CN104364241A - Compositions and methods for suppression of carbonic anhydrase activity - Google Patents
Compositions and methods for suppression of carbonic anhydrase activity Download PDFInfo
- Publication number
- CN104364241A CN104364241A CN201380030632.6A CN201380030632A CN104364241A CN 104364241 A CN104364241 A CN 104364241A CN 201380030632 A CN201380030632 A CN 201380030632A CN 104364241 A CN104364241 A CN 104364241A
- Authority
- CN
- China
- Prior art keywords
- disease
- composition
- molecular bond
- compound
- independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CXGNGMANBKYIEF-UHFFFAOYSA-N CC(Nc1nnc(SCc2ccccc2)[s]1)=O Chemical compound CC(Nc1nnc(SCc2ccccc2)[s]1)=O CXGNGMANBKYIEF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Emergency Medicine (AREA)
- Otolaryngology (AREA)
- Gastroenterology & Hepatology (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Vascular Medicine (AREA)
Abstract
Provided are the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for treating or preventing or modulating carbonic anhydrase activity in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral admimstration, syrup, or injection. Such compositions may be used to treatment of glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dural ectasia, congestive heart failure, drug induced edema, diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia.
Description
Right of priority
This application claims the rights and interests of the India temporary patent application No.1810/CHE/2012 submitted on May 8th, 2012, all objects are depended on to whole disclosures of this temporary patent application, and this whole disclosure is incorporated in the application by reference.
Technical field
Present disclosure relates in general to compound and composition for suppressing carbonic anhydrase activity.More specifically, the present invention relates to the compound with pharmaceutically acceptable dosage, steric isomer, enantiomer, crystal, ester, salt, hydrate, prodrug or their mixture and carry out treatment target.
Background technology
Carbonic anhydrase (CAs; Also carbonate dehydratase EC 4.2.1.1 is referred to as) be the ubiquitous metalloenzyme in prokaryotic organism and eukaryote of being encoded by four upper incoherent gene families of evolving.CAs catalysis CO
2be converted into the simple physiological response of bicarbonate ion and proton.The avtive spot of most of CAs is containing the necessary zine ion (Zn of promising catalyzed reaction
2+).CA reaction participates in much physiology and pathologic process, comprises breathing and CO
2and the transport of bicarbonate radical between metabolizing tissue and lung; PH and CO
2homeostasis; Electrolyte secretion in various tissue and organ; Biosynthesizing reaction (such as glyconeogenesis, steatogenesis and uric acid are formed); Bone resorption; Calcification; And tumorigenicity.
The many CA isozymes participated in these processes are all important therapy target, and they have the suppressed potentiality comprising numerous diseases of oedema, glaucoma, obesity, cancer, epilepsy and osteoporosis for treatment.The CA inhibitor (CAIs) that known two classes are main: metal-complex anion and unsubstituted sulfa drugs and their bioisostere thing.CAIs comprises traditional inhibitor acetazolamide, methazolamide, Ethoxzolamide, Trolone and Antidrasi.
Have compared with sterically hindered disulphide with corresponding, the volume of reduction-state compound (mercaptan) is little, and demonstrate excellent CA inhibit activities (in low nanomolar range), disulphide is difficult in the limited space of the avtive spot entering enzyme, and its bioavailability is low, also have not good pharmacokinetics, there is common side effect simultaneously, as toe is numb, the sense of taste is malfunctioning, ataxia, face and meropresthesia and blurred vision.
Manage acute pathology and often depend on the potential pathology of solution disease and symptom.At present, this area needs new composition to treat or postpones the morbidity of carbonic anhydrase enzymic activity and the progress of related complication thereof.
Summary of the invention
The invention provides compound, composition containing these compounds and use their treatments, prevention and/or alleviate the method showing as the impact of the symptom of the such as complication or disease of carbonic anhydrase enzymic activity.
The present invention provides the composition of contained I or its pharmacologically acceptable salt at this.The present invention also providing package contains the compound of one or more formula I or the pharmaceutical composition of its intermediate and one or more pharmaceutically acceptable carrier, medium or thinner.These compositions may be used for suppressing carbonic anhydrase activity and related complication thereof.
In certain embodiments, the present invention relates to compound and the composition of formula I, or its pharmacologically acceptable salt,
Wherein,
R
1represent independently of one another D, H,
R
2represent independently of one another
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d is H, D ,-OH ,-OD, C independently of one another
1to C
6alkyl ,-NH
2or-COCH
3;
R
3represent H, D, methyl, F, Cl, ethyl or ethanoyl independently.
In an exemplary embodiment, the example of formula I is listed below:
Present invention also provides the test kit comprising in pharmaceutical composition disclosed herein any one.Described test kit can comprise the operation instruction for suppressing carbonic anhydrase activity or its related complication.
Disclosed herein as well is the pharmaceutical composition comprising pharmaceutically acceptable carrier and described any compound herein.In some respects, described pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subcutaneous administration or transcutaneous applications.
Herein, the other providing package of the application is containing the test kit of pharmaceutical composition described herein.Described test kit can also comprise the operation instruction for suppressing carbonic anhydrase activity or its related complication.
Composition described herein has some purposes.The application provides such as to the related complication suffering from carbonic anhydrase activity and regulate or show as nerve degenerative diseases, neurological dysfunction, metabolic condition or disorder, metabolism syndrome, chronic disease or disorder; The patient of hyperinsulinemia, insulin resistant, glucose intolerance, hepatopathy, cancer, respiratory system, blood, bone, cardiovascular, kidney, skin, nerve or eyes complication carries out the method for the treatment of.
Embodiment
Definition
As used herein, following term and phrase should have implication hereinafter described.Unless otherwise defined, otherwise whole scientific and technical terminology used herein has the identical meanings usually understood with those of ordinary skill in the art.
Compound of the present invention can exist with the form of pharmacologically acceptable salt.Compound of the present invention also can exist with the form of pharmaceutically acceptable ester (that is, waiting methyl and the ethyl ester of the acid of the formula I being used as prodrug).Compound of the present invention can also be completely solvated, i.e. hydration.Solvation can during manufacturing processed, namely the initial anhydrous compound of factor I hygroscopic nature and work or occur (hydration).
There is same molecular formula but different compounds is called as " isomers " in character or its atom order of connection or its steric arrangement.Isomerss different on its steric arrangement is called as " steric isomer ".Diastereomer is and the steric isomer with one or more chiral centre with opposite configuration of diastereomer.Mirror image can not be called as " enantiomer " by the overlapping steric isomer with one or more center of asymmetry each other.When compound has center of asymmetry, such as, if carbon atom group different from four connects, then a pair enantiomer is likely formed.Enantiomer can be characterized by the absolute configuration of its center of asymmetry or multiple center of asymmetry, and by R and the S ordering rule of Cahn, Ingold and Prelog or be described by the mode that molecule makes polarized light flat rotate and be appointed as dextrorotation or left-handed (being namely appointed as (+) or (-) isomers respectively).Chipal compounds can exist with the form of the enantiomer of single kind or their mixture.The mixture of the enantiomer containing equal proportion is called as " racemic mixture ".
As used herein, term " metabolic condition " refers to inborn errors of metabolism (or inherited metabolic symptom), its heredopathia for causing because of the defect in one or more pathways metabolism; Specifically, the function of enzyme is affected, causes the shortage of enzyme or do not exist completely.
In some embodiments, molecular bond comprises the compound be selected from LA (CAS No.1200-22-2), salsalate (CAS No.552-94-3), acetylcysteine (CAS No.616-91-1), timnodonic acid (CAS No.10417-94-4), docosahexenoic acid (CAS No.6217-54-5).
As used herein, the term " polymorphic form " approve to by this area and refer to a kind of crystalline structure of given compound.
Phrase as used in this article " parenteral administration " and " non-bowel dispenser " refer to except the dispenser pattern (such as inject) in intestines and except local drug delivery, and include, without being limited in intravenously, intramuscular, pleura, in Ink vessel transfusing, pericardium, in intra-arterial, sheath, in capsule, in socket of the eye, in heart, intracutaneous, intraperitoneal, under tracheae, subcutaneous, epidermis, under intraarticular, capsule, under arachnoid membrane, in backbone and intrasternal injection and transfusion.
Treat that " patient ", " object " or " host " treated by this subject methods can refer to that the mankind or non-human animal are as primates, Mammals and vertebrates.
Phrase " pharmaceutically acceptable " is by being approved this area.In certain embodiments, this term is included within the scope of abundant medical judgment and is applicable to and Mammals, human and animal's contact tissue and do not have the composition of overdosage toxicity, pungency, transformation reactions or other problem or complication, polymkeric substance and other material and/or formulation, and itself and rational income/Hazard ratio match.
Phrase " pharmaceutically acceptable carrier " is by being approved this area, and comprise and such as delivering or carrying pharmaceutically acceptable material, composition or medium involved in any theme composition from an organ of body or part to another organ of body or part, the weighting agent of such as liquid or solid, thinner, solvent or coating material.Often kind of carrier must the meaning of other component compatibility with theme composition be " acceptable ", and harmless for patient.In certain embodiments, pharmaceutically acceptable carrier is nonthermal.Some examples that can be used as pharmaceutically acceptable carrier comprise: (1) sugar, as lactose, dextrose plus saccharose; (2) starch, as W-Gum and yam starch; (3) cellulose and its derivates, as Xylo-Mucine, ethyl cellulose and cellulose ethanoate; (4) powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) theobroma oil and suppository wax; (9) oil, as peanut oil, Oleum Gossypii semen, sunflower seed oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) glycol, as propylene glycol; (11) polyvalent alcohol, as glycerine, Sorbitol Powder, mannitol and polyoxyethylene glycol; (12) ester, as ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent, as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) Ringer's solution (Ringer's solution); (19) ethanol; (20) phosphate buffer soln; And other non-toxic compatible material that (21) use in pharmaceutical formulations.
Term " prodrug " is intended to comprise the compound being converted into therapeutic activity medicament of the present invention in physiological conditions.The common methods making prodrug is comprise the selected part being hydrolyzed to discharge desired molecule in physiological conditions.In other embodiments, prodrug is transformed by the enzymic activity of host animal.
Term " preventative or therapeutic " treatment by being approved this area, and comprises and uses one or more theme compositions to host.If dispenser before clinical manifestation goes out undesirable symptom (disease of such as host animal or other undesirable state), then treatment is for preventative, namely protects host to avoid developing undesirable symptom; And if dispenser after showing undesirable symptom, then treatment is curative (being namely intended to reduce, alleviate or stablize and existingly do not wish symptom or its side effect).
As used herein, the term " prediction " refer in the future time window (prediction window) of specifying, assessed by the probability of deformity or complication and/or end platelet aggregation or exhaustion and/or death (i.e. mortality ratio) for related disorder patients.Described mortality ratio can be caused by central nervous system or complication.Described prediction window is that object will develop the timed interval of one or more above-mentioned complication according to prediction probability.When being analyzed by method of the present invention, prediction window can be whole residual lifes of object.
Term " treatment " by being approved this area, and comprises and prevents disease, disorder or symptom from can tend in advance this disease, disorder and/or symptom occur but being not yet diagnosed as in the animal suffering from this disease, disorder or symptom occur; Suppress described disease, disorder or symptom, such as, hinder the development of this disease, disorder or symptom; And alleviate described disease, disorder or symptom, such as cause this disease, the disappearing of disorder and/or symptom.Disease therapy or symptom are included in even without when having influence on essence physiopathology, alleviate at least one symptom of specified disease or symptom, such as, treat glaucoma, epileptic seizures, idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and endocranium expansion, congestive heart failure, drug-induced oedema, limb vessel blocks the intermittent claudication and vascular dementia that cause, improve blood flow by peripheral blood vessel and therefore contribute to the blood circulation in arms and legs (i.e. intermittent claudication) and brain (therefore using in vascular dementia), Peyronie's disease and nervosa injury, preventing apoplectic for controlling sickle cell disease, what treatment high mountain caused feels sick and headache (altitude sickness), and show the mortality ratio that can alleviate acute alcohol and non-alcohol fat hepatitis and alcoholic liver disease, reduce the severity of the fibrosis lesion brought out by the radiotherapy of mammary cancer, the intravenous therapy of cytokines release syndrome, type 1 diabetes and diabetes B, asthma, bronchiectasis, neuroprotective properties, vasorelaxation, Alzheimer, dementia, apoplexy, and the treatment of endometriosis.By using medicament, even if when the symptom origin cause of formation do not treated by this medicament, be also used for the treatment of the venous disease of object.As used herein, the term " treatment " comprise the treatment of healing property, prevention property (such as preventative), complementary and palliative.
Phrase " treatment significant quantity " is the term approved for this area.In certain embodiments, this term refers to the amount of salt disclosed herein or composition, and described amount produces the effect of certain expection with the reasonable benefit/Hazard ratio being applicable to any therapeutic treatment.In certain embodiments, this term refers to and to be eliminated by medical symptom within for some time or to reduce the necessary or enough amount of institute.Significant quantity can according to the disease in such as treatment or symptom, use in factor from particular target to the seriousness of the size of construct, object or disease or symptom and change.Those of ordinary skill in the art can empirically determine particular composition significant quantity and without the need to undo experimentation.
In certain embodiments, described herein pharmaceutical composition is to make described composition can be delivered to patient to treat significant quantity thus to prepare as mode that is preventative or therapeutic treatment part.Desired composition amount to patient to be administered will depend on the absorption of medicine, inactivation and discharge rate and salt and the composition delivery rate by theme composition.It should be noted that dose value also can change along with the seriousness of symptom to be slowed down.It is to be further understood that for any specific object, should according to individual need and the professional judgement using or instruct the people using composition, along with time lapse regulates concrete dosage.Typically, dosage will utilize technology known to those of skill in the art to determine.
In addition, can regulate to the optimum concn of any specific salt or composition and/or amount or dosage the change that adapts to treat parameter.These treatment parameters comprise the clinical application (position of such as treating) of preparation trend of purchasing, the type (the such as mankind or non-human, adult or children) of patient, and the character of disease or symptom.
In certain embodiments, the dosage of the theme composition provided herein can be determined by reference to the plasma concentration of therapeutic composition or other coating material.Such as, can use under maximal plasma concentration (Cmax) and plasma concentration v. time curve from the time be 0 to infinitely-great area.
When using in pharmaceutical composition or other material, term " sustained release " is by being approved this area.Such as, with make the material disposable biological of all dosage can single fast (bolus) type use contrary, through time h substance theme composition can demonstrate the characteristic of sustained release.Such as, in certain embodiments, when contacting with body fluid (comprising blood, spinal fluid, mucus secretion or lymph liquid etc.), one or more pharmaceutically acceptable vehicle can (compared with discharging fast with single) is carried out progressively or postponed within the time continued or extend degraded (such as pass through be hydrolyzed), discharges any material (such as medicine and/or bioactive salts and/or composition) wherein comprised simultaneously.This release can make the prolongation of the treatment significant quantity of any healing potion disclosed herein send.
Phrase " systemic administration ", " general is used ", " periphery is used " and " peripheral use " by being approved this area, and are included in and use theme composition, medicine or other material away from disease therapy position.For the using of medicament being used for the treatment of disease, unless be applied directly in central nervous system and (such as passed through subcutaneous administration), even if otherwise this medicament systemically distributes subsequently, still can be called as " local ", " locally " or " regionality " use, thus enter patient body system, and carry out the processes such as metabolism thus.
Phrase " treatment significant quantity " is the term approved for this area.In certain embodiments, this term refers to the amount of salt disclosed herein or composition, and described amount produces the effect of certain expection with the reasonable benefit/Hazard ratio being applicable to any therapeutic treatment.In certain embodiments, this term refers to and to be eliminated by medical symptom within for some time or to reduce the necessary or enough amount of institute.Significant quantity can according to the disease in such as treatment or symptom, use in factor from particular target to the seriousness of the size of construct, object or disease or symptom and change.Those of ordinary skill in the art can empirically determine particular composition significant quantity and without the need to undo experimentation.
Present disclosure has also thought over the prodrug of composition disclosed herein, and the pharmacologically acceptable salt of described prodrug.
Disclosed herein as well is the pharmaceutical composition comprising pharmaceutically acceptable carrier, and the composition can preparing the compound of formula I is for whole body, local or Orally administered.Also the preparation of this pharmaceutical composition can be used for Orally administered, oral solution, injection, subcutaneous administration or applied dermally.Described pharmaceutical composition can also comprise at least one in pharmaceutically useful stablizer, thinner, tensio-active agent, weighting agent, tackiness agent and lubricant.
In many embodiments, pharmaceutical composition described herein comprises disclosed compound to be delivered and composition (formula I) by with the amount of the treatment significant quantity of enough compounds to patient delivery formula I or composition, as part that is preventative or therapeutic treatment.Required formula I or the concentration of its pharmacologically acceptable salt will depend on the absorption of medicine, inactivation and discharge rate and salt and the composition delivery rate by theme composition.It should be noted that dose value also can change along with the seriousness of symptom to be slowed down.It is to be further understood that for any specific object, should according to individual need and the professional judgement using or instruct the people using composition, along with time lapse regulates concrete dosage.Typically, dosage will utilize technology known to those of skill in the art to determine.
In addition, can regulate to the optimum concn of the compound of any specific formula I and/or amount or dosage the change that adapts to treat parameter.These treatment parameters comprise the clinical application (position of such as treating) of preparation trend of purchasing, the type (the such as mankind or non-human, adult or children) of patient, and the character of disease or symptom.
By making regular check on animal (such as mouse), suitably test can be adopted to check a series of concentration and/or the dosage of material to be determined, easily determines concentration and/or the dosage of the compound of any formula I.Known method also can be used for examining and determine is using rate of diffusion and the regional blood flow of local tissue concentration, salt or composition before and after medicine preparation disclosed herein.One of such method is micro-dialysis, if T.E.Robinson etc. is described in the microdialysis in the neurosciences of Techniques the 7th volume the 1st chapter of 1991.In brief, the method described in Robinson can be implemented as follows.Micro-dialysis ring original position is placed in experimental animal.By this ring with pump delivery dialyzate.When the compound of this ring injection such as formula I disclosed herein, the medicine discharged is to be gathered in pro rata in dialyzate with its local tissue concentration.Thus, known salt or the concentration of composition can be utilized, be determined the diffusion process of salt or composition by suitable correction program.
In certain embodiments, the dosage of the compound of the subject-type I provided herein can be determined by reference to the plasma concentration of therapeutic composition or other coating material.Such as, can use under maximal plasma concentration (Cmax) and plasma concentration v. time curve from the time be 0 to infinitely-great area.
Generally speaking, when implementing the method described in detail in the application, the effective dose of the compound of formula I be single dose or divided dose at about 0.01mg/kg/ days to about 100mg/kg/ days, such as single dose or divided dose are in the scope of 0.01mg/kg/ days to about 50mg/kg/ days.The compound of formula I can according to be such as less than 0.2mg/kg/ days, 0.5mg/kg/ days, 1.0mg/kg/ days, 5mg/kg/ days, 10mg/kg/ days, 20mg/kg/ days, 30mg/kg/ days or 40mg/kg/ days dosage use.The compound of formula I also can according to such as between 0.1mg and 1000mg, between 5mg and 80mg or be less than 1.0 every day, 9.0,12.0,20.0,50.0,75.0,100,300,400,500,800,1000,2000, the dosage of 5000mg is applied to human patients.In certain embodiments, composition herein be less than the compound of the formula I obtained needed for identical treatment income 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% amount use.
The significant quantity of the compound of formula I described herein refers to and can suppress or the amount of prophylactic a kind of described salt or composition.
In existence because nerve injury or demyelination and/or reactive oxidants-nitrogenize kind raise and/or the autologous dysregulation of physiology and cause in the patient of complication risk, significant quantity can be enough to the development stoping, treat, alleviate, alleviate, suspend, suppress, delay or reverse this type of complication, or reduces the severity of this complication.Thus, these methods optionally comprise using of medical thera-peutic (acute) and/or preventative (prevention).Certainly, using the dosage of composition and time will depend on the judgement meeting subject object, ailing severity, the mode used and prescriber.Therefore, due to the difference between patient, dosage given is above a kind of guidance, and doctor the dosage of titration of medicines can realize doctor and think the treatment being suitable for patient.When considering the treatment degree of expection, doctor must weigh many factors, the age of such as patient, the existing existence of disease and the existence of Other diseases.
The composition provided by the application can by various conventional drug delivery route, comprise oral, locally, parenteral (such as intravenous injection, subcutaneous injection or intramedullary injection) and be applied to the object of needs treatment.Further, described composition can fill a prescription in nose, as rectal suppository or use " fast " (even if medicine dissolve in the oral cavity and without the need to using water) use.In addition, said composition can be sent by Co ntrolled release formulation, privileged site drug delivery, transdermal drug delivery, paster (active/passive) mediate drug, by stereotaxical injection, or be applied to the object needing treatment with the form of nanoparticle.
Described composition can with single dose or multiple doses individually or with pharmaceutically acceptable carrier, medium or thinner combined administration.Suitable pharmaceutical carrier, medium and thinner comprise inert solid diluent or weighting agent, aseptic aqueous solution and multiple organic solvent.Easily used with various formulation such as tablet, powder, lozenge, syrup and injection solution etc. subsequently by the pharmaceutical composition that above-mentioned composition and pharmaceutically acceptable carrier, medium or mixing diluents are formed.If needed, these pharmaceutical compositions can containing extra composition, such as seasonings, tackiness agent and vehicle etc.Therefore, for Orally administered object, can by containing multiple vehicle if the tablet of L-arginine, Trisodium Citrate, calcium carbonate and calcium phosphate and multiple disintegrating agent are as starch, alginic acid and specific composition silicate, together with tackiness agent as polyvinylpyrrolidone, sucrose, gelatin and Sudan Gum-arabic use.In addition, lubricant is if Magnesium Stearate, sodium lauryl sulphate and talcum are through being usually used in the object making sheet.Also the solids composition of similar type can be used as the weighting agent in soft and hard filling gelatine capsule.The suitable material of used as said purpose comprises the polyoxyethylene glycol of lactose (lactose) or lactose (milk sugar) and high molecular.When for Orally administered and when needing aqueous suspensions or elixir, can by essence effective constituent wherein and multiple sweet taste or seasonings, coloring material or dyestuff and emulsification or suspending agent (if needs), together with thinner as water, ethanol, propylene glycol, glycerine and combination thereof mix.As known in pharmacy field, the compound of formula I can also comprise the enteric coating (enterically coated) containing multiple vehicle.
For parenteral administration, the solution of described composition can be prepared in (such as) sesame or peanut oil, aqueous propylene glycol, or can use aseptic aqueous solution.If necessary, suitably should cushion this aqueous solution, and should first make liquid diluent and enough physiological saline or glucose isotonic.These specific aqueous solution are particularly suitable for intravenously, intramuscular, subcutaneous and intraperitoneal are used.Thus, the sterile aqueous media used all easily obtains by standard technique well known by persons skilled in the art.
The preparation of such as tablet can containing such as 10 to 100,50 to 250,150 to 500mg or 350 to 800mg, such as 10,50,100,300,500,700, the compound of 800mg formula I disclosed herein, the pharmacologically acceptable salt of the compound of such as formula I or the compound of formula I.
Typically, composition as described herein can be used by oral or parenteral (such as in intravenously, intramuscular, subcutaneous or marrow).Also can indicate topical application, such as when patient just suffering from hinder Orally administered gastrointestinal dysfunction, or when attending doctor determine by medicament administration in tissue or organ surface the most suitable time.Spot application can also be indicated, such as, when target tissue or organ place need higher dosage.Use for cheek, active composition can take the form of tablet or the lozenge prepared in a usual manner.
The dosage used will depend on the characteristic of metabolic disease; Relate to the type (comprising its age, healthy state and weight) of host; The kind of synchronous therapeutic (if there is); Therapeutic frequency and treatment ratio.
Exemplarily, using activeconstituents based on the dosage level of host's body weight is: intravenous injection, and 0.1 to about 200mg/kg; Intramuscular injection, 1 to about 500mg/kg; Oral, 5 to about 1000mg/kg; Instil in nose, 5 to about 1000mg/kg; Sprays, 5 to about 1000mg/kg.
State with concentration, in skin periphery, nose, the fixed point of throat, segmental bronchus, intravaginal, rectum or eye uses, the concentration containing activeconstituents in composition of the present invention can be about 0.01 of said composition to about 50%w/w; Be preferably about 1 of said composition to about 20%w/w; And parenteral is used, concentration can be about 0.05 of said composition to about 50%w/v; Be preferably about 5 to about 20%w/v.
Composition of the present invention preferably proposes to be applied to humans and animals with the form of the unitary dose containing appropriate activeconstituents, such as tablet, capsule, pill, powder, granule, suppository, sterile injectable solution or suspensoid, aseptic non-injection solution or suspensoid, and oral solution or suspensoid etc.For oral administration, the form of the unitary dose of solid or liquid can be prepared into.
As discussed above, label contains one or more hydrophilic polymers.Suitable hydrophilic polymer includes but not limited to water swellable cellulose derivative, polyalkylene glycol, thermoplastic polyalkalene's base oxide, acrylic polymers, hydrophilic colloid, clay, jelling starch, swellable crosslinked polymers and their mixture.The example of suitable water swellable cellulose derivative includes but not limited to Xylo-Mucine, cross-linked hydroxypropyl base Mierocrystalline cellulose, hydroxypropylcellulose (HPC), Vltra tears (HPMC), hydroxyl isopropyl cellulose, hydroxybutyl cellulose, hydroxyphenylcellulose, Natvosol (HEC), hydroxyl amyl cellulose, Hydroxypropyl ethyl cellulose, hydroxypropyl butylcellulose and Hydroxypropyl ethyl cellulose and their mixture.The example of suitable polyalkylene glycol includes but not limited to polyoxyethylene glycol.The example of suitable thermoplastic polyalkalene's base oxide includes but not limited to gather (oxyethane).The example of suitable acrylic polymers includes but not limited to that methacrylic acid potassium-divinyl benzene copolymer, polymethylmethacrylate, high molecular weight crosslinked acrylate homopolymer and multipolymer (such as can be called CARBOPOL purchased from the commodity of Noveon Chemicals
tMhigh molecular weight crosslinked acrylate homopolymer and multipolymer).The example of suitable hydrophilic colloid includes but not limited to alginate, agar, guar gum, Viscogum BE, kappa carrageenan, ι-carrageenin, tara gum, Sudan Gum-arabic, tragacanth, pectin, xanthan gum, gelling gum, maltodextrin, polygalactomannan, pustulan (pusstulan), laminarin, Sclerotium gum, Sudan Gum-arabic, inulin, pectin, gelatin, Welan gum (whelan), neutral gum, zoogloea (zooglan), the blue glue (methylan) of first, chitin, cyclodextrin, chitosan and their mixture.The example of suitable clay includes but not limited to that montmorillonite is as wilkinite, kaolin and hectorite; Magnesium Trisilicate; Neusilin; And their mixture.The example of suitable jelling starch includes but not limited to that acidified starch, swollen starches are as sodium starch glycollate and derivative thereof, and their mixture.The example of suitable swellable crosslinked polymers includes but not limited to cross-linked polyvinylpyrrolidone, Cross-linked Agar and croscarmellose sodium, and their mixture.
Described carrier can containing the preparation of one or more suitable vehicle for tablet.The example of suitable vehicle includes but not limited to weighting agent, sorbent material, tackiness agent, disintegrating agent, lubricant, glidant, release modifying excipient, super-disintegrant, antioxidant and their mixture.
Suitable tackiness agent includes but not limited to: dry adhesives, as polyvinylpyrrolidone and Vltra tears; Wet binder, such as water-soluble polymers, comprise hydrophilic colloid as Sudan Gum-arabic, alginate, agar, guar gum, Viscogum BE, carrageenin, carboxymethyl cellulose, tara gum, Sudan Gum-arabic, tragacanth, pectin, xanthan gum, gelling gum, gelatin, maltodextrin, polygalactomannan, pustulan, laminarin, Sclerotium gum, inulin, Welan gum, neutral gum, zoogloea, first blue glue, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulosics, sugarcane sugar and starch, and their mixture.Suitable disintegrating agent includes but not limited to sodium starch glycollate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, starch, Microcrystalline Cellulose and their mixture.
Proper lubrication agent includes but not limited to longer chain fatty acid and salt (such as Magnesium Stearate and stearic acid), talcum, glyceryl ester, wax and their mixture.Suitable glidant includes but not limited to colloid silica.Suitable release modifying excipient includes but not limited to insoluble edible material, pH dependent polymers and their mixture.
The insoluble edible material being suitable as release modifying excipient includes but not limited to insoluble polymer and low melting point hydrophobic material, their multipolymer and their mixture.The example of suitable insoluble polymer includes but not limited to ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose ethanoate and derivative thereof, acrylate, methacrylic ester, acrylic copolymer, their multipolymer and their mixture.Suitable low melting point hydrophobic material includes but not limited to fat, fatty acid ester, phosphatide, wax and their mixture.The example of suitable fat includes but not limited to that hydrogenated vegetable oil is as theobroma oil, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil and hydrogenated soybean oil, free fatty acids and salt thereof, and their mixture.The example of suitable fatty acid ester includes but not limited to sucrose fatty ester; glycerine list, two and three ester docosoic glyceryl ester, palmitostearate, glyceryl monostearate; Tristearoylglycerol; trilaurin, tetradecanoic acid glyceryl ester, GlycoWax-932; lauroyl polyoxyethylene glycol-32 glyceryl ester, stearyl-polyoxyethylene glycol-32 glyceryl ester and their mixture.The example of suitable phosphatide comprises phosphatidylcholine, phosphatidylserine (phosphotidyl serene), phosphatidylinositols (phosphotidyl enositol), phosphatidic acid and their mixture.The example of suitable wax includes but not limited to carnauba wax, spermaceti, beeswax, gama wax, shellac wax, Microcrystalline Wax and solid paraffin; Fatty mixture is as chocolate, and their mixture.The example of super-disintegrant includes but not limited to croscarmellose sodium, sodium starch glycollate and polyvinylpolypyrrolidone (polyvinylpolypyrrolidone).In one embodiment, label contains this super-disintegrant up to about 5 % by weight.
The example of antioxidant includes but not limited to tocopherol, xitix, Sodium Pyrosulfite, butylhydroxy toluene, butylated hydroxy anisole, ethylenediamine tetraacetic acid (EDTA) and edetate, and their mixture.The example of sanitas includes but not limited to citric acid, tartrate, lactic acid, oxysuccinic acid, acetic acid, phenylformic acid and Sorbic Acid, and their mixture.
In one embodiment, the mean thickness discharging coating layer is immediately at least 50 microns, such as, from about 50 microns to about 2500 microns (such as from about 250 microns to about 1000 microns).In one embodiment, as by measured by the weight and volume of this specific layer, to discharge coating layer immediately and be usually compressed into density and exceed about 0.9g/cc.
In one embodiment, discharge coating layer immediately and comprise first part and second section, wherein at least one part contains the second pharmaceutical activity medicament.In one embodiment, described two parts contact with each other at the central shaft of tablet.In one embodiment, first part comprises the first pharmaceutical activity medicament and second section comprises the second pharmaceutical activity medicament.
In one embodiment, the first pharmaceutical activity medicament is contained and second section contains the second pharmaceutical activity medicament in first part.In one embodiment, a described part contains the 3rd pharmaceutical activity medicament.In one embodiment, described part comprises and second of contained same medicine active agents in label the release portion immediately.
In one embodiment, coating part, before being introduced into coated label, is first made into the intermingling material done.In another embodiment, coating part comprises the dry granulation containing pharmaceutical activity medicament.
The preparation with above-mentioned different pharmaceutical releasing mechanism can be combined into containing single or multiunit final formulation.Multiunit example comprises multilayer tablet, the capsule of the sheet containing solid or liquid form, pearl or particle.Typically, immediate release formulation comprises compressed tablets, gel, film, coating layer, can be encapsulated in liquid in example gel capsule and particle.Method much for the preparation of coating layer, covering or bound drug is all as known in the art.
The unit of releasing dosage immediately in formulation, the i.e. outer formulation of tablet, pearl containing multi-medicament, particle or piller or coated core, the active agents containing treatment significant quantity and conventional drug excipient.The described unit of releasing dosage immediately can by or be not wrapped by, and can with or do not carry out with delayed release dosage device mixing (being mixed into containing the particle discharging medicine immediately, piller or pearl with containing the particle of delayed release medicine or the encapsulation mixture of pearl).
Delayed release preparation is made into diffusion or osmosis system usually, such as, as at " Remington-The Science andPractice of Pharmacy " (20th.Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000).Diffusion system is made up of one, container and matrix in two kinds of devices usually, and it is for known in the art and described in having.Matrix device is usually by being compressed into Tabules to prepare together with slow dissolve polymer carrier by medicine.
By utilizing coated or compression process coated immediate release layer on delayed release core, or such as containing postponing and discharging in the multiple-unit system of capsule of pearl immediately, will can join in delayed release system by release portion immediately.
Delayed release dosage particles is by with being insoluble to stomach sour environment but the coated solid dosage of film being dissolved in the polymkeric substance of small intestine neutral environment makes.Delayed release dosage device can such as by preparing with the coating material coating medicine selected or drug containing composition.Described drug containing composition can be the tablet added in capsule, the tablet being used as inner core in " coated core " formulation, or add in tablet or capsule containing the pearl of multi-medicament, piller or particle.
Pulsed release dosage form is for simulating repeatedly dosing process but not repeating dosing, and dosing frequency usually can be made to reduce the formulation of at least twice as compared to the medicine of traditional dosing form (such as, as the traditional solid dosage forms of solution or instant drug release).The feature of pulse release process is, without release (time of lag) or decrement release in for some time, then carries out quick medicament release.
Often kind of formulation all contains the active agents for the treatment of significant quantity.Simulate in the embodiment of the formulation of dosing process twice daily at one, the about 30wt.% to 70wt.% of active agents total amount in formulation is released in first time pulse, preferred 40wt.% to 60wt.%, and in second time pulse, correspondingly release the about 70wt.% to 30wt.% of active agents total amount in formulation, preferred 60wt.% to 40wt.%.For the formulation simulating dosing process twice daily, second time pulse preferably after administration about 3 hours to being less than 14 hours, more preferably littlely to discharge in 12 hours about 5.
Another kind of formulation contains compressed tablets or capsule, and described compressed tablets or capsule comprise the unit of releasing dosage immediately, delayed release dosage device and optional second delayed release dosage device containing medicine.In this formulation, immediately releasing dosage unit contain after oral administration, much discharge medicine immediately in a large number pearl, particle, piller to be to provide predose.Delayed release dosage device contains a lot through coated pearl or particle, its after oral administration about 3 little up to 14 hours release medicines to provide second-dose.
In order to use through skin (such as local), can prepare sterile, aqueous or the partially aqueous solution (concentration is generally about 0.1% to 5%) of dilution, other side is similar to injection liquid mentioned above.
For a person skilled in the art, preparing various is known containing the compound of one or more formula I of specified quantitative or the method for the pharmaceutical composition of other active agents, or will be apparent according to present disclosure.For the example of the method for pharmaceutical compositions, refer to Remington's Pharmaceutical Sciences (Mack PublishingCompany, Easton, Pa., 19th Edition (1995)).
In addition, in certain embodiments, the theme composition of the application can be lyophilized or pass through another suitable dry technology, such as spraying dry.Described theme composition can be disposable employed, or part can be divided into multiple less dosage according to the rate of release of composition and required dosage and use under Different periods.
The preparation that can be used for institute's supplying method herein comprises the preparation being applicable to mouth, nose, locally (comprise cheek and sublingual), rectum, vagina, spraying and/or parenteral administration.Described preparation can present with the form of unitary dose easily, and can be prepared by any method known in pharmacy field.The amount that can be combined the theme composition making single dose with solid support material can change according to connecing subject object and specific dispenser pattern.
The method preparing these preparations or composition comprises makes theme composition and carrier and the optional step that combines of one or more ancillary components.Generally speaking, described preparation by make theme composition and liquid vehicle, the solid carrier ground or both evenly and be fully combined, then if necessary, make the formed product of gained to prepare.
The compound of formula I described herein can be used with the form of suction or spray agent.Described suction or spray agent can comprise one or more medicaments that can be used in anapnotherapy, such as adjuvant, diagnostic reagent, photographic developer or therapeutical agent.Final spray agent such as can contain the medicine of 0.005-90%w/w (as 0.005-50%, 0.005-5%w/w or 0.01-1.0%w/w) relative to the gross weight of said preparation.
For in the solid dosage (capsule, tablet, pill, drageeing, powder and particle etc.) of oral administration, make theme composition and one or more pharmaceutically acceptable carrier and/or following in any one mix mutually: (1) weighting agent or extender, as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) tackiness agent, as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or Sudan Gum-arabic; (3) wetting Agent for Printing Inks, as glycerine; (4) disintegrating agent, as agar, calcium carbonate, potato or tapioca (flour), alginic acid, specific silicate and sodium carbonate; (5) retarding solvent, as paraffin; (6) absorption enhancer, as quaternary ammonium compound; (7) wetting agent, as acetyl alcohol and glyceryl monostearate; (8) absorption agent, as kaolin and wilkinite; (9) lubricant, as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture; And (10) tinting material.When capsule, tablet and pill, described pharmaceutical composition also can comprise buffer reagent.The solids composition of similar type can also be used as the weighting agent in the gelatine capsule using the soft of the polyoxyethylene glycol of lactose and high molecular etc. and hard to fill.
Liquid dosage form for oral administration comprises pharmaceutically useful emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except theme composition, described liquid dosage form can containing inert diluent conventional in this area, such as water or other solvent, solubilizing agent and emulsifying agent, such as ethanol, Virahol, diethyl carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1, the fatty acid ester of 3-butyleneglycol, oils (particularly cottonseed, corn, peanut, sunflower seeds, soybean, olive, castor-oil plant and sesame oil), glycerine, tetrahydrofurfuryl carbinol, polyoxyethylene glycol and sorbitanic, and their mixture.
Except theme composition, suspensoid can contain suspension agent, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol (polyoxyethylene sorbitol) and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminium hydroxide, wilkinite, agar and tragacanth, and their mixture.
Preparation for rectum or medicine applicating vaginal can be rendered as suppository, this suppository is prepared by being mixed by non-irritating carriers suitable to theme composition and one or more, described non-irritating carriers comprises such as theobroma oil, polyoxyethylene glycol, suppository wax or salicylate, and be at room temperature liquid under body temperature for solid, thus will dissolve in suitable body cavity and discharge encapsulated compound and composition.The preparation being suitable for medicine applicating vaginal also comprises vaginal suppository, tapon, emulsifiable paste, gel, paste, foam or spray agent containing applicable carrier known in this area.
Formulation for applied dermally comprises powder, sprays, ointment, paste, emulsifiable paste, washing lotion, gel, solution, paster and inhalation.Can by theme composition aseptically with pharmaceutically acceptable carrier, and any sanitas, buffer reagent or propelling agent that may need mixes.For transcutaneous applications, mixture can comprise lipotropy and hydrophilic radical to realize required water-soluble and transport properties.
Except theme composition, ointment, paste, emulsifiable paste and gel can containing other carriers, such as animal and plant fat, oil, wax, paraffin, starch, tragacanth, derivatived cellulose, polyoxyethylene glycol, silicone resin, wilkinite, silicic acid, talcum and zinc oxide, or their mixture.Except theme composition, powder and sprays can contain vehicle as lactose, talcum, silicic acid, aluminium hydroxide, Calucium Silicate powder and polyamide powder, or the mixture of these materials.Sprays can also in addition containing conventional propelling agent, such as Chlorofluorocarbons (CFCs) and volatilely do not replace hydrocarbon (as butane and propane).
The method being carried out delivering compositions by transdermal patch is as known in the art.Exemplary paster and paster delivering method at U.S. Patent number 6,974,588,6,564,093,6,312,716,6,440,454,6,267,983,6,239,180 and 6,103, be described in 275.
In another embodiment, transdermal patch can comprise: the substrate sheet comprising composite membrane, and described composite membrane is formed by the resin combination containing 100 weight part polyvinyl chloride-polyurethane compositions and 2-10 parts by weight of styrene-ethylene-butylene, Styrene multipolymer; At the first bonding coat of described composite membrane side; The polyakylene terephthalate's film on composite membrane side is pasted onto by described first bonding coat; Comprise saturated polyester resin and the prime coat formed on the surface at described polyakylene terephthalate's film; And the second bonding coat formed on described prime coat, this second bonding coat comprises the styrenic-diene-styrene block copolymer containing pharmaceutical agent.The method preparing above-mentioned substrate sheet comprises: prepare above-mentioned resin combination; By rolling process, this resin combination is molded as composite membrane; Then by bonding coat, polyakylene terephthalate's film is pasted onto on the side of this composite membrane, forms substrate sheet thus; And on the outside surface of described polyakylene terephthalate's film, form the prime coat comprising saturated polyester resin.
The paster of another kind of type comprises directly to be introduced medicine in pharmaceutically acceptable tackiness agent, and is combined in by the binder layer of this drug containing on suitable substrate film (such as polyester substrate film).Described medicine should not affect the character of tackiness agent, and the concentration of simultaneously sending required clinical dosage exists.
Transdermal patch can be passive or active.Passive transdermal drug delivery systems (such as Nicotine, oestrogenic hormon and nitroglycerine paster) available at present sends small-molecule drug.Protein and peptide drug much newly developed is excessive and cannot by being sent by percutaneous plaster, and they can adopt the macromolecular drug technology of such as electron assistant (iontophoresis) to send.
Iontophoresis is used for improving the technology of ionization material by the flux of film by applying electric current.An example of iontophoretic film provides in U.S. Patent number 5,080,646 to Theeuwes.Iontophoresis strengthens the transdermal dominant mechanism of molecule: (a) repels charged ion from the electrode of identical charges; B () osmosis, when applying electric field as the response of gegenion preferred path, by the convective motion of charged hole generation solvent; Or the perviousness of skin (c) is improved owing to applying electric current.
In some cases, may need to use with the form of test kit, described test kit can comprise the container for holding independent composition, such as sectional bottle or the Foilpac (divided foil packet) that separates.Typically, what test kit comprised independent component uses explanation.When independent component is preferably used, uses with different dosing intervals or need as prescriber to carry out titration to each component of composition with different formulations (such as oral and parenteral), the form of test kit is especially favourable.
The example of this test kit is so-called Blister Package.Blister Package known by people, and is widely used in the packaging of pharmaceutical unit dosage forms (Tablet and Capsula etc.) in Packaging Industry.Blister Package is made up of the material of a slice relative rigid usually, and it can be transparent plastic material paper tinsel that described material is coated with.
For suppressing the method and composition of carbonic anhydrase activity.Wherein, provide a kind for the treatment of to show as the complication of carbonic anhydrase enzymic activity or the method for disease herein, comprise the compound of the formula I to patient therapeuticallv's significant quantity in need:
Wherein,
R
1represent independently of one another D, H,
R
2represent independently of one another
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d is H, D ,-OH ,-OD, C independently of one another
1to C
6alkyl ,-NH
2or-COCH
3;
R
3represent H, D, methyl, F, Cl, ethyl or ethanoyl independently.
The method of use formula I:
The present invention also comprises the method for the treatment of following disease: glaucoma, epileptic seizures, idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and endocranium expansion, congestive heart failure, drug-induced oedema, diuresis, limb vessel blocks the intermittent claudication caused, and vascular dementia, improve blood flow by peripheral blood vessel and therefore contribute to the blood circulation in four limbs (i.e. intermittent claudication) and brain (therefore using in vascular dementia), venous disease, Peyronie's disease, nervosa injures, apoplexy, sickle cell disease, what high mountain caused feels sick and headache (altitude sickness), nonalcoholic fatty liver disease and alcoholic liver disease, the fibrosis lesion caused by the radiotherapy of mammary cancer, cytokines release syndrome, type 1 diabetes and diabetes B, asthma, bronchiectasis, ephrosis, kidney is protected, blood vessel ischemic, neuroprotective, vasorelaxation, Alzheimer, dementia, apoplexy, the treatment of endometriosis.
Preparation method
To list with following example for the preparation of the example of the synthesis path of formula I and be summarized as scheme 1.
Scheme-1:
Step-1: the synthesis of compound 2:
Add the potassium hydroxide of 85% of 301g (5.36 moles) in the suspension of the 2-amido-1,3,4-thiadiazoles-5-mercaptan 1 containing 608g (4.56 moles) in the water of 456cc, obtain brown solution.Making it clarify this solution Darco (g-60) (for filtering), then using 1300cc alcohol dilution.Adding Benzyl Chloride (575g, 4.56 moles) fast when stirring, forming dense thick reaction mixture immediately and stirring, being cooled to 0 DEG C, keeping 30 minutes, then with the dilution of 2L cold water.Removing solid compounds 2 by filtering, then being used water and washed with diethylether.
Step-2: the synthesis of compound 3:
Suspension containing 4.0 mole compounds 2 and 1500cc acetic acid in the diacetyl oxide of 4.4 moles is heated to 60 DEG C, keeps 10 minutes, obtain settled solution.This solution is slowly cooled, and adds 2L water when crystal occurs first.Suspension is cooled to 0 DEG C, by collecting by filtration solid compounds 3.
Step-3: the synthesis of compound 4:
By in 50% acetic acid aqueous solution of 40cc containing the suspension of 0.50g compound 3 chlorination half an hour at 50 DEG C.After this time, filter out solid, then this solid is joined in the liquefied ammonia of 20cc.Evaporated at ammonia and after the dried residue of dilute with water gained, the aqueous solution filtered.After hcl acidifying, obtain solid compounds 4, fusing point is 260 DEG C.
Step-4: the synthesis of compound 5:
By the vlil of compound 4 (15g, 67.5mmol) in the mixture of ethanol (100mL) and concentrated hydrochloric acid (30mL) 4.5 hours, solid deposited lentamente during this period.After solution cooling, in a vacuum except desolventizing, and solid residue is dissolved in H again
2in O (75mL).Alkalize solution 5M sodium hydroxide to pH 7, the product of precipitation, by collecting by filtration, then recrystallization in water, obtains product 5 (10.6g, 58.9mmol, 87%), mp 228-229 DEG C (lit15mp230-232 DEG C).
Step-5: the synthesis of compound 7:
Under argon gas, at room temperature, in the chloroformic solution of the 6ml drying of the EPA 6 containing 605mg, add the oxalyl chloride of 0.25ml.Mixture reaction 2 hours.From reaction mixture, remove chloroform and remaining oxalyl chloride by distillation under a reduced pressure, obtain EPA acyl chlorides 7, and this compound is directly used in next step.
Step-6: the synthesis of compound 8:
At room temperature, the DMF solution (10ml) of the drying containing compound 5 (2mmol) is suspended in Anhydrous potassium carbonate (2.2mmol).In 15 minutes, in this reaction mixture, be dropwise added in the DMF solution of the EPA acyl chlorides 7 of the 2mmol containing above-mentioned preparation in 2ml DMF solution, and this mixture is heated to 100 DEG C, keep 8 hours.By filtering, from reaction mixture, removing insolubles, then in filtrate, add water.By mixture ethyl acetate (2x10ml) extracting twice.The organic layer washed with water of this extraction liquid, and use anhydrous sodium sulfate drying.Then, solvent under reduced pressure distills removing, and the resistates obtained, by silica gel chromatography, obtains pure compound 8.
Term " sample " refers to humoral sample, refers to separated cell sample or refers to the sample from tissue or organ.Humoral sample can obtain by knowing technology, and preferably includes blood, blood plasma, serum or urine sample, more preferably comprises blood, blood plasma or serum sample.
equivalent
Present disclosure provides the composition and method that are used for the treatment of and show as carbonic anhydrase enzymic activity disease and complication thereof among other things.Although discussed the specific embodiments of present disclosure, above specification sheets has only played illustrative effect and has not played restricted effect.Once browsing this specification sheets, many modification of system and method herein will become apparent for a person skilled in the art.The full breadth of system and method required for protection, should by referring to the full breadth of claim together with its equivalent, and this specification sheets is determined together with this kind of modification.
quote and be incorporated to
As being specifically incorporated to the same by reference with being appointed as individually by each independent publication or patent, whole publication mentioned herein and patent, comprise the above project enumerated, and its full content is incorporated to herein thus by reference.When there is conflict, the application, comprises done any restriction herein, by its claimed scope of control.
Claims (17)
1. a compound of formula I, or its pharmacologically acceptable salt, hydrate, polymorphic form, solvate, prodrug, enantiomer or steric isomer:
Wherein,
R
1represent D, H independently,
R
2represent independently of one another
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d is H, D ,-OH ,-OD, C independently of one another
1to C
6alkyl ,-NH
2or-COCH
3;
R
3represent H, D, methyl, F, Cl, ethyl or ethanoyl independently.
2. one kind comprises the compound of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
3. pharmaceutical composition according to claim 2, this pharmaceutical composition be formulated with by oral administration, delayed release or sustained release, thoroughly mucous membrane, syrup, locally, parenteral administration, injection, subcutaneous, oral liquid, rectal administration, cheek dispenser or transcutaneous applications, significant quantity is applied to patient in need to treat the potential cause of disease.
4. be used for the treatment of by the method for carbonic anhydrase activity as the disease of the potential cause of disease, the method comprises the pharmaceutical composition of the claim 3 of significant quantity is applied to patient in need.
5. prepare the compound of claim 4 and composition, be wherein selected from glaucoma by carbonic anhydrase activity as the disease of the potential cause of disease, epileptic seizures, idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and endocranium expansion, congestive heart failure, drug-induced oedema, diuresis, limb vessel blocks the intermittent claudication caused, and vascular dementia, osteoporosis, improve blood flow by peripheral blood vessel and therefore contribute to the blood circulation in arms and legs (i.e. intermittent claudication) and brain (therefore using in vascular dementia), venous disease, nervosa injures, apoplexy, sickle cell disease, what high mountain caused feels sick and headache (altitude sickness), nonalcoholic fatty liver disease and alcoholic liver disease, the fibrosis lesion caused by the radiotherapy of mammary cancer, cytokines release syndrome, type 1 diabetes and diabetes B, asthma, bronchiectasis, ephrosis, kidney is protected, vascular ischaemia, neuroprotective, vasorelaxation, Alzheimer, dementia, apoplexy, the treatment of endometriosis.
6. the molecular bond of an acetazolamide and LA.
7. the molecular bond of an acetazolamide and timnodonic acid.
8. the molecular bond of an acetazolamide and docosahexenoic acid.
9. the molecular bond of an acetazolamide and acetylcysteine.
10. the molecular bond of an acetazolamide and salsalate.
The molecular bond of 11. 1 kinds of acetazolamide and fumaric acid.
The molecular bond of 12. 1 kinds of methazolamides and timnodonic acid.
The molecular bond of 13. 1 kinds of methazolamides and docosahexenoic acid.
The molecular bond of 14. 1 kinds of methazolamides and acetylcysteine.
The molecular bond of 15. 1 kinds of methazolamides and salsalate.
The molecular bond of 16. 1 kinds of methazolamides and fumaric acid.
The molecular bond of 17. 1 kinds of methazolamides and LA.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1810/CHE/2012 | 2012-05-08 | ||
| IN1810CH2012 | 2012-05-08 | ||
| PCT/IB2013/050899 WO2013167994A1 (en) | 2012-05-08 | 2013-02-03 | Compositions and methods for suppression of carbonic anhydrase activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104364241A true CN104364241A (en) | 2015-02-18 |
Family
ID=54193691
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380030632.6A Pending CN104364241A (en) | 2012-05-08 | 2013-02-03 | Compositions and methods for suppression of carbonic anhydrase activity |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP2847175A4 (en) |
| JP (1) | JP2015520748A (en) |
| CN (1) | CN104364241A (en) |
| AU (1) | AU2013257715B2 (en) |
| CA (1) | CA2872978A1 (en) |
| SG (1) | SG11201407317SA (en) |
| WO (1) | WO2013167994A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2847197A4 (en) * | 2012-05-07 | 2015-11-04 | Cellix Bio Private Ltd | Prodrugs of anti-platelet agents |
| SG11201407328TA (en) * | 2012-07-03 | 2014-12-30 | Cellix Bio Private Ltd | Compositions and methods for the treatment of moderate to severe pain |
| AU2015212733B2 (en) * | 2014-02-03 | 2018-06-07 | Eidgenoessische Technische Hochschule Zurich | Small molecule drug conjugates |
| WO2018211474A1 (en) | 2017-05-19 | 2018-11-22 | Trudell Medical International | Positive expiratory pressure device |
| CN108969521A (en) * | 2017-05-31 | 2018-12-11 | 邱正廸 | The purposes of acetazolamide treatment cerebral hemorrhage |
| USD903097S1 (en) | 2018-05-18 | 2020-11-24 | Trudell Medical International | Mask |
| USD874064S1 (en) | 2018-05-18 | 2020-01-28 | Trudell Medical International | Mask |
| USD893806S1 (en) | 2018-11-09 | 2020-08-18 | Trudell Medical Internationl | Mask and shroud |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991014430A1 (en) * | 1990-03-19 | 1991-10-03 | Research Corporation Technologies, Inc. | Topically active ocular thiadiazole sulfonamide carbonic anhydrase inhibitors |
| WO1993005029A1 (en) * | 1991-08-28 | 1993-03-18 | University Of Iowa Research Foundation | Topical ophthalmic imino substituted 2-imino-3-methyl-δ4-1,3,4-thiadiazoline-5-sulfonamides carbonic anhydrase inhibitors |
| CN101921245A (en) * | 2010-08-30 | 2010-12-22 | 中国人民解放军军事医学科学院卫生学环境医学研究所 | Sulfonamides compound for inhibiting carbonic anhydrase II and synthesis method and application thereof |
| WO2010147666A1 (en) * | 2009-06-19 | 2010-12-23 | Memorial Sloan-Kettering Cancer Center | Compounds useful as carbonic anhydrase modulators and uses thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2554816A (en) * | 1950-04-04 | 1951-05-29 | American Cyanamid Co | Heterocyclic sulfonamides and methods of preparation thereof |
| US4134792A (en) * | 1976-12-06 | 1979-01-16 | Miles Laboratories, Inc. | Specific binding assay with an enzyme modulator as a labeling substance |
| NZ192673A (en) * | 1979-02-02 | 1984-07-06 | Merck & Co Inc | Ophthalmic compositions for lowering intraocular pressure |
| US5157044A (en) * | 1983-02-04 | 1992-10-20 | University Of Iowa Research Foundation | Analogs of carbonic anhydrase inhibitors and their use as topical IOP inhibitors |
| CA2092565A1 (en) * | 1990-09-28 | 1992-03-29 | Robert T. Sims | Ibuprofen-diuretic combinations |
| US6051576A (en) * | 1994-01-28 | 2000-04-18 | University Of Kentucky Research Foundation | Means to achieve sustained release of synergistic drugs by conjugation |
| US6576636B2 (en) * | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
| GB0821537D0 (en) * | 2008-11-25 | 2008-12-31 | Union Life Sciences Ltd | Therapeutic target |
| EP2585066B1 (en) * | 2010-06-24 | 2018-09-26 | Alkermes Pharma Ireland Limited | Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
-
2013
- 2013-02-03 EP EP13787577.9A patent/EP2847175A4/en not_active Withdrawn
- 2013-02-03 CN CN201380030632.6A patent/CN104364241A/en active Pending
- 2013-02-03 WO PCT/IB2013/050899 patent/WO2013167994A1/en active Application Filing
- 2013-02-03 JP JP2015510896A patent/JP2015520748A/en active Pending
- 2013-02-03 SG SG11201407317SA patent/SG11201407317SA/en unknown
- 2013-02-03 CA CA2872978A patent/CA2872978A1/en not_active Abandoned
- 2013-02-03 AU AU2013257715A patent/AU2013257715B2/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991014430A1 (en) * | 1990-03-19 | 1991-10-03 | Research Corporation Technologies, Inc. | Topically active ocular thiadiazole sulfonamide carbonic anhydrase inhibitors |
| WO1993005029A1 (en) * | 1991-08-28 | 1993-03-18 | University Of Iowa Research Foundation | Topical ophthalmic imino substituted 2-imino-3-methyl-δ4-1,3,4-thiadiazoline-5-sulfonamides carbonic anhydrase inhibitors |
| WO2010147666A1 (en) * | 2009-06-19 | 2010-12-23 | Memorial Sloan-Kettering Cancer Center | Compounds useful as carbonic anhydrase modulators and uses thereof |
| CN101921245A (en) * | 2010-08-30 | 2010-12-22 | 中国人民解放军军事医学科学院卫生学环境医学研究所 | Sulfonamides compound for inhibiting carbonic anhydrase II and synthesis method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| MONICA ILIES ET AL.: "Carbonic Anhydrase Inhibitors: Sulfonamides Incorporating Furan-, Thiophene- and Pyrrole-carboxamido Groups Possess Strong Topical Intraocular Pressure Lowering Properties as Aqueous Suspensions", 《BIOORGANIC & MEDICINAL CHEMISTY》 * |
| TURAN BAYRAM ET AL.: "Purification of carbonic anhydrase from dog erythrocytes and investigation of in vivo inhibition by various compounds", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
| UMIT CAKIR ET AL.: "In Vitro Inhibition Effects of some New Sulfonamide Inhibitors on Human Carbonic Anhydrase I and II", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2015520748A (en) | 2015-07-23 |
| AU2013257715B2 (en) | 2016-05-05 |
| AU2013257715A1 (en) | 2014-11-27 |
| EP2847175A1 (en) | 2015-03-18 |
| CA2872978A1 (en) | 2013-11-14 |
| SG11201407317SA (en) | 2014-12-30 |
| WO2013167994A1 (en) | 2013-11-14 |
| EP2847175A4 (en) | 2016-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104364241A (en) | Compositions and methods for suppression of carbonic anhydrase activity | |
| CN104603090A (en) | Compositions and methods for the treatment of metabolic syndrome | |
| US10201519B2 (en) | Stabilized pediatric suspension of carisbamate | |
| EP2046727B1 (en) | Positively charged water-soluble prodrugs of diclofenac with very fast skin penetration rate | |
| EP2623495B1 (en) | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate | |
| DK2041068T3 (en) | POSITIVELY CHARGED, WATER SOLUBLE PRODRUGS OF IBUPROFEN WITH VERY FAST SKIN PENETRATION SPEED | |
| CN104583182A (en) | Compositions and methods for treatment of mucositis | |
| EP2084165B1 (en) | Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate | |
| CN104603100A (en) | Compositions and methods for treatment of inflammatory bowel disease | |
| CN104603096A (en) | Compositions and methods for treatment of neuromuscular disorders and neurodegenerative disorders | |
| CN101795691A (en) | Salts of potassium atp channel openers and uses thereof | |
| CN104603097A (en) | Compositions and methods for the treatment of multiple sclerosis | |
| CN105612155A (en) | Compositions and methods for the treatment of local pain | |
| BG104568A (en) | Pharmaceutical compositions containing sibutramine and orlistat | |
| CN110167542A (en) | Nitrite, pharmaceutical composition and the application method of 1,1- melbine | |
| CN104350041A (en) | Compositions and methods for the treatment of neurological disorders | |
| CN104583162A (en) | Compositions and methods for the treatment of moderate to severe pain | |
| CN104797568A (en) | Compositions and methods for the treatment of neurological disorders | |
| CN104364230A (en) | Compositions and methods for the treatment of diabetes | |
| JP2003503349A (en) | Pharmaceutical composition containing sibutramine and orlistate | |
| CN110167548A (en) | For treating the composition and method of Polyp of gastrointestinal tract | |
| CN104379589A (en) | Prodrugs of anti-platelet agents | |
| CN109640965A (en) | For treating the composition and method of irritable bowel syndrome | |
| CN104812737A (en) | Compositions and methods for treatment of hyperglycemia | |
| CN104364231A (en) | Compositions and methods for treatment of inflammation and lipid disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150218 |
|
| WD01 | Invention patent application deemed withdrawn after publication |