WO2017085733A2 - Procédé amélioré pour la synthèse de 2,6-xylidine et de ses dérivés - Google Patents

Procédé amélioré pour la synthèse de 2,6-xylidine et de ses dérivés Download PDF

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Publication number
WO2017085733A2
WO2017085733A2 PCT/IN2016/000266 IN2016000266W WO2017085733A2 WO 2017085733 A2 WO2017085733 A2 WO 2017085733A2 IN 2016000266 W IN2016000266 W IN 2016000266W WO 2017085733 A2 WO2017085733 A2 WO 2017085733A2
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compound
test
formula
disease
reaction mixture
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PCT/IN2016/000266
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WO2017085733A3 (fr
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Satya Surya Visweswara Srinivas Akella
Krishnam Raju Kalidindi
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Krisani Biosciences (P) Ltd.
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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

Definitions

  • This disclosure generally relates to a compound made, of 2, 6 xylidine derivative, method of synthesizing the compound and method of treating pain using the compound of formula 1. More particularly, this disclosure relates to treating subjects suffering from neuropathic pain with pharmaceutically acceptable dose of compound of formula 1 or the prodrug of the compound formula l.This disclosure, also relates to an improved and modified process for the synthesis of 2, 6 xylidine derivatives.
  • Pain attributed to tissue injury is mainly caused by inflammation.
  • the mechanism of peripheral inflammation includes local liberation of mediators released by cell lyses,inflarnmatory 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.
  • lesions may be in the form of per nodal retraction of myelin or frank demyelination. Demyelination with emphatic 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.
  • the instant disclosure presents a compound of formula 1, method of synthesizing the compound of formula 12, 6, Xylidine derivative, and using the compound of formula 1 for treating a mammal suffering with pain.
  • a pharmaceutical composition comprising one or more compounds of formula 1 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 and may be distributed as a kit.
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1, 2 or 6;
  • c and d are each independently H, D, -OH, -OD, C C 6 -alkyl, -NH 2 or -COCH 3 ;
  • n 1, 2, 3, 4, 5, or 6.
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1, 2 or 6;
  • c and d are each independently H, D, -OH, -OD, d-C 6 -alkyl, -N3 ⁇ 4 or -COCH 3 ;
  • n 1, 2, 3, 4, 5, or 6.
  • the compound of formula 1 contains thioctic acid, enantiomers of thioctic acid in a R(+)-stereoisomeric form only.
  • the pharmaceutically acceptable amount of the compound of formula l may be administered, but not limited to, as an injection.
  • administration of the drug may include peroral, topical, transmucosal, inhalation, targeted delivery and sustained release formulations.
  • kits comprising the compound of formula 1 and/or the pharmaceutically acceptable form of compound of formula 1.
  • the kit may comprise instructions for use the compound of formula 1 and/or pharmaceutically acceptable form of compound of formula 1 to be used as a treatment for pain or related complications.
  • the disclosure also describes a pharmaceutical compound comprising a pharmaceutically acceptable carrier and the compound of formula 1 herein.
  • the compound described herein has several uses.
  • the present disclosure 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 1 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.
  • 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.” Diasteroismoers 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, conductiondisrurbances, 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
  • 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, intra-articular, 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.
  • pharmaceutically acceptable carrier 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.
  • pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) 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)
  • 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.
  • the present disclosure also contemplates prodrugs of the compounds disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
  • 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 byadministration 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.
  • the phrase "therapeutically 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 adniinistering 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) withconcomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/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.
  • Most common routes of administration include the non-invasive peroral (through the mouth), topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular and rectal) and inhalation routes.
  • an effective dosage for the compound of formula 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 compound of formula 1 may be aclministered 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 1 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 1 required for the same therapeutic benefit.
  • kits may comprise a container for containing the separate compound 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.
  • a compound of formula l is disclosed as follows:
  • Step-1 Synthesis: To a stirred solution of 2,6-dimethyl aniline(30.0 g, 0.24 mole; 1.0 eq) in DCM (600 mL; LR grade) was added Chloroacetyl chloride at 0 °C over 30 min and the reaction mixture was stirred for 3 h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (200 mL) and washed with water (2 x 250 mL) followed by saturated aqueous NaHC0 3 solution (2 x 250 mL). The combined organic layer was washed with brine solution (1 x 100 mL) and dried over anhydrous Na 2 S0 4 .
  • Step-2 Synthesis:ToStep-l material (40.5 g, 0.2 moles; 1.0 eq) was added 2- (ethylamino) ethanol (91.4 g, 1.02 moles; 5.0 eq) drop wise at room temperature over 15-20 min and the reaction mixture was stirred on over head stirrer over night. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (350 mL) and stirred for further 1 hr.
  • Step -3 Synthesis: To a mixture of Stepe 2 material (46.0 g, 0.184 mol; 1.0 eq), Dimethylamino pyridine (22.5 g, 0.184 mol; 1 eq) and R-Lipoic acid (41.7 g, 0.202 mol, 1.1 eq) was added dichloromethane (920 mL, LR) and finally EDC.HCl (53 g, 0.276 mol, 1.5 eq) at room temperature. The reaction mixture was stirred for 3 h at room temperature & reaction was monitored by TLC. On completion of the reaction, the reaction mixture was washed with water (1 x 700 mL) followed by brine wash (1 x 250 mL).
  • Step-1 Synthesis.To a stirred solution of 2-(ethylamino)ethanol (3.0 g, 0.033 moles; 1.0 eq) in DCM (20 mL) was added triethylamine (6.8 g, 0.067 moles; 2.0 eq) followed by drop wise addition of t-butyl chloroacetate (5.56 g, 0.037 moles; 1.1 eq) in DCM (25 mL) at room temperature. Stirred mass for overnight at room temperature.
  • Step-2 Synthesis: To a stirred solution of Step-1 material (2.0 g, 0.0098 moles; 1.0 eq) in DCM (50 mL) was added DMAP (0.6 g, 0.0049 moles; 0.5 eq), R-Lipoic acid (2.2 g, 0.0106 moles; 1.08 eq) and EDC. HCl (2.8 g, 0.014 moles; 1.5 eq) and the reaction mixture were stirred for overnight. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (50 mL) and washed with water (1 x 50 mL) followed by brine solution (1 x 50 mL).
  • Step-4 Synthesis: To Step-3 material (2.2 g, 0.0049 moles; 1.2 eq) in DCM (30 mL) was added N-ethyl-diisopropyl amine (2.13 g, 0.0165 moles; 4.0 eq) and HATU (2.35 g, 0.0061 moles; 1.5 eq) at ⁇ 10 °C. Stirred mass for 15-20 min and 2,6-dimethyl aniline (0.5 g, 0.0041 moles; 1.0 eq) was added to reaction mass. The mixture was stirred for overnight at room temperature.
  • reaction mixture On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (150 mL) and washed with water (2 x 150 mL) followed by brine solution (1 x 150 mL). Dried organic layer over anhydrous Na 2 S0 4 and evaporate under reduced pressure to get 4.5 g of crude compound, which was purified over 100-200 mesh silica using 38 % of pet ether (60-80) and ethyl acetate to get yellow colour oily mass. Yield%: 0.4 g (22 %).
  • ⁇ - ⁇ (CDCb): ⁇ 1.13 - 1.17 (t, 3H), 1.27 - 1.58 (m, 6H), 1.83 - 1.90 (m, 1H), 2.16 - 2.19 (t, 2H), 2.23 (s, 6H), 2.40 - 2.46 (m, 1H), 2.72 - 2.77 (m, 2H), 2.89 - 2.92 (t, 2H), 3.07 - 3.19 (m, 2H), 3.32 (s, 2H), 3.46 - 3.50 (m, 1H), 4.22 - 4.24 (t, 2H), 7.06 - 7.10 (m, 3H), 8.83 (bs,
  • the objective of the study was to evaluate the metabolic stability of KB-CN-001, Lidocaine and Gabapentin in human and rat plasma at 1 ⁇ test concentration. Plasma stability was carried out using Human and rat plasma in duplicates for test/ reference items.
  • the final composition of the assay included 1 ⁇ of test item or 10 ⁇ of reference item Benfluorex or Propranolol in Human/ Rat plasma. The mixture was incubated at 37° C with brief shaking and the samples were removed at 0, 15, 30, 60 and 120 minutes. The samples were extracted in presence of internal standard and were analyzed using LC-MS/MS. The percent of the test/reference item remaining after specified incubation period was calculated with respect to the peak area ratio at time 0 min.
  • Lidocaine (Rat plasma) 100.00 97.87 97.80 102.20 104.85
  • test / reference item(s) in Human and Rat plasma was prepared at concentration of 1 ⁇ (test items) and 10 ⁇ (reference items) by using 1 mM and 10 mM DMSO stocks, respectively (final DMSO concentration was 0.1%).
  • the samples were incubated at 37°C for 120 minutes, with shaking at 400 rpm.At 0, 15, 30, 60 and 120 minutes, an aliquot of 100 ⁇ , specimen was removed.
  • the specimen was subjected to sample extraction in presence of internal standard Haloperidol by protein precipitation method, 100 iL of sample was added into tube containing 200 ⁇ - of cold acetonitrile and 50 uL of internal standard. Samples were centrifuged at 10000 rpm for 10 minutes at 4° CAfter extraction, -200 ⁇ sample was transferred into labeled auto sampler vials and submitted for LC-MS/MS analysis.
  • Metabolic stability of KB-CN-001, Lidocaine and Gabapentin was determined in Human and Rat plasma at 1 ⁇ test concentration. Plasma stability was carried out using Human and rat plasma in duplicates for test/ reference items. The final composition of the assay included 1 ⁇ of test item or 10 ⁇ of reference item Benfluorex or Propranolol in Human/ Rat plasma. The mixture was incubated at 37° C with brief shaking and the samples were removed at 0, 15, 30, 60 and 120 minutes. The samples were extracted in presence of internal standard and were analyzed using LC-MS/MS. The percent of the test/reference item remaining after specified
  • Lidocaine and Gabapentin were found to be stable in both Human and rat plasma.
  • the objective of the study was to evaluate the metabolic stability of KB-CN-001, Lidocaine and Gabapentin in human and rat liver microsomes at 1 ⁇ test concentration. Metabolic stability was carried out using Human and rat liver microsomes in duplicates for test/ reference items.
  • the final composition of the assay included 1 ⁇ of test item or 5 ⁇ of reference item (Diclofenac or Imipramine, prepared from 5 mM DMSO stocks to get final 0.1% DMSO respectively), 0.125 mg/mL microsomal protein and cofactors (5.0 mM G-6-P, 0.06 U/mL G-6-PDH, 2.0 mM MgCl 2 , 1.0 mM NADP ).
  • Test item/ reference items were incubated with Human and Rat liver microsomes with cofactors and without cofactors.
  • a reaction mixture of 100 ⁇ L was removed at specified time period (With Cofactors: 0, 15, 30, 60 and 120 minutes; without cofactors: 0 and 120 minutes) and the reaction was stopped by addition of stop solution.
  • the samples were extracted in presence of internal standard and were analyzed using LC- MS/MS. The percent of the test/reference item remaining after specified incubation period was calculated with respect to the peak area ratio at time 0 min.
  • test item (4 ⁇ ) / reference items (40 ⁇ with final 0.1% DMSO) was prepared in Potassium phosphate buffer (50 mM, pH 7.40) using respective stocks solutions.
  • 5X working concentration of Cofactors (5.0 mM NADP+, 25.0 mM G-6-P, 3.0 IU/mL G-6-PDH and 10.0 mM MgC12) was prepared in Potassium phosphate buffer (50 mM, pH 7.40) and pre incubated for 10 minutes at 37 oC using water bath.
  • test item/reference item in presence of Cofactors Each reaction mixture of 100 ⁇ L was prepared by adding 45 ⁇ , Potassium phosphate buffer (50 mM, pH 7.40), 10 ⁇ of 10X working solution of respective liver microsomal solution (1.25 mg mL), 25 ⁇ , of 4X working solution of test items/reference items and 20 ⁇ , of 5X working solution of pre incubated Cofactors.
  • test item/ reference item in absence of Cofactors Each reaction mixture of 100 ⁇ , was prepared by adding 45 ⁇ Potassium phosphate buffer (50 mM, pH 7.40), 10 uL of 10X working solution of respective liver microsomal solution (1.25 mg/mL), 25 ⁇ , of 4X working solution of test items/reference items and 20 of Potassium phosphate buffer (50 mM, pH 7.40).
  • reaction mixture was incubated in 24-weU plate at 37 °C for specified incubation time points (With Cofactors: 0.0, 15, 30, 60 and 120 min and Without Cofactors: 0.0 and 120 minutes).
  • test/reference item lost over time was quantified by LC-MS/MS analysis.
  • Metabolic stability of KB-CN-001, Lidocaine and Gabapentin was determined in Human and Rat liver microsomes at 1 ⁇ test concentrations.
  • the test item was incubated with human/rat liver microsomes at 1.25 mg/mL with and without cofactors.
  • a volume of 100 ⁇ was removed at 0, 15, 30, 60 and 120 from reaction mixtures with cofactors and at 0 and 120 minutes for reaction mixtures without cofactors, the removed samples were subjected to sample extraction and analyzed by LC-MS/MS analysis.
  • the test item KB-CN-001 was administered intravenously and intraperitoneal at a dose equivalent to 5 mg kg of Lidocaine.
  • Lidocaine and Gabapentin were administered at 5 mg/kg through intravenous or intraperitoneal routes to healthy male Sprague Dawley rats aged 8-10 weeks.
  • the test items KB-CN-001 and Lidocaine was dosed in the formulation vehicle of 5% (v/v) N-Methyl-2-pyrrolidone (NMP), 50% (v/v) of 60% (w/v) Hyudroxypropyl beta cyclodextrin (HPpCD) and 45% (v/v) sterile water for injection.
  • NMP N-Methyl-2-pyrrolidone
  • HPpCD Hyudroxypropyl beta cyclodextrin
  • test item KB-CN-001 was weighed and transferred into graduated container, Then 0.532 mL of N-Methyl-2-pyrrolidone (NMP) was added and thoroughly vortex mixed and briefly sonicated to dissolve the test item. Then 5.319 mL of 60% (w/v) Hydroxypropyl beta cyclodextrin was added and mixed. Finally the volume was made up to 10.638 mL with the addition of 4.787 mL of sterile water for injection. The final strength of the KB-CN-001 was 1.88 mg mL which is equivalent to 1 mg/mL of Lidocaine. The pH of the final formulation was recorded.
  • NMP N-Methyl-2-pyrrolidone
  • test item Lidocaine Exactly 10.0(3 mg of test item Lidocaine was Weighed and transferred into graduated container, Then 0.500 mL of N-Methyl-2-pyrrolidone (NMP) was added and thoroughly vortex mixed and briefly sonicated to dissolve the test item. Then 5.00 mL of 60% (w/v) Hydroxypropyl beta cyclodextrin was added and mixed. Finally the volume was made up to 10.00 mL with the addition of 4.500 mL of sterile water for injection. The final strength of the test item Lidocaine will be 1 mg/mL. The pH of the final formulation will be recorded
  • NMP N-Methyl-2-pyrrolidone
  • Housing Three animals will be housed in a standard polypropylene cage (Size: L 421 x B 290 x H 190 mm) with a stainless steel mesh top grill having facilities for holding pelleted food and drinking water in water bottle fitted with stainless steel sipper tube. Clean sterilized corncob will be provided as bedding material.
  • Randomization/ Grouping The animals for the experiment will be weighed and arranged in ascending order of their body weights. These stratified body weight of rat will be distributed to all the experimental groups, such that body weight variation of animals selected for the study does not exceed ⁇ 20% of the mean body weight. The grouping will be done one day prior to the initiation of treatment.
  • Dose selection and justification for selection The doses of 5 mg/kg body weight are selected for intravenous and intraperitoneal route of administration. The 5 mg/kg is the preferred dose for comparative pharmacokinetic studies and the dose is approved by the sponsor
  • test item will be administered through intravenous and intraperitoneal route.
  • Intravenous route of administration is one of the intended routes of administration in humans and hence this route has been selected based on sponsor's suggestion.
  • NCA Non- compartmental analysis
  • AUClast Area under the concentration-time curve from time zero to last quantifiable concentration
  • AUCinf Area under the concentration-time curve from time zero to infinity
  • AUC extrap (%) Percentage extrapolated Area under the curveTl/2: Half-life
  • MRT Mean residence time
  • the test item KB-CN-001 was administered intravenously and intraperitoneal at a dose equivalent to 5 mg/kg of Lidocaine.
  • Lidocaine and Gabapentin were administered at 5 mg/kg through intravenous or intraperitoneal routes to healthy male Sprague Dawley rats aged 8-10 weeks.
  • the test items KB-CN-001 and Lidocaine was dosed in the formulation vehicle of 5% (v/v) N-Methyl-2-pyrrolidone (NMP), 50% (v/v) of 60% (w/v) Hyudroxypropyl beta cyclodextrin (HPpCD) and 45% (v/v) sterile water for injection.
  • the test item Gabapentin was dosed in 100% sterile water for injection.
  • Plasma concentrations of KB-CN-001 and Lidocaine were not observed in the rats dosed with KB-CN-001 and analysis was performed for ILS-01KB-03-095 and Lipoic acid, the mean PK parameters are presented in tabular form below: j Single Dose Intravenous and Intraperitoneal Pharmacokinetics Study of KB-CN-001
  • KB-CN-001 Pharmacokinetics of KB-CN-001 was studied following Single dose IV and IP administration in male Sprague Dawley rats at a dose of 5 mg kg bodyweight.
  • the formulation vehicle used was 5% (v/v) N-Methyl-2-pyrrolidone (NMP), 50% (v/v) of 60% (w/v) Hydroxypropyl beta cyclodextrin (HPpCD) and 45% (v/v) sterile water for injection.
  • NMP N-Methyl-2-pyrrolidone
  • HPpCD Hydroxypropyl beta cyclodextrin
  • the objective of the study was to evaluate the metabolic stability of ILS08-KB03-085 in human and rat plasma at 1 ⁇ test concentration. Plasma stability was carried out using Human and rat plasma in duplicates for test/ reference items.
  • the final composition of the assay included 1 ⁇ of test item or 10 ⁇ of reference item Benfluorex or Propranolol.
  • the test item and plasma mixture was incubated at 37° C with brief shaking and the samples were removed at 0, 15, 30, 60 and 120 minutes.
  • the samples were extracted in presence of internal standard and were analyzed using LC-MS/MS.
  • the percent of the test/reference item remaining after specified incubation period was calculated with respect to the peak area ratio of ⁇ spiked and extracted standard. Formation of ILS01-KB03-095 and Ecosapentaenoic acid was also determined.
  • test/ reference item(s) in Human and Rat plasma was prepared at concentration of 1 ⁇ (ILS08-KB03-085) and 10 ⁇ (reference items) by using 1 mM and 10 mM DMSO stocks, respectively (final DMSO concentration was 0.1%).
  • Metabolic stability of ILS08-KB03-085 was determined in Human and Rat plasma at 1 ⁇ test concentration. Plasma stability was carried out using Human and rat plasma in duplicates for test/ reference items. The final composition of the assay included 1 ⁇ of test item or 10 ⁇ of reference item Benfluorex or Propranolol in Human/ Rat plasma. The mixture was incubated at 37° C with brief shaking and the samples were removed at 0, 15, 30, 60 and 120 minutes. The samples were extracted in presence of internal standard and were analyzed using LC-MS/MS. The percent of the test/reference item remaining after specified incubation period was calculated with respect to the peak area ratio at time 0 min.
  • the objective of the study was to evaluate the metabolic stability of ILA08-KB03-085 in human and rat liver microsomes at 1 ⁇ test concentration. Metabolic stability was carried out using Human and rat liver microsomes in duplicates for test/ reference items.
  • the final composition of the assay included 1 ⁇ of test item or 5 ⁇ of reference item (Diclofenac or Imipramine, prepared from 5 mM DMSO stocks to get final 0.1% DMSO respectively), 0.125 mg/mL microsomal protein and cofactors (5.0 mM G-6-P, 0.06 U/mL G-6-PDH, 2.0 mM MgCl 2 , 1.0 mM NADP*).
  • Test item/ reference items were incubated with Human, and Rat liver microsomes with cofactors and without cofactors.
  • a reaction mixture of 100 ⁇ was removed at specified time period (With Cofactors: 0, 15, 30, 60 and 120 minutes; without cofactors: 0 and 120 minutes) and the reaction was stopped by addition of stop solution.
  • the samples were extracted in presence of internal standard and were analyzed using LC-MS MS. The percent of the test/reference item remaining after specified incubation period was calculated with respect to the peak area ratio of extracted 1 ⁇ spiked standard.
  • test item (4 ⁇ ) / reference items (40 ⁇ with final 0.1% DMSO) was prepared in Potassium phosphate buffer (50 mM, pH 7.40) using respective stocks solutions.
  • 5X working concentration of Cofactors (5.0 mM NADP+, 25.0 mM G-6-P, 3.0 lU/mL G-6-PDH and 10.0 mM MgC12) was prepared in Potassium phosphate buffer (50 mM, pH 7.40) and pre incubated for 10 minutes at 37 oC using water bath.
  • test item/reference item in presence of Cofactors Each reaction mixture of 100 ⁇ , was prepared by adding 45 ⁇ .. Potassium phosphate buffer (50 mM, pH 7.40), 10 ⁇ . of 10X working solution of respective liver microsomal solution (1.25 mg/mL), 25 ⁇ . of 4X working solution of test items/reference items and 20 ⁇ . of 5X working solution of pre incubated Cofactors.
  • test item/ reference item in absence of Cofactors Each reaction mixture of 100 ⁇ . was prepared by adding 45 ⁇ , Potassium phosphate buffer (50 mM, pH 7.40), 10 ⁇ L of 10X working solution of respective liver microsomal solution (1.25 mg/mL), 25 ⁇ , of 4X working solution of test items/reference items and 20 ⁇ . of Potassium phosphate buffer (50 mM, pH 7.40).
  • reaction mixture was incubated in 24- well plate at 37 °C for specified incubation time points (With Cofactors: 0.0, 15, 30, 60 and 120 min and Without Cofactors: 0.0 and 120 minutes).
  • test/reference item remaining at specified time intervals was quantified by LC-MS/MS analysis.
  • Metabolic stability of ILS08-KB03-085 was tested in Human and Rat liver microsomes with and without cofactors at 1 ⁇ test concentrations.
  • the test item was incubated with human/rat liver microsomes at 0.125 mg/mL with and without cofactors.
  • a volume of 100 ⁇ L was removed at 0, 15, 30, 60 and 120 from reaction mixtures with cofactors and at 0 and 120 minutes for reaction mixtures without cofactors, the removed samples were subjected to sample extraction and analyzed by LC-MS/MS analysis.
  • 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.
  • the illustrative figure 3 shows the timeline and experimental mile stones carried out for the given experiment.
  • 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 1 discussed in the instant disclosure.
  • Three types of experimental groups were formed. Different types of chemicals such as Vehicle and Control were used to determine the efficacy of the chemicals as well comparison of the instant disclosed compound of formula 1, with a positive control was performed.
  • the final compound of the instant disclosure 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. The force withdrawal results of the von frey test for 21 days were observed.
  • N 10 KB- IP 150 5 ml/kg Once daily Von Frey testing ⁇
  • Pain Response Evaluation Pain response was evaluated using Von Frey test for mechanical allodynia.
  • the Von Frey test for mechanical allodynia is based on applying short pulses of pressure that are not painful to a naive animal. In fact, in order to achieve paw withdrawal from a naive animal, the pressure applied is sometimes higher than 60 g. This often requires the researcher to apply enough pressure with the Von Frey filament to actually lift the paw of the naive animal. However, in disease conditions, the animals are sensitive to much lower pressure and experience pain as a result of a normally non-painful stimulus.
  • Rodents exhibit a paw withdrawal reflex when its paw is unexpectedly touched.
  • the Touch TestTM Sensory Evaluator can be used on the plantar surfaces of the rat's foot. The animal will indicate sensation by pulling back its paw. The minimal force needed to elevate the withdrawal reflex is designated / considered as the value of reference.
  • Body Weights Body weight was measured starting on study day -1 for baseline values and again, seven days after the surgery (study day 7). In addition, animals that demonstrated criterion for mechanical allodynia on study day 14 were also weighed after selection and grouping on study day 14 and again, on day 21. Statistics and Data Evaluation: All data are presented as means+SEM. The values were analyzed using a one-way ANOVA following by a Tukey post-test (GraphPad Prism) to compare the Vehicle group (Group 1) and positive control group, gabapentin, (Group 6) to each treatment at each time point. A p value ⁇ 0.05 is considered to represent a significant difference.
  • Body Weight All animals gained weight during the study, which indicated good general health throughout the study. There were no significant differences in weight gain between the groups. At baseline (day -1), the mean body weight for all animals was 240.65+1.38 g-
  • Von Frey Test Results are presented as the mean force (g) required inducing a withdrawal response for the left operated leg. Mechanical allodynia was observed as an increase in the animal sensitivity to the Von Frey filaments at different time points on study days 14 and 21 (0.5 hr, 2 hr, 4.5 hr and 6.5 hr post treatment).
  • the baseline average force required to induce a withdrawal response for the left operated leg of the Vehicle-treated animals was 60.00+0.00 g.
  • the withdrawal force of the left leg was significantly lower than the baseline measurement indicating the presence of mechanical allodynia (10.15+1.01 g; p ⁇ 0.05 vs.baseline).
  • mechanical allodynia was still present (8.31+0.89 g; p ⁇ 0.05 vs. baseline).
  • Gabapentin was also significantly effective at reducing mechanical allodynia at 2 hours post treatment on study day 21 compared to the Vehicle: 48.69+4.96 g vs. 7.85+0.48 g for the Vehicle (p ⁇ 0.05).
  • B-CN-001at a dose of 150 mg/kg On study day 14 at 2 hours post-treatment, KB-CN- 001 at a dose of 150 mg/kg was significantly effective in reducing mechanical allodynia compared to the Vehicle-treated group: 39.00+7.19 g vs. 8.15+0.36 for the Vehicle (p ⁇ 0.05). This analgesic effect continued to be significant compared to the Vehicle group at the 4.5 hours post-treatment time point: 44.20+6.55 g vs. 8.38+0.73 g for the Vehicle (p ⁇ 0.05).
  • KB-CN-001 was significantly effective in reducing mechanical allodynia compared to the Vehicle-treated group: 26.20+5.81 g vs.9.08+0.86 for the Vehicle (p ⁇ 0.05).
  • the Von Frey response of KB-CN-001 was significantly more effective than positive control, gabapentin, as indicated by the greater force required for withdrawal: 26.20+5.81 g vs. 10.62+0.90 g for gabapentin (p ⁇ 0.05).
  • Treatment with KB-CN-001 demonstrates prolonged analgesic activity compared to gabapentin, which was active only at 2 hours post dosing.
  • the instant final compound of formula 1 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 1 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 1 and treating pain in mammals using the compound of formula 1. While specific embodiments of the subject 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.
  • compound of formula I compound of formula 1 with pharmaceutically acceptable additives to treat mammals suffering from pain, more specifically neuropathic pain in general. These compounds may be used in the treatment of diseases related to pain and its related complications.
  • test item ILS01-KB03-095 was administered at 5 mg/kg body weight and the test item ILS08-KB03-085 was administered at a dose equivalent to 5 mg of ILS01-KB03-095/ kg body weight. Both the test items were dosed either by intravenous or intraperitoneal routes.
  • the test items ILS01-KB03-095 and ILS08-KB03-085 were dosed in the formulation vehicle of 5% (v/v) N-Methyl-2-pyrrolidone (NMP), 50% (v/v) of 60% (w/v) Hydroxy propyl beta cyclodextrin (HPPCD) and 45% (v/v) sterile water for injection.
  • NMP N-Methyl-2-pyrrolidone
  • HPPCD Hydroxy propyl beta cyclodextrin
  • test item ILS01-KB03-095 was weighed and transferred into graduated container, then 0.500 mL of N-Methyl-2-pyrrolidone (NMP) was added and thoroughly vortex mixed to dissolve the test item. Then 5.0 mL of 60% (w/v) Hydroxypropyl beta cyclodextrin was added and mixed. Finally the volume was made up to 10 mL with the addition of 4.5 mL of sterile water for injection, thoroughly vortex mixed and briefly sonicated for 30 seconds to get a clear solution with final strength of 1 mg mL. The pH of the final formulation was recorded and was 7.76.
  • NMP N-Methyl-2-pyrrolidone
  • test item ILS08- B03-085 was weighed and transferred into graduated container, then 0.465 mL of N-Methyl-2-pyrrolidone (NMP) was added and thoroughly vortex mixed to dissolve the test item. Then 4.652 mL of 60% (w/v) Hydroxypropyl beta cyclodextrin was added anct mixed. Finally the volume was made up to 9.305 mL with the addition of 4487 mL of sterile water for injection, thoroughly vortex mixed for 30 seconds to get a light yellow solution with final strength of 2.34 mg/mL of ILS08-KB03-085 equivalent to 1 mg/mL of ILS01-KB03-095. The pH of the final formulation was recorded and was found to be 5.83.
  • NMP N-Methyl-2-pyrrolidone
  • Housing Three animals were housed in a standard polypropylene cage (Size: L 421 x B 290 x H 190 mm) with a stainless steel mesh top grill having facilities for holding pelleted food and drinking water in water bottle fitted with stainless steel sipper tube. Clean sterilized corncob will be provided as bedding material.
  • Feed The animals were fed ad libitum throughout the acclimatization and experimental period except for a period of fasting, if applicable. Amrut rodent feed (Manufactured by Pranav Agro Industries Ltd.,) was provided.
  • Water was provided ad libitum throughout the acclimatization and experimental period. Water from Aqua guard water filter cum purifier was autoclaved and provided in polypropylene water bottles with stainless steel sipper tubes.
  • Intravenous route of administration is one of the intended routes of administration in humans and hence this route has been selected based on sponsor 's suggestion.
  • Test item administration and specimen collection procedure Adult healthy male Sprague dawley rats aged 6-9 weeks were used for experimentation after a minimum 3 days of acclimatization. Non fasted animals were administered with test item in a recommended vehicle by intravenous or intraperitoneal route at a dose of 5 mg/kg body weight at dose volume of 5 mL/kg b.w.
  • ILS-01KB-03-095 CC range: -11.641, 15.521, 31.043, 62.086, 124.172, 248.343, 496.686, 993.373, 1986.745, 3973.490, 7946.980 and 9933.725 ng/mL.
  • NCA Non-compartmental analysis
  • Tmax Time to reach the peak plasma concentration
  • AUClast Area under the concentration-time curve from time zero to last quantifiable concentration
  • AUCinf Area under the concentration-time curve from time zero to infinity
  • AUC extrap (%) Percentage extrapolated Area under the curveTl/2: Half-life [00232] MRT: Mean residence time
  • the test item ILS01-KB03-095 was administered intravenously and intraperitoneally at a dose of 5 mg/kg.
  • the test item ILS08-KB03-085 was administered at a dose equivalent to 5 mg of ILS01-KB03-095/kg body weight.
  • the test items were dosed in the formulation vehicle of 5% (v/v) N-Methyl-2-pyrrolidone (NMP), 50% (v/v) of 60% (w/v) Hydroxypropyl beta cyclodextrin (HPpCD) and 45% (v/v) sterile water for injection.
  • NMP N-Methyl-2-pyrrolidone
  • HPpCD Hydroxypropyl beta cyclodextrin
  • Plasma concentrations of ILS01-KB03-095 were observed after intravenous or intraperitoneal administration of ILS01-KB03-095 with the exposure of 1874.806 and 1162.335 h*ng/mL respectively.
  • ILS08-KB03-085 Plasma concentrations of ILS08-KB03-085 were not observed after intravenous or intraperitoneal administration of ILS08-KB03-085, however ILS01-KB03-095 were observed following intravenous and intraperitoneal route of administration with the exposure of 600.968 and 466.017h*ng/mL respectively. Dosing of ILS01-KB03-095 resulted in better exposure of ILS01-KB03-095 in either of the routes.

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Abstract

L'invention concerne une composition de composé de formule 1. L'invention concerne également un procédé de synthèse du composé de formule 1 et ses procédés améliorés. Le composé de formule 1 ou ses sels pharmaceutiquement acceptables, ainsi que leurs polymorphes, solvates et hydrates peuvent être formulés en tant que composition pharmaceutique à utiliser dans le traitement de la douleur. La composition pharmaceutique du composé de formule 1 ou le composé final peuvent être formulés pour une administration non invasive perorale, topique (par exemple transdermique), entérale, transmuqueuse, ciblée, une administration à libération prolongée, des procédés de libération retardée, de libération pulsée et parentéraux. Ces compositions peuvent être utilisées pour traiter la douleur chronique qui se manifeste avec des maladies chroniques ou leurs complications associées. Le composé de formule 1 peut également être proposé sous forme de kit.
PCT/IN2016/000266 2015-11-19 2016-11-09 Procédé amélioré pour la synthèse de 2,6-xylidine et de ses dérivés WO2017085733A2 (fr)

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