CA2189131C - Use of pteridine derivatives as no-synthase inhibitors - Google Patents
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- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Abstract
The present invention relates to the use of pteridine derivatives of the formula I
(see formula I) in which X is O, NH or N-(C1-C5)-alkanoyl, R3 is the radical -OR4, -NR5R6 or -S(O)m R7, and R, R1, R2, R4, R5, R6, R7 and m have the meanings given in claim 1, which are nitric oxide synthase inhibitors, for the treatment of diseases which are caused by an increased nitric oxide level.
(see formula I) in which X is O, NH or N-(C1-C5)-alkanoyl, R3 is the radical -OR4, -NR5R6 or -S(O)m R7, and R, R1, R2, R4, R5, R6, R7 and m have the meanings given in claim 1, which are nitric oxide synthase inhibitors, for the treatment of diseases which are caused by an increased nitric oxide level.
Description
~18~131 WO 95/31987 PCT/$P95/01731 Use of pteridine derivatives as NO synthase inhibitors The present invention relates to pteridine derivatives of the formula I
X
HN N~ CH2-R
ci) R1-N~N~N~ R2 R
which on account of their ability to modulate endogenous nitric oxide production are useful pharmaceuticals for the prevention and control of states which are charac-terized by a disturbed nitric oxide level.
Nitric oxide (NO) plays an important part in all sorts of physiological processes (see, for example, R.Henning, Nachr. Chem. Tech. Lab. 41 (1993), 413; H.H.H.W.Schmidt et al., Biochim. Biophys. Acta 1178 (1993), 153). It has, for example, a relaxing effect on the smooth vascular musculature and in this way is substantially involved in the regulation of blood pressure. It controls blood clotting via inhibition of platelet aggregation, and it is involved, for example, as a neurotransmitter in the brain in the building up of long-term memory. NO also functions as a messenger substance in the NANC nerves of the peripheral nervous system. The cytotoxic action of NO
is utilized by macrophages for defense against infection.
Endogenous NO is formed from arginine with the aid of at least three different NO synthase isoenzymes (see, for example, J.F.Rerwin, Jr. and M.Heller, Med. Res. Rev. 14 (1994), 23). They differ with respect to their localiza-tion in the body, their regulability by Ca2'"/calmodulin and their inducibility by endotoxins and cytokines. The constitutive, calcium-dependent NO syntheses are found, for example, in endothelium (Type III) and in the brain (Type I) and are involved there in the regulation of ~~8~~.31 blood pressure and coagulation and in conduction pro-cesses. The cytokine-inducible, calcium-independent isoform (Type II) occurs in macrophages, smooth muscle cells and hepatocytes. It is able, over the long term, to produce relatively large amounts of NO and is held responsible for inflammatory processes and the cytotoxic activity of the macrophages.
A disturbed NO balance results in serious disorders and damage. Thus excessive formation of NO in septic or hemorrhagic shock leads to massive pathological blood pressure decreases. Excess NO production is involved in the formation of type 1 diabetes and atherosclerosis and also appears to be responsible for glutamate-induced neurotoxicity after cerebral ischemia. High NO concen-trations can moreover lead to DNA damage as a result of deamination of cytosine. Examples of disorders which are caused indirectly or directly by a lack of endogenous NO
are arterial high blood pressure, hemostasis disorders, coronary heart disease and erectile dysfunction.
The attempt to use modulation of NO production for the treatment of these syndromes has until now only been realized with the aid of arginine analogs (GB-A-2240041;
WO-A-93/13055). Further potential NO synthase inhibitors discussed in the literature are N-iminoethylornithine (McCall et al., Br. J. Pharmacol. 102 (1991), 234), aminoguanidine (T.P.Misko et al., Eur. J. Pharmacol. 233 (1993), 119; EP-A-547588) and 7-nitroindazole (P.R.Moore et al., Br.J.Pharmacol. 108 (1993), 296).
Various pteridine derivatives occur in nature, and uses of pteridine derivatives as pharmaceutical active com-pounds have also been described. The cytostatic metho-trexate is a pteridine derivative. EP-B-290819 discloses the use of pteridines, among them also those of the formula I in which R3 is hydroxyl, for the treatment of cognitive pathologies. For investigations on NO synthase which considered mechanistic questions, until now hydro-_ - 3 -genated pteridine derivatives were especially used (see, for example, Kwon et al. (J. Biol. Chem. 264 (1989), 20496) or Giovanelli et al. (Proc. Natl. Acad. Sci.
USA 88 (1991), 7091)). Accordingly, tetrahydrobiopterin stimulates NO production and is a cofactor of NO
synthases. Stimulation of NO production was also found for 7,8-dihydrobiopterin. Revel and Marletta (Bio-chemistry 31 (1992) , 7160) report on an increase in NO
synthase activity due to 6-methyl-5,6,7,8-tetrahydrop-terin. Nonhydrogenated pteridines, such as, for example, biopterin, pterin, folic acid or 6-hydroxymethylpterin, showed no significant effects in investigations of this type (Kwon et al., J. Biol. Chem. 264 (1989), 20496).
Surprisingly, it has now been found that pteridine derivatives of the formula I, in particular, have an inhibiting modulatory effect on endogenous NO production and are thus suitable as pharmaceuticals in diseases which are characterized by an excessive NO level.
The present invention relates to the use of pteridine derivatives of the formula I
X
X
HN N~ CH2-R
ci) R1-N~N~N~ R2 R
which on account of their ability to modulate endogenous nitric oxide production are useful pharmaceuticals for the prevention and control of states which are charac-terized by a disturbed nitric oxide level.
Nitric oxide (NO) plays an important part in all sorts of physiological processes (see, for example, R.Henning, Nachr. Chem. Tech. Lab. 41 (1993), 413; H.H.H.W.Schmidt et al., Biochim. Biophys. Acta 1178 (1993), 153). It has, for example, a relaxing effect on the smooth vascular musculature and in this way is substantially involved in the regulation of blood pressure. It controls blood clotting via inhibition of platelet aggregation, and it is involved, for example, as a neurotransmitter in the brain in the building up of long-term memory. NO also functions as a messenger substance in the NANC nerves of the peripheral nervous system. The cytotoxic action of NO
is utilized by macrophages for defense against infection.
Endogenous NO is formed from arginine with the aid of at least three different NO synthase isoenzymes (see, for example, J.F.Rerwin, Jr. and M.Heller, Med. Res. Rev. 14 (1994), 23). They differ with respect to their localiza-tion in the body, their regulability by Ca2'"/calmodulin and their inducibility by endotoxins and cytokines. The constitutive, calcium-dependent NO syntheses are found, for example, in endothelium (Type III) and in the brain (Type I) and are involved there in the regulation of ~~8~~.31 blood pressure and coagulation and in conduction pro-cesses. The cytokine-inducible, calcium-independent isoform (Type II) occurs in macrophages, smooth muscle cells and hepatocytes. It is able, over the long term, to produce relatively large amounts of NO and is held responsible for inflammatory processes and the cytotoxic activity of the macrophages.
A disturbed NO balance results in serious disorders and damage. Thus excessive formation of NO in septic or hemorrhagic shock leads to massive pathological blood pressure decreases. Excess NO production is involved in the formation of type 1 diabetes and atherosclerosis and also appears to be responsible for glutamate-induced neurotoxicity after cerebral ischemia. High NO concen-trations can moreover lead to DNA damage as a result of deamination of cytosine. Examples of disorders which are caused indirectly or directly by a lack of endogenous NO
are arterial high blood pressure, hemostasis disorders, coronary heart disease and erectile dysfunction.
The attempt to use modulation of NO production for the treatment of these syndromes has until now only been realized with the aid of arginine analogs (GB-A-2240041;
WO-A-93/13055). Further potential NO synthase inhibitors discussed in the literature are N-iminoethylornithine (McCall et al., Br. J. Pharmacol. 102 (1991), 234), aminoguanidine (T.P.Misko et al., Eur. J. Pharmacol. 233 (1993), 119; EP-A-547588) and 7-nitroindazole (P.R.Moore et al., Br.J.Pharmacol. 108 (1993), 296).
Various pteridine derivatives occur in nature, and uses of pteridine derivatives as pharmaceutical active com-pounds have also been described. The cytostatic metho-trexate is a pteridine derivative. EP-B-290819 discloses the use of pteridines, among them also those of the formula I in which R3 is hydroxyl, for the treatment of cognitive pathologies. For investigations on NO synthase which considered mechanistic questions, until now hydro-_ - 3 -genated pteridine derivatives were especially used (see, for example, Kwon et al. (J. Biol. Chem. 264 (1989), 20496) or Giovanelli et al. (Proc. Natl. Acad. Sci.
USA 88 (1991), 7091)). Accordingly, tetrahydrobiopterin stimulates NO production and is a cofactor of NO
synthases. Stimulation of NO production was also found for 7,8-dihydrobiopterin. Revel and Marletta (Bio-chemistry 31 (1992) , 7160) report on an increase in NO
synthase activity due to 6-methyl-5,6,7,8-tetrahydrop-terin. Nonhydrogenated pteridines, such as, for example, biopterin, pterin, folic acid or 6-hydroxymethylpterin, showed no significant effects in investigations of this type (Kwon et al., J. Biol. Chem. 264 (1989), 20496).
Surprisingly, it has now been found that pteridine derivatives of the formula I, in particular, have an inhibiting modulatory effect on endogenous NO production and are thus suitable as pharmaceuticals in diseases which are characterized by an excessive NO level.
The present invention relates to the use of pteridine derivatives of the formula I
X
HN R~ ~H2 R
(I) R -N ~N N R 2 R
in which X is O, NH or N-(Cl-C5)-alkanoyl;
R is hydrogen and R1 is hydrogen or (Cl-C5)-alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
R2 is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 is the radical -OR4, -NR5R6 or -S (O) where m mR~, is the numbers 0, 1 or 2;
R4 is hydrogen, (Cl-Cloy-alkyl, cyclohexyl, benzyl, ~~.$~13~
(I) R -N ~N N R 2 R
in which X is O, NH or N-(Cl-C5)-alkanoyl;
R is hydrogen and R1 is hydrogen or (Cl-C5)-alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
R2 is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 is the radical -OR4, -NR5R6 or -S (O) where m mR~, is the numbers 0, 1 or 2;
R4 is hydrogen, (Cl-Cloy-alkyl, cyclohexyl, benzyl, ~~.$~13~
phenyl which is unsubstituted or substituted by chlorine or the radical -CORa, aminocarbonylmethyl which is unsubstituted or substituted on the nitrogen by one or two identical or different (Cl-C4)-alkyl radicals, 2-methoxyethyl, the (2,2-di-methyl-1,3-dioxolan-4-yl)methyl radical or the radical -COR9;
R5 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)propyl, benzyl which carries one or two chlorine atoms or the radical -CORlo on the phenyl ring, (C1-C5)-alkanoyl, the radical -CORlo or the radical -(CHZ)4-CORlo;
R~ is (Cl-C4)-alkyl, benzyl, phenyl which is unsubsti-tuted or substituted by chlorine, the radical -CORE
or the radical -CO-O-CO-(Cl-C4)-alkyl or naphthyl;
Re is hydroxyl, methoxy, amino or Rlo;
R9 is (C1-C4)-alkyl, hydroxymethyl, trifluoromethyl, (C1-C2) -alkoxy or Rli;
Rlo is the radical -NH-CH-(CH2)2-COR12 ' R11 is the radical R13 ' R12 is hydroxyl or (C1-C2)-alkoxy;
R13 is (C1-C4) -alkyl or benzyl;
Rl4 is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and their pharmacologically tolerable salts for the prevention and treatment of diseases which are caused by an increased nitric oxide ~~8~1~1 level.
Alkyl groups can be straight-chain or branched. This also applies if they occur in other groups, for example in alkoxy, alkylmercapto, alkoxycarbonyl or alkanoyl groups.
Examples of alkyl groups which can occur in the compounds of the formula I to be used according to the invention as such, i.e. as (Cl-C4)- or (Cl-Cloy-alkyl, or in other groups, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Examples especially of (Cl-C5)-alkanoyl are formyl, acetyl, propionyl, n-butyryl, i-butyryl, n-valeroyl, 3-methyl-n-butyryl or 2,2-dimethylpropionyl.
Examples of (Cl-C2)-alkoxy are methoxy and ethoxy.
A pyridyl radical can be a 2-pyridyl, 3-pyridyl or 4-pyridyl radical, preferably it is a 2-pyridyl radical.
A phenyl radical which carries a substituent can carry this in the 2-, the 3- or the 4-position. The 3- and the 4-positions are preferred, the 4-position is particularly preferred. If the phenyl radical carries two sub-stituents, these can be, for example, in the 2,3-, 2,4-, 3,4- or 3,5-position. Preferably they are in the 2,4- or 3,4-position. A naphthyl radical can be a 1-naphthyl or 2-naphthyl radical; a 2-naphthyl radical is preferred. In phenylethyl and pyridylethyl radicals the phenyl or pyridyl radical can be in the 1-position or 2-position;
it is preferably in the 2-position.
The compounds of the formula I can be present in various tautomeric forms and in various stereoisomeric forms . The present invention comprises not only the use of all tautomeric forms, but also that of all stereoisomeric forms, i.e., for example, that of pure enantiomers, of enantiomer mixtures and racemates, of pure diastereomers and diastereomer mixtures.
R5 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)propyl, benzyl which carries one or two chlorine atoms or the radical -CORlo on the phenyl ring, (C1-C5)-alkanoyl, the radical -CORlo or the radical -(CHZ)4-CORlo;
R~ is (Cl-C4)-alkyl, benzyl, phenyl which is unsubsti-tuted or substituted by chlorine, the radical -CORE
or the radical -CO-O-CO-(Cl-C4)-alkyl or naphthyl;
Re is hydroxyl, methoxy, amino or Rlo;
R9 is (C1-C4)-alkyl, hydroxymethyl, trifluoromethyl, (C1-C2) -alkoxy or Rli;
Rlo is the radical -NH-CH-(CH2)2-COR12 ' R11 is the radical R13 ' R12 is hydroxyl or (C1-C2)-alkoxy;
R13 is (C1-C4) -alkyl or benzyl;
Rl4 is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and their pharmacologically tolerable salts for the prevention and treatment of diseases which are caused by an increased nitric oxide ~~8~1~1 level.
Alkyl groups can be straight-chain or branched. This also applies if they occur in other groups, for example in alkoxy, alkylmercapto, alkoxycarbonyl or alkanoyl groups.
Examples of alkyl groups which can occur in the compounds of the formula I to be used according to the invention as such, i.e. as (Cl-C4)- or (Cl-Cloy-alkyl, or in other groups, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Examples especially of (Cl-C5)-alkanoyl are formyl, acetyl, propionyl, n-butyryl, i-butyryl, n-valeroyl, 3-methyl-n-butyryl or 2,2-dimethylpropionyl.
Examples of (Cl-C2)-alkoxy are methoxy and ethoxy.
A pyridyl radical can be a 2-pyridyl, 3-pyridyl or 4-pyridyl radical, preferably it is a 2-pyridyl radical.
A phenyl radical which carries a substituent can carry this in the 2-, the 3- or the 4-position. The 3- and the 4-positions are preferred, the 4-position is particularly preferred. If the phenyl radical carries two sub-stituents, these can be, for example, in the 2,3-, 2,4-, 3,4- or 3,5-position. Preferably they are in the 2,4- or 3,4-position. A naphthyl radical can be a 1-naphthyl or 2-naphthyl radical; a 2-naphthyl radical is preferred. In phenylethyl and pyridylethyl radicals the phenyl or pyridyl radical can be in the 1-position or 2-position;
it is preferably in the 2-position.
The compounds of the formula I can be present in various tautomeric forms and in various stereoisomeric forms . The present invention comprises not only the use of all tautomeric forms, but also that of all stereoisomeric forms, i.e., for example, that of pure enantiomers, of enantiomer mixtures and racemates, of pure diastereomers and diastereomer mixtures.
X is preferably O or NH.
Preferably, R is hydrogen.
R1 is preferably hydrogen.
R2 is preferably hydrogen. If R2 is (Cl-C5)-alkanoyl, acetyl, i-butyryl and pivaloyl are preferred.
R3 is preferably (Cl-Cloy-alkyloxy, phenyloxy, amino, methylamino, dimethylamino or the radical -COR11. Par-ticularly preferably, R3 is (C5-Cloy-alkyloxy, amino or the radical -COR11, where the R14 contained in R11 is benzyloxycarbonyl and the R13 contained in R11 is methyl, isopropyl or benzyl.
The compounds of the formula I are known and can be prepared according to or analogously to known processes.
Known synthesis methods for pteridine derivatives of the formula I are, for example, the method of Gabriel-Isay or the Taylor method (see, for example, D.J. Brown, Fused Pyrimidines III, Pteridines (E.C. Taylor and A. Weissberger (Ed.), Wiley & Sons, New York)). In detail, the preparation of compounds of the formula I is described, for example, in EP-A-108 890, in the thesis of Iiermann Michael Traub (Dissertation der Universitat Konstanz, Deutschland (1987)), or in J. Med. Chem. 30 (1987), 40.
The compounds of the formula I to be used according to the invention can form salts with inorganic or organic acids. Suitable acids for the formation of pharmaco-logically acceptable acid addition salts are, for example: hydrochloric acid, hydrobromic acid, naphtha-lenedisulfonic acids, in particular 1,5-naphthalene-disulfonic acid, or phosphoric, nitric, sulfuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, malefic, malic, sulfamic, phenylpro-~~~~~J~
_ 7 _ pionic, gluconic, ascorbic, isonicotinic, methanesul-fonic, p-toluenesulfonic, citric or adipic acid. The compounds of the formula I can add one or more acid equivalents. The acid addition salts can be prepared in the customary manner by combination of the components, expediently in a suitable solvent or diluent. Acid addition salts can be converted into one another by anion exchange. Compounds of the formula I which contain acidic groups can form salts with inorganic or organic bases.
Examples of such salts are, for example, alkali metal salts, in particular sodium and potassium salts, or ammonium salts, in particular those with organic radicals on the ammonium nitrogen.
The inhibition of NO release by the compounds of the formula I can be determined by an activity assay based on the studies of Bredt and Snyder and also Schmidt et al.
(see D.S. Bredt and S.S. Snyder, Isolation of nitric oxide synthase, a calmodulin-requiring enzyme, Proc.
Natl. Acad. Sci. USA 87 (1990), 682; H.H.H.W. Schmidt et al., Purification of a soluble isoform of guanylyl cyclase-activating factor synthase, Proc. Natl. Acad.
Sci. USA 88 (1991), 365). In this assay for purified NO
synthase (NOS) the coproduct L-citrulline obtained during NO formation is determined quantitatively. This is carried out by the use of 3H-radiolabeled L-arginine as a substrate of the enzyme reaction, which is reacted to give 3H-L-citrulline and NO. After the enzyme incubation is complete, resulting L-citrulline is removed from unused L-arginine by means of ion-exchange chromatography of the reaction mixture; the 3H-activity determined by liquid scintillation measurement then corresponds to the amount of L-citrulline. Details of the procedure are given further below.
Diseases which arise due to an increased NO level and which can thus be treated according to the invention with the compounds of the formula I or which can be prevented using these, are, in particular, pathological blood - 8 _ pressure decreases, such as occur in septic or hemorrhagic shock, in tumor or cancer therapy with cytokines or in cirrhosis of the liver. In addition, inflammatory disorders, such as rheumatoid arthritis and in particular ulcerative colitis, as well as insulin-dependent diabetes mellitus and transplant rejection reactions.
However, the following disorders are also connected with increased production of nitric oxide and can be treated or prevented according to the invention. In the cardiovascular field, these are arteriosclerosis, post-ischemic tissue damage and infarct damage, reperfusion damage, myocarditis based on a Coxsackie virus infection and cardiomyopathy; in the nervous system/central nervous system field they are neuritides of varying etiogeneses (forms of neuritis), encephalomyelitides, viral neurodegenerative disorders, Alzheimer's disease, hyperalgesia, epilepsy and migraine, the treatment or prevention of Alzheimer's disease being excluded if R3 in the formula I is hydroxyl; in the kidney field they are acute kidney failure and nephritides of varying etiogeneses, especially glomerulonephritis.
Additionally, treatments in the stomach and the uterus/placenta field and also affecting sperm motility are also fields of use for the compounds of the formula I.
The compounds of the formula I and their pharmacologi-cally acceptable salts can be employed in research and in diagnostic processes as auxiliaries in biochemical and pharmacological studies, and they can be administered to animals, preferably to mammals, and in particular to humans, as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one 2~~9131 _ g _ compound of the formula I or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives.
The therapeutics can be administered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures.
Administration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions or infusion solutions, or percutaneously, e.g. in the form of ointments or tinctures.
In addition to the active compounds and excipients, the pharmaceutical preparations can also contain additives, such as, for example, fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsi-fiers, preservatives, sweetening agents, colorants, flavorings or aromatizers, buffer substances, and furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants.
They can also contain two or more compounds of the formula I or their pharmacologically acceptable salts and also other therapeutically active substances.
Other therapeutically active substances of this type are, for example: ~B-receptor blockers, such as, for example, propranolol, pindolol, metoprolol; vasodilators, such as, for example, carbocromene; tranquilizers, such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics, such as, for example, chloro-thiazide; cardiotonic agents, such as, for example, digitalis preparations; hypotensive agents, such as, for example, hydralazine, dihydralazine, ramipril, prazosin, clonidine, Rauwolfia alkaloids; agents which lower the fatty acid level in the blood, such as, for example, bezafibrate, fenofibrate; agents for thrombosis prophy-2~8~1~.~
laxis, such as, for example, phenprocoumon; anti-inflammatory substances, such as, for example, cortico-steroids, salicylates or propionic acid deriva-tives, such as, for example, ibuprofen; antibiotics, such as, for example, penicillins or cephalosporins; NO
donors, such as, for example, organic nitrates or sydnone imines or furoxanes.
The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. In general, a daily dose of approximately 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is appro-priate in the case of oral administration. In the case of other administration forms too, the daily dose is in similar ranges of amounts, i.e. in general likewise at 0.5 to 100 mg/person. The daily dose can be divided into several, e.g. 2 to 4, part administrations.
To prepare the pharmaceutical preparations, pharmaceuti-cally inert inorganic or organic excipients can be used.
To prepare pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc . Suitable excipients for the produc-tion of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
Until now, no pharmacological effects or medicinal uses were known for various pteridine derivatives of the formula I. For such compounds, the present invention gives the first medicinal indication. The present invention also relates to pteridine derivatives of the formula I
~~~~~ 31 X
HN N~ CHZ-R
(I) R -td N N R 2 R
in which X is O, NH or N-(Cl-C5)-alkanoyl;
R is hydrogen and Rl is hydrogen or (Cl-C5)-alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
RZ is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 is the radical -OR4, -NR5R6 or -S (O)~R~, where m is the numbers 0, 1 or 2;
R4 is hydrogen, (Cl-Cloy-alkyl, cyclohexyl, benzyl, phenyl which is unsubstituted or substituted by chlorine or the radical -CORa, aminocarbonylmethyl which is unsubstituted or substituted on the nitrogen by one or two identical or different (Cl-C4)-alkyl radicals, 2-methoxyethyl, the (2,2-di-methyl-1,3-dioxolan-4-yl)methyl radical or the radical -COR9;
R5 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)propyl, benzyl which carries one or two chlorine atoms or the radical -CORlo on the phenyl ring, (Cl-C5)-alkanoyl, the radical -CORlo or the radical -(CH2)4-CORlo~
R~ is (Cl-C4)-alkyl, benzyl, phenyl which is unsubsti tuted or substituted by chlorine, the radical -CORE
or the radical -CO-O-CO-(Cl-C4)-alkyl or naphthyl;
Ra is hydroxyl, methoxy, amino or Rlo R9 is (Cl-C4)-alkyl, hydroxymethyl, trifluoromethyl, (Cl-CZ) -alkoxy or R11;
Rlo is the radical -NH-CH-(CHZ)2-COR12 ' R11 is the radical ;
R12 is hydroxyl or (C1-C2)-alkoxy;
R13 is (C1-C4) -alkyl or benzyl;
R14 is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and also their pharmacologi cally tolerable salts where, however, compounds of the formula I in which R3 is hydroxyl are excluded, as phar macological active compounds. For preferred pteridine derivatives of this type, that stated above correspond ingly applies.
The following examples give compounds of the formula I
which can be employed according to the invention. In the examples the following abbreviations are used:
Me - methyl Et - ethyl iPr = isopropyl iBu = isobutyl tBu = tert-butyl Ph - phenyl Py - 2-pyridyl Z - benzyloxycarbonyl Ph-4-COON, Ph-4-C1 and corresponding particulars are a phenyl radical which is substituted in the 4-position by the radical -COOH or by chlorine or by the group indica-ted in the particular example. Rloa~ Riob and Rloc are the ~~~~13~
radical of the formula -NH-CH-(CH2)2-COR12 where in the case of Rloa the radical R12 is hydroxyl, in the case of Rlob the radical R12 is ethoxy and in the case of Rloc the radical R12 is methoxy.
Ra is the (2,2-dimethyl-1,3-dioxolan-4-yl)methyl radical (D-form) .
In Examples Nos. 1 to 109, R in the formula I is hydrogen.
No. X R1 R2 R3 1 0 H ~ H OH
2 0 tBuCO H OH
3 0 H OH OMe 5 O H H OEt 6 0 H H OiPr 7 0 ' H H OiHu 8 0 H H Ot8u 9 0 H H OPh 10 0 H H 0-(Ph-4-COON) 11 0 H H 0-(Ph-4-COOMe) 12 0 H H 0-(Ph-4-CORlOa) 13 0 H H 0-n-Octyl 14 0 H H O-n-Decyl 15 0 H H OCH2CH20Me 16 0 H H OCOMe 17 0 MeCO H OCOMe 18 0 H H OCOtBu 19 0 tBuCO H OCOtBu 20 o H H ococH2oH
Preferably, R is hydrogen.
R1 is preferably hydrogen.
R2 is preferably hydrogen. If R2 is (Cl-C5)-alkanoyl, acetyl, i-butyryl and pivaloyl are preferred.
R3 is preferably (Cl-Cloy-alkyloxy, phenyloxy, amino, methylamino, dimethylamino or the radical -COR11. Par-ticularly preferably, R3 is (C5-Cloy-alkyloxy, amino or the radical -COR11, where the R14 contained in R11 is benzyloxycarbonyl and the R13 contained in R11 is methyl, isopropyl or benzyl.
The compounds of the formula I are known and can be prepared according to or analogously to known processes.
Known synthesis methods for pteridine derivatives of the formula I are, for example, the method of Gabriel-Isay or the Taylor method (see, for example, D.J. Brown, Fused Pyrimidines III, Pteridines (E.C. Taylor and A. Weissberger (Ed.), Wiley & Sons, New York)). In detail, the preparation of compounds of the formula I is described, for example, in EP-A-108 890, in the thesis of Iiermann Michael Traub (Dissertation der Universitat Konstanz, Deutschland (1987)), or in J. Med. Chem. 30 (1987), 40.
The compounds of the formula I to be used according to the invention can form salts with inorganic or organic acids. Suitable acids for the formation of pharmaco-logically acceptable acid addition salts are, for example: hydrochloric acid, hydrobromic acid, naphtha-lenedisulfonic acids, in particular 1,5-naphthalene-disulfonic acid, or phosphoric, nitric, sulfuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, malefic, malic, sulfamic, phenylpro-~~~~~J~
_ 7 _ pionic, gluconic, ascorbic, isonicotinic, methanesul-fonic, p-toluenesulfonic, citric or adipic acid. The compounds of the formula I can add one or more acid equivalents. The acid addition salts can be prepared in the customary manner by combination of the components, expediently in a suitable solvent or diluent. Acid addition salts can be converted into one another by anion exchange. Compounds of the formula I which contain acidic groups can form salts with inorganic or organic bases.
Examples of such salts are, for example, alkali metal salts, in particular sodium and potassium salts, or ammonium salts, in particular those with organic radicals on the ammonium nitrogen.
The inhibition of NO release by the compounds of the formula I can be determined by an activity assay based on the studies of Bredt and Snyder and also Schmidt et al.
(see D.S. Bredt and S.S. Snyder, Isolation of nitric oxide synthase, a calmodulin-requiring enzyme, Proc.
Natl. Acad. Sci. USA 87 (1990), 682; H.H.H.W. Schmidt et al., Purification of a soluble isoform of guanylyl cyclase-activating factor synthase, Proc. Natl. Acad.
Sci. USA 88 (1991), 365). In this assay for purified NO
synthase (NOS) the coproduct L-citrulline obtained during NO formation is determined quantitatively. This is carried out by the use of 3H-radiolabeled L-arginine as a substrate of the enzyme reaction, which is reacted to give 3H-L-citrulline and NO. After the enzyme incubation is complete, resulting L-citrulline is removed from unused L-arginine by means of ion-exchange chromatography of the reaction mixture; the 3H-activity determined by liquid scintillation measurement then corresponds to the amount of L-citrulline. Details of the procedure are given further below.
Diseases which arise due to an increased NO level and which can thus be treated according to the invention with the compounds of the formula I or which can be prevented using these, are, in particular, pathological blood - 8 _ pressure decreases, such as occur in septic or hemorrhagic shock, in tumor or cancer therapy with cytokines or in cirrhosis of the liver. In addition, inflammatory disorders, such as rheumatoid arthritis and in particular ulcerative colitis, as well as insulin-dependent diabetes mellitus and transplant rejection reactions.
However, the following disorders are also connected with increased production of nitric oxide and can be treated or prevented according to the invention. In the cardiovascular field, these are arteriosclerosis, post-ischemic tissue damage and infarct damage, reperfusion damage, myocarditis based on a Coxsackie virus infection and cardiomyopathy; in the nervous system/central nervous system field they are neuritides of varying etiogeneses (forms of neuritis), encephalomyelitides, viral neurodegenerative disorders, Alzheimer's disease, hyperalgesia, epilepsy and migraine, the treatment or prevention of Alzheimer's disease being excluded if R3 in the formula I is hydroxyl; in the kidney field they are acute kidney failure and nephritides of varying etiogeneses, especially glomerulonephritis.
Additionally, treatments in the stomach and the uterus/placenta field and also affecting sperm motility are also fields of use for the compounds of the formula I.
The compounds of the formula I and their pharmacologi-cally acceptable salts can be employed in research and in diagnostic processes as auxiliaries in biochemical and pharmacological studies, and they can be administered to animals, preferably to mammals, and in particular to humans, as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one 2~~9131 _ g _ compound of the formula I or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives.
The therapeutics can be administered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures.
Administration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions or infusion solutions, or percutaneously, e.g. in the form of ointments or tinctures.
In addition to the active compounds and excipients, the pharmaceutical preparations can also contain additives, such as, for example, fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsi-fiers, preservatives, sweetening agents, colorants, flavorings or aromatizers, buffer substances, and furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants.
They can also contain two or more compounds of the formula I or their pharmacologically acceptable salts and also other therapeutically active substances.
Other therapeutically active substances of this type are, for example: ~B-receptor blockers, such as, for example, propranolol, pindolol, metoprolol; vasodilators, such as, for example, carbocromene; tranquilizers, such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics, such as, for example, chloro-thiazide; cardiotonic agents, such as, for example, digitalis preparations; hypotensive agents, such as, for example, hydralazine, dihydralazine, ramipril, prazosin, clonidine, Rauwolfia alkaloids; agents which lower the fatty acid level in the blood, such as, for example, bezafibrate, fenofibrate; agents for thrombosis prophy-2~8~1~.~
laxis, such as, for example, phenprocoumon; anti-inflammatory substances, such as, for example, cortico-steroids, salicylates or propionic acid deriva-tives, such as, for example, ibuprofen; antibiotics, such as, for example, penicillins or cephalosporins; NO
donors, such as, for example, organic nitrates or sydnone imines or furoxanes.
The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. In general, a daily dose of approximately 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is appro-priate in the case of oral administration. In the case of other administration forms too, the daily dose is in similar ranges of amounts, i.e. in general likewise at 0.5 to 100 mg/person. The daily dose can be divided into several, e.g. 2 to 4, part administrations.
To prepare the pharmaceutical preparations, pharmaceuti-cally inert inorganic or organic excipients can be used.
To prepare pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc . Suitable excipients for the produc-tion of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
Until now, no pharmacological effects or medicinal uses were known for various pteridine derivatives of the formula I. For such compounds, the present invention gives the first medicinal indication. The present invention also relates to pteridine derivatives of the formula I
~~~~~ 31 X
HN N~ CHZ-R
(I) R -td N N R 2 R
in which X is O, NH or N-(Cl-C5)-alkanoyl;
R is hydrogen and Rl is hydrogen or (Cl-C5)-alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
RZ is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 is the radical -OR4, -NR5R6 or -S (O)~R~, where m is the numbers 0, 1 or 2;
R4 is hydrogen, (Cl-Cloy-alkyl, cyclohexyl, benzyl, phenyl which is unsubstituted or substituted by chlorine or the radical -CORa, aminocarbonylmethyl which is unsubstituted or substituted on the nitrogen by one or two identical or different (Cl-C4)-alkyl radicals, 2-methoxyethyl, the (2,2-di-methyl-1,3-dioxolan-4-yl)methyl radical or the radical -COR9;
R5 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)propyl, benzyl which carries one or two chlorine atoms or the radical -CORlo on the phenyl ring, (Cl-C5)-alkanoyl, the radical -CORlo or the radical -(CH2)4-CORlo~
R~ is (Cl-C4)-alkyl, benzyl, phenyl which is unsubsti tuted or substituted by chlorine, the radical -CORE
or the radical -CO-O-CO-(Cl-C4)-alkyl or naphthyl;
Ra is hydroxyl, methoxy, amino or Rlo R9 is (Cl-C4)-alkyl, hydroxymethyl, trifluoromethyl, (Cl-CZ) -alkoxy or R11;
Rlo is the radical -NH-CH-(CHZ)2-COR12 ' R11 is the radical ;
R12 is hydroxyl or (C1-C2)-alkoxy;
R13 is (C1-C4) -alkyl or benzyl;
R14 is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and also their pharmacologi cally tolerable salts where, however, compounds of the formula I in which R3 is hydroxyl are excluded, as phar macological active compounds. For preferred pteridine derivatives of this type, that stated above correspond ingly applies.
The following examples give compounds of the formula I
which can be employed according to the invention. In the examples the following abbreviations are used:
Me - methyl Et - ethyl iPr = isopropyl iBu = isobutyl tBu = tert-butyl Ph - phenyl Py - 2-pyridyl Z - benzyloxycarbonyl Ph-4-COON, Ph-4-C1 and corresponding particulars are a phenyl radical which is substituted in the 4-position by the radical -COOH or by chlorine or by the group indica-ted in the particular example. Rloa~ Riob and Rloc are the ~~~~13~
radical of the formula -NH-CH-(CH2)2-COR12 where in the case of Rloa the radical R12 is hydroxyl, in the case of Rlob the radical R12 is ethoxy and in the case of Rloc the radical R12 is methoxy.
Ra is the (2,2-dimethyl-1,3-dioxolan-4-yl)methyl radical (D-form) .
In Examples Nos. 1 to 109, R in the formula I is hydrogen.
No. X R1 R2 R3 1 0 H ~ H OH
2 0 tBuCO H OH
3 0 H OH OMe 5 O H H OEt 6 0 H H OiPr 7 0 ' H H OiHu 8 0 H H Ot8u 9 0 H H OPh 10 0 H H 0-(Ph-4-COON) 11 0 H H 0-(Ph-4-COOMe) 12 0 H H 0-(Ph-4-CORlOa) 13 0 H H 0-n-Octyl 14 0 H H O-n-Decyl 15 0 H H OCH2CH20Me 16 0 H H OCOMe 17 0 MeCO H OCOMe 18 0 H H OCOtBu 19 0 tBuCO H OCOtBu 20 o H H ococH2oH
21 0 H H OCOCH(Me)-NHZ
2Z 0 H H OCOCH(iPr)-NHZ
23 0 H H OCOCH(CH2Ph)-NHZ
25 0 H H OCOOEt 27 0 H H NHMe 28 0 H H ~e2 29 0 H H NH-CH2-(Ph-4-CORlOa) 30 0 H H NH-CH2-(Ph-4-CORlOb) No. X R1 R2 R3 31 0 tBuCO H N(Me)-CH2CH2-Py 32 0 tHuCO H N(CH2CH2-Py)2 33 0 tBuCO H N(CH2-Py)2 34 0 H H N(CH2CH2-OH)2 35 0 H H N(CH2CH2-C1)2 36 0 H H NH-CORlOa 37 0 H H SMe 38 0 H H SEt 39 0 H H S-n-Propyl 49 0 H H S-n-Butyl 41 0 H H S-(Ph-4-CO-0-COiBu) 42 0 H H S-(Ph-4-COOH) 43 0 H H S-(Ph-4-COOMe) 44 0 H H S-(Ph-4-CORlOa) 45 0 H H S-(Ph-4-CORlOb) 46 0 H H S(O)2Me 47 0 t8uC0 H S(0)2Me 49 NH H Me OH
50 NH H OMe OH
52 NH H H OMe 53 NH H H OEt 54 NH H H 0-n-Propyl 55 NH H H OiPr 56 NH H H 0-n-Butyl 57 NH H H OiHu 58 NH H H OtHu 59 NH H H 0-n-Octyl 60 NH H H 0-n-Decyl z~s~~~~
No. X R1 R2 R3 61 NH H H OCH2CH20Me 62 NH H H 0-Cyclohexyl 63 NH H H 0-CH2Ph 64 NH H H OPh 65 NH H H 0-(Ph-4-C1) 66 NH H H 0-(Ph-4-COOH) 67 NH H H 0-(Ph-4-CONH2) 68 NH H H 0-(Ph-4-CORlOa) 6g ~ H H 0-(Ph-4-CORlOb) 70 NH ~ H H 0-Ra 71 NH H H OCOMe 72 NH COMB H OCOMe 74 NH H H OCOCH(Me)-NHZ
75 NH H H OCH2CONEt2 77 NH H H NHMe 78 NH H H NMe2 79 NH H ~2 ~e2 80 NH H H NEt2 81 ~ H H NH-CH2CH2Ph 82 NH H H NH-CH2(Ph-4-CORlOa) 83 NH H H NH-CH2(Ph-4-CORlOb) 84 NH H H N(Me)-(CH2)4-CORlOa 85 NH H H N(Me)-(CH2)4-CORlOb 86 NH H H N(Me)-(CH2)4-CORlOc 87 ~ H H NH-CH2-( 2, 4-Dichlorophenyl) 8$ ~ H H NH-CH2-( 3, 4-Dichlorophenyl) 89 NH H H NH-(CH2)3-O-(CH2)2-OEt 0 ~ H H NH-Cyclohexyi ~1$~~3~.
No. X Rl R2 R3 91 I~ki H H N ( ~2~2-~ ) 2 92 I~ki H H N(~2~2~ ) 2 93 Iii H H Iii-~OiP~' 94 Iii H H SMe 95 NH H H SCH2Ph 96 HIi H H SPh 97 Iii H H S-( Ph-4-Vii) 98 Iii H H S-( Ph-4-ate ) 99 Iii H H S-(Ph-4~OOEt) 100 Iii H H S-(Ph-4-C1) 101 NH H H S(O)-(Ph-4-C1) 102 lei H H S(O)2-(Ph-4-C1) 103 Iii H H S-(Ph-4-CO-O-COiHu) 104 Iii H H S--(Ph-4-~1~) 105 rgi H H S-(ph-4..C~lOb) X106 NH H H S-(2-Nanhthyl) -107 NC~e ~ H
108 NCCMe MeCO H N(C~)2 109 NCOiPr iP~O H Iii-COiPr Example 110 Compound of the formula HN H~ CHZ-OH
Me N-HC=N N N H
Measurement of inhibition of the activity of purified nitric oxide synthase (NOS) The coproduct L-citrulline obtained during the formation of NO by purified NOS is determined quantitatively in this activity assay. The substrate of the enzyme reaction employed is 3H-radiolabeled L-arginine, which is reacted to give 3H-L-citrulline and NO. After the enzyme ~i~913i incubation is complete, resulting L-citrulline is removed from unused L-arginine by means of ion-exchange chromato-graphy of the reaction mixture; the 3H activity measured by liquid scintillation then corresponds to the amount of L-citrulline, which is a direct measure of the activity of NOS.
The base medium for carrying out the enzyme reaction is TE buffer (triethanolamine, EDTA, pH 7.0). The final volume of each incubation is 100 ~.1. The reaction mixture is obtained by mixing the following 6 components on ice:
1. "REA mix" (pH 7.0), which contains triethanolamine, calcium chloride, magnesium chloride, EDTA, L-arginine, calmodulin and flavine adenine dinucleotide (FAD);
2. freshly prepared stock solution of ~-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH);
3. (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride stock solution (BH4) or - for experiments without BH4 -TE buffer instead of this;
4, purified NO synthase from pig cerebellum or from pig 2 0 1 fiver;
5. L-[2,3,4,5-3H]-arginine hydrochloride stock solution (1.5-2.6 TBq/mmol);
6. substance to be tested.
The final concentrations of the components in the incu-bation volume of 100 ~.1 are:
Triethanolamine 50 mM, EDTA 0.5 mM, CaCl2 226 ~,M, MgCl2 477 ~,M, L-arginine 50 ~M, calmodulin 0.5 ~,M, FAD 5 ~.M, NADPH 1 mM, BH4 (if added) 2 ~.M, substance to be tested 100 ~,M. After mixing the components on ice the reaction mixture is immediately incubated in a water bath at 37°C for 15 minutes. After this incubation time, the reaction is stopped by the addition of 900 ~.1 of ice-cold "stop buffer" (20 mM sodium acetate, 2 mM EDTA, pH 5.5) and the mixture (total volume now 1.0 ml) is placed on ice. To separate off the unreacted 3H-L-arginine, the mixture is added to an ion-exchange column with 0.8 ml of ~~8913I
Dowex AG 50 WX-8 (100-200 mesh), which was previously rinsed and equilibrated with 2 ml of stop buffer. After the application of the sample, the column is eluted twice with 1 ml of water each time. The runnings of the sample and the eluate are collected in scintillation containers and purified (total volume 3 ml) . 9 ml of scintillator solution are added to the 3 ml aqueous measuring solution and the homogeneous mixture is measured for 1 minute per sample in a Tricarb 2500 TR (Packard) liquid scintilla-tion counter. The activity found with the substance to be tested is given in percent of the activity of the con-trol. Each substance is tested for antagonistic action at a concentration of 100 ~.M in the presence of 2 ~.M tetra-hydrobiopterin and for agonistic action on the NOS in the absence of tetrahydrobiopterin. All incubations are set up in triplicate. Each experiment is repeated three times with various enzyme preparations. Some results are given in the following table.
Compound Enzyme from Citrulline forma-of example tion (~ of the con-trol) 1 pig cerebellum 61.7 21 pig cerebellum 60.8 23 pig cerebellum 2.5 37 pig cerebellum 22.9 60 pig cerebellum 26.2 76 pig liver 22.4 Example A
Gelatin soft capsules, comprising 100 mg of active compound per capsule:
per capsule Active compound 100 mg Triglyceride mixture fractionated from coconut fat 400 mg Capsule contents 500 mg ~~89131 Example s Injection solution, comprising 2.0 mg of active compound per ml:
per ml Active compound 2.0 mg Polyethylene glycol 400 5.0 mg Sodium chloride 2.7 mg Water for injection purposes to 1 ml Example C
Emulsion, comprising 60 mg of active compound per 5 ml:
per 100 ml of emulsion Active compound 1.2 g Neutral oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2.0 g Flavoring q.s.
Water (demineralized or distilled) to 100 ml Example D
Rectal pharmaceutical form, comprising 40 mg of active compound per suppository:
per suppository Active compound 40 mg Suppository base mass to 2 g Example E
Tablets, comprising 40 mg of active compound per tablet:
per tablet Active compound 40 mg Lactose 600 mg Corn starch 300 mg Soluble starch 20 mg Magnesium stearate 40 mg 1000 mg Example F
Coated tablets, comprising 50 mg of active compound per coated tablet:
per coated tablet Active compound 50 mg Corn starch 100 mg Lactose 60 mg sec. calcium phosphate 30 mg Soluble starch 5 mg Magnesium stearate 10 mg Colloidal silicic acid 5 mg 260 mg Example G
For the preparation of the contents of hard gelatin capsules, the following recipes are suitable:
a) Active compound 100 mg Corn starch 300 mg 400 mg b) Active compound 140 mg Milk sugar 180 mg Corn starch 180 mg 500 mg Example H
Drops can be prepared according to the following recipe (100 mg of active compound in 1 ml = 20 drops):
Active compound 10 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 g Ethanol, 96 ~ strength 5 ml Demineralized water to 100 ml
2Z 0 H H OCOCH(iPr)-NHZ
23 0 H H OCOCH(CH2Ph)-NHZ
25 0 H H OCOOEt 27 0 H H NHMe 28 0 H H ~e2 29 0 H H NH-CH2-(Ph-4-CORlOa) 30 0 H H NH-CH2-(Ph-4-CORlOb) No. X R1 R2 R3 31 0 tBuCO H N(Me)-CH2CH2-Py 32 0 tHuCO H N(CH2CH2-Py)2 33 0 tBuCO H N(CH2-Py)2 34 0 H H N(CH2CH2-OH)2 35 0 H H N(CH2CH2-C1)2 36 0 H H NH-CORlOa 37 0 H H SMe 38 0 H H SEt 39 0 H H S-n-Propyl 49 0 H H S-n-Butyl 41 0 H H S-(Ph-4-CO-0-COiBu) 42 0 H H S-(Ph-4-COOH) 43 0 H H S-(Ph-4-COOMe) 44 0 H H S-(Ph-4-CORlOa) 45 0 H H S-(Ph-4-CORlOb) 46 0 H H S(O)2Me 47 0 t8uC0 H S(0)2Me 49 NH H Me OH
50 NH H OMe OH
52 NH H H OMe 53 NH H H OEt 54 NH H H 0-n-Propyl 55 NH H H OiPr 56 NH H H 0-n-Butyl 57 NH H H OiHu 58 NH H H OtHu 59 NH H H 0-n-Octyl 60 NH H H 0-n-Decyl z~s~~~~
No. X R1 R2 R3 61 NH H H OCH2CH20Me 62 NH H H 0-Cyclohexyl 63 NH H H 0-CH2Ph 64 NH H H OPh 65 NH H H 0-(Ph-4-C1) 66 NH H H 0-(Ph-4-COOH) 67 NH H H 0-(Ph-4-CONH2) 68 NH H H 0-(Ph-4-CORlOa) 6g ~ H H 0-(Ph-4-CORlOb) 70 NH ~ H H 0-Ra 71 NH H H OCOMe 72 NH COMB H OCOMe 74 NH H H OCOCH(Me)-NHZ
75 NH H H OCH2CONEt2 77 NH H H NHMe 78 NH H H NMe2 79 NH H ~2 ~e2 80 NH H H NEt2 81 ~ H H NH-CH2CH2Ph 82 NH H H NH-CH2(Ph-4-CORlOa) 83 NH H H NH-CH2(Ph-4-CORlOb) 84 NH H H N(Me)-(CH2)4-CORlOa 85 NH H H N(Me)-(CH2)4-CORlOb 86 NH H H N(Me)-(CH2)4-CORlOc 87 ~ H H NH-CH2-( 2, 4-Dichlorophenyl) 8$ ~ H H NH-CH2-( 3, 4-Dichlorophenyl) 89 NH H H NH-(CH2)3-O-(CH2)2-OEt 0 ~ H H NH-Cyclohexyi ~1$~~3~.
No. X Rl R2 R3 91 I~ki H H N ( ~2~2-~ ) 2 92 I~ki H H N(~2~2~ ) 2 93 Iii H H Iii-~OiP~' 94 Iii H H SMe 95 NH H H SCH2Ph 96 HIi H H SPh 97 Iii H H S-( Ph-4-Vii) 98 Iii H H S-( Ph-4-ate ) 99 Iii H H S-(Ph-4~OOEt) 100 Iii H H S-(Ph-4-C1) 101 NH H H S(O)-(Ph-4-C1) 102 lei H H S(O)2-(Ph-4-C1) 103 Iii H H S-(Ph-4-CO-O-COiHu) 104 Iii H H S--(Ph-4-~1~) 105 rgi H H S-(ph-4..C~lOb) X106 NH H H S-(2-Nanhthyl) -107 NC~e ~ H
108 NCCMe MeCO H N(C~)2 109 NCOiPr iP~O H Iii-COiPr Example 110 Compound of the formula HN H~ CHZ-OH
Me N-HC=N N N H
Measurement of inhibition of the activity of purified nitric oxide synthase (NOS) The coproduct L-citrulline obtained during the formation of NO by purified NOS is determined quantitatively in this activity assay. The substrate of the enzyme reaction employed is 3H-radiolabeled L-arginine, which is reacted to give 3H-L-citrulline and NO. After the enzyme ~i~913i incubation is complete, resulting L-citrulline is removed from unused L-arginine by means of ion-exchange chromato-graphy of the reaction mixture; the 3H activity measured by liquid scintillation then corresponds to the amount of L-citrulline, which is a direct measure of the activity of NOS.
The base medium for carrying out the enzyme reaction is TE buffer (triethanolamine, EDTA, pH 7.0). The final volume of each incubation is 100 ~.1. The reaction mixture is obtained by mixing the following 6 components on ice:
1. "REA mix" (pH 7.0), which contains triethanolamine, calcium chloride, magnesium chloride, EDTA, L-arginine, calmodulin and flavine adenine dinucleotide (FAD);
2. freshly prepared stock solution of ~-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH);
3. (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride stock solution (BH4) or - for experiments without BH4 -TE buffer instead of this;
4, purified NO synthase from pig cerebellum or from pig 2 0 1 fiver;
5. L-[2,3,4,5-3H]-arginine hydrochloride stock solution (1.5-2.6 TBq/mmol);
6. substance to be tested.
The final concentrations of the components in the incu-bation volume of 100 ~.1 are:
Triethanolamine 50 mM, EDTA 0.5 mM, CaCl2 226 ~,M, MgCl2 477 ~,M, L-arginine 50 ~M, calmodulin 0.5 ~,M, FAD 5 ~.M, NADPH 1 mM, BH4 (if added) 2 ~.M, substance to be tested 100 ~,M. After mixing the components on ice the reaction mixture is immediately incubated in a water bath at 37°C for 15 minutes. After this incubation time, the reaction is stopped by the addition of 900 ~.1 of ice-cold "stop buffer" (20 mM sodium acetate, 2 mM EDTA, pH 5.5) and the mixture (total volume now 1.0 ml) is placed on ice. To separate off the unreacted 3H-L-arginine, the mixture is added to an ion-exchange column with 0.8 ml of ~~8913I
Dowex AG 50 WX-8 (100-200 mesh), which was previously rinsed and equilibrated with 2 ml of stop buffer. After the application of the sample, the column is eluted twice with 1 ml of water each time. The runnings of the sample and the eluate are collected in scintillation containers and purified (total volume 3 ml) . 9 ml of scintillator solution are added to the 3 ml aqueous measuring solution and the homogeneous mixture is measured for 1 minute per sample in a Tricarb 2500 TR (Packard) liquid scintilla-tion counter. The activity found with the substance to be tested is given in percent of the activity of the con-trol. Each substance is tested for antagonistic action at a concentration of 100 ~.M in the presence of 2 ~.M tetra-hydrobiopterin and for agonistic action on the NOS in the absence of tetrahydrobiopterin. All incubations are set up in triplicate. Each experiment is repeated three times with various enzyme preparations. Some results are given in the following table.
Compound Enzyme from Citrulline forma-of example tion (~ of the con-trol) 1 pig cerebellum 61.7 21 pig cerebellum 60.8 23 pig cerebellum 2.5 37 pig cerebellum 22.9 60 pig cerebellum 26.2 76 pig liver 22.4 Example A
Gelatin soft capsules, comprising 100 mg of active compound per capsule:
per capsule Active compound 100 mg Triglyceride mixture fractionated from coconut fat 400 mg Capsule contents 500 mg ~~89131 Example s Injection solution, comprising 2.0 mg of active compound per ml:
per ml Active compound 2.0 mg Polyethylene glycol 400 5.0 mg Sodium chloride 2.7 mg Water for injection purposes to 1 ml Example C
Emulsion, comprising 60 mg of active compound per 5 ml:
per 100 ml of emulsion Active compound 1.2 g Neutral oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2.0 g Flavoring q.s.
Water (demineralized or distilled) to 100 ml Example D
Rectal pharmaceutical form, comprising 40 mg of active compound per suppository:
per suppository Active compound 40 mg Suppository base mass to 2 g Example E
Tablets, comprising 40 mg of active compound per tablet:
per tablet Active compound 40 mg Lactose 600 mg Corn starch 300 mg Soluble starch 20 mg Magnesium stearate 40 mg 1000 mg Example F
Coated tablets, comprising 50 mg of active compound per coated tablet:
per coated tablet Active compound 50 mg Corn starch 100 mg Lactose 60 mg sec. calcium phosphate 30 mg Soluble starch 5 mg Magnesium stearate 10 mg Colloidal silicic acid 5 mg 260 mg Example G
For the preparation of the contents of hard gelatin capsules, the following recipes are suitable:
a) Active compound 100 mg Corn starch 300 mg 400 mg b) Active compound 140 mg Milk sugar 180 mg Corn starch 180 mg 500 mg Example H
Drops can be prepared according to the following recipe (100 mg of active compound in 1 ml = 20 drops):
Active compound 10 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 g Ethanol, 96 ~ strength 5 ml Demineralized water to 100 ml
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. ~The use of pteridine derivatives of the formula I
in which X ~is O, NH or N-(C1-C5)-alkanoyl;
R ~is hydrogen and R1 ~is hydrogen or (C1-C5) -alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
R2 ~is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 ~is the radical -OR4, -NR5R6 or -S(O)m R7, where m is the numbers 0, 1 or 2;
R4 ~is hydrogen, (C1-C10)-alkyl, cyclohexyl, benzyl, phenyl which is unsubstituted or substituted by chlorine or the radical -COR8, aminocarbonylmethyl which is unsubstituted or substituted on the nitrogen by one or two identical or different (C1-C4)-alkyl radicals, 2-methoxyethyl, the (2,2-dimethyl-1,3-dioxolan-4-yl)methyl radical or the radical -COR9;
R5 ~is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 ~independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)-propyl, benzyl which carries one or two chlorine atoms or the radical -COR10 on the phenyl ring, (C1-C5)-alkanoyl, the radical -COR10 or the radical -(CH2)4-COR10;
R7 ~is (C1-C4)-alkyl, benzyl, phenyl which is unsubstituted or substituted by chlorine, the radical -COR8 or the radical -CO-O-CO-(C1-C4)-alkyl or naphthyl;
R8 ~is hydroxyl, methoxy, amino or R10;
R9 ~is (C1-C4)-alkyl, hydroxymethyl, trifluoromethyl, (C1-C2)-alkoxy or R11;
R10 ~is the radical R11 ~is the radical R12 ~is hydroxyl or (C1-C2)-alkoxy;
R13 ~is (C1-C4)-alkyl or benzyl;
R14 ~is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and their pharmacologically tolerable salts for the prevention and treatment of diseases which are caused by an increased nitric oxide level.
in which X ~is O, NH or N-(C1-C5)-alkanoyl;
R ~is hydrogen and R1 ~is hydrogen or (C1-C5) -alkanoyl or R and R1 together with the nitrogen atom to which they are bonded form a dimethylaminomethyleneamino group;
R2 ~is hydrogen, methyl, phenyl, hydroxyl, methoxy or amino;
R3 ~is the radical -OR4, -NR5R6 or -S(O)m R7, where m is the numbers 0, 1 or 2;
R4 ~is hydrogen, (C1-C10)-alkyl, cyclohexyl, benzyl, phenyl which is unsubstituted or substituted by chlorine or the radical -COR8, aminocarbonylmethyl which is unsubstituted or substituted on the nitrogen by one or two identical or different (C1-C4)-alkyl radicals, 2-methoxyethyl, the (2,2-dimethyl-1,3-dioxolan-4-yl)methyl radical or the radical -COR9;
R5 ~is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-chloroethyl, benzyl, pyridylmethyl, phenylethyl, pyridylethyl or acetyl;
R6 ~independently of the meaning of R5 has the meanings indicated for R5 or, if R5 is hydrogen or methyl, is also cyclohexyl, 3-(2-ethoxyethoxy)-propyl, benzyl which carries one or two chlorine atoms or the radical -COR10 on the phenyl ring, (C1-C5)-alkanoyl, the radical -COR10 or the radical -(CH2)4-COR10;
R7 ~is (C1-C4)-alkyl, benzyl, phenyl which is unsubstituted or substituted by chlorine, the radical -COR8 or the radical -CO-O-CO-(C1-C4)-alkyl or naphthyl;
R8 ~is hydroxyl, methoxy, amino or R10;
R9 ~is (C1-C4)-alkyl, hydroxymethyl, trifluoromethyl, (C1-C2)-alkoxy or R11;
R10 ~is the radical R11 ~is the radical R12 ~is hydroxyl or (C1-C2)-alkoxy;
R13 ~is (C1-C4)-alkyl or benzyl;
R14 ~is hydrogen or benzyloxycarbonyl;
and their tautomeric forms and their pharmacologically tolerable salts for the prevention and treatment of diseases which are caused by an increased nitric oxide level.
2. The use as claimed in claim 1, wherein R is hydrogen and X is O or NH.
3. The use as claimed in claim 1 or 2, wherein R1 and/or R2 is hydrogen.
4. The use as claimed in any one of claims 1 to 3, wherein R3 is (C1-C10) -alkyloxy, phenyloxy, amino, methylamino, dimethylamino or the radical -COR11.
5. The use as claimed in claim 4, wherein R3 is (C5-C10)-alkyloxy, amino or the radical COR11, in which the R14 contained in R11 is benzyloxycarbonyl and the R13 contained in R11 is methyl, isopropyl or benzyl.
6. The use as claimed in any one of claims 1 to 4 for the treatment and prevention of pathological blood pressure decreases.
7. The use as claimed in claim 6, wherein the pathological blood pressure decrease is in septic shock or tumor therapy with cytokines.
8. The use as claimed in any one of claims 1 to 4 for the treatment and prevention of inflammatory disorders.
9. The use as claimed in claim 8, wherein the inflammatory disorder is ulcerative colitis.
10. The use as claimed in any one of claims 1 to 4 for the treatment and prevention of infarct damage and/or reperfusion damage.
11. The use as claimed in any one of claims 1 to 4 for the treatment and prevention of transplant rejection reactions.
12. The use as claimed in any one of claims 1 to 4 for the treatment and prevention of disorders of the nervous system selected from the group consisting of Alzheimer's disease, epilepsy and migraine, but where the treatment or prevention of Alzheimer's disease by compounds of the formula I in which R3 is hydroxyl is excluded.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4418096.9 | 1994-05-24 | ||
| DE4418096A DE4418096A1 (en) | 1994-05-24 | 1994-05-24 | Use of pteridine derivatives as inhibitors of NO synthase |
| PCT/EP1995/001731 WO1995031987A1 (en) | 1994-05-24 | 1995-05-06 | Use of pteridine derivatives as no-synthase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2189131A1 CA2189131A1 (en) | 1995-11-30 |
| CA2189131C true CA2189131C (en) | 2007-03-06 |
Family
ID=6518841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002189131A Expired - Lifetime CA2189131C (en) | 1994-05-24 | 1995-05-06 | Use of pteridine derivatives as no-synthase inhibitors |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5902810A (en) |
| EP (1) | EP0760664B1 (en) |
| JP (1) | JP4138870B2 (en) |
| AT (1) | ATE223220T1 (en) |
| CA (1) | CA2189131C (en) |
| DE (2) | DE4418096A1 (en) |
| ES (1) | ES2180633T3 (en) |
| PT (1) | PT760664E (en) |
| WO (1) | WO1995031987A1 (en) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE177078T1 (en) * | 1993-10-21 | 1999-03-15 | Searle & Co | AMIDINO DERIVATIVES AS NO-SYNTHETASE INHIBITORS |
| DE69629364T2 (en) * | 1995-04-20 | 2004-06-09 | G.D. Searle & Co., Chicago | CYCLIC AMIDINO AGENT AS NITROGEN OXIDE SYNTHASE INHIBITORS |
| US5945408A (en) * | 1996-03-06 | 1999-08-31 | G.D. Searle & Co. | Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors |
| IL123884A (en) * | 1996-07-31 | 2002-04-21 | Cmic Co Ltd | 6-formylpterin derivatives and oligomers and polymers thereof, for use as active oxygen scavengers |
| US5922713A (en) * | 1997-06-26 | 1999-07-13 | Werner; Ernst | Inhibition of nitric oxide synthase |
| US5981556A (en) * | 1997-07-22 | 1999-11-09 | G.D. Searle & Co. | 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors |
| DE59703603D1 (en) * | 1997-10-06 | 2001-06-28 | Ernst Werner | Pteridine derivatives as NO synthase inhibitors |
| CA2319495A1 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Multibinding inhibitors of microsomal triglyceride transferase protein |
| CA2333691A1 (en) | 1998-06-10 | 1999-12-16 | G.D. Searle & Co. | Heterobicyclic and tricyclic nitric oxide synthase inhibitors |
| WO2000039129A1 (en) * | 1998-12-28 | 2000-07-06 | K.U. Leuven Research & Development | Immunosuppressive effects of pteridine derivatives |
| US7276506B2 (en) | 1998-12-28 | 2007-10-02 | 4 Aza Bioscience Nv | Immunosuppressive effects of pteridine derivatives |
| DE19944767A1 (en) * | 1999-09-17 | 2001-03-29 | Vasopharm Biotech Gmbh & Co Kg | N-substituted 4-aminopteridines, process for their preparation and their use as medicines |
| US6344473B1 (en) | 2000-08-07 | 2002-02-05 | G.D. Searle & Co. | Imidazoles useful as nitric oxide synthase inhibitors |
| WO2002076954A1 (en) * | 2001-03-23 | 2002-10-03 | Smithkline Beecham Corporation | Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases |
| CA2500952C (en) * | 2002-10-04 | 2011-04-26 | Prana Biotechnology Limited | Neurologically-active compounds |
| WO2005037286A1 (en) | 2003-03-25 | 2005-04-28 | Vasopharm Biotech Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure and secondary ischemia |
| GB2405793A (en) * | 2003-09-12 | 2005-03-16 | 4 Aza Bioscience Nv | Pteridine derivatives for treating TNF-alpha related disorders |
| PL3138566T3 (en) | 2003-11-17 | 2022-03-07 | Biomarin Pharmaceutical Inc. | Treatment of phenylketonuria with bh4 |
| WO2006055511A2 (en) | 2004-11-17 | 2006-05-26 | Biomarin Pharmaceutical Inc. | Stable tablet formulation of tetrahydrobiopterin |
| JP5290147B2 (en) * | 2006-04-14 | 2013-09-18 | プラナ バイオテクノロジー リミティッド | Method for treating age-related macular degeneration (AMD) |
| WO2008009079A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | Substituted pteridines useful for the treatment and prevention of viral infections |
| MX2010013152A (en) | 2008-06-05 | 2011-05-02 | Dow Pharmaceutical Sciences | Topical pharmaceutical formulations containing a low concentration of benzoyl peroxide in suspension in water and a water-miscible organic solvent. |
| US9216178B2 (en) | 2011-11-02 | 2015-12-22 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
| US9670205B2 (en) | 2015-03-04 | 2017-06-06 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
| WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
| WO2018045144A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
| TW202210480A (en) | 2019-04-17 | 2022-03-16 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
| TWI751517B (en) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
| TW202115056A (en) | 2019-06-28 | 2021-04-16 | 美商基利科學股份有限公司 | Processes for preparing toll-like receptor modulator compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4079056A (en) * | 1975-03-31 | 1978-03-14 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Method of making pteridine compounds |
| AU572792B2 (en) * | 1982-09-20 | 1988-05-19 | Wellcome Foundation Limited, The | 2-amino, 4-oxo-pteridine derivatives |
| IL74207A (en) * | 1984-02-03 | 1988-06-30 | Research Corp | Pteridine derivatives,process for the preparation thereof,and pharmaceutical compositions containing the same |
| IT1204612B (en) * | 1987-05-14 | 1989-03-10 | Bioresearch Spa | PTERIDINS SUITABLE FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR ANTI-MAGNESIC ACTIVITIES |
| JP2534423B2 (en) * | 1991-12-26 | 1996-09-18 | コーネル・リサーチ・ファンデーション・インコーポレイテッド | Inhibitors that prevent vascular disorders resulting from overproduction of nitric oxide |
| JPH0656669A (en) * | 1992-06-11 | 1994-03-01 | Asahi Breweries Ltd | Pterine derivative preparation having active oxygen-scavenging action |
| AU5704594A (en) * | 1992-12-18 | 1994-07-19 | Wellcome Foundation Limited, The | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
| JPH0834782A (en) * | 1994-05-20 | 1996-02-06 | Nissan Chem Ind Ltd | Imino-type sulfonylurea and herbicide |
-
1994
- 1994-05-24 DE DE4418096A patent/DE4418096A1/en not_active Withdrawn
-
1995
- 1995-05-06 DE DE59510362T patent/DE59510362D1/en not_active Expired - Lifetime
- 1995-05-06 CA CA002189131A patent/CA2189131C/en not_active Expired - Lifetime
- 1995-05-06 ES ES95919422T patent/ES2180633T3/en not_active Expired - Lifetime
- 1995-05-06 JP JP53001495A patent/JP4138870B2/en not_active Expired - Lifetime
- 1995-05-06 EP EP95919422A patent/EP0760664B1/en not_active Expired - Lifetime
- 1995-05-06 US US08/737,657 patent/US5902810A/en not_active Expired - Lifetime
- 1995-05-06 PT PT95919422T patent/PT760664E/en unknown
- 1995-05-06 WO PCT/EP1995/001731 patent/WO1995031987A1/en active IP Right Grant
- 1995-05-06 AT AT95919422T patent/ATE223220T1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| JP4138870B2 (en) | 2008-08-27 |
| PT760664E (en) | 2003-01-31 |
| DE59510362D1 (en) | 2002-10-10 |
| EP0760664B1 (en) | 2002-09-04 |
| DE4418096A1 (en) | 1995-11-30 |
| JPH10504023A (en) | 1998-04-14 |
| CA2189131A1 (en) | 1995-11-30 |
| ES2180633T3 (en) | 2003-02-16 |
| EP0760664A1 (en) | 1997-03-12 |
| WO1995031987A1 (en) | 1995-11-30 |
| ATE223220T1 (en) | 2002-09-15 |
| US5902810A (en) | 1999-05-11 |
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