs have a certain neuroprotective effect.
- Parkinson's disease is a progressive, incurable neurological disease that requires long-term use, and rasagiline needs to be administered daily. Because Parkinson's disease is mainly caused by the elderly, and the elderly have the characteristics of poor memory and easy to forget things, there will be a huge market for the development of long-acting Parkinson's disease drugs, and the drugs have not yet been successful. Public reports on drugs.
- WO 2013088255 and US 20150210712 report a series of prodrugs of rasagiline.
- the melting point of the compound reported in the patent is lower than room temperature (25 ° C), which can not meet the ideal physical and chemical properties of long-acting suspension drugs. It is required that such low-melting compounds are easily fused during long-term placement or after entering the body, and it is difficult to control the release rate of the drug in the body, and thus is not suitable for a growth-effect drug.
- room temperature 25 ° C
- we designed and synthesized a series of compounds with high melting point and low solubility in water The in vivo drug test showed that these compounds are evenly released in vivo and are more suitable for growth-effect drugs.
- the present invention prepares prodrugs having long-acting properties by modifying the structure of rasagiline.
- the medicaments are prepared by intramuscular, subcutaneous or intravenous injection preparation, and the drug reservoir is formed in the body by muscle, subcutaneous or intravenous injection, and the medicine is slowly, continuously and stably released from the reservoir and converted into a mine.
- Shajilan thus playing a long-term role.
- the present invention provides a long-acting rasagiline prodrug or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, the long-acting rasagiline prodrug having the structure of Formula I :
- T is selected from Or not;
- R 1 and R 2 are each independently selected from hydrogen, hydrazine or C 1-4 alkyl
- W is selected from (CH 2 ) n or not, and n is selected from an integer of 1 to 15;
- X is selected from (CH 2 ) m or not, and m is selected from an integer of 1 to 10;
- each substituted alkyl group is 1, 2, 3 or 4 groups independently selected from the group consisting of oxygen, sulfur, fluorine, chlorine, amine, carbonyl, cycloalkyl, aryl and heteroaryl. ;
- each substituted alkenyl group is 1, 2, 3 or 4 groups independently selected from the group consisting of oxygen, sulfur, fluorine, chlorine, amine, carbonyl, cycloalkyl, aryl and heteroaryl. ;
- the substituent on the substituted alkynyl group is 1, 2, 3 or 4 groups independently selected from the group consisting of oxygen, sulfur, fluorine, chlorine, amine, carbonyl, cycloalkyl, aryl and heteroaryl. ;
- each substituted C 3 -C 10 cycloalkyl group is 1, 2, 3 or 4 independently selected from the group consisting of oxygen, sulfur, fluorine, chlorine, aminocarbonyl, cycloalkyl, aryl and hetero a group of an aryl group;
- R 1 is hydrogen or deuterium
- R 2 is methyl, hydrogen or deuterium; more preferably, R 1 and R 2 are each independently hydrogen, deuterium or methyl.
- aromatic group e.g. naphthyl
- R 3 is selected from the following cholane fatty chains:
- the long-acting rasagiline prodrug has the structure of Formula II:
- r is an integer from 1 to 10; and R 3 is a C 7 -C 27 linear alkyl group;
- r is an integer from 1 to 6, and R 3 is a C 9 -C 25 linear alkyl group;
- R 3 is a C 11 -C 25 linear alkyl group, further preferably, R 3 is a C 11 -C 21 linear alkyl group, and R 3 is C 11 -C 20 straight chain alkyl group of, R 3 is C 11 -C 19 straight chain alkyl group of, R 3 is C 11 -C 18 straight chain alkyl group of, R 3 is C 11 -C 17 linear alkyl a group, R 3 is a C 11 -C 16 linear alkyl group, R 3 is a C 11 -C 15 linear alkyl group, R 3 is a C 11 -C 14 linear alkyl group, and R 3 is C 11 - A linear alkyl group of C 13 , and R 3 is a C 11 -C 12 linear alkyl group.
- the long-acting rasagiline prodrug structure is selected from the group consisting of:
- the present invention provides a method of preparing the above prodrug, the method comprising:
- Rasagiline is reacted with chloromethyl chloroformate in an aprotic solvent using an organic or inorganic base as an acid binding agent, and the resulting intermediate is then reacted with MOCOWTXYR 3 in an aprotic solvent (in the reaction).
- M is a metal ion
- R 1 , R 2 , R 3 , W, T, X, Y are as defined above, or is an acid or an alkali base in an aprotic solvent with MOCOR 3
- the reaction is obtained under the conditions of the agent (in the reaction, M is H, and the definitions of R 1 , R 2 , R 3 , W, T, X, Y are as described above)
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the above formula I, or a stereoisomer, solvate thereof, and a pharmaceutically acceptable carrier or adjuvant.
- the above pharmaceutical composition is prepared by using a low solubility rasagiline prodrug as an active ingredient, a suspending solvent and a pharmaceutically acceptable excipient to prepare a suspension for injection, and forming a drug depot in the body.
- the drug is slowly released from the depot, and is digested into the original drug in the body to exert its therapeutic effect, achieving the purpose of long-term treatment.
- the pharmaceutical composition is a lyophilized powder, a suspension or a dry suspension.
- the advantages of the dry suspension and the lyophilized powder are that the long-term stability of the preparation is good, which is advantageous for the quality control of the preparation.
- the advantage of the suspension is that it is convenient to prepare, and the mixture of the prodrug and the auxiliary material can be ground and dispensed, the process is small, the operation is simple, and the production is favorable for large-scale production.
- the present invention provides the use of a compound of the above formula I, or a stereoisomer or solvate thereof, for the manufacture of a medicament for the prevention and/or treatment of a central nervous disease; and the preparation of the above pharmaceutical composition Use in medicines for preventing and/or treating central nervous diseases.
- the drug is a long acting drug.
- the central nervous disease is Parkinson's disease.
- the present invention provides a method of preventing and/or treating a central nervous disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound or a stereoisomer, solvate thereof or The aforementioned pharmaceutical composition; preferably, the central nervous disease is Parkinson's disease.
- the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
- a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
- Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
- Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
- Diastereomer refers to a stereoisomer that has two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
- optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
- the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
- the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
- Compounds prefixed with (+) or d are dextrorotatory.
- a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
- any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
- each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
- the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
- the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
- racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
- HPLC high performance liquid chromatography
- tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
- proton tautomers also known as prototropic tautomers
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
- Another example of tautomerization is phenol-keto tautomerization.
- a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
- substituted refers to the replacement of a hydrogen group in a particular structure with a group of the specified substituent.
- Substitution on an alkyl or cycloalkyl group in the present invention if not indicated to occur on a particular carbon atom, means that it can occur on a carbon atom whose number of substituents has not reached saturation. When a plurality of substituents are selected from the same series, they may be the same or different.
- Substitutions on a benzene ring, an aromatic heterocycle or a heterocycle in the present invention if not indicated to occur on a particular atom, indicate that it can occur at any position that is not replaced by a hydrogen atom and other atoms.
- substituents of the present invention include, but are not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , oxygen, sulfur, carboxyl, alkyl, haloalkyl, alkene. Alkyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
- C 1-30 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, ..., C 12 alkyl, ..., C 20 alkyl, ..., and C 30 alkyl.
- linking substituents are described.
- the Markush variable recited for the group is understood to be a linking group.
- the definition of a Markush group for the variable recites “alkyl” or “aryl”, it will be understood that the “alkyl” or “aryl” are respectively Represents a linked alkylene group or an arylene group.
- alkyl refers to a saturated chain alkyl group
- chain alkyl refers to a straight or branched alkyl group, such as C 1 -C 30 alkyl refers to having from 1 to 30 carbon atoms.
- a saturated linear or branched alkyl group wherein examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, butyl, C 5 alkyl, C 6 alkyl, ..., C 12 alkane Base, ..., C 20 alkyl, ..., and C 30 alkyl.
- Examples of branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- C 1 -C 27 alkyl means a saturated straight or branched alkyl group having 1 to 27 carbon atoms, and examples of the linear alkyl group include, but are not limited to, methyl, ethyl, n-propyl, butyl. , C 5 alkyl, C 6 alkyl, ..., C 12 alkyl, ..., C 20 alkyl, ..., and C 27 alkyl.
- Examples of branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- C 1 -C 25 alkyl means a saturated straight or branched alkyl group having 1 to 25 carbon atoms
- examples of the linear alkyl group include, but are not limited to, methyl, ethyl, n-propyl and butyl groups.
- Examples of branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- C 1 -C 20 alkyl means a saturated straight or branched alkyl group having 1 to 20 carbon atoms, and examples of the linear alkyl group include, but are not limited to, methyl, ethyl, n-propyl and butyl groups. , C 5 alkyl, C 6 alkyl, ..., C 12 alkyl, ... and C 20 alkyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- C 1 -C 15 alkyl means a saturated straight or branched alkyl group having 1 to 15 carbon atoms, and examples of the linear alkyl group include, but are not limited to, methyl, ethyl, n-propyl and butyl groups. , C 5 alkyl, C 6 alkyl, ..., C 12 alkyl, ... and C 15 alkyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- C 1 -C 12 alkyl means a saturated straight or branched alkyl group having 1 to 12 carbon atoms
- linear alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, butyl , C 5 alkyl, C 6 alkyl, ..., C 12 alkyl.
- branched alkyl groups include, but are not limited to, isopropyl, t-butyl, and the like.
- the alkyl group can be optionally substituted with one or more substituents described herein.
- Alkenyl represents a straight or branched chain group containing a double bond, such as a C 2 -C 30 alkenyl group, which represents a straight or branched chain group having one double bond having 2 to 30 carbon atoms, an example including but not limited to, ethenyl, propenyl, butenyl, pentenyl group, C 6 alkenyl group, ising, C 12 alkenyl, C 30 alkenyl group and .
- the alkenyl group can be optionally substituted with one or more substituents described herein.
- Alkynyl represents a straight or branched chain group containing a triple bond.
- a C 2 -C 30 alkynyl group means a straight or branched chain group having one triple bond having 2 to 30 carbon atoms, and examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyne.
- the alkynyl group can be optionally substituted with one or more substituents described herein.
- the alkynyl group can be optionally substituted with one or more substituents described herein.
- alkoxy denotes a straight or branched alkyl group having an oxygen atom at the end, and examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
- cycloalkyl refers to an alkyl group having a cyclic structure, such as a C 3 -C 10 cyclic alkyl group, which refers to a saturated or unsaturated alkyl group having a cyclic structure of from 3 to 10 carbon atoms, wherein saturation
- examples of the cyclic alkyl group include, but are not limited to, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a . . . , a C 10 cycloalkyl group, and the like
- examples of the unsaturated cyclic alkyl group include, but are not limited to, cyclopentene and the like.
- the cycloalkyl group can be optionally substituted with one or more substituents described herein.
- heteroaryl refers to an aromatic ring radical formed by the replacement of at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic heteroaryl or 7- 12-membered bicyclic heteroaryl. Examples include, but are not limited to, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, trinitrogen Azolyl, tetrazolyl, and the like.
- the heteroaryl group can be optionally substituted with one or more substituents described herein.
- unsaturated as used in the present invention means that the group contains one or more unsaturations.
- heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. The form in which hydrogen is replaced.
- prodrug denotes a compound which is converted in vivo to a compound of formula I-XXI. Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
- solvate is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol.
- solvent molecules such as ethanol.
- hydrate is used when the solvent is water.
- the present invention has the following beneficial effects:
- the rasagiline prodrug of the invention has high melting point and low solubility, and can form a drug depot in vivo by preparing a suspension by intramuscular injection or subcutaneous injection, thereby prolonging the release rate of the drug in the body, and achieving Play the purpose of long-term treatment.
- Figure 1 shows the pharmacokinetic profile of rasagiline after intramuscular injection of rasagiline prodrugs in Beagle dogs.
- TBS-protected ferulic acid was added to a solution of 3.0 g of rasagiline-N-carbonyl chloride, 2.0 g of DIPEA and 0.9 g of TBAI in acetonitrile, and the mixture was stirred at 45 ° C overnight.
- the reaction solution was spin-dry concentrate plus PE (60mL), EA (20mL ), water (50mL) was stirred layers were separated organic phase was separated, washed successively with saturated NaHCO 3 (30mL), 0.05mol / L diluted hydrochloric acid (40 mL) wash, water (40 mL) wash, washed with saturated NaCl (40 mL), dried over anhydrous Na 2 SO 4, filtered, and spin dry.
- the concentrate was dissolved in 15mLDCM, deprotected by adding 1.68g of triethylamine trifluoride, the reaction solution was spun dry, dissolved in EA (60mL), washed with water (30mL), saturated NaCl (30mL), anhydrous Na 2 SO 4 Dry, filter, spin dry, concentrate with 30 mL of tert-butyl ether and silica gel column chromatography (DCM) to give a white solid powder.
- the tert-butyl ether was beaten twice to give 1.16 g of product as a white solid powder.
- DIPEA 1.14 g of DIPEA was added to a mixture of 1.7 g of rasagiline-N-carbonyl chloride, 2.7 g of chenodeoxycholic acid and 0.5 g of TBAI in acetonitrile and DMF (20+5 ml), and stirred at an external temperature of 45 ° C. overnight.
- reaction solution was spun dry, and the concentrate was dissolved in EA, washed successively with saturated NaCl (30 mL ⁇ 2), 0.05 mol/L diluted hydrochloric acid (30mL ⁇ 2), washed with water (30mL), saturated NaHCO 3 (30mL), saturated NaCl wash (30 mL), dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, silica gel column chromatography (PE / EA 3: 1 ⁇ 1: 1) to give 1.51g product as a white solid, yield: 42.78%.
- reaction solution was spun dry, and the concentrate was dissolved in EA, washed successively with saturated NaCl (30 mL ⁇ 2), 0.05 mol/L diluted hydrochloric acid (30mL ⁇ 2), washed with water (30mL), saturated NaHCO 3 (30mL), saturated NaCl wash (30 mL), dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, silica gel column chromatography (PE / EA 3: 1 ⁇ 1: 1) to give 2.1g product as a white solid, a yield of 59.50%.
- Methyl ((rasagiline-N-formyl)oxy) 4-stearyl amidobutanoate was obtained in the same manner as in Example 13 in a yield of 22.6% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy) 4-palmitoylaminobutyrate was obtained in the same manner as in Example 13 in a yield of 30.9% as a white solid powder.
- Methyl (lasagiline-N-formyl)oxy) 4-lauroylaminobutanoate was obtained in the same manner as in Example 13 in a yield of 16.25% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy) 4-myristoylaminobutyrate was obtained in the same manner as in Example 13 in a yield of 23.80% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy) 4-stearylaminohexanoate was obtained in the same manner as in Example 13 in a yield of 15.9% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy) 4-stearoylglycine was obtained in the same manner as in Example 13 in a yield of 51.38% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy)4-behenamidobutanoic acid was obtained in the same manner as in Example 13 in a yield of 31% as a white solid powder.
- Example 21 (manufactured by methyl (Risagiline-N-formyl)oxy) 5-palmitoylaminopentanoate
- Methyl ((rasagiline-N-formyl)oxy) 5-palmitoylaminopentanoate was obtained in the same manner as in Example 13 in a yield of 17.6% as a white solid powder.
- Methyl ((rasagiline-N-formyl)oxy)5-stearoylaminopentanoate was prepared in the same manner as in Example 13 in a yield of 14.6% as a white solid powder.
- the compounds of the present invention have higher melting points relative to the control, particularly Examples 8, 12, 13, 14, 15, 17, 20 and 23.
- Example 13 Example 15, Example 14, Example 20, and Example 8 were administered at a dose of 0.47 mg/kg rasagiline (converted to 1.72 mg/dose, respectively).
- Plasma sample treatment The sample was treated in an ice bath, 30 ⁇ L of methanol, 20 ⁇ L of internal standard (2 ⁇ g/mL of apigenin, dissolved in 50% methanol), 300 ⁇ L of plasma sample was added, vortexed, 4 mL of ethyl acetate was added, and vortexed. After centrifugation at 9000 g for 2 min, the organic phase was evaporated under vacuum, 150 ⁇ L of methanol was reconstituted, and 30 ⁇ L was injected for analysis.
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Abstract
提供一种长效雷沙吉兰前药及其制备方法和用途,所述长效雷沙吉兰前药的结构如式(I)所示。其中,T选自(II)或者没有;R1和R2分别独立地选自氢、氘和甲基;W选自(CH2)n或者没有,n选自1到15的整数;X选自(CH2)m或者没有,m选自1到10的整数;Y选自-C(=O)NH-、-NHC(=O)-或没有;R 3选自选自取代或未取代的C1-C30的烷基、取代或未取代的C2-C30烯基、取代或未取代的C2-C30炔基、取代或未取代的C3-C30环烷基、胆烷类脂肪链、-R3a-C(=O)O-R3b、-R3a-OC(=O)-R3b、-R3a-C(=O)NH-R3b、-R3a-NHC(=O)-R3b、或-R3a-S(=O)1-2O-R3b和-R3a-OS(=O)1-2-R3b;提供的雷沙吉兰前药,其熔点高,溶解度低,能够通过制成注射剂给药后在体内形成一个药物贮库,延长了药物在体内的释放速度,达到了发挥长效治疗的目的。
Description
相关申请的交叉引用
本申请要求于2017年8月25日递交的中国专利申请CN201710742461.X的优先权,并在此将其全部内容以引用方式并入本文。
本发明属于药物化学领域,特别是涉及一种长效雷沙吉兰前药及其制备方法和用途。
帕金森病(Parkinson′s disease,PD)又称为震颤性麻痹,是一种常见的神经退行性疾病,具有进行性、多发性和起病隐匿等特点,主要表现为行动迟缓、肌强直、静止性震颤和姿势不稳。PD在50岁以前人群中发病很少,60岁以后发病迅速上升。据估计,中国PD患者超过200万名,其中65岁以上人群发病率约为1.7%,随着中国逐渐步入老龄化这个数字有上升的趋势。
PD的主要病理学特征是在黑质中多巴胺能神经元细胞死亡,黑质纹状体通路退化。此外,在残存的多巴胺能神经元胞浆内存在路易小体。脑内产生多巴胺的细胞逐渐丧失了影响神经***的功能,使患者控制肌肉的能力越来越受到限制。
PD药物治疗上以左旋多巴为主。随着左旋多巴治疗帕金森病的口服剂量逐渐增大,服药时间逐渐缩短,其效力已减弱,开关现象、运动症状的波动及药物耐受等不良反应的发生率也不断增加。脑内单胺氧化酶(MAO-B)是多巴胺分解代谢的关键酶之一,在多巴胺分解代谢同时产生一些自由基,引起氧化应激使神经元死亡。
雷沙吉兰(英文名rasagiline)是第二代单胺氧化酶抑制剂,能阻滞神经递质多巴胺的分解,与司来吉兰(selegiline)(第一代单胺氧化酶抑制剂,包括思吉宁、咪哆吡、金思平等)相比抑制作用强5-10倍,对长期应用多巴制剂 药效出现衰退的患者也有改善的作用。另外,与司来吉兰相比,雷沙吉兰的代谢产物是一种无活性的非***物质,副作用小,重要的是,该药有一定的症状缓解的作用,并有较多证据证明这类药物有一定的神经保护的作用。
帕金森症是一种进行性、无法治愈的神经***疾病,需要长期用药,雷沙吉兰需要每日给药。由于帕金森症主要发病对象为老年人,而老年人又有记忆力差,容易忘事的特点,因此开发长效帕金森症药物将有极大的市场,而该类药物目前尚未有成功的长效药物的公开报道。
WO 2013088255和US 20150210712报道了一系列雷沙吉兰的前药,我们在试验中发现,专利中所报道的化合物熔点低于室温(25℃),无法满足长效混悬剂药物理想的理化性质要求,这类低熔点的化合物在长期放置过程中或进入体内后,固体颗粒很容易发生融合,很难控制体内药物的释放速度,因此并不适合做成长效药物。我们通过结构优化,设计并合成了一系列熔点高,水中溶解度低的化合物,动物体内药代试验表明,这些化合物体内释放均匀,更适合做成长效药物。
发明内容
本发明通过对雷沙吉兰的结构进行修饰,制备出具有长效属性的前体药物。该类药物通过制剂手段制备成可肌内、皮下或静脉注射的制剂,通过肌肉、皮下或静脉注射后在体内形成药物贮库,药物从贮库内缓慢、持续、稳定地释放并转化为雷沙吉兰,从而发挥长效作用。
本发明采用以下技术方案来实现:
一方面,本发明提供一种长效雷沙吉兰前药或其药学上可接受的盐、立体异构体、溶剂合物,所述长效雷沙吉兰前药具有式I所示结构:
其中,
R
1和R
2分别独立地选自氢、氘或C
1-4烷基;
W选自(CH
2)
n或者没有,n选自1到15的整数;
X选自(CH
2)
m或者没有,m选自1到10的整数;
Y选自C(=O)NH-、-NHC(=O)或没有;
R
3选自取代或未取代的C
1-C
30烷基、取代或未取代的C
2-C
30烯基、取代或未取代的C
2-C
30炔基、取代或未取代的C
3-C
10环烷基、胆烷类脂肪链、-R
3a-C(=O)O-R
3b、-R
3a-OC(=O)-R
3b、-R
3a-C(=O)NH-R
3b、-R
3a-NHC(=O)-R
3b、-R
3a-S(=O)
1-2O-R
3b或-R
3a-OS(=O)
1-2-R
3b,其中各R
3a和R
3b分别独立地为取代或未取代的C
1-20烷基、取代或未取代的C
2-20烯基、或取代或未取代的C
2-20炔基;
所述各取代的烷基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;
所述各取代的烯基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;
所述个取代的炔基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;
所述各取代的C
3-C
10环烷基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基羰基、环烷基、芳基和杂芳基的基团;
优选地,R
1为氢或氘,R
2为甲基、氢或氘;更优选地,R
1和R
2各自独立地为氢、氘或甲基。
优选地,W、T均没有;X选自(CH
2)
m或没有,m选自1到10的整数;Y选自-C(=O)NH和-NHC(=O);R
3选自芳基(例如萘基)、取代的C
1-C
6的烷基或C
7-C
27的直链或支链的饱和或不饱和的烷基。
优选地,R
3为-CH=CHR
4,其中,R
4选自1个或者多个OH或烷氧基取代的苯基。
优选地,R
3选自以下胆烷类脂肪链:
在一些实施方案中,所述长效雷沙吉兰前药具有式II所示结构:
其中,r为1到10的整数;R
3为C
7-C
27的直链烷基;
优选地,其中,r为1至6的整数,R
3为C
9-C
25的直链烷基;
更优选地,其中,r为3至6的整数,R
3为C
11-C
25的直链烷基,进一步优选地,R
3为C
11-C
21的直链烷基,R
3为C
11-C
20的直链烷基,R
3为C
11-C
19的直链烷基,R
3为C
11-C
18的直链烷基,R
3为C
11-C
17的直链烷基,R
3为C
11-C
16的直链烷基,R
3为C
11-C
15的直链烷基,R
3为C
11-C
14的直链烷基,R
3为C
11-C
13的直链烷基,R
3为C
11-C
12的直链烷基。
在一些实施方案中,所述长效雷沙吉兰前药结构选自:
另一方面,本发明提供一种制备上述前药的方法,该方法包括:
路线一:
雷沙吉兰在非质子性溶剂中,以有机碱或无机碱为缚酸剂与氯甲酸氯甲酯反应,所得到的中间体再与MOCOWTXYR
3在非质子性溶剂中反应得到(在该反应中,M为金属离子,R
1、R
2、R
3、W、T、X、Y的定义如前所述),或者与MOCOR
3在非质子性溶剂中以有机碱或无机碱为缚酸剂条件下反应得到(在该反应中,M为H,R
1、R
2、R
3、W、T、X、Y的定义如前所述)
路线二:
雷沙吉兰在非质子性溶剂中,以有机碱或无机碱为缚酸剂与ClCOOCR
1R
2OCOWTXYR
3(R
1、R
2、R
3、W、T、X、Y的定义如前所述)反应得到。
又一方面,本发明提供一种药物组合物,所述药物组合物包括前述式I化合物或其立体异构体、溶剂合物以及药学上可接受的载体或辅料。
上述药物组合物,以低溶解度的雷沙吉兰前药为活性成分,配合悬浮溶 剂和药学上可接受的辅料制成可供注射的混悬型注射液,在体内形成一个药物贮库,前药从贮库中缓慢释放,在体内酶解成原药进而发挥疗效,达到了发挥长效治疗的目的。
在其中一个实施例中,所述药物组合物为冻干粉、混悬剂或干混悬剂。其中,干混悬剂和冻干粉这两种剂型的优势在于制剂长期放置稳定性好,这对制剂的质量控制较为有利。而混悬剂的优势在于制备方便,前药和辅料混合后研磨分装即可,工序少,操作简单,有利于规模化生产。
再一方面,本发明还提供本前述式I化合物或其立体异构体、溶剂合物在制备用于预防和/或治疗中枢神经性疾病的药物中的应用;以及上述的药物组合物在制备用于预防和/或治疗中枢神经性疾病的药物中的应用。
优选地,所述药物为长效药物。
优选地,所述中枢神经性疾病为帕金森病。又一方面,本发明还提供一种预防和/或治疗中枢神经性疾病的方法,所述方法包括向有需要的患者施用治疗有效量的前述的化合物或其立体异构体、溶剂合物或者前述的药物组合物;优选地,所述中枢神经性疾病为帕金森病。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。
许多有机化合物以光学活性形式存在,即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时,使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体,这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或过程中没有立体选择性或立体特异性时,可出现这种情况。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有一个双键,取代基可能为E或Z构型;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒 (low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“取代”是指用指定取代基的基团置换特定结构中的氢基。本发明中烷基或环烷基上的取代,如没有指明发生在特定的碳原子上,则表示可以发生在任何取代基个数尚未达到饱和的碳原子上。多个取代基从同一系列中选择时,它们可以相同,也可以不同。本发明中苯环、芳杂环或者杂环上的取代,如没有指明发生在特定的原子上,则表示可以发生在任何未被除氢与外的其它原子取代的位置。多个取代基从同一系列中选择时,它们可以相同,也可以不同。本发明所述的取代基包括,但不限于D、F、Cl、Br、I、N
3、CN、NO
2、OH、SH、NH
2、氧、硫、羧基、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基等。
术语“未取代的”,表示指定基团不带有取代基。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C
1-30烷基”特别指独立公开的甲基、乙基、C
3烷基、C
4烷基、C
5烷基、C
6烷基、……、C
12烷基、……、C
20烷基、……、和C
30烷基。
在本发明的各部分,描述了连接取代基。当所述结构清楚地需要连接基团时,针对所述基团所列举的马库什变量应理解为连接基团。例如,如 果所述结构需要连接基团并且针对所述变量的马库什基团定义列举了“烷基”或“芳基”,则应理解,所述“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本文所用术语“烷基”是指饱和链状烷基,“链状烷基”是指直链或支链的烷基,如C
1-C
30烷基是指具有1-30个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基、……、C
20烷基、……、和C
30烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。C
1-C
27烷基是指具有1-27个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基、……、C
20烷基、……、和C
27烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。C
1-C
25烷基是指具有1-25个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基、……、C
20烷基、……、和C
25烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。C
1-C
20烷基是指具有1-20个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基、……和C
20烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。C
1-C
15烷基是指具有1-15个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基、……和C
15烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。C
1-C
12烷基是指具有1-12个碳原子的饱和直链或支链的烷基,其中直链烷基的示例包括但不限于甲基、乙基、正丙基、丁基、C
5烷基、C
6烷基、……、C
12烷基。支链烷基的示例包括但不限于异丙基,叔丁基等。所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
“烯基”代表含有双键的直链或支链基团,如C
2~C
30烯基表示碳原子数为2个到30个的具有一个双键的直链或支链基团,示例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、C
6烯基、……、C
12烯基、……和C
30烯基。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。
“炔基”代表含有三键的直链或支链基团。如C
2~C
30炔基表示碳原子数为2个到30个的具有一个三键的直链或支链基团,示例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基、C
6炔基、……、C
12炔基、……和C
30 炔基。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“烷氧基”表示末端含有一个氧原子的直链或支链烷基,示例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。
术语“环烷基”是指具有环状结构的烷基,如C
3-C
10环状烷基指具有3至10个碳原子的饱和或不饱和的具有环状结构的烷基,其中饱和环状烷基的示例包括但不限于环丙基,环戊基、环己基、…..、C
10环烷基等,不饱和环状烷基的示例包括但不限于环戊烯等。所述环烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂芳基”是指至少有一个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团,可为5-7元单环杂芳基或7-12元双环杂芳基。示例包括但不限于吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、噻唑基、噁唑基、异噁唑基、异噻唑基、咪唑基、吡唑基、三氮唑基、四氮唑基等。所述杂芳基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“羰基”,无论是单独使用还是和其他术语连用,如“氨基羰基”或“酰氧基”,表示-(C=O)-。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si,包括N、S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式I-XXI所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。
术语“溶剂合物”在文中用来描述包含本发明化合物和化学计量的一种或多种药学上可接受的溶剂分子(如乙醇)的分子络合物。当所述溶剂是水时采用术语“水合物”。
与现有技术相比,本发明具有以下有益效果:
本发明的雷沙吉兰前药,其熔点高,溶解度低,能够通过制成混悬剂肌内注射或皮下注射,在体内形成一个药物贮库,延长了药物在体内的释放速度,达到了发挥长效治疗的目的。
附图的简要说明
图1为比格犬肌肉注射雷沙吉兰前药后雷沙吉兰的药时曲线。
以下实施例对本发明做进一步的描述,但该实施例并非用于限制本发明的保护范围。
实施例1((雷沙吉兰-N-甲酰基)氧基)-棕榈酸甲酯的制备(参见国际专利申请WO2013088255)
将1.0g雷沙吉兰-N-碳酰氯甲酯和0.3g TBAI溶于THF/DMF(5+4mL)中,加入1.5g棕榈酸钾盐,外温57℃,氩气保护下加热过夜。停止反应,旋蒸掉THF,加入异丙醚30mL搅拌10min,过滤,滤液依次用水洗(15mL滤液),饱和NaHCO
3洗,无水硫酸钠干燥,浓缩,浓缩物经硅胶柱层析(PE/EA=20:1-10:1),得0.76g产品,为粘稠状物,收率:41.53%。
1H-NMR(CDCl
3,400MHz)δ7.26(m,2H),7.19(m,2H),5.87(m,2.5H),5.78(m,0.5H),4.17(d,J=14.0Hz,0.5H),4.02(d,J=14.0Hz,0.5H),3.62(d,J=14.0Hz,0.5H),3.52(d,J=14.0Hz,0.5H),3.06(m,1H),2.86(m,1H),2.47(m,1H),2.36(m,2H),2.24(m,1H),2.21(s,0.5H),2.15(s,0.5H),1.64(m,2H),1.28(m,24H),0.88(t,J=5.2Hz,3H)。
ESI-MS,C
30H
45NO
4(483.3),实测值506.4[M+Na]
+。
实施例2((雷沙吉兰-N-甲酰基)氧基)-萘乙酸甲酯的制备
将0.9g雷沙吉兰-N-碳酰氯甲酯和0.25g TBAI溶于15mL乙腈中,加入0.92g萘乙酸钾,外温60℃,氩气保护下加热反应5h。停止反应,旋蒸掉溶剂,加入乙酸乙酯20mL溶解,依次用饱和NaHCO
3洗(10mL×3),饱和NaCl洗(10mL),无水Na
2SO
4干燥,过滤,旋干得1.38g粗品,为淡棕色糖浆状物。粗品经甲醇重结晶得到雷沙吉兰-N-碳酰甲酯萘乙酸酯纯品0.65g,为白色固体粉末。
1HNMR(CDCl
3,400MHz)δ8.01(dd,J=14.8,8.4Hz,1H),7.84(m,2H),7.5(m,4H),7.22(m,3H),7.09(m,1H),5.90(m,1.5H),5.82(dd,J=14.8,6.0Hz1H),5.54(t,J=8.0Hz,0.5H),4.16(s,1.07H),4.13(s,0.93H),4.08(d,J=18.4Hz,0.51H),3.87(d,J=18.4Hz,0.54H),3.53(d,J=18.4.6Hz,0.49H),3.39(d,J=18.4Hz,1H),3.03(m,1H),2.87(m,1H),2.82(m,1H),2.76(m,1H),2.46(m,0.5H),2.26(m,0.5H),2.15(m,1.5H),1.93(s,0.5H)。
ESI-MS,C
26H
23NO
4(413.1),实测值436.1[M+Na]
+。
实施例3((雷沙吉兰-N-甲酰基)氧基)-硬脂酸甲酯的制备(参见国际专利申请WO2013088255)
将2.0g雷沙吉兰碳酰氯甲酯、0.56g TBAI溶于40mL DMF中,加入3.2g硬脂酸钾,外温65℃,氩气保护下加热反应过夜。停止反应,加水80mL,加异丙醚80mL萃取,依次用饱和NaHCO
3洗(30mL×2),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干得4.32g粗品。粗品经硅胶柱层析(PE/EA=10:1),得3g产品,为淡黄色糖浆状物,收率51.55%。
1HNMR(CDCl
3,400MHz)δ7.25(m,2H),7.19(m,2H),5.87(m,2.5H),5.66(m,0.5H),4.12(d,J=17.6Hz,0.5H),3.98(d,J=17.6Hz,0.5H),3.57(d,J=17.6Hz,0.5H),3.47(d,J=17.6Hz,0.5H),3.06(m,1H),2.85(m,1H),2.46(m,1H),2.37(m,2H),2.24(m,1H),2.16(s,0.5H),2.10(s,0.5H),1.64(m,2H),1.26(m,28H),0.88(t,J=6.4Hz,3H)。
ESI-MS,C
32H
49NO
4(511.37),实测值534.2[M+Na]
+。
实施例4((雷沙吉兰-N-甲酰基)氧基)-特戊酸甲酯的制备
将2.0g雷沙吉兰碳酰氯甲酯、0.56g TBAI溶于30mL DMF中,加入1.38g特戊酸钾,外温60℃,氩气保护下加热过夜。停止反应,加水80mL,加异丙醚80mL萃取,依次用饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,所得到粗品经硅胶柱层析(PE/EA=15:1),得1.89g产品,为淡黄色糖浆状物,收率75.60%。
1HNMR(CDCl
3,400MHz)δ7.25(m,2H),7.19(m,1H),7.16(m,1H),5.85(m,2.5H),5.84(m,0.5H),4.13(d,J=14.4Hz,0.5H),3.99(d,J=14.4Hz,0.5H),3.56(d,J=14.4Hz,0.5H),3.47(d,J=14.4Hz,0.5H),3.06(m,1H),2.87(m,1H),2.46(m,1H),2.24(m,1H),2.16(s,0.5H),2.11(s,0.5H),1.23(m,9H)。
ESI-MS,C
19H
23NO
4(329.16),实测值330.1[M+H]
+。
实施例5((雷沙吉兰-N-甲酰基)氧基)-花生酸甲酯的制备(参见国际专利申请WO2013088255)
将1.73g雷沙吉兰-N-碳酰氯甲酯、0.50g TBAI溶于30mL DMF中,加入3.0g花生酸钾,外温60℃,氩气保护下加热过夜。停止反应,加水80mL,加异丙醚80mL萃取,依次用饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(PE/EA=15:1),得1.55g产品,为淡黄色半固体,收率43.78%。
1HNMR(CDCl
3,400MHz)δ7.25(m,2H),7.18(m,2H),5.85(m,2.5H),5.78(m,0.5H),4.12(d,J=17.6Hz,0.5H),3.98(d,J=17.6Hz,0.5H),3.57(d,J=17.6Hz,0.5H),3.47(d,J=17.6Hz,0.5H),3.06(m,1H),2.86(m,1H),2.47(m,1H),2.37(m,2H),2.24(m,1H),2.16(s,0.5H),2.10(s,0.5H),1.64(m,2H),1.26(m,32H),0.88(t,J=6.8Hz,3H)。
ESI-MS,C
34H
53NO
4(539.4),实测值562.3[M+Na]
+。
实施例6((雷沙吉兰-N-甲酰基)氧基)-猪去氧胆酸甲酯的制备
将1.48g雷沙吉兰-N-碳酰氯甲酯、0.44g TBAI溶于8mL DMF中,加入2.3g猪去氧胆酸,外温60℃,氩气保护下加热过夜。停止反应,加30mL饱和NaCl和40mL乙酸乙酯搅拌,分出有机相,依次用饱和NaCl洗(30mL搅拌),水洗(30mL搅拌),饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(PE/EA 3:1有机相,),得1.4g白色泡末状固体。收率:40.23%。
1H-NMR(CDCl
3,400MHz)δ7.25(m,2H),7.17(m,2H),5.85(m,1.6H), 5.78(s,1H),5.66(m,0.4H),4.12(d,J=17.6Hz,0.53H),4.05(m,1H),3.98(d,J=17.6Hz,0.47H),3.62(m,1H),3.57(d,J=17.6Hz,0.47H),3.48(d,J=17.6Hz,0.53H),3.07(m,1H),2.87(m,1H),2.42(m,2H),2.35(s,1H),2.27(m,1H),2.16(s,0.47H),2.11(s,0.53H),1.86(m,6H),1.65(m,2H),1.38(m,9H),1.12(m,10H),0.91(m,6H),0.63(s,3H).
ESI-MS,C
38H
53NO
6(619.39),实测值642.2[M+Na]
+。
实施例7((雷沙吉兰-N-甲酰基)氧基)-生物素甲酯的制备
将1.5g雷沙吉兰-N-碳酰氯甲酯、2.0g生物素钾盐、0.44g TBAI,溶于DMF中,外温60℃,氩气保护反应过夜。停止反应,加30mL饱和NaCl和40mL乙酸乙酯搅拌,分出有机相,依次用饱和NaCl洗(30mL×3),水洗(30mL×2),饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(EA-EA/MeOH=10:1),得1.9g产品,为白色固体粉末,收率70.90%。
1H-NMR(CDCl
3,400MHz),δ7.25(m,2H),7.18(m,2H),5.89(s,1H),5.81(m,3H),5.05(s,1H),4.52(m,1H),4.33(m,1H),4.13(d,J=18.0Hz,0.5H),4.01(d,J=18.0Hz,0.5H),3.60(d,J=18.0Hz,0.5H),3.50(d,J=18.0Hz,0.5H),3.17(m,2H),3.09(m,1H),2.90(m,2H),2.78(s,0.6H),2.75(s,0.4H),2.44(m,3H),2.27(m,1H),1.72(m,2H),1.49(m,2H),1.18(m,2H)。
实施例8((雷沙吉兰-N-甲酰基)氧基)-阿魏酸甲酯的制备
将3.8g TBS保护的阿魏酸加到3.0g雷沙吉兰-N-碳酰氯甲酯、2.0g DIPEA和0.9g TBAI的乙腈溶液中,外温45℃搅拌过夜。反应液旋干,浓 缩物加PE(60mL)、EA(20mL)、水(50mL)搅拌分层,分出有机相,依次用饱和NaHCO
3洗(30mL),0.05mol/L稀盐酸(40mL)洗,水(40mL)洗,饱和NaCl洗(40mL),无水Na
2SO
4干燥,过滤,旋干。浓缩物加15mLDCM溶解,加入1.68g三乙胺三氟化氢脱保护,反应液旋干,加EA(60mL)溶解,依次用水洗涤(30mL依次),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,浓缩物加30mL甲叔醚打浆,硅胶柱层析(DCM)得白色固体粉末。甲叔醚打浆两次,得1.16g产品,为白色固体粉未。
1H-NMR(CDCl
3,400MHz),δ7.74(m,1H),7.25(m,2H),7.19(m,2H),7.12(dd,J=8.0,2.0Hz,1H),7.07(m,1H),6.96(s,0.52H)6.95(s,0.48H),6.34(dd,J=16.0,11.2Hz,1H),6.00(m,3H),5.88(t,J=8.0Hz,0.52H),5.72(t,J=8.0Hz,0.48H),4.15(dd,J=18.0,2.8Hz,0.48H),4.03(dd,J=18.0,2.8Hz,0.52H),3.96(s,3H),3.60(dd,J=18.0,2.8Hz,0.48H),3.51(dd,J=18.0,2.8Hz,0.52H),3.09(m,1H),2.88(m,1H),2.49(m,1H),2.27(m,1H),2.19(s,0.48H),2.12(s,0.52H)。
ESI-MS,C
24H
23NO
6(421.15),实测值422.1[M+H]
+。
实施例9((雷沙吉兰-N-甲酰基)氧基)-鹅去氧胆酸甲酯的制备
将1.14g DIPEA加到1.7g雷沙吉兰-N-碳酰氯甲酯、2.7g鹅去氧胆酸和0.5g TBAI的乙腈与DMF的混合(20+5ml)溶液中,外温45℃搅拌过夜。反应液旋干,浓缩物加EA溶解,依次用饱和NaCl洗(30mL×2),0.05mol/L稀盐酸(30mL×2)洗,水(30mL)洗,饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(PE/EA=3:1)得1.21g产品,为白色固体,收率30.25%。
1H-NMR(CDCl
3,400MHz)δ7.25(m,2H),7.17(m,2H),5.85(m,2.24H),5.78(s,0.76H),4.12(d,J=17.6Hz,0.5H),3.98(d,J=17.6Hz,0.5H),3.85(m,1H),3.57(d,J=17.6Hz,0.5H),3.47(m,1.5H),3.06(m,1H),2.86(m,1H),2.43(m,2H),2.35(s,1H),2.28(m,2H),2.18(s,0.5H),2.11(s,0.5H),1.98(m,2H),1.82(m,4H),1.70(m,2H),1.40(m,12H),1.15(m,6H),0.99(m,2H),0.92(m,6H),0.66(m,3H)。
ESI-MS,C
38H
53NO
6(619.39),实测值642.2[M+Na]
+。
实施例10((雷沙吉兰-N-甲酰基)氧基)-熊去氧胆酸甲酯的制备
将1.5g雷沙吉兰-N-碳酰氯甲酯加到1.0g DIPEA、2.8g熊去氧胆酸和0.44g TBAI的乙腈与DMF的混合(20/5ml)溶液中,外温45℃搅拌过夜。反应液旋干,浓缩物加EA溶解,依次用饱和NaCl洗(30mL×2),0.05mol/L稀盐酸(30mL×2)洗,水(30mL)洗,饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(PE/EA 3:1→1:1)得1.51g产品,为白色固体,收率:42.78%。
1H-NMR(CDCl
3,400MHz),δ7.25(m,2H),7.17(m,2H),5.84(m,2H),5.77(s,1H),4.12(d,J=18.0Hz,0.55H),4.05(m,1H),3.98(d,J=18.0Hz,0.45H),3.62(m,1H),3.57(d,J=18.0Hz,0.55H),3.48(d,J=18.0Hz,0.55H),3.07(m,1H),2.86(m,1H),2.42(m,2H),2.35(s,1H),2.26(m,2H),2.16(s,0.45H),2.10(s,0.55H),1.87(m,6H),1.67(m,3H),1.37(m,10H),1.13(m,8H),0.91(m,6H),0.63(m,3H)。
ESI-MS,C
38H
53NO
6(619.39),实测值642.2[M+Na]
+。
实施例11((雷沙吉兰-N-甲酰基)氧基)-去氧胆酸甲酯的制备
将1.5g雷沙吉兰碳酰氯甲酯加到DIPEA、去氧胆酸和TBAI的乙腈与DMF的混合(20+5)溶液中,外温45℃搅拌过夜。反应液旋干,浓缩物加EA溶解,依次用饱和NaCl洗(30mL×2),0.05mol/L稀盐酸(30mL×2)洗,水(30mL)洗,饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,硅胶柱层析(PE/EA 3:1→1:1)得2.1g产品,为白色固体,收率59.50%。
1H-NMR(CDCl
3,400MHz)δ7.25(m,2H),7.18(m,2H),5.85(m,2.55H),5.65(m,0.45H),4.12(d,J=17.6Hz,0.45H),3.98(m,1.55H),3.60(m,1H),3.57(d,J=17.6Hz,0.45H),3.48(d,J=17.6Hz,0.55H),3.06(m,1H),2.87(m,1H),2.45(m,2H),2.35(s,1H),2.27(m,2H),2.17(s,0.45H),2.11(s,0.55H),1.82(m,5H),1.61(m,10H),1.40(m,7H),1.26(m,2H),1.11(m,3H),0.98(d,J=4.8Hz,3H),0.91(s,3H),0.67(d,J=2.4Hz,3H)。
ESI-MS,C
38H
53NO
6(619.39),实测值642.2[M+Na]
+。
实施例12((雷沙吉兰-N-甲酰基)氧基)-4-花生酰氨基己酸甲酯的制备
将0.5g雷沙吉兰碳酰氯甲酯加到0.46g DIPEA、0.5g花生酰胺基己酸和100mg TBAI的THF/DMF的混合溶液(40+10mL)中,外温60℃搅拌过夜。反应液旋干,浓缩物加异丙醚溶解,依次用0.05mol/L稀盐酸(30mL×2)洗,水(30mL)洗,饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL), 无水Na
2SO
4干燥,过滤,旋干,TLC制备(PE/EA=2:1),得0.22g产品。收率17.74%,为白色固体粉末。
1H-NMR(CDCl
3,400MHz)δ7.25(m,2H),7.18(m,2H),5.85(m,2.5H),5.66(m,0.5H),5.54(brs,1H),4.12(d,J=23.6Hz,0.46H),3.98(d,J=23.6Hz,0.55H),3.57(d,J=23.6Hz,0.46H),3.48(d,J=23.6Hz,0.54H),3.24(m,2H),3.07(m,1H),2.86(m,1H),2.42(m,3H),2.26(m,1H),2.15(t,J=10.4Hz,2H),1.63(m,4H),1.50(m,2H),1.28(m,32H),0.88(t,J=8.8Hz,3H)。
ESI-MS,C
40H
64N
2O
5(652.48),实测值653.5[M+H]
+。
实施例13((雷沙吉兰-N-甲酰基)氧基)4-花生酰氨基丁酸甲酯的制备
将0.4g雷沙吉兰碳酰氯甲酯加到0.2g DIPEA、0.2g 4-花生酰胺基丁酸和50mg TBAI的THF/DMF的混合溶液(40+10mL)中,外温60℃搅拌过夜。反应液旋干,浓缩物加异丙醚溶解,依次用0.05mol/L稀盐酸(30mL×2)洗,水(30mL)洗,饱和NaHCO
3洗(30mL),饱和NaCl洗(30mL),无水Na
2SO
4干燥,过滤,旋干,TLC制备(PE/EA=2:1),得0.15g产品,为白色固体粉末,收率15.95%。
1H-NMR(CDCl
3,400MHz)δ7.25(m,2H),7.19(m,2H),5.87(m,2H),5.67(m,1H),4.33(brs,1H),4.11(d,J=18.0Hz,0.44H),3.98(d,J=18.0Hz,0.56H),3.58(d,J=18.0Hz,0.44H),3.48(d,J=18.0Hz,0.56H),3.29(m,2H),3.07(m,1H),2.86(m,1H),2.44(m,3H),2.24(m,1H),2.15(m,3H),1.86(m,2H),1.57(m,2H),1.25(m,32H),0.88(t,J=6.8Hz,H)。
ESI-MS,C
38H
60N
2O
5(624.45),实测值647.4[M+Na]
+。
实施例14((雷沙吉兰-N-甲酰基)氧基)4-硬酯酰氨基丁酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-硬酯酰氨基丁酸甲酯,收率22.6%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.25(m,2H),7.19(m,2H),5.92–5.60(m,4H),4.11(d,J=18.0Hz,0.44H),3.98(d,J=18.0Hz,0.56H),3.58(d,J=18.0Hz,0.44H),3.48(d,J=18.0Hz,0.56H),3.31(m,2H),3.07(m,1H),2.87(m,1H),2.43(m,3H),2.25(m,1H),2.15m,3H),1.87(m,2H),1.60(s,2H),1.25(m,28H),0.88(t,J=6.7Hz,3H)。
ESI-MS,C
36H
56N
2O
5(596.42),实测值619.7[M+Na]
+。
实施例15((雷沙吉兰-N-甲酰基)氧基)4-棕榈酰氨基丁酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-棕榈酰氨基丁酸甲酯,收率30.9%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.25(m,2H),7.23–7.13(m,2H),5.91–5.59(m,4H),4.11(d,J=18.0Hz,0.44H),3.98(d,J=18.0Hz,0.56H),3.58(d,J=18.0Hz,0.44H),3.48(d,J=18.0Hz,0.56H),3.30(m,2H),3.07(m,1H),2.87(m,1H),2.44(m,3H),2.32–2.20(m,1H),2.15(m,3H),1.87(m,2H),1.62(m,2H),1.25(s,24H),0.88(t,J=6.7Hz,3H)。
ESI-MS,C
34H
52N
2O
5(568.39),实测值591.4[M+Na]
+。
实施例16((雷沙吉兰-N-甲酰基)氧基)4-月桂酰氨基丁酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-月桂酰氨基丁酸甲酯,收率16.25%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.26–7.15(m,4H),5.88–5.65(m,4H),4.13(d,J=18.0Hz,0.44H),3.96(d,J=18.0Hz,0.56H),3.60(d,J=18.0Hz,0.44H),3.47(d,J=18.0Hz,0.56H),3.30(t,2H),3.09(m,1H),2.87(m,1H),2.49-2.40(m,3H),2.26–2.20(m,1H),2.15(t,3H),1.87(m,2H),1.62-1.58(m,2H),1.25(s,16H),0.88(t,J=6.7Hz,3H)。
实施例17((雷沙吉兰-N-甲酰基)氧基)4-肉豆蔻酰氨基丁酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-肉豆蔻酰氨基丁酸甲酯,收率23.80%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.26-7.15(m,4H),5.87–5.65(m,4H),4.13(d,J=18.0Hz,0.44H),3.96(d,J=18.0Hz,0.56H),3.60(d,J=18.0Hz,0.44H),3.47(d,J=18.0Hz,0.56H),3.30(t,2H),3.07(m,1H),2.87(m,1H),2.44(m,3H),2.26–2.22(m,1H),2.15(t,3H),1.87(t,2H),1.60(t,2H),1.25(s,20H),0.88(t,J=6.7Hz,3H)。
实施例18((雷沙吉兰-N-甲酰基)氧基)4-硬脂酰氨基己酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-硬脂酰氨基己酸甲酯,收率15.9%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.26–7.17(m,4H),5.87–5.48(m,4H),4.14(d,J=18.0Hz,0.44H),3.96(d,J=18.0Hz,0.56H),3.60(d,J=18.0Hz,0.44H),3.46(d,J=18.0Hz,0.56H),3.20(t,2H),3.06(m,1H),2.86(m,1H),2.46-2.35(m,3H),2.29–2.20(m,1H),2.16-2.12(m,3H),1.68-1.52(m,4H),1.38(m,2H),1.26(s,30H),0.88(t,J=6.7Hz,3H)。
实施例19((雷沙吉兰-N-甲酰基)氧基)4-硬脂酰甘氨酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-硬脂酰甘氨酸甲酯,收率51.38%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.26–7.16(m,4H),5.94–5.80(m,4H),4.14(d,J=18.0Hz,0.44H),3.93(d,J=18.0Hz,0.56H),3.62(d,J=18.0Hz,0.44H),3.46(d,J=18.0Hz,0.56H),3.30(q,2H),3.07(m,1H),2.87(m,1H),2.53-2.41(m,1H),2.26–2.21(m,3H),2.17(s,1H),1.65(m,2H),1.25(s,24H),0.88(t,J=6.7Hz,3H)。
实施例20((雷沙吉兰-N-甲酰基)氧基)4-山嵛酰氨基丁酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)4-山嵛酰氨基丁酸甲酯,收率31%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.21–7.26(m,2H),7.17–7.20(m,2H),5.81–5.88(m,2.56H),5.65(br,1.44H),4.11(d,J=17.6Hz,0.44H),3.98(d,J=17.2Hz,0.56H),3.58(d,J=17.6Hz,0.44H),3.49(d,J=18.8Hz,0.56H),3.30-3.31(m,2H),3.03–3.11(m,1H),2.83–2.89(m,1H),2.43–2.49(m,3H),2.22–2.27(m,1H),2.13–2.17(m,3H),1.84–1.89(m,2H),1.57–1.63(m,2H),1.25(m,36H),0.88(t,J=6.8Hz,3H)。
实施例21((雷沙吉兰-N-甲酰基)氧基)5-棕榈酰氨基戊酸甲酯的制
备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)5-棕榈酰氨基戊酸甲酯,收率17.6%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.21–7.26(m,2H),7.15–7.19(m,2H),5.81–5.87(m,2.55H),5.65(t,J=4.0Hz,0.45H),5.54(br,1H),4.11(d,J=18.0Hz,0.45H),3.98(d,J=18.4Hz,0.55H),3.57(d,J=17.6Hz,0.45H),3.48(d,J=18.4Hz,0.55H),3.25-3.27(m,2H),3.03–3.10(m,1H),2.81–2.91(m,1H),2.38–2.45(m,3H),2.21–2.29(m,1H),2.13–2.17(m,3H),1.65–1.71(m,2H),1.56–1.62(m,4H),1.25(m,26H),0.89(t,J=6.8Hz,3H)。
实施例22((雷沙吉兰-N-甲酰基)氧基)5-硬脂酰氨基戊酸甲酯的制备
按照实施例13同样的方法,制备得到了((雷沙吉兰-N-甲酰基)氧基)5-硬脂酰氨基戊酸甲酯,收率14.6%,为白色固体粉末。
1H NMR(CDCl
3,400MHz)δ7.23–7.26(m,2H),7.17–7.21(m,2H),5.78–5.88(m,2.50H),5.65(t,J=4.0Hz,0.50H),5.51(br,1H),4.12(d,J=18.4Hz,0.50H),3.98(d,J=18.4Hz,0.50H),3.58(d,J=17.2Hz,0.50H),3.48(d,J=15.6Hz,0.50H),3.25-3.28(m,2H),3.03–3.11(m,1H),2.84–2.90(m,1H),2.40–2.48(m,3H),2.22–2.29(m,1H),2.13–2.17(m,3H),1.66–1.69(m,2H),1.59–1.63(m,4H),1.25(m,30H),0.88(t,J=6.8Hz,3H)。
实施例23((雷沙吉兰-N-甲酰基)氧基)4-十八氨基丁二酸甲酯的制备
250mL单口瓶中加入十八胺(3.0g,11.13mmol,1.0当量)和四氢呋喃(60mL),然后加入4-二甲氨基吡啶(DMAP,408mg,3.34mmol,0.3当量)、二异丙基乙胺(DIPEA,2.87g,22.26mmol,2.0当量)、丁二酸 酐(1.36g,13.36mmol,1.2当量),加热回流搅拌反应3天。TLC监测仍有十八胺没反应,且不再变化。停止反应,降温至室温,加入浓盐酸调PH值到2-3,抽滤,滤液用饱和食盐水洗一遍,有机相用无水硫酸钠干燥、过滤、旋干,再用油泵抽干,得4-(十八烷基氨基)丁二酸2.7g,白色固体,粗品。直接用于下一步。
100mL单口瓶中加入4-(十八烷基氨基)丁二酸(2.7g,7.3mmol,1.0当量)和四氢呋喃100mL,依次加入二异丙基乙胺(DIPEA,1.88g,14.6mmol,2.0当量)、雷沙吉兰碳酰氯甲酯(2.31g,8.76mmol,1.2当量)、四丁基碘化铵(TBAI,539mg,1.46mmol,0.2当量),置于80℃下搅拌反应3.5天,TLC监测原料仍有少量未反应完全,停止反应。降温至室温,过滤,乙酸乙酯冲洗,旋干,用二氯甲烷溶解,1M HCl水溶液洗一遍,无水硫酸钠干燥、过滤、旋干,硅胶柱层析分离(PE/EA=5:1至PE/EA=1:1),合并馏分,旋干,加甲醇5mL溶解,置-10℃下搅拌析晶,析出固体,快速抽滤,滤饼油泵抽干得((雷沙吉兰-N-甲酰基)氧基)4-十八氨基丁二酸甲酯200mg,白色固体,Y=4.6%。
1H NMR(CDCl
3,400MHz)δ7.23–7.26(m,2H),7.18–7.22(m,2H),5.79–5.89(m,2.56H),5.59-5.67(m,1.44H),4.11(d,J=18.0Hz,0.44H),3.97(d,J=16.8Hz,0.56H),3.58(d,J=18.8Hz,0.44H),3.47(d,J=17.2Hz,0.56H),3.20-3.25(m,2H),3.03–3.10(m,1H),2.83–2.91(m,1H),2.72–2.78(m,2H),2.45–2.48(m,3H),2.24–2.26(m,1H),2.16(t,J=6.0Hz,1H),1.48(m,2H),1.25(m,28H),0.88(t,J=6.8Hz,3H)。
实施例24雷沙吉兰前药理化性质检测
将所合成的雷沙吉兰前药化合物分别测定熔点和溶解度(pH 7.4的磷酸盐缓冲液),结果如表1所示:
由表中数据可知,本发明化合物相对于对照具有更高熔点,特别是实施例8,12,13,14,15,17,20和23表现尤佳。
表1雷沙吉兰前药化合物熔点和溶解度数据
序号 | 实施例号 | 熔点(℃) | 溶解度(μg/ml) |
1 | 1(对照) | <25 | <5 |
2 | 2 | 66-70 | <5 |
3 | 3(对照) | <25 | <5 |
4 | 4 | <25 | <5 |
5 | 5(对照) | <25 | <5 |
6 | 6 | <50 | <5 |
7 | 7 | / | 31.7 |
8 | 8 | 130.4-133.8 | <5 |
9 | 9 | <50 | <5 |
10 | 10 | <50 | <5 |
11 | 11 | <50 | <5 |
12 | 12 | 77.2-80.8 | <5 |
13 | 13 | 80-82 | <5 |
14 | 14 | 76-78 | <5 |
15 | 15 | 73-75 | <5 |
16 | 16 | 56.1-59.4 | <5 |
17 | 17 | 66.3-71.8 | <5 |
18 | 18 | 58.9-64.2 | <5 |
19 | 20 | 87.4-87.8 | <5 |
20 | 21 | 55.4-56.2 | <5 |
21 | 22 | 58.3-58.9 | <5 |
22 | 23 | 75.3-77.1 | <5 |
实施例25雷沙吉兰前药体内药代试验
本试验采用普通级雄性比格犬各1只,给药前禁食12h,饮水自由。将实施例13、实施例15、实施例14、实施例20、实施例8等的注射用混悬剂按0.47mg/kg雷沙吉兰的给药剂量(换算成前药分别是1.72mg/kg、1.56mg/kg、1.64mg/kg、1.80mg/kg、1.16mg/kg)肌肉注射,给药前及给药后1h、2h、4h、8h、12h、18h、24h、48h、96h、144h、192h、240h、288h、360h,比格犬经前肢静脉采全血约1.0mL,置肝素化离心管中,4℃、 6000rpm离心10min,分离血浆,-80℃保存待测。
血浆样品处理:样品于冰浴中处理,取30μL甲醇,20μL内标(芹菜素2μg/mL,50%甲醇溶解),加入300μL血浆样品,涡旋混合,加入4mL乙酸乙酯,涡旋混合,9000g离心力离心2min,取有机相真空下挥干,150μL甲醇复溶,30μL进样分析。
数据分析:样品采用LC-MS/MS检测,根据药物的血药浓度数据,采用DAS 2.0软件进行计算药物代谢动力学参数,提供AUC(0-t)、AUC(0-∞)、MRT(0-t)、MRT(0-∞)、C
max、T
max、和t
1/2等参数。
实验结果:比格犬分别进行肌肉注射上述雷沙吉兰前药后,原药雷沙吉兰的血药浓度详细见表2。以表2数据作图,见图1。由表2和表3数据可知,本发明化合物在体内均可缓慢、持续、稳定地释放并转化为雷沙吉兰,从而发挥长效作用。特别是实施例13、实施例20这两个前药药物释放更加平稳,可很好地满足长效注射混悬剂的要求。而实施例14和实施例15两个前药在给药后两天释放较快,但后续则平稳释放,均达到长效释放效果。
表2雷沙吉兰前药比格犬肌肉注射后的雷沙吉兰血药浓度
比格犬分别进行肌肉注射上述雷沙吉兰前药后,原药雷沙吉兰的药物代谢动学参数如表3所示。
表3雷沙吉兰前药比格犬肌肉注射后的雷沙吉兰药动学参数
Claims (10)
- 一种长效雷沙吉兰前药或其立体异构体、溶剂合物,其特征在于,所述长效雷沙吉兰前药具有式I所示结构:其中,R 1和R 2分别独立地选自氢、氘或C 1-4烷基;W选自(CH 2) n或者没有,n选自1到15的整数;X选自(CH 2) m或者没有,m选自1到10的整数;Y选自-C(=O)NH-、-NHC(=O)-或没有;R 3选自取代或未取代的C 1-C 30的烷基、取代或未取代的C 2-C 30烯基、取代或未取代的C 2-C 30炔基、取代或未取代的C 3-C 10环烷基、胆烷类脂肪链、-R 3a-C(=O)O-R 3b、-R 3a-OC(=O)-R 3b、-R 3a-C(=O)NH-R 3b、-R 3a-NHC(=O)-R 3b、-R 3a-S(=O) 1-2O-R 3b或-R 3a-OS(=O) 1-2-R 3b,其中各R 3a和R 3b分别独立地为取代或未取代的C 1-20烷基、取代或未取代的C 2-20烯基、或取代或未取代的C 2-20炔基;所述各取代的烷基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;所述各取代或未取代的烯基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;所述各取代或未取代的炔基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团;所述取代或未取代的C 3-C 10环烷基上的取代基为1、2、3或4个独立地选自氧、硫、氟、氯、胺基、羰基、环烷基、芳基和杂芳基的基团。
- 根据权利要求1所述的前药或立体异构体、溶剂合物,其特征在于,R 1为氢或氘,R 2为甲基、氢或氘;更优选地,R 1和R 2各自独立地为氢、氘或甲基。
- 根据权利要求1或2所述的前药或立体异构体、溶剂合物,其特征在于,W、T均没有;X选自(CH 2) m或没有,m选自1到10的整数;Y选自-C(=O)NH-和-NHC(=O)-;R 3选自芳基(例如萘基)、取代的C 1-C 6的烷基和C 7-C 27的直链或支链的饱和或不饱和的烷基。
- 根据权利要求1至3中任一项所述的前药或立体异构体、溶剂合物,其特征在于,R 3为-CH=CHR 4,其中,R 4选自1个或者多个OH或烷氧基取代的苯基。
- 一种药物组合物,所述药物组合物包括权利要求1至7中任一项所述的化合物或其立体异构体、溶剂合物以及药学上可接受的载体或辅料。
- 权利要求1至7中任一项所述的化合物或其立体异构体、溶剂合物以及权利要求8所述的药物组合物在制备用于预防和/或治疗中枢神经性疾病的药物中的应用;优选地,所述药物为长效药物;优选地,所述中枢神经性疾病为帕金森病。
- 一种预防和/或治疗中枢神经性疾病的方法,所述方法包括向有需要的患者施用治疗有效量的权利要求1至7中任一项所述的化合物或其立体异构体、溶剂合物或者权利要求8所述的药物组合物;优选地,所述中枢神经性疾病为帕金森病。
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