WO2007017126A2 - POLYMORPH OF N-PIPERIDINYL-5- (4-CHLOROPHENYL) -1- (2, 4-DICHLOROPHENYL) -4, 5-DIHYDRO-lH-PYRAZOLE- 3 -CARBOXAMIDE AND ITS USE AS A CAMNABINOID RECEPTOR MODULATOR - Google Patents
POLYMORPH OF N-PIPERIDINYL-5- (4-CHLOROPHENYL) -1- (2, 4-DICHLOROPHENYL) -4, 5-DIHYDRO-lH-PYRAZOLE- 3 -CARBOXAMIDE AND ITS USE AS A CAMNABINOID RECEPTOR MODULATOR Download PDFInfo
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- WO2007017126A2 WO2007017126A2 PCT/EP2006/007418 EP2006007418W WO2007017126A2 WO 2007017126 A2 WO2007017126 A2 WO 2007017126A2 EP 2006007418 W EP2006007418 W EP 2006007418W WO 2007017126 A2 WO2007017126 A2 WO 2007017126A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Definitions
- the present invention relates to a polymorph of a substituted pyrazoline, methods for its preparation, medicaments comprising the compound as well as use for the preparation of a medicament for the treatment of humans and animals.
- Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana.
- the most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly ⁇ 9 -THC.
- cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
- CBi and CB 2 are involved in a variety of physiological or pathophysiological processes in humans and animals, e.g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.
- the CBrReceptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type Il diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
- bulimia or obesity
- type Il diabetes non-insulin-dependent diabetes
- compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
- these active substances should be suitable for the modulation of Cannabinoid receptors, more particularly for the modulation of Cannabinoid 1 (CBi) receptors.
- these compounds have a high affinity for cannabinoid receptors, particularly for the CBi-receptor, and that they act as modulators e.g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or reproduction in humans and/or animals, preferably humans including infants, children and grownups.
- the present invention relates to the ⁇ -Polymorph of (rac)-
- An aspect of the present invention is the ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide, which crystallizes as a monoclinic cell with a beta angle of 90.6°.
- An aspect of the present invention is the ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-r ⁇ rboxamide, which shows a standard X-Ray powder diffraction according to figure 3.
- ⁇ -Polymorph shows the beta angle of 90.6° and a standard X-Ray powder diffraction according to figure 3.
- the present invention also provides a process for the preparation of the ⁇ -Polymorph of(rac)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydro-1 H-pyrazole-3-carboxamide, according to which at least one benzaldehyde compound of general formula Il
- G represents an OR group with R being a branched or unbranched C ⁇ - ⁇ alkyl radical or G represents an O ' K group with K being a cation, to yield a compound of formula (IV)
- A represents a leaving group, said compound being optionally isolated and/or optionally purified, and at least one compound of formula (VII) is reacted with a compound of formula
- the temperature during evaporation is either between +35° and +40° C or between +55° and +65° C.
- the temperature during evaporation is between -10° and -20° C.
- the reaction of the benzaldehyde compound of formula Il with a pyruvate compound of formula III is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11 ), 2229-33, (1996).
- an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide
- sodium pyruvate may be used as the pyruvate compound.
- said reaction is carried out in a protic reaction medium such as a C 1 - 4 alkyl alcohol or mixtures of these. Mixtures of such alcohols with water, e.g. ethanol/water may also be used.
- Reaction temperature as well as the duration of the reaction may vary over a broad range.
- Preferred reaction temperatures range from -10 0 C to the boiling point of the reaction medium.
- Suitable reaction times may vary for example from several minutes to several hours.
- reaction of the benzaldehyde compound of formula Il with a pyruvate compound of formula III is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001.
- acid catalysed conditions more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001.
- the respective description is hereby incorporated by reference and forms part of the disclosure.
- reaction of the compound of formula (IV) with an substituted phenyl hydrazin of formula (V) is preferably carried out in a suitable reaction medium such as d- 4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
- a suitable reaction medium such as d- 4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
- said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
- reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
- a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
- Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
- the carboxylic group of the compound of formula (Vl) may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art. Preferably the compounds of formula (Vl) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci- 4 alkyl ester, an activated ester such as p-nitrophenylester.
- said activated compound of formula (VII) is an acid chloride
- it is preferably prepared by reaction of the corresponding acid of formula (Vl) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent.
- an additional solvent may be used.
- Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used.
- Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times from several minutes to several hours.
- said activated compound of formula (VII) is a mixed anhydride
- said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of formula (Vl) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
- racJ-N-piperidinyl- ⁇ - ⁇ -chlorophenylJ-i- ⁇ . ⁇ dichlorophenyl ⁇ . ⁇ - dihydro-1 H-pyrazole-3-carboxamide is preferably carried out in presence of a base such as triethylamine in a reaction medium such as methylenchloride.
- the temperature is preferably in the range from O 0 C to the boiling point of the reaction medium.
- the reaction time may vary over a broad range, e.g. from several hours to several days.
- the Polymorph according to the invention is suitable as pharmaceutical active substance for the preparation of medicaments. It has been found that the compound whose polymorph is claimed has a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. it is a selective ligand for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
- the compound whose polymorph is claimed shows little or no development of tolerance during treatment, particularly with respect to food intake, i.e. if the treatment is interrupted for a given period of time and then continued afterwards, the inventively used compound will again show the desired effect. After ending the treatment with the compound, the positive influence on the body weight is found to continue. This will highly likely also apply to its polymorph
- this compounds show relatively weak Herg channel affinity, thus a low risk of prolongation of the QT-interval is to be expected for this compound. This will deary also apply to its polymorph.
- the inventively used polymorph is distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
- another aspect of the present invention relates to a medicament comprising the ⁇ -Polymorph of (racJ-N-piperidinyl- ⁇ -chlorophenylJ-i ⁇ -dichlorophenyl ⁇ . ⁇ - dihydro-1 H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients.
- Another aspect of the present invention is the use of the ⁇ -Polymorph of (rac)-N- piperidinyl-5-(4-chlorOphenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3- carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
- cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
- ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4-chlorOphenyl)- 1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the prophylaxis and/or treatment of psychosis.
- ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
- ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
- Medicaments/drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
- ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g.
- ⁇ -Polymorph of (rac)-N-piperidinyl-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide according to the invention, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of metabolic syndrome, especially weight independent, cardiovascular diseases, cardiovascular risk factors, glucose intolerance and insulin resistance; for the prophylaxis and/or treatment and/or influencing of blood parameters exppecially lipid parameters, seeming to lower LDL bodies while increasing HDL bodies, including also the treatment of food dispredrs (obesity) under conditions of developed diabetes, especially Type II.
- Another preferred aspect of the invention is also a method of treatment encompassing all the abovementioned uses, wherein the ⁇ -Polymorph of (rac)-N- piperidinyl-5-(4-chlorophenyl)-1-(2 l 4-dichloiOphenyl)-4,5-dihydro-1H-pyrazole-3- carboxamide according to the invention, is applied to a person in need thereof, treating metabolic syndrome, especially weight independent, cardiovascular diseases especially fighting cardiovascular risk factors, influencing the blood parameters, especially the lipid parameters, diabetes, especially type II, glucose intolerance and insulin resistance, bone disorders, preferably osteoporosis (e.g.
- the medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
- the composition of the medicament may vary depending on the route of administration.
- the medicament of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
- conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
- These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
- Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
- the compositions may take any convenient form, such as tablets, pellets, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
- liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
- Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
- compositions of the present invention may also be administered topically or via a suppository.
- the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
- the daily dosage for humans may preferably be in the range fromi to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
- Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are higly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
- mice with a weight of 20-30 g Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.
- mice are acclimatized to the experimental setting.
- Pre-Treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
- the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.
- the hot plate analgesia is determined according to the method described in Woolfe D. et al. ,,The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. The respective description is hereby incorporated by reference and forms part of the present disclosure.
- mice are placed on a hot plate (Harvard Analgesimeter) at 55 ⁇ 0.5 0 C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B).
- B basal value
- PC cut-off time
- mice Fifteen minuts after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).
- PT post-treatment reading
- the degree of analgesia is calculated from the formula :
- % MPE of Analgesia ( PT- B) / (PC-B) x 100
- Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. ..Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975.
- the respective description is hereby incorporated by reference and forms part of the present disclosure.
- the chosen scoring system is
- the percentage of sedation is determined according to the formula:
- % of sedation arithmetic mean / 3 X 100
- the base-line rectal temperatures are determined with a thermometer (YeIIo Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of ⁇ -2 0 C are considered to represent activity.
- Catalepsy is determined according to the method described in Alpermann H. G. et al. ..Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is hereby incorporated by reference and forms part of the present disclosure.
- the cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.
- the chosen scoring system is:
- the percentage of catalepsy is determined according ot the following formula:
- % Catalepsy arithmetic mean / 6 X 100
- step a) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), 2,4-dichlorophenyIhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 ml_) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 0 C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
- N-aminopiperidine (0.6 ml_, 5.6 mmoles) and triethylamine (4 ml_) were dissolved in methylene chloride (25 ml_).
- methylene chloride 25 ml_.
- the resulting mixture was ice-cooled down to 0 0 C and a solution of ⁇ - ⁇ chlorophenyl)-!- ⁇ , ⁇ dichlorophenyl ⁇ . ⁇ -dihydro-pyrazole-S-carboxylic acid chloride obtained in step (c) in methylene chloride (15 ml.) was added dropwise.
- the resulting reaction mixture was stirred at room temperature (approximately 25 0 C) overnight.
- the ⁇ -Polymorph was obtained by evaporation of a solution of the compound according to example 1 (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydro-1 H-pyrazole-3-carboxamide ) in dimethylformamide (DMF) at 36.5 0 C.
- the ⁇ -Polymorph was obtained by evaporation of a solution of the compound according to example 1 (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydro-1 H-pyrazole-3-carboxamide ) in dimethylformamide (DMF) at 6O 0 C.
- Example 2c ⁇ -Polymorph of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydro-1 H-pyrazole-3-carboxamide
- the ⁇ -Polymorph was obtained by evaporation of a solution of the compound according to example 1 (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydro-1 H-pyrazole-3-carboxamide ) in chloroform (DMF) at -18 0 C.
- the ⁇ -Polymorph forms a monoclinic cell with the beta angle of 90.6 0 C with the crystals typically growing in form of twinned blocks.
- the DSC analysis of the ⁇ -Polymorph presents a melting peak with an onset of 182-184 0 C and a maximum at 184-186 0 C and an enthalpy of -89 ⁇ 1 J/g.
- the FTIR Spektrum of the ⁇ -Polymorph shows a doublet in the region at 783-789 cm "1 .
- the FTRaman spectrum of the ⁇ -Polymorph shows intense bands at 1647, 1593, 1253, 783, 861, 549 and 165 cm “1 and Raman shifts around 1253, 1084, 533 and 364 cm “1 .
- inventive pyrazoline compounds are particularly suitable for regulating the CBrReceptor.
- inventive pyrazoline compounds show an antagonistic effect.
- the second group of rats was treated with the inventive compound N-piperidinyl-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide according to Example 1. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (10 mg/kg body weight).
- the third group of rats was treated with Amphetamine, an active ingredient known to reduce appetite. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (5 mg/kg body weight).
- Figure 2 shows the reduction of food intake due to the administration of the inventive compound according to example 1.
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EP05384032.8 | 2005-07-29 | ||
EP05384032A EP1757588A1 (en) | 2005-07-29 | 2005-07-29 | Polymorph of N-Piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide and its use as a cannabinoid receptor modulator |
US70545505P | 2005-08-05 | 2005-08-05 | |
US60/705,455 | 2005-08-05 |
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WO2008017381A1 (en) | 2006-08-08 | 2008-02-14 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
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WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120052A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
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- 2006-07-27 ES ES200850021A patent/ES2326461B1/en not_active Expired - Fee Related
- 2006-07-27 WO PCT/EP2006/007418 patent/WO2007017126A2/en active IP Right Grant
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EP0576357A1 (en) * | 1992-06-23 | 1993-12-29 | Sanofi | Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them |
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Cited By (11)
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WO2008017381A1 (en) | 2006-08-08 | 2008-02-14 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
WO2010003624A2 (en) | 2008-07-09 | 2010-01-14 | Sanofi-Aventis | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
WO2011023754A1 (en) | 2009-08-26 | 2011-03-03 | Sanofi-Aventis | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
WO2011157827A1 (en) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2012120056A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120052A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
WO2012120054A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
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WO2007017126A3 (en) | 2007-04-26 |
ES2326461A1 (en) | 2009-10-09 |
ES2326461B1 (en) | 2010-04-19 |
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