[go: up one dir, main page]

CN110668980A - 2-substituted homotaurine derivative - Google Patents

2-substituted homotaurine derivative Download PDF

Info

Publication number
CN110668980A
CN110668980A CN201810715261.XA CN201810715261A CN110668980A CN 110668980 A CN110668980 A CN 110668980A CN 201810715261 A CN201810715261 A CN 201810715261A CN 110668980 A CN110668980 A CN 110668980A
Authority
CN
China
Prior art keywords
homotaurine
substituted
derivative
salt
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810715261.XA
Other languages
Chinese (zh)
Inventor
黄悦
郑飞
唐春兰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
Original Assignee
SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd, Zhejiang Jingxin Pharmaceutical Co Ltd filed Critical SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd
Priority to CN201810715261.XA priority Critical patent/CN110668980A/en
Publication of CN110668980A publication Critical patent/CN110668980A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Addiction (AREA)
  • General Chemical & Material Sciences (AREA)
  • Toxicology (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a preparation method and application of a 2-substituted homotaurine derivative or a stereoisomer or a salt thereof. The 2-substituted homotaurine derivative is shown as a formula I, and shown by a pharmacodynamic test, the 2-substituted homotaurine derivative has excellent alcohol inhibition effect and has an ideal application prospect of alcohol inhibition medicines.
Figure DDA0001717321200000011

Description

2-substituted homotaurine derivative
Technical Field
The invention relates to a 2-substituted homotaurine derivative, a preparation method and a pharmaceutical composition thereof, in particular to a homotaurine derivative for alcohol inhibition.
Background
Homotaurine (3-amino-1-propanesulfonic acid or hemiprosate (inn)3APS) is a sulfamic acid isolated from centipede (centipeda) sp. The homotaurine has the effects of resisting abnormal aggregation and precipitation of amyloid in the brain and inhibiting neurotoxic aggregation caused by the amyloid in the brain by combining with A beta protein amylase through a blood brain barrier due to the low molecular weight of homotaurine, and has the effects of slowing down memory decline and cognitive decline as a Potential therapeutic drug for treating Alzheimer's Disease (AD) (Alzheimer: A Potential Treatment for Alzheimer's Disease Current Alzheimer Research,2007,4, 473-478).
Figure BDA0001717321180000011
It has been reported that calcium acamprosate is formed by further performing acetylation modification on the structure of homotaurine, and is further applied to the continued alcohol withdrawal state of alcohol-dependent patients after alcohol detoxification, and the pharmacological effect is exerted by directly inhibiting glutamatergic receptors in GABA and brain nucleus accumbens (Nacc), but the oral bioavailability of calcium acamprosate is only 11%.
Figure BDA0001717321180000012
Disclosure of Invention
The invention provides a 2-substituted homotaurine derivative or a stereoisomer or a salt thereof, which is characterized in that the structure of the homotaurine derivative is shown as a formula I:
Figure BDA0001717321180000021
wherein,
R1is H, and R2And R3Each independently selected from the group consisting of: H. c1-C6Alkyl, but R2And R3Not being H or R at the same time2Is H or R3Not being tert-butyl, or R3Is H or R2Is not a tert-butyl group;
or R1Is an amino acid residue, and R2And R3Each independently selected from the group consisting of: h or C1-C6Alkyl, but R2And R3Not H at the same time;
or R1Is an amino acid residue, and R2And R3And the C atoms to which they are attached are linked to form C3-C8A cycloalkyl group.
In one embodiment, the homotaurine derivative is an amino acid prodrug of the compound of formula I; wherein R is1Is natural amino acid; preferably, R1An amino acid residue selected from the group consisting of L-valine, L-phenylalanine, L-lysine, L-leucine, L-serine, L-alanine, L-isoleucine, L-histidine, L-cysteine, L-glutamic acid, L-tyrosine, L-proline and L-histidine, or a pharmaceutically acceptable salt thereof.
In one embodiment, said C1-C6Alkyl or said C3-C8Cycloalkyl is substituted or unsubstituted alkyl; when said C is1-C6Alkyl is substituted alkyl or said C3-C8When cycloalkyl is substituted alkyl, the substituted alkyl is substituted with a substituent selected from the group consisting of: halogen, NH2Or OH.
In one embodiment, R2And R3Each independently selected from the group consisting of: h or C1-C4Alkyl, but R2And R3Not H at the same time; preferably, said C1-C4Alkyl includes methyl, ethyl, dimethyl, propyl, isopropyl, isobutyl, n-butyl;
wherein, R is2And R3C of formation of a connection3-C8Cycloalkyl is selected from cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl.
In one embodiment, the compound exists as an isomer.
In one embodiment, the salt of the homotaurine derivative is formed by a homotaurine derivative and a base, when an acidic proton present in the 2-substituted homotaurine derivative is replaced with a metal ion including an alkali metal ion, an alkaline earth metal ion, or other metal ion;
preferably, the alkali metal ions are lithium, sodium, potassium;
preferably, the alkaline earth metal ions are magnesium, calcium, barium;
preferably, the other metal ions are aluminum, zinc, iron.
In one embodiment, the homotaurine derivative is selected from the group formed by:
Figure BDA0001717321180000031
compound 1: 1- (methylamino) -3-methylbutane-1-sulfonic acid
Figure BDA0001717321180000032
Compound 2: 2- (aminomethyl) 4-methylpentane-1-sulfonic acid
Figure BDA0001717321180000033
Compound 3: 3-amino-2-methylpropane-1-sulfonic acid
Figure BDA0001717321180000034
Compound 4: 2- (aminomethyl) -4-methylpentanesulfonic acid phenylalanine prodrugs
Compound 5: 1- (aminomethyl) cyclohexaneethanesulfonic acid valine prodrugs
Figure BDA0001717321180000042
Compound 6: 2-aminomethyl-4-methylpentanesulfonic acid valine prodrug.
The present invention also provides a method for preparing the above 2-substituted homotaurine derivative or a stereoisomer or a salt thereof, characterized by comprising the steps of:
Figure BDA0001717321180000043
R2and R3As defined in claim 1;
step (1): carrying out reduction reaction on an initiator beta-amino acid to obtain beta-amino alcohol;
step (2): brominating the obtained beta-amino alcohol to obtain bromine substituted beta-amino alkane;
and (3): the obtained bromine substituted beta-amino alkane is subjected to sulfonation reaction to obtain the homotaurine derivative shown in the formula I;
the above reaction conditions were as follows:
the reducing agent for the reduction reaction in the step (1) is selected from borane and lithium aluminum hydride;
the reagent for bromination reaction in the step (2) is selected from hydrogen bromide, NBS and bromine;
the reagent for sulfonation in step (3) is selected from sodium sulfite.
The present invention also provides a method for preparing the above 2-substituted homotaurine derivative or a stereoisomer or a salt thereof, comprising the steps of:
the R group is C1-C6Alkyl or C3-C8A cycloalkyl group;
step (1): the R radical of the initiator substitutes the brominated methyl ketone to obtain unsaturated R radical sultone through reaction;
step (2): carrying out double bond reduction reaction on the obtained unsaturated R-base sultone to obtain saturated R-base sultone;
and (3): carrying out ammonolysis reaction on the obtained saturated R-based sultone to obtain a homotaurine derivative shown in a formula I;
the above reaction conditions were as follows:
the reagent reacted in step (1) is selected from LiCH2SO3Et；
The reagent for double bond reduction reaction in the step (2) is selected from Pd/C-H2；
And (3) the reagent for ammonolysis reaction in the step (3) is selected from ammonium hydroxide and ammonia gas.
The invention also provides the effect of the 2-substituted homotaurine derivative or the stereoisomer or the salt thereof on the aspect of alcohol inhibition.
The invention also provides a pharmaceutical composition, which comprises the 2-substituted homotaurine derivative or a stereoisomer or a salt thereof and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is a solid or liquid formulation for oral, gastrointestinal, buccal, sublingual, nasal, rectal or transdermal administration.
The pharmaceutical composition provided by the invention is a pharmaceutical composition consisting of the homotaurine derivative as an active ingredient and a pharmaceutic adjuvant.
The pharmaceutical compositions of the present invention may be selected from any convenient mode of administration. Such as oral, gastrointestinal, buccal, sublingual, nasal, rectal or transdermal administration. Can be developed into different dosage forms such as solid dosage forms and liquid dosage forms, such as suspending agents, tablets and capsules.
The composition in the form of a solid tablet may contain fillers, lubricants, binders, disintegrants, which are conventionally used in formulations. Liquid preparations employ suitable liquid carriers such as suspensions or solutions in water-miscible solvents, for example water, ethanol or glycerol, or water-immiscible solvents, for example polyethylene glycol, or oils.
Preferably, the pharmaceutical composition is a solid tablet which is composed of the homotaurine derivative shown in the formula I as an active ingredient and a pharmaceutical adjuvant.
In one embodiment, the solid tablet consists of the following ingredients in parts by weight:
Figure BDA0001717321180000052
Figure BDA0001717321180000061
the diluent is selected from starch, lactose or microcrystalline cellulose, the binder is selected from hydroxybenzyl cellulose, hydroxypropyl methyl cellulose or polyvinylpyrrolidone, the disintegrant is selected from hydroxyethyl starch sodium or crospovidone, and the lubricant is magnesium stearate.
Preferably, the composition of the invention is a suspension composed of the compound of formula I as an active ingredient and a pharmaceutical adjuvant; the suspension consists of the following components in parts by weight:
Figure BDA0001717321180000062
the suspending agent is selected from xanthan gum or microcrystalline cellulose; the preservative is selected from sodium benzoate, methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate, and the diluent is selected from water or sorbitol; the buffer is citrate; the cosolvent is selected from cyclodextrin, ethanol, propylene glycol or polyethylene glycol; the flavoring agent is a sweetener selected from sugar or saccharin; the colorant is fat-soluble colorant or water-soluble colorant, and is selected from carotene, cacao pigment or caramel pigment.
Name interpretation
The term "amino acid" generally refers to organic compounds containing a carboxylic acid group and an amino group, which includes both "natural" and "unnatural" amino acids. An "amino acid" herein is represented by an "amino acid residue" in formula I. The term "prodrug" refers to a substance that can be converted, directly or indirectly, to an active form in vitro or in vivo. "amino acid prodrug" refers to R in the compound of formula I1Compounds in which the radical is an amino acid residue. The amino acid may be the pure L or D isomer or a mixture of L and D isomers, including a racemic mixture. The term "natural amino acid" and equivalent expressions refer to the L-amino acids that are common in naturally occurring proteins. Natural amino acidsExamples of (b) include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), beta-alanine (beta-Ala), and gamma-aminobutyric acid (GABA). The term "unnatural amino acid" refers to any derivative of a natural amino acid, including the D configuration, as well as alpha-and beta-amino acid derivatives.
The term "alkyl" refers to saturated hydrocarbons having from one to twelve carbon atoms, including straight-chain, branched-chain, and cyclic alkyl groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term alkyl includes both unsubstituted alkyl groups and substituted alkyl groups. Wherein "C1-C6Alkyl "refers to an alkyl group having 1 to 6 carbon atoms.
The term "cycloalkyl" and equivalent expressions refer to groups containing a saturated or partially unsaturated carbocyclic ring in a single carbocyclic ring system having three to fifteen ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptene, and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term "C3-C8Cycloalkyl "refers to a cycloalkyl group having 3 to 8 carbon atoms.
The reagents and starting materials used in the present invention are commercially available.
The 2-substituted homotaurine derivative has the following beneficial effects: animal drug efficacy tests show that the homotaurine derivatives of the present invention have an excellent alcohol inhibitory effect.
Drawings
FIG. 1 shows the results of the alcohol inhibitory effect of the 2-substituted homotaurine derivatives of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The compounds of the invention can be obtained according to the following embodiments:
scheme I,
Figure BDA0001717321180000081
R2，R3As defined above.
The starting 2-substituted β -amino acids of the above-described reactions are commercially available or can be prepared according to known methods for preparing 2-substituted β -amino acids, for example, the preparation of γ -aminobutyric acid as shown in US 6197819.
And in the second scheme, substituted alpha bromoethanone is adopted to form cyclic acyl lactone, and after reduction reaction, the cyclic acyl lactone is aminolyzed to form 2-substituted gamma-homotaurine.
Figure BDA0001717321180000082
Where the radical R is R in the above definition2Or R3In the case of H.
In general, the resulting 2-substituted γ -homotaurine can be coupled with a natural amino acid or an unnatural amino acid to form an amino acid prodrug.
Example 1: preparation of Compound 4 (amino acid prodrug)
Figure BDA0001717321180000083
1.71 g of 1- (methylamino) cyclohexanecarboxylic acid is dissolved in 20ml of tetrahydrofuran solution, cooled to 0 ℃, kept at the temperature, stirred for 1 hour, 25ml (1M) of borane tetrahydrofuran solution is slowly added dropwise, and after the addition, the reaction is maintained for 30min, and then the reflux reaction is carried out for 12 hours. It is then cooled to 0 ℃ and 2ml of methanol are added over half an hour to quench the reaction and concentrate to an oil which crystallizes in 4: 1 ethyl acetate and petroleum ether to give 1.1 g of the solid 1- (methylamino) cyclohexanemethanol product.
1.02 g of the solid (1- (methylamino) cyclohexanemethanol product) described above was placed in a round-bottomed flask, 10ml (48%) of concentrated aqueous hydrogen bromide was slowly added dropwise thereto, and after refluxing under heating for 8 hours, the mixture was concentrated to dryness.
Adding the bromide in the previous step into a mixed solvent of 1.26 g of sodium sulfite in water and 1, 4-epoxy hexacyclic ring, heating and refluxing for 6 hours, then concentrating to dryness, dissolving the residue into 10ml of hot ethanol solution, filtering while the solution is hot, concentrating half of the filtrate, and precipitating 0.51 g of 1- (methylamino) cyclohexane ethanesulfonic acid as a white solid at room temperature;
0.29 g of the above-mentioned 1- (methylamino) cyclohexaneethanesulfonic acid was dissolved in 5ml of anhydrous dichloromethane, and DMAP (50mg) and 0.35 g of Boc-L-phenylalanine were added thereto and stirred for 5 minutes. DCC (0.2 g) was added and a white precipitate formed immediately, the mixture was stirred overnight at room temperature and concentrated, and column chromatography was carried out on 400 mesh silica gel (1: 10, methanol: dichloromethane) to give 0.36 g of a pale yellow solid. The product of the step is directly dissolved in 10ml of methanol solvent, 2ml of trifluoroacetic acid is added and stirred overnight, the reaction solution is extracted for 3 times by using 10ml of ethyl acetate and saturated sodium bicarbonate water, the pH value is adjusted to be neutral by hydrochloric acid, the organic phase is concentrated and is separated by column chromatography through 400 meshes of silica gel (1: 10, methanol: dichloromethane) to obtain 0.21 g of (S) -2-aminomethyl-4-methyl pentanesulfonic acid phenylalanine prodrug. ESI [ M +1] was 373.4.
Example 2: preparation of Compound 2
Figure BDA0001717321180000091
Dissolving 1.6 g of (S) -3-aminomethyl-5-methyl pentanoic acid in 20ml of tetrahydrofuran solution, cooling to 0 ℃, keeping the temperature, stirring for 1 hour, slowly and dropwise adding 25ml (1M) of borane tetrahydrofuran solution, maintaining the reaction for 30min after the addition is finished, and then carrying out reflux reaction for 12 hours. After cooling to 0 ℃ and quenching the reaction and concentration by adding 2ml of methanol over half an hour to give an oil which crystallizes from ethyl acetate and petroleum ether at a ratio of 3: 1 to give 1.02 g of the solid (S) -3-aminomethyl-5-methylpentanol product.
1.02 g of the solid (S) -3-aminomethyl-5-methylpentanol product described above was placed in a round-bottom flask, 10ml (48%) of concentrated aqueous hydrogen bromide was slowly added dropwise thereto, and the mixture was refluxed for 8 hours and concentrated to dryness. The crude bromide is directly used for the next reaction.
Adding the bromide obtained in the previous step into a mixed solvent of 1.26 g of sodium sulfite and 1, 4-epoxy hexacyclic ring, heating and refluxing for 6 hours, then concentrating to dryness, dissolving the residue into 10ml of hot ethanol solution, filtering while the solution is hot, concentrating the filtrate to half, and precipitating 0.47 g of (S) -2-aminomethyl-4-methyl pentanesulfonic acid as a white solid at room temperature. ESI [ M +1 ]: 196.1.
EXAMPLE 3 preparation of Compound 3
Figure BDA0001717321180000092
Dissolving 1.7 g of hexamethyldisilazane lithium LiHMDS and 1.26 g of ethyl methanesulfonate in a 10ml tetrahydrofuran round-bottom flask, cooling to-78 ℃, dissolving 1.36 g of 1-bromo-2-acetone in 5ml tetrahydrofuran solution, slowly dropping into a reaction bottle, slowly returning to-50 ℃ for reaction for 10 hours to form unsaturated 4-methyl sultone, quenching the reaction, extracting and separating ethyl acetate, and dissolving and condensing an organic layer to obtain a crude product which is directly used for the next reaction.
Dissolving the reaction product in the previous step in 10ml of methanol solution, adding 0.5 g of palladium carbon (10%), carrying out room temperature reduction reaction in 5 atmospheric pressure hydrogen environment, reacting for 2 hours, filtering the palladium carbon, and concentrating the methanol to obtain 0.8 g of crude product of 2-methyl propane sultone for the next step.
Slowly adding the 2-methyl propane sultone in the step into ammonium hydroxide (28-30%, 10m1) in 10ml of tetrahydrofuran solvent, stirring at room temperature for 4 hours, concentrating to obtain a solid, virtually floating in tetrahydrofuran, adding the solid to reflux for 30 minutes, and cooling to room temperature. 0.6 g of 3-amino-2-methylpropane-1-sulfonic acid is collected as a solid. ESI [ M +1 ]: 154.2.
example 4: preparation of Compound 6 (amino acid prodrug)
Figure BDA0001717321180000101
0.2 g of (S) -2-aminomethyl-4-methylpentanesulfonic acid from example 2 was dissolved in 5ml of anhydrous dichloromethane, and DMAP (50mg) and 0.2 g of Boc-L-valine were added thereto and stirred for 5 minutes. DCC (0.2 g) was added and a white precipitate formed immediately, the mixture was stirred overnight at room temperature and concentrated, and column chromatography was carried out on 400 mesh silica gel (1: 10, methanol: dichloromethane) to give 0.31 g of a pale yellow solid. The product of this step was directly dissolved in 10ml of methanol solvent, 2ml of trifluoroacetic acid was added thereto and stirred overnight, the reaction solution was extracted 3 times with ethyl acetate 10ml and saturated sodium bicarbonate, the pH was adjusted to neutral with hydrochloric acid, the organic phase was concentrated and subjected to column chromatography on 400 mesh silica gel (1: 10, methanol: dichloromethane) to obtain 0.12 g of (S) -2-aminomethyl-4-methylpentanesulfonic acid valine prodrug. ESI [ M +1] was 295.4.
The racemate with the structure can be prepared into liquid phase separation under the gradient of acetonitrile and water of 80: 20 by adopting an AD-H chiral liquid phase column.
Example 5
Solid tablets of compound 5
1000 tablets were prepared according to the formulation in the following table, each tablet weighing 200 mg.
Figure BDA0001717321180000102
Figure BDA0001717321180000111
The preparation method comprises the following steps: mixing active ingredient compound 5, lactose, microcrystalline cellulose and hydroxyethyl starch sodium, adding into a high-shear wet granulator, and stirring at a certain rotation speed; then adding 50.0g of hydroxypropyl methylcellulose aqueous solution into the mixture, and preparing proper particles under the condition of high-speed shearing; then drying the wet particles by adopting a fluidized bed; mixing the obtained dry granules with magnesium stearate, and tabletting.
Example 6
Oral suspensions of Compound 6
1000 bottles of 5ml each were prepared according to the formulation of the oral suspension in the table below (according to specification 10mg/m 1).
Figure BDA0001717321180000112
The preparation method comprises the following steps: dissolving methyl p-hydroxybenzoate in hot water, cooling to room temperature (25 + -2 deg.C), sequentially adding sorbitol, polyethylene glycol, xanthan gum, citrate, compound 6 with average particle size of 30 μm and microcrystalline cellulose, and stirring to obtain oral suspension.
Example 7 efficacy test
Alcohol intake test in rats
Experimental reagent: the compounds 1-6 are self-made, and the homotaurine and other reagents are purchased from markets.
Experimental animals: the rats were from Shanghai Sprenbikhae laboratory animals Co.
The experimental method comprises the following steps: the test rats were individually fed with water deprivation for 24 hours prior to alcohol intake in individual mouse cages, followed by 1 hour daily administration of 10% v/v alcohol and 10% w/v sucrose in water for 4 consecutive days. Sucrose concentration was decreased by a gradient (from 10%, 5%, 2%, 0%) every 4 days, and body weight, ethanol intake, etc. were measured. The administration group was administered by intraperitoneal injection 1h before the ethanol solution twice a week.
The experimental results are as follows: the results of the experiment are shown in FIG. 1. At the doses given as shown in the figure, compounds 1, 2, 3 had better inhibitory effects on rat alcohol intake than homotaurine, while compounds 4, 5, 6 had slightly better effects than compounds 1, 2, 3.

Claims (10)

1. A2-substituted homotaurine derivative or a stereoisomer or a salt thereof, wherein the structure of the homotaurine derivative is shown as formula I:
Figure FDA0001717321170000011
wherein,
R1is H, and R2And R3Each independently selected from the group consisting of: h or C1-C6Alkyl, but R2And R3Not being H or R at the same time2Is H or R3Not being tert-butyl, or R3Is H or R2Is not a tert-butyl group;
or R1Is an amino acid residue, and R2And R3Each independently selected from the group consisting of: h or C1-C6Alkyl, but R2And R3Not H at the same time;
or R1Is an amino acid residue, and R2And R3And the C atoms to which they are attached are linked to form C3-C8A cycloalkyl group.
2. A 2-substituted homotaurine derivative of claim 1, which is an amino acid prodrug of a compound of formula I, or a stereoisomer or salt thereof; wherein R is1Is natural amino acid; preferably, R1An amino acid residue selected from the group consisting of L-valine, L-phenylalanine, L-lysine, L-leucine, L-serine, L-alanine, L-isoleucine, L-histidine, L-cysteine, L-glutamic acid, L-tyrosine, L-proline and L-histidine, or a pharmaceutically acceptable salt thereof.
3. The 2-substituted homotaurine derivative or a stereoisomer or salt thereof of claim 1, wherein C is1-C6Alkyl or said C3-C8Cycloalkyl is substituted or unsubstituted alkyl; when said C is1-C6Alkyl is substituted alkyl or said C3-C8When cycloalkyl is substituted alkyl, the substituted alkyl is substituted with a substituent selected from the group consisting of: halogen, NH2Or OH.
4. The 2-substituted homotaurine derivative or a stereoisomer or salt thereof according to claim 1, wherein R2And R3Each independently selected from the group consisting of: h or C1-C4Alkyl, but R2And R3Not H at the same time; preferably, said C1-C4Alkyl includes methyl, ethyl, dimethyl, propyl, isopropyl, isobutyl, n-butyl;
wherein, R is2And R3C of formation of a connection3-C8Cycloalkyl is selected from cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl.
5. The 2-substituted homotaurine derivative or a stereoisomer or a salt thereof according to claim 1, wherein the salt of the homotaurine derivative is formed by a homotaurine derivative and a base, and is formed when an acidic proton present in the 2-substituted homotaurine derivative is replaced with a metal ion including an alkali metal ion, an alkaline earth metal ion, or another metal ion;
preferably, the alkali metal ions are lithium, sodium, potassium;
preferably, the alkaline earth metal ions are magnesium, calcium, barium;
preferably, the other metal ions are aluminum, zinc, iron.
6. The 2-substituted homotaurine derivative or a stereoisomer or salt thereof according to claim 1, wherein the homotaurine derivative is selected from the group consisting of:
Figure FDA0001717321170000021
compound 1: 1- (methylamino) -3-methylbutane-1-sulfonic acid
Figure FDA0001717321170000022
Compound 2: 2- (aminomethyl) 4-methylpentane-1-sulfonic acid
Figure FDA0001717321170000023
Compound 3: 3-amino-2-methylpropane-1-sulfonic acid
Figure FDA0001717321170000024
Compound 4: 2- (aminomethyl) -4-methylpentanesulfonic acid phenylalanine prodrugs
Figure FDA0001717321170000031
Compound 5: 1- (aminomethyl) cyclohexaneethanesulfonic acid valine prodrugs
Figure FDA0001717321170000032
Compound 6: 2-aminomethyl-4-methylpentanesulfonic acid valine prodrug.
7. A method for preparing a 2-substituted homotaurine derivative or a stereoisomer or a salt thereof according to claims 1 to 6, comprising the steps of:
Figure FDA0001717321170000033
R2and R3As defined in claim 1;
step (1): carrying out reduction reaction on an initiator beta-amino acid to obtain beta-amino alcohol;
step (2): brominating the obtained beta-amino alcohol to obtain bromine substituted beta-amino alkane;
and (3): the obtained bromine substituted beta-amino alkane is subjected to sulfonation reaction to obtain the homotaurine derivative shown in the formula I;
the above reaction conditions were as follows:
the reducing agent for the reduction reaction in the step (1) is selected from borane and lithium aluminum hydride;
the reagent for bromination reaction in the step (2) is selected from hydrogen bromide, NBS and bromine;
the reagent for sulfonation in step (3) is selected from sodium sulfite.
8. A method for preparing a 2-substituted homotaurine derivative or a stereoisomer or a salt thereof according to claims 1 to 6, comprising the steps of:
Figure FDA0001717321170000041
the R group is C1-C6Alkyl or C3-C8A cycloalkyl group;
step (1): the R radical of the initiator substitutes the brominated methyl ketone to obtain unsaturated R radical sultone through reaction;
step (2): carrying out double bond reduction reaction on the obtained unsaturated R-base sultone to obtain saturated R-base sultone;
and (3): carrying out ammonolysis reaction on the obtained saturated R-based sultone to obtain a homotaurine derivative shown in a formula I;
the above reaction conditions were as follows:
the reagent reacted in step (1) is selected from LiCH2SO3Et；
The reagent for double bond reduction reaction in the step (2) is selected from Pd/C-H2；
And (3) the reagent for ammonolysis reaction in the step (3) is selected from ammonium hydroxide and ammonia gas.
9. A2-substituted homotaurine derivative or a stereoisomer or a salt thereof according to claims 1 to 6, which has an alcohol inhibitory effect.
10. A pharmaceutical composition comprising the 2-substituted homotaurine derivative or a stereoisomer or a salt thereof of claims 1-6 and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is a solid or liquid formulation for oral, gastrointestinal, buccal, sublingual, nasal, rectal or transdermal administration.
CN201810715261.XA 2018-07-03 2018-07-03 2-substituted homotaurine derivative Pending CN110668980A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810715261.XA CN110668980A (en) 2018-07-03 2018-07-03 2-substituted homotaurine derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810715261.XA CN110668980A (en) 2018-07-03 2018-07-03 2-substituted homotaurine derivative

Publications (1)

Publication Number Publication Date
CN110668980A true CN110668980A (en) 2020-01-10

Family

ID=69065616

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810715261.XA Pending CN110668980A (en) 2018-07-03 2018-07-03 2-substituted homotaurine derivative

Country Status (1)

Country Link
CN (1) CN110668980A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111214843A (en) * 2020-03-02 2020-06-02 黄冈永安药业有限公司 Distillation device and production method of high-quality sodium methyl taurate
CN112225679A (en) * 2020-10-13 2021-01-15 苏州亚科科技股份有限公司 Preparation method of 3- (cyclohexylamine) -2-hydroxy-1-propanesulfonic acid
CN112409224A (en) * 2020-11-20 2021-02-26 四川大学 Synthetic method of sulfonamide compound

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197819B1 (en) * 1990-11-27 2001-03-06 Northwestern University Gamma amino butyric acid analogs and optical isomers
CN101124200A (en) * 2004-11-12 2008-02-13 神经化学（国际）有限公司 Methods and fluorinated compositions for treating amyloid-related diseases
CN101128421A (en) * 2004-12-22 2008-02-20 神经化学（国际）有限公司 Methods and compositions for treating amyloid-related diseases
CN101600730A (en) * 2006-10-12 2009-12-09 贝鲁斯健康(国际)有限公司 Send method, compound, composition and the carrier of 3-amino-1-propanesulfonic acid
CN102659643A (en) * 2012-04-18 2012-09-12 北京化工大学 Method for preparing substituted homotaurine from alpha, beta-unsaturated amide
CN106170563A (en) * 2014-03-21 2016-11-30 爱尔真公司 Methods for treating neurological disorders

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197819B1 (en) * 1990-11-27 2001-03-06 Northwestern University Gamma amino butyric acid analogs and optical isomers
CN101124200A (en) * 2004-11-12 2008-02-13 神经化学（国际）有限公司 Methods and fluorinated compositions for treating amyloid-related diseases
CN101128421A (en) * 2004-12-22 2008-02-20 神经化学（国际）有限公司 Methods and compositions for treating amyloid-related diseases
CN101600730A (en) * 2006-10-12 2009-12-09 贝鲁斯健康(国际)有限公司 Send method, compound, composition and the carrier of 3-amino-1-propanesulfonic acid
CN103787927A (en) * 2006-10-12 2014-05-14 Bhi有限合资公司 Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
CN102659643A (en) * 2012-04-18 2012-09-12 北京化工大学 Method for preparing substituted homotaurine from alpha, beta-unsaturated amide
CN106170563A (en) * 2014-03-21 2016-11-30 爱尔真公司 Methods for treating neurological disorders

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BENOIT BACHAND等: "A novel synthetic route to 2-alkylpropane-1,3-sultones and its application to the synthesis of 2-alkyl derivatives of tramiprosate", 《TETRAHEDRON LETTERS》 *
M. FOSTER OLIVE等: "Effects of acute acamprosate and homota urine on ethanol intake and ethanol-stimulat ed mesolimbic dopamine release", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 *
S. ROUHANI等: "Effects of Alcohol Dependence on Shock-Induced Fighting: Action of Muscimol and Homotaurine", 《PHARMACOLOGY BIOCHEMISTRY & BEHAVIOR》 *
S. ROUHANI等: "Effects of Muscimol or Homotaurine onSleep–Wake States in Alcohol-Dependent Rats During Withdrawal", 《 PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR》 *
无: "无", 《REG,STN ON THE WBD》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111214843A (en) * 2020-03-02 2020-06-02 黄冈永安药业有限公司 Distillation device and production method of high-quality sodium methyl taurate
CN111214843B (en) * 2020-03-02 2022-04-26 黄冈永安日用化工有限公司 Distillation device and production method of high-quality sodium methyl taurate
CN112225679A (en) * 2020-10-13 2021-01-15 苏州亚科科技股份有限公司 Preparation method of 3- (cyclohexylamine) -2-hydroxy-1-propanesulfonic acid
CN112409224A (en) * 2020-11-20 2021-02-26 四川大学 Synthetic method of sulfonamide compound

Similar Documents

Publication Publication Date Title
USRE46555E1 (en) Deuterated catecholamine derivatives and medicaments comprising said compounds
US5385904A (en) Organic salts of N,N'-diacetyl cystine
FI78684B (en) FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA CIS, ENDO-2-AZABICYKLO- / 5.3.0 / -DECAN-3-CARBOXYLSYRADERIVAT OCH MELLANPRODUKTER.
US7462737B2 (en) Pregabalin free of isobutylglutaric acid and a process for preparation thereof
EP2453900A1 (en) Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof
KR20120089806A (en) Prodrugs of guanfacine
AU2013298773B2 (en) Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof
CN110668980A (en) 2-substituted homotaurine derivative
WO2022053696A1 (en) Novel safrylamine derivatives having prodrug properties
JP2018528205A (en) Brain-permeable chromone oxime derivatives for levodopa-induced dyskinesia therapy
JP2007056026A (en) Dipeptide
AU2003289841B2 (en) Deuterated catecholamine derivatives and medicaments comprising said compounds
WO2017179058A1 (en) Methods and compositions for treatment of prader-willi syndrome
CN104387288A (en) Compound as neuraminidase inhibitor and application of compound in medicine
KR20120068678A (en) (s)-n,n-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine derivatives, pharmaceutical compositions containing them, and manufacturing methods thereof
CN101906069A (en) (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method and application
FR3067711A1 (en) INHIBITORS OF CATECHOL-O-METHYL-TRANSFERASE (COMT)
CN119136846A (en) Combination therapy of NTSR1-targeted radiopharmaceuticals and DNA damage response inhibitors
CN116763768A (en) Isotopically enriched 3-amino-1-propanesulfonic acid derivatives and uses thereof
CA3207957A1 (en) Benzazepine compounds, preparation method therefor and pharmaceutical use thereof
CN117534595A (en) Isotopically enriched 3-amino-1-propanesulfonic acid derivatives and uses thereof
CN117586330A (en) Novel nucleoside derivative, pharmaceutical composition and application thereof
FR2896801A1 (en) New chelates of alkaline earth metal/transition metal with a glutamic/aspartic dipeptide, useful to treat e.g. infantile hyperactivity, autism, hyper excitability syndromes and anemia
EP1992637A1 (en) 1-Aminocyclopentane-1,3,4- tricarboxylic acids derivatives
OA18597A (en) Brain-penetrant chromone oxime derivative for the therapy of levodopa-induced dyskinesia.

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20200110