WO2014041446A2 - Compositions et méthodes de traitement de maladies métaboliques - Google Patents

Compositions et méthodes de traitement de maladies métaboliques Download PDF

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Publication number
WO2014041446A2
WO2014041446A2 PCT/IB2013/056715 IB2013056715W WO2014041446A2 WO 2014041446 A2 WO2014041446 A2 WO 2014041446A2 IB 2013056715 W IB2013056715 W IB 2013056715W WO 2014041446 A2 WO2014041446 A2 WO 2014041446A2
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independently
formula
administration
compositions
compound
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PCT/IB2013/056715
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English (en)
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WO2014041446A3 (fr
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Mahesh Kandula
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Mahesh Kandula
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Priority to US14/399,530 priority Critical patent/US20150291590A1/en
Publication of WO2014041446A2 publication Critical patent/WO2014041446A2/fr
Publication of WO2014041446A3 publication Critical patent/WO2014041446A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of metabolic diseases. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantionier, stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.
  • Tetrahydrobiopterin was subsequently found to be an essential cefaclor for several other aromatic amino acid hydroxylases (tyrosine and tryptophane) involved with neurotransmitter biosynthesis, glyceryl -ether mono-oxygenase, and nitric oxide synthase (NOS).
  • tyrosine and tryptophane aromatic amino acid hydroxylases
  • NOS nitric oxide synthase
  • This co-factor is involved in the hydroxylation of Phe to tyrosine by PAH.
  • the cofactor BH4 is also utilized in the hydroxylation reacti oiis of tyrosine, and tryptophan.
  • the inability to hydroxylate these amino acids leads to deficient levels of the neurotransmitters L-DOPA. from tyrosine, and serotonin, from tryptophan.
  • Treatment of cofactor defects is completely different from for Phenylketonuria (P U). Patients with PKU are able to make adequate amounts of B.H4 and have normal regeneration of BH4.
  • BH4 is an essential cofactor for all 3 NOS isoforms, and basal enzyme activity correlates with the amount of BH4 bound tightly to the protein.
  • NOS is a homodimeric oxid ⁇ reductase containing iron protoporphyrin IX (heme), flavin adenine dinucleotide, flavin mononucleotide, and BH4.
  • BH4 improves endothelial function in those who smoke, diabetic subjects, hypertensive subjects, patients with hypercholesterolemia, and those with coronary artery disease. Unlike hypertension, hypertrophy, and oxidant stress stimulation, other stimuli such as inflammatory cytokines have been found to increase BH4 biosynthesis, and this may play a role in atherosclerosis.
  • the present invention provides compounds, compositions containing these compounds and methods for using the same to treat prevent and/or ameliorate the effects of the conditions such as metabolic diseases.
  • the invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof.
  • the invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of metabolic diseases and its associated complications.
  • the present invention relates to the compound compositions of formula L or pharmaceutically acceptable salts thereof,
  • f , R ⁇ R 3 each independently represents H, D, C3 ⁇ 4CO,a1 ⁇ 4CO, C3 ⁇ 4 CH3 ⁇ 4
  • a is independently 1, 2, 3. 4 or 5;
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently I, 2 or 6;
  • c and d are each independently H. D, -OIL -OD, -NH 2 or -CGCH 3 ; R 4 represents H, D, C3 ⁇ 4CO, CD 3 CO, CD , CI3 ⁇ 4
  • n is independently 1, 2, 3, 4 or 5;
  • a is independently 2,3 or 7;
  • each b is independently 3 f 5 or 6;
  • e is independently 1. 2 or 6;
  • c and d are each independently H, D ; -OR -OD, Crt aikvL ⁇ NH 2 or -COCH 5 .
  • R f , R 2 , R 3 each independently represems H, D, C3 ⁇ 4CO, C.D 3 CO, CD 3 , C3 ⁇ 4
  • n is independently 1, 2, 3. 4 or 5;
  • 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 arc each independently H, D. -Oil -OD, CrQralkyL ⁇ i3 ⁇ 4 or -COCH ? ;
  • R represents H, D, O CCX. CD-.CO. CD 3 , C3 ⁇ 4,
  • n is independently 1, 2, 3, 4 or 5;
  • 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. ⁇ -OR -OD, Cj-CraikyL ⁇ NR or -CGCH ;s .
  • R 1 , R 2 each independently represents H, D, CHjCO, CD s CO, CD 3 , C3 ⁇ 4,
  • n is independently 1 , 2, 3, 4 or 5;
  • a is independently 2,3 or 7:
  • each fa is independently 3, 5 or 6;
  • e is independently 1 , 2 or 6;
  • c and d arc each indepcndetttly H, D, -OH, -OD, CrOaikyl, - 3 ⁇ 4 or -COCH,; represents H, D, CH. 3 CO, CD 3 CO, CD .. CH 3 ,
  • n is independently 1, 2, 3, 4 or .5;
  • a is independently 2,3 or 7;
  • each b is independently 3 f 5 or 6;
  • e is independently 1 , 2 or 6;
  • c and d are each independently H, D s -OR ⁇ OD, CrGi-aik L -NH j or -COCH 3 ;
  • kits com rising any of the pharmaceutical compositions disclosed herein may comprise instructions for use in the treatment of metabolic diseases or its related complications.
  • the application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein, in some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration. sustained release, parenteral administration, injection, subdermai administration, or tran sderraal admi ni strati on .
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment of metabolic diseases or its related complications.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from metabolic diseases or its related complications manifested from metabolic or genetic conditions or disorders, metabolic diseases, chronic diseases or disorders; neurodegenerati e disorders, Hepatoiog , Cancer, Respiratory, Hematological, Orthopedic. Cardiovascular, Renal , Skin, Vascular or Ocul ar compl i cati on s .
  • 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 meihyi and ethyl ester of the acids of formula I, formula II and formula 111 to be used as prodrugs).
  • the compounds of the present invention can also be soivated, i.e. hydrated. The solvation can he 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 I, formula II and formula HI (hydration).
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the - and S- sequencing rules of Calm, Ingokl 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 detect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent,
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • 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, intraperi cardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradennal, 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, stiitabie 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.
  • 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 corn position, from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • sugars such as lactose, glucose and sucrose
  • starches such as com starch and potato starch
  • cellulose, and its derivatives such as sodium carboxym ethyl cellulose, ethyl cellulose and cellulose acetate
  • (4) powdered tragacanth (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes
  • oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil
  • glycols such as propylene glycol
  • (1 1 ) poiyoSs such as glycerin, sorbitol, mantiitol and polyethylene glycol
  • esters such as ethyl oieate and ethyl iaurate
  • (13) agar (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • algtnic acid 16
  • 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
  • the term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or 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 he the entire remaining lifespan of the subject upon analysis by the method of the present invention.
  • treating includes preventing a disease, disorder or condition from occurring in an animal which may he 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 iiiciudes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating phenylketonuria, cardiovascular disease, autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease of a subject by administration of an agent even though such agent does not treat the cause of the condition.
  • the term "treating”, “treat” or “treatment” as used herein includes curative, preventative (e g., prophylactic), adjunct and palliative treatment. j0 34]
  • the phrase "therapeutally 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. In certain embodiments, 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.
  • the pharmaceutical compositions described herei are formul led 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, iiiactivation, and excretion rates of the drug as well a the delivery rate of the salts and compositions from the subject compositions.
  • 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 he used.
  • 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, i 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.
  • terapéuticaally effective amount is an art-recognized term, in certain embodiments, 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. In certain embodiments, 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 admi istered, 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.
  • This application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I. formul II or formula III ma be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration, oral solution, injection, s bdermal 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 (Formula I, formula II and formula ill) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I, formula II or formula ill or composition as part of a prophylactic or therapeutic treatment.
  • the desired concentration of formula L formula II or formula III or its pharmaceutical acceptable salts will depend on absorption, inaetivation, 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 concentrati on and/or quantities or amounts of any particular compound of formula I, formula II or formula III 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.
  • L formul II or formula III 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 neuroses en ces, 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.
  • compounds with formula. 1, formula 0 or formula ill such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysafce in proportion to their local tissue concentrations.
  • the progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concenirations of salts or compositions.
  • the dosage of the subject compounds of formula I, formula if or formula III provided herein may he determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cniax) 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 1 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 I, formula II or formula 111 may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 nag and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 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, formula II or formula III required for the same therapeutic benefit.
  • An effective amount of the compounds of formula 1, formula II or formula 01 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
  • 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-iiitrosative species and/or abnormalities in neurotransmitter homeostasis ⁇ , 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 daig 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 intranasaSly, 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 drag 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 diiuents, in either single or multiple doses.
  • Suitabie phannaceuticai carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed fay combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily admini tered i 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 poly vinylpyrroli done, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryi sulfate and talc are often useful for tab-letting 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 Savoring 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.
  • the compounds of formula I, formula II or formula 111 may also comprise entericaJIy 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 nig e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I, formula It or formula HI disclosed herein, for instance, compounds of formula I, formula If or formula 10 or pharmaceutical acceptable salts of a compounds of Formula 1,
  • a composition as described herein may be administered orally, or parenteral! ⁇ ' (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 metabolic disease; the ty pe 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, 0.3 to about 200 rag kg; intramuscular, 1 to about 500 mg kg; orally. 5 to about 1000 tng/kg; Intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 mg/kg of host body weight,
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasai!y. pharyngdlaryngeally, bronchiaily, intra vagi ally, 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 admi nistration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteraS 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-parenteraS 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-parenteraS solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • sterile parenteral solutions or suspensions ster
  • the tablet core contains one or more hydropliilic polymers.
  • Suitable hydropliilic polymers include, but are not limited to, water sweilable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water sweilable cellulose derivatives include, but are not limited to, sodium carboxymethylcelluiose, cross-linked hydroxypropy !cell ulose., hydroxy-propyl ce!lul ose (HPC), hydroxypropy !terrorismhy I cell ulose (HPMC), hydroxyi sopropy 1 cellulose, hydroxybuty cellulose, hydroxypherry leell ulose, hydroxyet y !ceil ulose (HEC), hydroxy pertty I ceil ulose, hy droxy propyl eihy 1 cell ul ose, hydroxy propy Ibutyl eel lul ose, and hydroxyprop lethylcell ulose, and mixtures thereof.
  • HPC hydroxy-propyl ce!lul ose
  • HPMC hydroxypropy !loishy I cell ulose
  • HPMC hydroxyi sopropy 1 cellulose
  • HPMC hydroxy
  • suitable polyalkylene glycols include, but are not limited to, polyethylene glycol.
  • suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethyleiie oxide).
  • suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzeiie copolymer, polymethylmethacrylate, high-mol ecular weight cross! inked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL , .
  • hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacantJh, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, iaminarin, sclerogiucan, 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 tri silicate; magnesium aluminum silicate; and mixtures thereof
  • suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch giycoiate and derivatives thereof, and mixtures thereof.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked poi vinyl pyrroiidone, cross-linked agar, and cross-linked earboxymethyiceiSulose sodium, and mixtures thereof.
  • 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 thereo
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrroiidone and hydroxy propylrnethylcellulose; wet binders such as water-soluble polymers, including ydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylceliulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, !amma in, sclerog!ucan, inulin, whelan, rhamsan, zooglan, methylan, c tin, cyclodextrin, chitosan, polyvinyl pyrroiidone, cellulosies, sucrose, and starches; and mixtures thereof.
  • Suitable disintegrants include, but are not
  • 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, pit- 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, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaproiactones, celkiiose acetate and its derivatives, acrylates, methacrySates, acrylic acid copolymers, copolymers thereof, and mixtures thereof.
  • Suitable low-melting hydrophobic materials include, but are not Iimited 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 tristearaie, glyceryl tri!aurylate, glyceryl myristate, GIycoWax-932., lauro l macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof
  • suitable phospholipids include phosphatidyl choline, phosphatidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax. shellac wax, microcrvstalline wax, and paraffin wax; fat-containina mixtures such as chocolate, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax. shellac wax, microcrvstalline wax, and paraffin wax; fat-containina mixtures such as chocolate, and mixtures thereof.
  • super disintegrants include, but are not limited to, croscarmeliose sodium, sodium starch glycol ate and cross-linked povidone (crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosuiflte, vatyl hydroxy toluene, buty!ated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
  • preservatives include, but are not limited to, citric acid, tartaric acid, iactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
  • the immediate release coating has an average thickness of at least
  • the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific laye
  • the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent.
  • the portions contact each other at a center axis of the tablet.
  • the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.
  • the first portion contai ns the first pharmaceutically acti ve agent and the second portion contains the second pharmaceutically active agent, in one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.
  • the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.
  • Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units.
  • multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form .
  • Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art.
  • the immediate release dosage, unit of the dosage form i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical exxipients.
  • the immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit, or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).
  • J Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington— The Science and Practice of Pharmacy", 20th.
  • a diffusion system typically consists of one of two types of devices, reservoir and matrix, which are eSlfcnowii and described in die art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • a pulsed release dosage fomi is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form).
  • a pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.
  • Each dosage form contains a thera eutically effective amount of active agent
  • approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wi. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. 3 ⁇ 4, preferably 60 wt % to 40 wt. %, of the total amount of acti ve agent in the dosage form is released in the second pulse.
  • the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.
  • Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit, in this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose.
  • the delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.
  • transdermal e.g., topical
  • dilute sterile, aqueous or partially aqueous solutions usually in about 0.1% to 5% concentration, otherwise similar to the above parenteral solutions, may be prepared.
  • subject compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying.
  • the subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.
  • Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art. of pharmacy.
  • the amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid caniers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compounds of formula 1, formula O or formula III described herein may be administered in inhalant or aerosol formulations.
  • the inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.
  • the final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01-1 .0% w/w, of medicament relative to the total weight of the formulation.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (I) fillers or extenders, such a starches, lactose, sucrose, glucose, mannhol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monoste
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also foe employed as fillers in soft and hard-filled, gelatin. capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, mieroetriulsions, solutions, suspensions, syrups and elixirs, hi addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, soiubilizing agents and emul sifiers, such as ethyl alcohol, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, i,3 ⁇ buiy1ene glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofury! alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, poiyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum meialiydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, poiyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum meialiydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository? wax, or salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated eompound(s) and composition(s).
  • suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository? wax, or salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated eompound(s) and composition(s).
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • a subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with an preservatives, buffers, or propellants that may be required.
  • the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.
  • the ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragaeantli, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poly amide powder, or mixtures of such substances.
  • Sprays may additionally contain customary propellants, such as chlorofluor hydrocarbons and volatile unsubstiiuted hydrocarbons, such as butane and propane.
  • a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition compri sing 100 parts by weight of a polyvinyl chioride-polyurethane composite and 2-10 parts by weight of a styrene- ethyiene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polvaikylene terephthaiate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the poiyalkylene terephthaiate film, and a second adhesive layer comprising a styrene-dieoe-styrene block; copolymer containing a pharmaceutical agent layered on the primer layer.
  • A. method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a poiyalkylene terephthaiate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and .forming a primer layer comprising a saturated polyester resin on the outer surface of the poiyalkylene terephthaiate film.
  • Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.
  • Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-mo!ecu!e drugs Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.
  • iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current.
  • iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current.
  • One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes.
  • the principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) eleetroosmosis, the convective movement of solven that occurs through a charged pore in response the preferential passage of counter- ions when an electric field is applied or (c) increase skin permeability due to application of electrical current,
  • kits 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.
  • An example of such a kit is a so-called blister pack.
  • 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.
  • R* , R 2 , R each independently represents H, D, CH CO, O3 ⁇ 4C0, CD 3 , CH*
  • R is independently I. 2, 3, 4 or 5;
  • a is independently 2,3 or 7;
  • each b is independently 3 f 5 or 6;
  • e is independently 1 , 2 or 6;
  • e and d are each independently H, D. -OR ⁇ OD, C f ralkyi, -NR or -COCH>;.
  • R 4 represents H, D, Cl hCO, CD-CO.
  • n is independently ] , 2, 3. 4 or 5,
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1 , 2 or 6;
  • c nd d arc each independently H, D, -OR -OD, d-CVaikyl, -NR or -COCH j ;
  • R f , R 2 , R* each independentl represents H, D, CEfeCO, CD3CO, C 3, CH 3 ⁇ 4
  • n is independently 1, 2. 3, 4 or 5;
  • a is independently 2,3 or 7;
  • each b is independentl 3. 5 or 6;
  • e is independently 1 , 2 or 6;
  • c and d are each independently H, D. -OR -OD, Cj ⁇ C ( ra!kyL - H 2 or -COCH 3 ;
  • R 4 represents H, D, CH.,CO, CD 3 CO, CD CH*
  • ⁇ is independently 1 , 2, 3, 4 or 5;
  • 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 R D, -OH, -OD. CrC-ralkyl, -N3 ⁇ 4 or -CQCR;
  • R f s R 2 each independently represents H 5 D, C3 ⁇ 4CO, CD ; ,CO ? C3 ⁇ 4 CH 3 ⁇ 4
  • n is independently 1 , 2, 3. 4 or 5;
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1 , 2 or 6;
  • e and d are each independently H, D ; -OR -OD, CrtValkvL ⁇ NJ3 ⁇ 4 or -COCH,; represents H, D, C3 ⁇ 4CO, CDsCO, C3 ⁇ 4 CH ,
  • n is independently 1, 2, 3, 4 or .5;
  • a is independently 2,3 or 7;
  • each b is independently 3 f 5 or 6;
  • e is independently 1 , 2 or 6;
  • c and d are each independently H, D s -OR ⁇ OD, CrGi-aik L -NH j or -COCH 3 .
  • the obtained solid was crystallized from 800 rnl of boiling water. Water was put to boil, and when the water started to boll, the solid was added in small portions to the water with stirring in such a way thai every portion was added immediately after the dissolution of the previously added portion. After all the solid was added to the water and the mixture became an almost clear solution (slightly emulsified), the clear solution was filtered hi a sufficiently hot condition and the filtrate was cooled overnight. The cooled filtrate was further filtered and the obtained solid was dried in a desiccator of give 94.3 g of L-(+)-arabinose-dieihyi mercaptal 2 (yield; 92%).
  • Step-1 1 Synthesis of compound 15:
  • sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting.
  • cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.

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  • Heart & Thoracic Surgery (AREA)
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Abstract

La présente invention concerne des composés de formules I, II et III ou leurs sels pharmaceutiquement acceptables, ainsi que leurs formes polymorphes, leurs solvates, leurs énantiomères, leurs stéréoisomères et leurs hydrates. Elle concerne des compositions pharmaceutiques comprenant une quantité efficace de composés de formules I, II ou III ; et des méthodes de traitement ou de prévention de maladies métaboliques. Ces compositions peuvent être formulées pour administration par voie orale, buccale, rectale, topique, transdermique, transmuqueuse, intraveineuse, parentérale, sous forme de sirop ou d'injection. De telles compositions peuvent être utilisées pour le traitement de la phénylcétonurie, des troubles cardiovasculaires, de l'autisme, de le TDAH, de l'hypertension, de la dysfonction endothéliale et de la néphropathie chronique.
PCT/IB2013/056715 2012-09-17 2013-08-18 Compositions et méthodes de traitement de maladies métaboliques WO2014041446A2 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550109A (en) * 1984-05-31 1985-10-29 The Board Of Regents, The University Of Texas System Lipoidal biopterin compounds
US4920122A (en) * 1985-06-04 1990-04-24 Suntory Limited Pharmaceutical composition and method for the treatment of infantile autism
WO2006120176A2 (fr) * 2005-05-11 2006-11-16 Nycomed Gmbh Combinaison d'un inhibiteur de pde4 et un derive de tetrahydrobiopterine
WO2008089008A2 (fr) * 2007-01-12 2008-07-24 Biomarin Pharmaceutical Inc. Analogues de ptérine
CN102633799A (zh) * 2012-04-10 2012-08-15 凯莱英医药集团（天津）股份有限公司 一种从消旋体中间体拆分路线合成二盐酸沙丙蝶呤的方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4550109A (en) * 1984-05-31 1985-10-29 The Board Of Regents, The University Of Texas System Lipoidal biopterin compounds
US4920122A (en) * 1985-06-04 1990-04-24 Suntory Limited Pharmaceutical composition and method for the treatment of infantile autism
WO2006120176A2 (fr) * 2005-05-11 2006-11-16 Nycomed Gmbh Combinaison d'un inhibiteur de pde4 et un derive de tetrahydrobiopterine
WO2008089008A2 (fr) * 2007-01-12 2008-07-24 Biomarin Pharmaceutical Inc. Analogues de ptérine
CN102633799A (zh) * 2012-04-10 2012-08-15 凯莱英医药集团（天津）股份有限公司 一种从消旋体中间体拆分路线合成二盐酸沙丙蝶呤的方法

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