Patent Application
20230286946
The present invention relates to difluoromethyl-pyridin-2-yl triazoles of general formula (I) which are modulators of GABAA receptors containing the α5 subunit. The compounds are useful in treating central nervous system and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacturing the compounds according to the invention.
It has been suggested that the GABAA α5 subunit represents a therapeutic target for treatment of various diseases and disorders of the central nervous system. A nexus has been established between the GABAA α5 subunit as therapeutic target, and various neurological disorders, disorders of circadian rhythms, pain conditions. Compounds capable of modulating GABAA receptors containing the α5 subunit are in particular expected to be useful candidates for the treatment of i.a. cognitive disorders, Alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia and cognitive deficits associated with Down syndrome, with autism, with neurofibromatosis type I, or after stroke.
WO 2012/062687 A1 (corresponding to EP-2638029-A1) discloses triazole derivatives for treating neurological disorders.
WO 2020/016443 A1 discloses difluoromethyl-phenyl triazoles as GABA receptor modulators for treating nervous system diseases. Said compounds contain a difluoromethyl group attached to a phenyl group linked to a triazole ring.
The present invention describes difluoromethyl-pyridin-2-yl triazoles. Said compounds contain a difluoromethyl group attached to a 2-pyridine group linked to a triazole ring. The combination of a 2-pyridine group with an attached difluoromethyl group surprisingly led to compounds being considerably more potent modulators of GABAA receptors containing the α5 subunit than the similar compounds described in WO 2020/016443. Modulatory potency of a compound can be measured as Ki value of the compound in assay A described in the following. In the present case, the combination of a pyridine group instead of the phenyl group used in the phenyl triazoles of WO 2020/016443 and the difluoromethyl group in position 4 unexpectedly increases the potency of the claimed compounds by a factor of at least about 10 or more in general.
The potency is related to the GABAA5R binding constant Ki, wherein an increased potency translates into a lower efficacious dose of the respective compound for disease treatment.
Surprisingly it has been found that pyridine-2-yl-triazoles of the general formula (I),
wherein:
Therefore, one aspect of the invention refers to compounds according to formula (I), or salts thereof which are negative modulators of the GABAA5R.
Another aspect of the invention refers to compounds according to formula (I), or pharmaceutically acceptable salts thereof which are negative modulators of the GABAA5R with high GABAA5R binding properties.
Another aspect of the invention refers to compounds according to formula (I), or pharmaceutically acceptable salts thereof which are negative modulators of the GABAA5R with high GABAA5R binding properties and excellent CNS penetration with low efflux ratio from the brain compartment and high metabolic stability.
Yet a further aspect the invention relates to pharmaceutical compositions, containing at least one compound according to formula (I), or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.
An additional aspect of the invention relates to processes of manufacture of the compounds of the present invention.
In particular the present invention relates to compounds according to formula (I), or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising compounds according to formula (I), or pharmaceutically acceptable salts thereof for the use in the prevention and/or treatment of diseases or conditions which can be influenced by negative modulation of the GABAA5R such as acute neurological disorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, post operative cognitive decline, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis, dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, major depressive disorder, neuropsychiatric conditions, psychosis, attention-deficit hyperactivity disorder, neuropathic pain, stroke, attentional disorders, eating disorders, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain conditions, chronic pain, nociceptive pain, post-operative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, ocular pain, pain due to inflammation, pain due to bone fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemia pain, fibromyalgia, chronic headache, migraine, tension-type headache, diabetic neuropathic pain, phantom limb pain, visceral pain and cutaneous pain.
Other results or conclusions of the present invention become apparent to the skilled man directly from the foregoing and following remarks.
The present invention relates to compounds of general formula (I)
or a salt thereof, wherein
In particular either Xa or Xb is C.
R1 is preferably selected from the group consisting of
Unless otherwise stated, the groups, residues, and substituents, particularly R1 are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given hereinafter.
In a further embodiment of the invention R1 is selected from the group consisting of
and
In a further embodiment of the invention R1 is
In a further embodiment of the invention R1 is selected from the group consisting of compound of claim 1 or a salt thereof, wherein R1 is
In a further embodiment of the invention R1 is
In a further embodiment of the invention R1 is
In a further embodiment of the invention R1 is
In yet a further embodiment of the invention R1 is
Further preferred are the following compounds listed in Table 1:
Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely.
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general in groups like HO—, H2N—, (O)S—, (O)2S—, NC— (cyano), HOOC—, F3C— or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-3-alkyl-” means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
In general, the attachment site of a given residue to another group shall be variable, i.e. any capable atom, bearing hydrogens to be replaced, within this residue may be the linking spot to the group being attached, unless otherwise indicated.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
The phrase “pharmaceutically acceptable” or “physiologically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salt” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
Further pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.
The term “substituted” as used herein means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's viable valence number is not exceeded, and that the substitution results in a stable compound.
The term “partially unsaturated” as used herein means that in the designated group or moiety 1, 2, or more, preferably 1 or 2, double bonds are present. Preferably, as used herein, the term “partially unsaturated” does not cover fully unsaturated groups or moieties.
The term “halogen” generally denotes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
The term “C1-n-alkyl”, wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.
The term “C3-n-cycloalkyl”, wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably, the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
General Chemical Synthetic Routes Used for the Compounds Disclosed Herein are
Analytical HPLC Methods
Method A
Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method B
Analytical column: Xbridge BEH C18, 2.1×30 mm, 1.7 μm; column temp: 60° C.
Method C
Analytical column: Sunfire (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method D
Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method E
Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method F
Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method G
Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method H
Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method I
Analytical column: XBridge BEH C18_2.1×30 mm 1.7 μm; column temp: 60° C.
Method J
Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method K
Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temp: 60° C.
Method L
Analytical column: Hypercarb_3.0×30 mm_3 μm; column temp: 60° C.
Method M
Analytical column: Acquity UPLC 1.8 μm C18 (2.1×50 mm), 100 Å; column temp: 25° C.
Method N
Analytical column: Kinetex XB-C18 2.6 μm (4.6×50 mm), 100 Å; column temp: 25° C.
Preparation of Starting Compounds I to XVIII
2-Azido-5-difluoromethyl-pyridine (25.7 g, 151 mmol) in 50 mL But-2-an-1-ol is stirred for 5 days at 120° C. The excess of the alcohol is evaporated in vacuo as much as possible. The 3-(5-Difluoromethyl-pyridin-2-yl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol 9.00 g is obtained by column chromatography on silica gel as a white solid utilazing DCM/acetone (10:1) as the eluent.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.43 (m, 3H) 4.86 (s, 2H) 7.26 (t, J=56 Hz 1H) 8.11 (d, J=8.59 Hz, 1H) 8.31 (s, 1H) 8.84 (d, J=0.76 Hz, 1H)
To a solution of 6-Bromo-pyridine-3-carbaldehyde (186 g, 1.00 mol) in 1.86 L Dichloromethane at 0° C. is added dropowise diethylaminosulfur trifluoride (185 ml; 1.40 mol). The mixture is stirred at rt for 18 h. The reaction mixture is poured into ice and saturated NaHCO3. The aqueous phase is extracted 3 times with DCM. The combined organic layers are dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, hexane/EE (4/1)) to afford 170 g of the product.
C6H4BrF2N (M=208.0 g/mol)
ESI-MS: 208 [M+H]+
1H NMR (DMSO-d6, 400 MHz): δ=8.65 (d, J=1.3 Hz, 1H), 7.91-8.08 (m, 1H), 7.76-7.92 ppm (m, 1H), 7.17 (t, J=56 Hz, 1H)
To a mixture of example II (120 g, 0.58 mol), bis(triphenylphosphine)palladium(II)chloride (20.2 g, 0.03 mol), copper(I) iodide (5.49 g, 0.03 mol) and triethylamine (250 mL, 1.73 mol) in 600 mL tetrahydrofuran at 0° C. is added dropwise ethynyl-trimethyl-silane (160 mL, 1.15 mol). The resulting mixture is stirred at RT for 18 h. The mixture is filtered through celite. The cake is washed with EtOAc. The filtrate is washed with water, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (silica gel, hexane/EE (19/1)) afforded 117 g of the product.
C11H13F2NSi (M=225.3 g/mol)
ESI-MS: 226 [M+H]+
1H NMR (DMSO-d6, 400 MHz): δ=8.76 (d, J=0.8 Hz, 1H), 8.01 (dt, J=8.1, 0.9 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.16 (t, J=56 Hz, 1H) 0.23-0.30 ppm (m, 9H)
To a solution of example III (100.0 g, 0.42 mol) 800 mL tetrahydrofuran is added water (15.0 mL, 834 mmol). The resulting solution is cooled to 0° C. an then tetrabutylammonium fluoride 1.0 M in THF (143 mL; 0.50 mol) is added dropwise. After 1 h, TLC indicated that the reaction is completed. Water is added and the aqueous layer is extracted 3 times with diethyl ether. The combined organic layers are dried, filtered and carefully concentrated. The residue is purified by column chromatography (silica gel, hexane/DCM (1/1 to 0/1)) to afford the product.
C8H5F2N (M=153.1 g/mol)
ESI-MS: 154 [M+H]+
1H NMR (DMSO-d6, 400 MHz): δ=8.77 (d, J=0.8 Hz, 1H), 8.03 (br d, J=8.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.17 (t, J=56 Hz, 1H) 4.50 ppm (s, 1H)
To a solution of example IV (50.0 g, 0.30 mol) in 1.5 L DMF, Copper (I) iodide (10.9 g, 0.06 mol) and N,N-diisopropylethylamine (50.360 mL 0.29 mol) is added, followed by dropwise addition of trimethylsilylmethyl azide (50.6 mL, 0.34 mol). The resulting mixture is stirred at rt for 24 h. The reaction is quenched by addition of water/brine, then EtOAc is added and the mixture is filtered through celite. The filtrate is extracted 3 times with EtOAc, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (silica gel, hexane/EE (3/1)) followed by trituration of the solids with pentane and drying afforded 68.0 g of the product.
C12H16F2N4Si (M=282.4 g/mol)
ESI-MS: 283 [M+H]+
Rt (HPLC): 3.52 min (Method M)
1H NMR (DMSO-d6, 400 MHz): δ=8.78 (s, 1H), 8.52 (s, 1H), 8.13-8.20 (m, 1H), 8.05-8.12 (m, 1H), 7.17 (t, J=56 Hz, 1H) 4.10 (s, 2H), 0.11 ppm (s, 9H)
To a solution of example V (93.0 g, 0.33 mol in 1.86 L Tetrahydrofuran is added water (11.9 ml, 0.66 mol). The resulting solution is cooled to 0° C. and tetrabutylammonium fluoride (395.2 ml, 0.40 mol) is added dropwise. The reaction mixture is stirred at 0° C. for 1.5 h. Water is added and the THF is evaporated. The precipitate formed is filtered, washed with water and dried to afford 51.0 g of the product.
C9H8F2N4 (M=210.1 g/mol)
ESI-MS: 211 [M+H]+
1H NMR (DMSO-d6, 400 MHz): δ=8.80 (d, J=1.0 Hz, 1H), 8.65 (s, 1H), 8.14-8.19 (m, 1H), 8.03-8.13 (m, 1H), 7.17 (t, J=56 Hz, 1H), 4.13 ppm (s, 3H)
To a solution of example VI (40.0 g, 0.19 mol) in 1.2 L Tetrahydrofuran at −65° C. is added dropwise a 2.5 M solution of N-Butyllithium (114.2 mL, 0.29 mol) in hexanes. The resulting mixture is stirred at this temperature for 1.5 h. Then, N,N-Dimethylformamide (147.4 mL, 1.90 mol) is added dropwise and then reaction mixture is stirred at 0° C. for 30 min. The reaction is quenched by slowly addition of aqueous NH4Cl. The aqueous layer is extracted 3 times with EtOAc. The combined organic layers are dried over Na2SO4, filtered and concentrated. Purification by column chromatography (silica gel, DCM/EE (7/3 to 5/5)) followed by trituration with pentane afforded 19.9 g of the product.
C9H8F2N4 (M=238.2 g/mol)
ESI-MS: 239 [M+H]+
Rt (HPLC): 2.68 min (Method M)
1H NMR (DMSO-d6, 400 MHz): δ=10.68 (s, 1H), 8.92 (d, J=0.8 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.22 (dd, J=8.1, 1.0 Hz, 1H), 7.23 (t, J=56 Hz, 1H), 4.29 ppm (s, 3H)
Example VII (19.9 g, 0.08 mol) is dissolved in 199 mL Methanol and 99.5 mL Tetrahydrofuran. The resulting solution is cooled to 0° C. Then sodium borohydride (6.32 g, 0.17 mol) is added portionwise and the reaction mixture is stirred at this temperature for 2 h. The reaction is quenched by addition of water. The MeOH is evaporated and the resulting precipitate is collected by filtration, washed with water and dried. The solids are triturated with pentane to afford 19.4 g of the product.
C9H8F2N4 (M=240.2 g/mol)
ESI-MS: 241 [M+H]+
Rt (HPLC): 3.52 min (Method N)
1H NMR (DMSO-d6, 400 MHz): δ=8.83 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.11 (br d, J=8.1 Hz, 1H), 7.18 (t, J=56 Hz, 1H), 5.53 (s, 1H), 5.09 (d, J=3.8 Hz, 2H), 4.11 ppm (s, 3H)
To example I (4.00 g, 16.6 mmol) in 50 mL THF is added sodium hydride (1.10 g, 25.0 mmol) and 3,6-Diiodo-pyridazine (5.50 g, 17.0 mmol) The reaction mixture is stirred at 80° C. overnight. The reaction mixture is evaporated. The residue is quenched with water and the product is extracted with DCM. The organic phases are combined and the organic phase is dried with MgSO4 and is evaporated. The crude product is purified by column chromatography (silica gel, CH/EE (6/4)) to afford 6.30 g of the product.
C14H11F2N6O (M=444.2 g/mol)
ESI-MS: 445 [M+H]+
Rt (HPLC): 0.57 min (Method A)
1H NMR (DMSO-d6, 400 MHz): δ=8.53-8.80 (m, 1H), 8.33 (dt, J=8.5, 1.1 Hz, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.22 (t, J=52 Hz, 1H), 6.95 (d, J=9.1 Hz, 1H), 5.95 (s, 2H), 2.36-2.45 ppm (m, 3H)
Examples IX.2 to IX.4 mentioned in the following table of the compounds of examples IX.2 to IX.4 are prepared according to the general procedure of Example IX.1 described above.
The reaction conditions mentioned in the Table below were used for examples IX.2 to IX.4
1H NMR (DMSO-d6, 400 MHz): δ =
1H NMR (DMSO-d6, 400 MHz): δ = 8.78
To 4-Cyanopyrazole (312 mg, 3.40 mmol) in 5 mL DMF are added 3,6-dichloropyridazine (500 mg, 3.40 mmol) and potassium carbonate (1.40 g, 10.1 mmol) and the reaction mixture is stirred at RT overnight. The mixture is quenched with iced water and the precipitation is filtered. The residue is washed with water and the isolated solid is dried in the vacuum drying cabinet to get 524 mg of the product.
C8H4ClN5 (M=205.6 g/mol)
ESI-MS: 206 [M+H]+
Rt (HPLC): 0.80 min (Method C)
The following compounds are prepared according to the general procedure of Example X.1 described above:
6-Chloro-pyridazin-3-yl)-hydrazine (16.4 g, 113 mmol) and N-[1-Dimethylamino-meth-(E)-ylidene]-acetamide (15.5 g, 136 mmol) are dissolved in 164 mL acetic acid. The mixture is placed in a pre-heated oil bath at 80° C. The reaction is stirred at this temperature for 30 min (TLC monitoring) and acetic acid is evaporated in vacuo. The residue is dissolved in EtOAc and the organic layer is slowly neutralized with NaHCO3 (conc. water colution). The organic layer is dried over Na2SO4 and the solvent is evaporated. The product is purified on silica gel utilizing EtOAc/hehane (3:1) as an eluent. 10.2 g 3Chloro-6-(5-methyl-[1,2,4]triazol-1-yl)-pyridazine is obtained as a creamy solid.
To sodium hydride (1.74 g, 43.6 mmol) in 50 mL DMF is added methyl 1H-imidazole-4-carboxylate (5.00 g, 39.6 mmol) at 0° C. The reaction mixture is stirred for 30 min. To the reaction mixture is added a solution of 3,6-dichloropyridazine (5.90 g, 39.6 mmol) in 30 mL DMF at 0° C. and the mixture is stirred for 20 h to reach RT. The reaction mixture is quenched with water under ice cooling and the precipitation is filtered, washed and dried to give 3.90 g of the product.
C9H7ClN4O2 (M=238.6 g/mol)
ESI-MS: 239 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ=8.74 (d, J=1.3 Hz, 1H), 8.72 (d, J=1.0 Hz, 1H), 8.43 (d, J=9.3 Hz, 1H), 8.25 (d, J=9.3 Hz, 1H), 3.82 (s, 3H)
To example XII (3.80 g, 15.8 mmol) in 100 mL 1,4-dioxane is added 1M NaOH (16.0 mL, 16.0 mmol) and is stirred for 18 h at RT. The reaction mixture is quenched with ice and 1 M HCl (16.0 mL, 16.0 mmol). The precipitation is filtered, washed and dried to yield 3.30 g of the product.
C8H5ClN4O2 (M=224.6 g/mol)
ESI-MS: 225 [M+H]+
Rt (HPLC): 0.58 min (Method C)
To example VI (1.00 g, 4.50 mmol) in 10 mL DMF are added DIPEA (2.30 mL, 13.4 mmol) and TBTU (1.40 g, 4.50 mmol) and is stirred for 10 min at RT. Ammonium bicarbonate (1.10 g, 13.4 mmol) is added and the reaction mixture is stirred for 1 h at RT. The mixture is quenched with ice and the precipitation is filtered, washed and dried to afford 0.80 g of the product.
C8H6ClN5O (M=223.6 g/mol)
ESI-MS: 224 [M+H]+
Rt (HPLC): 0.54 min (Method C)
To 1H-imidazole-4-carbonitrile (9.30 g, 99.9 mmol) in 100 mL DMF are added example III (20.5 g, 99.9 mmol) and potassium carbonate (41.4 g, 299 mmol) and the reaction mixture is stirred at 50° C. for 18 h. Addition of 1H-imidazole-4-carbonitrile (5.00 g, 53.7 mmol) and the mixture is stirred at 50° C. for 3 days.
The mixture is quenched with water and the precipitate is filtered to give after drying 25.8 g of the product.
C12H6N8 (M=262.2 g/mol)
ESI-MS: 263 [M+H]+
Rt (HPLC): 0.74 min (Method C)
To 4-chloro-1H-pyrazole (688 mg, 7.00 mmol) in 5 mL DMF are added 3,6-Dichloro-pyridazine (500 mg, 3.36 mmol) and cesium carbonate (2.40 g, 7.38 mmol) and the reaction mixture is stirred at RT overnight. The mixture is quenched with water and the precipitate is filtered to give 686 mg of the product.
C8H6N8 (M=215.0 g/mol)
ESI-MS: 216 [M+H]+
Rt (HPLC): 0.51 min (Method A)
The following compounds are prepared according to the general procedure (Example XVI.1) described above:
To 2-oxoacetic acid hydrate (2.26 g, 25.0 mmol) in aq. K2CO3-solution (6.79 g, 49.0 mmol in 30 mL water) is added acetylpyrazine (3.00 g, 24.6 mmol). The mixture is stirred at RT for 6 h. Then acetic acid (12.9 mL, 221 mmol) and hydrazine hydrate (1.42 mL, 29.0 mmol) are added and the reaction mixture is refluxed for 2 h. The solution is cooled to RT and basified to pH7 with K2CO3. The precipitate is filtered, dried in the oven at 40° C. to get 1.29 g of the product.
C8H16N4O (M=174.1 g/mol)
ESI-MS: 175 [M+H]+
Rt (HPLC): 0.23 min (Method A)
Example XVII (1.50 g, 6.03 mmol) in POCl3 (5.00 mL, 53.6 mmol) is stirred at 100° C. for 1 h. The reaction mixture is evaporated and the residue is diluted with DCM under cooling. 10 mL sat. NaHCO3-solution is added and this solution is added dropwise under stirring to an icy sat. NaHCO3-solution until the solution is neutral. After 30 min the solution is filtered over celite and it is extracted with DCM. The organic layers are collected, dried and the solvent is evaporated. The product is purified by column chromatography (silica gel, CH/EE (1/1)) to afford 570 mg of the product.
C8H6ClN4 (M=192.6 g/mol)
ESI-MS: 193 [M+H]+
Rt (HPLC): 0.33 min (Method A)
Preparation of Final Compounds
To 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (159 mg, 0.70 mmol) is added example IX.1 (250 mg, 0.60 mmol) in 1.5 mL methanol, 3 mL 1,4 dioxane, 2M aq sodium carbonate solution (0.60 mL, 1.10 mmol) and Pd-PEPPSI (9.50 mg 0.01 mmol) under argon and the reaction mixture is stirred for 3 h at 100° C. The mixture is purified by preparative HPLC to obtain 96.1 mg of the product.
C20H17F2N7O2 (M=425.4 g/mol)
ESI-MS: 426 [M+H]+
Rt (HPLC): 0.58 min (Method D)
1H NMR (400 MHz, DMSO-d6) δ ppm 2.41-2.46 (m, 3H) 3.48-3.57 (m, 3H) 5.96-6.08 (m, 2H) 6.47-6.58 (m, 1H) 7.21 (t, J=56 Hz 1H) 7.23 (s, 1H) 7.95-8.06 (m, 1H) 8.13-8.22 (m, 2H) 8.29-8.38 (m, 1H) 8.51 (d, J=2.66 Hz, 1H) 8.65-8.71 (m, 1H)
The following compounds are prepared according to the general procedure of Example 1 described above:
For the example compounds the reaction conditions in Table 2 were used.
To example I (50.0 mg, 0.20 mmol) and example XIV (46.5 mg, 0.20 mmol) in 2 mL DMSO is added dropwise at 0° C. a solution of sodium tert-pentoxide 2 mol/L in Me-THF (83.9 μL, 0.20 mmol). The reaction mixture is stirred at RT overnight, then at 50° C. overnight and then at 75° C. for 3 days. The mixture is purified by preparative HPLC to obtain 3.20 mg of the product.
C18H15F2N9O2 (M=427.4 g/mol)
ESI-MS: 428 [M+H]+
Rt (HPLC): 0.77 min (Method C)
The following compounds are prepared according to the general procedure of example 36 described above:
For the example compounds 37-41 the reaction conditions in the Table below were used.
1H NMR (400 MHZ,
To example I (200 mg, 1.00 mmol) in 5 mL ACN are added cesium carbonate (814 mg, 2.00 mmol) and example XV (273 mg, 1.00 mmol) and the mixture is stirred overnight at 90° C. The reaction mixture is quenched with water and the precipitation is filtered to get the crude product. The crude product is purified by silica gel column (CH/EE), recrystallization in MeOH/EE/Ether at the end give 151 mg of the product.
C18H13F2N9O (M=409.3 g/mol)
ESI-MS: 410 [M+H]+
Rt (HPLC): 0.50 min (Method A)
1H NMR (400 MHz, DMSO-d6) δ ppm 2.34-2.48 (m, 3H) 5.97-6.14 (m, 2H) 7.22 (t, J=56 Hz, 1H) 7.50-7.64 (m, 1H) 8.16-8.19 (m, 1H) 8.19-8.21 (m, 1H) 8.31-8.43 (m, 1H) 8.67 (d, J=1.14 Hz, 1H) 8.73 (d, J=1.27 Hz, 1H) 8.90-8.95 (m, 1H)
The following compounds 43-47 of the Table below are prepared according to the general procedure of Example 42 described above:
For the example compounds 43-47 the reaction conditions in the table below were used.
1H NMR (400 MHZ, DMSO-d6) δ ppm 2.47 (s, 3
To example VIII (200 mg, 0.83 mmol) and example XI (163 mg, 0.83 mmol) in 10 mL Dioxan is added sodium tert-pentoxide (101 mg, 0.92 mmol). The reaction mixture is stirred at 90° C. overnight, then at RT over the weekend. The reaction mixture is diluted with water and the precipitate is filtered. The crude solid is recrystallized in MeOH to obtain 212 mg of the product.
C17H15F2N9O (M=399.4 g/mol)
ESI-MS: 400 [M+H]+
Rt (HPLC): 0.46 min (Method A)
The following compounds 49 and 50 are prepared according to the general procedure of example 48 described above:
For the example compounds 49-50 the reaction conditions in the Table below were used.
To example VIII (100 mg, 0.42 mmol) and example XVI.1 (89.5 mg, 0.42 mmol) in 2 mL DCM is added sodium hydride (21.8 mg, 0.50 mmol). The reaction mixture is stirred at RT overnight. The reaction mixture is directly purified by preparative HPLC to obtain 41.6 mg of the product.
C17H13ClF2N8O (M=418.8 g/mol)
ESI-MS: 397 [M+1-1]+
Rt (HPLC): 0.86 min (Method F)
The following compounds are prepared according to the general procedure (example 51) described above:
For the example compounds 52-53 the reaction conditions in the Table below were used.
1H NMR (DMSO-d6, 400 MHz): δ = 8.95 (d, J =
1H NMR (DMSO-d6, 400 MHZ): δ = 8.97 (d, J =
To 4-Fluoro-1H-pyrazole (6.00 mg, 0.10 mmol) in 1 mL dioxane is added example IX.1 (30.0 mg, 0.10 mmol), copper(I)iodide (5.10 mg, 0.03 mmol), potassium phosphate (57.3 mg, 0.30 mmol) and (1R,2R)—N,N′-Dimethyl-1,2-cyclohexanediamine (8.50 μL, 0.05 mmol) under argon. Then 100 μL 25% ammonia is added and the mixture is stirred another 15 min. The reaction mixture is filtered over alox cartridge and SPE-thiol cartridge and then it is purified by preparative HPLC to obtain 20.2 mg of the product.
C17H13F3N8O (M=402.3 g/mol)
ESI-MS: 403 [M+H]+
Rt (HPLC): 0.84 min (Method F)
The following compound 55 is prepared according to the general procedure of Example 54 described above:
For the example compound 55 the following reaction conditions were used.
To 2-Tributylstannylpyrazine (83.0 mg, 0.23 mmol) in 2 mL dioxane is added to example IX.2 (53.0 mg, 0.15 mmol), cesium fluoride (46.0 mg, 0.30 mmol) and xphos (26.0 mg, 0.03 mmol) under argon. The reaction mixture is purified by preparative HPLC to obtain 17.0 mg of the product.
C18H14F2N8O (M=396.3 g/mol)
ESI-MS: 397 [M+H]+
Rt (HPLC): 0.92 min (Method G)
1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H) 6.11 (s, 2H) 7.22 (t, J=56 Hz, 1H) 7.35 (d, J=9.25 Hz, 1H) 8.20 (d, J=8.49 Hz, 1H) 8.32-8.37 (m, 1H) 8.39 (d, J=9.25 Hz, 1H) 8.67 (d, J=1.14 Hz, 1H) 8.74-8.84 (m, 2H) 9.55-9.66 (m, 1H)
Assay A: In Vitro Inhibition of 3H-Flumazenil (3H-Ro 15-1788) Binding HEK Cells Expressing the Human GABAA α5β3γ2s Receptor
The benzodiazepine modulator unit can selectively be labelled with the antagonist 3H-flumazenil.
The affinity of 3H-flumazenil for different subunit combinations have been reported to be 1.0 nM, 1.1 nM, 1.5 nM and 0.4 nM for α1ß2γ2; α2ß2γ2; α3ß2γ2 and α5ß2γ2s receptors, respectively, and 107 nM and 90 nM for a α4ß2γ2 and α6ß2γ2 receptors (see Sieghart; Pharmacol. Rev. 1995 47 181-234).
The pharmacology of the mutated α5ß3γ2s GABAA receptor is similar to that of the wild type receptor with respect 3H-flumazenil binding.
Cell Cultures and Membrane Preparation
HEK-293 cell lines with stable expression of recombinant human GABAA α5ß3 γ2s receptors (plasmid H46/E9/B10) are seeded in T175 polystyrene flasks or roller bottles (1700 cm2, Fisher Scientific CCI-431191), and cultured (37° C., 5% CO2) in Dulbecco's Modified Eagle Medium (DMEM) with GlutaMAX™ supplemented with 10% fetal bovine serum and one or both of the following antibiotics: hygromycin B (50 pg/ml; γ2 subunit) or G418 (0.5 mg/ml; Ω5 subunit).
When the cultures reach confluency, the DMEM is removed and the cells are washed (10 ml for T175 flasks; 50 ml for roller bottles) once in Dulbecco's Phosphate Buffered Saline (DPBS). Following addition of DPBS to the cultures (10 ml for T175 flasks; 100 ml for roller bottles) for approximately 5 min cells are easily detached from the surface by shaking or tapping the flask gently. The cell suspension is transferred to Falcon tubes and centrifuged at 23,500×g for 10 min at 2° C. The pellet is washed once in 15 ml Tris-citrate buffer (50 mM, pH 7.1) using an Ultra-Turrax homogenizer and centrifuged at 2° C. for 10 min at 27,000×g. The washed pellet is re-suspended in 15 ml Tris-citrate buffer and frozen at −80° C. until the day of the binding experiment.
Assay
On the day of the experiment the cell membrane preparation is thawed and centrifuged at 2° C. for 10 min at 27,000×g. The pellet is re-suspended, using an Ultra-Turrax homogenizer in Tris-citrate buffer, to 15-50 pg protein per assay and then used for binding assays.
Aliquots of 500 μl cell suspension are added to 25 μl of test compound solution and 25 μl of 3H-flumazenil (1 nM, final concentration), mixed and incubated for 40 min at 2° C. Non-specific binding is determined using clonazepam (1 final concentration).
All dilutions of test compounds and incubation of assay are performed in glass vials/96-vial plates. Solutions of test compounds and 3H-flumazenil are prepared 22× the desired final concentration. Compounds are dissolved in 100% DMSO (10 mM stock), diluted in 48% ethanol-water, and tested in triplicate in serial 1:3 or 1:10 dilutions. When screening large numbers of compounds only one concentration of each compound is tested in single wells. Reference compounds are not included routinely, but for each experiment performed total and nonspecific binding is compared to data obtained during validation of the assay.
Binding is either terminated by rapid filtration onto
1) Whatman GF/C glass fibre filters using a Brandel Cell harvester, followed by 5 washes with 1 ml ice-cold buffer or onto 2) UniFilter GF/C glass fibre filter plates using a Tomtec cell harvester, followed by washing with approximately 5 ml ice-cold buffer.
The amount of radioactivity on the filters is determined by conventional liquid scintillation counting using a
1) Tri-Garb™ counter (PerkinElmer Life and Analytical Sciences) for separate large filters or
2) Topcount™ counter (PerkinElmer Life and Analytical Sciences) for 96-well filter plates.
Specific binding is total binding minus non-specific binding.
Calculations
25-75% inhibition of specific binding must be obtained before calculation of an IC50 (the concentration (0/1) of the test compound which inhibits the specific binding of 3H-flumazenil by 50%).
The IC50 value for a test compound is determined based on the equation:
B=100−(100*Cn/(IC50n+Cn))
where B is the binding in percentage of total specific binding; C is the concentration of test compound; and n is the Hill coefficient. For screening purposes n is set to 1. The IC50 value is calculated from the concentration response curves by the non-linear regression method using the curve-fitting program GraphPad Prism.
The Ki value for a test compound can be calculated from the IC50 value using the equation by Cheng and Prusoff:
K=IC50/(1+L/Kd)
where the Kd for 3H-flumazenil is 0.36 nM, and L is the measured concentration of 3H-flumazenil in the inhibition assay.
Results
The potency observed in Assay A for example compounds 1, 13, 10 and 28 of WO 2020/016433 as well as example compounds 42, 56, 5 and 55 of the present invention are shown in the tables below.
Assay B: In Vitro Evaluation of Modulation of α5ß2 γ2 GABAA Receptor.
Modulatory efficacy of compounds of formular (I) is determined electrophysiological recordings in oocytes using the two-electrode voltage clamp (TEVC) technique. Oocytes are injected with cRNA for human GABAA receptor subunits α5, ß2 and γ2 in a 3:1:3 ratio and modulatory efficacy is evaluated by co-applications with a submaximal EC5-20 GABA concentration (0.5 μM) termed GABA control. As a standard, the compounds are tested in five concentrations (3.16, 0.316, 0.0316, 0.00316 and 0.000316 μM) on each oocyte starting with the lowest concentration. Background subtracted peak current amplitudes are normalized to the respective GABAcontrol current, converted to % change and depicted +/−S.E.M. as a function of increasing compound concentrations. Plotted datapoints are fitted to the empirical Hill equation using non-linear regression. 95% confidence intervals for maximal efficacy (Bottom) and potency (Log EC50) are derived from this fitting routine.
These data show that the compounds of the present invention show target engagement and a strong negative modulation of the GABA receptor function. The data also show that the compounds, in particular in comparison to the compounds known from WO 2020/016433, have improved properties with respect to GABAA5R binding, which translates in lower efficacious doses of the compounds for disease treatment (see also: Ballard, T. M., et al. (2009). R04938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors. Psychopharmacology (2009) 202: 207-223; J. Pharmacol. Exp. Ther. (2006) 316: 1335-1345.)
Assessment of efflux in Madin-Darby canine kidney (MDCK) cells transfected with the human MDR1 gene to assess brain penetration (Drug Metabolism and Disposition February 2008, 36 (2) 268-275; DOI: https://doi.org/10.1124/dmd.107.017434)
Apparent permeability coefficients (PE) of the compounds across the MDCK-MDR1 cell monolayers are measured (pH 7.4, 37° C.) in apical-to-basal (AB) and basal-to-apical (BA) transport direction. AB permeability (PEAB) represents drug absorption from the blood into the 35 brain and BA permeability (PEBA) drug efflux from the brain back into the blood via both passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters that are expressed on the MDCK-MDR1 cells, predominantly by the overexpressed human MDR1 P-gp. The compounds are assigned to permeability/absorption classes by comparison of the AB permeabilities with the AB permeabilities of reference compounds with known in vitro permeability and oral absorption in the human. Identical or similar permeabilities in both transport directions indicate passive permeation, vectorial permeability points to additional active transport mechanisms. Higher PEBA than PEAB indicates the involvement of active efflux mediated by MDR1 P-gp. Active transport is concentration-dependently saturable.
MDCK-MDR1 cells (1-2×10e5 cells/1 cm2 area) are seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 7 days. Subsequently, the MDR1 expression is boosted by culturing the cells with 5 mM sodium butyrate in full medium for 2 days. Compounds are dissolved in appropriate solvent (like DMSO, 1-20 mM stock solutions). Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4×7H2O, 0.41 mM NaH2PO4×H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare the transport solutions (0.1-300 μM compound, final DMSO <=0.5%). The transport solution (TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (3 filter replicates), respectively. The receiver side contains the same buffer as the donor side. Samples are collected at the start and end of experiment from the donor and at various time intervals for up to 2 hours also from the receiver side for concentration measurement by HPLC-MS/MS or scintillation counting. Sampled receiver volumes are replaced with fresh receiver solution.
These data shows that the compounds of the present invention have excellent brain penetration properties with low efflux ratio from the brain compartment.
Assessment of Metabolic Stability in Human Liver Microsomes (Human MST)
The metabolic stability of the compounds according to the invention may be investigated as follows:
The metabolic degradation of the test compound is assayed at 37° C. with pooled human liver microsomes. The final incubation volume of 100 μL per time point contains TRIS buffer pH 7.6 at room temperature (0.1 M), MgCl2 (5 mM), microsomal protein (1 mg/mL) and the test compound at a final concentration of 1 μM. Following a short pre-incubation period at 37° C., the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring an aliquot into solvent after different time points. After centrifugation (10000 g, 5 min), an aliquot of the supernatant is assayed by LCMS/MS for the amount of parent compound. The half-life (t1/2) is determined by the slope of the semi-logarithmic plot of the concentration-time profile.
In view of their ability to modulate the activity of GABAA receptors containing the α5 subunit and their advantaneouges pharmacokinetic properties the compounds of general formula (I) according to the invention, or the physiologically acceptable salts thereof, are suitable for the treatment and/or preventative treatment of all those diseases or conditions which can be influenced by modulation of GABAA receptors containing the α5 subunit. Therefore, compounds according to the invention, including the physiologically acceptable salts thereof, are particularly suitable for the prevention or treatment of diseases, particularly acute neurological disorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, post operative cognitive decline, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis, dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, major depressive disorder, neuropsychiatric conditions, psychosis, attention-deficit hyperactivity disorder, neuropathic pain, stroke, attentional disorders, eating disorders, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain conditions, chronic pain, nociceptive pain, post-operative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, ocular pain, pain due to inflammation, pain due to bone fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemia pain, fibromyalgia, chronic headache, migraine, tension-type headache, diabetic neuropathic pain, phantom limb pain, visceral pain and cutaneous pain.
The compounds according to the invention, including the physiologically acceptable salts thereof, are even more suitable for the treatment of i.a. cognitive disorders, post operative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type I, or cognitive deficits after stroke.
In a further aspect of the present invention the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula (I), or the pharmaceutically acceptable salts thereof, to a human being.
The dose range of the compounds of general formula (I) applicable per day is usually from 0.1 to 1000 mg, preferably from 1 to 500 mg by oral route, in each case administered 1 to 4 times a day.
Each dosage unit may conveniently contain from 0.1 to 500 mg, preferably 1 to 100 mg.
The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
Suitable preparations for administering the compounds of formula I, including the pharmaceutically acceptable salts thereof, will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives, powders, etc. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% of the composition as a whole.
Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers.
For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.
The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. A list of example is: Donepezil, Memantine, Acetazolamide, Carbamazepine, Eslicarbazepine acetate, Ethosuximide, Gabapentin, Lacosamide, Lamotrigine, Levetiracetam, Brivaracetam, Nitrazepam, Oxcarbazepine, Perampanel, Piracetam, Phenobarbital, Phenytoin, Pregabalin, Primidone, Rufinamide, Sodium valproate, Stiripentol, Tiagabine, Topiramate, Vigabatrin, Zonisamide, Levodopa, Carbidopa, Haloperidol, Loxapine, Thioridazine, Molindone, Thiothixene, Fluphenazine, Mesoridazine, Trifluoperazine, Perphenazine, Chlorpromazine, Aripiprazole, Asenapine Maleate, Clozapine, Iloperidone, Lurasidone, Olanzapine, Paliperidone, Quetiapine, Risperidone, Ziprasidone and Zolpidem.
The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions described above.
The use of the compound according to the invention in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a pharmaceutically acceptable salt thereof and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
The compound according to the invention may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20189671.9 | Aug 2020 | EP | regional |
| 20197363.3 | Sep 2020 | EP | regional |
| 20204664.5 | Oct 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/071755 | 8/4/2021 | WO |
