WO2015014768A1 - 1,7-naphthyridine derivatives - Google Patents
1,7-naphthyridine derivatives Download PDFInfo
- Publication number
- WO2015014768A1 WO2015014768A1 PCT/EP2014/066123 EP2014066123W WO2015014768A1 WO 2015014768 A1 WO2015014768 A1 WO 2015014768A1 EP 2014066123 W EP2014066123 W EP 2014066123W WO 2015014768 A1 WO2015014768 A1 WO 2015014768A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- naphthyridine
- carboxamide
- formula
- compound
- halogen
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions
- R 1 is phenyl or pyridinyl, which are optionally substituted by one, two or three substituents, selected from halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(0)2-lower alkyl, or is
- R 2 is hydrogen
- neurodegenerative and neuropsychiatric diseases including schizophrenia, obsessive- compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain”), Down syndrome, autism spectrum disorders, hearing loss (Neuro science, 167 (2010) 1216-1226; Nature Medicine, Vol.
- pharmaceutically acceptable salt or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
- a mixture of 5-bromo-l,7-naphthyridine-3-carboxylic acid of formula 5, N, N- diisopropylethylamine and 0-(7-azabenzotriazol- 1 -yl)-N,N,N' , ⁇ ' -tetramethyluronium hexafluorophosphate (HATU) in dimethylformamide is stirred at room temperature for 10 minutes.
- the corresponding amine of formula 2 is added and stirring is continued over two day to yield a compound of formula 3.
- Neurogenic properties of small molecules are determined based on the proliferation of human embryonic stem cell derived neural stem cells (NSCs) which were derived via a dual smad inhibition as previously described (Chambers, S.M., et al., Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling, Nature biotechnology, 2009. 27(3): p. 275-80.)
- NSCs human embryonic stem cell derived neural stem cells
- the value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells.
- the neurogenic compound response is calculated for each compound as (compound/Negative Control)*100.
- the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety, attention deficit hyperactivity disorder (ADHD) and diabetes.
- disorders of the central nervous system for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety, attention deficit hyperactivity disorder (ADHD) and diabetes.
- ADHD attention deficit hyperactivity disorder
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Abstract
The present invention relates to compounds of general formula (I) wherein R1 is phenyl or pyridinyl, which are optionally substituted by one, two or three substituents, selected from halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(O)2-lower alkyl, or is morpholinyl, dihydropyranyl or piperidinyl, wherein piperidinyl is optionally substituted by halogen, or is C(O)O-lower alkyl; R2 is hydrogen; R3 is hydrogen, lower alkyl substituted by halogen, –(CH2)n-S(O)2-lower alkyl, –(CH2)n- cycloalkyl or –(CH2)n-lower alkoxy; R4 is hydrogen or lower alkyl; n is 0, 1 or 2; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.
Description
1,7-NAPHTHYRIDINE DERIVATIVES
The present invention relates to compounds of general formula
wherein
R1 is phenyl or pyridinyl, which are optionally substituted by one, two or three substituents, selected from halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(0)2-lower alkyl, or is
morpholinyl, dihydropyranyl or piperidinyl, wherein piperidinyl is optionally substituted by halogen, or is
C(0)0-lower alkyl;
R2 is hydrogen;
R3 is hydrogen, lower alkyl substituted by halogen, -(CH2)n-S(0)2-lower alkyl,
-(CH2)n-cycloalkyl or -(CH2)n-lower alkoxy;
R4 is hydrogen or lower alkyl;
n is 0, 1 or 2;
or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its
corresponding enantiomer and/or optical isomers thereof.
Now it has been shown that the present compounds stimulate neurogenesis from neural stem cells (NSCs). Neurogenesis occurs in the developing and adult brain. Conceptually, this process of neurogenesis can be divided into four steps: (i) proliferation of NSCs; (ii) neuronal fate determination of NSC; (iii) survival and maturation of new neurons; and (iv) functional integration of new neurons into the neuronal network.
Adult neurogenesis is a developmental process that occurs throughout live in the adult brain whereby new functional neurons are generated from adult neural stem cells. Constitutive adult neurogenesis under physiological conditions occurs mainly in two "neurogenic" brain regions, 1) the sub-granular zone (SGZ) in the dentate gyrus of the hippocampus, where new dentate granule cells are generated, 2) the sub-ventricular zone (SVZ) of the lateral ventricles,
Pop/19.03.2014
where new neurons are generated and then migrate through the rostral migratory stream (RMS) to the olfactory bulb to become interneurons.
Extensive evidence suggests that hippocampal adult neurogenesis plays an important role in cognitive and emotional states albeit the precise function remains elusive. It has been argued that the relatively small number of newborn granule neurons can affect global brain function because they innervate many interneurons within the dentate gyrus, each of which inhibits hundreds of mature granule cells leading to a neurogenesis -dependent feedback inhibition. In combination with a low threshold for firing the newborn neurons trigger responses to very subtle changes in context. Disturbances in this process may manifest behaviorally in deficits in pattern separation related to psychiatric diseases. For example, adult hippocampal neurogenesis correlates with cognitive and emotional capacity, e.g. physical exercise, exposure to an enriched environment and typical antidepressants concomitantly promote adult hippocampal
neurogenesis and cognition and/or emotional states, while chronic stress, depression, sleep deprivation and aging decrease adult neurogenesis and associate with negative cognitive and/or emotional states (Neuron 70, May 26, 2011, pp 582 -588 and pp 687 - 702; WO 2008/046072). Interestingly, antidepressants promote hippocampal adult neurogenesis and their effects on certain behaviors require the stimulation of neurogenesis. Neurogenesis in other adult CNS regions is generally believed to be very limited under normal physiological conditions, but could be induced after injury such as stroke, and central and peripheral brain damage.
It is therefore believed that stimulation of adult neurogenesis represents a neuro- regenerative therapeutic target for normal aging and in particular for a variety of
neurodegenerative and neuropsychiatric diseases, including schizophrenia, obsessive- compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss (Neuro science, 167 (2010) 1216-1226; Nature Medicine, Vol. 11, number 3, (2005), 271-276) tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine (US 2012/0022096).
The stimulation of adult neurogenesis represents also a therapeutic target for optic neuropathy (S. Isenmann, A. Kretz, A. Cellerino, Progress in Retinal and Eye Research,
22, (2003) 483) and macular degeneration (G. Landa, O. Butovsky, J. Shoshani, M. Schwartz, A. Pollack, Current Eye Research 33, (2008) 1011).
Hence, chemical stimulation of adult neurogenesis offers new regenerative avenues and opportunities to develop novel drugs for treating neurological diseases and neuropsychiatric disorders.
Therefore, the object of the present invention was to identify compounds that modulate neurogenesis. It has been found that the compounds of formula I are active in this area and they may therefore be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine.
The most preferred indications for compounds of formula I are Alzheimer's disease, depression, anxiety disorders and stroke.
One object of the present invention is the use of a compound of formula I for the preparation of medicaments for the therapeutic and/or prophylactic treatment of the above- mentioned diseases,
A further object of the invention is a method for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post- traumatic stress disorder, panic disorder, Parkinson's disease, dementia,
Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, optic neuropathy or macular degeneration, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine, which method comprises administering an effective amount of a compound of formula I.
One embodiment of the invention are compounds of formula I, wherein R1 is phenyl or pyridinyl, which are optionally substituted by one, two or three substituents, selected from
halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(0)2-lower alkyl, for example the following compounds
5-(4-chlorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(2-fluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(3,4,5-trifluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(3,4-difluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-cyanophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(methylsulfonyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-2-methyl- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-l,7-naphthyridine-3-carboxamide
5-(2-fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(4-(methylsulfonyl)benzyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(3-(methylsulfonyl)benzyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(cyclopropylmethyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(2-methoxyethyl)-l,7-naphthyridine-3-carboxamide
5-(3-methoxyphenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(6-chloropyridin-3-yl)-l,7-naphthyridine-3-carboxamide or
5-(2,4-dichlorophenyl)- 1 ,7-naphthyridine-3-carboxamide.
One embodiment of the invention are further compounds of formula I, wherein R1 is morpholinyl, dihydropyranyl or piperidinyl, wherein piperidinyl is optionally substituted by halogen, for example
5-morpholino- 1 ,7-naphthyridine-3-carboxamide
methyl 3-carbamoyl- 1 ,7-naphthyridine-5-carboxylate
5-(3,6-dihydro-2H-pyran-4-yl)-l,7-naphthyridine-3-carboxamide or
5-(4,4-difluoropiperidin- 1 -yl)- 1 ,7-naphthyridine-3-carboxamide.
One embodiment of the invention are further compounds of formula I, wherein R2 and R3 are both hydrogen, for example the compounds
5-(4-chlorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3,4,5-trifluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3,4-difluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-cyanophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(methylsulfonyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-2-methyl- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-morpholino- 1 ,7-naphthyridine-3-carboxamide
5-(3-methoxyphenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
methyl 3-carbamoyl-l,7-naphthyridine-5-carboxylate
5-(3,6-dihydro-2H-pyran-4-yl)-l,7-naphthyridine-3-carboxamide
5-(4,4-difluoropiperidin- 1 -yl)- 1 ,7-naphthyridine-3-carboxamide
5-(6-chloropyridin-3-yl)- 1 ,7-naphthyridine-3-carboxamide or
5-(2,4-cichlorophenyl)- 1 ,7-naphthyridine-3-carboxamide.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1 - 4 carbon atoms. Examples for "alkyl" are methyl, ethyl, n-propyl, and isopropyl.
The term "alkoxy" denotes a group -O-R' wherein R' is lower alkyl as defined above.
The term "lower alkyl substituted by halogen" denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom. The preferred group is
CF3.
The term "lower alkoxy substituted by halogen" denotes a lower alkoxy group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom. The preferred group is
OCF3.
The term "halogen" denotes chlorine, bromine, fluorine or iodine.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid addition salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
The present new compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula
with a compound of formula
NHR2R3 2
to a compound of formula
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or
b) reacting a compound of formula 3
HO
B-R
HO to a compound of formula
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following scheme 1. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in scheme 1 , however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
Scheme 1
Furthermore, to a suspension of 5-bromo-l,7-naphthyridine 3-carboxamide of formula 3 and a boronic acid of formula 4 and cesium carbonate in dioxane and water is added
bis(diphenylphosphino)ferrocene-palladium(II)dichloride. The mixture is stirred at 80 °C for 3 hours. Removal of the solvent by distillation and chromatography yields the compound of formula I.
Isolation and purification of the compounds
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
Salts of compounds of formula I
The compounds of formula I are basic and may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the
compounds of the present invention have an activity as neurogenic agents.
The compounds were investigated in accordance with the test given hereinafter.
Neurogenesis assay
Neural Stem Cell Proliferation Assay
Neurogenic properties of small molecules are determined based on the proliferation of human embryonic stem cell derived neural stem cells (NSCs) which were derived via a dual smad inhibition as previously described (Chambers, S.M., et al., Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling, Nature biotechnology, 2009. 27(3): p. 275-80.)
Compounds respond is measured by the increase in cells based on ATP levels
(Promega:CellTiterGlo®) after an incubation period of 4 days.
NSCs are thawed and expanded over 3 passages. On the 14th day, NSCs are seeded in
Polyornithin/ Laminin coated 384 well plates at a cell density of 21 '000 cells/cm2 in a media volume of 38 μΐ.
4 hours after cell seeding, compound solutions are added at a volume of 2 μΐ. Stock solutions of the compounds (water, 5% DMSO) are diluted to obtain a dose response (11 points, dilution factor is 2), ranging from 8 μΜ to 8 nM. Controls are run to consistently determine the neurogenic properties of the cells:
Negative (neutral) control is cell culture Media (final DMSO concentration: 0.25 ).
Positive controls are:
1. cell culture Media + 100 ng/ml FGF2 (final DMSO concentration: 0.1 %)
2. cell culture Media + 20 ng/ml EOF (final DMSO concentration: 0.1 )
3. cell culture Media + 100 ng/ml Wnt3a (final DMSO concentration: 0.1 )
After 4 days incubation at 37° C, 5 % C02, the amount of ATP per well is quantified. The ATP concentration is proportional to the cell number. ATP is quantified by using the Promega CellTiterGlo® kit. The CellTiterGlo® reagents contain a cell lysis buffer, a thermo stable luciferase (UltraGlo™ recombinant luciferase), magnesium and luciferin. Luciferin reacts with ATP producing oxyluciferin, AMP and light. The luminescence signal is proportional to the ATP content.
The value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells. The neurogenic compound response is calculated for each compound as (compound/Negative Control)*100.
The values of EC 150 from the dose response curve are determined for each test compound. The EC 150 is the compound concentration at which 150 % activity of control (100 %) is reached. The preferred compounds show a EC 150 (μΜ) in the range of < 2.5 μΜ as shown in Table 1 below.
Table 1
List of examples and ECjjo data of novel compounds
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety, attention deficit hyperactivity disorder (ADHD) and diabetes.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
Tablet Formulation (Wet Granulation)
Item Ingredients mg/tablet
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Lactose Anhydrous DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1 1 1 1
Total 167 167 167 831
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.
Capsule Formulation
Item Ingredients mg/capsule
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Hydrous Lactose 159 123 148 —
3. Corn Starch 25 35 40 70
4. Talc 10 15 10 25
5. Magnesium Stearate 1 2 2 5
Total 200 200 300 600
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
Examplel
-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxamide
Ethyl- l,7-naphthyridine-3-carboxylate (CAS949922-44-5, 50.0 mg, 247 μιηοΐ) and N- bromosuccinimide (52.8 mg, 297 μιηοΐ) in acetic acid (3 ml) were stirred at 80 °C for 1 hour.
The crude reaction mixture was concentrated in vacuo and purified by chromatography (silica gel, ethyl acetate / heptane = 30:70 to 100:0) to yield the title compound as light brown solid (62 mg, 89 %). MS: m/e = 281.2, 283.3 [M+H]+. -(4-chlorophenyl)-l,7-naphthyridine-3-carboxylate
To a suspension of ethyl-5-bromo-l,7-naphthyridine-3-carboxylate (55 mg, 196 μιηοΐ) and 4- chlorophenylboronic acid (30.6 mg, 196 μιηοΐ) and cesium carbonate (70.1 mg, 215 μιηοΐ) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (7.16 mg, 9.78 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 20:80 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as light brown solid (54 mg, 88 %). MS: m/e = 313.4 [M+H]+. c) 5-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxylic acid
Ethyl-5-(4-chlorophenyl)-l,7-naphthyridine-3-carboxylate (50 mg, 160 μηιοΐ) was combined with dioxane (6 ml) to give a light brown solution. Lithiumhydroxide (4.59 mg, 192 μιηοΐ) in water (1 ml) was added and the mixture was stirred at room temperature for 3 hours. The crude reaction mixture was concentrated in vacuo, poured into water (10 ml), acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate to yield the title compound as light brown solid (24 mg, 53 %). MS: m/e = 285.4 [M+H]+. -(4-Chlorophenyl)- 1 ,7-naphthyridine-3-carboxamide
A mixture of 5-(4-chlorophenyl)-l,7-naphthyridine-3-carboxylic acid (240 mg, 843 μιηοΐ), 1,1 '- carbonyldiimidazole (137 mg, 843 μιηοΐ) in dichloromethane (40 ml) was stirred at room temperature for 1 hour. Aqueous ammonium hydroxide (25 %, 40 ml, 1.03 mol) was added and stirring was continued for 1 hour. Extraction with water / dichloromethane and chromatography ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as light yellow solid (55 mg, 23 %). MS: m/e = 284.5 [M+H]+.
Example 2
5-(4-(Trifluoromethoxy)phenyl)-l,7-naphthyridine-3-carboxamide
-Bromo-l,7-naphthyridine-3-carboxylic acid
Ethyl-5-bromo-l,7-naphthyridine-3-carboxylate (1.893 g, 6.73 mmol) was combined with dioxane (100 ml) to give a light brown solution. Lithiumhydroxide (194 mg, 8.08 mmol) in water (16.7 ml) was added and the mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and poured into water. The mixture was acidified with 2N aqueous hydrochloric acid. The precipitate was filtered and dried to yield the title compound as light brown solid (1.55 g, 91 ). MS: m/e = 253.4, 255.3 [M+H]+. -Bromo- 1 ,7-naphthyridine-3-carboxamide
A mixture of 5-bromo-l,7-naphthyridine-3-carboxylic acid (1.00 g, 3.95 mmol), 1,1'- carbonyldiimidazole (641 mg, 3.95 mmol) in dichloromethane (188 ml) was stirred at room temperature for 1 hour. Aqueous ammonium hydroxide (25 %, 143 ml, 3.7 mol) was added and stirring was continued for 2 hours. Extraction with water / dichloromethane and trituration with methanol (0.5 ml) yielded the title compound as off-white solid (435 mg, 44 ). MS: m/e = 252.4, 254.4 [M+H]+. -(4- (Trifluoromethoxy)phenyl) - 1 ,7 -naphthyridine- 3 -c arboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 4- (trifluoromethoxy)phenylboronic acid (32.7 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (25 mg, 47 %). MS: m/e = 334.4 [M+H]+.
Example 3
5-(2-Fluorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 2- fluorophenylboronic acid (22.2 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as light brown solid (40 mg, 94 %). MS: m/e = 268.4 [M+H]+. Example 4
5-(3,4,5-Trifluorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 3,4,5- trifluorophenylboronic acid (27.9 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (25 mg, 52 %). MS: m/e = 304.4 [M+H]+.
Example 5
5-(4-Fluorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 4- fluorophenylboronic acid (22.2 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (29 mg, 68 %). MS: m/e = 268.4 [M+H]+. Example 6
5-(3,4-Difluorophen -l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 3,4- difluorophenylboronic acid (25.1 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (35 mg, 77 %). MS: m/e = 286.4 [M+H]+.
Example 7
5-(2,4-Difluorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 2,4- difluorophenylboronic acid (25.1 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (42 mg, 93 %). MS: m/e = 286.4 [M+H]+.
Example 8
5-(4-Cyanopheny -l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 4- cyanophenylboronic acid (23.3 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (25 mg, 57 %). MS: m/e = 275.4 [M+H]+.
Example 9
5-(4-(Methylsulfonyl)phenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 4- (methylsulfonyl)phenylboronic acid (31.7 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (37 mg, 71 %). MS: m/e = 328.4 [M+H]+.
Example 10
5-(4-(Trifluoromethyl)phenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (20 mg, 79.3 μιηοΐ) and 4- (trifluoromethyl)phenylboronic acid (15.1 mg, 79.3 μιηοΐ) and cesium carbonate (28.4 mg, 87.3 μιηοΐ) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (2.9 mg, 3.97 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (18 mg, 72 %). MS: m/e = 318.4 [M+H]+.
Example 11
5-(4-Chlorophenyl)-2-methyl-l,7-naphthyridine-3-carboxamide
Ethyl-2-methyl-l,7-naphthyridine-3-carboxylate (CAS55234-62-3, 760 mg, 3.51 mmol) and N- bromosuccinimide (751 mg, 4.22 mmol) in acetic acid (50 ml) was heated at 80 °C for 2 hours. The crude reaction mixture was concentrated in vacuo and purified by chromatography (silica gel, ethyl acetate / heptane = 0: 100 to 50:50) to yield the title compound as off-white solid (266mg, 26 %). MS: m/e = 295.3, 297.3 [M+H]+. -Bromo-2-methyl-l,7-naphthyridine-3-carboxylic acid
Ethyl-5-bromo-2-methyl-l,7-naphthyridine-3-carboxylate (260 mg, 881 μιηοΐ) was combined with dioxane (30 ml) to give a light brown solution. Lithiumhydroxide (25.3 mg, 1.06 mmol) in water (5 ml) was added and the mixture was stirred at room temperature for 4 days. The crude reaction mixture was concentrated in vacuo, poured into water (10 ml), acidified with 2N aqueous hydrochloric acid. The precipitate was filtered and dried in vacuo to yield the title compound as off white solid (215 mg, 91 %). MS: m/e = 267.3, 269.2 [M+H]+. -Bromo-2-methyl-l ,7-naphthyridine-3-carboxamide
A mixture of 5-bromo-2-methyl-l,7-naphthyridine-3-carboxylic acid (210 mg, 786 μιηοΐ), Ι, - carbonyldiimidazole (127 mg, 786 μιηοΐ) in dichloromethane (10 ml) was stirred at room
temperature for 1 hour. Aqueous ammonium hydroxide (25 %, 3.0 ml, 77 mol) was added and stirring was continued for 1 hour. Extraction with water / dichloromethane yielded the title compound as off-white solid (154 mg, 74 %). MS: m/e = 266.3, 268.3 [M+H]+. -(4-Chlorophenyl)-2-methyl-l ,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-2-methyl-l,7-naphthyridine-3-carboxamide (100 mg, 376 μιηοΐ) and 4-chlorophenylboronic acid (58.8 mg, 376 μιηοΐ) and cesium carbonate (135 mg, 413 μιηοΐ) in dioxane (15 ml) and water (1.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (13.7 mg, 18.8 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 20:80 to 100:0) and trituration with diethyl ether yielded the title compound as off-white solid (69 mg, 62 %). MS: m/e = 298.4 [M+H]+.
Example 12
5-(4-Chloro-2-fluorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (40 mg, 159 μιηοΐ) and 4-chloro- 2-fluorophenylboronic acid (27.7 mg, 159 μιηοΐ) and cesium carbonate (56.9 mg, 175 μιηοΐ) in dioxane (5 ml) and water (0.6 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (5.81 mg, 7.93 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 20:80 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as off- white solid (41 mg, 86 %). MS: m/e = 302.4 [M+H]+.
Example 13
5-(4-Chloro-2-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-l,7-naphthyridine-3-carboxamide
a) 5-Bromo-N-(2-(methylsulfonyl)ethyl)- 1 ,7-naphthyridine-3-carboxamide
5-Bromo-l,7-naphthyridine-3-carboxylic acid (500 mg, 1.98 mmol) in dichloromethane (30 ml) was combined with 3 drops of dimethylformamide. Under cooling oxalyl chloride (2.51 g, 1.73 ml, 19.8 mmol) was added slowly. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (30 ml) and was added at 0 °C to a mixture of 2-
(methylsulfonyl)ethanamine hydrochloride (315 mg, 1.98 mmol) and triethylamine (420 mg, 578 μΐ, 4.15 mmol) in dichloromethane (30 ml). The mixture was stirred for 30 minutes at 0 °C and then at room temperature for 2 hours. Extraction with dichloromethane / water and trituration with ethyl acetate (5 ml) yielded the title compound as light brown solid (470 mg, 66 ). MS: m/e = 358.4, 360.4 [M+H]+. -(4-Chloro-2-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-N-(2-(methylsulfonyl)ethyl)-l,7-naphthyridine-3-carboxamide (100 mg, 279 μιηοΐ) and 4-chloro-2-fluorophenylboronic acid (48.7 mg, 279 μιηοΐ) and cesium carbonate (100 mg, 307 μιηοΐ) in dioxane (10 ml) and water (1 ml) was added
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (10.2 mg, 14.0 μιηοΐ). The mixture
was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as off-white solid (60 mg, 53 ). MS: m/e = 408.4 [M+H]+. Example 14
5-(2-Fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
-Bromo-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-Bromo-l,7-naphthyridine-3-carboxylic acid (300 mg, 1.19 mmol) in dichloromethane (20 ml) was combined with 3 drops of dimethylformamide. Under cooling oxalyl chloride (752 mg, 519 μΐ, 5.93 mmol) was added slowly. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (30 ml) and was added at 0 °C to a mixture of 2,2,2- trifluoroethanamine (117 mg, 1.19 mmol) and triethylamine (252 mg, 347 μΐ, 2.49 mmol) in dichloromethane (20 ml). The mixture was stirred for 30 minutes at 0 °C and then at room temperature for 1 hour. Extraction with dichloromethane / water and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as light brown solid (230 mg, 58 %). MS: m/e = 334.3, 336.3 [M+H]+. -(2-Fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide (100 mg, 299 μιηοΐ) and 2-fluorophenylboronic acid (41.9 mg, 299 μιηοΐ) and cesium carbonate (107 mg,
329 μιηοΐ) in dioxane (15 ml) and water (1.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (11.0 mg, 15.0 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as off- white solid (101 mg, 97 %). MS: m/e = 350.4 [M+H]+.
Example 15
5-(2,4-Difluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide (100 mg, 299 μιηοΐ) and 2,4-difluorophenylboronic acid (47.3 mg, 299 μιηοΐ) and cesium carbonate (107 mg, 329 μιηοΐ) in dioxane (15 ml) and water (1.5 ml) was added
bis(diphenylphosphino)ferrocene-palladium(II)dichloride (11.0 mg, 15.0 μιηοΐ). The mixture was stirred at 80 °C for 3 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as off-white solid (86 mg, 78 ). MS: m/e = 368.4 [M+H]+.
Example 16
5-Morpholino- -naphthyridine-3-carboxamide
a) Ethyl 5-morpholino-l,7-naphthyridine-3-carboxylate
Ethyl-5-morpholino-l,7-naphthyridine-3-carboxylate (495 mg, 1.72 mmol) was combined with dioxane (20 ml) to give a yellow solution. Lithiumhydroxide (49.5 mg, 2.07 mmol) in water (3 ml) was added and the mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo, poured into water (20 ml) and acidified with 2N aqueous hydrochloric acid. The precipitate was dried in vacuo to yield the title compound as yellow solid (415 mg, 93 %). MS: m/e = 260.4 [M+H]+.
A mixture of 5-morpholino-l,7-naphthyridine-3-carboxylic acid (200 mg, 771 μιηοΐ), 1,1 '- carbonyldiimidazole (125 mg, 771 μιηοΐ) in dichloromethane (15 ml) was stirred at room temperature for 1 hour. Aqueous ammonium hydroxide (25 %, 3.0 ml, 77 mol) was added and stirring was continued overnight. Extraction with water / dichloromethane and chromatography (silica gel, ethyl acetate / heptane = 40:60 to 100:0 and then preparative HPLC, C18 reverse phase, water (0.1 % formic acid) / acetonitrile = 80:20 to 98:2) yielded the title compound as off- white solid (7 mg, 4 %). MS: m/e = 259.4 [M+H]+.
Example 17
5-(4-Fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide (115 mg, 293 μιηοΐ) and 4-fluorophenylboronic acid (40.9 mg, 293 μιηοΐ) and cesium carbonate (105 mg, 322 μιηοΐ) in dioxane (18 ml) and water (1.8 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (10.7 mg, 14.6 μιηοΐ). The mixture was stirred at 80 °C for 3 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) and trituration with diethyl ether / pentane yielded the title compound as off- white solid (45 mg, 44 %). MS: m/e = 350.4 [M+H]+.
Example 18
5-(4-Chlorophenyl)-N-(4-(methylsulfonyl)benzyl)-l,7-naphthyridine-3-carboxamide
5-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxylic acid (34 mg, 119 μιηοΐ) in dichloromethane (10 ml) was combined with 2 drops of dimethylformamide. Oxalyl chloride (75.8 mg, 52.3 μΐ, 597 μιηοΐ) was added slowly at 0 °C. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (10 ml) and was added at 0 °C to a mixture of (4- (methylsulfonyl)phenyl)methanamine hydrochloride (26.5 mg, 119 μιηοΐ) and triethylamine (37.5 mg, 51.6 μΐ, 370 μιηοΐ) in dichloromethane (10 ml). The mixture was stirred for 30 minutes at 0 °C and then at room temperature for 1 hour. Extraction with dichloromethane / water and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as off-white solid (25 mg, 46 ). MS: m/e = 452.4 [M+H]+.
Example 19
5-(4-Chlorophenyl)-N-(3-(methylsulfonyl)benzyl)-l,7-naphthyridine-3-carboxamide
5-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxylic acid (70 mg, 246 μιηοΐ) in dichloromethane (20 ml) was combined with 2 drops of dimethylformamide. Oxalyl chloride (156 mg, 108 μΐ, 1.23 mmol) was added slowly at 0 °C. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (20 ml) and was added at 0 °C to a mixture of (3- (methylsulfonyl)phenyl)methanamine (45.5 mg, 246 μιηοΐ) and triethylamine (77.1 mg, 106 μΐ, 762 μιηοΐ) in dichloromethane (20 ml). The mixture was stirred for 20 minutes at 0 °C and then at room temperature for 1 hour. Extraction with dichloromethane / water and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as off-white solid (62 mg, 56 %). MS: m/e = 452.3 [M+H]+.
Example 20
5-(4-Chlorophenyl)-N-(cyclopropylmethyl)-l,7-naphthyridine-3-carboxamide
5-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxylic acid (100 mg, 351 μιηοΐ) in dichloromethane (30 ml) was combined with 3 drops of dimethylformamide. Oxalyl chloride (223 mg, 154 μΐ, 1.76 mmol) was added slowly at 0 °C. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (30 ml) and was added at 0 °C to a mixture of
cyclopropylmethanamine (25.0 mg, 30.5 μΐ, 351 μιηοΐ) and triethylamine (110 mg, 152 μΐ, 1.09 mmol) in dichloromethane (30 ml). The mixture was stirred for 20 minutes at 0 °C and then at room temperature for 1 hour. Extraction with dichloromethane / water and chromatography
(silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as off-white solid (111 mg, 94 %). MS: m/e = 338.4 [M+H]+.
Example 21
5-(4-Chlorophenyl)-N-(2-methoxyethyl)-l,7-naphthyridine-3-carboxamide
5-(4-Chlorophenyl)-l,7-naphthyridine-3-carboxylic acid (70 mg, 246 μιηοΐ) in dichloromethane (10 ml) was combined with 3 drops of dimethylformamide. Oxalyl chloride (156 mg, 108 μΐ, 1.23 mmol) was added slowly at 0 °C. The mixture was stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. The crude reaction mixture was concentrated in vacuo. It was taken up in dichloromethane (20 ml) and was added at 0 °C to a mixture of 2- methoxyethanamine (22.2 mg, 25.4 μΐ, 295 μιηοΐ) and triethylamine (74.6 mg, 103 μΐ, 738 μιηοΐ) in dichloromethane (10 ml). The mixture was stirred for 20 minutes at 0 °C and then at room temperature for 1 hour. Extraction with dichloromethane / water and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as off-white solid (71 mg, 85 %). MS: m/e = 342.4 [M+H]+.
Example 22
5-(3-Methoxyphen -l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (60 mg, 238 μιηοΐ) and 3- methoxyphenylboronic acid (36.2 mg, 238 μιηοΐ) and cesium carbonate (85.3 mg, 262 μιηοΐ) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (8.71 mg, 11.9 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate) and
trituration with diethyl ether / pentane yielded the title compound as off-white solid (60 mg, 90 %). MS: m/e = 280.4 [M+H]+.
Example 23
5-(3-(Trifluoromethoxy)phenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (60 mg, 238 μιηοΐ) and 3- (trifluoromethoxy)phenylboronic acid (49.0 mg, 238 μιηοΐ) and cesium carbonate (85.3 mg, 262 μιηοΐ) in dioxane (5 ml) and water (0.5 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (8.71 mg, 11.9 μιηοΐ). The mixture was stirred at 80 °C for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate) and trituration with diethyl ether / pentane yielded the title compound as off-white solid (68 mg, 86 %). MS: m/e = 334.4 [M+H]+.
Example 24
Methyl 3-carbamoyl-l,7-naphthyridine-5-carboxylate
A solution of 5-bromo-l,7-naphthyridine-3-carboxamide (100 mg, 397 μιηοΐ) and triethylamine (80.3 mg, 111 μΐ, 793 μιηοΐ) in methanol (5 ml) and ethyl acetate (5.00 ml) in a steel reactor (35 ml) was combined under argon atmosphere with bis(diphenylphosphino)ferrocene- palladium(II)dichloride (14.5 mg, 19.8 μιηοΐ). The reactor was flushed 3 times with carbon monoxide (10 bar) and was then set under carbon monoxide atmosphere (50 bar) and heated to 110 °C. After 2 hours the mixture was filtered and concentrated in vacuo to yield the title compound as off-white solid (65 mg, 71 ). MS: m/e = 232.4 [M+H]+.
Example 25
5-(3,6-Dihydro-2H-pyran-4-yl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (100 mg, 397 μιηοΐ) and 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (83.3 mg, 397 μmol) and cesium carbonate (142 mg, 436 μιηοΐ) in dioxane (3 ml) and water (0.3 ml) was added bis(diphenylphosphino)ferrocene-palladium(II)dichloride (14.5 mg, 19.8 μιηοΐ). The mixture was stirred at 80 °C for one hour. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / methanol = 100:0 to 50:50) yielded the title compound as brown solid (45 mg, 44%). MS: m/e = 256.3 [M+H]+.
Example 26
5-(4,4-Difluoropiperid -l-yl)-l,7-naphthyridine-3-carboxamide
To a suspension of ethyl 5-bromo-l,7-naphthyridine-3-carboxylate (500 mg, 1.78 mmol) and palladium (II) acetate (39.9 mg, 178 μιηοΐ) and (l,l'-binaphthalene-2,2'- diyl)bis(diphenylphosphine) (222 mg, 356 μιηοΐ) and cesium carbonate (1.74 g, 5.34 mmol) in toluene (30 ml) was added 4,4-difluoropiperidine (215 mg, 1.78 mmol). The mixture was stirred at 80 °C for 15 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 20:80 to 100:0) yielded the title compound as yellow solid (452 mg, 79 %). MS: m/e = 322.4 [M+H]+. b) 5-(4,4-Difluoropiperidin- 1 -yl)- 1 ,7-naphfhyridine-3-carboxylic acid
Ethyl-5-(4,4-difluoropiperidin-l-yl)-l,7-naphthyridine-3-carboxylate (445 mg, 1.38 mmol) was combined with dioxane (20 ml) to give a yellow suspension. Lithiumhydroxide (39.8 mg, 1.66 mmol) in water (3 ml) was added and the mixture was stirred at room temperature for 3 hours. The crude reaction mixture was concentrated in vacuo, poured into water (15 ml), and acidified with IN aqueous hydrochloric acid. The precipitate was filtered and dried to yield the title compound as light yellow solid (285 mg, 70 ). MS: m/e = 292.5 [M-H]~. c) 5-(4,4-Difluoropiperidin-l -yl)- 1 ,7-naphthyridine-3-carboxamide
A mixture of 5-(4,4-difluoropiperidin-l-yl)-l,7-naphthyridine-3-carboxylic acid (280 mg, 955 μιηοΐ) and Ι,Γ-carbonyldiimidazole (325 mg, 2.00 mmol) in dichloromethane (20 ml) was stirred at room temperature for 1 hour. Ammonium chloride (255 mg, 4.77 mmol) and triethylamine (483 mg, 665 μΐ, 4.77 mmol) was added and stirring was continued for 2 hours. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate / heptane = 50:50 to 100:0) yielded the title compound as yellow solid (144 mg, 52%). MS: m/e = 293.4 [M+H]+.
Example 27
5-(6-Chloropyridin-3-yl)-l,7-naphthyridine-3-carboxamide
Example 28
5-(2,4-Dichlorophenyl)-l,7-naphthyridine-3-carboxamide
To a suspension of 5-bromo-l,7-naphthyridine-3-carboxamide (70 mg, 278 μιηοΐ) and 2,4- dichlorophenylboronic acid (53.0 mg, 278 μιηοΐ) and cesium carbonate (99.5 mg, 305 μιηοΐ) in dioxane (10 ml) and water (1.0 ml) was added bis(diphenylphosphino)ferrocene- palladium(II)dichloride (10.2 mg, 13.9 μιηοΐ). The mixture was stirred at 80 °C overnight. Removal of the solvent by distillation and chromatography (silica gel, ethyl acetate) yielded the title compound as white solid (79 mg, 90 ). MS: m/e = 318.3 [M+H]+.
Claims
1. A compound of formula I
wherein
R1 is phenyl or pyridinyl, which are optionally substituted by one, two or three
substituents, selected from halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(0)2-lower alkyl, or is morpholinyl, dihydropyranyl or piperidinyl, wherein piperidinyl is optionally substituted by halogen, or is
C(0)0-lower alkyl;
R2 is hydrogen;
R3 is hydrogen, lower alkyl substituted by halogen, -(CH2)n-S(0)2-lower alkyl, -
(CH2)n-cycloalkyl or -(CH2)n-lower alkoxy;
R4 is hydrogen or lower alkyl;
n is 0, 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its
corresponding enantiomer and/or optical isomers thereof.
2. A compound of formula I according to claim 1 , wherein R1 is phenyl or pyridinyl, which are optionally substituted by one, two or three substituents, selected from halogen, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano or S(0)2-lower alkyl.
3. A compound of formula I according to any one of claims 1 or 2, which compounds are 5-(4-chlorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(2-fluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(3,4,5-trifluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(3,4-difluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)-l ,7-naphthyridine-3-carboxamide
5-(4-cyanophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(methylsulfonyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-2-methyl- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-l,7-naphthyridine-3- carboxamide
5-(2-fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(4-(methylsulfonyl)benzyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(3-(methylsulfonyl)benzyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(cyclopropylmethyl)-l,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-N-(2-methoxyethyl)-l,7-naphthyridine-3-carboxamide
5-(3-methoxyphenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(6-chloropyridin-3-yl)- 1 ,7-naphthyridine-3-carboxamide or
5-(2,4-dichlorophenyl)- 1 ,7-naphthyridine-3-carboxamide.
4. A compound of formula I according to claim 1, wherein R1 is morpholinyl, dihydropyranyl or piperidinyl, wherein piperidinyl is optionally substituted by halogen.
5. A compound of formula I according to any one of claims 1 or 4, which compounds are 5-morpholino- 1 ,7-naphthyridine-3-carboxamide
methyl 3-carbamoyl- 1 ,7-naphthyridine-5-carboxylate
5-(3,6-dihydro-2H-pyran-4-yl)-l,7-naphthyridine-3-carboxamide or
5-(4,4-difluoropiperidin- 1 -yl)- 1 ,7-naphthyridine-3-carboxamide.
6. A compound of formula I according to claim 1, wherein R2 and R3 are both hydrogen,
7. A compound of formula I according to any one of claims 1 or 6, which compounds are 5-(4-chlorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3,4,5-trifluorophenyl)-l,7-naphthyridine-3-carboxamide
5-(4-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3 ,4-difluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(2,4-difluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-cyanophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(methylsulfonyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-(trifluoromethyl)phenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(4-chlorophenyl)-2-methyl- 1 ,7-naphthyridine-3-carboxamide
5-(4-chloro-2-fluorophenyl)- 1 ,7-naphthyridine-3-carboxamide
5-morpholino- 1 ,7-naphthyridine-3-carboxamide
5-(3-methoxyphenyl)- 1 ,7-naphthyridine-3-carboxamide
5-(3-(trifluoromethoxy)phenyl)- 1 ,7-naphthyridine-3-carboxamide
methyl 3-carbamoyl- 1 ,7-naphthyridine-5-carboxylate
5-(3,6-dihydro-2H-pyran-4-yl)-l,7-naphthyridine-3-carboxamide
5-(4,4-difluoropiperidin- 1 -yl)- 1 ,7-naphthyridine-3-carboxamide
5-(6-chloropyridin-3-yl)- 1 ,7-naphthyridine-3-carboxamide or
5-(2,4-cichlorophenyl)- 1 ,7-naphthyridine-3-carboxamide.
8. A process for the manufacture of a compound of formula I as defined in any one of claims 1 to 7, which process comprises a) reacting a compound of formula
with a compound of formula
NHR2R3 2
to a compound of formula
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or
b)reacting a compound of formula 3
with a compound of formula
HO
B- R
HO to a compound of formula
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
9. A compound of formula I according to any one of claims 1 - 7 for use as
therapeutically active substances.
10. A compound of formula I according to any one of claims 1- 7 for use in the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder,
Parkinson's disease, dementia, Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, optic
neuropathy or macular degeneration, abuse of neuro-active drugs, selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.
11. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claim 1 - 7 and pharmaceutically acceptable excipients.
12. The use of a compound of formula I according to any one of claims 1 - 7 for the preparation of a medicament for the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, optic neuropathy or macular degeneration, abuse of neuro-active drugs, selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.
13. A method for the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, optic neuropathy or macular degeneration, abuse of neuro-active drugs, selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine, which method comprises administering an effective amount of a compound of formula I as claimed in any one of claims 1 - 7.
14. The invention as hereinbefore described.
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| KR1020167002439A KR101781762B1 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives |
| CN201480042466.6A CN105473568B (en) | 2013-07-29 | 2014-07-28 | 1,7 7-naphthyridine derivatives |
| MX2016000895A MX362532B (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives. |
| RU2016104890A RU2669943C2 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthridine-3-carboxamide derivatives, useful as neurogenisis agents |
| JP2016528556A JP6130071B2 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives |
| EP14744539.9A EP3027597B1 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives |
| ES14744539.9T ES2630317T3 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives |
| CA2917602A CA2917602A1 (en) | 2013-07-29 | 2014-07-28 | 1,7-naphthyridine derivatives |
| US15/007,631 US9688675B2 (en) | 2013-07-29 | 2016-01-27 | 1,7-naphthyridine derivatives |
| HK16104541.8A HK1216749A1 (en) | 2013-07-29 | 2016-04-20 | 1,7-naphthyridine derivatives 17- |
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| EP (1) | EP3027597B1 (en) |
| JP (1) | JP6130071B2 (en) |
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| CN (1) | CN105473568B (en) |
| AR (1) | AR097088A1 (en) |
| CA (1) | CA2917602A1 (en) |
| ES (1) | ES2630317T3 (en) |
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| JP2016536320A (en) * | 2013-11-12 | 2016-11-24 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Pyrido [4,3-b] pyrazine-2-carboxamide as a neurogenesis agent for the treatment of neurodegenerative diseases |
| WO2019002132A1 (en) | 2017-06-30 | 2019-01-03 | Bayer Animal Health Gmbh | New azaquinoline derivatives |
| WO2019031990A1 (en) | 2017-08-07 | 2019-02-14 | Закрытое Акционерное Общество "Биокад" | Novel heterocyclic compounds as cdk8/19 inhibitors |
| WO2020027704A1 (en) * | 2018-08-03 | 2020-02-06 | Закрытое Акционерное Общество "Биокад" | Cdk8/19 inhibitors |
| US10829466B2 (en) | 2015-12-31 | 2020-11-10 | Beijing Institute Of Technology | Stilbene derivative and preparation method thereof |
| RU2739489C2 (en) * | 2018-03-06 | 2020-12-24 | Закрытое Акционерное Общество "Биокад" | Novel heterocyclic compounds as cdk8/19 inhibitors |
| CN113603675A (en) * | 2015-12-17 | 2021-11-05 | 默克专利有限公司 | Polycyclic TLR7/8 antagonists and their use in the treatment of immune disorders |
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| US20080242694A1 (en) * | 2006-09-18 | 2008-10-02 | D Sidocky Neil R | Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith |
| WO2008046072A2 (en) * | 2006-10-13 | 2008-04-17 | The Board Of Regents Of The University Of Texas System | Chemical inducers of neurogenesis |
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| AU2010221417A1 (en) * | 2009-03-02 | 2011-09-22 | Sirtris Pharmaceuticals, Inc. | 8-substituted quinolines and related analogs as sirtuin modulators |
| ES2667049T3 (en) * | 2010-02-05 | 2018-05-09 | Merck Patent Gmbh | Heteroaryl- [1,8] naphthyridine derivatives |
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2014
- 2014-07-25 TW TW103125591A patent/TWI529171B/en not_active IP Right Cessation
- 2014-07-28 ES ES14744539.9T patent/ES2630317T3/en active Active
- 2014-07-28 RU RU2016104890A patent/RU2669943C2/en not_active IP Right Cessation
- 2014-07-28 KR KR1020167002439A patent/KR101781762B1/en active IP Right Grant
- 2014-07-28 EP EP14744539.9A patent/EP3027597B1/en not_active Not-in-force
- 2014-07-28 JP JP2016528556A patent/JP6130071B2/en active Active
- 2014-07-28 WO PCT/EP2014/066123 patent/WO2015014768A1/en active Application Filing
- 2014-07-28 CA CA2917602A patent/CA2917602A1/en not_active Abandoned
- 2014-07-28 MX MX2016000895A patent/MX362532B/en active IP Right Grant
- 2014-07-28 CN CN201480042466.6A patent/CN105473568B/en not_active Expired - Fee Related
- 2014-07-28 AR ARP140102800A patent/AR097088A1/en unknown
-
2016
- 2016-01-27 US US15/007,631 patent/US9688675B2/en not_active Expired - Fee Related
- 2016-04-20 HK HK16104541.8A patent/HK1216749A1/en not_active IP Right Cessation
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| US20070078155A1 (en) * | 2005-10-05 | 2007-04-05 | Georg Jaeschke | Naphthyridin derivatives |
| WO2014079787A1 (en) * | 2012-11-20 | 2014-05-30 | F. Hoffmann-La Roche Ag | Substituted 1,6-naphthyridines |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016536320A (en) * | 2013-11-12 | 2016-11-24 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Pyrido [4,3-b] pyrazine-2-carboxamide as a neurogenesis agent for the treatment of neurodegenerative diseases |
| CN113603675A (en) * | 2015-12-17 | 2021-11-05 | 默克专利有限公司 | Polycyclic TLR7/8 antagonists and their use in the treatment of immune disorders |
| US10829466B2 (en) | 2015-12-31 | 2020-11-10 | Beijing Institute Of Technology | Stilbene derivative and preparation method thereof |
| WO2019002132A1 (en) | 2017-06-30 | 2019-01-03 | Bayer Animal Health Gmbh | New azaquinoline derivatives |
| WO2019031990A1 (en) | 2017-08-07 | 2019-02-14 | Закрытое Акционерное Общество "Биокад" | Novel heterocyclic compounds as cdk8/19 inhibitors |
| EP3666770A4 (en) * | 2017-08-07 | 2021-04-07 | Joint Stock Company "Biocad" | Novel heterocyclic compounds as cdk8/19 inhibitors |
| AU2018312836B2 (en) * | 2017-08-07 | 2022-12-08 | Joint Stock Company "Biocad" | Novel heterocyclic compounds as CDK8/19 inhibitors |
| RU2739489C2 (en) * | 2018-03-06 | 2020-12-24 | Закрытое Акционерное Общество "Биокад" | Novel heterocyclic compounds as cdk8/19 inhibitors |
| WO2020027704A1 (en) * | 2018-08-03 | 2020-02-06 | Закрытое Акционерное Общество "Биокад" | Cdk8/19 inhibitors |
| CN113166140A (en) * | 2018-08-03 | 2021-07-23 | 拜奥卡德联合股份公司 | CDK8/19 inhibitors |
| RU2761824C2 (en) * | 2018-08-03 | 2021-12-13 | Закрытое Акционерное Общество "Биокад" | Cdk8/19 inhibitors |
| US11840531B2 (en) | 2018-08-03 | 2023-12-12 | Joint Stock Company “Biocad” | CDK8/19 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2016000895A (en) | 2016-05-05 |
| ES2630317T3 (en) | 2017-08-21 |
| US9688675B2 (en) | 2017-06-27 |
| JP2016525142A (en) | 2016-08-22 |
| RU2016104890A (en) | 2017-08-31 |
| HK1216749A1 (en) | 2016-12-02 |
| KR101781762B1 (en) | 2017-09-25 |
| CN105473568A (en) | 2016-04-06 |
| CN105473568B (en) | 2018-02-13 |
| RU2016104890A3 (en) | 2018-05-15 |
| TWI529171B (en) | 2016-04-11 |
| MX362532B (en) | 2019-01-23 |
| RU2669943C2 (en) | 2018-10-17 |
| US20160137643A1 (en) | 2016-05-19 |
| JP6130071B2 (en) | 2017-05-17 |
| EP3027597A1 (en) | 2016-06-08 |
| KR20160027068A (en) | 2016-03-09 |
| AR097088A1 (en) | 2016-02-17 |
| EP3027597B1 (en) | 2017-05-03 |
| TW201516044A (en) | 2015-05-01 |
| CA2917602A1 (en) | 2015-02-05 |
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