WO2010128345A1 - Kynurenic acid analogues, pharmaceutical compositions containing same and use of said compounds for the treatment of headache - Google Patents
Kynurenic acid analogues, pharmaceutical compositions containing same and use of said compounds for the treatment of headache Download PDFInfo
- Publication number
- WO2010128345A1 WO2010128345A1 PCT/HU2010/000050 HU2010000050W WO2010128345A1 WO 2010128345 A1 WO2010128345 A1 WO 2010128345A1 HU 2010000050 W HU2010000050 W HU 2010000050W WO 2010128345 A1 WO2010128345 A1 WO 2010128345A1
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- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- carbonyl
- quinolin
- hydrochloride
- aryl
- Prior art date
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- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical class C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 206010019233 Headaches Diseases 0.000 title claims abstract description 20
- 231100000869 headache Toxicity 0.000 title claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 title claims description 64
- 238000011282 treatment Methods 0.000 title abstract description 14
- 206010027599 migraine Diseases 0.000 claims abstract description 36
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- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000000203 mixture Substances 0.000 claims abstract description 20
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000001408 amides Chemical class 0.000 claims abstract description 17
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 146
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 94
- 125000000217 alkyl group Chemical group 0.000 claims description 80
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- 125000003118 aryl group Chemical group 0.000 claims description 43
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- Kynurenic acid analogues pharmaceutical compositions containing same and use of said compounds for the treatment of headache
- the present invention relates to kynurenic acid (KYNA) analogues, process for the preparation thereof and pharmaceutical compositions containing same as well as use of said compounds for the treatment of headaches, particularly migraine.
- KYNA kynurenic acid
- Migraine is one of the most common neurological disorders affecting approximately 10-12% of the adult population (Stewart, WF., Lipton, RB. The economic and social impact of migraine. Eur. Neurol. 1994; 34 Suppl. 2:12-7. Review).
- the exact pathomechanism of migraine is not fully understood.
- migraine is a neurovascular disorder with a complex interrelationship between neuronal and vascular mechanisms.
- migraine attack is also possible by the use of the nonselective serotonin agonist dihydroergotamine or the selective serotonin 1B/D agonists so called triptans.
- NTG nitroglycerin
- NO nitric oxide
- NTG produces a rapid vasodilatation which is probably responsible for the immediate headache that may occur in healthy subjects but more often so in migraineurs. After a delay of several hours it also triggers typical attacks of migraine without aura in many migraine patients, but not in healthy volunteers (Sicuteri, F., Del Bene, E., Poggioni, M., Bonazzi, A. Unmasking latent dysnociception in healthy subjects. Headache, 1987 Apr;27(4): 180-5).
- NTG increases neuronal nitric oxide synthase (nNOS) and calcium-calmodulin dependent protein kinase II (CamKII) expression in these neurons
- nNOS neuronal nitric oxide synthase
- CamKII calcium-calmodulin dependent protein kinase II
- Kynurenic acid is an intermediate product of the tryptophan - nicotinic amide adenine dinucleotid metabolism, possessing neuroactive property.
- KYNA next to its multiple receptorial activities is an efficient antagonist of the subtype of strychnine-insensitive glycine site of the N- methyl-D-aspartate (NMDA) glutamate receptors.
- KYNA cannot pass the blood-brain barrier, it cannot be applied directly. Therefore we had to find such synthetic compounds, which are more suitable for medical use due to their better blood- brain barrier passage and their higher solubility.
- the therapeutic significance of the KYNA analogues is also enhanced by the fact that they are similar to the starting molecule formed in the organism also under normal conditions and thus compared to the known anti migraine drugs the novel pharmaceutical compositions possess a considerably better side effect profile providing next to the good therapeutic effect a further benefit for the patients.
- KYNA derivatives disclosed in US 5 270 309 proved to be effective in neurodegenerative disorders.
- the compounds according to the present invention not disclosed in the above patent specification proved to be active against migraine and the mechanism of the action of the novel compounds is quite different.
- the present invention is directed to KYNA derivatives of the general formula (I), pharmaceutical acceptable salts thereof, all possible stereoisomers, i.e. diastereoisomers and/or enantiomers, racemates and mixtures thereof and their use in treating migraine and other headaches.
- the present invention is also related to a process for the preparation of the novel compounds and pharmaceutical compositions containing same as active ingredient next to pharmaceutically acceptable carriers.
- the novel compounds according to the invention can be characterized by the following general formula (I)
- Ri stands for -(O-C,-C 6 )alkyl-, -Oaryl-, -O(CH 2 ) n aryl or -NR'(CH 2 ) n NR 2 R3, this latter group may optionally be substituted in the alkylene chain by alkyl containing 1 to 6 carbon atoms, and wherein R' stands for hydrogen or alkyl containing 1 to 6 carbon atoms, n stands for an integer from 1 to 6,
- R 2 and R 3 stand independently of each other for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, alkinyl containing 2 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part or
- R 2 and R 3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-8 membered heterocyclic ring comprising 1 or 2 N, O, and/or S heteroatoms, substituted by one or more substituents, preferably selected from a group of alkyl containing 1 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms and aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, or a saturated or unsaturated 5-8 membered heterocyclic ring comprising a further nitrogen atom attached to the carbonyl group via nitrogen, wherein the heterocyclic ring may optionally be substituted with alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, R 7 stands for hydrogen or straight or branched al
- R' stands for hydrogen or alkyl containing 1 to 4 carbon atoms
- n has the value of 1 , 2 or 3 and R 2 and R 3 are independently of each other hydrogen, straight or branched alkyl containing 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec. butyl, particularly methyl or ethyl or
- R 2 and R 3 preferably together with the nitrogen to which they are attached form a 5 to 6 membered saturated or unsaturated heterocycle comprising 1 or 2 nitrogen, oxygen and/or sulphur heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl, substituted by one or more susbtituents selected from the group comprising alkyl containing 1 to 6 carbon atoms, preferably alkyl containing 1 to 4 carbon atoms, preferably methyl or aryl containing 6 to 10 carbon atoms, preferably phenyl and aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, preferably benzyl or a 5 to 8 membered saturated or unsaturated heterocyclic ring containing a further nitrogen attached to the carbonyl group via nitrogen, optionally substituted by alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing
- R 7 stands for hydrogen, or straight or branched alkyl containing 1 to 6 carbon atoms and
- X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF 3 , cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the ring may not be substituted in the 5 and 7 position of the ring by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, amino, nitro, trifluormethyl, alkenyl containing 2 to 4 carbon atoms and in the 6 position by halogen or trifluormethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
- R stands for -NR'(CH 2 ) n NR 2 R3, wherein
- R' stands for hydrogen n has the value of 1 , 2 or 3 and
- R 2 and R 3 are independently of each other hydrogen, straight or branched alkyl containing 1 to 4 carbon atoms, preferably methyl, ethyl or
- R 2 and R 3 preferably together with the nitrogen to which they are attached form a 5 to 6 membered saturated or unsaturated heterocycle comprising 1 or 2 nitrogen, oxygen and/or sulphur heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl, preferably substituted by one or more substituents selected from group comprising alkyl containing 1 to 4 carbon atoms, preferably methyl or aryl containing 6 to 10 carbon atoms, preferably phenyl or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and - 1 to 4 carbon atoms in the alkyl part, preferably benzyl or a piperazyl group attached to the carbonyl group via nitrogen, optionally substituted by alkyl containing 1 to 4 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms, preferably phenyl, aryl alkyl containing 6 to 10 carbon atoms in the
- X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF 3 , cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the ring may not be substituted in the 5 and 7 position of the ring by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifluormethyl, alkenyl containing 2 to 4 carbon atoms and in the 6 position by halogen or trifluormethyl.
- Kynurenic acid derivatives of the general formula (I) according to the present invention are based on kynurenic acid of the following formula 1 :
- the compounds of the general formula (I) can be prepared by methods known per se (e.g. by the processes mentioned in: Spath, Monatsh, 1921 ; 42: 89; WaId, Joullie, J Org Chem 1966; 31 : 3369).
- the invention is further directed to the preparation of the compounds of the general formula (1), pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof, wherein the substituents are defined as follows: LU lU
- Ri stands for - ⁇ O-C r C 6 )alkyl-, -Oaryl-, -O(CH 2 ) n aryl or -NR'(CH 2 ) ⁇ NR 2 R 3 , latter group may optionally be substituted in the alkylene chain by alkyl containing 1 to 6 carbon atoms, and wherein R' stands for hydrogen or alkyl containing 1 to 6 carbon atoms, n stands for an integer from 1 to 6, R 2 and R 3 stand independently of each other for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, alkinyl containing 2 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part or R 2 and R 3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-8 membered
- -O(CH 2 ) n aryl may be prepared by replacing the OH group of the kynurenic acid appropriately substituted by R 7 , X, Y, Z and W -wherein R 7 , X, Y, Z and W are as given above- by a method known per se with a group of alkoxy containing 1 to 10 carbon atoms, -O-aryl or -O(CH 2 ) n aryl, or in order to prepare compounds of the general formula (I) containing as Ri a group of the formula -NR'(CH 2 ) n NR 2 R 3 reacting kynurenic acid appropriately substituted by R 7 , X, Y, Z and W - wherein R 7 , X, Y, Z and W are as given above, with a compound of the formula NH 2 R'(CH 2 ) n NR 2 R 3 , wherein n, R', R 2 , and R 3 are as defined above, in order to prepare compounds of the
- Salts with higher solubility as compared with the original or basic chemicals can be especially suitable for medical use.
- These salts may contain medically acceptable anionic or cationic components.
- the salts appropriate for medical use are those formed by inorganic acids, e.g.
- hydrochloric acid hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulphuric acid, and also salts formed by organic acids such as acetic acid, benzosulphonic acid, benzoic acid, citric acid, ethanesulphonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, p- toluenesulphonic acid and tartaric acid.
- organic acids such as acetic acid, benzosulphonic acid, benzoic acid, citric acid, ethanesulphonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, p- toluenesulphonic acid and tartaric acid.
- Salts appropriate for medical use are the ammonium salts, alkali metal salts (sodium and potassium salts), alkaline earth metal salts (magnesium and calcium salts), and salts formed with amines. Description of the examinations
- NMDA antagonist kynurenate analogues (compounds No. 2 and 7) was examined in two experimental models, on the systemic administration of the NTG and s.c. administered formalin injection in the trigeminal area.
- the expression of nNOS, CamKII and c-fos and the area covered by CGRP-immunoreactive (IR) fibers of the caudal trigeminal nucleus were measured in different groups of animals.
- NTG model The animals received a single s.c. injection of NTG (prepared from Nitrolingual Pumpspray, Pohl- Boskamp GmbH, Germany) at a dose of 10 mg/kg. Four hours later, the rats were deeply anesthetized with chloral hydrate and transcardially perfused with 125 ml of 0.1 M phosphate- buffered saline (PBS) followed by 500 mL 4% paraformaldehyde (PFA) in 0.1 M phosphate buffer (PB). The cervical (C1-C2) spinal cord was removed and the tissue blocks were post-fixed overnight for immunohistochemistry.
- PBS phosphate- buffered saline
- PFA paraformaldehyde
- the immunocytochemical reaction was visualized using the avidin-biotin kit (ABC) of Vecastain (Vector Laboratories Inc., PK-6101) and stained with nickel ammonium sulfate- intensified 3',3'-diaminobenzidine. Specificity of the immune reaction was controlled by omitting the primary antiserum.
- nNOS- and CamKII-IR cells were counted by an observer blinded to the procedures in laminae I— 111 of the region of spinal dorsal horn of the sections of the C 1 -C2 spinal cord segment.
- the stained sections were examined under light microscope (Nikon Phase Contrast 085 59762) under a 10x magnifier objective. In each animal three different series of sections were counted and as within the segments in different heights there was no significant difference in the distribution of cells, the results were averaged.
- the nNOS-positive neurons were scored, if they contained a cytoplasmic and dendritic staining and a nucleus.
- the area covered by CGRP- fibres in laminae I— III of the cervical dorsal horns was determined by video imaging using an Image Pro Plus 6.0 image analysis software (Media Cybernetics, Silver Spring, MD, USA). Stained sections were examined under light microscope (Nikon Phase Contrast 085 59762 Japan) fixed and digitalized with an Olympus DP 70 CCD camera (Tokyo, Japan) under a 10x magnifier objective and transmitted to the frame grabber, which converts the image into a digital matrix of 1600x1200 pixels. After image acquisition, a threshold grey level was established in order to detect IR fibres in the digitized microscopic image, the so called discrimination step.
- the threshold was determined on the basis of the density histogram displayed by the program. It was set on the point where the flat part of the histogram (pixels with high densities) started to rise steeply.
- the program expressed the area innervated by the IR fibres as number of pixels having densities above the threshold. For the calibration we measured known areas of different shapes. When counting the c-fos-IR cells, we watched to put the sections subsequently from the obex in caudal direction and thus it could be compared how the c-fos reactivity changes upon the effect of formalin. The averages of the obtained results ANOVA were examined by Scheffe posthoc statistical tests (SPSS, Windows). The significance level was determined at a value of ⁇ 0.05.
- the animals were randomly allotted to one or other of any groups.
- the animals were divided in 2 main groups on the day of the experiment.
- Subgroup 1 was the so called control group, i.e. no pre-treatment was used, but they obtained the vehicle of KYNA derivatives used in the experiment.
- Subgroup 2 was treated with compound No. 2 (1 mmol/kg b.w, i.p.) as a pre-treatment in the form of an intraperitoneal (i.p.) injection.
- NTG NonrolinguaP; Pohl-Boskamp GmbH, Hohenlockstedt, Germany
- 10 mg/kg for 4 h 10 mg/kg for 4 h and the other half of the animals in each subgroup were injected with the vehicle of NTG (Pohl-Boskamp GmbH, Hohenlockstedt, Germany).
- NTG NonrolinguaP; Pohl-Boskamp GmbH, Hohenlockstedt, Germany
- subgroup 1 was injected with formalin (50 ⁇ l, 5 % PFA) in the V/2 area for 4 h
- subgroup 2 was pre-treated with compound No. 2 (1 mmol/kg bw, i.p.) 1 h before formalin injection
- subgroup 3 was pre-treated with compound No. 7 (1 mmol/kg bw, i.p.) as in the subgroup 2.
- nNOS-IR cells are mainly small to medium sized neurones (8-15 ⁇ m in diameter) with few dendrites. There was no significant difference in the number of IR cells at different levels of the C1-C2 region.
- NTG produced significant increase of both nNOS- and CamKII-positive cells in the superficial layers of the TNC in the non-pre-treated rats.
- Systemic administration of KYNA analogues (compound No. 2, compound No. 7) attenuated the effect of NTG on nNOS- and CamKII-IR neurons (Fig. 1., 2.).
- Fig. 1 Mean number of nNOS-IR cells in dorsal horns of C1-C2 segments pre-treated with placebo and KYNA analogues (both compound No. 2, and compound No. 7) after vehicle (light) or NTG (dark) injections. Pre-treatment with KYNA analogues attenuated the NTG-induced increase in nNOS-activation (**p ⁇ 0.01; ***p ⁇ 0.001). U 06. 2Q]Q
- Fig. 2 Mean number of CamKII-IR neurons in laminae I and II of the TNC pre-treated with placebo and KYNA analogues after vehicle (light) or NTG (dark) injections. Pre-treatment with both compound No. 2 and compound No. 7 attenuated the NTG-induced increase in CamKII-activation (**p ⁇ 0.01 ; ***p ⁇ 0.001).
- Fig. 3 Diagram showing the area covered by CGRP-IR fibres in superficial laminae I— 11 of spinal TNC at C 1 -C2 pre-treated with placebo, compound No. 2 and compound No. 7 after vehicle or NTG injections. Both analogues mitigated the NTG-induced decrease of the area covered by CGRP-IR fibres (*p ⁇ 0.05).
- Fig. 4. The mean number of c-fos-IR neurons in laminae I and II of the cervical dorsal horns pre- treated with placebo and compound 7 after vehicle or NTG injections. (*p ⁇ 0.05; **p ⁇ 0.01). Fig. 5.
- Histogram showing the number of c-fos-IR neurons in the TNC at increasing caudal distances from obex, ipsi- and contralateral ⁇ to an s.c. formalin injection.
- KYNA analogues compound No. 2, compound No. 7
- the number of c-fos-positive cells on the formalin side diminished significantly compared to non-pre-treatment.
- KYNA analogues can be administered in the treatment of migraine and other headache entities involving the trigeminal system. More specifically, KYNA analogues appear suitable for the treatment of:
- KYNA derivatives of general formula (I) can be administered into the organism by various routes e.g. iv. or per orally.
- the necessary daily amount of an active KYNA derivative of general formula (I) primarily depends on the specific compound actually used, but additionally on other factors, e.g. the method of the dosage, and the age and status of the patient. It can be advantageous if the daily dosage leads to relatively constant blood concentration. This can be achieved by dividing the necessary daily dose into two, three, four or more doses or by administering a continuous infusion of active substance for a longer period.
- the present invention further provides pharmaceutical compositions, comprising as active ingredient at least one compound of the general formula (I), pharmaceutical acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof, wherein the substituents are as given above together with pharmaceutically acceptable carriers.
- pharmaceutically acceptable carriers comprising as active ingredient at least one compound of the general formula (I), pharmaceutical acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof, wherein the substituents are as given above together with pharmaceutically acceptable carriers.
- compositions according to the invention contain at least one of the following active ingredients: 2-(2-N,N-dimethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(4-benzy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride,
- compositions according to the invention are useful for treating migraine or other headaches accompanied by trigeminal activation.
- the invention further relates to the use of compounds of the general formula (I), pharmaceutically acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof for the preparation of pharmaceutical compositions for the treatment of migraine or other headaches accompanied by trigeminal activation.
- the active ingredient may be a compound selected from the group of 2-(2-N,N-dimethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethy Ipropylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-benzy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l-carbony I)-I H-quinolin-4-one hydrochloride, 2-[2-(2-N,N-di
- a compound with general formula (I) or a physiologically functioning derivative of this compound will be mixed with one or more therapeutically acceptable vehicles or with other auxiliary substances and in some cases with other active substances.
- the therapeutic products will be materials that can be administered by oral, rectal, nasal, local (e.g. transdermal, buccal or sublingual), vaginal, parenteral (e.g. subcutaneous, intramuscular, intravenous or intradermal), etc. routes.
- the products will be manufactured in appropriate daily doses by the conventionally used methods of drug production.
- the active substance will be intermixed with a vehicle containing one or more supplementary components.
- the active substance will usually be mixed regularly and evenly with the fluid vehicle or finally distributed solid material or mixture, and thereafter the mixture will be further treated if necessary.
- the various routes of administration may exhibit various individual advantages. For example, we may consider the invention of therapeutic products for oral dosage in physically separated units of previously defined amounts of the active substance, e.g. tablets, capsules, wafer products, powders or granulates; aqueous or nonaqueous (e.g.
- Extruded tablets may be made, for instance, in such a way, known to a specialist, that a free-rolling agent in a powder or granulated form, for example, is mixed with a bonding vehicle (povidone, gelatine or hydroxypropylmethyl cellulose), sliding agents, inert diluents, anti-fouling agents, disintegrating agents (e.g.
- poured tablets are produced by pouring powdered agents wetted with inert, liquid diluents into appropriately shaped devices. Tablets can if necessary be supplied with a coating or pattern, and converted into forms ensuring the slow or regulated release of the active agent with the desired release profile, e.g. by admixture of hydroxypropylmethyl cellulose in varying proportions.
- Forms of products convenient for parenteral administration may contain antioxidants, buffers, bacteriostatic agents, and an aqueous or nonaqueous, isotonic sterile injection solution which makes the product isotonic to the recipient's blood; or an aqueous or nonaqueous sterile suspension which consists of suspending and condensing agents, e.g. liposomes or other microparticle systems, for delivery of the active agent to the blood components or to one or more organs.
- Products can be presented in the form of enclosed containers, e.g. ampoules or tubes including a unit or multiple dose, or stored in a Iyophilic phase, to which it is sufficient to add before use the appropriate liquid vehicle, e.g. water suitable , for the preparation of injections. Ready-to-use injections and suspensions can be produced from the tablets described above.
- Advantageous unit-dose products may contain the above-described daily dose or unit, the daily divided dose, or an appropriate fraction of that.
- Therapeutic products covered by the invention naturally contain, in addition to the vehicles mentioned above, other vehicles conventionally used in pharmaceutical production, depending on the form of the product in question, e.g. an oral dosing product may further contain sweetening agents, condensing agents and aromatic agents.
- KYNA derivatives may have substantially more moderate side-effect profiles than those of the synthetic molecules applied to date in the required indications, which signifies an absolute advantage from the aspect of the patient.
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Abstract
The present invention is directed to novel kynurenic acid (KYNA) derivatives of the general formula (I) - and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof, as well as a process for the preparation thereof, pharmaceutical compositions containing same, and use thereof for the manufacture of pharmaceutical compositions useful in the treatment of headaches, particularly non- neurodegenerative migraine.
Description
Kynurenic acid analogues, pharmaceutical compositions containing same and use of said compounds for the treatment of headache
Field of the invention The present invention relates to kynurenic acid (KYNA) analogues, process for the preparation thereof and pharmaceutical compositions containing same as well as use of said compounds for the treatment of headaches, particularly migraine. Background of the invention Migraine is one of the most common neurological disorders affecting approximately 10-12% of the adult population (Stewart, WF., Lipton, RB. The economic and social impact of migraine. Eur. Neurol. 1994; 34 Suppl. 2:12-7. Review). Despite of recent advances, the exact pathomechanism of migraine is not fully understood. There is evidence that migraine is a neurovascular disorder with a complex interrelationship between neuronal and vascular mechanisms. The activation and the sensitization of the trigeminal system is crucial in the pathomechanism of this type of headache. (Ferrari MD. Lancet, 1998 Apr 4; 351(9108): 1043-51). This disease generally improves with age, it does not shorten life-time, the neurological status of the patients does not show any deviation, their intellect is maintained and in most of the patients no morphological injury can be observed. Therefore in the prevailing part of the cases, migraine cannot be said to be a progressive change and the presence of deviations characterizing the neurodegenerative diseases cannot be proved. (Goadsby, PJ. Is migraine a progressive disorder? Considering the clinical implications of new research data on migraine and brain lesions. Med. J. Aust. 2005. Feb.7; 182(3): 103-4). Although the long term outcome of migraine is benign, the social and economic impact of this disorder due to its high prevalence is, however enormous. Despite recent advances of the therapy the appropriate treatment is yet to be achieved. Conventional analgesic drugs inhibiting the cyclooxygenase system are often referred to as non specific treatment of migraine attack since they are also effective in other pain conditions. Gastrointestinal side effects are common due to the well known damage of the mucosa barrier. Specific treatment of the migraine attack is also possible by the use of the nonselective serotonin agonist dihydroergotamine or the selective serotonin 1B/D agonists so called triptans. Besides the various central nervous system (CNS) side effects (like paraesthesias etc.) due to the possibility of vasoconstriction, the use of these drugs is not suggested to migraineurs with vascular diseases (Rappaport AM. Acute and prophylactic treatment for migraine: present and future. Neurol Sci. 2008 29:S110-S122). Recently calcitonin gene-related peptide (CGRP) antagonists were approved for acute migraine treatment as well (Jes Olesen, Hans-Christoph Diener, Ingo W. Husstedt, Peter J. Goadsby, David Hall, Ulrich Meier, Stephane Pollentier, Lynna M. Lesko, for the BlBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. NEJM 2004 350:1 104-1 110).
One of the human migraine models is the systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor. NTG produces a rapid vasodilatation which is probably responsible for the immediate headache that may occur in healthy subjects but more often so in migraineurs. After a delay of several hours it also triggers typical attacks of migraine without aura in many migraine patients, but not in healthy volunteers (Sicuteri, F., Del Bene, E., Poggioni, M., Bonazzi, A. Unmasking latent dysnociception in healthy subjects. Headache, 1987 Apr;27(4): 180-5). In rats systemic NTG activates a widespread set of neurons including second-order nociceptors in the caudal trigeminal nucleus (TNC) (Tassorelli, C, Joseph, SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995 Jun 5;682(1- 2): 167-81.), where most trigeminovascular nociceptive afferents project (Goadsby, PJ., Hoskin, KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat. 1997 Apr;190:367-75. 1997). NTG increases neuronal nitric oxide synthase (nNOS) and calcium-calmodulin dependent protein kinase II (CamKII) expression in these neurons (Pardutz, A., Krizbai, I., Multon, S., Vecsei, L., Schoenen J.et al Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport. 2000 Sep 28;l l(14):3071-5., Pardutz, A., Hoyk, Z., Varga, H., Vecsei, L., Schoenen, J. Oestrogen- modulated increase of calmodulin-dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin. Cephalalgia. 2007 Jan;27(l):46-53), which next to the trigeminal activation can also be interpreted as a sensitization phenomenon and can be correlated with the changes in the migraine.
For some years, a new formalin model has been developed in the rat to assess trigeminal nociceptive processes in the orofacial region (P. Clavelou, J. Pajot, R. Dallel and P. Raboisson, Application of the formalin test to the study of orofacial pain in the rat. Neurosci Lett 103 (1989), pp. 349-353.), in the course of which the activation and sensitization of the trigeminal system can be observed like in case of migraine.
Recently increasing number of experimental results has emphasized the importance of the role of glutamate in the activation of the trigeminal system (Vikelis, M. and Mitsikostas, D. D. The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 2007; 6:251-257). Kynurenic acid (KYNA) is an intermediate product of the tryptophan - nicotinic amide adenine dinucleotid metabolism, possessing neuroactive property. KYNA next to its multiple receptorial activities is an efficient antagonist of the subtype of strychnine-insensitive glycine site of the N- methyl-D-aspartate (NMDA) glutamate receptors. On the basis of data in the state of art in vivo and in vitro experimental data prove that the excitotoxic injury of the neurons in the KIR is reduced by KYNA (Faden Al, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science. 1989, 244:798-800). One can also find data in the literature concerning a KYNA analogue capable of preventing the NTG-induced c-fos activation in rat TNC (Knyihar-Csillik, E. Mihaly, A., Krisztin-Peva, B. Robotka, H., Szatmari, I., Fulop, F.,
Toldi, J., Csillik, B., Vecsei, L., 2008. The kynurenate analogue SZR-72 prevents the nitroglycerol- induced increase of the c-fos immunoreactivity in the rat caudal trigeminal nucleus: comparative studies of the effects of SZ-72 and kynurenic acid. Neurosci. Res. 61, 429-432). In the present invention we have found that novel derivatives of KYNA unexpectedly show increased anti migraine activity. We have examined how the nNOS, CamKII and CGRP immunreactivity playing a key role in the pathomechanism of migraine is changed upon the effect of the pre-treatment carried out with our novel KYNA analogues in an NTG and formalin induced migraine model.
As KYNA cannot pass the blood-brain barrier, it cannot be applied directly. Therefore we had to find such synthetic compounds, which are more suitable for medical use due to their better blood- brain barrier passage and their higher solubility. The therapeutic significance of the KYNA analogues is also enhanced by the fact that they are similar to the starting molecule formed in the organism also under normal conditions and thus compared to the known anti migraine drugs the novel pharmaceutical compositions possess a considerably better side effect profile providing next to the good therapeutic effect a further benefit for the patients.
KYNA derivatives disclosed in US 5 270 309 proved to be effective in neurodegenerative disorders. The compounds according to the present invention not disclosed in the above patent specification proved to be active against migraine and the mechanism of the action of the novel compounds is quite different.
Detailed disclosure of the invention
The present invention is directed to KYNA derivatives of the general formula (I), pharmaceutical acceptable salts thereof, all possible stereoisomers, i.e. diastereoisomers and/or enantiomers, racemates and mixtures thereof and their use in treating migraine and other headaches. The present invention is also related to a process for the preparation of the novel compounds and pharmaceutical compositions containing same as active ingredient next to pharmaceutically acceptable carriers. The novel compounds according to the invention can be characterized by the following general formula (I)
(I)
- wherein the definition of the substituents is as follows: Ri stands for -(O-C,-C6)alkyl-, -Oaryl-, -O(CH2)naryl or -NR'(CH2)nNR2R3, this latter group
may optionally be substituted in the alkylene chain by alkyl containing 1 to 6 carbon atoms, and wherein R' stands for hydrogen or alkyl containing 1 to 6 carbon atoms, n stands for an integer from 1 to 6,
R2 and R3 stand independently of each other for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, alkinyl containing 2 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part or
R2 and R3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-8 membered heterocyclic ring comprising 1 or 2 N, O, and/or S heteroatoms, substituted by one or more substituents, preferably selected from a group of alkyl containing 1 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms and aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, or a saturated or unsaturated 5-8 membered heterocyclic ring comprising a further nitrogen atom attached to the carbonyl group via nitrogen, wherein the heterocyclic ring may optionally be substituted with alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, R7 stands for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the 5 and 7 position of the ring may not be substituted by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifluoromethyl, alkenyl containing 2 to 4 carbon atoms, and position 6 of the ring may not be substituted by halogen or trifluoromethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
Preferred are those compounds of the general formula (I) -wherein Ri stands for
-NR'(CH2)nNR2R3, wherein
R' stands for hydrogen or alkyl containing 1 to 4 carbon atoms, n has the value of 1 , 2 or 3 and R2 and R3 are independently of each other hydrogen, straight or branched alkyl containing 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec. butyl, particularly methyl or ethyl or
R2 and R3 preferably together with the nitrogen to which they are attached form a 5 to 6 membered saturated or unsaturated heterocycle comprising 1 or 2 nitrogen, oxygen and/or sulphur heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl, substituted by one or more susbtituents selected from the group comprising alkyl containing 1 to 6 carbon atoms, preferably alkyl containing 1 to 4 carbon atoms, preferably methyl or aryl containing 6 to 10 carbon atoms, preferably phenyl
and aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, preferably benzyl or a 5 to 8 membered saturated or unsaturated heterocyclic ring containing a further nitrogen attached to the carbonyl group via nitrogen, optionally substituted by alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms-, preferably phenyl, aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, preferably benzyl
R7 stands for hydrogen, or straight or branched alkyl containing 1 to 6 carbon atoms and
X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the ring may not be substituted in the 5 and 7 position of the ring by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, amino, nitro, trifluormethyl, alkenyl containing 2 to 4 carbon atoms and in the 6 position by halogen or trifluormethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
Compounds of the general formula (I), pharmaceutically acceptable salts, amides, all possible stereoisomers, i.e. diastereoisomers and/or enantiomers, racemates thereof and mixtures thereof are particularly preferred, wherein
R, stands for -NR'(CH2)nNR2R3, wherein
R' stands for hydrogen n has the value of 1 , 2 or 3 and
R2 and R3 are independently of each other hydrogen, straight or branched alkyl containing 1 to 4 carbon atoms, preferably methyl, ethyl or
R2 and R3 preferably together with the nitrogen to which they are attached form a 5 to 6 membered saturated or unsaturated heterocycle comprising 1 or 2 nitrogen, oxygen and/or sulphur heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl, preferably substituted by one or more substituents selected from group comprising alkyl containing 1 to 4 carbon atoms, preferably methyl or aryl containing 6 to 10 carbon atoms, preferably phenyl or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and - 1 to 4 carbon atoms in the alkyl part, preferably benzyl or a piperazyl group attached to the carbonyl group via nitrogen, optionally substituted by alkyl containing 1 to 4 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms, preferably phenyl, aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, preferably benzyl
R7 stands for hydrogen, or straight or branched alkyl containing 1 to 4 carbon atoms and
X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the ring may not be substituted in the 5 and 7 position of the ring by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifluormethyl, alkenyl containing 2 to 4 carbon atoms and in the 6 position by halogen or trifluormethyl.
The following compounds are particularly preferred: 2-(2-N,N-dimethy laminoethy lamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
2-(2-N,N-diethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride
2-(3-N,N-dimethylpropylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride
2-(4-benzy Ipiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
2-(2-N-morpholino-ethylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l -carbonyl)- 1 H-quinolin-4-one hydrochloride,
2-[2-(2-N-methylpiperidyl)-methylamino-l -carbonyl]- 1 H-quinolin-4-one hydrochloride
2-(2-N-piperidylethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
2-(4-methylpiperazy 1- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
2-(piperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
Kynurenic acid derivatives of the general formula (I) according to the present invention are based on kynurenic acid of the following formula 1 :
Formula 1. KYNA (4-hydroxy-quinoline-2-carboxylic acid) The compounds of the general formula (I) according to the invention as defined above are especially suitable for the treatment of migraine type headache.
The compounds of the general formula (I) can be prepared by methods known per se (e.g. by the processes mentioned in: Spath, Monatsh, 1921 ; 42: 89; WaId, Joullie, J Org Chem 1966; 31 : 3369).
The invention is further directed to the preparation of the compounds of the general formula (1), pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof, wherein the substituents are defined as follows:
LU lU
Ri stands for -{O-CrC6)alkyl-, -Oaryl-, -O(CH2)naryl or -NR'(CH2)πNR2R3, latter group may optionally be substituted in the alkylene chain by alkyl containing 1 to 6 carbon atoms, and wherein R' stands for hydrogen or alkyl containing 1 to 6 carbon atoms, n stands for an integer from 1 to 6, R2 and R3 stand independently of each other for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, alkinyl containing 2 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part or R2 and R3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-8 membered heterocyclic ring comprising 1 or 2 N, O, and/or S heteroatoms, substituted by one or more substituents, preferably selected from alkyl containing 1 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms and aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part or a saturated or unsaturated 5-8 membered heterocyclic ring comprising a further nitrogen atom attached to the carbonyl group via nitrogen, wherein the heterocyclic ring may optionally be substituted with alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, R7 stands for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the 5 and 7 position of the ring may not be substituted by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifluoromethyl, alkenyl containing 2 to 4 carbon atoms, and position 6 of the ring may not be substituted by halogen or trifluoromethyl. Compounds of the general formula (I) -wherein Ri stands for alkoxy, aryloxy or
-O(CH2)naryl may be prepared by replacing the OH group of the kynurenic acid appropriately substituted by R7, X, Y, Z and W -wherein R7, X, Y, Z and W are as given above- by a method known per se with a group of alkoxy containing 1 to 10 carbon atoms, -O-aryl or -O(CH2)naryl, or in order to prepare compounds of the general formula (I) containing as Ri a group of the formula -NR'(CH2)nNR2R3 reacting kynurenic acid appropriately substituted by R7, X, Y, Z and W - wherein R7, X, Y, Z and W are as given above, with a compound of the formula NH2 R'(CH2)nNR2R3, wherein n, R', R2, and R3 are as defined above, in order to prepare compounds of the general formula (I) wherein R1 stands for a 5 to 8 membered saturated or unsaturated heterocycle containing as heteroatoms 2 nitrogen atoms, preferably a piperazyl ring optionally substituted by alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms preferably phenyl, or aryl alkyl wherein the aryl part contains 6 to
10 and the alkyl part contains 1 to 4 carbon atoms, preferably benzyl, reacting kynurenic acid appropriately substituted by R7, X, Y, Z and W -wherein R7, X, Y, Z and W are as given above with a compound containing a 5 to 8 membered saturated or unsaturated heterocycle containing as heteroatoms 2 nitrogen atoms, preferably a piperazyl ring, optionally substituted by alkyl containing
1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms preferably phenyl, or aryl alkyl wherein the aryl part contains 6 to 10 and the alkyl part contains 1 to 4 carbon atoms, preferably benzyl, and converting the obtained compound of the general formula (I), if desired to a pharmaceutically acceptable salt, amide or all possible stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof.
The synthesis is illustrated by the following reaction scheme 1 :
Reaction scheme 1
/: 1-HOBT, DCI, DMF, room temperature, 24 h; //. Bz-Br, Na2CO3, H2C7Toluol, room temperature, 6 h
Salts with higher solubility as compared with the original or basic chemicals can be especially suitable for medical use. These salts may contain medically acceptable anionic or cationic components. According to the invention, the salts appropriate for medical use are those formed by inorganic acids, e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulphuric acid, and also salts formed by organic acids such as acetic acid, benzosulphonic acid, benzoic acid, citric acid, ethanesulphonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, p- toluenesulphonic acid and tartaric acid.
Salts appropriate for medical use are the ammonium salts, alkali metal salts (sodium and potassium salts), alkaline earth metal salts (magnesium and calcium salts), and salts formed with amines.
Description of the examinations
The effect of NMDA antagonist kynurenate analogues (compounds No. 2 and 7) was examined in two experimental models, on the systemic administration of the NTG and s.c. administered formalin injection in the trigeminal area. The expression of nNOS, CamKII and c-fos and the area covered by CGRP-immunoreactive (IR) fibers of the caudal trigeminal nucleus were measured in different groups of animals.
Methods NTG model The animals received a single s.c. injection of NTG (prepared from Nitrolingual Pumpspray, Pohl- Boskamp GmbH, Germany) at a dose of 10 mg/kg. Four hours later, the rats were deeply anesthetized with chloral hydrate and transcardially perfused with 125 ml of 0.1 M phosphate- buffered saline (PBS) followed by 500 mL 4% paraformaldehyde (PFA) in 0.1 M phosphate buffer (PB). The cervical (C1-C2) spinal cord was removed and the tissue blocks were post-fixed overnight for immunohistochemistry.
Formalin model
The orofacial formalin test was carried out using a 50 μl s.c. injection of 5% formalin. Under anaesthesia, formalin is injected into the upper lip of the rat, just laterally to the nose. Injections directed to the centre of the vibrissal pad have also successfully been carried out (E. Eisenberg, B. P. Vos and A.M. Strassman, The NMDA antagonist Memantine blocks pain behaviour in a rat model of formalin-induced facial pain. Pain 54 (1993), pp. 301-307. , B.G. Klein, B.R. Misra and CF. White, Orofacial pain sensitivity in adult rats following neonatal infraorbital nerve trans-section. Behav. Brain Res 46 (1991), pp. 197-201.) After the injection animals remained under anaesthesia for 4 h prior perfusion. After the 4 h resting period animals were transcardially perfused with 125 ml of 0.1 M PBS followed by 500 ml of 4% paraformaldehyde in 0.1 M PB. After perfusion, the upper cervical cord and lower medulla were dissected and post-fixed in the same fixative overnight.
Immunohistochemical methods After post-fixation spinal cord segments were placed into a sucrose solution (10% sucrose for two hours, 20% sucrose until it sank and 30% sucrose for one night). After cryoprotection 30 μm cryostat sections were cut. The free-floating sections were rinsed in PBS and immersed in 0.3% H2O2 in PBS for 30 min to suppress endogenous peroxidase activity. After several rinses in 0.1 M PBS containing 1% Triton X-100, sections were kept for 2 nights at 4°C in polyclonal anti-nNOS antibody (Euro- Diagnostica, B220-1) at a dilution of 1 :2000 or in anti-CGRP antibody (Sigma, C8198) at a dilution of 1 :20000 or for 1 night in anti-c-fos antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) at a dilution of 1:20000 or 4 nights at 4°C in anti-CamKII antibody (Sigma, C265) at a
dilution of 1:2000. The immunocytochemical reaction was visualized using the avidin-biotin kit (ABC) of Vecastain (Vector Laboratories Inc., PK-6101) and stained with nickel ammonium sulfate- intensified 3',3'-diaminobenzidine. Specificity of the immune reaction was controlled by omitting the primary antiserum.
Data processing, statistical analysis nNOS- and CamKII-IR cells were counted by an observer blinded to the procedures in laminae I— 111 of the region of spinal dorsal horn of the sections of the C 1 -C2 spinal cord segment. The stained sections were examined under light microscope (Nikon Phase Contrast 085 59762) under a 10x magnifier objective. In each animal three different series of sections were counted and as within the segments in different heights there was no significant difference in the distribution of cells, the results were averaged. The nNOS-positive neurons were scored, if they contained a cytoplasmic and dendritic staining and a nucleus. The area covered by CGRP- fibres in laminae I— III of the cervical dorsal horns was determined by video imaging using an Image Pro Plus 6.0 image analysis software (Media Cybernetics, Silver Spring, MD, USA). Stained sections were examined under light microscope (Nikon Phase Contrast 085 59762 Japan) fixed and digitalized with an Olympus DP 70 CCD camera (Tokyo, Japan) under a 10x magnifier objective and transmitted to the frame grabber, which converts the image into a digital matrix of 1600x1200 pixels. After image acquisition, a threshold grey level was established in order to detect IR fibres in the digitized microscopic image, the so called discrimination step. To avoid the subjective bias of manual thresholding, the threshold was determined on the basis of the density histogram displayed by the program. It was set on the point where the flat part of the histogram (pixels with high densities) started to rise steeply. The program expressed the area innervated by the IR fibres as number of pixels having densities above the threshold. For the calibration we measured known areas of different shapes. When counting the c-fos-IR cells, we watched to put the sections subsequently from the obex in caudal direction and thus it could be compared how the c-fos reactivity changes upon the effect of formalin. The averages of the obtained results ANOVA were examined by Scheffe posthoc statistical tests (SPSS, Windows). The significance level was determined at a value of <0.05.
Experimental groups and protocol
The animals were randomly allotted to one or other of any groups.
The animals were divided in 2 main groups on the day of the experiment. The animals in the I. Group (n=36) were divided into 3 subgroups, each subgroup consisting of 12 rats. Subgroup 1 was the so called control group, i.e. no pre-treatment was used, but they obtained the vehicle of KYNA derivatives used in the experiment.
Subgroup 2 was treated with compound No. 2 (1 mmol/kg b.w, i.p.) as a pre-treatment in the form of an intraperitoneal (i.p.) injection. Animals of subgroup 3 (n=12) were treated with compound No. 7
(1 mmol/kg bw, i.p.)- An hour later half of the animals in each subgroup were injected s.c. with NTG (NitrolinguaP; Pohl-Boskamp GmbH, Hohenlockstedt, Germany) 10 mg/kg for 4 h and the other half of the animals in each subgroup were injected with the vehicle of NTG (Pohl-Boskamp GmbH, Hohenlockstedt, Germany). In Group II. (n=18) the animals were divided into 3 subgroups, each consisting of 6 rats. Animals of all the three subgroups were narcotized with urethane before formalin injection. Subgroup 1 was injected with formalin (50 μl, 5 % PFA) in the V/2 area for 4 h, subgroup 2 was pre-treated with compound No. 2 (1 mmol/kg bw, i.p.) 1 h before formalin injection, subgroup 3 was pre-treated with compound No. 7 (1 mmol/kg bw, i.p.) as in the subgroup 2.
Results
Transverse sections of the spinal dorsal horn demonstrated numerous nNOS- and CamKII-IR neurons in the superficial laminae of the dorsal horns. nNOS-IR cells are mainly small to medium sized neurones (8-15 μm in diameter) with few dendrites. There was no significant difference in the number of IR cells at different levels of the C1-C2 region. NTG produced significant increase of both nNOS- and CamKII-positive cells in the superficial layers of the TNC in the non-pre-treated rats. Systemic administration of KYNA analogues (compound No. 2, compound No. 7) attenuated the effect of NTG on nNOS- and CamKII-IR neurons (Fig. 1., 2.). There were abundant CGRP-IR fibres in the superficial layers of the TNC. The area covered by these fibres was not significantly different between the various rostro-caudal levels, nor between sides of the C 1 -C2 segments. NTG-induced a significant decrease of the area covered by CGRP-IR fibres compared to control group. Pre-treatment with KYNA analogues (compound No. 2 compound No. 7) attenuated the NTG-induced decrease of the CGRP-immunoreactivity (Fig. 3.). Under normal conditions, c-fos-immunoreactivity was present in a restricted number of second-order sensory cells in the TNC. The administration of NTG resulted in a tremendous increase in the number of c-fos-IR neurons and pre-treatment with KYNA analogues (compound No. 7) successfully attenuated this effect (Fig. 4.).
In animals which were given an s.c. formalin injection in the V/2 area, the number of c-fos-positive cells in the TNC increased ipsilaterally to the injection in the appropriate segment of the cervico- medullary junction. Pre-treatment with KYNA analogues induced a significant decrease in the number of c-fos expressing cells (Fig. 5.).
Legend to figures
Fig. 1. Mean number of nNOS-IR cells in dorsal horns of C1-C2 segments pre-treated with placebo and KYNA analogues (both compound No. 2, and compound No. 7) after vehicle (light) or NTG (dark) injections. Pre-treatment with KYNA analogues attenuated the NTG-induced increase in nNOS-activation (**p<0.01; ***p<0.001).
U 06. 2Q]Q
Fig. 2. Mean number of CamKII-IR neurons in laminae I and II of the TNC pre-treated with placebo and KYNA analogues after vehicle (light) or NTG (dark) injections. Pre-treatment with both compound No. 2 and compound No. 7 attenuated the NTG-induced increase in CamKII-activation (**p<0.01 ; ***p<0.001).
Fig. 3. Diagram showing the area covered by CGRP-IR fibres in superficial laminae I— 11 of spinal TNC at C 1 -C2 pre-treated with placebo, compound No. 2 and compound No. 7 after vehicle or NTG injections. Both analogues mitigated the NTG-induced decrease of the area covered by CGRP-IR fibres (*p<0.05). Fig. 4. The mean number of c-fos-IR neurons in laminae I and II of the cervical dorsal horns pre- treated with placebo and compound 7 after vehicle or NTG injections. (*p<0.05; **p<0.01). Fig. 5. Histogram showing the number of c-fos-IR neurons in the TNC at increasing caudal distances from obex, ipsi- and contralateral^ to an s.c. formalin injection. After pre-treatment with KYNA analogues (compound No. 2, compound No. 7) the number of c-fos-positive cells on the formalin side diminished significantly compared to non-pre-treatment.
In summary, we have shown that a specific influence on changes in the trigeminovascular system can be achieved by the administration of compound No. 2, compound No. 7 in case of trigeminal activation in headache models. The glutamate receptor antagonist KYNA analogues afford pharmacologically exploitable possibilities in the treatment of migraine and other headaches involving the activation of the trigeminal system. Unfortunately, KYNA does not cross the blood- brain barrier (BBB), so its use to influence the trigeminovascular system is therefore not practicable. Thus, KYNA analogues can be administered in the treatment of migraine and other headache entities involving the trigeminal system. More specifically, KYNA analogues appear suitable for the treatment of:
• acute migraine attack without aura
• acute migraine attack with aura
• tension type headache
• secondary headaches • polyneuropathy
KYNA derivatives of general formula (I) can be administered into the organism by various routes e.g. iv. or per orally. The necessary daily amount of an active KYNA derivative of general formula (I) primarily depends on the specific compound actually used, but additionally on other factors, e.g. the method of the dosage, and the age and status of the patient.
It can be advantageous if the daily dosage leads to relatively constant blood concentration. This can be achieved by dividing the necessary daily dose into two, three, four or more doses or by administering a continuous infusion of active substance for a longer period.
The present invention further provides pharmaceutical compositions, comprising as active ingredient at least one compound of the general formula (I), pharmaceutical acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof, wherein the substituents are as given above together with pharmaceutically acceptable carriers. The pharmaceutical compositions according to the invention contain at least one of the following active ingredients: 2-(2-N,N-dimethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(4-benzy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride,
2-[2-(2-N-methy lpiperidyl)-methylamino- 1 -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methylpiperazyl-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazyl-l -carbonyl)-lH-quinolin-4-one hydrochloride
The pharmaceutical compositions according to the invention are useful for treating migraine or other headaches accompanied by trigeminal activation.
The invention further relates to the use of compounds of the general formula (I), pharmaceutically acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof for the preparation of pharmaceutical compositions for the treatment of migraine or other headaches accompanied by trigeminal activation.
In the course of the above use the active ingredient may be a compound selected from the group of 2-(2-N,N-dimethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethy Ipropylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-benzy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l-carbony I)-I H-quinolin-4-one hydrochloride, 2-[2-(2-N-methy !piperidyl)-methylamino- 1 -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
The invention further provides compounds of the general formula (I), pharmaceutically acceptable salts, amides, stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof for use as pharmaceuticals against migraine or other headaches accompanied by trigeminal activation, wherein the active ingredient may be selected from the group of 2-(2-N,N-dimethylaminoethylamin-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(2-N,N-diethy laminoethy lamin- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(4-benzy lpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethylamino- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride,
2-[2-(2-N-methylpiperidyl)-rnethylamino-l -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methylpiperazyl-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazy 1- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
For manufacture of the therapeutic product according to the invention, a compound with general formula (I) or a physiologically functioning derivative of this compound (henceforward the active substance) will be mixed with one or more therapeutically acceptable vehicles or with other auxiliary substances and in some cases with other active substances. The therapeutic products will be materials that can be administered by oral, rectal, nasal, local (e.g. transdermal, buccal or sublingual), vaginal, parenteral (e.g. subcutaneous, intramuscular, intravenous or intradermal), etc. routes.
The products will be manufactured in appropriate daily doses by the conventionally used methods of drug production. During the production method, the active substance will be intermixed with a vehicle containing one or more supplementary components. For manufacture of the products, the active substance will usually be mixed regularly and evenly with the fluid vehicle or finally distributed solid material or mixture, and thereafter the mixture will be further treated if necessary. The various routes of administration may exhibit various individual advantages. For example, we may consider the invention of therapeutic products for oral dosage in physically separated units of previously defined amounts of the active substance, e.g. tablets, capsules, wafer products, powders or granulates; aqueous or nonaqueous (e.g. alcohol) fluids or suspensions; or in the form of oil-in- water or water-in-oil type fluid emulsions. Tablets can be produced if necessary by the admixture of one or more vehicles, and extrusion or pouring. Extruded tablets may be made, for instance, in such a way, known to a specialist, that a free-rolling agent in a powder or granulated form, for example, is mixed with a bonding vehicle (povidone, gelatine or hydroxypropylmethyl cellulose), sliding agents, inert diluents, anti-fouling agents, disintegrating agents (e.g. sodium starch-glycolate or crospovidone), surfactant agents or dispersing agents, and by means of an appropriate apparatus is
extruded into tablets. Poured tablets are produced by pouring powdered agents wetted with inert, liquid diluents into appropriately shaped devices. Tablets can if necessary be supplied with a coating or pattern, and converted into forms ensuring the slow or regulated release of the active agent with the desired release profile, e.g. by admixture of hydroxypropylmethyl cellulose in varying proportions.
Forms of products convenient for parenteral administration may contain antioxidants, buffers, bacteriostatic agents, and an aqueous or nonaqueous, isotonic sterile injection solution which makes the product isotonic to the recipient's blood; or an aqueous or nonaqueous sterile suspension which consists of suspending and condensing agents, e.g. liposomes or other microparticle systems, for delivery of the active agent to the blood components or to one or more organs.
Products can be presented in the form of enclosed containers, e.g. ampoules or tubes including a unit or multiple dose, or stored in a Iyophilic phase, to which it is sufficient to add before use the appropriate liquid vehicle, e.g. water suitable, for the preparation of injections. Ready-to-use injections and suspensions can be produced from the tablets described above. Advantageous unit-dose products may contain the above-described daily dose or unit, the daily divided dose, or an appropriate fraction of that.
Therapeutic products covered by the invention naturally contain, in addition to the vehicles mentioned above, other vehicles conventionally used in pharmaceutical production, depending on the form of the product in question, e.g. an oral dosing product may further contain sweetening agents, condensing agents and aromatic agents.
KYNA, derivatives may have substantially more moderate side-effect profiles than those of the synthetic molecules applied to date in the required indications, which signifies an absolute advantage from the aspect of the patient.
Further details of the invention are illustrated by the following examples serving merely as illustration and are not intended to restrict the scope of claims.
Example 1
2-(2-N,N-dimethyl-amino-ethylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride (2) 0.40 g (2.13 mmol) of kynurenic acid are dissolved in 30 ml of dimethylformamide (DMF), 0.28 g (2.13 mmol) of 1 -hydroxy benztriazole and 0.19 g (2.13 mmol) of N,N-dimethylethylene diamine are added. The mixture thus obtained is stirred at O0C for 30 minutes whereafter 0.4 ml (2.34 mmol) of N,N'-diisopropyl carbodiimide (DCI) are added. The mixture is allowed to warm up to room temperature and it is further stirred for 24 hours. After removing the solvent, the product is purified by column chromatography, using methanol as eluent.
After evaporation the obtained free base is converted to a salt by using hydrochloric acid - ethanol- Et2O.
0,54 g (86 %); m.p.: 178-179 0C. 1H NMR (D2O); 3,00 (6H, s, N-CH3); 3,47 (2H, t, J = 5,8 Hz, CH2); 3,87 (2H, t, J = 5,7 Hz, CH2); 6,90 (IH, s, C3-H); 7,58 (IH, t, J = 7,2 Hz, Ar-H); 7,81- 7,86 (2H, m, Ar-H); 8,18 (IH, d, J = 8,1 Hz, Ar-H).
Example 2
2-(3-N,N-dimethyl-propylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride (3)
We proceed as disclosed in Example 1 using 0.22 g (2.13 mmol) of 3-dimethlyamino-l- propylamine.
0.51 g (77%), m.p.: 149-150 0C. 1H NMR (D2O); 2,10 (2H, t, J = 8,2 Hz, CH2); 2,92 (6H, s, N-CH3); 3,25 (2H, t, J = 7,9 Hz, CH2); 3,55 (2H, t, J = 6,7 Hz, CH2); 6,87 (IH, s, C3-H); 7,57 (IH, t, J = 7,4 Hz, Ar-H); 7,83-7,86 (2H, m, Ar-H); 8,18 (IH, d, J = 8,2 Hz, Ar-H).
Example 3
2-(2-N,N-diethy 1-amino-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride (4) We proceed as disclosed in Example 1 using 0.25 g (2.13 mmol) of N,N-diethylene diamine.
0.55 g (80%). M.p.: 192-194 0C. 1H NMR (D2O); 1,34 (6H, t, J = 7,3 Hz, N-CH2-CH3); 3,30- 3,38 (4H, m, N-CH2-CH3); 3,47 (2H, t, J = 6,4 Hz, CH2); 3,86 (2H, t, J = 6,4 Hz, CH2); 6,89 (IH, s, C3-H); 7,57 (IH, t, J = 7,6 Hz, Ar-H); 7,59-7,87 (2H, m, Ar-H); 8,16 (IH, d, J = 8,3 Hz, Ar-H).
Example 4
2-(2-N-morpholinylethyl-amino-ethylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride (5)
We proceed as disclosed in Example 1 using 0.27 g (2.13 mmol) of 2-morpholinyl-ethylene diamine. 0.54 g (75%), m.p.: 230-232 0C. 1H NMR (D2O); 3,30 (2H, bs, CH2), 3,51 (2H, t, J = 6,12
Hz, CH2); 3,67 (2H, bs, CH2); 3,90 (2H, t, J = 5,9 Hz, CH2); 3,91 (2H, bs, CH2); 4,13 (2H, bs, CH2); 6,89 (IH, s, C3-H); 7,57 (IH, t, J = 7,4 Hz, Ar-H); 7,86 (IH, d, J = 8,4 Hz, Ar-H); 8,19 (IH, t, J =
7,1 Hz1 Ar-H).
Example 5
2-(2-N-piperidylethyl-arnino-ethylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride (6) We proceed as disclosed in Example 1 using 0.27 g (2.13 mmol) of 1 -(2-aminoethyl)-piperidine.
0.58 g (81%). M.p.: 206-208 0C. 1H NMR (D2O); 1,48-1,99 (6H, m), 3,02 (2H, t, J = 12,5 Hz, CH2); 3,41 (2H, t, J = 6,2 Hz, CH2); 3,63-3,67 (2H, m, CH2); 3,86 (2H, t, J = 6,2 Hz, CH2); 6,88 (IH, s, C3-H); 7,57 (IH, t, J = 7,4 Hz, Ar-H); 7,81-7.89 (2H, m, Ar-H); 8,19 (IH, d, J = 8,2 Hz, Ar-H).
Example 6
2-(2-N-pirrolidylethyl-amino~l-carbonyl)-l H-quinolin-4-one hydrochloride (7)
We proceed as disclosed in Example 1 using 0.24 g (2.13 mmol) of l-(2-aminoethyl)-pyrrolidine.
0.56 g (82%). M.p.: 185-187 0C. 1H NMR (D2O); 2,02-2,19 (4H, m), 3,15"-372O (TW, m CH2); 3,52 (2H, t, J = 6,0 Hz, CH2); 3,74-3,77 (2H, m, CH2); 3,85 (2H, t, J = 6,0 Hz, CH2); 6,89 (IH, s, C3-H); 7,56 (IH, t, J = 7,4 Hz, Ar-H); 7.79-7.7.86 (2H, m, Ar-H); 8,17 (IH, d, J = 8,2 Hz, Ar-H).
Example 7
2-/2(2-N-methyIpiperidyl)-methyl-amino-l-carbonyl/-lH-quinolin-4-one hydrochloride (8)
We proceed as disclosed in Example 1 using 0.27 g (2.13 mmol) of 2-N-methyl-piperidyl- methylamine.
0.55 g (77%) ; m.p.: 218-220 0C. 1H NMR (D2O); 1,55-2,32 (6H, m), 3,02 (3H, s); 3, 1 1-3,95 (5H, m); 6,85 (IH, s, C3-H); 7,53 (IH, t, J = 7,4 Hz, Ar-H); 7,77-7.82 (2H, m); 8, 17 (IH, d, J = 8,2 Hz, Ar-H).
Example 8
2-(4-methy 1-piperazy 1- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride (9) We proceed as disclosed in Example 1 using 0.21 g (2.13 mmol) of N-methyl-piperazine.
0.60 g (82%). M.p.: 192-194 0C. 1H NMR (D2O); 2,92 (3H, s), 3,12-3,97 (8H, m); 6,65 (IH, s, C3-H); 7,51 (IH, t, J = 7,4 Hz, Ar-H); 7,67 (IH, d, J = 8,4 Hz, Ar-H); 7,80 (IH, t, J = 7,1 Hz, Ar- H); 8,12 (I H, d, J = 8,2 Hz, Ar-H).
Example 9
2-(piperazyl-l-carbonyl)-l H-quinolin-4-one hydrochloride (10)
We proceed as disclosed in Example 1 using 0.18 g (2.13 mmol) of 2-N-methyl-piperazine.
0.47 g (67%), m.p. > 35O0C. 1H NMR (D2O); 3.21-3.98 (8H, m), 6,51 (I H, s, C3-H); 7,51
(IH, t, J = 7,4 Hz, Ar-H); 7,67 (IH, d, J = 8,4 Hz, Ar-H); 7,80 (IH, t, J = 7,1 Hz, Ar-H); 8,15 (IH, d, J = 8,2 Hz, Ar-H).
Example 10
2-(4-benzyl-piperazyl-l -carbonyl)-l H-quinolin-4-one hydrochloride (11)
0.165 g (0.5 mmol) of a compound No. 10 are dissolved in 10 ml of ethanol and 0.126 g (1.25 mmol) of Et3N are added. To the mixture thus obtained 5 ml of a solution of 0.073 g (0.55 mmol) of benzyl bromide in ethanol is added drop wise. The reaction mixture is then further stirred at room temperature for 10 hours and purified by column chromatography using methanol as eluent. From the free base obtained after evaporation a salt is separated by hydrochloric acid-ethanol-Et2O.
0.1 1 18 g (62%) m.p. 213-215 0C. 1H NMR (D2O); 3,15-4,17 (8H, m); 4,38 (2H, s); 6,55 (IH, s, C3-H); 7,42-7,61 (6H, m, Ar-H); 7,70 (IH, d, J = 8,4 Hz, Ar-H); 7,82 (I H, t, J = 7,1 Hz, Ar-H);
8,17 (IH, d, J = 8,2 Hz, Ar-H).
Claims
1. Compounds of the general formula (I), wherein the substituents are as follows:
X
(I)
Ri stands for -(O-Ci-C6)alkyl-, -Oaryl-, -O(CH2)naryl or -NR'(CH2)nNR2R3, latter may optionally be substituted in the alkylene chain by alkyl containing 1 to 6 carbon atoms, and wherein R' stands for hydrogen or alkyl containing 1 to 6 carbon atoms, n stands for an integer from 1 to 6,
R2 and R3 are independently of each other hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, alkenyl containing 2 to 10 carbon atoms, alkinyl containing 2 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part or
R2 and R3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-8 membered heterocyclic ring comprising 1 or 2 N, O, and/or S heteroatoms, substituted by one or more substituents, preferably selected from alkyl containing 1 to 10 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part, or a saturated or unsaturated 5-8 membered heterocyclic ring comprising a further nitrogen atom attached to the carbonyl group via nitrogen, wherein the heterocyclic ring may optionally be substituted with alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part,
R7 stands for hydrogen or straight or branched alkyl containing 1 to 10 carbon atoms, X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the 5 and 7 position of the ring may not substituted by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifluoromethyl, alkenyl containing 2 to 4 carbon atoms, and position 6 of the ring may not be substituted by halogen or trifluoromethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
2. Compounds of the general formula (I) as claimed in claim-wherein Ri stands for -NR'(CH2)nNR2R3, wherein wherein R' stands for hydrogen or alkyl containing 1 to 4 carbon atoms, n stands for an integer from 1, 2 or 3, R2 and R3 are independently of each other hydrogen or straight or branched alkyl containing 1 to 6 carbon atoms, preferably alkyl containing 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, particularly preferably methyl or ethyl or R2 and R3 together with the nitrogen to which they are attached form a saturated or unsaturated 5-6 membered heterocyclic ring comprising 1 or 2 N, O, and/or S heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl substituted by one or more substituents, preferably selected from alkyl containing 1 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms, preferably phenyl or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part, preferably benzyl, or a saturated or unsaturated 5-8 membered heterocyclic ring comprising a further nitrogen atom attached to the carbonyl group via nitrogen, wherein the heterocyclic ring may optionally be substituted with alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms, preferably phenyl or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part, preferably benzyl, R7 stands for hydrogen or straight or branched alkyl containing 1 to 6 carbon atoms, X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the 5 and 7 position of the ring may not substituted by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, cyano, trifiuoromethyl, alkenyl containing 2 to 4 carbon atoms, and position 6 of the ring may not be substituted by halogen or trifiuoromethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
3. Compounds of the general formula (I) as claimed in claim 1-wherein Ri stands for -NR'(CH2)nNR2R3, wherein R' stands for hydrogen, n has the value of 1 , 2 or 3 and
R2 and R3 are independently of each other hydrogen, straight or branched alkyl containing 1 to 4 carbon atoms, preferably methyl or ethyl or
R2 and R3 preferably together with the nitrogen to which they are attached form a 5 to 6 membered saturated or unsaturated heterocycle comprising 1 or 2 nitrogen, oxygen and/or sulphur heteroatoms, preferably morpholinyl, pyrrolidyl, piperidyl, piperazyl, preferably substituted by one or more susbtituents selected from group comprising alkyl containing 1 to 4 carbon atoms, preferably methyl or aryl containing 6 to 10 carbon atoms, preferably phenyl or aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part, preferably benzyl or a piperazyl group attached to the carbonyl group via nitrogen, optionally substituted by alkyl containing 1 to 4 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms-, preferably phenyl, aryl alkyl containing 6 to 10 carbon atoms in the aryl part and containing 1 to 4 carbon atoms in the alkyl part, preferably benzyl
R7 stands for hydrogen, or straight or branched alkyl containing 1 to 4 carbon atoms and
X, Y, Z, W may stand for hydrogen, OH, amino, nitro, CF3, cyano, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms- carbonyl, alkenyl containing 2 to 4 carbon atoms, or halogen, with the proviso that the ring may not be substituted in the 5 and 7 position of the ring by halogen and/or alkyl containing 1 to 4 carbon atoms, OH, amino, nitro, trifluormethyl, alkenyl containing 2 to 4 carbon atoms and in the 6 position by halogen or trifluormethyl and pharmaceutically acceptable salts, amides, all possible stereoisomers, including diastereoisomers and/or enantiomers, racemates and mixtures thereof.
4. 2-(2-N,N-dimethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(4-benzy lpiperazy 1- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
2-(2-N-morpholino-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride, 2-[2-(2-N-methylpiperidyl)-methylamino- 1 -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methylpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride
5. Process for the compounds of the general formula (I), pharmaceutically acceptable salts, amides and all possible stereoisomers, including diastereoisomesr and/or enantiomers, racemates or mixtures thereof, wherein Ri, R2, R3 and n, R7, X, Y, Z, W are as given in claim 1, which comprises in order to prepare compounds of the general formula (I) -wherein R1 stands for alkoxy, aryloxy or - -O(CH2)naryl, the OH group of the kynurenic acid appropriately substituted by R7, X, Y, Z and W - wherein R7, X, Y, Z and W are as given above- is replaced by a method known per se with a group of alkoxy containing 1 to 10 carbon atoms, -O-aryl or-O(CH2)naryl, or in order to prepare compounds of the general formula (I) containing as Ri a group of the formula -NR'(CH2)nNR2R3 reacting kynurenic acid appropriately substituted by R7, X, Y, Z and W - wherein R7, X, Y, Z and W are as given above with a compound of the formula NH2 R'(CH2)nNR2R3, wherein n, R', R2, and R3 are as defined above, in order to prepare compounds of the general formula (I) wherein Ri stands for a 5 to 8 membered saturated or unsaturated heterocycle containing as heteroatoms 2 nitrogen atoms, preferably a piperazyl ring, optionally substituted by alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms preferably phenyl, or aryl alkyl wherein the aryl part contains 6 to 10 carbon atoms and the alkyl part contains 1 to 4 carbon atoms, preferably benzyl, reacting kynurenic acid appropriately substituted by R7, X, Y, Z and W -wherein R7, X, Y, Z and W are as given above - with a compound containing a 5 to 8 membered saturated or unsaturated heterocycle containing as heteroatoms 2 nitrogen atoms, preferably a piperazyl ring optionally substituted by alkyl containing 1 to 6 carbon atoms, preferably methyl, aryl containing 6 to 10 carbon atoms preferably phenyl, or aryl alkyl, wherein the aryl part contains 6 to 10 carbon atoms and the alkyl part contains 1 to 4 carbon atoms, preferably benzyl, and converting the obtained compound of the general formula (I), if desired to a pharmaceutically acceptable salt, amide or all possible stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof.
6. Pharmaceutical composition, comprising as active ingredient a pharmaceutically efficient amount of at least one compound of the general formula (I), pharmaceutically acceptable salt, amide or all possible stereoisomers including diastereoisomers and/or enantiomers, racemates or mixtures thereof, wherein the substituents are as defined above, together with pharmaceutically acceptable carriers.
7. Pharmaceutical compositions as claimed in claim 6 comprising as active ingredient a compound selected from the group of
2-(2-N,N-dimethy laminoethy lamin- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethy laminoethy lamin- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-l H-quinolin-4-one hydrochloride 2-(4-benzy lpiperazy 1- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidyl-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride, 2-[2-(2-N-methy lpiperidy l)-methylamino- 1 -carbony I]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methy lpiperazy 1-1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazy 1- 1 -carbony I)- 1 H-quinolin-4-one hydrochloride and pharmaceutically acceptable additives.
8. Pharmaceutical compositions as claimed in claim 6, characterized by an activity against migraine or an activity against other headaches accompanied by trigeminal activation.
9. Use of a compound of the general formula (I), pharmaceutically acceptable salt, amide or all possible stereoisomers including diastereoisomers and/or enantiomers, racemates for the manufacture of a medicine having an activity against migraine or an activity against other headaches accompanied by trigeminal activation.
10. Use as claimed in claim 9, wherein the active ingredient is selected from the group of
2-(2-N,N-dimethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethylaminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(3-N,N-dimethylpropylamino-l-carbonyl)-lH-quinolin-4-one hydrochloride 2-(4-benzylpiperazyl- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidy 1-ethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride, 2-[2-(2-N-methylpiperidyl)-methylamino- 1 -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methyIpiperazyl-l -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazy 1- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride.
11. A compound of the general formula (I), pharmaceutically acceptable salt, amide or all possible stereoisomers including diastereoisomers and/or enantiomers, racemates for use against migraine or other headaches accompanied by trigeminal activation.
12. A compound as claimed in claim 11 as given below for use against migraine or other headaches accompanied by trigeminal activation:
2-(2-N,N-dimethy laminoethylamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N,N-diethy laminoethy lamin- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(3 -N,N-dimethy lpropy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-benzy lpiperazy 1- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-morpholino-ethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(2-N-pyrrolidy 1-ethy lamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride, 2-[2-(2-N-methylpiperidyl)-methylamino- 1 -carbonyl]- 1 H-quinolin-4-one hydrochloride 2-(2-N-piperidylethylamino- 1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(4-methy lpiperazy 1-1 -carbonyl)- 1 H-quinolin-4-one hydrochloride 2-(piperazyl-l -carbonyl)-! H-quinolin-4-one hydrochloride.
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Cited By (2)
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WO2017149333A1 (en) | 2016-03-04 | 2017-09-08 | Szegedi Tudományegyetem | Novel types of c-3 substituted kinurenic acid derivatives with improved neuroprotective activity |
US10870633B2 (en) | 2016-03-04 | 2020-12-22 | Szegedi Tudományegyetem | Types of C-3 substituted kynurenic acid derivatives with improved neuroprotective activity |
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