Selective modulators of gpr55 receptor activity: chromenopyrazole derivatives (Machine-translation b

专利摘要:
Selective modulators of gpr55 receptor activity: chromenonirazole derivatives. The present invention relates to a family of chromenopyrazole-derived compounds of formula (I): {image-01} Having the ability to modulate the gpr55 cannabinoid family receptor, whereby the invention also relates to the use of these compounds for the manufacture of a medicament for the treatment of diseases in which the gpr55 receptor has a physiological role, such as diabetes, parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis and cancers such as cholangiocarcinoma, breast cancer, ovarian and prostate cancer, glioblastoma and cutaneous carcinoma. (Machine-translation by Google Translate, not legally binding)
公开号:ES2593057A1
申请号:ES201530608
申请日:2015-05-05
公开日:2016-12-05
发明作者:Nadine Jagerovic；Paula MORALES LAZARO；Ruth ROSS；Lauren WHYTE
申请人:University of Toronto；Consejo Superior de Investigaciones Cientificas CSIC；
IPC主号:

专利说明:

TECHNICAL SECTOR
The present invention is encompassed in the field of pharmacology. Specifically, the present invention relates to piperazines derived from 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole and 7-methoxy-4,4-dimethyl-2,4-dihydrochromen [4 , 3-c] pyrazole, its use for the manufacture of a medicine, the use of this medicine for the treatment and / or prevention of a disorder associated with the GPR55 receptor and the use of these compounds for pharmacological tests related to GPR55.
STATE OF THE PREVIOUS TECHNIQUE
The GPR55 receptor was first cloned and identified in 1999. It is a transmembrane receptor associated with protein G. Although it shares only 14% homology with the CB1 and CB2 cannabinoid receptors, it was proposed as a new member of the endocannabinoid system. Indeed, it was discovered that cannabinoid receptor ligands were capable of activating the GPR55 receptor (GlaxoSmithKline WO0186305; AstraZeneca WO2004074844). Currently, there is controversy surrounding the pharmacology of GPR55. Today, GPR55 is still considered an orphan receiver. However, it has been described that endogenous lysophosphatidylinositol (LPI) derivatives were capable of stimulating the GPR55 receptor by phosphorylation of ERK1 / 2 in HEK293 cells that overexpress hGPR55. To date, there are very few agonists and / or specific antagonists of the GPR55 receptor. Some benzoylpiperazine derivatives were identified as GPR55 agonists with no action on CB1 and CB2 cannabinoid receptors. Several families of GPR55 agonists and selective GPR55 antagonists that resulted in molecular modeling studies were discovered by a pharmacological evaluation of high screening using β-arrestin assays in hGPR55-U2OS cells.
It has been shown that the GPR55 receptor is involved in the processes of inflammatory pain, neuropathic pain, metabolic disorder, bone development, and tumor cell proliferation processes. Therefore, GPR55 is considered a biological target for the treatment of GPR55-related diseases such as diabetes, Parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis, cholangiocarcinoma, breast cancer, ovarian and prostate cancer, glioblastoma and cutaneous carcinoma.
The compounds claimed in the present invention have chromenopyrazole as the base skeleton. In WO2010109050, chromenopyrazoles are described as cannabinoids with analgesic activity. More recently, in WO2014013117 and P201430372, chromenopyrazoles are described as antitumor related to cannabinoid activity.
DESCRIPTION OF THE INVENTION
The present invention faces the problem of providing new compounds useful as a pharmacological tool for the validation of the GPR55 receptor and as therapeutic agents related to GPR55. The new compounds of the present invention act on the GPR55 receptors. Therefore, they are useful for treating diseases and disorders related to the GPR55 receptor, such as diabetes, Parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis, cholangiocarcinoma, breast cancer, cancer of ovary and prostate glioblastoma and cutaneous carcinoma.
The authors of the present invention have found that the compounds of formula
(I) act on the orphan GPR55 receptor selectively and are therefore useful for modulating processes in which said receptor is involved.
In a first aspect, the present invention relates to a compound of general formula (I)
Formula (I)
or a tautomer, a pharmaceutically acceptable salt or solvate thereof; where:
5 !R1 is selected from optionally substituted aryl or a group -C (O) R3; R3 se
selects from aryl, heterocycle, C1-C6 alkyl, C3-C6 cycloalkyl or a
group - (CH2) n-O-aryl, where n is a value selected from 1, 2, 3 or 4.
! R2 is selected from C1-C6 alkylene or a group -R4-C (O) -NH-R5-, being
R4 and R5 C1-C6 alkylenes the same or different
10
Another aspect of the invention relates to a compound of general formula (II)
Formula (II)
15 or a tautomer, a pharmaceutically acceptable salt, or solvate thereof; where R1 and R2 are defined as above.
Another aspect of the present invention relates to a compound of the general formula
(III)
5 Formula (III)
or a tautomer, a pharmaceutically acceptable salt, or solvate thereof; where R1 and R2 are defined as above.
In a preferred embodiment, R1 is a group -C (O) R3 wherein R3 is any of the above-mentioned possibilities, although preferably R3 is aryl and more preferably phenyl.
In another preferred embodiment, R3 is heterocycle and more preferably R3 is selected from furan, thiophene or tetrahydrofuran.
In another preferred embodiment, R3 is cyclohexyl.
In another preferred embodiment, R3 is C1-C4 alkyl. In another preferred embodiment, R2 is C1-C4 alkylene, and more preferably ethylene.
According to a preferred embodiment, the compound of formula (I) is selected from the group consisting of: -1-1 (2- (4- (2-furoyl) piperazinyl) ethyl) -1,4-dihydro-7 -methoxy-4,4-dimethylchromen [4,3c] pyrazole
-2- (2- (4-furoyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazole -1- (2- (4-benzoyl-piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazol -2- (2- (4-benzoyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy- 4,4-dimethylchromen [4,3c] pyrazol -1- (2- (4- (2-thienoyl) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- (2-thienoyl) piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- phenoxyacetyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- (2-tetrahydrofuroyl) piperazinyl) ethyl) -2,4 -dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4-cyclohexylcarbonyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4, 3-c] pyrazol -2- (2- (4-pivaloyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazole
In another preferred embodiment, R1 is an optionally substituted phenyl. In a more preferred embodiment, R1 is a phenyl substituted by a C1-C4 alkyl or a C1-C4 alkyloxy and more preferably, by a methyl or a methoxy.
In another preferred embodiment R2 is a group -R4-C (O) -NH-R5-, R4 and R5 being C1-C4 alkylenes the same or different. In a more preferred embodiment, R4 and R5 are methylene.
According to a preferred embodiment, the compound of formula (II) is selected from the group consisting of:
-1- (2- (4-phenylpiperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4-phenylpiperazinyl) acetamidomethyl) -2 , 4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -1- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4 , 4-dimethylchromen [4,3-c] pyrazole
-2- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole -1- (2- (4- ( 2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- (2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -1- (2- (4- (4-methoxyphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7 -methoxy-4,4-dimethylchromen [4,3-c] pyrazole.
The term "alkyl" refers, in the present invention, to aliphatic, linear, cycled or branched, saturated or unsaturated chains, having 1 to 6 carbon atoms. For example, but not limited to, the alkyl group may be methyl, ethyl, cyclohexane etc. The alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl or carboxylic acid.
The term "aryl" refers, in the present invention, to single or multiple aromatic rings, having between 5 and 18 links in which a proton has been removed from the ring. The aryl groups are for example, but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthracil. Preferably the aryl group has 5 to 7 carbon atoms and more preferably the aryl group is a phenyl. The aryl radicals may be optionally substituted by one or more substituents such as (C1-C6) alkyl, alkoxy, halogen, hydroxy or carboxylic acid and more preferably the aryl group is substituted by one or two methoxyls.
The term "cycloalkyl" refers, in the present invention, to radicals of cyclic hydrocarbon chains, preferably of 3 to 6 carbon atoms and more preferably of 6, which is saturated or partially saturated, and which only consists of carbon atoms and hydrogen, such as cyclopropyl, cyclopentyl or cyclohexyl and which may be optionally substituted by one or more groups such as alkyl, halogens, hydroxyl, amines, amides, cyano etc.
The term "heterocycle" refers, in the present invention, to a cyclic structure containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The structure can be aromatic or hydrogenated. Preferably, the heterocycle may be selected from thienyl, furyl, tetrahydrofuryl, pyridyl, imidazolyl, pyrazolyl, morpholino but not limited to them. Heterocyclic radicals may be optionally substituted by one or more substituents such as (C1-C6) alkyl, alkoxy, halogen, hydroxyl or carboxylic acid.
Unless otherwise indicated, the compounds of the invention also refer to that they include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the compounds having the present structures, except for the substitution of a hydrogen for a deuterium or for tritium, or the substitution of a carbon for a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.
The term "tautomer" or "tautomeric form", as used in the present invention, refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, protonic tautomers (also known as prototropic tautomers) that include interconversions by migration of a proton, such as keto-enolic or imine-enamine isomerizations. Valencia tautomers include interconversions by reorganization of some bond electrons.
The term "pharmaceutically acceptable salts or solvates" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound that, when administered to a receptor, is capable of providing (directly or indirectly) a compound as described herein. document. However, it will be appreciated that pharmaceutically acceptable salts are also within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and derivatives can be carried out by methods known in the art.
For example, pharmaceutically acceptable salts of compounds provided herein are synthesized by conventional chemical methods from an original compound containing a basic or acidic moiety. Generally, such salts are prepared, for example, by reacting the free acid or base forms of the compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iohydrate, sulfate, nitrate, phosphate and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and ptoluenesulfonate. Examples of base addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, and salts of organic bases such as, for example, ethylenediamine, ethanolamine, N, N -dιalquιlenetanolamιna, tπethanolamine, glucamine and basic amino acid salts
Particularly preferred derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by making a compound administered orally more easily absorbed by the blood), or that enhances the release of the original compound in a biological compartment (for example, the brain or lymphatic system) in relation to the original species.
The compounds of formula (I), (II) or (III) may be in crystalline form as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. Solvation methods are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
The compounds of formula (I), of formula (II) and of formula (III) or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable means, among others, that they have a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably, greater than 70%, more preferably, greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts or.
The compounds of formula (I), of formula (II) and of formula (III) defined above can be obtained by a combination of synthetic reactions known in the state of the art such as those mentioned in the article Press JB, J. Heterocyclic Chem. , 1985, 22, 561-564.
In another aspect, the present invention relates to the use of a compound of formula (I), of formula (II) or of formula (III) for the manufacture of a medicament.
In another aspect, the present invention relates to the use of a compound of formula (I), of formula (II) or of formula (III) for the manufacture of a medicament for the treatment and / or prevention of a disorder associated with GPR55 receivers.
According to a preferred embodiment, the disorder associated with GPR55 receptors is selected from diabetes, Parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis, cholangiocarcinoma, breast cancer, ovarian and prostate cancer, glioblastoma and cutaneous carcinoma
In another aspect, the present invention relates to a compound of formula (I) or of formula (II) or of formula (III) for use in the treatment of and / or prevention of a disorder associated with cannabinoid receptors .
The term "disorder", as used in the present invention, refers to the presence of a behavior or a group of identifiable symptoms in clinical practice, which in most cases are accompanied by discomfort or interfere with the habitual activity of the individual.
The compounds of formula (I), of formula (II) or of formula (III), their pharmaceutically acceptable salts or solvates thereof, can therefore be used in the prevention and / or treatment of a disorder that requires modulation of GPR55 receivers. Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or formula (II), its pharmaceutically acceptable salts or solvates thereof, together with pharmaceutically acceptable excipients, constitute a further aspect of the present invention.
The amount of compound of formula (I), of formula (II) or of formula (III), its pharmaceutically acceptable salts or solvates thereof, therapeutically effective to be administered as well as its dosage to treat a pathological state with said compounds will depend on numerous factors, including age, patient status, disease severity, route and frequency of administration, modulator compound to be used, etc.
In another aspect, the present invention also relates to pharmaceutical compositions comprising at least one compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, together with a pharmaceutically acceptable carrier or carrier, an excipient or a vehicle, for administration to a patient.
In a preferred embodiment, the pharmaceutical composition further comprises another active ingredient.
Some examples of the pharmaceutical compositions are solids (tablets, pills, capsules, granulated solid, etc.) or liquids (solutions, suspensions or emulsions) prepared for oral, nasal, topical or parenteral administration.
In a preferred embodiment of the present invention, the pharmaceutical compositions are suitable for oral administration, in solid or liquid form. Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.
Compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.
The pharmaceutical compositions can be adapted for parenteral administration, as sterile solutions, suspensions, or lyophilized products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, can be used.
The administration of the compounds or compositions of the present invention can be performed by any suitable method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.
The amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
The compounds and compositions of this invention may be employed alone or together with other drugs to provide a combination therapy. The other drugs may be part of the same composition, or be provided as a separate composition, for administration at the same time or at a different time.
A combination therapy can be especially interesting for the type of pathologies to be treated with these compounds as defined in the present invention, these pathologies are especially complex, since patients in general have a combination of symptoms as well as a variety of damages or alterations Therefore, it may be interesting to combine several drugs, each directed to prevent, alleviate or specifically cure a specific symptom, damage or alteration, or also to several of them, resulting in a combination therapy directed at the disease or condition in a way global, taking into account many, most, or all aspects involved in it.
The drugs to be combined with the compounds of the present invention may be drugs approved for the treatment of any of the diseases, or be newly developed.
In another aspect, the present invention relates to the use of a compound of formula (I), of formula (II) or of formula (III) for the manufacture of a reagent in biological assays related to GPR55 receptors.
In the present invention, the term "reagent" refers to a test substance that is added to a system to give rise to a reaction or check if a reaction occurs.
In the present invention, the term "biological assay" refers to a method for measuring a substance, either quantitatively or qualitatively, in a living organism.
or in vitro Qualitative tests are used to determine the physical effects of a substance in that organism. Quantitative tests are used to estimate the concentration or potency of a substance by measuring the biological response produced by that substance.
Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
FIGURES
Figure 1. Concentration-response curves of LPI and examples 2, 6 and 8 in hGPR55-HEK293 and HEK293 cells. The values represent the mean ± SEM from 4 independent experiments performed in duplicate. The values correspond to a percentage of the maximum stimulation produced by LPI.
Figure 2. Concentration-response curve in the presence or absence of LPI of example 10 in hGPR55-HEK293 cells. The values represent the mean ± SEM from 4 independent experiments performed in duplicate. The values correspond to a percentage of the maximum stimulation produced by LPI.
EXAMPLES
The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the product of the invention.
General methods
The purification of the reaction products was carried out by column chromatography using 60 Merck 230-400 mesh silica gel as support. The separation by semi-preparative high performance liquid chromatography was performed on a Waters chromatograph composed of a 2767 Sample Manager injector / collector module, a System Fluidic Organizer separation module, a 2998 Photodiode Array detector (UV-visible) and a mass spectrophotometer 3100 Mass Detector A SunFireTM C18 reverse phase column (19 mm x 150 mm) is used for separation. The mobile phases used are: A (MeCN + 0.1% formic acid) and B (H2O + 0.1% formic acid). The gradient was made using a flow of 24 mL / min in 70 minutes monitoring at λ = 254 nm. The exact mass spectra were recorded on an Agilent Technologies 6520 Accurate-Mass QTOF LC / MS spectrometer with a positive electrospray source. NMR analyzes were performed in the solvent
5 deuterated indicated in each case. The 1 H-NMR, 13 C-NMR, heteronuclear correlation HMBC and HSQC spectra were recorded on a Mercury 400 spectrometer (400 and 101 MHz) or on a Varian 500 (500 and 126 MHz) at 25 ° C. Melting points were measured in an MP 70 Mettler Toledo apparatus.
The starting product for obtaining the compounds of formula (I) of the present invention is 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole.
To prepare 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole, the 2-hydroxy-4-methoxyacetophenone was cycled with acetone. Α-Formulation of 7-methoxy-2,2-dimethyl
15 2,3-dihydrochromen-4-one with microwave irradiation led to 3-hydroxymethylenechromen-4-one. Finally, condensation with anhydrous hydrazine resulted in obtaining 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole.
The process for preparing 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,320 c] pyrazole is summarized in the following scheme (I):
Scheme (I)
Preparation and obtaining of 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole.
A solution of 3- (hydroxymethylene) -7-methoxy-2,2-dimethylchroman-4-one (1.46 g, 6.27 mmol) and anhydrous hydrazine (0.58 mL, 18.83 mmol) is stirred for 2 h at 60 ° C ) in EtOH. After evaporating the solvent under vacuum, the crude was purified by
30 medium pressure silica gel chromatography (hexane / AcOEt, 1: 1). 7-Methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole (0.99 g, 69%) was obtained as a white solid. mp: 158-160 ° C. MS (ES +, m / z) 231 [M + H] +.
A. Preparation and obtaining of the 1- (2- (4- (2-ketone) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (III ) and 2- (2- (4- (2-ketone) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole of formula (I) where R1 It is a group -C (O) -R3.
5 For the synthesis of 1- (2- (4- (2-ketone) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (III) and of the 1- (2- (4- (2-ketone) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (IV) herein invention the 7-methoxy-4,4-dimethyl-1,4 was rented
10 dihydrochromen [4,3-c] pyrazole with 1,2-dibromoethane. The 2 regioisomers obtained, 1- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole and 2- (2-bromoethyl) -7-methoxy-4 , 4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole, were isolated by chromatography. Finally, reaction with acylpiperazines led to the example compounds of formula (III) and the example compounds of formula (IV).
15 This procedure is summarized in the following scheme (II):
Scheme (II)
Preparation Yobtainingof the1- (2-Bromoethyl) -7-methoxy-4,4-dimethyl-1,4
dihydrochromen [4,3-c] pyrazole Yof the2- (2-Bromoethyl) -7-methoxy-4,4-dimethyl-1,4
dihydrochromen [4,3-c] pyrazole
A suspension of NaH (28 mg, 1.19 mmol) in dried THF was added to a solution of 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole (0.23 g , 0.99 mmol) in THF. The mixture was heated at reflux for 4 h. The solvent was removed under vacuum. The crude dissolved in AcOEt was washed with water, dried with MgSO4 and the solvent was evaporated under vacuum. Chromatography on silica gel (hexane / AcOEt, 1: 1) led to the separation of the 2 isomers, 1- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3- c] pyrazole and 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole.
1- (2-Bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole (75 mg, 20%); 1H NMR (400 MHz, CDCl3) δ: 7.34 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 6.50 (dd, J = 7.9, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz), 4.61 (t, J = 6.6 Hz), 4.09 (t, J = 6.6 Hz), 3.92 (s, 3H), 1.45 (s, 6H) ppm; 13C-NMR (101 MHz, CDCl3) δ: 161.7, 155.3, 144.7, 133.4, 123.9, 121.9, 108.5, 103.4, 101.8, 76.7, 59.3, 55.8, 29.6, 28.5 ppm; MS (ES +, m / z) 337 [M + H] +; HRMS C15H17BrN2O2: teor. 336.0473, exp. 336.0478. 2- (2-Bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole (0.19 g, 51%); 1H-NMR (400 MHz, CDCl3) δ: 7.68 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 6.63 (dd, J = 8.4, 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 3.80 (t, J =
6.5 Hz, 2H), 1.66 (s, 6H) ppm; 13C-NMR (101 MHz, CDCl3) δ: 161.1, 154.7, 143.8, 124.6, 123.2, 120.9, 110.9, 108.1, 103.2, 76.6, 55.5, 53.8, 30.7, 29.4 ppm; MS (ES +, m / z) 337 [M + H] +; HRMS C15H17BrN2O2: teor. 336.0473, exp. 336.0470.
Example 1-Preparation and obtaining 1- (2- (4- (2-furoyl) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
1- (2-Furoyl) piperazine (12 mg, 0.06 mmol) and K2CO3 (27 mg, 0.19 mmol) dissolved in THF was stirred at room temperature for 10 min. A solution of 1- (2-Bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3-c] pyrazole (22 mg, 0.06 mmol) in THF was added to the reaction mixture and heated to reflux for one night. The solvent was evaporated under vacuum. The crude dissolved in EtOAc was washed with water, dried with MgSO4, and after filtration the solvent was evaporated. 1- (2- (4- (2Furoyl) piperazinyl) ethyl) -1,4-dihydro -7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole was isolated by medium pressure chromatography (7 mg , 25%); 1H-NMR (CDCl3) δ: 7.57 (d, J = 8.5 Hz), 7.33-7.28 (m, 1H), 7.11 (s, 1H), 6.96-6.92 (m, 1H), 6.60 (dd, J = 8.5 , 2.5 Hz, 1H), 6.53
(d, J = 2.5 Hz, 1H), 6.39-6.36 (m, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.78 (s, 3H), 3.39-3.21 (m, 4H), 2.83 ( t, J = 6.6 Hz, 2H), 2.72-2.64 (m, 4H), 1.52 (s, 6H) ppm; 13C-NMR (101 MHz, CDCl3) δ: 162.0, 155.6, 153.1, 145.3, 142.6, 141.8, 124.1, 123.2, 121.3, 117.0, 112.2, 109.2, 108.4, 103.2, 76.1, 57.5, 55.1, 54.1, 50.7, 49.5 , 28.9 ppm; MS (ES +, m / z) 437 [M + H] +; HRMS C24H28N4O4: teor. 436.2110, exp. 436.2107.
Example 2-Preparation and obtaining 2- (2- (4- (2-furoyl) piperazinyl) ethyl) -2,4dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (20 mg, 0.06 mmol) and 1- (2-furoyl) piperazine (11 mg, 0.06 mmol). Yellow oil (6 mg, 24%); 1H-NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.48-7.45 (m, 1H), 7.18 (s, 1H), 7.00-6.94 (m, 1H), 6.54 ( dd, J = 8.4, 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.46-6.44 (m, 1H), 4.23 (t, J = 6.5 Hz, 2H), 3.76-3.62 (br s, 7H), 2.86 (t, J = 6.5 Hz, 2H), 2.70-2.66 (m, 4H), 1.58 (s, 6H) ppm; 13C-NMR (101 MHz, CDCl3) δ: 160.9, 159.3, 154.5, 148.0, 143.9, 142.9, 124.2, 123.1, 121.0, 116.7, 111.5, 111.2, 108.0, 103.2, 76.7, 58.0, 55.5, 53.6, 51.3, 50.4 , 29.5 ppm; MS (ES +, m / z) 437 [M + H] +; HRMS C24H28N4O4: teor. 436.2110, exp. 436.2121.
Example 3-Preparation and obtaining 1- (2- (4-benzoyl-piperazinyl) ethyl) -1,4-dihydro -7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 1- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (20 mg, 0.06 mmol) and benzoylpiperazine (11 mg, 0.06 mmol). Yellow amorphous solid (8 mg, 30%); 1H-NMR (CDCl3) δ: 7.55 (d, J = 8.4 Hz, 1H), 7.38-7.29 (m, 5H),
7.13 (s, 1H), 6.49 (dd, J = 8.4, 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 4.41 (t, J = 6.7 Hz, 2H), 3.73 (s, 3H ), 3.41-3.26 (m, 4H), 2.81 (t, J = 6.7 Hz, 2H), 2.59-2.37 (m, 4H), 1.52 ppm (s, 6H); 13C-NMR (101 MHz, CDCl3) δ: 170.3, 165.1, 160.7, 154.3, 130.2, 129.7, 128.5, 127.1, 124.4, 123.9, 122.8, 107.9, 107.6, 103.0, 76.4, 57.8, 55.4, 55.3, 53.6, 50.1 , 29.2 ppm; MS (ES +, m / z) 447 [M + H] +; HRMS C26H30N4O3: teor. 446.2317, exp. 446.2324.
Example 4-Preparation and obtaining 2- (2- (4-benzoyl-piperazinyl) ethyl) -2,4-dihydro -7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (28 mg, 0.08 mmol) and benzoylpiperazine (16 mg, 0.08 mmol). Yellow oil (30 mg, 81%); 1H-NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 8.4 Hz, 1H), 7.46-7.32 (m, 5H), 7.17 (s, 1H), 6.55 (dd, J = 8.4, 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.41-3.20 (m, 4H), 2.87 (t, J = 6.6 Hz, 2H), 2.73-2.60 (m, 4H),
1.58 ppm (s, 6H, OC (CH3) 2); 13C-NMR (101 MHz, CDCl3) δ: 170.4 (CO), 160.8, 154.5, 142.9, 135.8, 129.9, 128.6, 127.1, 124.1, 123.0, 120.9, 111.1, 107.9, 103.1, 76.6, 57.9, 55.4, 53.7, 50.2, 47.9, 29.4 ppm; MS (ES +, m / z) 447 [M + H] +; HRMS C26H30N4O3: teor. 446.2317, exp. 446.2311.
Example 5-Preparation and obtaining 1- (2- (4- (2-thienoyl) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 1- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (20 mg, 0.06 mmol) and 1- (2-thienoyl) piperazine trifluoroacetate (18 mg, 0.06 mmol). Yellow amorphous solid (6 mg, 23%); 1 H-NMR (400 MHz, CDCl 3) δ: 7.49 (d, J =
8.8 Hz, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 7.28 (s, 1H), 7.23-7.21 (m, 1H), 7.03 (dd, J = 5.0, 3.6 Hz, 1H), 6.61-6.58 (m, 1H), 6.57 (d, J = 2.6 Hz, 1H), 4.54 (t, J = 7.1 Hz, 2H),
3.82 (s, 3H), 3.77-3.64 (m, 4H), 2.93-2.87 (m, 2H), 2.67-2.43 (m, 4H), 1.58 ppm (s, 6H); 13C-NMR (101 MHz, CDCl3) δ: 163.7, 161.0, 154.6, 150.3, 137.1, 132.8, 129.1, 128.9, 126.9, 122.7, 121.4, 109.1, 107.9, 104.1, 764, 57.4, 55.6, 53.6, 51.3, 49.5 , 28.6 ppm; MS (ES +, m / z) 453 [M + H] +; HRMS C24H28N4O3S: teor. 452.1882, exp. 452.1891.
Example 6-Preparation and obtaining 2- (2- (4- (2-thienoyl) piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (30 mg, 0.09 mmol) and 1- (2-thienoyl) piperazine trifluoroacetate (28 mg, 0.09 mmol). Yellow solid (22 mg, 55%); mp: 163-165 ° C; 1 H-NMR (400 MHz, CDCl 3) δ: 7.62 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 7.25-7.23 (m, 1H), 7.20 (s, 1H), 7.03 (dd, J = 5.0, 3.6 Hz, 1H), 6.55 (dd, J = 8.4, 2.5 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H),
4.27 (t, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.78-3.72 (m, 4H), 3.01-2.91 (m, 2H), 2.63-2.43 (m, 4H), 1.59 ppm (s , 6H); 13C-NMR (101 MHz, CDCl3) δ: 163.8, 161.0, 154.6, 143.1, 137.0, 129.1, 128.9, 126.9, 124.3, 123.1, 121.0, 111.1, 108.0, 103.2, 76.7, 57.9, 55.5, 53.5, 50.2, 46.1 , 29.5 ppm; MS (ES +, m / z) 453 [M + H] +; HRMS C24H28N4O3S: teor. 452.1882, exp. 452.1889.
Example 7-Preparation and obtaining 2- (2- (4-phenoxyacetyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (30 mg, 0.09 mmol) and phenoxyacetyl piperazine (20 mg, 0.09 mmol). Orange solid (16 mg, 38%); mp: 177-179 ° C; 1H-NMR (500 MHz, CD3OD) δ: 7.56 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.31-7.21 (m, 2H), 7.00-6.90 (m, 3H), 6.56 ( dd, J = 8.5, 2.5 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 4.76 (s, 2H), 4.26 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.63
3.50 (m, 4H), 2.84 (t, J = 6.4 Hz, 2H), 2.56-2.46 (m, 4H), 1.56 ppm (s, 6H); 13C-NMR (126 MHz, CD3OD) δ: 167.4, 161.1, 158.0, 154.5, 142.5, 129.1, 125.4, 122.3, 121.1, 120.5, 114.3, 110.4, 107.2, 102.8, 76.2, 66.1, 57.2, 54.3, 52.8, 52.3 , 49.1, 44.7, 43.7,
28.0 ppm; MS (ES +, m / z) 477 [M + H] +; HRMS C27H32N4O4: teor. 476.2423, exp. 476.2427.
Example 8-Preparation and obtaining 2- (2- (4- (2-tetrahydrofuroyl) piperazinyl) ethyl) 2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (30 mg, 0.09 mmol) and tetrahydrofuroyl) piperazine (16 mg, 0.09 mmol). Yellow solid (14 mg, 36%); mp: 158-160 ° C; 1H-NMR (500 MHz, CD3OD) δ: 7.46 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 6.46 (dd, J = 8.5, 2.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.67-4.54 (m, 1H), 4.17 (t, J = 6.5 Hz, 2H), 3.83-3.81 (m, 1H), 3.76-3.70 (m, 1H), 3.68 (s, 3H ), 3.55-3.39 (m, 4H), 2.76 (t, J = 6.5 Hz, 2H), 2.46-2.33 (m, 4H), 2.12-1.99 (m, 1H), 1.95
1.86 (m, 1H), 1.85-1.75 (m, 2H), 1.47 ppm (s, 6H); 13C-NMR (126 MHz, CD3OD) δ: 171.3, 161.1, 154.5, 142.5, 125.4, 122.3, 120.5, 110.4, 107.2, 102.8, 76.2, 75.2, 68.7, 57.2, 54.3, 52.9, 52.3, 47.5, 44.9, 43.7 , 28.8, 28.0, 25.1 ppm; MS (ES +, m / z) 441 [M + H] +; HRMS C24H32N4O4: teor. 440.2423, exp. 440.2436.
Example 9-Preparation and obtaining 2- (2- (4-cyclohexylcarbonyl-piperazinyl) ethyl) 2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (30 mg, 0.09 mmol) and tetrahydrofuroyl) piperazine (17 mg, 0.09 mmol). Yellow solid (25 mg, 62%); mp: 151-152 ° C; 1H-NMR (400 MHz, CDCl3) δ: 7.63 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 6.56 (dd, J = 8.5, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.66-3.39 (m, 4H), 2.85 (t, J = 6.6 Hz, 2H), 2.54-2.35 ( m, 4H), 1.82-1.75 (m, 1H), 1.73-1.61 (m, 4H), 1.59 (s, 6H), 1.57-1.42 ppm (m, 6H); 13C-NMR (101 MHz, CDCl3) δ: 174.8, 160.9, 154.6, 143.0, 124.2, 123.1, 121.0, 111.2,
108.0, 103.2, 76.7, 58.0, 55.5, 53.2, 50.3, 45.6, 41.7, 30.6, 29.6, 26.1 ppm; MS (ES +, m / z) 453 [M + H] +; HRMS C26H36N4O3: teor. 452.2787, exp. 452.2773.
Example 10-Preparation and obtaining 2- (2- (4-pivaloyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the embodiment described for Example 1, using 2- (2-bromoethyl) -7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (20 mg, 0.06 mmol) and pivaloyl piperazine (10 mg, 0.09 mmol). Yellow amorphous solid (8 mg, 32%); 1H-NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 6.55 (dd, J = 8.4, 2.5 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H),
3.79 (s, 3H), 3.63 (t, J = 5.0 Hz, 4H), 2.84 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 5.0 Hz, 4H),
1.59 (s, 6H), 1.26 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ: 176.5, 160.9, 154.6, 142.9, 124.2, 123.1, 121.0, 111.2, 108.0, 103.2, 76.7, 58.0, 55.5, 53.6, 50.2, 45.3, 38.8, 29.5,
28.6 ppm; MS (ES +, m / z) 427 [M + H] +; HRMS C24H34N4O3: teor. 426.2630, exp. 426.2618.
B. Preparation and obtaining of 1- (2- (4-arylpiperazinyl) acetamidomethyl) -1,4dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (V) and 2 - (2- (4-arylpiperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (I) in which R 1 is an aryl.
For the synthesis of 1- (2- (4-arylpiperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles and 2- (2- (4- arylpiperazinyl) acetamidomethyl) -2,4dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (I) in which R1 is an aryl, 7-methoxy-4,4-dimethyl -1,4-dihydrochromen [4,3-c] pyrazole with the corresponding N (hydroxymethyl) -2- (4-phenylpiperazinyl) acetamide.
This procedure is summarized in the following scheme (III):
Scheme (III)
5 The N- (hydroxymethyl) -2- (4-phenylpiperazinyl) acetamides were prepared by N-alkylation of the phenylpiperazine with the corresponding 2-chloro-N-hydroxymethylacetamide.
This procedure is summarized in the following scheme (IV): 10
Scheme (IV)
Preparation and obtaining of the N- (hydroxymethyl) -2- (4-phenylpiperazinyl) acetamides
A solution of 2-chloro-N-hydroxymethylacetamide (2eq) in acetonitrile is added to a mixture of the corresponding phenylpiperazine (1eq) with K2CO3 (1.5 eq) in acetonitrile. It is heated at reflux for 2-5 h. The solvent was evaporated under vacuum. The crude dissolved in AcOEt was washed with water, dried with MgSO4 and the solvent was evaporated.
20 under vacuum. Medium pressure chromatography on silica gel (AcOEt) led to the corresponding N- (hydroxymethyl) -2- (4-phenylpiperazinyl) acetamide.
N- (Hydroxymethyl) -2- (4-phenylpiperazinyl) acetamide (41%). mp: 112-114 ° C; 1 H-NMR (400MHz, CDCl3) δ: 8.10-8.02 (br s, 1H), 7.39-7.22 (m, 2H), 7.06-6.85 (m, 3H), 4.82 (s, 2H),25 3.28-3.19 (m, 4H), 3.13 (s, 2H), 2.90-2.57 ppm (m, 4H); 13C-NMR (101 MHz, CDCl3) δ:173.6, 151.5, 129.8, 129.7, 120.5, 119.3, 116.7, 73.1, 62.0, 54.1, 53.7, 50.9, 49.8 ppm;
MS (ES +, m / z) 250 [M + H] +; Anal. C13H19N3O2: Theor. C 62.63%, H 7.68%, exp. C 62.41%, H 7.83%.
N- (Hydroxymethyl) -2- (4- (2-methoxyphenyl) piperazinyl) acetamide (63%). mp: 134-136 ° C; 1H-NMR (400 MHz, CDCl3) δ: 8.14-8.11 (br s, 1H), 7.03-6.96 (m, 2H), 6.89-6.78 (m, 2H),
4.79 (s, 2H), 3.94-3.64 (m, 5H), 3.17-2.89 (m, 4H), 2.84-2.66 ppm (m, 4H); 13C-NMR (101 MHz, CDCl3) δ: 171.4, 151.7, 140.4, 122.6, 120.5, 117.6 and 110.8, 63.0, 61.0, 54.8, 53.6, 53.2, 51.0, 50.1 ppm; MS (ES +, m / z) 280 [M + H] +; Anal. C14H21N3O3: Theor. C 60.20%, H 7.58%, exp .: C 60.31%, H 7.72%.
N- (Hydroxymethyl) -2- (4- (2,3-dimethylphenyl) piperazinyl) acetamide (25%). mp: 126-127 ° C; 1H-NMR (400 MHz, CDCl3) δ: 8.19-8.14 (br s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.98-6.90 (m, 2H), 5.59-5.57 (br s, 1H ), 4.82 (s, 2H), 3.14 (s, 2H), 2.94-2.92 (m, 4H), 2.77-2.73 (m, 4H), 2.27 (s, 3H), 2.21 ppm (s, 3H); 13C-NMR (101 MHz, CDCl3) δ: 173.8, 172.0, 151.2, 138.0, 131.3, 125.8, 125.1, 74.6, 67.3, 63.7, 61.5, 54.1, 52.2, 20.6, 13.9 ppm; MS (ES +, m / z) 278 [M + H] +; Anal. C15H23N3O2: teor. C 64.96%, H 8.36%, exp .: C 65.09%, H 8.03%.
N- (Hydroxymethyl) -2- (4- (4-methoxyphenyl) piperazinyl) acetamide (24%). mp: 140-143 ° C; 1H-NMR (400 MHz, CDCl3) δ: 7.09-6.95 (m, 2H), 6.71-6.54 (m, 2H), 4.83 (s, 2H), 3.78
3.60 (m, 5H), 3.14-3.05 (m, 4H), 2.77-2.71 ppm (m, 4H); 13C-NMR (101 MHz, CDCl3) δ: 173.0, 152.4, 143.6, 123.4, 122.1, 118.6, 112.3, 65.7, 63.2, 55.1, 54.3, 53.8, 51.8, 51.2 ppm; MS (ES +, m / z) 280 [M + H] +; Anal. C14H21N3O3: Theor. C 60.20%, H 7.58%, exp. C 60.56%, H 7.25%.
General method of obtaining 1- (2- (4-arylpiperazinyl) acetamidomethyl) -1,4-dihydro7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (V) and 2- (2- (4-arylpiperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazoles of formula (VI)
A solution of 7-methoxy-4,4-dimethyl-1,4-dihydrochromen [4,3c] pyrazole (1eq) in anhydrous THF was slowly added to a suspension of NaH (3 eq) in anhydrous THF at 0 ° C under atmosphere of nitrogen After 10 min. The corresponding N- (hydroxymethyl) -2- (4-phenylpiperazinyl) acetamide (2 eq) was added at room temperature. The reaction mixture was heated at reflux for 12-72 h. The solvent was evaporated under vacuum. The crude dissolved in AcOEt was washed with water, dried with MgSO4 and the solvent was evaporated under vacuum. Semi-preparative chromatography on C18 silica (CH3CN / H2O) led to the separation of 1- (2- (4-arylpiperazinyl) acetamidomethyl) 1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole and the corresponding 2- (2- (4-arylpiperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole.
Example 11-Preparation and obtaining 1- (2- (4-phenylpiperazinyl) acetamidomethyl) 1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. White solid (13%). fp: 196-198 ° C; 1 H-NMR (500 MHz, CDCl 3) δ: 8.02-7.97 (br t, J = 6.3 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 6.85-6.74 (m, 2H), 6.55 (dd, J = 8.6,
2.6 Hz, 2H), 6.53-6.46 (m, 2H), 6.45 (d, J = 2.5 Hz, 1H), 5.73 (d, J = 6.3 Hz, 2H), 3.71 (s, 3H), 3.13-3.07 ( m, 4H), 3.03 (s, 2H), 2.57-2.48 (m, 4H), 1.52 (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 170.2, 165.1, 161.0, 154.3, 149.2, 133.8, 132.5, 129.1, 123.3, 121.4, 120.0, 116.2, 107.8, 103.85, 76.73, 61.3, 55.3, 54.32, 53.4, 49.1 , 28.24 ppm; MS (ES +, m / z) 462 [M + H] +; HRMS C26H31N5O3: teor. 461.2426, exp. 461.2433.
Example 12-Preparation and obtaining 2- (2- (4-phenylpiperazinyl) acetamidomethyl) 2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. Amorphous solid (5%); 1H-NMR (500 MHz, CD3OD) δ: 8.44-8.40 (br s, 1H), 7.51 (d, J = 8.5, 1H), 7.44 (s, 1H), 7.15 - 7.04 (m, 2H), 6.82 ( dd, J = 7.4, 1.0 Hz, 2H), 6.72 (tt, J = 7.4, 1.0 Hz, 1H), 6.47 (dd, J = 8.5, 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H ), 5.40 (s, 2H),
3.69 (s, 3H), 3.10-3.07 (m, 4H), 3.02 (s, 2H), 2.55-2.49 (m, 4H), 1.46 ppm (s, 6H); 13C-NMR (126 MHz, CD3OD) δ: 173.7, 162.7, 156.1, 152.7, 144.6, 130.0, 126.6, 123.9, 122.4, 121.1, 117.5, 111.5, 108.8, 104.2, 77.6, 62.1, 55.8, 55.4, 54.3, 54.2 , 50.5, 50.4,
29.3 ppm; MS (ES +, m / z) 462 [M + H] +; HRMS C26H31N5O3: teor. 461.2426, exp. 461.2421.
Example 13-Preparation and obtaining 1- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. White amorphous solid (3%); 1H-NMR (500 MHz, CDCl3) δ: 7.35 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.71-6.59 (m, 4H), 6.42 (dd, J = 8.1, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 3.59 (s, 3H), 3.54 (s, 3H), 3.29 (s, 2H), 3.10-3.03 (m, 4H ), 2.98-2.86 (m, 4H),
1.69 ppm (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 175.0, 160.4, 155.6, 155.1, 149.5, 147.1, 130.2, 127.5, 124.9, 118.7, 116.9, 116.3, 113.3, 111.4, 106.8, 104.2, 75.8, 61.4,
55.9, 55.1, 54.0, 53.7, 51.3, 25.9 ppm; MS (ES +, m / z) 492 [M + H] +; HRMS C27H33N5O4: teor. 491.2532, exp. 491.2528.
Example 14-Preparation and obtaining 2- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. Yellow oil (8%); 1H-NMR (500 MHz, CDCl3) δ: 7.04 (d, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.69-6.51 (m, 5H), 6.42 (d, J = 2.6 Hz, 1H) , 5.51 (s, 2H), 3.64 (s, 3H), 3.59 (s, 3H),
3.16 (s, 2H), 2.92-2.89 (m, 4H), 2.76-2.70 (m, 4H), 1.54 ppm (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 173.2, 163.1, 156.7, 153.1, 148.1, 144.9, 132.6, 126.1, 125.6, 120.9, 118.2, 117.5, 114.0, 110.6, 109.4, 106.0, 75.3, 60.2, 56.8, 56.1 , 54.6, 52.5, 50.7, 26.4 ppm; MS (ES +, m / z) 492 [M + H] +; HRMS C27H33N5O4: teor. 491.2532, exp. 491.2540.
Example 15-Preparation and obtaining 1- (2- (4- (2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. Yellow oil (2%); 1H-NMR (500 MHz, CDCl3) δ: 8.08-8.02 (bt, J = 6.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.61 (dd, J = 8.1, 2.6 Hz, 1H), 6.48 (d, J = 2.6 Hz, 1H), 5.61 (d, J =
6.4 Hz, 2H), 3.84 (s, 3H), 3.08 (s, 2H), 2.77-2.69 (m, 4H), 2.64-2.59 (m, 4H), 2.31 (s, 3H), 2.27 (s, 3H ), 1.48 ppm (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 169.8, 162.4, 156.0, 151.3, 144.2, 140.3, 132.5, 126.1, 125.0, 123.9, 123.1, 121.8, 117.2, 109.8, 108.4, 104.9, 75.7, 61.3, 56.0, 54.7 , 53.3, 51.9, 28.8, 19.7, 14.1 ppm; MS (ES +, m / z) 490 [M + H] +; HRMS C28H35N5O3: teor. 489.2739, exp. 489.2746.
Example 16-Preparation and obtaining 2- (2- (4- (2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. White solid (4%); mp: 199-201 ° C; 1H-NMR (500 MHz, CDCl3) δ: 8.22-8.17 (br t, J =
6.9  Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.08 (t, J = 7.7 Hz, 1H), 6.91 (d, J =
7.7  Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.57 (dd, J = 8.5, 2.5 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 5.54 (d, J = 6.9 Hz, 2H), 3.79 (s, 3H), 3.11 (s, 2H), 2.87 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 4.8 Hz, 4H), 2.25 (s, 3H), 2.18 (s, 3H), 1.58 ppm (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 171.5, 161.0, 154.6, 151.1, 143.5, 138.0, 131.2, 125.8, 125.2, 124.7, 122.8,
121.5, 116.6, 110.4, 108.0, 103.0, 76.5, 61.4, 55.3, 54.2, 53.9, 52.0, 29.1, 20.6, 13.8 ppm; MS (ES +, m / z) 490 [M + H] +; HRMS C28H35N5O3: teor. 489.2739, exp. 489.2750.
Example 17-Preparation and obtaining 1- (2- (4- (4 (methoxyphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
The desired compound was prepared according to the general method of preparation described above. Yellow oil (14%); 1H-NMR (500 MHz, CDCl3) δ: 7.50-7.48 (br t, J = 5.1 Hz, 1H), 6.81-6.76 (m, 4H), 6.76-6.68 (m, 2H), 6.47 (dd, J = 8.5, 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.39 (d, J = 5.1 Hz, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.01 (s, 2H), 2.97-2.94 (m, 4H), 2.55-2.47 (m, 4H), 1.46 ppm (s, 6H); 13C-NMR (126 MHz, CDCl3) δ: 172.2, 161.2, 154.6, 154.2, 145.2, 143.2, 125.1, 122.4, 120.9, 118.7, 113.8, 110.0, 107.3, 102.7, 76.1, 60.6, 54.4, 54.3, 53.9, 52.9 , 50.4, 27.8 ppm; MS (ES +, m / z) 492 [M + H] +; HRMS C27H33N5O4: teor. 491.2532, exp. 491.2524.
C. Biological tests
In the present invention, the activity on the GPR55 receptor of the compounds of the invention was assessed by carrying out in vitro assays of real-time cellular impedance measurements (xCELLigence experiments). These tests were performed on a human embryo kidney cell line HEK293 that stably overexpress the recombinant GPR55 receptor (hGPR55-HEK293). The cells were seeded one day before carrying out the stimulation with the example compounds of the present invention.
GPR55 agonist activity. Activation of the GPR55 receptor by an agonist compound causes a cellular impedance that detects the system and compares with the activity of a reference GPR55 ligand, lysophosphatidylinositol (LPI). The effect of the LPI measured at a concentration of 1μM was set at 100%. The maximum response was observed 5 minutes after the addition of the example compound of the invention. Therefore, dose-response curves were determined at this time. The cell impedance values were normalized for each well just before the addition of the example compound of the invention to be evaluated. The EC50 (nM) effective concentration values of some example compounds of the present invention and the percentage of the maximum effect Emax (%) relative to the activity of LPI are given below by way of illustration:
Table 1. Agonist action of compounds examples of the patent on GPR55 measured
by the xCELLigence system.
GPR55 Examples EC50 (nM) Emax (%)
2 0.88 (0.05-14.56) 43 (31-54)4 0.60 (0.12-3.03) 51 (42-60)6 0.51 (0.06-4.22) 45 (36-54)7 1.28 (0.20-9.46) 52 (41-63)8 0.40 (0.03-4.61) 51 (40-62)9 8.67 (1.18-63.45) 47 (36-58)10 0.69 (0.06-7.63) 49 (37-62)14 6.36 (0.98-41.52) 51 (36-67)LPI 2.82 (0.64-12.30) 100 (81-118)
These values represent the average with a 95% confidence interval calculated with 4 independent experiments performed in duplicate.
The compounds of examples 2, 4, 6∀10, and 14 are partial agonists of the GPR55 receptor.
GPR55 antagonist activity. The ability of the patent example compounds to inhibit stimulation of the LPR-mediated GPR55 receptor has been evaluated. The EC50 (nM) effective concentration values of LPI in the presence of some example compounds of the present invention at a concentration of 1 μM and the percentage of the maximum effect Emax (%) relative to the activity of LPI are given below and by way of illustration :
Table 2. Antagonistic action of compounds examples of the patent on the effect produced by LPI through GPR55 and measured by the xCELLigence system.
GPR55 Examples EC50 (nM) Emax (%)
LPI + 7 18.2 (4.6-71.1) 100 (91-115)
LPI + 8 24.6 (7.9-66.8) 102 (91-106)
LPI + 9 25.4 (6.6-96.7) 99 (90-113)
LPI + 10 21.9 (5.5-87.6) 100 (86-114)
LPI 1.6 (0.6-4.2) 99 (90-108)
The values represent the average with a 95% confidence interval calculated with 4 independent experiments performed in duplicate. Significant differences with respect to the LPI values are considered due to the lack of overlap of the confidence intervals.
The compounds of examples 7-10 are antagonists of the GPR55 agonist effect produced by LPI.
As a control experiment, it was found that the example compounds of the present invention have no action on HEK293 cells that do not overexpress the GPR55 receptor. None of the compounds showed cellular impedance.
Regarding the cannabinoid activity, no example compound of the present invention binds to the CB1 cannabinoid receptor. With respect to the binding with the CB2 receptor, of all the compounds examples only 3 have an affinity constant lower than micromolar: example 2 (698 ± 107 nM), example 6 (15.4 ± 7.8 nM), example 9 ( 523 ± 144 nM).
D. Pharmacokinetic properties: in silico predictions
The pharmacokinetic profile of the example compounds of the invention was determined by predicting physicochemical parameters in silico using the QikProp program implemented in Maestro (Schrödinger, LLC, New York, USA). The values shown in the table by the example compounds of the patent comply with the Lipinski rules, therefore, it is estimated that they are acceptable candidates to be part of a pharmaceutical composition.
Table 3. Physicochemical descriptors calculated by QikProp 3.5 integrated in Maestro (Schrödinger, LLC, New York, USA) [95% range of drugs].
% Oral Absorption Comp. QPlogSa QlogBBb QPlogHERGc QPPCacod
human in GIe1 -4.1 -0.05 -6,779 559 1002 -4.1 0.08 -7.051 774 1003 -4.7 0.01 -7.076 641 1004 -5.2 0.08 -7.524 796 1005 -4.8 0.12 -6.755 642 1006 -4.9 0.25 -7.085 880 1007 -4.4 0.03 -6.334 589 1008 -2.9 0.13 -5.028 512 899 -4.6 0.30 -5,133 832 10010 -3.9 0.27 -5.041 750 10011 -4.8 0.11 -5,803 529 10012 -4.7 0.10 -6.064 504 10013 -4.8 0.05 -5.588 529 10014 -4.7 0.04 -5.842 504 10015 -5.5 0.10 -5.543 529 10016 -5.5 0.09 -5.789 504 10017 -4.5 0.06 -5.395 529 100LPI -3.4 -4.84 -4.139 5 11
a Water solubility prediction [-6.5 / 0.5]; b Blood brain barrier passage prediction [-3.0 / 1.2]; c HERG K + channel lock (log IC50) [> -5]; d Apparent permeability in nm / s in Caco-2 cells [<25 low,> 500 excellent]; 10 e Human oral absorption in the gastrointestinal (GI) tract [<25% low].

权利要求:
Claims (24)
[1]
1. Compound of formula (I)
Formula (I)
or a tautomer, a pharmaceutically acceptable salt or solvate thereof; where:
10 !R1 is selected from optionally substituted aryl or a group -C (O) R3; R3 se
selects from aryl, heterocycle, C1-C6 alkyl, C3-C6 cycloalkyl or a
group - (CH2) n-O-aryl, where n is a value selected from 1, 2, 3 or 4,
! R2 is selected from C1-C6 alkylene or a group -R4-C (O) -NH-R5-, being
R4 and R5 C1-C6 alkylenes the same or different.
fifteen
[2]
2. Compound of formula (II)
Formula (II)
or a tautomer, a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are defined as in claim 1.
[3]
3. Compound of formula (III)
Formula (III)
or a tautomer, a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are defined as in claim 1.
[4]
4. Compound according to any of the preceding claims wherein R1 is a group -C (O) R3.
5. A compound according to the preceding claim wherein R3 is aryl.
[6]
6. Compound according to the preceding claim wherein R3 is phenyl.
[7]
7. Compound according to claim 4 wherein R3 is heterocycle. twenty
[8]
8. Compound according to the preceding claim wherein R3 is selected from furan, thiophene or tetrahydrofuran.
[9]
9. Compound according to claim 4 wherein R3 is cyclohexyl. 25
[10]
10. Compound according to claim 4 wherein R3 is C1-C4 alkyl.
[11]
eleven. Compound according to any one of claims 1 to 10 wherein R2 is C1-C4 alkylene.
[12]
12. Compound according to the preceding claim wherein R2 is ethylene.
[13]
13. Compound according to any of claims 1 to 12 selected from the group consisting of:
-1- (2- (4- (2-furoyl) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazole -2- (2- (4- ( 2-Furoyl) piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -1- (2- (4-benzoyl-piperazinyl) ethyl) -1,4- dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazol -2- (2- (4-benzoyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4 , 3c] pyrazole -1- (2- (4- (2-thienoyl) piperazinyl) ethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole -2- (2- (4- (2-thienoyl) piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4-phenoxyacetyl-piperazinyl) ethyl) - 2,4-Dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- (2-tetrahydrofuroyl) piperazinyl) ethyl) -2,4-dihydro-7-methoxy- 4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4-cyclohexylcarbonyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole -2 - (2- (4-pivaloyl-piperazinyl) ethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3c] pyrazole.
[14]
14. Compound according to any one of claims 1 to 3 wherein R1 is an optionally substituted phenyl.
[15]
fifteen. Compound according to the preceding claim wherein R1 is a phenyl substituted by a C1-C4 alkyl or a C1-C4 alkyloxy.
[16]
16. Compound according to the preceding claim wherein R1 is a phenyl substituted by at least one methyl or a methoxy.
[17]
17. Compound according to any of claims 14 to 16 wherein R2 is a group -R4-C (O) -NH-R5-, R4 and R5 being C1-C4 alkylenes the same or different.
[18]
18. Compound according to the preceding claim wherein R4 and R5 are methylene.
[19]
19. Compound according to any of claims 14 to 18 selected from the group consisting of: -1- (2- (4-phenylpiperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole -1- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole -1- (2- (4- (2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -1- (2- (4- (4-methoxyphenyl) piperazinyl) acetamidomethyl ) -1,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4-phenylpiperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazol -2- (2- (4- (2-methoxyphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole
- 2- (2- (4- (2,3-dimethylphenyl) piperazinyl) acetamidomethyl) -2,4-dihydro-7-methoxy-4,4-dimethylchromen [4,3-c] pyrazole.
[20]
twenty. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 19.
[21]
twenty-one. Pharmaceutical composition according to claim 20 further comprising another active ingredient.
[22]
22 Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament.
[23]
2. 3. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment and / or prevention of a disorder associated with the GPR55 receptor.
[24]
24. Use according to claim 23 wherein the disorder is selected from diabetes, Parkinson's disease, multiple sclerosis, neuropathic pain, osteoporosis, cholangiocarcinoma, breast cancer, ovarian and prostate cancer, glioblastoma and cutaneous carcinoma.
[25]
25. Use of a compound according to any of claims 1 to 19 for the manufacture of a reagent in biological assays related to the GPR55 receptor.
...... GPR55-HEK293
~ HEK293
-10 -9 -8 -7 -6 -5log [LPI] (M)
or 100
"'C
neither
N 80
(ij
AND
"-o 60
z
"
not 40
~
Q;
u 20
...... GPR55-HEK293
Q, J
or"'C O
~ HEK293
~
-10 -9 -8 -7 -6 -5 log [6] (M)
FIG. 1
- + -GPR55-HEK293
- or
fUN 80
~ HEK293
(ij
AND
"-60
or
z
"
~
u 20
QI
or-o OR
~
-10 -9 -8 -7 -6 -5 log [2] (M)
or 100
- or
- + -GPR55-HEK293
fUN 80
~ HEK293
(ij
AND
"-60
or
z
"
~
u 20
QI
or
- or
~
-10 -9 -8 -7 -6 -5 log [8] (M)
FIG. 1 cont.
or 120
"'Cneither
.! ::! 100nor ....... LPI
E 80
___ LPI + example 10
orz 60
The
neither
-
:: l 40cvu 20
cv
.-or
"'C
.
and
, -
-10 -9 -8 -7 -6 -5 log [ligand] (M)
FIG. 2

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US15/571,671| US10435412B2|2015-05-05|2016-04-27|Selective modulators of the activity of the GPR55 receptor: chromenopyrazole derivatives|

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PCT/ES2016/070314| WO2016177922A1|2015-05-05|2016-04-27|Selective modulators of the activity of the gpr55 receptor: chromenopyrazole derivatives|

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MX2017014145A| MX2017014145A|2015-05-05|2016-04-27|Selective modulators of the activity of the gpr55 receptor: chromenopyrazole derivatives.|

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IL255420A| IL255420D0|2015-05-05|2017-11-05|Selective modulators of the activity of the gpr55 receptor: chromenopyrazole derivatives|