WO2015118554A1 - Dérivés de dithiolan-3-ylpentanoate, compositions pharmaceutiques et méthodes de traitement de la douleur - Google Patents

Dérivés de dithiolan-3-ylpentanoate, compositions pharmaceutiques et méthodes de traitement de la douleur Download PDF

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Publication number
WO2015118554A1
WO2015118554A1 PCT/IN2014/000259 IN2014000259W WO2015118554A1 WO 2015118554 A1 WO2015118554 A1 WO 2015118554A1 IN 2014000259 W IN2014000259 W IN 2014000259W WO 2015118554 A1 WO2015118554 A1 WO 2015118554A1
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WIPO (PCT)
Prior art keywords
compound
formula
pain
administering
treatment
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PCT/IN2014/000259
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English (en)
Inventor
Mahesh Kandula
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Krisani Biosciences (P) Ltd.
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Publication of WO2015118554A1 publication Critical patent/WO2015118554A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • This disclosure generally relates to compound, method of synthesizing the compound and method for the treatment of pain. More particularly, this disclosure relates to treating subjects suffering from neuropathic pain with pharmaceutically acceptable dose of compound or the prodrug.
  • Pain attributed to tissue injury is mainly caused by inflammation.
  • the mechanism of peripheral inflammation includes local liberation of mediators released by cell lysis, inflammatory cells, and nerve endings. Nerve roots are vulnerable to compression (e.g., compressive radiculopathy, infections, and tumors). If the lesion is proximal to the dorsal root ganglion, there may be abnormality of the central axons but not necessarily of the peripheral axons. Therefore, tests aimed at the peripheral axons will not detect the injury in those situations. Likewise, complete degeneration of the axon is not necessary to produce clinical symptoms: lesions may be in the form of perinodal retraction of myelin or frank demyelination. Demyelination with ephaptic spread of action potentials between adjacent axons is believed to underlie bursts of lacerating pain because the action potentials transmitted along a few fibers can inappropriately spread many other axons.
  • Complex regional pain syndrome is one of the most severe and mysterious neuropathic pain syndromes.
  • the clinical symptoms of complex regional pain syndrome always include pain, hyperalgesia, and allodynia.
  • the instant disclosure presents a compound of formula I, formula II and formula III, method of synthesizing the compound of formula I, formula II and formula III and using the compound of formula I, formula II or formula III for treating a mammal suffering with pain.
  • a pharmaceutical composition comprising one or more compounds of formula I, formula II, formula III Or intermediates thereof with one or more of pharmaceutically acceptable carriers, vehicles or diluents are disclosed and used for treating pain.
  • these compounds may be used in the treatment of pain and related complications.
  • the compound of formula 1 contains thioctic acid, enantiomers of thioctic acid either in racemic, R-stereoisomer only.
  • the compound of formula II contains thioctic acid, enantiomers of thioctic acid either in racemic, R-stereoisomer only.
  • the compound of formula III contains thioctic acid, enantiomers of thioctic acid either in racemic, R-stereoisomer only.
  • the pharmaceutically acceptable amount may be administered, * but not limited to, as an injection.
  • Other embodiments for administration may include peroral, topical, transmucosal, inhalation, targeted delivery and sustained release formulations.
  • kits comprising any of the pharmaceutical compounds disclosed herein.
  • the kit may comprise instructions for use in the treatment of pain or related complications.
  • the application also discloses a pharmaceutical compound comprising a pharmaceutically acceptable carrier and any of the compounds herein.
  • the compounds described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from pain manifested from chronic diseases or disorders, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Neurological, Metastasis (cancer) or Ocular complications.
  • the compounds may also be used in biochemical research, for example in studying and modulating neural voltage transmission and homeostasis and also neural channels.
  • compound of formula I, formula II or formula III and its physiologically compatible acid-addition salts are used for the pharmaceutical preparations for the treatment and/or prophylaxis of pain, more specifically neuropathic pain.
  • the compounds of the present disclosure can be present in the form of pharmaceutically acceptable salts.
  • the compounds of the present disclosure can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formulal to be used as prodrugs).
  • the compounds of the present disclosure can also be solvated, i.e. hydrated. The solvation can be effected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I, formula II or formula III (hydration).
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the term "pain” refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage caused by or resulting in stimulation of nociceptors in the peripheral nervous system, or by damage to or malfunction of the peripheral or central nervous systems and neural voltage channel transmission.
  • Pain related diseases or disorders includes such as Cancer (chemotherapy and surgery related), Neurologic (bradykinesia, rigidity, tremor, ataxia, dyskinesia, dysarthria, seizures, neuropathic pain), Psychiatric (behavioral disturbances, cognitive impairment, psychosis), Ophthalmologic (dry eye, cataracts), Hematologic (haemolysis, coagulopathy), Renal (renal tubular defects, diminished glomerular filtration, nephrolithiasis), Cardiovascular (cardiomyopathy, arrhythmias, conduction disturbances, autonomic dysfunction), Musculoskeletal (osteomalacia, osteoporosis, degenerative joint diseases), Gastrointestinal (cholelithiasis, pancreatitis, bacterial peritonitis), Surgery or amputation related or any other medical condition, is well understood in the art, and includes administration of a compound which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • Residue is an art-recognized term that refers to a portion of a molecule.
  • a residue of thioctic acid may be: dihydrolipoic acid, bisnorlipoic acid, tetranorlipoic acid, 6,8-bismethylmercapto-octanoic acid, 4,6-bismethylmercapto- hexanoic acid, 2,4-bismethylmeracapto-butanoic acid, 4,6-bismethylmercapto-hexanoic acid.
  • parenteral administration and “administered parenterally” as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: ( ⁇ ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) star
  • prodrug is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present disclosure.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compounds. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • treating is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • treating includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.
  • terapéuticaally effective amount is an art-recognized term.
  • the term refers to an amount of a salt or compound disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or Condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue.experimentation.
  • the pharmaceutical compositions described herein are formulated in a manner such that said compounds will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment.
  • the desired amount of the compound to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compounds from the subject compounds. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the optimal concentration and/or quantities or amounts of any particular salt or compound may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • solvate refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).
  • sustained release When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized.
  • a subject compound which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • one or more of the pharmaceutically acceptable excipient may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt arid/or compound, for a sustained or extended period (as compared to the release from a bolus).
  • This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.
  • systemic administration means administration of a subject compound, therapeutic or other material at a site remote from the disease being treated.
  • Administration of an agent directly into, onto, or in the vicinity of pain sensation of the disease being treated, even if the agent is subsequently distributed systemically, may be termed “local” or “topical” or “regional” administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • the present disclosure also contemplates prodrugs of the compounds disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
  • an effective dosage for the compounds of Formulas 1 is in the range of about 0.3 mg/kg/day to about 60 mg/kg/day in single or divided doses, for instance 1 mg/kg/day to about 50 mg/kg/day in single or divided doses.
  • the compounds of Formulas I may be administered at a dose of, for example, less than 2 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg kg/day.
  • Compounds of Formula I, formula II or formula III may also be administered to a human patient at a dose of, for example, between 50 mg and 1000 mg, between 100 mg and 800 mg, or less than 1000, 900, 800, 700, 600, 500, 400, 300, 200, or 100 mg per day.
  • the compounds herein are administered at an amount that is less than 95% ' , 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I, formula II or formula III required for the same therapeutic benefit.
  • kits may comprise a container for containing the separate compounds such as a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Compound of formula I is disclosed as follows: In one embodiment, a com ound of formula 1 is disclosed.
  • Compound of formula II is disclosed as follows: In one embodiment, a com ound of formula 1 is disclosed.
  • Compound of formula III is disclosed as follows: In one embodiment, compound of formula 1 is disclosed.
  • reaction mixture was diluted with DCM (1 L), washed with saturated sodium bicarbonate (1 L) followed by brine solution (1 L), dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure to get product 2 (210 g) as light yellow solid, which was recrystalized in hexane to yield 160 g (85.7 %) of compound 2 as a off white solid.
  • reaction mixture was poured into water (1 L) and extracted with DCM (2 x 1 L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 mL), dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure.
  • the crude was purified by column chromatography over 100-200 mesh silica gel by using 0 to 10% ethyl acetate in pet ether as an eluent to yield 63 g (32%) of compound 4 as a yellow liquid.
  • the crude was purified by column chromatography over 100-200 mesh silicagel by using 0 to 8 % ethyl acetate-pet ether as eluent to yield 8.5 (27.6 %) of compound of formula I as a pale yellow gummy solid.
  • the compound is dissolved in 10 % ethyl acetate in hexane & left at 0° C for 24 h, the obtained solid filtered to provide 97.2% LCMS purity as off white solid.
  • reaction mixture was diluted with DCM (100 mL), washed with water (2x100 mL) followed by brine solution (100 mL), dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure.
  • the crude residue 3 was purified by column chromatography over 100-200 mesh silica gel by using 5% ethyl acetate-pet ether as eluent to yield 8.4 g (79 %) of compound 3 a pale yellow as oil.
  • reaction mixture On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (100 mL), washed with water (2x100 mL) followed by brine solution (100 mL), dried over anhydrous Na 2 S0 and evaporated under reduced pressure to get crude product as viscous oil which was purified by column chromatography over neutral alumina by using 30 % ethyl acetate-pet ether as eluent to yield 5.0 g (60 ) of compound 4 as a pale yellow liquid.
  • reaction mixture was added slowly to the solution of lipoic acid (3.3 g, 16.34 mmol; 1.2 eq) & anhydrous K 2 C0 3 (5.6 g, 40.87 mmol; 3.0 eq) in dry DMF (50 mL) at 0 °C and the reaction mixture was allowed to stir for 16 h at rt. Reaction was monitored by TLC. On completion of the reaction, reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine solution (100 mL)* dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using 10 % ethyl acetate-pet ether as eluent to yield 3.0 g (35 %) of compound 6 as a yellow liquid.
  • reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL), the combined organic layers were washed with brine solution (100 mL), dried over anhydrous Na 2 S04 and evaporated under reduced pressure. The crude was purified by column chromatography over 100 ⁇ 200 mesh silica gel by using 25% ethyl acetate-pet ether as eluent to yield 0.18 g (23 %) of compound 7 as a yellow oil.
  • reaction mixture was diluted with DCM (200 mL), washed with water (2x300 mL) followed by brine solution (300 mL) and dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure.
  • the crude was purified by column chromatography over 100-200 mesh silica gel by using 15 % ethyl acetate-pet ether as eluent to yield 10.0 g (68.58 %) of compound 8 as a pale yellow gum.
  • reaction mixture was diluted with DCM (500 mL), washed with saturated sodium bicarbonate (500 mL) followed by brine solution (500 mL), dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure to get product 4 as viscous oil which was purified by column chromatography over neutral alumina by using 30 % ethyl acetate-pet ether as eluent to yield 100 g (76 %) of compound 4 as a pale yellow liquid.
  • reaction mixture was diluted with water (250mL), adjusted the reaction mixture to acidic (PH ⁇ 5) using saturated citric acid solution, then extracted the aq acidic solution with ethyl acetate (1000 mL), separated the organic layer washed with brine solution (100 mL), dried over anhydrous Na 2 S04 and evaporated under the reduced pressure.
  • the crude product was triturated with 500 mL of hexane, filtered and dried under vacuum to yield 60 g (69.4 %) of compound 4b as a half white solid.
  • Neuropathic pain inducement was done by following principles of Chung induced model.
  • the SD rats were anesthetized using ketamine/xylazine sodium.
  • the rats were shaved and placed in prone position for surgery.
  • the L5-L6 spinal nerves were surgically litigated.
  • the rats were returned to their cages for recuperation and recovery under comfortable warm conditions using heat lamps.
  • Second level of selection of the rats was done on day 14 after the surgery. Von Frey test was performed on the preselected rats after day 7 on day 14. Using Von Frey methodology, animals with a pain threshold of ⁇ 26 g for the operated leg will be included in the study. After this selection step, the animals were randomly placed into their experimental groups.
  • Blank, positive control and test compound Blank was just the medium used for dissolving other compounds.
  • the positive control was Gabapentin and the test compound was the final compound of formula I discussed in the instant disclosure.
  • Three types of experimental groups were formed. Three different types of chemicals were used to determine the efficacy of the chemicals as well comparison of the instant disclosed compound with a positive control was performed.
  • the final compound of the instant application was administered at lOOmg/kg and 150 mg/kg body weight as two different groups.
  • the Gabapentin was administered at 150 mg/kg body weight.
  • N 10 KRB-2/Pre IP 5 ml/kg and at 4.5 mg/kg day 14 through
  • the instant final compound of formula I at a dose of 150 mg/kg was effective in treating the spinal nerve ligation model for neuropathic pain in rats as reflected in the parameters of mechanical allodynia at 2 hours post-treatment on study days 14 and 21.
  • the activity of the instant final compound of formula I at a dose of 150 mg/kg was similar to the activity of Gabapentin, the positive control in this study.
  • the present disclosure provides among other things compound, method to synthesize the compound for formula I and treating pain in mammals using the compound of formula I. While specific embodiments of the subj ect disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the compounds, compounds and methods herein will become apparent to those skilled in the art upon review of this specification.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de 5-(1,2-dithiolan-3-yl)pentanoate de 1-carbamyloxyéthyle de formule I, de formule II et de formule III. L'invention concerne également un procédé de synthèse du composé de formule I, de formule II et de formule III. Le composé de formule I, de formule II et de formule III ou ses sels pharmaceutiquement acceptables, ainsi que ses polymorphes, solvates et hydrates peuvent être formulés sous la forme d'une composition pharmaceutique. La composition pharmaceutique du composé de formule I, de formule II et de formule III ou le composé final de formule I, de formule II ou la formule III peut être formulé pour une administration non invasive par voie pérorale, topique (par exemple transdermique), entérale, transmucosale, ciblée, à libération prolongée, à libération retardée, à libération pulsée et parentérale. Ces compositions peuvent être utilisées pour traiter les douleurs chroniques qui se manifestent avec des maladies chroniques ou leurs complications associées.
PCT/IN2014/000259 2014-02-06 2014-04-22 Dérivés de dithiolan-3-ylpentanoate, compositions pharmaceutiques et méthodes de traitement de la douleur WO2015118554A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017085733A3 (fr) * 2015-11-19 2017-07-06 Krisani Biosciences (P) Ltd. Procédé amélioré pour la synthèse de 2,6-xylidine et de ses dérivés
CN114716341A (zh) * 2022-03-07 2022-07-08 上海农帆生物科技有限公司 一种一锅法制备二甲草胺的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117749A1 (fr) * 2010-03-23 2011-09-29 Mahesh Kandula Composé et procédé pour le traitement de la douleur
WO2013024320A1 (fr) * 2011-08-17 2013-02-21 Mahesh Kandula Dérivés de 2,6-xylidine pour le traitement de la douleur
WO2013167993A1 (fr) * 2012-05-08 2013-11-14 Mahesh Kandula Compositions et méthodes de traitement de troubles neurologiques dégénératifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117749A1 (fr) * 2010-03-23 2011-09-29 Mahesh Kandula Composé et procédé pour le traitement de la douleur
WO2013024320A1 (fr) * 2011-08-17 2013-02-21 Mahesh Kandula Dérivés de 2,6-xylidine pour le traitement de la douleur
WO2013167993A1 (fr) * 2012-05-08 2013-11-14 Mahesh Kandula Compositions et méthodes de traitement de troubles neurologiques dégénératifs

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017085733A3 (fr) * 2015-11-19 2017-07-06 Krisani Biosciences (P) Ltd. Procédé amélioré pour la synthèse de 2,6-xylidine et de ses dérivés
CN114716341A (zh) * 2022-03-07 2022-07-08 上海农帆生物科技有限公司 一种一锅法制备二甲草胺的方法
CN114716341B (zh) * 2022-03-07 2024-05-03 上海农帆生物科技有限公司 一种一锅法制备二甲草胺的方法

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