GB2291422A - 4-phenyl-pyrido[2,3-b]pyrazin-4-ones - Google Patents
4-phenyl-pyrido[2,3-b]pyrazin-4-ones Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Pyridopyrazine derivatives of the following formula: <IMAGE> wherein R<1> is a lower alkyl, carboxy or protected carboxy, and R<2> is aryl which may have protected amino, and pharmaceutically acceptable salts thereof. A process for preparing such compounds is also described. These compounds possess inhibitory activity against both phosphodiesterase IV (PDE-IV) and the production of tumour necrosis factor (TNF), and can therefore be used for the prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases, such as chronic inflammatory diseases, autoimmune diseases and sepsis-induced organ injury.
Description
NEW HETEROBICYCLIC DERIVATIVES
This invention relates to new heterobicyclic derivatives. More particularly, this invention relates to pyridopyrazine derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
Accordingly, one object of this invention is to provide the new and useful pyridopyrazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase IV (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).
Another object of this invention is to provide processes for preparation of the pyridopyrazine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and
TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.
The object pyridopyrazine derivatives of the present invention are novel and can be represented by the following general formula (I)
wherein R1 is lower alkyl, carboxy or protected carboxy,
and
R2 is aryl which may have protected amino.
The object compound (I) of the present invention can be prepared by the following process.
Process (1)
or a salt thereof
0 o HOOC-C-R1 (III) or a salt thereof W N ss N < O R1 R2 (I) or a salt thereof wherein R1 and R2 are each as defined above.
The starting compound (II) of the present invention can be prepared by the following processes.
Process (A)
or a salt thereof
H2N-R2 (v) or a salt thereof
or a salt thereof
reduction
or a salt thereof
Process (B)
or a salt thereof
elimination reaction of the amino protective group
or a salt thereof
Process (C)
or a salt thereof
acylation
or a salt thereof wherein R2 is as defined above,
R3 is aryl having amino, a is aryl having protected amino, is is aryl having acylamino, and X is a leaving group.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided,
Suitable "lower alkyl" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like.
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,.
pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable "aryl" may include phenyl, naphthyl and the like.
Suitable "halogen" may include fluorine, bromine, chlorine and iodine.
Suitable "leaving group" may include acid residue, lower alkoxy as exemplified above, and the like.
Suitable "acid residue" may include halogen as exemplified above, acyloxy and the like.
Suitable "protected carboxy" may include esterified carboxy and the like. And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy (lower) alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, l-(or 2-) [methoxycarbonyloxy)ethyl ester, l-(or 2-) [ethoxycarbonyloxy]ethyl ester, 1- (or 2-) [propoxycarbonyloxy]ethyl ester, 1-( or 2-) [isopropoxycarbonyloxy]ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1- (or 2-)methoxycarbonyloxyethyl ester, l-(or 2)ethoxycarbonyloxyethyl ester, l-(or 2-)isopropoxycarbonyloxyethyl ester, etc.); phthalidylidene( lower) alkyl ester; (5-lower alkyl-2-oxo1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester1 bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,4-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkyl silyl ester; lower alkylthioester (e.g., methylthioester, ethylthioester, etc.) and the like.
Suitable protected amino" may include acylamino or an amino group substituted by a conventional protecting group such as mono(or di or tri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.) or the like.
Suitable "acyl" and "acyl moiety" in the terms "acylamino" and "acyloxy" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows
Carbamoyl; Thiocarbamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2 -dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); cyclo(lower)alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); or the like;
Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.); ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylcarbamoyl (e.g., phenylcarbamoyl, naphthylcarbamoyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;
Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", "heterocyclic(lower)alkanoyl", heterocyclic(lower)alkenoyl" and "heterocyclicglyoxyloyl" as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;;
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;;
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.,
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; ;
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
The acyl moiety as stated above may have one to ten, same or different, suitable substituent(s) such as lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkylthio wherein lower alkyl moiety is as exemplified above, lower alkylamino wherein lower alkyl moiety is as exemplified above, cyclo(lower)alkyl, cyclo(lower)alkenyl, halogen as exemplified above, aryl as exemplified above, amino, protected amino as exemplified above, hydroxy, protected hydroxy, cyano, nitro, carboxy, protected carboxy as exemplified above, sulfo, sulfamoyl, imino, oxo, amino(lower)alkyl wherein lower alkyl moiety is as exemplified above, carbamoyloxy, mono(or di or tri)halo(lower)alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, or the like.
The processes for preparing the object and starting compounds are explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
Process (A)- The compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt therec with the compound (V) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N ,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, di ethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
When the starting compound is in liquid, it can be also used as a solvent.
Process (A)
The compound (II) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to reduction reaction.
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g., reduced copper, Raney copper, Ullman copper, etc.) and the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane,
N,N-dimethylformamide, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process (B)
The compound (VII) or a salt thereof can be prepared by subjecting the compound (VIa) or a salt thereof to elimination reaction of the amino protective group.
The reaction can be carried out in the manner disclosed in Preparation 3 or similar manners thereto.
Process (C)
The compound (VIb) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to acylation reaction.
The reaction can be carried out in the manner disclosed in Preparation 4 or similar manners thereto.
Suitable salts of the object and the starting compounds in Processes (1) and (A)-(C) can be referred to the ones as exemplified for the compound (I).
The new pyridopyrazine derivatives (I) and pharmaceutically acceptable salts thereof hardly possess a strong inhibitory activity against phosphodiesterase III (PDE III), but possess a strong inhibitory activity against phosphodiesterase IV (PDE IV) and a strong inhibitory activity on the tumor necrosis factor (TNF).
That is, the pyridopyrazine derivatives (I) and pharmaceutically acceptable salts thereof are selective inhibitors of phosphodiesterase IV (PDE IV) and inhibitors on the production of tumor necrosis factor (TNF).
Accordingly, the new pyridopyrazine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and therapeutic treatment of PDE-IV and
TNF mediated diseases such as chronic inflammatory diseases (e.g., rheumatoid arthritis, osteoarthritis, emphysema, chronic bronchiolitis, etc.), osteoporosis, rejection by transplantation, asthma, eosinophilia, cystic fibrosis, hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmune diseases [e.g., ankylosing spondylitis, autoimmune hematological disorders (e.g., hemolyticodo anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, etc.), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulamotosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, atopic dermatitis, psoriasis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis, Crohn1s disease, etc.), endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter's syndrome, non infection uveitis, autoimmune keratitis (e.g., keratoconjunctivitis sicca, vernal keratoconjunctivitis, etc.), interstitial lung fibrosis, psoriatic arthritis, etc.], cancer cachexia, AIDS cachexia, thrombosis, and the like.
In order to show the utilities of the pyridopyrazine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the pyridopyrazine derivatives (I) are illustrated in the following.
(a) Inhibition of U937 phosphodiesterase IV (PDE IV)
1. Test method
Harvested U937 was freezed in -80 C and throwed to destroy the cell body. The pellet of destroyed cell was washed by Phosphate-buffered saline (PBS).
The washed cell pellet was homogenized with Dounce homogenizer (20 strokes) in homogenizing buffer (0.5% deoxycholate [DOC], 5 mM 2-mercaptoethanol, 1 AM leupeptin, 100 AM PMSF, 20 WM p-tosyl-L-lysinechloromethyl ketone (TLCK] in PBS). The homogenate was centrifuged at 100,000 g x 90 minutes (4"C) and the supernatant containing PDE IV activity was dialyzed against dialysis buffer, which was the same component as homogenizing buffer without DOC. The dialyzed supernatant of homogenate was stored in freezer (-80 C) as PDE IV enzyme preparation.
Enzyme preparation was diluted in assay buffer (10 mM
Tris-HCl, 5 mM MgCl, 1 mM 2-Mercaptoethanol [pH 8.0]). In advance the rate of dilution was choosen every new lot of homogenizing preparation. For blank, a part of the enzyme preparation was boiled for 10 minutes.
Test compounds were dissolved in dimethylsulfoxide (DMSO) at a concentration of 4 x 10(-2) [M] (final conc.
1 x 10(-5)M), then serial dilutions were made in DMSO to achieve desired concentrations. The diluted compounds of each concentration were further diluted 1:500 in assay buffer (0.2% DMSO). Final DMSO concentration in assay tube was 0.025%.
In duplicate, the followings were added to a glass tube, in order, at OOC (all concentrations are given as final concentrations in assay tube).
50 ul compound of assay buffer for control or blank
50 ul 8 x 10(-5)[M] CI-930 (final 10 AM) : (CI-930
is PDE III inhibitor)
200 ssl enzyme preparation or boiled enzyme
preparation for blank.
The reaction tube was preincubated in a water bath (300C) for 5 minutes, then 100 ul [3H]-cAMP (37.0 MBq/ml [3H]-cAMP : 4 AM cold cAMP = 1:800) was added thereto.
After 15 minutes, 2.5 units/ml alkaline phosphatase was added to the reaction mixture and the reaction was continued for 15 minutes. Dowex 1 x 8 gel was added to the reaction mixture and was vortexed well. The mixture was centrifuged at 1000 rpm x 5 minutes, and then 500 ul of the supernatant was added to 10 ml scintillation fluid in appropriate vial, vortexed, and counted for [3H].
The inhibitory activity was calculated according to the following equation
avg.cpm[test compound]
avg.cpm[blank(boiled enzyme)] % Inhibition = 100 - - x 100
avg.cpm[control(no compound)] avg.cpmEblank(boiled enzyme)]
2. Test compound
(a) 2-Isobutyl-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]- phenyl]-3, 4-dihydropyrido[ 2,3-b]pyrazine 3. Test result
Test compound IC50 (M) (a) 2.4 x 10-8 (b) Inhibition on TNF-a production in human mononuclear
cells 1. Test method
Blood was drawn from healthy volunteers with heparin.
The mononuclear cell (MNC) fraction was obtained by gradient centrifugation (1800 rpm, 15 minutes), diluted with the same volume of RPMI-1640 culture medium, over
Ficoll-Paque (Pharmacia LKB Biotechnology). MNC were washed twice with RPMI-1640. Then, MNC were resuspended in RPMI-1640 culture medium supplemented with 2 mM Lglutanine and 1% fetal bovine serum. MNC were incubated at 37 C for 16 hours in 96-well micro culture plate at a concentration of 3 x 10-5 cells/well with or without 1 ug/ml lipopoly saccharide (LPS) (from E. coli) and various amounts of test compound. At the end of incubation, the supernatant was obtained and its TNF-a activity was measured by enzyme-linked immunosorbent assay (ELISA).
ELISA was performed with TNF-a ELISA kit (Otsuka
Pharmaceutical Co., Ltd.).
2. Test compound
(a) 2-Isobutyl-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]- phenyl]-3,4-dihydropyrido[2,3-b]pyrazine 3. Test result
Test compound IC50 (M) (a) (a) | 3.1 x 10-8 For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
The effective ingredient may usually be administered with a uint dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method.
Preferred embodiments of the object compound (I) are as follows.
R1 is lower alkyl, carboxy or esterified carboxy
(more preferably lower alkoxycarbonyl), and
R2 is phenyl which may have acylamino [more
preferably lower alkanoylamino, or
arylcarbamoyl (more preferably phenylcarbamoylj which may have 1 to 3 (more preferably one or
two; most preferably one) suitable
substituent(s) (more preferably lower alkoxy)].
More preferred embodiments of the object compound (I) are as follows.
R1 is lower alkyl, carboxy or lower alkoxycarbonyl,
and
R2 is phenyl, lower alkanoylaminophenyl or (lower
alkoxyphenyl)carbamoylaminophenyl.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
Preparation 1
A mixture of 2-(3-acetamidophenyl)amino-3nitropyridine (5.85 g) and 10% palladium on carbon (0.8 g) in ethanol (100 ml) and 1,4-dioxane (100 ml) was stirred under hydrogen (3 atm) at room temperature for 3 hours.
The catalyst was removed and the solvent was evaporated.
The resultant solids were collected and washed with isopropyl ether to give 2-(3-acetamidophenyl)amino-3aminopyridine (5.05 g).
NMR (DMSO-d6, 6) : 2.03 (3H, s), 5.09 (2H, s), 6.63 (1H, dd, J=5Hz, 8Hz), 6.89 (1H, dd, J=1.5Hz,
8Hz), 7.0-7.25 (2H, m), 7.33 (1H, m), 7.49 (1H,
dd, J=1.5Hz, 5Hz), 7.71 (1H, s), 7.87 (1H, s),
9.80 (1H, s)
Preparation 2
A mixture of 2-chloro-3-nitropyridine (6.12 g), 3'aminoacetanilide (5.80 g) and potassium carbonate (5.34 g) in toluene (50 ml) was ref fluxed for 5 hours. The mixture was cooled and the solids were collected, washed with water, ethanol and isopropyl ether successively to give 2 (3-acetamidophenylamino)-3-nitropyridine (5.88 g) as an orange solid.
NMR (DMSO-d6, 6) : 2.06 (3H, s), 6.99 (1H, dd,
J=5Hz, 8Hz), 7.2-7.4 (3H, m), 7.91 (1H, s),
8.5-8.6 (2H, m), 9.93 (lH, s), 9.99 (1H, s)
Preparation 3
A mixture of 2-(3-acetamidophenylamino)-3nitropyridine (10 g) and 3N hydrochloric acid (100 ml) was stirred under reflux for an hour. After cooling, the reaction was adjusted to pH 7 with sodium bicarbonate solution, and precipitated materials were collected, washed with water and dried to give 2-(3aminophenylamino)-3-nitropyridine (8.2 g).
NMR (CDCl3, S) : 3.75 (2H, br s), 6.51 (lH, m), 6.81 (1H, m), 6.96 (1H, m), 7.15 (2H, m), 8.50 (2H,
m), 10.05 (1H, br s)
Preparation 4
A mixture of 2-(3-aminophenylamino)-3-nitropyridine (0.65 g) and 2-methoxyphenyl isocyanate (0.63 g) in dioxane (10 ml) was ref fluxed for 2 hours. After evaporation of the solvent, crude crystals were washed with ethanol to give 3-nitro-2-[3-[3-(2 methoxyphenyl)ureido]phenylamino]pyridine (1.02 g).
NMR (DMSO-d6, 6) : 3.89 (3H, s), 7.00 (4H, m), 7.27
(3H, m), 7.81 (1H, m), 8.12 (1H, m), 8.26 (lH,
s), 8.55 (2H, m), 9.39 (lH, s), 9.93 (lH, s)
Preparation 5
A solution of 3-nitro-2-[3-(3-(2- methoxyphenyl)ureido]phenylamino]pyridine (11.65 g) in dioxane (200 ml) and methanol (100 ml) containing 10% palladium on charcoal (0.8 g) was hydrogenated at 3 atoms at room temperature. After removal of the catalyst and evaporation of solvents, residual crystals were washed with ether and dried to give 3-amino-2-[3-[3-(2 methoxyphenyl)uredio]phenylamino]pyridine (12.31 g).
NMR (DMSO-d6, 8) : 3.90 (3H, s), 5.10 (2H, s), 6.63 (1H, m), 6.90 (3H, m), 7.03 (2H, m), 7.13 (1H, in), 7.25 (lH, m), 7.50 (1H, m), 7.71 (1H, m),
7.77 (1H, m), 8.15 (1H, m), 8.24 (1H, s), 9.20
(1H, s)
Example 1
A mixture of 2-phenylamino-3-aminopyridine (0.5 g) and 2-oxobutyric acid (276 mg) in ethanol (10 ml) was ref fluxed for 2 hours. The reaction mixture was cooled and the precipitate was filtrated by suction. The crystal was washed with ethanol to obtain 2-ethyl-3-oxo-4-phenyl-3,4dihydropyrido[2,3-b]pyrazine (594 mg).
NMR (DMSO-d6, 6) : 1.28 (3H, t, J=7Hz), 2.89 (2H, q,
J=7Hz), 7.27-7.61 (6H, m), 8.25 (1H, d, J=lOHz),
8.37 (1H, d, J=5Hz)
Example 2
The following compounds were obtained according to a similar manner to that of Example 1.
(1) 2-Methyl-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]- pyrazine
Mass (FAB) m/e : 238 (M+1)
(2) 2-Hexyl-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]- pyrazine
NMR (DMSO-d6, 6) : 0.88 (3H, t, J=7Hz), 1.25-1.50
(6H, m), 1.75 (2H, quint, J=6Hz), 2.87 (2H, t,
J=8Hz), 7.3-7.52 (6H, m), 8.25 (1H, dd, J=lHz, 1OHz), 8.37 (1H, dd, J=1Hz, 5Hz)
(3) 2-Hexyl-3-oxo-4-[3-[3-(2-methoxyphenyl) ureido]phenyl] -3, 4-dihydropyrido[ 2, 3-b]pyrazine NMR (DMSO-d6, o) : 0.90 (3H, m), 1.2-1.5 (6H, m),
1.75 (2H, m), 2.85 (2H, m), 4.90 (3H, s), 6.9
7.1 (4H, m), 7.4 (3H, m), 7.58 (1H, s), 8.1 (1H, m), 8.25 (2H, m), 8.4 (1H, m), 9.50 (1H, s)
(4) 2-Propyl-3-oxo-4-[3-[3-(2-methoxyphenyl) ureido]phenyl]-3 , 4-dihydropyrido[ 2, 3-b]pyrazine mp : 198-2000C
NMR (DMSO-d6, 6) : 1.02 (3H, t, J=7Hz), 1.80 (2H, m), 2.85 (2H, t, J=7Hz), 3.88 (3H, s), 6.85-7.1
(4H, m), 7.42 (3H, m), 7.57 (1H, s), 8.08 (1H, m), 8.26 (2H, m), 8.40 (1H, m), 9.52 (1H, s) (5) 2-[(1RS)-1-Methylpropyl]-3-oxo-4-[3-[3-(2-
methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido
[2,3-b]pyrazine mp : 214-2150C NMR (DMSO-d6, 6) : 0.95 (3H, t, J=7Hz), 1.27 (3H, d,
J=7Hz), 1.57 (1H, m), 1.87 (1H, m), 3.35 (1H, m), 3.89 (3H, s), 6.8-7.1 (4H, m), 7.45 (3H, m),
7.58 (1H, s), 8.09 (1H, d, J=7Hz), 8.28 (2H, m),
8.40 (1H, m), 9.52 (lH, s) (6) 2-Isobutyl-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]-
phenyl]-3,4-dihydropyrido[2,3-b]pyrazine
mp : 211-2130C NMR (DMSO-d6, 6) : 1.00 (6H, d, J=7Hz), 2.30 (1H,
m), 2.75 (2H, d, J=7Hz), 3.88 (3H, s),6.8-7.05
(4H, m), 7.40 (3H, m), 7.60 (1H, s), 8.10 (1H,
d, J=7Hz), 8.27 (2H, m), 8.40 (1H, m), 9.52 (1H, s) (7) 2-Ethoxycarbonyl-3-oxo-4-[3-[3-(2-methoxyphenyl)-
ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine
mp : 177-1780C NMR (DMSO-d6, 6) : 1.33 (3H, t, J=7Hz), 3.89 (3H,
s), 4.40 (2H, q, J=7Hz), 6.8-7.05 (4H, m), 7.45
(3H, m), 7.65 (1H, s), 8.10 (1H, d, J=7Hz), 8.30 (1H, s), 8.39 (1H, d, J=7Hz), 8.53 (1H, d,
J=3Hz) (8) 2-Ethoxycarbonyl-3-oxo-4-(3-acetamidophenyl)-3,4
dihydropyrido[2,3-b]pyrazine
mp : 182-1850C NMR (DMSO-d6, 6) : 1.34 (3H, t, J=7Hz), 2.06 (3H,
s), 4.41 (2H, q, J=7Hz), 7.05 (1H, m), 7.50 (2H, m), 7.60 (1H, m), 7.70 (1H, m), 8.38 (1H, d,
J=7Hz), 8.52 (1H, m), 10.15 (1H, s)
(9) 2-Ethyl-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]- phenyl]-3,4-dihydropyrido[2,3-b]pyrazine NMR (DMSO-d6, 6) : 1.30 (3H, t, J=7Hz), 2.90 (2H, q,
J=7Hz), 3.86 (3H, s), 6.85-7.15 (4H, m), 7.40
(3H, m), 7.58 (1H, s), 8.05-8.5 (4H, m), 9.50 (1H, s) (10) 4-(3-Acetamidophenyl)-2-ethyl-3-oxo-3,4-dihydro-
pyrido[2,3-b]pyrazine
NMR (DMSO-d6, 6) : 1.28 (3H, t, J=7Hz), 2.05 (3H,
s), 2.88 (2H, q, J=7Hz), 6.99 (1H, m), 7.40 (1H, m), 7.46 (1H, d, J=7Hz), 7.58 (1H, m), 7.64 (1H,
s), 8.25 (1H, d, J=7Hz), 8.37 (1H, d, J=3Hz)
Claims (2)
- What we claim is 1. A compound of the formulawherein R1 is lower alkyl, carboxy or protected carboxy, and R2 is aryl which may have protected amino, and a pharmaceutically acceptable salt thereof.
- 2. A process for preparing a compound of the formulawherein R1 is lower alkyl, carboxy or protected carboxy, and R2 is aryl which may have protected amino, or a salt thereof, by reacting a compound of the formulawherein R2 is as defined above, or a salt thereof with a compound of the formulawherein R1 is as defined above, or a salt thereof.
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Publications (2)
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GB2291422A true GB2291422A (en) | 1996-01-24 |
Family
ID=10758501
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998052549A2 (en) * | 1997-05-20 | 1998-11-26 | Fumapharm Ag | Use of fumaric acid derivatives |
US7320999B2 (en) | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
US7722886B2 (en) | 2003-05-20 | 2010-05-25 | Wyeth | Compositions and methods for treatment of severe acute respiratory syndrome (SARS) |
EP2241328A1 (en) | 2000-05-12 | 2010-10-20 | Immunex Corporation | Interleukin-1 inhibitors in the treatment of diseases |
US8119605B2 (en) | 1999-04-19 | 2012-02-21 | Immunex Corporation | Soluble tumor necrosis factor receptor treatment of medical disorders |
US8399514B2 (en) | 2007-02-08 | 2013-03-19 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
US8980832B2 (en) | 2003-09-09 | 2015-03-17 | Biogen Idec International Gmbh | Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0008864A1 (en) * | 1978-08-15 | 1980-03-19 | FISONS plc | Pyridopyrazine and quinoxaline derivatives, processes for their preparation, and pharmaceutical compositions containing them |
-
1994
- 1994-07-18 GB GB9414453A patent/GB2291422A/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0008864A1 (en) * | 1978-08-15 | 1980-03-19 | FISONS plc | Pyridopyrazine and quinoxaline derivatives, processes for their preparation, and pharmaceutical compositions containing them |
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WO1998052549A3 (en) * | 1997-05-20 | 1999-04-08 | Fumapharm Ag | Use of fumaric acid derivatives |
US6436992B1 (en) | 1997-05-20 | 2002-08-20 | Fumapharm Ag | Use of fumaric acid derivatives |
WO1998052549A2 (en) * | 1997-05-20 | 1998-11-26 | Fumapharm Ag | Use of fumaric acid derivatives |
CZ299960B6 (en) * | 1997-05-20 | 2009-01-07 | Fumapharm Ag | Use of fumaric acid derivative |
US7915310B2 (en) | 1998-11-19 | 2011-03-29 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
US7612110B2 (en) | 1998-11-19 | 2009-11-03 | Biogen Idec International Ag | Utilization of dialkylfumarates |
US7619001B2 (en) | 1998-11-19 | 2009-11-17 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
US7803840B2 (en) | 1998-11-19 | 2010-09-28 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
US7320999B2 (en) | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
US8524773B2 (en) | 1998-11-19 | 2013-09-03 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
US8759393B2 (en) | 1998-11-19 | 2014-06-24 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
US8119605B2 (en) | 1999-04-19 | 2012-02-21 | Immunex Corporation | Soluble tumor necrosis factor receptor treatment of medical disorders |
EP2241328A1 (en) | 2000-05-12 | 2010-10-20 | Immunex Corporation | Interleukin-1 inhibitors in the treatment of diseases |
US7722886B2 (en) | 2003-05-20 | 2010-05-25 | Wyeth | Compositions and methods for treatment of severe acute respiratory syndrome (SARS) |
US7892563B2 (en) | 2003-05-20 | 2011-02-22 | Wyeth Holdings Corporation | Methods for treatment of severe acute respiratory syndrome (SARS) |
US8980832B2 (en) | 2003-09-09 | 2015-03-17 | Biogen Idec International Gmbh | Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
US8399514B2 (en) | 2007-02-08 | 2013-03-19 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
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GB9414453D0 (en) | 1994-09-07 |
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