CA2115755A1 - New pyrazine derivatives, their preparation and their use - Google Patents
New pyrazine derivatives, their preparation and their useInfo
- Publication number
- CA2115755A1 CA2115755A1 CA002115755A CA2115755A CA2115755A1 CA 2115755 A1 CA2115755 A1 CA 2115755A1 CA 002115755 A CA002115755 A CA 002115755A CA 2115755 A CA2115755 A CA 2115755A CA 2115755 A1 CA2115755 A1 CA 2115755A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkyl
- formula
- substituted
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Abstract The new compounds of formula
Description
~; ~
,~ FIL!E~, J~ THIS AM~NDED
T~:~ TRANSLATION 21~ ~ 7 ~ S
New pyrazine derivatives the preparation and use thereof The invention relates to new tetra-substituted pyrazine derivatives, the preparation thereof by conventional methods and their use in the production of pharmaceutical substances or drugs.
The new compounds correspond to the formula N
Cl_~ / ~ Co-NR3-c=NR4 N~ ~LNH2 ~ ~
/ N
R
' ,~ ' and may occur in the form of bases or salts with acids.
.
In formula I, independently of one another:
R1 represents H or a (Cl~)alkyl group, R2 represents a 1-morpholinyl group, a straight-chained or branched (C18)alkyl chain which may be substituted, a) by a substituted or unsubstituted N,O,S-heterocyclic group, b) by the phenyl group which is optionally mono-or polysubstituted by a tCl 4) alkoxy group, which may in turn be functionalised by a hydroxyl or alkylamino group of formula .. .. .
!: ` ' '~ ~ ' '` ' ` ' ' - -```` 2 ~ 7 3 ~
, .
-N (II), wherein R7 and R8 independently of each other denote hydrogen or a (C14)alkyl group;
c) by an aminocarbonyl group of the formula R7 ~ :
I
O l8 (III), R :
wherein R7 and R8 are defined as hereinbefore;
d) independently of one another by one or more (C14~alkoxy groups, the hydroxyl or a ~ ~`
hydroxyl(C14)-alkyl group or a phenoxy group which may in turn be mono- or polysubstituted by halogen (F, Cl), a cyano group, (C14)alkyl, (cl4)alkoxy or (C1.4)alkoxy-(Cl.4)alkyl;
e) by an amino group of the formula -N \ (IV), wherein the groups R9 and R10 independently of each other denote hydrogen, a mono- or polynuclear N,O,S-heterocyclic group, a mono~
or polysubstituted phenyl group substituted either homogeneously or by a mixture of :
halogen (F, Cl), (C14)alkyl or a sulphonamide ~ :~
group, an N,O-heterocyclic acyl ~roup, a di-or trichlorophenylsulphonyl group substituted ,,.. ~ 2~1 j7 by an amine group, or a (C14)alkyl chain, which may be substituted independently of each other by the hydroxy group, or by a phenyl group which is optionally mono- or polysubstituted by halogen (F, cl), hydroxy, (C~ 4) alkyl or (C14)alkoxy-(C14)alkyl, or R9 and R10 form a morpholine ring together with the nitrogen atom to which they are bound and an oxygen atom;
a 4-piperidinyl group which may be substituted in the 1-position ~ -a) by the acyl group of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid;
b) by a (C18)alkyl chain which in turn is substituted, independently of each other, by the hydroxy group or by a (C14)alkoxy- or (C14)alkoxy-(C14)alkyl-substituted phenoxy group or by an ~-naphthoxy group;
and amidino group of the formula -C-NHRll (V), . .
NH
wherein R11 represents a phenyl group which is mono- or polysubstituted by halogen ~F, Cl) or a (Cl 4) alkyl group;
Rl and R2 together denote, together with the nitrogen atom to which they are bound, a piperazine ring which may be substituted a) by an N,O,S-heterocyclic group, , 211~7~
b) by the acyl group of an aliphatic, alicyclic, aromatic or heterocyclic carboxylic acid, c) by a (C18)alkyl chain, which may in turn be substituted indep~ndently of one another, by the hydroxy group or by a (C14~alkoxy- or (C14)alkoxy-(Cl4)alkyl-subs-tituted phenoxy group or an ~-naphthoxy group;
R3, R4, Rs and R6 have identical or different meanings and represent hydrogen, (C18)alkyl or benzyl.
The phrase "N,O,S-heterocyclic group" denotes those ring systems which contain one or more identical or different heteroatoms of the type specified. The term "polynuclear heterocyclic groups" also refers to those ring systems which are made up of heterocyclic and carbocyclic rings, such as quinoline and quinazoline.
These ring systems may contain one or more substituents such as C14-alkyl, C16-alkoxy and/or amino. Similarly, "N,O-heterocyclic group" encompasses both pure N-heterocyclic groups such as piperidine, piperazine and also morpholine. If the alkyl groups in the above definitions may contain up to 8 carbon atoms, those containing up to ~ carbon atoms are preferred; of the (C1~4)alkyl or alkoxy groups, those which are preferred are the ones which contain up to three carbon atoms.
The preferred substituents in phenyl or phenoxy groups are alkyl or alkoxy groups having one or two carbon atoms as well as F and Cl. R3 and Rs preferably denote hydrogen, R4 and R6 preferably denote hydrogen, methyl or ethyl, and one of the two groups also denotes butyl or benzyl. The acyl groups of the aliphatic carboxylic -~
acids contain up to 18 carbon atoms, those of the alicyclic carboxylic acid contain up to 8 carbon atoms.
The short-chained aliphatic carboxylic acids may also be substituted by phenyl or heteroaryl, the aromatic .,. ;,,"~ , ,,,, .,," ~,~" ","~ ~ ,".,,,, ~ ",; ~ , ",,~
,~ FIL!E~, J~ THIS AM~NDED
T~:~ TRANSLATION 21~ ~ 7 ~ S
New pyrazine derivatives the preparation and use thereof The invention relates to new tetra-substituted pyrazine derivatives, the preparation thereof by conventional methods and their use in the production of pharmaceutical substances or drugs.
The new compounds correspond to the formula N
Cl_~ / ~ Co-NR3-c=NR4 N~ ~LNH2 ~ ~
/ N
R
' ,~ ' and may occur in the form of bases or salts with acids.
.
In formula I, independently of one another:
R1 represents H or a (Cl~)alkyl group, R2 represents a 1-morpholinyl group, a straight-chained or branched (C18)alkyl chain which may be substituted, a) by a substituted or unsubstituted N,O,S-heterocyclic group, b) by the phenyl group which is optionally mono-or polysubstituted by a tCl 4) alkoxy group, which may in turn be functionalised by a hydroxyl or alkylamino group of formula .. .. .
!: ` ' '~ ~ ' '` ' ` ' ' - -```` 2 ~ 7 3 ~
, .
-N (II), wherein R7 and R8 independently of each other denote hydrogen or a (C14)alkyl group;
c) by an aminocarbonyl group of the formula R7 ~ :
I
O l8 (III), R :
wherein R7 and R8 are defined as hereinbefore;
d) independently of one another by one or more (C14~alkoxy groups, the hydroxyl or a ~ ~`
hydroxyl(C14)-alkyl group or a phenoxy group which may in turn be mono- or polysubstituted by halogen (F, Cl), a cyano group, (C14)alkyl, (cl4)alkoxy or (C1.4)alkoxy-(Cl.4)alkyl;
e) by an amino group of the formula -N \ (IV), wherein the groups R9 and R10 independently of each other denote hydrogen, a mono- or polynuclear N,O,S-heterocyclic group, a mono~
or polysubstituted phenyl group substituted either homogeneously or by a mixture of :
halogen (F, Cl), (C14)alkyl or a sulphonamide ~ :~
group, an N,O-heterocyclic acyl ~roup, a di-or trichlorophenylsulphonyl group substituted ,,.. ~ 2~1 j7 by an amine group, or a (C14)alkyl chain, which may be substituted independently of each other by the hydroxy group, or by a phenyl group which is optionally mono- or polysubstituted by halogen (F, cl), hydroxy, (C~ 4) alkyl or (C14)alkoxy-(C14)alkyl, or R9 and R10 form a morpholine ring together with the nitrogen atom to which they are bound and an oxygen atom;
a 4-piperidinyl group which may be substituted in the 1-position ~ -a) by the acyl group of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid;
b) by a (C18)alkyl chain which in turn is substituted, independently of each other, by the hydroxy group or by a (C14)alkoxy- or (C14)alkoxy-(C14)alkyl-substituted phenoxy group or by an ~-naphthoxy group;
and amidino group of the formula -C-NHRll (V), . .
NH
wherein R11 represents a phenyl group which is mono- or polysubstituted by halogen ~F, Cl) or a (Cl 4) alkyl group;
Rl and R2 together denote, together with the nitrogen atom to which they are bound, a piperazine ring which may be substituted a) by an N,O,S-heterocyclic group, , 211~7~
b) by the acyl group of an aliphatic, alicyclic, aromatic or heterocyclic carboxylic acid, c) by a (C18)alkyl chain, which may in turn be substituted indep~ndently of one another, by the hydroxy group or by a (C14~alkoxy- or (C14)alkoxy-(Cl4)alkyl-subs-tituted phenoxy group or an ~-naphthoxy group;
R3, R4, Rs and R6 have identical or different meanings and represent hydrogen, (C18)alkyl or benzyl.
The phrase "N,O,S-heterocyclic group" denotes those ring systems which contain one or more identical or different heteroatoms of the type specified. The term "polynuclear heterocyclic groups" also refers to those ring systems which are made up of heterocyclic and carbocyclic rings, such as quinoline and quinazoline.
These ring systems may contain one or more substituents such as C14-alkyl, C16-alkoxy and/or amino. Similarly, "N,O-heterocyclic group" encompasses both pure N-heterocyclic groups such as piperidine, piperazine and also morpholine. If the alkyl groups in the above definitions may contain up to 8 carbon atoms, those containing up to ~ carbon atoms are preferred; of the (C1~4)alkyl or alkoxy groups, those which are preferred are the ones which contain up to three carbon atoms.
The preferred substituents in phenyl or phenoxy groups are alkyl or alkoxy groups having one or two carbon atoms as well as F and Cl. R3 and Rs preferably denote hydrogen, R4 and R6 preferably denote hydrogen, methyl or ethyl, and one of the two groups also denotes butyl or benzyl. The acyl groups of the aliphatic carboxylic -~
acids contain up to 18 carbon atoms, those of the alicyclic carboxylic acid contain up to 8 carbon atoms.
The short-chained aliphatic carboxylic acids may also be substituted by phenyl or heteroaryl, the aromatic .,. ;,,"~ , ,,,, .,," ~,~" ","~ ~ ,".,,,, ~ ",; ~ , ",,~
2 1 1 5 7 5 r . -~ .3 carboxylic acids optionally contain substituted phenyl, and the heteroaromatic carboxylic acids are derived from monocyclic heterocyclic groups which contain N, O and/or S. Whereas Rl is preferably hydrogen or methyl, R2 preferably represents larger groups, e.g. those contained in the following Tables, for example:
Cl ~\~ o-c~l2-cH(oH)-cH2-N(cH3)-(cH2)3 Cl <~NH-C- .
R
:: ~
j 2 CH30~ 7 3 ~ ~_NH-CH2-CH2-N
21~ ~7~
or R1 and R2 form a substituted heterocyclic group with the nitrogen to which they are bound, e.g.
CH30 \~ N~N N
3 ( 2 ) 14 \~
CH30-CH2-CH2~ < ~ o-CH2-CH(OH)-ICH2 ~ Methods of preparing the new compounds are known to : those skilled in the art:
1) a lower alkylester of 3-amino-5,6-dichloropyrazine~
2-carboxylic acid is reacted under anhydrous conditions with an amine of formula 7 ~ ~
HNR1R2 (VI) wherein R1 and R2 are as hereinbefore defined, and the resulting compound of formula Cl__ f ~ _ C02-alkyl R R N ~ NH2 (VII) (alkyl = (C14)alkyl) is converted with a guanidine of formula HNR3 C=NR4 NRSR6 (VIII) -:
wherein R3 to R6 are as hereinbefore defined, into the desired end product.
The reaction of the 3-amino-5,6-dichloropyrazine-2-carboxylic acid ester with the amine component VI
to obtain the intermediate compounds of general formula VII is carried out using methods known from the literature in an inert solvent at elevated temperature in the presence of an acid acceptor.
The amine component is generally used in equimolar amounts. However, it is also possible to use the amine component as the acid acceptor and solvent.
Preferably, however, the solvent used is dimethylformamide or dimethylsulphoxide or mixtures thereof~ The reaction temperature is not crucial.
As a rule, the reaction is carried out at a ~ 21157~
temperature in the range from 80 - 100C depending on the reactivity of the amine used. Under these conditions the reaction is finished after about l to 2 hours. Organic and inoryanic bases may be used as acid acceptors. Preferably, tertiary amines such as pyridine, N-methylpiperidine, dimethylaniline or triethylamine are used.
The 3,5-diaminopyrazine carboxylic acid esters of formula VII prepared in this way may, if desired, be subjected to subsequent treatment, e.g. a reaction of acylation or alkylation.
Acylation is carried out by known methods, e.g. by reacting a diamine of formula VII with a reactive carboxylic acid derivative.
The alkylation is used, for example, in the preparation of corresponding phenoxypropanolamine derivatives. For this purpose, a diamino compound of the substructure IX of formula VII:
.
H\ Cl ~ ~ _ COzalkyl N-alk-N ~ ~ _ NH2 (IX) RS / ¦ \N
,., ~ .
(alk = (Cl~B)alkylene, alkyl, Rs as above) is reacted in a suitable solvent e.g. with a phenoxypropyleneoxide of general formula ~;
~; 2 1 ~ 5 7 ~ ~
~-CH2 -cH-cH2 ~(=~ \ / (X) Z
z = ~c14)alkoxy, (C14)alkoxy- (C1 4) alkyl at ambient temperature or slightly elevated temperature. Generally, the reaction is complete in about 0.5 to 1 hour.
However, the direct method of synthesis described above is preferred.
In order to prepare the end products of formula I
the 3,5-diaminopyrazine carboxylic acid esters of formula VII are reacted with a guanidine of formula VIII in a suitable solvent with heating. Simple alcohols are particularly suitable as the solvent.
Preferably, the reaction is carried out in methanol at boiling temperature. Under these conditions the reaction is generally complete after about 30 to 90 minutes.
2~ Reaction of a pyrazine derivative of formula ' ~'.:''.
Cl~ CO-NR -C=NR
~ ~ (XI), \N R N-R5 .
211~ 7 5 ~
wherein R3 to R6 are as hereinbefore defined, with an amine of formula ~NR1R2 (VI), wherein Rl and R2 are as hereinbefore defined.
The reaction is preferably carried out at elevated temperature in a polar solvent, if possible anhydrous, e.g. dimethylformamide, dimethylsulphoxide.
The starting compounds of formula XI are obtained by conventional methods. They may for example be obtained according to process 1) if pyrazine carboxylic acid esters are used which are of similar construction to the esters of formula VII
but contain a chlorine atom instead of NR1R2 in the 5-position. ;~
,: :
The compounds of formula I may be used as active substances in pharmaceutical preparations or may be used as intermediate products for preparing such active substances. The new compounds inhibit the Na~/H~- and Na~/Li~-exchange, inter alia. The active substances~ ~ -aceording to the invention may be used as antihypertensives, mucolytics, diuretics and caneerostatics; they may also be used in diseases connected with ischaemia (for example: cardiae, cerebral, gastrointestinal, pulmonary and renal isc~aemia, ischaemia of the liver, ischaemia of the skeletal musculature). Corresponding diseases include, for example, coronary heart disease, angina pectoris, ;
embolisms in the circulation of the lungs, acute or chronic kidney failure, chronic kidney insufficiency, cerebral infarct, chronic circulatory ~isorders of the brain. During reperfusion of the ischaemic heart (e.g.
``` 2~1~7~
after an attack of angina pectoris or a cardiac infarct) irreversible damage may occur to cardiomyocytes in the affected region. The compounds according to the invention may be used in such cases for cardioprotection.
The prevention of damage which may occur as a result of reduced circulation during transplants should also be included in the field of ischaemia.
The active substances may be administered in conventional forms, e.g. plain or coated tablets, capsules, granules, injectable solutions, and possibly nasally administered preparations, the active substance generally being present in an amount of 1 to 200 mg, preferably 20 to 100 mg per dosage unit. These pharmaceutical preparations are produced in a manner known per se.
2~ 1~rl~r~
Examples l. Tablets (Composition) Compound according to Example 40.0 mg Corn starch 144.0 mg Sec. calcium phosphate115.0 mg Magnesium stearate l.0 mq 300.0 mg 2. Gelatine capsules The contents of a capsule consist of 50.0 mg of a compound according to the invention and 150.0 mg of corn starch.
Note: Under the headings "Form" the Tables which follow indicate whether the preparation is a salt (HCl = . :~
hydrochloride, 2.HCl = dihydrochloride, etc.) or the base (BS).
',: . ~ ,.
: `~
2 ~ 1 3 7 ~ ~
Exam~le 1 a) Methyl 3-amino-6-chloro-5-(2-[1-(1,6-dimethyl-phenoxy)]propylamino)-pyrazine-2-carboxylate 4.44 g (20 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 3.6 g (20 mmol) of 2-amino-1-(2,6-dimethylphenoxy)propane and 2.2 g -(22 mmol) of triethylamine are heated to 9~ - 100C
in 40 ml of anhydrous dimethylformamide for 1~
hours. After the solvent has been distilled off ln vacuo the residue is purified on silica gel (eluant: ethyl acetate/isopropanol/NH3 (70:30:1).
Yield 7.3 g b) N-amidino-3-amino-6-chloro-5-(2-[1-(2,6-dimethylphenoxy)~propylamino)pyrazine-2-carboxamide-hydrochloride 7.3 g (0.02 mmol) of pyrazine carboxylic acid ester from Example la) are dissolved in 50 ml of methanol and heated with 80 ml of a 1 molar methanolic guanidine solution for 45 minutes over a boiling water bath. The solvent is distilled off in vacuo and the residue is purified over a silica gel column (eluant: ethyl acetate/isopropanol/NH3 (70:30:5) and the hydrochloride of the end product is prepared.
Yield 4.9 g; melting point 267 - 270C.
2 ~ 7 ~ ~
Example 2 ,~
a) Methyl 3-amino-6-chloro-~-[N'-(5-fluoro-2-methyl)phenyl]-guanidino-pyrazine-2-carboxylate 13.3 g ~60 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 15 g (90 mmol) o~
(5-fluoro-2-methyl)-phenylguanidine and 6 g of triethylamine are stirred into 100 ml of DMS0 for 2 hours at 90C. After cooling, 100 ml of CH2Cl2 are added. 100 ml of water are added dropwise, with cooling, the CH2Cl2 phase is separated off and the aqueous phase is extracted with 150 ml of CH2Cl2.
The CH2Cl2 phases collected are washed with a little water, dried over MgSO4 and concentrated by evaporation. The residue is pu~ified over silica gel (eluant: ethyl acetate/isopropanol (95:5).
Yield: 12.6 g /?
b) N-Amidino-3-amino-6-chloro- ~ '-(5-fluoro-2-methyl)-phenyl]guanidino-pyrazine-2-carboxamide ~
:: ~ :~:
Cl ~\~ o-c~l2-cH(oH)-cH2-N(cH3)-(cH2)3 Cl <~NH-C- .
R
:: ~
j 2 CH30~ 7 3 ~ ~_NH-CH2-CH2-N
21~ ~7~
or R1 and R2 form a substituted heterocyclic group with the nitrogen to which they are bound, e.g.
CH30 \~ N~N N
3 ( 2 ) 14 \~
CH30-CH2-CH2~ < ~ o-CH2-CH(OH)-ICH2 ~ Methods of preparing the new compounds are known to : those skilled in the art:
1) a lower alkylester of 3-amino-5,6-dichloropyrazine~
2-carboxylic acid is reacted under anhydrous conditions with an amine of formula 7 ~ ~
HNR1R2 (VI) wherein R1 and R2 are as hereinbefore defined, and the resulting compound of formula Cl__ f ~ _ C02-alkyl R R N ~ NH2 (VII) (alkyl = (C14)alkyl) is converted with a guanidine of formula HNR3 C=NR4 NRSR6 (VIII) -:
wherein R3 to R6 are as hereinbefore defined, into the desired end product.
The reaction of the 3-amino-5,6-dichloropyrazine-2-carboxylic acid ester with the amine component VI
to obtain the intermediate compounds of general formula VII is carried out using methods known from the literature in an inert solvent at elevated temperature in the presence of an acid acceptor.
The amine component is generally used in equimolar amounts. However, it is also possible to use the amine component as the acid acceptor and solvent.
Preferably, however, the solvent used is dimethylformamide or dimethylsulphoxide or mixtures thereof~ The reaction temperature is not crucial.
As a rule, the reaction is carried out at a ~ 21157~
temperature in the range from 80 - 100C depending on the reactivity of the amine used. Under these conditions the reaction is finished after about l to 2 hours. Organic and inoryanic bases may be used as acid acceptors. Preferably, tertiary amines such as pyridine, N-methylpiperidine, dimethylaniline or triethylamine are used.
The 3,5-diaminopyrazine carboxylic acid esters of formula VII prepared in this way may, if desired, be subjected to subsequent treatment, e.g. a reaction of acylation or alkylation.
Acylation is carried out by known methods, e.g. by reacting a diamine of formula VII with a reactive carboxylic acid derivative.
The alkylation is used, for example, in the preparation of corresponding phenoxypropanolamine derivatives. For this purpose, a diamino compound of the substructure IX of formula VII:
.
H\ Cl ~ ~ _ COzalkyl N-alk-N ~ ~ _ NH2 (IX) RS / ¦ \N
,., ~ .
(alk = (Cl~B)alkylene, alkyl, Rs as above) is reacted in a suitable solvent e.g. with a phenoxypropyleneoxide of general formula ~;
~; 2 1 ~ 5 7 ~ ~
~-CH2 -cH-cH2 ~(=~ \ / (X) Z
z = ~c14)alkoxy, (C14)alkoxy- (C1 4) alkyl at ambient temperature or slightly elevated temperature. Generally, the reaction is complete in about 0.5 to 1 hour.
However, the direct method of synthesis described above is preferred.
In order to prepare the end products of formula I
the 3,5-diaminopyrazine carboxylic acid esters of formula VII are reacted with a guanidine of formula VIII in a suitable solvent with heating. Simple alcohols are particularly suitable as the solvent.
Preferably, the reaction is carried out in methanol at boiling temperature. Under these conditions the reaction is generally complete after about 30 to 90 minutes.
2~ Reaction of a pyrazine derivative of formula ' ~'.:''.
Cl~ CO-NR -C=NR
~ ~ (XI), \N R N-R5 .
211~ 7 5 ~
wherein R3 to R6 are as hereinbefore defined, with an amine of formula ~NR1R2 (VI), wherein Rl and R2 are as hereinbefore defined.
The reaction is preferably carried out at elevated temperature in a polar solvent, if possible anhydrous, e.g. dimethylformamide, dimethylsulphoxide.
The starting compounds of formula XI are obtained by conventional methods. They may for example be obtained according to process 1) if pyrazine carboxylic acid esters are used which are of similar construction to the esters of formula VII
but contain a chlorine atom instead of NR1R2 in the 5-position. ;~
,: :
The compounds of formula I may be used as active substances in pharmaceutical preparations or may be used as intermediate products for preparing such active substances. The new compounds inhibit the Na~/H~- and Na~/Li~-exchange, inter alia. The active substances~ ~ -aceording to the invention may be used as antihypertensives, mucolytics, diuretics and caneerostatics; they may also be used in diseases connected with ischaemia (for example: cardiae, cerebral, gastrointestinal, pulmonary and renal isc~aemia, ischaemia of the liver, ischaemia of the skeletal musculature). Corresponding diseases include, for example, coronary heart disease, angina pectoris, ;
embolisms in the circulation of the lungs, acute or chronic kidney failure, chronic kidney insufficiency, cerebral infarct, chronic circulatory ~isorders of the brain. During reperfusion of the ischaemic heart (e.g.
``` 2~1~7~
after an attack of angina pectoris or a cardiac infarct) irreversible damage may occur to cardiomyocytes in the affected region. The compounds according to the invention may be used in such cases for cardioprotection.
The prevention of damage which may occur as a result of reduced circulation during transplants should also be included in the field of ischaemia.
The active substances may be administered in conventional forms, e.g. plain or coated tablets, capsules, granules, injectable solutions, and possibly nasally administered preparations, the active substance generally being present in an amount of 1 to 200 mg, preferably 20 to 100 mg per dosage unit. These pharmaceutical preparations are produced in a manner known per se.
2~ 1~rl~r~
Examples l. Tablets (Composition) Compound according to Example 40.0 mg Corn starch 144.0 mg Sec. calcium phosphate115.0 mg Magnesium stearate l.0 mq 300.0 mg 2. Gelatine capsules The contents of a capsule consist of 50.0 mg of a compound according to the invention and 150.0 mg of corn starch.
Note: Under the headings "Form" the Tables which follow indicate whether the preparation is a salt (HCl = . :~
hydrochloride, 2.HCl = dihydrochloride, etc.) or the base (BS).
',: . ~ ,.
: `~
2 ~ 1 3 7 ~ ~
Exam~le 1 a) Methyl 3-amino-6-chloro-5-(2-[1-(1,6-dimethyl-phenoxy)]propylamino)-pyrazine-2-carboxylate 4.44 g (20 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 3.6 g (20 mmol) of 2-amino-1-(2,6-dimethylphenoxy)propane and 2.2 g -(22 mmol) of triethylamine are heated to 9~ - 100C
in 40 ml of anhydrous dimethylformamide for 1~
hours. After the solvent has been distilled off ln vacuo the residue is purified on silica gel (eluant: ethyl acetate/isopropanol/NH3 (70:30:1).
Yield 7.3 g b) N-amidino-3-amino-6-chloro-5-(2-[1-(2,6-dimethylphenoxy)~propylamino)pyrazine-2-carboxamide-hydrochloride 7.3 g (0.02 mmol) of pyrazine carboxylic acid ester from Example la) are dissolved in 50 ml of methanol and heated with 80 ml of a 1 molar methanolic guanidine solution for 45 minutes over a boiling water bath. The solvent is distilled off in vacuo and the residue is purified over a silica gel column (eluant: ethyl acetate/isopropanol/NH3 (70:30:5) and the hydrochloride of the end product is prepared.
Yield 4.9 g; melting point 267 - 270C.
2 ~ 7 ~ ~
Example 2 ,~
a) Methyl 3-amino-6-chloro-~-[N'-(5-fluoro-2-methyl)phenyl]-guanidino-pyrazine-2-carboxylate 13.3 g ~60 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 15 g (90 mmol) o~
(5-fluoro-2-methyl)-phenylguanidine and 6 g of triethylamine are stirred into 100 ml of DMS0 for 2 hours at 90C. After cooling, 100 ml of CH2Cl2 are added. 100 ml of water are added dropwise, with cooling, the CH2Cl2 phase is separated off and the aqueous phase is extracted with 150 ml of CH2Cl2.
The CH2Cl2 phases collected are washed with a little water, dried over MgSO4 and concentrated by evaporation. The residue is pu~ified over silica gel (eluant: ethyl acetate/isopropanol (95:5).
Yield: 12.6 g /?
b) N-Amidino-3-amino-6-chloro- ~ '-(5-fluoro-2-methyl)-phenyl]guanidino-pyrazine-2-carboxamide ~
:: ~ :~:
5.5 g of 2-methylpyrazinecarboxylate from Example 2a) are dissolved in 25 ml of anhydrous dimethylformamide, 50 ml of a 1.2 molar methanolic guanidine solution are added and the resulting mixture is refluxed for 30 minutes. Then the methanol is distilled off and the residue is purified on silica gel (eluant: ethyl acetate/isopropanol/NH3 (70:30:5)) and the reaction product is converted into the hydrochloride.
Yield: 8.7 g; m.p. 242C.
::
211~7~
Example 3 N-Amidino-3-amino-6-chloro-5-(4-[2-(3-methoxy-phenoxy)ethyl~l-piperazinyl)-pyrazine-2-carboxamide-dihydrobromide 858 mg (3 mmol) of N-amidino-3-amino-5,6-dichloropyrazine-2-carboxamide, 924 (3 mmol) of N-[2-(3~methoxyphenoxy)ethyl]piperazine and 1.2 g (12 mmol) of triethylamine are heated to 95 - 100C
for 75 minutes. The solvent is distilled off in vacuo, the residue is purified over silica gel (eluant: ethyl acetate/isopropanol/NH3 (7:3:1)) and the reaction product obtained is converted into the dihydrobromide.
Yield: 1.13 g; m.p.: 159 - 162~C.
~::
_ample 4 a) Methyl 3-amino-6-chloro-5~[N-(2-pyrrolocarbonyl-amino)ethyl-N-methylamino]-pyrazine-2-carboxylate 2.73 g (10 mmol) of ethyl 3-amino-6-chloro-5-[N-(2-amino)ethyl-N-methyl]amino-pyrazine-2-carboxylate, 1.35 g (10 mmol) of l-hydroxy-lH-benzotriazole-hydrate and 1.11 g (10 mmol) of pyrrolo-2-carboxylic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and stirred with 2.06 g (10 mmol) of dicyclohexylcarbodiimide for 15 hours at ambient temperature, whilst cooling with ice. The reaction product is isolated in the usual way and purified over silica gel (eluant: ethyl acetate/isopropanol (7:3).
Yield: 3.09 g 21~7.~
b) N-Amidino-3-amino-6-chloro-5-[N-[2-(pyrrolyl-carbonylamino)ethyl]-N-methyl]aminopyrazine-2-carboxamide hydrochloride Prepared analogously to Example 1.
3.09 g (10 mmol) of methyl pyrazine-2-carboxylate from Example 3 yield 1.65 g of the title compound;
m.p. 181 - 184C.
Example 5 N-Amidino-3-amino-6-chloro-5-[4-[(4-amino-6,7-dimethoxy)-2-quinazolinyl]-1-piperazinyl]-pyrazi~e-2-carboxamide-dihydrochloride 13.1 g (45.3 mmol) of N-[(4-amino-6,7-dimethoxy)-2-quinazolinyl]-piperazine, 10 g (45.3 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate and 7 ml of triethylamine are reacted in 60 ml of dimethylsulphoxide for 2 hours at 80C. After cooling, the reaction product is precipitated by the addition of 100 ml of water, suction filtered, dried and converted into the end product without any further purification using the method described in Example la) by reacting with guanidine.
Yield: 10.5 g; m.p. > 290C.
The compounds listed in the Tables which follow may be obtained analogously to the Examples and in accordance with the remarks in the specification. If the compounds take the form of the base the abbreviation BS appears in the column "Form", otherwise the acid with which the salt is formed is specified~
2 ~ 7 ~ ~
Table 1 Compounds of formula >~ NH2 Nr. Rl ~2 Form m p [Cl ~ ~:
~ .
I CH3 CH3 HCl >280 H CH2-C~2 ~ 188-189 3 H CH2-CH2-Cll-N(cH3)2 HCl 262-264 4 H CH2 ~ CH2-CH(QH)-CH2-N(CH3)2 2 HCl amorph H CH2 ~ CCH3 2- HCl 6 H 2 ~ ~ ~ 2 HCl 252-253 7 H CH(CH3)-CH2 ~ 3 HCl 250-2S3 8 H CH(cH3)-cH2 ~ HCl 278 9 CH3 CH(CH3)-CH2 ~ HCl 232-235 ~ `" 211 ~7~
Nr. Rl R2 Form mp. L C]
==== === ==== ==== = ================_=========_= ===== = .
IH CH2-~i2 ~ HCl 145-148 ~`
O~i3 : : :
II H CH2-CH2 ~ 2-CH2-C~3 HCl - 117-119 l2 H CH2-CH(CH2OH) ~ i2-CH2-C-CH3 HCl 197-200 l3 H CH2-CH2 ~ 1 2 HCl 122-125 l4 C~i3 CH2-CH2 ~ i~Cl 141-143 CC~i3 H CH2-CH(OcH3)2 205-207 l6 CH3 C~i2-cH(o~ {~i2 ~ 2-CH2-c-cH3 HCl amorph l7 H CHz-CH(C~I)-C~i2 ~ CH2-c*i2-c-{~l3 HCl 116-119 l8 CH3 CH2-CH(OH)-CH2 ~ l HCl 112-115 Cl l9 CH3 Ci-i2-{~i(Oil)-C~i2 ~ 207-209 , .
2 ~ 7 ~ ~
-- 19 -- .
Form mp,lC]
______ _ _ _ _==================================================
Cl .20 H CH2-CH2-NH-sO2 ~ 1 HCl187-191 H ~
~ 3 21 H CH2-CH2-N(CH3)-C$I2-CH(c~) CH2 ~ 2- HCl118-120 Cl ( 22 H CH2--CH2-N(CH3)--CH(OH)--CH2 ~ ~S 83-87 Cl 23 H CH2-CH2-N~_~,0 200-202 24 CH3 CH2-CH2-N(CH3)-cH2-cH2 ~ 2-CH2-cCH3 BS 95-97 H CH2-CH2-NH ~ BS 210-215 26 H CH2-CH2-NH- ~ 1 225-228 ~ OCH3 27 H CH2-c*l2-NH ~N ~ cx~i3 2 HCl 230-235 Cl 28 H CH2-{~2-NH ~ NH2 2 HCl ~250 29 CH3 CH2-C~I2-NH-ICI ~ BS 140-142 O : :~
CH3 CH2-CH2-NI~-c ~ HCl 183-186 O H
~\
~ 2 ~ ~57~
Nr. R R2 Form mplC~
H3C~__ 31 H CH2-CH2-NH-C~l-cH(cH3)-cH2 ~ 2 HCl amorph . ., ( 32 H CH2-CH2-NH2 2 HCl >270 33 H CH2-CH2-N~ J 3 - HCl 195-200 H
34 H CH2-CH2-NH-502 ~ 2 HCl 168-171 ;
Cl 3 5 H CH2-CH2-CH2-N~-S02 ~ 1 HCl 250-252 Cl H CH2-CH2-C~12-NH ~ 502NH2 HCl 211-215 H2~25 37 H CH2-{~12-{~l2-N(CH3)2 2 HCl 268-270 : :~
~:: : .: ::
38 H CH2-cH2-cH2-N(cH3)-cH2-cH(oH)-cH2 ~ 1 BS amorph :~
Cl ~ :
39 H CH2-CH2-CH2-N(CH3)-CH2-CH(OH)-CH2 ~ 2-CH2-OCH3 ~;
2 HCl amorph : `\
211~7~
Tabl e 2 Compounds of formula Cl ~ N CC~-C-~I
~ ,1~ ,~ NH
R-~V~ N ~12 Nr . R Form mp. [ C]
( I CH2 - CH (0~) -CH2~2-cH2-ocH3 BS 184-187 2 CH2-CH(OH)-CH2~ BS 163-167 3 CH2-CH (Ol~) -{~2~ BS amorph 4 C~
o 187-190 .
S ~Cl-CH(cH3)2 ~5 21~-220 O ~ ';
: ~ :
`- 21~57~
Table 3 Compounds of formula ~ N ~ CcNH-c-~H2 H ~
Nr. R Form _mp.lC]
================================================== === ===========_= :
Cl .
'I ~ - ': '.
~=J 2 HCl 237-240 H3C~
2 ~ Cl Cl ~ 2 ~ICl 264-267 2 HCl 239-242 Cl Cl F -~
4 ~ 2 HCl 242 C ~ 177-180 '~
,': ~ ~ :.:-~
Table 4 Compounds of formula 21 1 ~75~
Nr . R Form mp. l Cl ===================================================================
OCH
I O CH2 - CH2~ 2 HBr 159-162 I I C~2--CH(OH)-C~I2~2-cH2--ocH3BS --180-182 12 CH2 - CHtoH)-c~l2~ 2 HCl 268-270 13 CH2 - CH(OH)-CH2~ 2 - HCl 287-290 ~. :
111 Cl~ BS196-198 - ~
O '~
: ~' ^' ~'~''
Yield: 8.7 g; m.p. 242C.
::
211~7~
Example 3 N-Amidino-3-amino-6-chloro-5-(4-[2-(3-methoxy-phenoxy)ethyl~l-piperazinyl)-pyrazine-2-carboxamide-dihydrobromide 858 mg (3 mmol) of N-amidino-3-amino-5,6-dichloropyrazine-2-carboxamide, 924 (3 mmol) of N-[2-(3~methoxyphenoxy)ethyl]piperazine and 1.2 g (12 mmol) of triethylamine are heated to 95 - 100C
for 75 minutes. The solvent is distilled off in vacuo, the residue is purified over silica gel (eluant: ethyl acetate/isopropanol/NH3 (7:3:1)) and the reaction product obtained is converted into the dihydrobromide.
Yield: 1.13 g; m.p.: 159 - 162~C.
~::
_ample 4 a) Methyl 3-amino-6-chloro-5~[N-(2-pyrrolocarbonyl-amino)ethyl-N-methylamino]-pyrazine-2-carboxylate 2.73 g (10 mmol) of ethyl 3-amino-6-chloro-5-[N-(2-amino)ethyl-N-methyl]amino-pyrazine-2-carboxylate, 1.35 g (10 mmol) of l-hydroxy-lH-benzotriazole-hydrate and 1.11 g (10 mmol) of pyrrolo-2-carboxylic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and stirred with 2.06 g (10 mmol) of dicyclohexylcarbodiimide for 15 hours at ambient temperature, whilst cooling with ice. The reaction product is isolated in the usual way and purified over silica gel (eluant: ethyl acetate/isopropanol (7:3).
Yield: 3.09 g 21~7.~
b) N-Amidino-3-amino-6-chloro-5-[N-[2-(pyrrolyl-carbonylamino)ethyl]-N-methyl]aminopyrazine-2-carboxamide hydrochloride Prepared analogously to Example 1.
3.09 g (10 mmol) of methyl pyrazine-2-carboxylate from Example 3 yield 1.65 g of the title compound;
m.p. 181 - 184C.
Example 5 N-Amidino-3-amino-6-chloro-5-[4-[(4-amino-6,7-dimethoxy)-2-quinazolinyl]-1-piperazinyl]-pyrazi~e-2-carboxamide-dihydrochloride 13.1 g (45.3 mmol) of N-[(4-amino-6,7-dimethoxy)-2-quinazolinyl]-piperazine, 10 g (45.3 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate and 7 ml of triethylamine are reacted in 60 ml of dimethylsulphoxide for 2 hours at 80C. After cooling, the reaction product is precipitated by the addition of 100 ml of water, suction filtered, dried and converted into the end product without any further purification using the method described in Example la) by reacting with guanidine.
Yield: 10.5 g; m.p. > 290C.
The compounds listed in the Tables which follow may be obtained analogously to the Examples and in accordance with the remarks in the specification. If the compounds take the form of the base the abbreviation BS appears in the column "Form", otherwise the acid with which the salt is formed is specified~
2 ~ 7 ~ ~
Table 1 Compounds of formula >~ NH2 Nr. Rl ~2 Form m p [Cl ~ ~:
~ .
I CH3 CH3 HCl >280 H CH2-C~2 ~ 188-189 3 H CH2-CH2-Cll-N(cH3)2 HCl 262-264 4 H CH2 ~ CH2-CH(QH)-CH2-N(CH3)2 2 HCl amorph H CH2 ~ CCH3 2- HCl 6 H 2 ~ ~ ~ 2 HCl 252-253 7 H CH(CH3)-CH2 ~ 3 HCl 250-2S3 8 H CH(cH3)-cH2 ~ HCl 278 9 CH3 CH(CH3)-CH2 ~ HCl 232-235 ~ `" 211 ~7~
Nr. Rl R2 Form mp. L C]
==== === ==== ==== = ================_=========_= ===== = .
IH CH2-~i2 ~ HCl 145-148 ~`
O~i3 : : :
II H CH2-CH2 ~ 2-CH2-C~3 HCl - 117-119 l2 H CH2-CH(CH2OH) ~ i2-CH2-C-CH3 HCl 197-200 l3 H CH2-CH2 ~ 1 2 HCl 122-125 l4 C~i3 CH2-CH2 ~ i~Cl 141-143 CC~i3 H CH2-CH(OcH3)2 205-207 l6 CH3 C~i2-cH(o~ {~i2 ~ 2-CH2-c-cH3 HCl amorph l7 H CHz-CH(C~I)-C~i2 ~ CH2-c*i2-c-{~l3 HCl 116-119 l8 CH3 CH2-CH(OH)-CH2 ~ l HCl 112-115 Cl l9 CH3 Ci-i2-{~i(Oil)-C~i2 ~ 207-209 , .
2 ~ 7 ~ ~
-- 19 -- .
Form mp,lC]
______ _ _ _ _==================================================
Cl .20 H CH2-CH2-NH-sO2 ~ 1 HCl187-191 H ~
~ 3 21 H CH2-CH2-N(CH3)-C$I2-CH(c~) CH2 ~ 2- HCl118-120 Cl ( 22 H CH2--CH2-N(CH3)--CH(OH)--CH2 ~ ~S 83-87 Cl 23 H CH2-CH2-N~_~,0 200-202 24 CH3 CH2-CH2-N(CH3)-cH2-cH2 ~ 2-CH2-cCH3 BS 95-97 H CH2-CH2-NH ~ BS 210-215 26 H CH2-CH2-NH- ~ 1 225-228 ~ OCH3 27 H CH2-c*l2-NH ~N ~ cx~i3 2 HCl 230-235 Cl 28 H CH2-{~2-NH ~ NH2 2 HCl ~250 29 CH3 CH2-C~I2-NH-ICI ~ BS 140-142 O : :~
CH3 CH2-CH2-NI~-c ~ HCl 183-186 O H
~\
~ 2 ~ ~57~
Nr. R R2 Form mplC~
H3C~__ 31 H CH2-CH2-NH-C~l-cH(cH3)-cH2 ~ 2 HCl amorph . ., ( 32 H CH2-CH2-NH2 2 HCl >270 33 H CH2-CH2-N~ J 3 - HCl 195-200 H
34 H CH2-CH2-NH-502 ~ 2 HCl 168-171 ;
Cl 3 5 H CH2-CH2-CH2-N~-S02 ~ 1 HCl 250-252 Cl H CH2-CH2-C~12-NH ~ 502NH2 HCl 211-215 H2~25 37 H CH2-{~12-{~l2-N(CH3)2 2 HCl 268-270 : :~
~:: : .: ::
38 H CH2-cH2-cH2-N(cH3)-cH2-cH(oH)-cH2 ~ 1 BS amorph :~
Cl ~ :
39 H CH2-CH2-CH2-N(CH3)-CH2-CH(OH)-CH2 ~ 2-CH2-OCH3 ~;
2 HCl amorph : `\
211~7~
Tabl e 2 Compounds of formula Cl ~ N CC~-C-~I
~ ,1~ ,~ NH
R-~V~ N ~12 Nr . R Form mp. [ C]
( I CH2 - CH (0~) -CH2~2-cH2-ocH3 BS 184-187 2 CH2-CH(OH)-CH2~ BS 163-167 3 CH2-CH (Ol~) -{~2~ BS amorph 4 C~
o 187-190 .
S ~Cl-CH(cH3)2 ~5 21~-220 O ~ ';
: ~ :
`- 21~57~
Table 3 Compounds of formula ~ N ~ CcNH-c-~H2 H ~
Nr. R Form _mp.lC]
================================================== === ===========_= :
Cl .
'I ~ - ': '.
~=J 2 HCl 237-240 H3C~
2 ~ Cl Cl ~ 2 ~ICl 264-267 2 HCl 239-242 Cl Cl F -~
4 ~ 2 HCl 242 C ~ 177-180 '~
,': ~ ~ :.:-~
Table 4 Compounds of formula 21 1 ~75~
Nr . R Form mp. l Cl ===================================================================
OCH
I O CH2 - CH2~ 2 HBr 159-162 I I C~2--CH(OH)-C~I2~2-cH2--ocH3BS --180-182 12 CH2 - CHtoH)-c~l2~ 2 HCl 268-270 13 CH2 - CH(OH)-CH2~ 2 - HCl 287-290 ~. :
111 Cl~ BS196-198 - ~
O '~
: ~' ^' ~'~''
Claims (7)
1. Compounds of formula (I) wherein R1 represents H or a (C1-8)alkyl group, R2 represents a 1-morpholinyl group, a straight-chained or branched (C1-8)alkyl chain which may be substituted, a) by a substituted or unsubstituted N,O,S-heterocyclic group, b) by the phenyl group which is optionally mono-or polysubstituted by a (C1-4) alkoxy group, which may in turn be functionalised by a hydroxyl or alkylamino group of formula (II), wherein R7 and R8 independently of each other denote hydrogen or a (C1-4)alkyl group;
c) by an aminocarbonyl group of the formula (III), wherein R7 and R8 are defined as hereinbefore;
d) independently of one another by one or more (C1-4)alkoxy groups, the hydroxyl or a hydroxyl(C1-4)-alkyl group or a phenoxy group which may in turn be mono- or polysubstituted by halogen (F, Cl), a cyano group, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkoxy-(C1-4)alkyl;
e) by an amino group of the formula (IV), wherein the groups R9 and R10 independently of each other denote hydrogen, a mono- or polynuclear N,O,S-heterocyclic group, a mono-or polysubstituted phenyl group substituted either homogeneously or by a mixture of halogen (F, Cl), (C1-4)alkyl or a sulphonamide group, an N,O-heterocyclic acyl group, a di-or trichlorophenylsulphonyl group substituted by an amine group, or a (C1-4)alkyl chain, which may be substituted independently of each other by the hydroxy group, or by a phenyl group which is optionally mono- or polysubstituted by halogen (F, Cl), hydroxy, (C1-4)alkyl or (C1-4)alkoxy-(C1-4)alkyl, or R9 and R10 form a morpholine ring together with the nitrogen atom to which they are bound and an oxygen atom;
a 4-piperidinyl group which may be substituted in the 1-position a) by the acyl group of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid;
b) by a (C1-8)alkyl chain which in turn is substituted, independently of each other, by the hydroxy group or by a (C1-4)alkoxy- or (C1-4)alkoxy-(C1-4)alkyl-substituted phenoxy group or by an .alpha.-naphthoxy group;
and amidino group of the formula (V), wherein R11 represents a phenyl group which is mono- or polysubstituted by halogen (F, Cl) or a (C1-4)alkyl group; or wherein R1 and R2 may together represent a piperidine or a piperazine ring, which may be N-substituted:
a) by an N,O,S-heterocyclic group, b) by the acyl group of an aliphatic, alicyclic, aromatic or heterocyclic carboxylic acid, c) by a (C1-8)alkyl chain, which may in turn be substituted independently of one another, by the hydroxy group or by a (C1-4)alkoxy- or (C1-4)alkoxy-(C1-4)alkyl-substituted phenoxy group or an .alpha.-naphthoxy group;
in the form of the bases or in the form of acid addition salts, with the proviso (a) that, if R1, R3, R4, R5 and R6 represent hydrogen, R2 does not represent alkyl, phenyl, chlorophenyl, benzyl, methyl-, fluoro- or chlorobenzyl, phenethyl, furfuryl, picolyl, hydroxyethyl, amino- or dimethylaminoethyl or HO-(CHOH)4-CH2;
and (b) that, if R3, R4, R5 and R6 represent hydrogen and R1 is C1-C3-alkyl, R2 does not represent C1-C4-alkyl;
and (c) that, if R3, R4, R5 and R6 represent hydrogen, R1 and R2 together do not represent CH3-N(CH2-CH3)2;
and (d) that, if R3 and R4 represent hydrogen, R5 and R6 represent methyl and R1 represents hydrogen or C1-C2-alkyl, R2 does not represent alkyl.
c) by an aminocarbonyl group of the formula (III), wherein R7 and R8 are defined as hereinbefore;
d) independently of one another by one or more (C1-4)alkoxy groups, the hydroxyl or a hydroxyl(C1-4)-alkyl group or a phenoxy group which may in turn be mono- or polysubstituted by halogen (F, Cl), a cyano group, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkoxy-(C1-4)alkyl;
e) by an amino group of the formula (IV), wherein the groups R9 and R10 independently of each other denote hydrogen, a mono- or polynuclear N,O,S-heterocyclic group, a mono-or polysubstituted phenyl group substituted either homogeneously or by a mixture of halogen (F, Cl), (C1-4)alkyl or a sulphonamide group, an N,O-heterocyclic acyl group, a di-or trichlorophenylsulphonyl group substituted by an amine group, or a (C1-4)alkyl chain, which may be substituted independently of each other by the hydroxy group, or by a phenyl group which is optionally mono- or polysubstituted by halogen (F, Cl), hydroxy, (C1-4)alkyl or (C1-4)alkoxy-(C1-4)alkyl, or R9 and R10 form a morpholine ring together with the nitrogen atom to which they are bound and an oxygen atom;
a 4-piperidinyl group which may be substituted in the 1-position a) by the acyl group of an aliphatic, alicyclic, aromatic or heteroaromatic carboxylic acid;
b) by a (C1-8)alkyl chain which in turn is substituted, independently of each other, by the hydroxy group or by a (C1-4)alkoxy- or (C1-4)alkoxy-(C1-4)alkyl-substituted phenoxy group or by an .alpha.-naphthoxy group;
and amidino group of the formula (V), wherein R11 represents a phenyl group which is mono- or polysubstituted by halogen (F, Cl) or a (C1-4)alkyl group; or wherein R1 and R2 may together represent a piperidine or a piperazine ring, which may be N-substituted:
a) by an N,O,S-heterocyclic group, b) by the acyl group of an aliphatic, alicyclic, aromatic or heterocyclic carboxylic acid, c) by a (C1-8)alkyl chain, which may in turn be substituted independently of one another, by the hydroxy group or by a (C1-4)alkoxy- or (C1-4)alkoxy-(C1-4)alkyl-substituted phenoxy group or an .alpha.-naphthoxy group;
in the form of the bases or in the form of acid addition salts, with the proviso (a) that, if R1, R3, R4, R5 and R6 represent hydrogen, R2 does not represent alkyl, phenyl, chlorophenyl, benzyl, methyl-, fluoro- or chlorobenzyl, phenethyl, furfuryl, picolyl, hydroxyethyl, amino- or dimethylaminoethyl or HO-(CHOH)4-CH2;
and (b) that, if R3, R4, R5 and R6 represent hydrogen and R1 is C1-C3-alkyl, R2 does not represent C1-C4-alkyl;
and (c) that, if R3, R4, R5 and R6 represent hydrogen, R1 and R2 together do not represent CH3-N(CH2-CH3)2;
and (d) that, if R3 and R4 represent hydrogen, R5 and R6 represent methyl and R1 represents hydrogen or C1-C2-alkyl, R2 does not represent alkyl.
2. N-Amidino-3-amino-6-chloro-5-[4-[(4-amino-6,7-dimethoxy)-2-quinazolinyl]-1-piperazinyl]-pyrazine-2-carboxamide and the acid addition salts thereof.
3. N-Amidino-3-amino-6-chloro-2-[N'-(5-fluoro-2-methyl)-phenyl]guanidinopyrazine-2-carboxamide and the acid addition salts thereof.
4. N-Amidino-3-amino-6-chloro-5-[2-[1-(2,6-dimethyl-phenoxy)]propylamino]pyrazine-2-carboxamide and the acid addition salts thereof.
5. Pharmaceutical compositions, characterized in that they contain a compound according to one of claims 1 to 4 together with conventional excipients and/or carriers.
6. Use of compounds according to claim 1, 2, 3 or 4 in the preparation of pharmaceutical compositions having an antihypertensive, mucolytic, diuretic, cancerostatic and PAF-antagonistic activity.
7. Process for preparing compounds according to claim 1, 2, 3 or 4 by methods known per se, characterized in that (a) a pyrazine carboxylic acid ester of formula (VII) (alkyl = (C1-4)alkyl) is reacted with a guanidine of formula (VIII) or (b) a pyrazine derivative of formula (XI) wherein R3 to R6 are as hereinbefore defined, is reacted with an amine of formula HNR1R2 (VI) wherein R1 and R2 are as hereinbefore defined and if desired the bases of formula I obtained are converted into acid addition salts.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4127026.6 | 1991-08-16 | ||
| DE4127026A DE4127026A1 (en) | 1991-08-16 | 1991-08-16 | New 3-amino-6-chloro:pyrazine 2-carboxamide derivs. - useful as hypotensive, mucolytic, diuretic and antitumoural drugs |
| DE19914130461 DE4130461A1 (en) | 1991-09-13 | 1991-09-13 | New 3-amino-5-substd. carboxamide chloro-pyrazine carbamide cpds. |
| DEP4130461.6 | 1991-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2115755A1 true CA2115755A1 (en) | 1993-03-04 |
Family
ID=25906394
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002115755A Abandoned CA2115755A1 (en) | 1991-08-16 | 1992-07-31 | New pyrazine derivatives, their preparation and their use |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0598770B1 (en) |
| JP (1) | JPH06509798A (en) |
| AT (1) | ATE159250T1 (en) |
| AU (1) | AU669122B2 (en) |
| CA (1) | CA2115755A1 (en) |
| CZ (1) | CZ280760B6 (en) |
| DE (1) | DE59208974D1 (en) |
| DK (1) | DK0598770T3 (en) |
| ES (1) | ES2108129T3 (en) |
| FI (1) | FI940696A0 (en) |
| GR (1) | GR3025742T3 (en) |
| HK (1) | HK1003137A1 (en) |
| HU (1) | HUT67661A (en) |
| IE (1) | IE922592A1 (en) |
| IL (1) | IL102814A0 (en) |
| MX (1) | MX9204637A (en) |
| NO (1) | NO301542B1 (en) |
| NZ (1) | NZ243959A (en) |
| RU (1) | RU2124008C1 (en) |
| SG (1) | SG46307A1 (en) |
| SK (1) | SK17594A3 (en) |
| TW (1) | TW213903B (en) |
| WO (1) | WO1993004048A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852046A (en) * | 1993-08-03 | 1998-12-22 | Hoechst Aktiengesellschaft | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6645969B1 (en) | 1991-05-10 | 2003-11-11 | Aventis Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
| IL109570A0 (en) * | 1993-05-17 | 1994-08-26 | Fujisawa Pharmaceutical Co | Guanidine derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
| DE4325822A1 (en) * | 1993-07-31 | 1995-02-02 | Hoechst Ag | Substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent, and medicament containing them |
| DE4337609A1 (en) * | 1993-11-04 | 1995-05-11 | Boehringer Ingelheim Kg | Novel pyrazinecarboxamide derivatives, their preparation and their use in medicines |
| DE4412334A1 (en) * | 1994-04-11 | 1995-10-19 | Hoechst Ag | Substituted N-heteroaroylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
| US5760230A (en) * | 1996-10-11 | 1998-06-02 | Bayer Aktiengesellschaft | 4, 4'-bridged bis-2, 4-diaminoquinazolines |
| US6420354B1 (en) * | 1998-06-08 | 2002-07-16 | Advanced Medicine, Inc. | Sodium channel drugs and uses |
| AU4952700A (en) | 1999-06-03 | 2000-12-28 | Takeda Chemical Industries Ltd. | Pernasal preparations |
| US6479498B1 (en) | 1999-06-04 | 2002-11-12 | Theravance, Inc. | Sodium channel drugs and uses |
| US6156758A (en) * | 1999-09-08 | 2000-12-05 | Isis Pharmaceuticals, Inc. | Antibacterial quinazoline compounds |
| OA12790A (en) * | 2002-03-13 | 2006-07-10 | Janssen Pharmaceutica Nv | New inhibitors of histone deacetylase. |
| WO2006074147A2 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics, Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
| US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
| JP2007504136A (en) | 2003-08-28 | 2007-03-01 | ニトロメッド インコーポレーティッド | Nitrosated and nitrosylated diuretic compounds, compositions and methods of use |
| US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| CA2597460A1 (en) | 2005-02-24 | 2006-08-31 | Nitromed, Inc. | Nitric oxide enhancing diuretic compounds, compositions and methods of use |
| DE102008061247A1 (en) | 2008-12-10 | 2010-06-24 | Christian-Albrechts-Universität Zu Kiel | Inhibitors of dimethylarginine dimethylaminohydrolase |
| JP5695200B2 (en) * | 2010-09-10 | 2015-04-01 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー．Ｈａｎｇｚｈｏｕ Ｂｅｎｓｈｅｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Heterocyclic aminoberbamine derivatives, their preparation and use |
| CN110041291B (en) * | 2018-01-15 | 2021-02-26 | 北京采瑞医药科技研究院有限公司 | Macamide derivative and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL299931A (en) * | 1962-10-30 | |||
| US3527758A (en) * | 1967-04-13 | 1970-09-08 | Merck & Co Inc | Process for the preparation of pyrazinoylguanidines from a pyrazinoic azide and a guanidine |
| US3539569A (en) * | 1968-08-21 | 1970-11-10 | Merck & Co Inc | Preparation of pyrazinoylguanidines from pyrazinoylureas |
| NL7803906A (en) * | 1978-04-12 | 1979-10-16 | Noordvos Schroeven Bv | METHOD, DEVICE AND PROPELLER FOR DISTRIBUTING A GAS, POWDER OR LIQUID MATERIAL IN A LIQUID. |
-
1992
- 1992-07-28 TW TW081105973A patent/TW213903B/zh active
- 1992-07-31 HU HU9400430A patent/HUT67661A/en unknown
- 1992-07-31 SG SG1996002613A patent/SG46307A1/en unknown
- 1992-07-31 CZ CZ94337A patent/CZ280760B6/en unknown
- 1992-07-31 ES ES92916697T patent/ES2108129T3/en not_active Expired - Lifetime
- 1992-07-31 DK DK92916697.3T patent/DK0598770T3/en active
- 1992-07-31 EP EP92916697A patent/EP0598770B1/en not_active Expired - Lifetime
- 1992-07-31 DE DE59208974T patent/DE59208974D1/en not_active Expired - Fee Related
- 1992-07-31 RU RU94015265A patent/RU2124008C1/en active
- 1992-07-31 CA CA002115755A patent/CA2115755A1/en not_active Abandoned
- 1992-07-31 AU AU23870/92A patent/AU669122B2/en not_active Ceased
- 1992-07-31 JP JP5504057A patent/JPH06509798A/en active Pending
- 1992-07-31 AT AT92916697T patent/ATE159250T1/en not_active IP Right Cessation
- 1992-07-31 WO PCT/EP1992/001738 patent/WO1993004048A1/en active IP Right Grant
- 1992-07-31 SK SK175-94A patent/SK17594A3/en unknown
- 1992-08-11 MX MX9204637A patent/MX9204637A/en not_active IP Right Cessation
- 1992-08-14 NZ NZ243959A patent/NZ243959A/en unknown
- 1992-08-14 IL IL102814A patent/IL102814A0/en unknown
- 1992-08-17 IE IE259292A patent/IE922592A1/en not_active IP Right Cessation
-
1994
- 1994-02-15 NO NO940523A patent/NO301542B1/en unknown
- 1994-02-15 FI FI940696A patent/FI940696A0/en unknown
-
1997
- 1997-12-23 GR GR970403392T patent/GR3025742T3/en unknown
-
1998
- 1998-03-17 HK HK98102228A patent/HK1003137A1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852046A (en) * | 1993-08-03 | 1998-12-22 | Hoechst Aktiengesellschaft | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE159250T1 (en) | 1997-11-15 |
| GR3025742T3 (en) | 1998-03-31 |
| HUT67661A (en) | 1995-04-28 |
| FI940696A (en) | 1994-02-15 |
| JPH06509798A (en) | 1994-11-02 |
| SG46307A1 (en) | 1998-02-20 |
| SK17594A3 (en) | 1994-12-07 |
| AU669122B2 (en) | 1996-05-30 |
| CZ280760B6 (en) | 1996-04-17 |
| NO940523D0 (en) | 1994-02-15 |
| HU9400430D0 (en) | 1994-05-30 |
| DK0598770T3 (en) | 1997-12-15 |
| HK1003137A1 (en) | 1998-10-09 |
| EP0598770A1 (en) | 1994-06-01 |
| NZ243959A (en) | 1995-07-26 |
| WO1993004048A1 (en) | 1993-03-04 |
| TW213903B (en) | 1993-10-01 |
| EP0598770B1 (en) | 1997-10-15 |
| MX9204637A (en) | 1993-02-01 |
| ES2108129T3 (en) | 1997-12-16 |
| NO940523L (en) | 1994-02-15 |
| IE922592A1 (en) | 1993-02-24 |
| IL102814A0 (en) | 1993-01-31 |
| RU94015265A (en) | 1997-02-20 |
| RU2124008C1 (en) | 1998-12-27 |
| NO301542B1 (en) | 1997-11-10 |
| AU2387092A (en) | 1993-03-16 |
| FI940696A0 (en) | 1994-02-15 |
| CZ33794A3 (en) | 1994-07-13 |
| DE59208974D1 (en) | 1997-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2115755A1 (en) | New pyrazine derivatives, their preparation and their use | |
| KR100359676B1 (en) | Benzoylguanidine and preparation method thereof | |
| US20050171357A1 (en) | Process for preparing indolinone derivatives | |
| CA2155307A1 (en) | Heterocyclic compounds as platelet aggregation inhibitors | |
| US5380724A (en) | Piperazine and homopiperazine derivatives, pharmaceutical compositions containing them and process for preparing same | |
| WO2008115738A1 (en) | Chemical compounds | |
| CN107827875B (en) | Application of benzimidazole derivative as cyclin-dependent kinase 4/6 inhibitor | |
| KR20120055571A (en) | Furazanobenzimidazoles as prodrugs to treat neoplastic or autoimmune diseases | |
| JP2927480B2 (en) | Piperidine compound, method for producing the same, and pharmaceutical composition containing the same | |
| CN114524772A (en) | Heterocyclic ring-containing tandem compound and preparation method and application thereof | |
| EP0256137B1 (en) | Bis-dioxopiperazine derivatives | |
| WO2005111020A2 (en) | Pyrimidine hydantoin analogues which inhibit leukocyte adhesion mediated by vla-4 | |
| CZ287261B6 (en) | Process for preparing 2,5-diamino-4,6-dichloropyrimidine and formamide thereof, N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide and 4,6-dichloropyrimidines | |
| US20040132786A1 (en) | Differential tumor cytotoxicity compounds and compositions | |
| JPH07138238A (en) | New quinazoline derivative and anti-tumor agent containing the derivative as active component | |
| CN114621206B (en) | 5-substituted pyrimidine diamine derivative and preparation method and application thereof | |
| DE4127026A1 (en) | New 3-amino-6-chloro:pyrazine 2-carboxamide derivs. - useful as hypotensive, mucolytic, diuretic and antitumoural drugs | |
| US5330985A (en) | 2-amino-N-[[4-(aminocarbonyl)pyrimidin-2-yl]amino]-alkyl]pyrimidine-4-carboxamide derivatives, their preparation and pharmaceutical compositions containing them | |
| CA2597903A1 (en) | Cationic lipids for the transfection of nucleic acids | |
| US5420130A (en) | 2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics | |
| JP3050598B2 (en) | Water-soluble bis-dioxopiperazine derivatives | |
| DE4130461A1 (en) | New 3-amino-5-substd. carboxamide chloro-pyrazine carbamide cpds. | |
| JP2010501007A (en) | Thiourea compounds | |
| JPS61152660A (en) | Bis-dioxopiperazine derivative | |
| CN116507611A (en) | Novel capsid assembly inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |