EP0532545A1 - Nicotinylalanine as a therapeutic agent acting on the central nervous system - Google Patents
Nicotinylalanine as a therapeutic agent acting on the central nervous systemInfo
- Publication number
- EP0532545A1 EP0532545A1 EP91909910A EP91909910A EP0532545A1 EP 0532545 A1 EP0532545 A1 EP 0532545A1 EP 91909910 A EP91909910 A EP 91909910A EP 91909910 A EP91909910 A EP 91909910A EP 0532545 A1 EP0532545 A1 EP 0532545A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nicotinylalanine
- nervous system
- central nervous
- therapeutic agent
- tryptophan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- FXUIIMLZBKKHLE-ZETCQYMHSA-N (2s)-2-(pyridin-3-ylmethylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NCC1=CC=CN=C1 FXUIIMLZBKKHLE-ZETCQYMHSA-N 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 229940124597 therapeutic agent Drugs 0.000 title claims description 4
- 210000003169 central nervous system Anatomy 0.000 title description 4
- 230000004060 metabolic process Effects 0.000 claims abstract description 6
- 230000002159 abnormal effect Effects 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 230000002964 excitative effect Effects 0.000 claims 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract description 12
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 abstract description 11
- 230000009540 excitatory neurotransmission Effects 0.000 abstract 1
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 14
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 12
- 206010010904 Convulsion Diseases 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 230000036461 convulsion Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229960005152 pentetrazol Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- FXUIIMLZBKKHLE-SSDOTTSWSA-N (2r)-2-(pyridin-3-ylmethylazaniumyl)propanoate Chemical compound OC(=O)[C@@H](C)NCC1=CC=CN=C1 FXUIIMLZBKKHLE-SSDOTTSWSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
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- 230000037361 pathway Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000034308 Grand mal convulsion Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010034759 Petit mal epilepsy Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XGNNOKSIFRVHHA-SNVBAGLBSA-N 2-[(4r)-5-oxo-3-phenylmethoxycarbonyl-1,3-oxazolidin-4-yl]acetic acid Chemical compound C1OC(=O)[C@@H](CC(=O)O)N1C(=O)OCC1=CC=CC=C1 XGNNOKSIFRVHHA-SNVBAGLBSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 108010033242 Kynurenine 3-monooxygenase Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029400 Nicotinic acid deficiency Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000002141 Pellagra Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000006633 Tonic-Clonic Epilepsy Diseases 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047627 Vitamin deficiencies Diseases 0.000 description 1
- 208000003554 absence epilepsy Diseases 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000002933 epilepsy with generalized tonic-clonic seizures Diseases 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- -1 nicotinyl Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
Definitions
- NICOTINYLALANINE AS A THERAPEUTIC AGENT ACTING ON THE CENTRAL NERVOUS SYSTEM
- the present invention relates to the use of nico- tinylalanine as a therapeutic agent in the treatment of diseases of the central nervous system.
- Nicotinylalanine which has the following structu ⁇ ral formula:
- the invention relates either to the use of one of the two enantiomers or to the use of the racemic mixture.
- the single enantiomers of nicotinylalanine can be obtained by conventional methods of optical resolution, starting from the racemic compound. Alternatively, they can be obtained by the stereoselective synthesis herei ⁇ nafter disclosed.
- Nicotinylalanine has been known for some time: about 30 years ago, it was believed to be a metabolic product of tryptophan and an intermediate metabolite of the so-called kynurenine pathway, which is the sequence of metabolic events leading to the opening of the indole ring of tryptophan and hence the formation of NAD.
- 3-hydroxyky ⁇ nurenine can be toxic for neuronal cells in culture and that quinolinic acid is a toxin capable of stimulating neurones and possibly causing their death, both in in vitro preparations and in vivo (Stone and Connick; Neu- roscience, 1985; 15; 597-618).
- the mechanism responsible for this neuronal death is one of competitive inhibition of kynurenine hy ⁇ droxylase and kynureninease.
- kynurenine hy ⁇ droxylase and kynureninease.
- kynurenic acid forms by a simple en ⁇ zymatic process that provides for the intervention of a transaminase.
- This acid is capable of inhibiting the toxic sti ⁇ mulant effect of quinolinic acid by acting as antagonist of the effects of the latter on the NMDA receptors by a modulating mechanism that has now been adequately clarified (Moroni et al. , Eur. J. Pharmac, 1989; 163; 123-126).
- Rats or mice treated with lipopolysaccharides ex ⁇ tracted from bacteria have concentrations of quinolinic acid and kynurenic acid in their biological fluids and brain that are three times higher than those in con- trols for approximately 70 hours. This is due to the induction of the enzyme indoleamino-2,3-dioxygenase and the resultant increased formation of all the substances originating from the kynurenine pathway.
- nico ⁇ tinylalanine 50-1000 mg/kg i.p.
- the in ⁇ crease in the concentrations of quinolinic acid is si ⁇ gnificantly reduced while that in the concentration of kynurenic acid is markedly enhanced.
- nicotinylalanine facilitates the formation of a metabo- lie product of tryptophan that has antagonistic pro ⁇ perties on the receptors for the stimulant amino acids and reduces the formation of a toxic stimulating sub ⁇ stance. Similar results were obtained when appropriate doses of nicotinylalanine were administered together with tryptophan.
- mice weighing 25-35 g were given ni ⁇ cotinylalanine and then leptazol administered (85 mg/kg subcutaneously) 1 hour later.
- leptazol administered (85 mg/kg subcutaneously) 1 hour later.
- nicotinylalanine protected against leptazol seizures, increasing the latency to convulsion from 270 to 588 seconds.
- the leptazol test is widely used as a test system for drugs useful in petit mal epilepsy.
- mice were used to determine the threshold electric current needed to induce convulsions from ear electrodes. After treat ⁇ ment with nicotinylalanine 370 mg/kg, intraperitone ⁇ ally, 40% of the test animals were protected against convulsions. This test is a frequent indicator of drug efficacy in grand mal epilepsy.
- Nicotinylalanine administration 200-350 mg/kg i.p.
- nicotinyl administration 150-400 mg/kg
- ethanol dependent C57 mice prevented withdrawal induced seizures, tremors and changes of body temperature (Ritzmann and Tabakoff 193, 158-170; 1976).
- nicotinylalanine increases the neosynthesis of kynurenic acid. It has been also observed that nicotinylalanine displaces radioactive glycine from its binding sites in cortical membranes.
- nicotinylalanine can be used to advantage in various diseases effecting the central nervous system that are characterised by an abnormal increase in the metabolism of tryptophan.
- Examples of such conditions in which there is an imbalance between toxic stimulant substances and their modulators or antagonists include:
- Neoplastic diseases particularly those affecting the immune system (lymphomas);
- nico- tinylalanine or physiologically equivalent derivatives thereof will gene ⁇ rally be administered in doses of between 10 and 100 mg/kg/day.
- the exact dosage will depend on various factors, such as the patient's condition and the nature and severity of the disease.
- the substance should be administered by mouth, rectally or parenterally, using conventional pharmaceu ⁇ tical formulations such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co. , N.Y. , USA, 17th Ed., 1985.
- Nicotinylalanine can be prepared by the methods described in J. Biol. Chem. 238, 1049 (1963) and J. Org. Chem. 28 ./ 383 (1953). Although the use of the sub ⁇ stance in the natural L steric configuration is prefer ⁇ red, the invention also relates to the use of the race ⁇ mic form and the D form of nicotinylalanine.
- the enan ⁇ tiomers can be prepared according to the following scheme and Examples.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Steroid Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2041890 | 1990-05-24 | ||
| IT02041890A IT1248486B (it) | 1990-05-24 | 1990-05-24 | Agente terapeutico ad attivita' sul sistema nervoso centrale |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0532545A1 true EP0532545A1 (en) | 1993-03-24 |
Family
ID=11166634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP91909910A Withdrawn EP0532545A1 (en) | 1990-05-24 | 1991-05-21 | Nicotinylalanine as a therapeutic agent acting on the central nervous system |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0532545A1 (enrdf_load_stackoverflow) |
| JP (1) | JPH05507086A (enrdf_load_stackoverflow) |
| AU (1) | AU7883291A (enrdf_load_stackoverflow) |
| BR (1) | BR9106500A (enrdf_load_stackoverflow) |
| CA (1) | CA2083507A1 (enrdf_load_stackoverflow) |
| HU (1) | HUT64695A (enrdf_load_stackoverflow) |
| IT (1) | IT1248486B (enrdf_load_stackoverflow) |
| WO (1) | WO1991017750A1 (enrdf_load_stackoverflow) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5536867A (en) * | 1994-04-27 | 1996-07-16 | Hoffmann-La Roche Inc. | Process for the manufacture of dicarboxamides |
| EP0684238A3 (en) * | 1994-04-27 | 1997-01-15 | Hoffmann La Roche | Process for the preparation of dicarboxamides. |
| AU707084B2 (en) * | 1995-03-14 | 1999-07-01 | Edward G. Shaskan | Compositions comprising nicotynylalanine and an inhibitor of glycine conjugation or vitamin B6 |
| KR102152445B1 (ko) * | 2017-09-28 | 2020-09-04 | 주식회사 엘지화학 | 의약품 합성용 중간체 화합물의 제조 방법 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3649649A (en) * | 1967-07-10 | 1972-03-14 | Nisso Kako Co Ltd | Fluoran derivatives and preparation thereof |
| FR1596106A (enrdf_load_stackoverflow) * | 1968-12-13 | 1970-06-15 | ||
| US4065566A (en) * | 1975-04-17 | 1977-12-27 | Interx Research Corporation | N-Nicotinoyl-3,4-dinicotinoyloxy-L-phenylalanine and derivatives pharmaceutical compositions and methods containing same |
-
1990
- 1990-05-24 IT IT02041890A patent/IT1248486B/it active IP Right Grant
-
1991
- 1991-05-21 BR BR919106500A patent/BR9106500A/pt unknown
- 1991-05-21 EP EP91909910A patent/EP0532545A1/en not_active Withdrawn
- 1991-05-21 HU HU9203634A patent/HUT64695A/hu unknown
- 1991-05-21 AU AU78832/91A patent/AU7883291A/en not_active Abandoned
- 1991-05-21 WO PCT/EP1991/000950 patent/WO1991017750A1/en not_active Application Discontinuation
- 1991-05-21 JP JP91509723A patent/JPH05507086A/ja active Pending
- 1991-05-21 CA CA002083507A patent/CA2083507A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9117750A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9106500A (pt) | 1993-05-25 |
| HU9203634D0 (en) | 1993-03-29 |
| CA2083507A1 (en) | 1991-11-25 |
| IT9020418A1 (it) | 1991-11-24 |
| JPH05507086A (ja) | 1993-10-14 |
| WO1991017750A1 (en) | 1991-11-28 |
| HUT64695A (en) | 1994-02-28 |
| IT9020418A0 (enrdf_load_stackoverflow) | 1990-05-24 |
| AU7883291A (en) | 1991-12-10 |
| IT1248486B (it) | 1995-01-19 |
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