WO2017060914A2 - Pénicillamine et ses dérivés pour leur utilisation dans le traitement de la toxicité du cuivre et de nash - Google Patents

Pénicillamine et ses dérivés pour leur utilisation dans le traitement de la toxicité du cuivre et de nash Download PDF

Info

Publication number
WO2017060914A2
WO2017060914A2 PCT/IN2016/000231 IN2016000231W WO2017060914A2 WO 2017060914 A2 WO2017060914 A2 WO 2017060914A2 IN 2016000231 W IN2016000231 W IN 2016000231W WO 2017060914 A2 WO2017060914 A2 WO 2017060914A2
Authority
WO
WIPO (PCT)
Prior art keywords
residue
thiol
alkyl
acid
compound
Prior art date
Application number
PCT/IN2016/000231
Other languages
English (en)
Other versions
WO2017060914A3 (fr
Inventor
Satya Surya Visweswara Srinivas AKELLA
Krishnam Raju KALIDINDI
Original Assignee
Krisani Biosciences (P) 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 Krisani Biosciences (P) Ltd. filed Critical Krisani Biosciences (P) Ltd.
Publication of WO2017060914A2 publication Critical patent/WO2017060914A2/fr
Publication of WO2017060914A3 publication Critical patent/WO2017060914A3/fr

Links

Classifications

    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P39/04—Chelating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds of the general formula (I), having compounds to treat copper toxicity, NASH and Leigh Syndrome, derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, tsolvates, pharmaceutically acceptable salts, pharmaceutical compositions, and prodrugs thereof.
  • the present invention more particularly provides novel compounds of the general formula (I) and general formula (II)
  • the present invention also provides a process for the preparation of the above said novel compounds of the general formula (I) and general formula (II),their derivatives, their analogs, their stereoisomer' s, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions.
  • novel compounds of the formula (I) and (II) of the present invention are useful for the treatment of copper toxicity andLiver related diseases, which is one of the leading causes of death in the present society.
  • NASH Non-alcoholic steatohepatitis
  • This disclosure generally relates to compound and their synthesis. More particularly, this disclosure relates to treating mammals with pharmaceutically acceptable amount of compounds, compositions, formulations and the prodrugs of the compound.
  • Pencillamine is a 3-mercapto-D-valine, a disease modifying antirheumatic drug used as a chelating agent in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol and insoluble in ether, acetone, benzene, as well as other organic solvents. Few drugs are already approved by the FDA and available in the market with brand names Cuprimine and Depen.
  • Metal toxicity may occur due to essential metal overload or exposure to heavy metals from various sources. Most metals are capable of forming covalent bonds with carbon, resulting in metal-organic compounds. Metals and metal compounds interfere with functions of various organ systems like the central nervous system (CNS), the haematopoietic system, liver, kidneys, etc. (Flora et al.2010).
  • CNS central nervous system
  • haematopoietic system liver, kidneys, etc.
  • hepatocerebral disorders have been responsible for many dysfunctions in liver diseases.
  • Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders such as Wilson's Disease, post-shunt myelopathy, hepatic encephalopathy, and acquired non-Wilsonian hepatocerebral degeneration are a major feature of hepatocerebral disorders.
  • Morphologic changes to astrocytes include neurotoxic effects of metals such as copper, manganese, and iron.
  • Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease) and liver transplantation among others.
  • compositions comprising of one or more compounds of Formulas 1, 2, 3, 4 and 5, an intermediate, a Prodrug, pharmaceutical acceptable salt of compound Formulas 1, 2, 3, 4 and 5with one or more of pharmaceutically acceptable carriers, and vehicles or diluents are disclosed. These compositions may be used in the treatment of diseases related to copper retention and its complications in hepatic diseases and/or disorders.
  • the present disclosure relates to the compound and composition of formula 1 , or pharmaceutically acceptable salts thereof,
  • Ri, R 2 , and R 3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol and
  • R 5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol and
  • X is represented by 0, S or NH
  • R4 represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine, thioctic acid, a residue of thioctic acid, a residue of acetyl cysteine, a residue of alpha-keto glutaric acid, a residue of dimercaprol, a residue of an NO donor, a residue of glutathione, (RS)-2, 3-disulfanylpropan-l-ol, (R)-2- acetamido-3- sulfanylpropanoic acid, Ecosapentanoic acid, different amino acids and an analog of any one of the foregoing and in general represented by the following structures:
  • n represents an integer from 0 to 8.
  • R 4 is R-(+)-thioctic acid, wherein n is an integer that equals between 0 to 4.
  • formula 1 may represent the following compound:
  • R 1 , R 2 and R 3 represents, hydrogen, methyl, ethyl or thiol and R 4 represents R-isomer of residue or analog or derivative or metabolite of thioctic acid.
  • the embodiment is represented by:
  • R , R and R represents, hydrogen, methyl, ethyl or thiol and R 4 represents (RS)-2, 3-disulfanylpropan-l-ol.
  • the embodiment is represented by:
  • R 1 , R 2 and R 3 represents, hydrogen, methyl, ethyl or thiol and R 4 represents (R)-2-acetamido-3-sulfanylpropanoic acid.
  • this disclosure provides an embodiment comprising a composition: a) R-(+j-lipoic acid or Thiocticacid; b) Zinc acetate or Triemylenetetramine; and c) a compound of Formula 1 as shown below:
  • Rl, R2, and R3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; and
  • R 4 represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine, thioctic acid, a residue of thioctic acid, a residue of acetyl cysteine, a residue of alpha-keto glutaric acid, a residue of dimercaprol, a residue of an NO donor, a residue of glutathione and an analog of any one of the foregoing.
  • R5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol.
  • a pharmaceutically acceptable salt for example, but not limited to, tartrate, esylate, mesylate, sulfate, hydrate and hydrochloride salt of formula 1 comprising: a) R-(+)-lipoic acid or Acetylcysteine orDimercaprol; b) Zinc acetate orTriethylenetetramine; and c) a compound of Formula 1 NH 2 .
  • Rl, R2, and R3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; and [00034] R 4 represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine,
  • R 5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol.
  • the therapeutically effective amount may be rendered, but not limited to, as an injection.
  • Other embodiments may include peroral, topical, transmucosal, inhalation, targeted delivery and sustained release formulations.
  • the topical application may be an ophthalmic drug used as drops, targeted delivery may be injection to the organ and peroral may be syrup, tablet or capsule.
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment of diseases related to copper retention, hepatic disorders or its related complications.
  • kits comprising a first composition and a second composition, wherein a) the first composition is R-(+)-lipoic acid or
  • the second composition is a combination of Compound 1A and/or Compound 2 and/or Compound 3 and c) the third composition is emylenetetramineor Zinc acetate or Ammonium tetrathiomolybdate: DETAILED DESCRIPTION
  • metal chelating compounds, compositions, formulations and their use are disclosed.
  • the compounds comprise derivatives of formula 1.
  • the composition of varies compounds comprise of R- lipoic acid, Dimercaprol, Zinc acetate, Ammonium tetrathiomolybdate or ethylenetetrarnine is combined with a pharmaceutically acceptable salt of the compounds derived from formula 1.
  • methods of making the formula 1 into different compounds are disclosed.
  • the compound may also comprise of tartrate, esylate, mesylate, sulfate salts and hydrate salt of formula 1.
  • the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instructions for use in the treatment of diseases associated to copper toxicity, hepatic disorders or related complications.
  • the thiol group was reacted with suitable protecting agents like acetyl, triphenyl, substituted benzyl insuitable solvent and a suitable base and forms compound 1(b).
  • acid group was reacted with suitable protecting agents like tert-butyl, tert-butyl dimethyl silane, Thesyldimetylsilane, methyl, ethyl, allyl, vinyl, isobutyl in suitable solvent and suitable bases like triethylamine, diisopropylethylamine, potassium carbonate, sodiumhydroxideforms compound 1(c).
  • This compound 1(e) was reacted with acids like Lipoic acid, Ecosapentanoic acid, amino acids, 3-Acetyl-l,3-tWazolidine-4-carboxylic acid (Folcisteine), (2,2-dimethyl-l,3-dithiolan-4-yl) Methanol in suitable solvents like THF, DMF, alcohol, DMSO and suitable base like triethylamine, diisopropylemylamine, potassium carbonate, sodiumhydroxide, sodiummethoxide, sodiumhydride forms compound 1(f).
  • acids like Lipoic acid, Ecosapentanoic acid, amino acids, 3-Acetyl-l,3-tWazolidine-4-carboxylic acid (Folcisteine), (2,2-dimethyl-l,3-dithiolan-4-yl) Methanol in suitable solvents like THF, DMF, alcohol, DMSO and suitable base like triethylamine, diisopropy
  • Step-2 of the synthesis is:
  • Step-2 material (1.27g, 0.0060 moles; 1.0 eq) in THF (15 mL, -12 vol) was added diisopropylethyl amine (2.32 g, 0.017 moles, 3 eq) and the reaction mixture was stirred for 15-20 min at room temperature, a-chloroethylchloroformate (1.29 g, 0.009 moles, 1.5 eq) in THF (5 mL) was added to reaction mass and the mixture was heat at 50 °C for 5 hrs. Progress of reaction wasmonitored by TLC.
  • Step 4 of the synthesis is:
  • Step-3 material (1.69g, 0.0060 moles; 1.0 eq) in DMF (10 mL) was added to reaction mass at room temperature. The mixture was further heated to 50 °C for 6 hrs and then stirred at room temperature for overnight. Progress of reaction wasmonitored by TLC.
  • reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). Collective organic layer was washed with brine solution (1 x 50 mL) and dried over anhydrous Na 2 S0 4 .organic layer was evaporate under reduced pressure to obtain 3.2 g of crude material, which was purified over 100-200 mesh silica using 9% ethyl acetate in hexane to get oily mass.
  • Step -2 of the synthesis is:
  • ProcedurerTo Step-2 material (6.5g, 0.0024 moles; 1.0 eq) in DCM (30 mL, 4.6 vol) was added 4-dimethyl amino pyridine (1.51 g, 0.012 moles, 0.5 eq) and allyl alcohol (1.73 g, 0.029 moles, 1.2 eq). Cool above mixture to 0 °C and EDC.HCl (4.78 g, 0.024 moles, 1 eq) was added at once. Reaction mixture was stirred for overnight at room temperature. On completion of the reaction (monitored by TLC), mass was dilute with DCM (50 mL) and washed with water (1 x 50 mL) followed by brine solution wash (1 x 50 mL). Collective organic layer dried over sodium sulfate and evaporate under reduced pressure to get 6.5 gm compound as oil. Yield%: 6.5 g (86 %).
  • Step-4 of thesynthesis is:
  • Step-5 of the Synthesis is:
  • ProcedurerTo Step-4 material (1.94 g, 0.0096 moles; 1.0 eq) in THF (25 mL, -12 vol) was added diisopropylethyl amine (2.50 g, 0.019 moles, 2 eq) and the reaction mixture was stirred for 15-20 min at room temperature, a-chloroethylchloroformate (1.93 g, 0.013 moles, 1.4 eq) in THF (5 mL) was added to reaction mass and the mixture was stirred at RT for 5 hrs. Progress of reaction wasmonitored by TLC. On completion of the reaction, the reaction mixture was filtered and mother liquor was evaporate under reduced pressure to get 4.4 gm of the crude material, which was as such used for next step (considering the 100 % yield).
  • Step-6 of thesynthesis is:
  • reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). Collective organic layer was washed with brine solution (1 x 100 mL) and dried over anhydrous Na 2 S04.0rganic layer was evaporate under reduced pressure to obtain 6.2 g of crude material, which was purified over 100-200 mesh silica using 12 - 30 % ethyl acetate in hexane yielded 0.269 gm of the product.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 - propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (propargyl, - CH2C ⁇ CH), and the like.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and Cx-Y aryl are typically used where X and Y indicate the number of carbon atoms in the ring.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group arid may be represented* for example, by the formula hydrocarbylC(0)NH-.
  • acylalkyi is art-recognized and refers to an alkyl group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)alkyl.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert- butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.
  • substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include "alkoxyalkyl” groups, hich may be represented by the general formula alkyl-O-alkyl. [00101] The terms "hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is hetefoaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two hetefoatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, mo holine, lactones, lactams, and the like.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • references to chemical moieties herein are understood to include substituted variants,
  • reference to an "aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isopropyl is an example of an ethylene moiety that is substituted by -CH3.
  • a ⁇ - hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (Ci-io) alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
  • substituents include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci io) alkoxy, (C4-12) aryloxy, hetero (Ci- io)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci- 10) alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci- 10) alkyl, halo (Ci-10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci- 10) alkyl, tbiocarbonyl (Ci_i0) alkyl, sulfonyl (Ci-10) alkyl, sulfinyl (Ci_io) alkyl, (CiJO) azaalkyl, imino (Ci-10) al
  • substituent is itself optionally substituted by a further substituent.
  • further substituent include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci-10) alkoxy, (C4-I2) aryloxy, hetero (Ci-10) aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10) alkyl, halo (Ci- 10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10) alkyl, thiocarbonyl (Ci-10) alkyl, sulfonyl (Ci- 10) alkyl, sulfinyl (Ci- 10) alkyl, (Ci-10) aza
  • the compounds of the present invention can be present in the form of pharmaceutically acceptable salts.
  • the compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1, 2 and 3to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected 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 1 , 2 and 3 (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 cart be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- arid S-sequencing rules of Cahn, higold 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".
  • metabolic condition refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. Metabolic condition associated diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Renal, Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastrointestinal.
  • 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 mammals, 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: (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)
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • prodrug is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention.
  • 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 compositions. 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
  • predicting refers to assessing the probability according to which a metabolic condition or neurodegenerative related diseases patient will suffer from abnormalities or complication and/or terminal renal failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future.
  • the mortality may be caused by the central nervous system or complication.
  • the predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability.
  • the predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.
  • the predictive window is an interval of one month, six months or one, two, three, four, five or ten years after appearance of the cardiovascular complication (more preferably and precisely, after the sample to be analyzed by the method of the present invention has been obtained).
  • an assessment is usually not intended to be correct for 100% of the subjects to be analyzed.
  • the term requires that the assessment will be valid for a statistically significant portion of the subjects to be analyzed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test, etc.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the probability envisaged by the present invention allows that the prediction will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort.
  • 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 metabolic condition or neurodegenerative disease condition of a subject by administration of an agent even though such agent does not treat the cause of the condition.
  • Treating includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.
  • Metabolic condition related diseases or disorders includes such as aspartylglusomarinuria, biotinidase deficiency, carbohydrate deficient glycoprotein syndrome (CDGS), Crigler-Najjar syndrome, cystinosis, diabetes insipidus, Fabry, fatty acid metabolism disorders, galactosemia, Gaucher, glucose-6-phosphate dehydrogenase (G6PD), glutaric aciduria, Hurler, Hurler-Scheie, Hunter, hypophosphatemia, I-cell, Krabbe, lactic acidosis, long chain 3 hydroxyacyl CoA dehydrogenase deficiency (LCHAD), lysosomal storage diseases, mannosidosis, maple syrup urine, Maroteaux- Lamy, metachromatic leukodystrophy, mitochondrial, Morquio, mucopolysaccharidosis, neuro-metabolic, Niemann-Pick, organic acidemias, purine, phenylketonuria (PKU), Pompe, porphyria
  • Neurodegenerative related diseases or disorders included such as Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Spinal muscular atrophy or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • terapéuticaally effective amount is an art-recognized term.
  • the term refers to an amount of a salt or composition 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 adniinistered, 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 composition without necessitating undue experimentation.
  • the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment.
  • the desired amount of the composition 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 compositions from the subject compositions. 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. Typically, dosing will be determined using techniques known to one skilled in the art.
  • the optimal concentration and/or quantities or amounts of any particular salt or composition 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.
  • the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • 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 composition 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 excipients 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 and/or composition, 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 composition, therapeutic or other material at a site remote from the disease being treated.
  • Administration of an agent for the disease being treated 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.
  • terapéuticaally effective amount is an art-recognized term.
  • the term refers to an amount of a salt or composition 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 composition without necessitating undue experimentation.
  • compositions disclosed herein are contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
  • compositions comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula 1, 2 and 3 may be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration.
  • the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.
  • the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formulas I) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula 1, 2 and 3 or composition as part of a prophylactic or therapeutic treatment.
  • the desired concentration of formula 1, 2 and 3 or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated.
  • the optimal concentration and/or quantities or amounts of any particular compound of formula 1, 2, 3, 4 or 5 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.
  • concentration and/or amount of any compound of formula 1, 2, 3, 4 or 5 may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays.
  • Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein.
  • One such method is microdialysis, as reviewed by T. E. Robinson et al., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1.
  • the methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop.
  • the dosage of the subject compounds of formula 1, 2, 3, 4 or 5provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • an effective dosage for the compounds of Formulas I is in the range of about 0.01 mg/kg/day to about 100 mg kg/day in single or divided doses, for instance 0.01 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 0.2 mg kg day, 0.5 mg/kg/day, 1.0 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, 2 and 3 may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000 mg per day.
  • the compositions 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 and 2 required for the same therapeutic benefit.
  • An effective amount of the compounds of formula 1, 2, 3, 4 or 5described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
  • Metabolic condition associated disease symptoms such as inborn errors of metabolism includescystinosis, NASH, diabetes and renal and Neurodegenerative diseases include disease symptoms associated to Alzheimer's, Huntingtons disease, Parkinsons disease and lateral sclerosis.
  • An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelization and/or elevated reactive oxidative- nitrosative species and/or abnormalities in neurotransmitter homeostasis 's, in patients who are at risk for such complications.
  • these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate.
  • the amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
  • the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
  • compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasal ly, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.
  • compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding , agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • the compounds of formula 1, 2, 3, 4 or 5 may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.
  • solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the formulations for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula 1, 2, 3, 4 or 5 disclosed herein, for instance, compounds of formula 1, 2, 3, 4 or 5or pharmaceutical acceptable salts of a compounds of formula 1, 2, 3, 4 or 5.
  • a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ.
  • the active composition may take the form of tablets or lozenges formulated in a conventional manner.
  • the dosage administered will be dependent upon the identity of the neoplastic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio.
  • dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 rag/kg of host body weight.
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.
  • compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent.
  • the diluent can be an edible carbohydrate material such as lactose or starch.
  • a sweetening agent or sugar is present as well as flavoring oil.
  • Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate, calcium stearate and the like is added to the powder mixture before the filling operation.
  • Soft gelatin capsules are prepared by machine encapsulation of slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.
  • Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets.
  • the powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicalciumphosphate and the like.
  • the powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forcing through a screen.
  • a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage
  • the powder mixture can be slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs).
  • the slugs can be lubricated to prevent sticking to the tablet- forming dies by means of the addition of stearic acid, a stearic saltj talc or mineral oil. The
  • the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methylcellulose and polish coating of carnauba wax.
  • Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of an active ingredient for administration.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent.
  • Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred.
  • the active ingredient depending on the form and concentration used, can be either suspended or dissolved in the vehicle.
  • the water- soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing.
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • the rectal and vaginal routes can be utilized.
  • An active ingredient can be administered by means of a suppository.
  • a vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized.
  • cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.
  • a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.P. water, a dry powder can be formulated when insufflation is the administration of choice.
  • a suitable pharmaceutical vehicle preferably P.P. water
  • the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.
  • a gaseous or liquified propellant for example, dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfiils, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.
  • the tablets of the present invention contain one or more pharmaceutically active agents that are released therefrom upon contact of the tablet with a liquid medium, for example a dissolution medium such as gastrointestinal fluids.
  • a liquid medium for example a dissolution medium such as gastrointestinal fluids.
  • Water soluble as used herein in connection with non-polymeric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non- polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208-209 (2000).
  • Water soluble as used herein in connection with polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level or dissolved in water.
  • modified release shall apply to tablets, matrices, particles, coatings, portions thereof, or compositions that alter the release of an pharmaceutically active agent in any manner.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.
  • the first pharmaceutically active agent and the hydrophilic polymer are mixed with a powder containing a pharmaceutical ly- acceptable carrier, which is also defined herein as the tablet matrix.
  • the powder has an average particle size of about 50 microns to about 500 microns, such as between 50 microns and 300 microns. Particles in this size range are particularly useful for direct compression processes.
  • the components of powder are blended together, for example as dry powders, and fed into the die cavity of an apparatus that applies pressure to form a tablet core. Any suitable compacting apparatus may be used, including, but not limited to, conventional unitary or rotary tablet press.
  • the tablet core may be formed by compaction using a rotary tablet press (e.g., such as those commercially available from Fette America Inc.* Rockaway, N.J., or Manesty Machines LTD, Liverpool, UK).
  • a rotary tablet press e.g., such as those commercially available from Fette America Inc.* Rockaway, N.J., or Manesty Machines LTD, Liverpool, UK.
  • a metered volume of powder is filled into a die cavity (where the powder is either gravity fed or mechanically fed from a feeder) of the rotary tablet press, and the cavity rotates as part of a "die table" from the filling position to a compaction position.
  • the powder is compacted between an upper and a lower punch, then the resulting tablet core is pushed from the die cavity by the lower punch and then guided to an injection chute by a stationary "take-off bar.
  • the tablet core may be a directly compressed tablet core made from a powder that is substantially free of water-soluble polymeric binders and hydrated polymers.
  • substantially free is less than 5 percent, such as less than 1 percent, such as less than 0.1 percent, such as completely free (e.g., 0 percent).
  • This composition is advantageous for minimizing processing and material costs and providing for optimal physical and chemical stability of the tablet core.
  • the density of the tablet core is greater than about 0.9 g/cc.
  • the tablet core may have one of a variety of different shapes.
  • the tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like.
  • a tablet core has one or more major faces.
  • the tablet core surface typically has opposing upper and lower faces formed by contact with the upper and lower punch faces in the compression machine.
  • the tablet core surface typically further includes a "belly-band" located between the upper and lower faces, and formed by contact with the die walls in the compression machine.
  • the tablet core contains one or more hydrophilic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocoUoids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof.
  • suitable polyalkylene glycols include, but are not limited to, polyethylene glycol.
  • suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide).
  • acrylic polymers examples include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high- molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOLTM.
  • hydrocoUoids examples include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures thereof.
  • Suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof.
  • suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof.
  • an osmogen is incorporated into the tablet core in order to draw water into the tablet upon contact with fluids, such as gastrointestinal fluids.
  • An osmogen as used herein is a water soluble component which preferentially draws water into the tablet core for the purposes of distributing the water throughout the core, so that the active ingredient contained in the core may be released.
  • the osmogen is a salt such as but not limited to sodium chloride, potassium chloride, sodium citrate, or potassium citrate.
  • the carrier may contain one or more suitable excipients for the formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.
  • Suitable fillers include, but are not limited to, watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar- alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrins, and maltodextrins), and water insoluble plastically deforming materials (e.g., microcrystalline cellulose or other cellulosic derivatives), and mixtures thereof.
  • watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar- alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol
  • Suitable adsorbents include, but are not limited to, water- insoluble adsorbents such as dicalcium phosphate, tricalcium phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesium aluminometasilicate (e.g., such as distributed under the NEUSILINTM brand (Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.), clays, silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum, and mixtures thereof.
  • water- insoluble adsorbents such as dicalcium phosphate, tricalcium phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesium aluminometasilicate (e.g., such as distributed under the N
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
  • Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrroli
  • Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide.
  • Suitable release- modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
  • Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof.
  • suitable water- insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof.
  • Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof.
  • suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof.
  • suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof.
  • Suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, phosphotidic acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross- linked povidone (crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrattt.
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyani sole, edetic acid, and edetate salts, and mixtures thereof.
  • preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol
  • kits it may comprise a container for containing the separate compositions 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.
  • Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

Landscapes

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

Abstract

Cette invention concerne la pénicillamine et ses dérivés, une composition les contenant, et des procédés de synthèse et d'utilisation du composé de formule 1. Les composés de formule 1 comprennent également les sels, polymorphes, solvates et hydrates de ceux-ci. Ces composés peuvent être formulés sous forme de compositions pharmaceutiques pour une administration par voie orale, topique, transmuqueuse, par inhalation, administration ciblée et sous forme de formulations à libération prolongée. Les compositions selon l'invention peuvent être utilisées dans le traitement des troubles hépatiques et génétiques liés à la toxicité du cuivre, de NASH et du syndrome de Leigh.
PCT/IN2016/000231 2015-09-21 2016-09-21 Pénicillamine et ses dérivés pour leur utilisation dans le traitement de la toxicité du cuivre et de nash WO2017060914A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN5035CH2015 2015-09-21
IN5035/CHE/2015 2015-09-21

Publications (2)

Publication Number Publication Date
WO2017060914A2 true WO2017060914A2 (fr) 2017-04-13
WO2017060914A3 WO2017060914A3 (fr) 2017-05-18

Family

ID=57794320

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/000231 WO2017060914A2 (fr) 2015-09-21 2016-09-21 Pénicillamine et ses dérivés pour leur utilisation dans le traitement de la toxicité du cuivre et de nash

Country Status (1)

Country Link
WO (1) WO2017060914A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108047159A (zh) * 2017-11-24 2018-05-18 江苏慈星药业有限公司 一种l-噻唑烷-4-甲酸乙酯盐酸盐的生产工艺

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107867A2 (fr) * 2010-03-05 2011-09-09 Mahesh Kandula Composé et composition et leurs utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DOWDY; WEARDEN: "Statistics for Research", 1983, JOHN WILEY & SONS, NEW YORK
REMINGTON: "The Science and Practice of Pharmacy", 2000, pages: 208 - 209
T. E. ROBINSON ET AL.: "microdialysis in the neurosciences, Techniques", vol. 7, 1991, article "chapter 1"

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108047159A (zh) * 2017-11-24 2018-05-18 江苏慈星药业有限公司 一种l-噻唑烷-4-甲酸乙酯盐酸盐的生产工艺

Also Published As

Publication number Publication date
WO2017060914A3 (fr) 2017-05-18

Similar Documents

Publication Publication Date Title
AU2011263423B2 (en) Cysteamine derivatives and their use in the treatment of NASH
WO2013008182A1 (fr) Précurseurs d'analogues de l'acide γ-aminobutyrique (gaba)
WO2013017974A1 (fr) Compositions et méthodes pour le traitement de troubles neuromusculaires et de maladies neurodégénératives
US9642915B2 (en) Compositions and methods for the treatment of neuromuscular disorders and neurodegenerative diseases
US8871805B2 (en) Compound, composition and uses thereof
US5350768A (en) Derivatives of cysteine
WO2017060914A2 (fr) Pénicillamine et ses dérivés pour leur utilisation dans le traitement de la toxicité du cuivre et de nash
CA2791457C (fr) Composes, compositions, formulations et leurs utilisations
EP0475214B1 (fr) Dérivés de l'acide caféique et compositions pharmaceutiques les contenant
EP0317540B1 (fr) Dérivés de cystéine, procédés de leur production et leur usage
WO2013014565A1 (fr) Compositions et procédés pour le traitement d'états métaboliques et de troubles musculaires
WO2014122621A2 (fr) Compositions et procédés pour le traitement d'états métaboliques et de maladies neuromusculaires
CA2996260A1 (fr) Compositions et methodes pour le traitement de la maladie de parkinson
WO2014147531A2 (fr) Compositions et méthodes pour le traitement du cancer
CA2798143A1 (fr) Compose, synthese, composition et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16825901

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16825901

Country of ref document: EP

Kind code of ref document: A2