WO2009050252A1 - Novel sulfamate compounds for medical use - Google Patents
Novel sulfamate compounds for medical use Download PDFInfo
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- WO2009050252A1 WO2009050252A1 PCT/EP2008/064007 EP2008064007W WO2009050252A1 WO 2009050252 A1 WO2009050252 A1 WO 2009050252A1 EP 2008064007 W EP2008064007 W EP 2008064007W WO 2009050252 A1 WO2009050252 A1 WO 2009050252A1
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- PJLYRKWWIUPULR-UEJVZZJDSA-N CC1(C)C2[C@H](COS(N)(=O)=O)CCC1C2 Chemical compound CC1(C)C2[C@H](COS(N)(=O)=O)CCC1C2 PJLYRKWWIUPULR-UEJVZZJDSA-N 0.000 description 1
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- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
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- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
Definitions
- This invention relates to the fields of pharmaceutical and organic chemistry, and provides new sulfamate compounds, medicaments comprising these compounds, pharmaceutical compositions comprising these compounds, and processes for the preparation of these compounds.
- the invention also concerns the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect.
- EP 0 138 441 discloses sulfamate derivatives of the following formula
- beta-D- fructopyranose sulfamates exhibit anticonvulsant activities analogously to that of phenytoin.
- Topiramate of formula below is a known representative, studied for the treatment of a variety of medicinal conditions such as epilepsy in both children and adults.
- Topiramate is also indicated for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays).
- Topiramate is also Food and Drug Administration (FDA) approved for, and now most frequently prescribed for the prevention of migraines.
- FDA Food and Drug Administration
- Topiramate has been used by psychiatrists to treat bipolar disorder although it is not FDA approved for this purpose.
- This drug has been investigated for use in treatment of obesity especially to aid in the reduction of binge eating, and also as a possible treatment for alcoholism.
- the drug is also used in clinical trials to treat post traumatic stress disorder.
- a pilot study suggests that Topiramate is possibly effective against infantile spasm. In May 2006 the U.S.
- Topiramate National Institutes of Health web site http://www.clinicaltrials.gov listed several studies sponsored by Ortho- McNeil which propose to examine the use of Topiramate on migraine, cluster and severe headaches within various demographics.
- Other off-label and investigational uses of Topiramate include: treatment of bulimia nervosa, obsessive-compulsive disorder, smoking cessation, and treatment of neuropathic pain.
- certain novel sulfamates and their pharmaceutically acceptable salts, hydrates and solvates are suitable for the treatment and/or prophylaxis of various diseases or conditions, such as obesity, diabetes mellitus type I, diabetes mellitus type II, metabolic syndrome, syndrome X, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, hypertension, in particular arterial hypertension, dyslipoproteinaemia, in particular as hypertriglyceridaemia accompanied by dyslipoproteinaemia occurring with/without lowered HDL-cholesterol; hyperuricaemia; asthma, glucose metabolism, in particular insulin resistance, hyperglycaemea and/or glucose intolerance, neuroprotection, Parkinson Disease, Alzheimer Disease, analgesia, angina, arrhythmia, coronary spasm, peripheral vascular diseases or conditions, such as obesity
- R1 and R2 are independently selected from the group consisting of: hydrogen, Ci to C 8 alkyl, C 4 to Cio cycloalkyl, aryl and heteroaryl, of which alkyl and cycloalkyl are optionally substituted with at least one substitutent Y and of which aryl and heteroaryl are optionally substituted with at least one substitutent Z, or wherein R1 and R2 form together a 5 or 6-membered ring which may additionally contain from 1 to 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and sulphur and which 5 or 6-membered ring is optionally substituted with at least one substituent Y;
- R3 is selected from the group consisting of: (1S,2S,5S)-6,6-dimethyl-bicyclo[3.1.1]hept-2- yl; (1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl; (1 S,2R,5S)-6,6
- Z is selected from the group consisting of: alkyl, alkoxy, thioalkyl, halogen, aryl, CO-aryl, CN, heteroaryl and carboxylalkyl; and its pharmaceutically acceptable salts, hydrates and solvates.
- the invention further relates to medicaments comprising compounds of Formula I, to pharmaceutical compositions comprising compounds of Formula I, and processes for the preparation of compounds of Formula I.
- the invention also concerns the uses of compounds of Formula I and of compositions comprising compounds of Formula I, particularly their use in administering them to patients to achieve a therapeutic effect.
- the invention particularly relates to compounds of Formula I wherein R1 and R2 are independently selected from the group consisting of: hydrogen and Ci to Cs alkyl, wherein Ci to C 8 alkyl are optionally substituted with at least one substituent Y selected from the group consisting of: CrC 4 alkyl, d-C 4 alkoxy, CrC 4 thioalkyl, C 6 -Ci 2 aryl, CO- C 6 -
- n is 1 or 2, more preferably n is 1.
- the compound is selected from the group consisting of [(1 S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methylsulfamate, [(1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methylsulfamate, [(1 S,2S,5S)-6,6-di- methylbicyclo[3.1.1]hept-2-yl]ethylsulfamate, [(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept- 2-yl]methylsulfamate, and (1 R,4S)-bicyclo-[2.2.1]hept-2-yl-methylsulfamate, and (4S)- bicyclo[2.2.1]hept-5-en-2-ylmethylsulfamate.
- the most preferred compound of the present invention is [(1S,2S,5S,6-d
- the invention relates to a medicament, comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising: A) a pharmaceutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient; and;
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- diabetes mellitus type I diabetes mellitus type II, metabolic syndrome, syndrome X, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, hypertension, in particular arterial hypertension, dyslipoproteinaemia, in particular as hypertriglyceridaemia accompanied by dyslipoproteinaemia occurring with/without lowered HDL-cholesterol; hyperuricaemia; asthma, glucose metabolism, in particular insulin resistance, hyperglycaemea and/or glucose intolerance, neuroprotection, Parkinson Disease, Alzheimer Disease, analgesia, angina, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain, including neuropathic pain and
- the compounds of the invention of Formula I as well as the pharmaceutically acceptable salts, hydrates and solvates thereof, have carbonic anhydrases enzyme inhibitory activity. They are useful in treating disorders involving carbonic anhydrase enzymes, or treatable by manipulation of those enzymes.
- the compounds of the invention possess carbonic anhydrases inhibitory activities.
- the inhibiting activities of the compounds of the invention are readily demonstrated, for example, using one or more of the assays described herein or known in the art.
- Isolation and purification of the compounds described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures.
- suitable separation and isolation procedures can be taken from the preparations and examples. However, other equivalent separation or isolation procedures could, of course, also be used.
- the compounds of the present invention contain one or more asymmetric centers and thus occur as single enantiomers, diastereomeric mixtures and individual diastereomers.
- the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers.
- the independent syntheses of these diastereomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
- Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
- Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
- the coupling often consists of the formation of salts using an enantiomerically pure acid or base.
- the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
- the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases: Methods well- known in the art.
- any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
- Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
- some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
- Isotopically-labeled compound of Formula I or pharmaceutically acceptable salts thereof including compounds of Formula I isotopically-labeled to be detectable by PET or SPECT, also fall within the scope of the invention.
- alkyl denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms.
- Representatives of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like.
- the alkyl group contains from 1 to 8 carbon atoms.
- the same carbon content applies to the parent term 'alkane', and to derivative terms such as 'alkoxy' and 'thioalkyl'.
- 'aryl' embraces monocyclic or fused bi- and polycyclic aromatic groups, including but not limited to phenyl, 1 ,2,3,4-tetrahydro-naphtyl, naphthyl, and azulenyl.
- heteroaryl embraces monocyclic or fused bi- and polycyclic aromatic ring systems in which one or more carbon atoms have been replaced by a heteroatom.
- the term 'heteroaryl' includes but is not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1 ,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1 ,2,3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,
- 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc. means containing one or more N, O or S atoms.
- substituted means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same.
- unsubstituted means that the specified group bears no substituents.
- Optionally substituted' means that the alkyl or cycloalkyl groups may or may not be further substituted by one or more groups Y, or, that the aryl group may or may not be further substituted by one or more groups Z.
- 'Crystal form' refers to various solid forms of the same compound, for example polymorphs, solvates and amorphous forms.
- 'Polymorphs' are crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Polymorphism is a frequently occurring phenomenon, affected by several crystallization conditions such as temperature, level of supersaturation, the presence of impurities, polarity of solvent, rate of cooling. Different polymorphs usually have different X-ray diffraction patterns, solid state NMR spectra, infrared or Raman spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
- Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
- 'Solvates' are generally a crystal form that contains either stoichiometric or non-stoichiometric amounts of a solvent. Often, during the process of crystallization some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvate is water, 'hydrates' may be formed.
- the compounds of Formula I and pharmaceutically acceptable salts thereof may exist in the form of a hydrate or a solvate, and such a hydrate and solvate are also encompassed in the present invention.
- Examples thereof include 1/10 hydrate, % hydrate, Vi hydrate, monohydrate, dihydrochloride Vi hydrate, dihydrochloride dihydrate, dihydrochloride 3/2 hydrate, and the like.
- 'Amorphous' forms are noncrystalline materials with no long range order, and generally do not give a distinctive powder X-ray diffraction pattern. Crystal forms in general have been described by Byrn (1995) and Martin (1995).
- the present invention provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally together with one or more pharmaceutically acceptable carriers and/or at least one pharmaceutically acceptable auxiliary substance.
- the carrier(s) and auxiliary substance(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
- this term encompasses a product comprising one or more active ingredients, and an optional carrier and/or auxiliary substances comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and optionally a pharmaceutically acceptable carrier and/or auxiliary substance.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the affinity of the compounds of the invention as inhibitors of carbonic anhydrases was determined as described below. From the potency measured for a given compound of Formula I, one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured inhibition constant, nearly 100% of the carbonic anhydrase enzyme likely will be occupied by the compound. By converting that concentration to mg of compound per kg of patient one obtains a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value.
- the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician.
- total daily dose administration to a patient in single or individual doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily, of total active ingredients of Formula I.
- Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically.
- terapéuticaally effective amount refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating the conditions listed herein.
- the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
- pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids (Berge, 1977). The 'free base' form may be regenerated by contacting the salt with a base or acid, and isolating the parent compound in the conventional matter.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- treatment refers to any treatment of a mammalian, for example human condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease.
- the term 'inhibit' includes its generally accepted meaning which includes prohibiting, preventing, restraining, alleviating, ameliorating, and slowing, stopping or reversing progression, severity, or a resultant symptom.
- the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
- medical therapy intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
- 'Mammals' include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- 'obesity' refers to a condition whereby a person has a Body Mass Index (BMI), calculated as weight per height squared (kg/m 2 ), of at least 30..
- BMI Body Mass Index
- those persons with a BMI of at least 25.9 to less than 30 are considered overweight.
- those persons with normal weight have a BMI of 19.9 to less than 25.9.
- the obesity herein may be due to any cause, whether genetic of environmental.
- Peakshapes in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double quartet), T (triplet), 'df (double triplet), 'd' (doublet), 'dd' (double doublet), 's' (singlet), 'bs' (broad singlet) and 'm' (multiplet).
- Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx software to acquire and reconstruct data. Exact masses were measured as quasimolecular ions [M+H] + .
- Reactions were monitored by using thin-layer chromatography (TLC) on silica coated plastic sheets (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualised by UV light (254 nm) or I 2 . All solvents were distilled freshly prior to use. All other commercially available chemicals were used without further purification.
- TLC thin-layer chromatography
- the process of scheme 1 is performed with compounds of formula II, wherein R1 and R2 are both hydrogen and wherein Hal is chloro.
- the process of scheme I is performed with compounds of Formula III selected from the group consisting of: [(1 S,2S,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-yl]methanol; [(1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]-hept-2- yl]methanol; [(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]ethanol, [(1 S,2R,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-yl]methanol, (1 R,4S)-bicyclo[2.2.1]hept-2-yl-methanol, and (4S)-bicyclo[2.2.1]hept-5-en-2ylmethanol, preferably [(1 S,2S,5S)-6,6-dimethylbicyclo- [3.1.1]hept-2-yl]methanol.
- compounds of Formula III selected from the group
- EXAMPLE 7 FORMULATION OF COMPOUND 1 USED IN ANIMAL STUDIES
- a vehicle containing 1 % methyl hydroxyethyl cellulose (m/m) and 0.1 % wetting agent poloxamer 188 (nonionic polyoxyethylene-polyoxypropylene copolymer) in water.
- the preparation was done in a mortar with pestle and the pH adjusted to neutral condition.
- test compounds of general Formula I in 96 well microplates were diluted with aqua bidest by using an automatic pipettor (CyBiWell ® ). From the different dilution plates, aliquots of 20 ⁇ l were transferred to the 96 well black assay plates with a pipetting station (Tecan Genesis ® ).
- potassium phosphate buffer (20 mM, pH 7.4) was added, and as a third step, 20 ⁇ l of enzyme solution (1 ⁇ M human carbonic anhydrase isoenzyme I from erythrocytes (Sigma-Aldrich) or human carbonic anhydrase Il from erythrocytes (Sigma Aldrich), or recombinant human carbonic anhydrase isoenzyme VB (R&D Systems), dissolved in potassium phosphate buffer) incubated for 60 min at room temperature and the fluorescence signal (Tecan Ultra ® fluorescence reader; excitation wavelength: 280 nm; emission wavelength: 465 nm) read at the end of the preincubation period (FLU-1 ).
- enzyme solution (1 ⁇ M human carbonic anhydrase isoenzyme I from erythrocytes (Sigma-Aldrich) or human carbonic anhydrase Il from erythrocytes (Sigma Aldrich), or recombinant
- the final concentration of carbonic anhydrase I was 10 "7 M/L
- the final concentration of carbonic anhydrase Il was 10 "7 M/L
- the final concentration of carbonic anhydrase VB was 5x10 "6 M/L
- of dansylamide 10 "7 or 2.5x10 “6 or 5x10 "6 respectively and of compounds 10 "7 M/L and 10 "6 M/L.
- Final concentration of DMSO as compound solvent was 0.1 %.
- Each microplate also contained blanks without compound and enzyme, controls without compound and ethoxzolamide (final concentration 5x10 "8 M/L) as validation standard compound. All data reflect single measurements. Data were expressed as % inhibition after calculation by the formula:
- % inhibition 100((1-(FLU-2 cpd -FLU-2 b
- %inhibition data for each compound and the respective final concentrations can be used for IC 50 calculations by using the Prism 4 software.
- Concentration action figures were calculated by applying the Prism algorithm for nonlinear regression (curve-fit): sigmoidal dose response with variable slope and the constraints: top: 100 and bottom 0.
- the test substances of general Formula I listed in Table 1 below showed the %inhibition data given below:
- the test compound of general Formula I was suspended in 1% methyl hydroxyethyl cellulose in water and 0.1% (v/v) of poloxamer 188 and administered by oral gavage at a dose of 50 mg/kg/day twice daily for 3 days. One half of the dose was administered at 8.00-10.00 h; the remaining half of the dose was administered between 14.00-15.0O h.
- test substance caused a decrease of the animals' 72h food intake when compared to control as given in Table 2 below.
- Neurite outgrowth is an important parameter to evaluate the neurotrophic potency of a compound.
- the ability of compound 1 to increase neurite outgrowth was tested in cultures of embyronal hippocampal neurons.
- the hippocampal neurons from pregnant Wistar female rats were dissociated by trypsinization for 30 min at 37°C (trypsin-EDTA, Gibco) in presence of DNAse I (Roche, Meylan).
- the reaction was stopped by addition of medium of Eagle modified by Dulbecco (DMEM; Gibco) with 10% of fetal bovine serum (Gibco).
- the suspension was triturated with a 10-ml pipette and using a 21 G needle syringe and centrifuged at 350 x g for 10 min at room temperature.
- the resulting pellet was re-suspended in culture medium containing Neurobasal medium (Gibco) with 2% of B27 supplement (Gibco) and 2 mM of glutamine (Gibco).
- Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test (Sigma) and seeded on the basis of 30 000 cells per Petri dish (Nunc) precoated with poly-L-lysine (Sigma). Cells were allowed to adhere 2h and maintained in a humidified incubator at 37°C in 5 % CO2-95 % air atmosphere.
- BDNF 50 ng/ml, 3.7 nM
- the test compound was tested in two independent cultures in parallel with control and BNDF cultures. After the 3 days exposure of the neurons to the test compounds, cultures were washed in phosphate-buffered saline (PBS, Gibco) and fixed using 2.5% glutaraldehyde in PBS.
- PBS phosphate-buffered saline
- Several pictures (-80) of cells with neurites without any branching were taken per condition using a digital camera (Coolpix 995; Nikon) fixed on the microscope (Nikon, objective 4Ox). Neurites were outlined on computer screen using imaging software (Image-Pro Plus, France), which automatically calculates the length.
- BDNF treatment was associated with neurite sprouting from hippocampal neurons.
- both cultures were normalized by the respective mean control neurite length there was a BNDF induced increase by 16.4 %.
- the most effective concentration was 30 ⁇ M, which was comparable to the BDNF response.
- mice were administered ECS (rectangular current, 0.4 s, 50 Hz) via corneal electrodes connected to a constant current shock generator (Ugo Basile: Type 7801 ).
- Compound 1 was tested in a dose of 10, 30 and 100 mg/kg administered p.o. 60 minutes before ECS. A group wherein the vehicle is administered orally 60 minutes before the ECS serves a control. Diazepam (8 mg/kg p.o.), administered under the same experimental conditions, served as a positive anti-convulsive reference substance.
- mice Treatment groups of 23 mice were exposed to ECS as follows: Animal n° 1 was exposed to 30 mA of ECS. If animal n° 1 did not convulse (tonic convulsions) within 5 seconds maximum, animal n° 2 was exposed to a higher current of 40 mA . If there were also no convulsions in animal n° 2, then the current was further increase in the following animals (increases of 10 mA) until the first tonic convulsion was observed. Once the first tonic convulsion was observed, the intensity of ECS was decreased by 5 mA for the next animal and then the intensity was decreased or increased by 5 mA from animal to animal depending on whether or the previous animal convulsed or not. The minimum intensity given was 25 mA and the maximum intensity given was 95 mA. The electroconvulsive shock threshold was determined as the mean current administered in the last 20 mice.
- results are represented as percent change from control. The number of deaths is also recorded approximately 30 minutes after the animal has been tested for convulsions. The test was performed blind. A positive percent change indicates an anticonvulsant effect. A negative percent change indicates a proconvulsant effect.
- Compound 1 (10, 30 and 100 mg/kg) administered p.o. 60 minutes before the test dose-dependently and significantly increased the current threshold for inducing tonic convulsions at all 3 doses (+10%, p ⁇ 0.05; +19%, p ⁇ 0.001 and +141 %, p ⁇ 0.001 , respectively).
- the maximal effect obtained at 100 mg/kg po was similar to the effect of the anti-convulsive reference compound diazepam.
- STZ streptozotocin
- mice were induced by intravenous (tail vein) injection of a buffered solution of streptozotocin (STZ; Sigma, L'lsle d'Abeau Chesnes, France) at a dose of 55 mg/kg.
- STZ was prepared in 0.1 mol/l citrate buffer pH 4.5.
- Control group received an equivalent volume of citrate buffer.
- the day of STZ injection was considered as day 0.
- blood glucose level was monitored using a tail incision and a glucosimeter (Glucotrend, Roche Diagnostic GmbH, Germany). Rats with glycemia ⁇ 260 mg/dl were deemed diabetic.
- the groups were: 1.) Non-diabetic control group treated with vehicle, 2.) STZ treated diabetes groups treated with vehicle, 3.) - 5.) STZ treated diabetes groups treated with 10, 30 or 50 mg/kg p.o. of compound
- Compound 1 and the vehicle were given p.o. 1 h before the behavioural assays. Morphine was injected subcutaneously 0.75 h before the behavioural assays.
- Cold bath test on day 10 Each animal was placed on a cold platform (1-4°C). The latency before the first reaction (licking, moving the paws, little leaps) was recorded with a maximal time of 30s. A control animal can support a 20-3Os time before the first reaction in contrast with a STZ-rat which displays a reduced time ( ⁇ 10s) before the first reaction. This test serves as a measure for cold allodynia.
- Warm plate (38°C) test on day 10 Animals were usually tested about 2-3 min after cold bath test. Each animal was placed into a glass cylinder on a warm plate (Slide warmer MH6616; Euromedex; France) adjusted to 38°C. The latency of the first reaction was recorded (licking, moving the paws, little leaps or a jump to escape the heat). Cut off time was set as 30 s. This test serves as a measure for warm allodynia.
- Compound 1 (10, 30 and 50 mg/kg) administered p.o. 1 hour before the test dose- dependently and significantly inhibited the STZ-diabetes-induced cold allodynia in the cold bath test at day 10.
- Compound 1 (30 and 50 mg/kg) administered p.o. 1 hour before the test dose-dependently and significantly inhibited the STZ-diabetes-induced warm allodynia in the warm plate test at day 10.
- compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein.
- Types of pharmaceutical compositions that may be used include, but are not limited to, tablet, pill, lozenge, dragee, troche, hard or soft capsule, powder, cachet, granule, suppository, solution, aqueous or oily suspension, emulsion, lotion, syrup, ointment, gel, paste, cream, foam, vapor, spray, aerosol or transdermal patch, and other types disclosed herein, or apparent to a person skilled in the art from the specification and general knowledge in the art.
- the active ingredient for instance, may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
- the compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
- the pharmaceutical formulation contains at least one compound of Formula I in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
- the total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 100% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w).
- the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
- auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- the mixture may then be processed into granules or pressed into tablets.
- a tablet is prepared using the ingredients below:
- the components are blended and compressed to form tablets each weighing 230 mg.
- the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
- the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
- Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
- Hard gelatin capsules may contain granules of the active ingredients.
- Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
- Hard gelatin capsules can be prepared using the following ingredients: Ingredient Quantity (mg/capsule)
- the above ingredients are mixed and filled into hard gelatin capsules in 120 mg quantities.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Suppositories, each containing 1 mg of active ingredient may be made as follows:
- the active ingredient is passed through a appropriately sized mesh sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
- the mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool.
- Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol.
- An intravenous formulation may be prepared as follows:
- liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents.
- Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use.
- Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
- compositions comprising preferred active compounds for systemic use or topical application.
- Other compounds of the invention or combinations thereof may be used in place of (or in addition to) said compounds.
- concentration of the active ingredient may be varied over a wide range as discussed herein.
- the amounts and types of ingredients that may be included are well known in the art.
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Abstract
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MX2010002869A MX2010002869A (en) | 2007-10-19 | 2008-10-17 | Novel sulfamate compounds for medical use. |
CA2700568A CA2700568A1 (en) | 2007-10-19 | 2008-10-17 | Novel sulfamate compounds for medical use |
EP08838679A EP2207766A1 (en) | 2007-10-19 | 2008-10-17 | Novel sulfamate compounds for medical use |
JP2010529391A JP2011500641A (en) | 2007-10-19 | 2008-10-17 | New sulfamate compounds for pharmaceutical use |
AU2008313663A AU2008313663A1 (en) | 2007-10-19 | 2008-10-17 | Novel sulfamate compounds for medical use |
CN200880107423A CN101801921A (en) | 2007-10-19 | 2008-10-17 | Medicinal new sulfamate compounds thing |
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JP (1) | JP2011500641A (en) |
CN (1) | CN101801921A (en) |
AR (1) | AR070949A1 (en) |
AU (1) | AU2008313663A1 (en) |
CA (1) | CA2700568A1 (en) |
MX (1) | MX2010002869A (en) |
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Cited By (3)
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JP2013508320A (en) * | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | Substituted halophenoxybenzamide derivatives |
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
US11660275B2 (en) | 2018-03-20 | 2023-05-30 | Eisai R&D Management Co., Ltd. | Epilepsy treatment agent |
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US9018260B2 (en) * | 2012-06-21 | 2015-04-28 | Eisai R&D Management Co., Ltd. | Indanesulfamide derivatives |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0138441A2 (en) * | 1983-09-26 | 1985-04-24 | McNeilab, Inc. | Anticonvulsant sulfamate derivatives |
-
2008
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- 2008-10-15 TW TW097139465A patent/TW200927090A/en unknown
- 2008-10-17 JP JP2010529391A patent/JP2011500641A/en active Pending
- 2008-10-17 MX MX2010002869A patent/MX2010002869A/en not_active Application Discontinuation
- 2008-10-17 AU AU2008313663A patent/AU2008313663A1/en not_active Abandoned
- 2008-10-17 CA CA2700568A patent/CA2700568A1/en not_active Abandoned
- 2008-10-17 WO PCT/EP2008/064007 patent/WO2009050252A1/en active Application Filing
- 2008-10-17 RU RU2010119646/04A patent/RU2010119646A/en unknown
- 2008-10-17 EP EP08838679A patent/EP2207766A1/en not_active Withdrawn
- 2008-10-17 CN CN200880107423A patent/CN101801921A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0138441A2 (en) * | 1983-09-26 | 1985-04-24 | McNeilab, Inc. | Anticonvulsant sulfamate derivatives |
Non-Patent Citations (1)
Title |
---|
B.E. MARYANOFF, ET AL.: "Anticonvulsant O-alkyl sulphamates. 2,3:4,5-Bis-O-(1- methylethylidene)-beta-D-fructopyranose sulphamate and related compounds", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 5, May 1987 (1987-05-01), AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, pages 880 - 887, XP000647869, ISSN: 0022-2623 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013508320A (en) * | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | Substituted halophenoxybenzamide derivatives |
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
US11660275B2 (en) | 2018-03-20 | 2023-05-30 | Eisai R&D Management Co., Ltd. | Epilepsy treatment agent |
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CN101801921A (en) | 2010-08-11 |
RU2010119646A (en) | 2011-11-27 |
AU2008313663A1 (en) | 2009-04-23 |
CA2700568A1 (en) | 2009-04-23 |
MX2010002869A (en) | 2010-03-31 |
AR070949A1 (en) | 2010-05-19 |
TW200927090A (en) | 2009-07-01 |
JP2011500641A (en) | 2011-01-06 |
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