CA1335989C - Substituted 3-aminosydnone imines, a process for their preparation and their use - Google Patents
Substituted 3-aminosydnone imines, a process for their preparation and their useInfo
- Publication number
- CA1335989C CA1335989C CA000602645A CA602645A CA1335989C CA 1335989 C CA1335989 C CA 1335989C CA 000602645 A CA000602645 A CA 000602645A CA 602645 A CA602645 A CA 602645A CA 1335989 C CA1335989 C CA 1335989C
- Authority
- CA
- Canada
- Prior art keywords
- atoms
- radical
- compound
- denotes
- acid addition
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
Substituted 3-aminosydnone imines of the formula I
(I) and their pharmacologically acceptable acid addition salts, in which A denotes, for example, -CH2-, R1 denotes hydrogen or the radical -COR5, R2, R3 denote alkyl having 1 to 4 C atoms, R5 denotes, for example, an aliphatic radical having 1 to 4 C
atoms, are prepared by cyclization of a compound of the formula II
(I) and their pharmacologically acceptable acid addition salts, in which A denotes, for example, -CH2-, R1 denotes hydrogen or the radical -COR5, R2, R3 denote alkyl having 1 to 4 C atoms, R5 denotes, for example, an aliphatic radical having 1 to 4 C
atoms, are prepared by cyclization of a compound of the formula II
Description
1335989 Ref.33gS
StO958 Substituted 3-aminosydnone imines, a process for their preParation and their use The invention relates to pharmacologically active sub-stituted 3-aminosydnone imines of the general formula I
\ /
C ~12 C N f H ( I ) 2 Cll 2 N~ C=N--R
and their pharmacologically acceptable acid addition salts, in which A denotes the radical -CH2-, -O-, -S(O) n~ ~ -N(R4)- or a direct bond;
R1 denotes hydrogen or the radical -CoR5;
R2, R3 denote alkyl having 1 to 4 C atoms;
R4 denotes alkyl having 1 to 4 C atoms; hydroxyalkyl having 2 to 4 C atoms; phenylalkyl having 1 to 4 C atoms in the alkyl radical;
R5 denotes an aliphatic radical having 1 to 4 C atoms which may also be substituted by alkoxy having 1 to 3 C
atoms; a cycloaliphatic radical having 5 to 7 C atoms; a bicycloaliphatic radical having 7 to 14 C atoms; a tri-cycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C
atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 3 C atoms and/or 1 to 3 alkoxy radicals having 1 to 3 C atoms and/or 1 or 2 nitro groups;
n denotes the number 0, 1 or 2.
The invention in addition relates to a process for the preparation of the compounds according to the invention and to their use.
If A denotes one of the radicals -CH2-, -O-, -S(O)~- or ~' 1 3 3 ~ g 8 9 23233-236 -N(R4)-, the radical of a heterocyclic 6-membered ring having one heteroatom (N) or having two hetero atoms (N,0 or N,S or N,N), which is dialkylated in the manner indicated, is in the 3-position of the sydnone imine. If A denotes a direct bond, a pyrrolidine radical dialkylated in the 2,2-position is in the 3-position of the sydnone imine.
Of the divalent radicals standing for A, the radicals:
-CH2-, -0- and -N(R )- are preferred.
Aliphatic radicals, alkyl radicals, hydroxyalkyl radicals and alkoxy radicals may be straight-chain or branched.
This also applies if they occur as substituents of other radicals, for example as substituents of aryl radicals, or combined with other radicals, for example as phenalkyl or as alkoxycarbonyl.
The alkyl radicals standing for R2 and R3 may be identical or different. They are usually identical. Suitable radicals for R and R are primarily straight-chain alkyl radicals. The radicals R2 and R3 particularly preferably denote methyl.
For R4, alkyl having 1 to 4 C atoms, in particular methyl, ethyl, isopropyl, tert.-butyl and benzyl, is preferred.
As aliphatic radicals standing for R5, alkyl radicals having 1 to 4 C atoms are particularly suitable. As aliphatic radicals standing for R5, which are substituted by alkoxy having 1 to 3 C atoms, the methoxymethyl radical may be mentioned in particular. As cycloaliphatic radicals standing for R5, cycloalkyl radicals having 5 to 7 C atoms, in particular cyclopentyl, and preferably cyclohexyl, are primarily suitable.
As a bicycloaliphatic radical standing for R5, the 2,6,6-trimethylbicyclo(3.1.1)-heptan-3-yl ~= 3-pinanyl) is particularly suitable. As a tricycloaliphatic radical standing for R5, the tricyclo(3.3.1.13'7)-decan-1-yl (= adamantanyl) is particularly suitable. As alkoxy radicals standing for R5, those having 1 to 4 C atoms, primarily methoxy and ethoxy radicals, are particularly suitable. As alkoxycarbonyl radicals standing for R5, those having a total of 2 to 4 C atoms, primarily the ethoxycarbonyl radical, are particularly suitable.
As aryl radicals standing for R5, a- or ~-naphthyl radicals, for example, but in particular the phenyl radical, may be mentioned.
As aryloxy radicals standing for R5, a- or ~-naphthoxy radicals, for example, but in particular the phenoxy radical, may be mentioned. The aryl radicals standing for R5 may be mono-, di-or trisubstituted, where, however, even on trisubstitution, only a maximum of 2 nitro groups may be present, such as, for example, 2-methyl-4,6-dinitrophenyl and 2-chloro-6-methyl-4-nitrophenyl. As halogen substituents for the aryl radicals, for example, chlorine and bromine atoms are suitable. Substituted aryl radicals standing for R5 which may be mentioned in particular are: methylphenyl (= tolyl), nitrophenyl and chlorophenyl, in particular 4-nitrophenyl and 4-chlorophenyl.
The following are preferred for R : alkyl radicals having 1 to 4 C atoms, alkoxy radicals having 1 or 2 C atoms, cycloalkyl radicals having 5 to 7 C atoms and phenyl. The following are very particularly preferred: methyl, ethyl, isopropyl, tert.-butyl, methoxy, ethoxy, isopropoxy, cyclohexyl, phenyl, 4-chlorophenyl.
The following are preferred for Rl: hydrogen and -COR , where R5 has the meanings previously indicated as preferred and, in particular, the meanings previously indicated as particularly preferred.
A compound of the general formula I can be prepared by a process in which a compound of the general formula II
/
N 1 2 ( II ) CH 2--CH 2 ~J
in which A, R2 and R3 have the meanings already mentioned, is cyclized to give a compound of the general formula Ia C H _C CH (Ia) \ C H _ C H 2 o and in which this compound or an acid addition salt thereof is acylated, in the case in which it is intended to prepare a compound of the formula I having R1 = -CoR5, with an acylating agent which introduces the radical -CoR5, and the compound thus obtained is optionally converted into a pharmacologically acceptable acid addition salt.
The cyclization of the compounds II to give the compounds Ia is carried out in a suitable organic or inorganic ^ 23233-236 solvent, dispersant or diluent with the addition of a cyclizing agent, normally at temperatures from -10 to 40C, in particular 0 to 40C, preferably at 0 to 20C.
Suitable cyclizing agents are those which establish a pH below 3 in aqueous solution, i.e., for example, mineral acids, such as sulphuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cyclization is normally carried out with ice cooling.
0.1 to 10 mol, preferably 1 to 5 mol, of the cyclizing agent are used, for example, relative to 1 mol of the compound of the formula II. The cyclizing agent is normally employed in excess. The use of hydrogen chloride as the cyclizing agent, which is normally introduced into the reaction mixture to saturation, is particularly convenient. The corresponding acid addition salts of the compound Ia is normally obtained in the cyclization.
Suitable solvents, dispersants or diluents are, for example: alcohols, for example those having 1 to 8 C atoms, in particular those having 1 to 6 C atoms, preferably those haYing 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture), benzyl alcohol; ethers, in particular those having 2 to 8 C atoms in the molecule such as, for example, diethyl ether, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl ~1 5 13~5983 23233-236 propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis-~-methoxyethyl ether; oligoethylene glycol dimethyl ethers such as, for example, tetraglyme or pentaglyme;
carboxylic acid alkyl esters, in particular those having 2 to 10 C atoms in the molecule such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate, methyl, ethyl or butyl propionate; ketones, in particular those having 3 to 10 C atoms in the molecule such as, for example, acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di-iso-butyl ketone, cyclopentanone, cyclohexanone, methylcyclohexanone, dimethylcyclohexanone, benzophenone, acetophenone; aliphatic hydrocarbons such as, for example, hexane, heptane, low- and high-boiling petroleum ethers, petroleum spirits and white spirit; cycloaliphatic hydrocarbons such as, for example, cyclopentane, cyclohexane, methylcyclohexane, tetralin, decalin;
aromatic hydrocarbons such as, for example, benzene, toluene, o-, m- and p-xylene, ethylbenzene; halogenated aliphatic or aromatic hydrocarbons such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene; hexamethylphosphoramide;
sulphoxides such as, for example, dimethyl sulphoxide;
tetramethylsulphone; water. Mixtures of different solvents or dispersants can also be used, for example water-methanol or preferably ethyl acetate-methanol.
The compounds of the formula Ia are compounds of the general formula I according to the invention in the case in which R1 is hydrogen.
The acylation of the compound of the formula Ia, which may also be present in the form of an acid addition salt, in order to introduce the radical R1 = -CoR5 can be carried out in a manner known per se using a suitable acylating agent of the formula III
1l 5 X-C-R (III) in which X represents a radical which can be removed by a nucleophile.
In formula III, X denotes, for example, in particular halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular having 1 to 5 C atoms; -O-aryl, in particular where the aryl radical is a phenyl radical which may also be monosubstituted or polysubstituted by alkyl, in particular methyl, and/or nitro and, for example is a tolyl, dinitrophenyl or nitrophenyl radical; -o-Co-R5; -O-CO-O-alkyl, in particular having 1 to 5 C
atoms in the alkyl radical, or the radical of an azole or benzazole bonded via an N atom and having at least 2 N atoms in the quasi-aromatic five-membered ring.
The acylation is expediently carried out in liquid phase in the presence of an inert solvent, dispersant or diluent or in an excess of the acylating agent, expediently with stirring.
In the acylation, the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is X 6a 133~989 23233-236 1:1. The acylating agent of the formula III is expediently employed in a slight molar excess. Excesses of up to 30 mol%
are usually sufficient, i.e. the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is normally 1:(1 to 1.3), preferably 1:(1 to 1.2).
If an acid is eliminated in the acylation reaction, the addition of an acid entrainer such as, for example, an alkali metal hydroxide such as, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, a tertiary organic amine such as, for example, pyridine or triethylamine, an alkali metal carbonate or alkali metal bicarbonate such as, for example, sodium carbonate or sodium bicarbonate, or an alkali metal salt of a weak organic acid such as, for example, sodium acetate is expedient. Suitable catalysts such as, for example, 4-dimethylaminopyridine can also be added to the acylation reaction.
The acylation can in principle be carried out at temperatures between -10C and the boiling point of the solvent, dispersant or diluent used. In many cases, the reaction is carried out at 0 to 50C, in particular at 0 to 30C and preferably at room temperature.
The compounds of the formula III are acylating agents and thus represent, for example: for X = halogen, acid halides or haloformic acid esters, of which acid chlorides and chloroformic acid esters are preferred; for -OH, carboxylic acids; for -O-alkyl and -O-aryl esters, of which the tolyl, 2,4-dinitro or 4-nitrophenyl esters are preferred; for -o-Co-R5, anhydrides; for -O-CO-O-alkyl, mixed carboxylic acid carbonic 13~ S 9 8 9 23233-236 acid anhydrides; or heterocyclic amides or azolides, in particular of N,N'-carbonyl-diazoles such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditriazole (compare, for example, H.A. Staab, M.
Lucking and F.H. Durr, Chem. Ber. 95, (1962), 1275 ff, H.A.
Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff.; H.A.
Staab and W. Rohr, "Sunthesen mit hetero-cyclischen Amiden (A zoliden)" ("Syntheses with heterocyclic amides (azolides)") in "Neuere Methoden der Praparativen Organischen Chemie" ("Newer Methods of Preparative Organic Chemistry"), Volume V, Verlag Chemie, 1967, p. 53 ff., in particular p. 65 to 69). The acylating agents of the formula III can be prepared by processes known per se.
6c 133~98g In the use of a carboxylic acid as an acylating agent, the addition of activating agent which has the object of increasing or activating the acylating potential of the car-boxylic acid or converting the carboxylic acid in situ or prefer-ably shortly before the reaction with the compound of the formula Ia into a reactive carboxylic acid derivative of the formula III
is expedient. Suitable activating agents of this type are, for example: N,N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical such as, for example, diisopropyl-, dicyclohexyl- or N-methyl-N'-tert.-butyl-carbodiimide (compare Methodicum Chimicum, Verlag G.Thieme, Stuttgart, Vol. 6, (1974), p. 682/683, and Houben-Weyl, Methoden der Org. Chemie (Methods of Org. Chemistry), Vol. 8, (1952), p.
521/522); carbonic acid derivatives such as, for example, phos-gene, chloroformic acid esters, in particular having 1 to 5 C
atoms in the alkyl radical (compare, for example Tetrahedron Letters 24 (1983), 3365 to 3368); carboxylic acid esters such as, for example, N,N'-disuccinimido carbonate, diphthalimido car-bonate, 1,1'-(carbonyldioxy)-dibenzo-triazole, or di-2-pyridyl carbonate (compare, for example, Tetrahedron Letters, Vol. 25, No. 43, 4943-4946), optionally in the presence of suitable cata-lysts such as, for example, 4-dimethylaminopyridine. In addition, suitable activating agents are N,N'-carbonyldiazoles such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditri-azole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditetrazole, N,N'-carbonyl-benzimidazole or N,N'-carbonylbenzotriazole (compare, for example, H.A. Staab, M. Lucking and F.H. Durr, loc. cit.; H.A. Staab and A. Mannschreck loc. cit.; H.A. Staab and W. Rohr loc. cit.).
Commercial N,N'-carbonyl-diimidazole is frequently used as N,N'-carbonyl-diazole. However, the other N,N'-carbonylazoles are also easily accessible from the respective azole and phosgene.
Suitable activating agents for carboxylic acids are additionally: derivatives of oxalic acid, such as, for example, oxalyl chloride (compare, for example, GB Patent Specification 2,139,225) or N,N~-oxalyl-diazoles such as, for example, 1,1'-oxalyldi-imidazole, l,1'-oxalyldi-1,2,4-triazole and l,1'-oxa-lyldi-1,2,3,4-tetrazole (compare, for example, Shizuaka Murata, Bull. Chem. Soc. Jap. 57, 3597-3598 (1984)); methyl ethyl phos-133598~
phinic anhydride (compare, for example, German Offenlegungs-schrift 3,101,427; cf. USP 4,426,325); diphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite ~Indian J. Chem. 21, 259 (1982)); or other reactive agents.
Suitable solvents, dispersants or diluents are, for example, those which have been mentioned for carrying out the cyclization, and moreover also, for example, pyridine and amides such as, for example, dimethylformamide. In addition to water, polar organic solvents, such as dimethylformamide, dimethyl sulphoxide or pyridine are preferred for the acylation. Solvent mixtures such as, for example, a mixture of water and methylene chloride are also suitable.
The substituted 3-amino-sydnone imines of the general formula I form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of acid addition salts of this type. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, naphthalenedisulphonic acids, in particular naphthalene-1,5-di-sulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicyclic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. Pharmacologically acceptable acid addition salts are preferred. The acid addition salts can be prepared as is customary by combining the components, expediently in a suitable solvent or diluent.
133~983 In the synthesis of the compounds of the formula Ia, the acid addition salts are normally obtained. If desired, the free compounds of the general formula I or Ia can be obtained from the acid addition salts in a known manner, i.e. by dissolving or suspending in water and rendering alkaline, for example with sodium hydroxide solution, and then isolating.
The required starting compounds of the general formula II can be prepared in a manner known per se by Strecker's amino-nitrile synthesis from compounds of the general formula IV
'H2 A~ N--NH ( I V
in which A, R2 and R3 have the meanings already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, a compound of the general formula V
~ /
CH 2 N--NH - CH 2 - CN ~ V
first being formed, which is converted by nitrosylation into the compound II. The nitrosylation is carried out in a known manner in a suitable solvent, preferably in water, for example at temperatures from 0 to 10C. The nitrous acid is in this case normally produced from an alkali metal nitrite, for example sodium nitrite, and hydrochloric acid. It is expedient to adjust the aqueous solution of the compound V to a pH of 1 to 3 "~, g '.
~ 23233-236 using hydrochloric acid and to add the alkali metal nitrite dropwise in the form of an aqueous solution to the stirred and cooled solution of the compound.
The solution of the compound II thus obtained can be subjected directly to the cyclization reaction. However, normally it is fitting to first take up the nitroso compound II
in a suitable organic solvent and to carry out the cyclization to the compound of the formula Ia in it, if appropriate after addition of a further solvent.
Some of the compounds of the general formula IV are known or can be prepared, starting from compounds of the general formula VI
R2 R~
CH --C ~ V I ) by a process in which either a) a compound of the formula VI is nitrosylated to give the N-nitroso compound VII and subsequently reduced, expediently with lithium aluminium hydride:
R~ R~ R2 R~
\ / 2 \ /
2 ~ ~C H C
V I ~ ) A N--NO ~ /~ N--NH
C~J --CH CH CH
lV~I ) l IV) or in which in a manner known per se 133~989 23233-236 b) a compound of the formula VI is converted using potassium cyanate in acidic medium into the urea derivative VIII which is then converted by the Hoffmann degradation into the compound IV
by oxidation with sodium hypochlorite.
R 2 R 3 \ /
\ / CH2 C
\C H C H C H C H
~ V I I I ) (VI ) \ / CH?' \C
C H 2--C H 2 N a O C 1 / \ N H
~VIII ) ( IV) The preparation of the starting compounds of the formulae IV and VI is known. Starting compounds of the formula VI can be prepared, for example, from compounds of the general formulae IX or X
R2=C-CH -A-CH -CH=CH (IX) R2-C=CH -A-CH =CH-CH (X) in which R2 and R3 and A have the meanings already indicated and which can be prepared by methods which are known per se, by ring closure with ammonia. The reaction with ammonia may be carried out at temperatures from 20 to 150C, preferably at 60 to 100C, with or without solvent.
13~5989 ~ 23233-236 The compound 3,3-dimethyl-1,4-thiazine l,l-dioxide can be prepared from methallylsulphonylethanol and hydrazine hydrate. This reaction can also be applied to other starting compounds of the formula IV.
The preparation of the starting compound IV is described, for example, in DE-A-2,351,865 (cf. US Patents 3,943,098 and 3,061,631). Other starting compounds of the formulae IV and VI can be prepared analogously to the previously mentioned instructions.
The compounds of the general formula I and their pharmacologically acceptable acid addition salts have useful pharmacological properties. Their effect on the cardiovascular system is particularly pronounced. Compared with known sydnone imine compounds substituted in the 3-position, for example those of EP-B-59,356 (cf. US Patents 4,436,743 and 4,551,454), and also the commercially available structurally similar compound molsidomin, they surprisingly possess a substantially longer duration of action. For example, they lower the blood pressure as well as the pulmonal artery pressure and the left ventricular end-diastolic pressure and thus contribute to relieve the action of the heart in the sense of an antianginal action, without provoking reflex tachycardia at the same time.
Due to inhibition of thrombocyte aggregation, the compounds may additionally show antithrombotic effects.
The compounds of the formula I and their pharmacologically acceptable acid addition salts may therefore be administered to humans as medicaments alone, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which contain an effective dose of at least one compound of the formula I or an acid addition salt thereof as active constituent, in addition to customary pharmaceutically acceptable excipients and additives.
The medicaments may be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. However, administration may also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions, or percutaneously, for example in the form of ointments or tinctures.
In order to prepare the pharmaceutical preparations, pharmaceutically inert inorganic or organic excipients may be used. For the preparation of pills, tablets, coated tablets and hard gelatin capsules, for example lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof etc.
may be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, dextrose, glucose, polyols etc.
Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
In addition to the active compounds and excipients, the pharmaceutical preparations may further contain additives such as, for example, fillers, extenders, disintegrants, ~7 13 binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavourings or aromatizers, buffer substances, and in addition solvents or solubilizers or agents for achieving a depot effect, and also salts for changing the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and other therapeutically active substances.
Other therapeutically active substances of this type are, for example: ~-receptor blockers such as, for example, propranolol, pindolol, metoprolol; vasodilators such as, for example, carbochromen; sedatives such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics such as, for example, chlorothiazide;
agents which increase cardiac tone such as, for example digitalis preparations; hypotensive agents such as, for example, hydralazine, dihydralazine, prazosine, clonidine, rauwolfia alkaloids; agents which lower the fatty acid level in the blood such as, for example, benzafibrate, fenofibrate; and agents for thrombosis prophylaxis such as, for example, phenprocoumon.
The compounds of the formula I, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula I or their pharmacologically acceptable acid addition salts as active compounds may be used in humans in the control or prophylaxis of disorders of the cardiovascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, and in the control or prophylaxis of angina __ 14 pectoris etc. The dosage may vary within wide limits and is to be adjusted to the individual condition in each individual case. In general, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is suitable on oral administration. Even with other administration forms the daily dose, on account of the good absorption of the active compound, lies in similar dose ranges, i.e. in general also at 0.5 to 100 mg/human. The daily dose is normally divided into a number of, for example 2 to 4, part administrations.
The pharmacological action of the compounds of the formula I was determined by a modified method of Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl.) 35 to 49, 1972) and of Schüman et al (Naunyn-Schmiedeberg's Arch. Pharmacol.
289, 409 to 418, 1975). In this connection, spiral strips of the pulmonal artery of the guinea pig are depolarized using 40 mmol/l of potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmol/l of CaCl2 then induces a contraction. The relaxant effect of the test substance is determined by cumulative addition in 1/2 log 10 graduated concentrations. The concentration of the test substance which inhibits the contraction by 50% (=IC50, mol/l) is determined from the concentration-effect curve (abscissa: -log mol.l of test substance, ordinate: % inhibition of the maximum contraction, average value of 4 to 6 vessel strips). The IC50 values thus obtained are indicated in the following table. As the comparison with the IC50 value 3.10-4 for the known compound molsidomin (N-ethoxycarbonyl-3-morpholino-sydnone imine), ~ 9 8 9 23233-236 compare DE-B-1,695,897, shows, the values for the compounds of the formula I are considerably more favourable.
IC50values in mol/l a) 3-~3,3-Dimethylmorpholin-4-yl)-sydnone imine hydrochloride 1.10 6 b) 3-(2,2-Dimethylpiperidin-1-yl)-sydnone imine hydrochloride 1.10 6 c) 3-~4-Isopropyl-2,2-dimethyl-piperazin-1-yl)-sydnone imine dihydrochloride 1.10 6 d) N-Ethoxycarbonyl-3-morpholino-sydnone imine 3.10 4 a to c: Compounds according to the invention d: Comparison compound molsidomin Example 1 3-(3,3-Dimethylmorpholin-4-yl)-sydnone imine hydrochloride a) 4-Nitroso-3,3-dimethylmorpholine A solution of 17 g of sodium nitrite is added dropwise at 0 to a mixture of 23 g of 3,3-dimethylmorpholine and 20 g of conc. hydrochloric acid in 30 ml of water and the reaction mixture is stirred for 15 hours. The product is extracted by shaking with diethyl ether. After drying over sodium sulphate and concentrating, a yellow oil remains.
Yield: 21.9 g The 3,3-dimethylmorpholine required as starting material can be prepared according to J. Org. Chem. 11, 288 (46).
X
133~989 ..
b) 4-Amino-3,3-dimethylmorpholine 21.6 g of the nitroso compound obtained in step a are dissolved in 150 ml of tetrahydrofuran and 6.3 g of lithium alanate are added in portions. An exothermic reaction occurs after addition of 1/3 of the reducing agent. The temperature is kept under 50C and the mixture is subsequently stirred at room temperature for 15 hours after completion of the addition. The flask is then cooled with ice and ice water is cautiously added dropwise for just as long as hydrogen is still evolved.
Precipitated aluminium hydroxide is filtered off with suction and the filtrate is extracted three times by shaking with diethyl ether. The aluminium hydroxide is suspended using diethyl ether and filtered off with suction, and the organic phases are combined, washed with saturated sodium chloride solution, then dried over sodium sulphate and distilled.
A colourless oil is thus obtained.
Yield: 14.6 g c) N-Nitroso-N-3,3-dimethYl-morpholin-4-yl-amino-acetonitrile 14.4 g of the 4-amino-3,3-dimethylmorpholine obtained in step b are dissolved in 70 ml of water, 11 g of conc. hydro-chloric acid are added and the mixture is cooled to 0-5 C. A
solution of 8.6 g of potassium cyanide in 25 ml of water and then 11 g of 39% strength aqueous formalin solution are then added dropwise with stirring. This mixture is subsequently stirred for 4 hours, cooled to 5C and adjusted to pH = 1 by addition of conc. hydrochloric acid, and a solution of 7.6 g of sodium nitrite in 20 ml of water is added dropwise. The reaction is complete after 1 hour. The product is extracted by 133~989 shaking with ethyl acetate, and the ethyl acetate solution is dried and concentrated. A red-brown oil remains.
Yield: 15 g d) 3-(3,3-Dimethyl-morpholin-4-yl)-sydnone imine hYdrochloride The nitroso compound from step c is dissolved in 70 ml of ethanol, and hydrogen chloride is introduced into this solution with ice cooling until it is saturated. After 1 day, the precipitate is filtered off with suction and the filtrate is concentrated. The remaining oil is stirred with ethyl acetate, and the solid is filtered off with suction and recrystallized from isopropanol.
Yield: 5.2 g m.p.: 155C (Decomposition) The following sydnone imines can be prepared in an analogous manner:
Example 2 3-(2,2-Dimethylpiperidin-1-yl)-sydnone imine hydrochloride Yield: 45% of theory m.p.: 168C (Decomposition) The preparation of the 2,2-dimethylpiperidine required as starting material is described in J. Org. Chem. 27, 1290 (1962).
Example 3 3-(2~2-Dimethyl-pyrrolidin-1-yl)-sydnone imine hydrochloride Yield: 41% of theory m.p.: 177C (Decomposition) The preparation of the 2,2-dimethylpyrrolidine required as starting material is described in Org. Synthesis Coll. Vol. IV, 354.
l33~989 Example 4 3-(4-Isopropyl-2~2-dimethyl-piperazin-1-yl)-sydnone imine dihydrochloride Yield: 38% of theory m.p.: 152C ~Decomposition) Example 5 N-(4-Chlorobenzoyl)-3-(2,2-dimethylpiperidin-1-yl)-sydnone imine A solution of 1.6 g of 4-chlorobenzoyl chloride in 20 ml of methylene chloride is added at 0C to a solution of 2.1 g of 3-(2,2-dimethylpiperidin-1-yl)-sydnone imine hydrochloride and 1.5 g of sodium bicarbonate in 15 ml of water. The mixture is stirred at room temperature for 15 hours, and the methylene chloride phase is separated off, dried and concentrated. The residue is recrystallized from diisopropyl ether.
Yield: 1.4 g m.p.: 138-141C
Example 6 N-Acetyl-3-(2,2-dimethylpiperidin-1-yl)-sYdnone imine The preparation is carried out analogously to Example 5, acetic anhydride being used instead of 4-chlorobenzoyl chloride.
Yield: 73% of theory m.p.: 83-84C
ExamPle 7 N-Ethoxycarbonyl-3-(2,2-dimethylpiperidin-1-yl)-sydnone imine The preparation is carried out analogously to Example 5, ethyl chloroformate being used instead of 4-chlorobenzoyl chloride.
Yield: 65% of theory m.p.: 70-75C
18a Example 8 N-Cyclohexylcarbonyl-3-(3,3-dimethylmorpholin-4-yl)-sydnone imine The preparation is carried out analogously to Example 5, cyclohexanecarbonyl chloride and 3-(3,3-dimethylmorpholin-4-yl)-sydnone imine hydrochloride being employed.
Yield: 68% of theory m.p.: 91-93 C
Example 9 N-Isobutyroyl-3-(2,2-dimethyl-4-isoproPyl-piperazin-1-yl)-sydnone imine The preparation is carried out analogously to Example 5, isobutyroyl chloride and 3-(2,2-dimethyl-4-isopropyl-piperazin-1-yl)-sydnone imine dihydrochloride being employed.
Yield: 61% of theory m.p.: 71-73C
Pharmaceutical preparations are described in the following Examples A to F.
Example A
Soft gelatin capsules containing 5 mg of active compound per capsule:
per capsule Active compound 5 mg Fractionated triglyceride mixture from coconut fat 150 mg Capsule content 155 mg Example B
Injection solution containing 1 mg of active compound per ml:
per ml Active compound 1.0 mg Polyethylene glycol 400 0.3 ml 18b Sodium chloride 2.7 mg Water for injection purposes to 1 ml Example C
Emulsion containing 3 mg of active compound per 5 ml per 100 ml of emulsion Active compound 0.06 g Neutral oil q.s.
Sodium carboxymethyl cellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2.0 g Flavouring q.s.
Water (demineralized or distilled)to 100 ml Example D
Rectal medicament containing 4 mg of active compound per suppository per suPpository Active compound 4 mg Suppository foundation to 2 g Example E
20 Tablets containing 2 mg of active compound per tablet per tablet Active compound 2 mg Lactose 60 mg Maize starch 30 mg Soluble starch 4 mg Magnesium stearate 4 mq 100 mg 18c Example F
Coated tablets containing 1 mg of active compound per coated tablet per coated tablet Active compound 1 mg Maize starch 100 mg Lactose 60 mg Sec. calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silica 4 mg 200 mg 18d
StO958 Substituted 3-aminosydnone imines, a process for their preParation and their use The invention relates to pharmacologically active sub-stituted 3-aminosydnone imines of the general formula I
\ /
C ~12 C N f H ( I ) 2 Cll 2 N~ C=N--R
and their pharmacologically acceptable acid addition salts, in which A denotes the radical -CH2-, -O-, -S(O) n~ ~ -N(R4)- or a direct bond;
R1 denotes hydrogen or the radical -CoR5;
R2, R3 denote alkyl having 1 to 4 C atoms;
R4 denotes alkyl having 1 to 4 C atoms; hydroxyalkyl having 2 to 4 C atoms; phenylalkyl having 1 to 4 C atoms in the alkyl radical;
R5 denotes an aliphatic radical having 1 to 4 C atoms which may also be substituted by alkoxy having 1 to 3 C
atoms; a cycloaliphatic radical having 5 to 7 C atoms; a bicycloaliphatic radical having 7 to 14 C atoms; a tri-cycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C
atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 3 C atoms and/or 1 to 3 alkoxy radicals having 1 to 3 C atoms and/or 1 or 2 nitro groups;
n denotes the number 0, 1 or 2.
The invention in addition relates to a process for the preparation of the compounds according to the invention and to their use.
If A denotes one of the radicals -CH2-, -O-, -S(O)~- or ~' 1 3 3 ~ g 8 9 23233-236 -N(R4)-, the radical of a heterocyclic 6-membered ring having one heteroatom (N) or having two hetero atoms (N,0 or N,S or N,N), which is dialkylated in the manner indicated, is in the 3-position of the sydnone imine. If A denotes a direct bond, a pyrrolidine radical dialkylated in the 2,2-position is in the 3-position of the sydnone imine.
Of the divalent radicals standing for A, the radicals:
-CH2-, -0- and -N(R )- are preferred.
Aliphatic radicals, alkyl radicals, hydroxyalkyl radicals and alkoxy radicals may be straight-chain or branched.
This also applies if they occur as substituents of other radicals, for example as substituents of aryl radicals, or combined with other radicals, for example as phenalkyl or as alkoxycarbonyl.
The alkyl radicals standing for R2 and R3 may be identical or different. They are usually identical. Suitable radicals for R and R are primarily straight-chain alkyl radicals. The radicals R2 and R3 particularly preferably denote methyl.
For R4, alkyl having 1 to 4 C atoms, in particular methyl, ethyl, isopropyl, tert.-butyl and benzyl, is preferred.
As aliphatic radicals standing for R5, alkyl radicals having 1 to 4 C atoms are particularly suitable. As aliphatic radicals standing for R5, which are substituted by alkoxy having 1 to 3 C atoms, the methoxymethyl radical may be mentioned in particular. As cycloaliphatic radicals standing for R5, cycloalkyl radicals having 5 to 7 C atoms, in particular cyclopentyl, and preferably cyclohexyl, are primarily suitable.
As a bicycloaliphatic radical standing for R5, the 2,6,6-trimethylbicyclo(3.1.1)-heptan-3-yl ~= 3-pinanyl) is particularly suitable. As a tricycloaliphatic radical standing for R5, the tricyclo(3.3.1.13'7)-decan-1-yl (= adamantanyl) is particularly suitable. As alkoxy radicals standing for R5, those having 1 to 4 C atoms, primarily methoxy and ethoxy radicals, are particularly suitable. As alkoxycarbonyl radicals standing for R5, those having a total of 2 to 4 C atoms, primarily the ethoxycarbonyl radical, are particularly suitable.
As aryl radicals standing for R5, a- or ~-naphthyl radicals, for example, but in particular the phenyl radical, may be mentioned.
As aryloxy radicals standing for R5, a- or ~-naphthoxy radicals, for example, but in particular the phenoxy radical, may be mentioned. The aryl radicals standing for R5 may be mono-, di-or trisubstituted, where, however, even on trisubstitution, only a maximum of 2 nitro groups may be present, such as, for example, 2-methyl-4,6-dinitrophenyl and 2-chloro-6-methyl-4-nitrophenyl. As halogen substituents for the aryl radicals, for example, chlorine and bromine atoms are suitable. Substituted aryl radicals standing for R5 which may be mentioned in particular are: methylphenyl (= tolyl), nitrophenyl and chlorophenyl, in particular 4-nitrophenyl and 4-chlorophenyl.
The following are preferred for R : alkyl radicals having 1 to 4 C atoms, alkoxy radicals having 1 or 2 C atoms, cycloalkyl radicals having 5 to 7 C atoms and phenyl. The following are very particularly preferred: methyl, ethyl, isopropyl, tert.-butyl, methoxy, ethoxy, isopropoxy, cyclohexyl, phenyl, 4-chlorophenyl.
The following are preferred for Rl: hydrogen and -COR , where R5 has the meanings previously indicated as preferred and, in particular, the meanings previously indicated as particularly preferred.
A compound of the general formula I can be prepared by a process in which a compound of the general formula II
/
N 1 2 ( II ) CH 2--CH 2 ~J
in which A, R2 and R3 have the meanings already mentioned, is cyclized to give a compound of the general formula Ia C H _C CH (Ia) \ C H _ C H 2 o and in which this compound or an acid addition salt thereof is acylated, in the case in which it is intended to prepare a compound of the formula I having R1 = -CoR5, with an acylating agent which introduces the radical -CoR5, and the compound thus obtained is optionally converted into a pharmacologically acceptable acid addition salt.
The cyclization of the compounds II to give the compounds Ia is carried out in a suitable organic or inorganic ^ 23233-236 solvent, dispersant or diluent with the addition of a cyclizing agent, normally at temperatures from -10 to 40C, in particular 0 to 40C, preferably at 0 to 20C.
Suitable cyclizing agents are those which establish a pH below 3 in aqueous solution, i.e., for example, mineral acids, such as sulphuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cyclization is normally carried out with ice cooling.
0.1 to 10 mol, preferably 1 to 5 mol, of the cyclizing agent are used, for example, relative to 1 mol of the compound of the formula II. The cyclizing agent is normally employed in excess. The use of hydrogen chloride as the cyclizing agent, which is normally introduced into the reaction mixture to saturation, is particularly convenient. The corresponding acid addition salts of the compound Ia is normally obtained in the cyclization.
Suitable solvents, dispersants or diluents are, for example: alcohols, for example those having 1 to 8 C atoms, in particular those having 1 to 6 C atoms, preferably those haYing 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture), benzyl alcohol; ethers, in particular those having 2 to 8 C atoms in the molecule such as, for example, diethyl ether, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl ~1 5 13~5983 23233-236 propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis-~-methoxyethyl ether; oligoethylene glycol dimethyl ethers such as, for example, tetraglyme or pentaglyme;
carboxylic acid alkyl esters, in particular those having 2 to 10 C atoms in the molecule such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate, methyl, ethyl or butyl propionate; ketones, in particular those having 3 to 10 C atoms in the molecule such as, for example, acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di-iso-butyl ketone, cyclopentanone, cyclohexanone, methylcyclohexanone, dimethylcyclohexanone, benzophenone, acetophenone; aliphatic hydrocarbons such as, for example, hexane, heptane, low- and high-boiling petroleum ethers, petroleum spirits and white spirit; cycloaliphatic hydrocarbons such as, for example, cyclopentane, cyclohexane, methylcyclohexane, tetralin, decalin;
aromatic hydrocarbons such as, for example, benzene, toluene, o-, m- and p-xylene, ethylbenzene; halogenated aliphatic or aromatic hydrocarbons such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene; hexamethylphosphoramide;
sulphoxides such as, for example, dimethyl sulphoxide;
tetramethylsulphone; water. Mixtures of different solvents or dispersants can also be used, for example water-methanol or preferably ethyl acetate-methanol.
The compounds of the formula Ia are compounds of the general formula I according to the invention in the case in which R1 is hydrogen.
The acylation of the compound of the formula Ia, which may also be present in the form of an acid addition salt, in order to introduce the radical R1 = -CoR5 can be carried out in a manner known per se using a suitable acylating agent of the formula III
1l 5 X-C-R (III) in which X represents a radical which can be removed by a nucleophile.
In formula III, X denotes, for example, in particular halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular having 1 to 5 C atoms; -O-aryl, in particular where the aryl radical is a phenyl radical which may also be monosubstituted or polysubstituted by alkyl, in particular methyl, and/or nitro and, for example is a tolyl, dinitrophenyl or nitrophenyl radical; -o-Co-R5; -O-CO-O-alkyl, in particular having 1 to 5 C
atoms in the alkyl radical, or the radical of an azole or benzazole bonded via an N atom and having at least 2 N atoms in the quasi-aromatic five-membered ring.
The acylation is expediently carried out in liquid phase in the presence of an inert solvent, dispersant or diluent or in an excess of the acylating agent, expediently with stirring.
In the acylation, the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is X 6a 133~989 23233-236 1:1. The acylating agent of the formula III is expediently employed in a slight molar excess. Excesses of up to 30 mol%
are usually sufficient, i.e. the molar ratio between the compound of the formula Ia and the acylating agent of the formula III is normally 1:(1 to 1.3), preferably 1:(1 to 1.2).
If an acid is eliminated in the acylation reaction, the addition of an acid entrainer such as, for example, an alkali metal hydroxide such as, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, a tertiary organic amine such as, for example, pyridine or triethylamine, an alkali metal carbonate or alkali metal bicarbonate such as, for example, sodium carbonate or sodium bicarbonate, or an alkali metal salt of a weak organic acid such as, for example, sodium acetate is expedient. Suitable catalysts such as, for example, 4-dimethylaminopyridine can also be added to the acylation reaction.
The acylation can in principle be carried out at temperatures between -10C and the boiling point of the solvent, dispersant or diluent used. In many cases, the reaction is carried out at 0 to 50C, in particular at 0 to 30C and preferably at room temperature.
The compounds of the formula III are acylating agents and thus represent, for example: for X = halogen, acid halides or haloformic acid esters, of which acid chlorides and chloroformic acid esters are preferred; for -OH, carboxylic acids; for -O-alkyl and -O-aryl esters, of which the tolyl, 2,4-dinitro or 4-nitrophenyl esters are preferred; for -o-Co-R5, anhydrides; for -O-CO-O-alkyl, mixed carboxylic acid carbonic 13~ S 9 8 9 23233-236 acid anhydrides; or heterocyclic amides or azolides, in particular of N,N'-carbonyl-diazoles such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditriazole (compare, for example, H.A. Staab, M.
Lucking and F.H. Durr, Chem. Ber. 95, (1962), 1275 ff, H.A.
Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff.; H.A.
Staab and W. Rohr, "Sunthesen mit hetero-cyclischen Amiden (A zoliden)" ("Syntheses with heterocyclic amides (azolides)") in "Neuere Methoden der Praparativen Organischen Chemie" ("Newer Methods of Preparative Organic Chemistry"), Volume V, Verlag Chemie, 1967, p. 53 ff., in particular p. 65 to 69). The acylating agents of the formula III can be prepared by processes known per se.
6c 133~98g In the use of a carboxylic acid as an acylating agent, the addition of activating agent which has the object of increasing or activating the acylating potential of the car-boxylic acid or converting the carboxylic acid in situ or prefer-ably shortly before the reaction with the compound of the formula Ia into a reactive carboxylic acid derivative of the formula III
is expedient. Suitable activating agents of this type are, for example: N,N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical such as, for example, diisopropyl-, dicyclohexyl- or N-methyl-N'-tert.-butyl-carbodiimide (compare Methodicum Chimicum, Verlag G.Thieme, Stuttgart, Vol. 6, (1974), p. 682/683, and Houben-Weyl, Methoden der Org. Chemie (Methods of Org. Chemistry), Vol. 8, (1952), p.
521/522); carbonic acid derivatives such as, for example, phos-gene, chloroformic acid esters, in particular having 1 to 5 C
atoms in the alkyl radical (compare, for example Tetrahedron Letters 24 (1983), 3365 to 3368); carboxylic acid esters such as, for example, N,N'-disuccinimido carbonate, diphthalimido car-bonate, 1,1'-(carbonyldioxy)-dibenzo-triazole, or di-2-pyridyl carbonate (compare, for example, Tetrahedron Letters, Vol. 25, No. 43, 4943-4946), optionally in the presence of suitable cata-lysts such as, for example, 4-dimethylaminopyridine. In addition, suitable activating agents are N,N'-carbonyldiazoles such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditri-azole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditetrazole, N,N'-carbonyl-benzimidazole or N,N'-carbonylbenzotriazole (compare, for example, H.A. Staab, M. Lucking and F.H. Durr, loc. cit.; H.A. Staab and A. Mannschreck loc. cit.; H.A. Staab and W. Rohr loc. cit.).
Commercial N,N'-carbonyl-diimidazole is frequently used as N,N'-carbonyl-diazole. However, the other N,N'-carbonylazoles are also easily accessible from the respective azole and phosgene.
Suitable activating agents for carboxylic acids are additionally: derivatives of oxalic acid, such as, for example, oxalyl chloride (compare, for example, GB Patent Specification 2,139,225) or N,N~-oxalyl-diazoles such as, for example, 1,1'-oxalyldi-imidazole, l,1'-oxalyldi-1,2,4-triazole and l,1'-oxa-lyldi-1,2,3,4-tetrazole (compare, for example, Shizuaka Murata, Bull. Chem. Soc. Jap. 57, 3597-3598 (1984)); methyl ethyl phos-133598~
phinic anhydride (compare, for example, German Offenlegungs-schrift 3,101,427; cf. USP 4,426,325); diphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite ~Indian J. Chem. 21, 259 (1982)); or other reactive agents.
Suitable solvents, dispersants or diluents are, for example, those which have been mentioned for carrying out the cyclization, and moreover also, for example, pyridine and amides such as, for example, dimethylformamide. In addition to water, polar organic solvents, such as dimethylformamide, dimethyl sulphoxide or pyridine are preferred for the acylation. Solvent mixtures such as, for example, a mixture of water and methylene chloride are also suitable.
The substituted 3-amino-sydnone imines of the general formula I form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of acid addition salts of this type. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, naphthalenedisulphonic acids, in particular naphthalene-1,5-di-sulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicyclic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. Pharmacologically acceptable acid addition salts are preferred. The acid addition salts can be prepared as is customary by combining the components, expediently in a suitable solvent or diluent.
133~983 In the synthesis of the compounds of the formula Ia, the acid addition salts are normally obtained. If desired, the free compounds of the general formula I or Ia can be obtained from the acid addition salts in a known manner, i.e. by dissolving or suspending in water and rendering alkaline, for example with sodium hydroxide solution, and then isolating.
The required starting compounds of the general formula II can be prepared in a manner known per se by Strecker's amino-nitrile synthesis from compounds of the general formula IV
'H2 A~ N--NH ( I V
in which A, R2 and R3 have the meanings already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, a compound of the general formula V
~ /
CH 2 N--NH - CH 2 - CN ~ V
first being formed, which is converted by nitrosylation into the compound II. The nitrosylation is carried out in a known manner in a suitable solvent, preferably in water, for example at temperatures from 0 to 10C. The nitrous acid is in this case normally produced from an alkali metal nitrite, for example sodium nitrite, and hydrochloric acid. It is expedient to adjust the aqueous solution of the compound V to a pH of 1 to 3 "~, g '.
~ 23233-236 using hydrochloric acid and to add the alkali metal nitrite dropwise in the form of an aqueous solution to the stirred and cooled solution of the compound.
The solution of the compound II thus obtained can be subjected directly to the cyclization reaction. However, normally it is fitting to first take up the nitroso compound II
in a suitable organic solvent and to carry out the cyclization to the compound of the formula Ia in it, if appropriate after addition of a further solvent.
Some of the compounds of the general formula IV are known or can be prepared, starting from compounds of the general formula VI
R2 R~
CH --C ~ V I ) by a process in which either a) a compound of the formula VI is nitrosylated to give the N-nitroso compound VII and subsequently reduced, expediently with lithium aluminium hydride:
R~ R~ R2 R~
\ / 2 \ /
2 ~ ~C H C
V I ~ ) A N--NO ~ /~ N--NH
C~J --CH CH CH
lV~I ) l IV) or in which in a manner known per se 133~989 23233-236 b) a compound of the formula VI is converted using potassium cyanate in acidic medium into the urea derivative VIII which is then converted by the Hoffmann degradation into the compound IV
by oxidation with sodium hypochlorite.
R 2 R 3 \ /
\ / CH2 C
\C H C H C H C H
~ V I I I ) (VI ) \ / CH?' \C
C H 2--C H 2 N a O C 1 / \ N H
~VIII ) ( IV) The preparation of the starting compounds of the formulae IV and VI is known. Starting compounds of the formula VI can be prepared, for example, from compounds of the general formulae IX or X
R2=C-CH -A-CH -CH=CH (IX) R2-C=CH -A-CH =CH-CH (X) in which R2 and R3 and A have the meanings already indicated and which can be prepared by methods which are known per se, by ring closure with ammonia. The reaction with ammonia may be carried out at temperatures from 20 to 150C, preferably at 60 to 100C, with or without solvent.
13~5989 ~ 23233-236 The compound 3,3-dimethyl-1,4-thiazine l,l-dioxide can be prepared from methallylsulphonylethanol and hydrazine hydrate. This reaction can also be applied to other starting compounds of the formula IV.
The preparation of the starting compound IV is described, for example, in DE-A-2,351,865 (cf. US Patents 3,943,098 and 3,061,631). Other starting compounds of the formulae IV and VI can be prepared analogously to the previously mentioned instructions.
The compounds of the general formula I and their pharmacologically acceptable acid addition salts have useful pharmacological properties. Their effect on the cardiovascular system is particularly pronounced. Compared with known sydnone imine compounds substituted in the 3-position, for example those of EP-B-59,356 (cf. US Patents 4,436,743 and 4,551,454), and also the commercially available structurally similar compound molsidomin, they surprisingly possess a substantially longer duration of action. For example, they lower the blood pressure as well as the pulmonal artery pressure and the left ventricular end-diastolic pressure and thus contribute to relieve the action of the heart in the sense of an antianginal action, without provoking reflex tachycardia at the same time.
Due to inhibition of thrombocyte aggregation, the compounds may additionally show antithrombotic effects.
The compounds of the formula I and their pharmacologically acceptable acid addition salts may therefore be administered to humans as medicaments alone, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which contain an effective dose of at least one compound of the formula I or an acid addition salt thereof as active constituent, in addition to customary pharmaceutically acceptable excipients and additives.
The medicaments may be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. However, administration may also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions, or percutaneously, for example in the form of ointments or tinctures.
In order to prepare the pharmaceutical preparations, pharmaceutically inert inorganic or organic excipients may be used. For the preparation of pills, tablets, coated tablets and hard gelatin capsules, for example lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof etc.
may be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, dextrose, glucose, polyols etc.
Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
In addition to the active compounds and excipients, the pharmaceutical preparations may further contain additives such as, for example, fillers, extenders, disintegrants, ~7 13 binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavourings or aromatizers, buffer substances, and in addition solvents or solubilizers or agents for achieving a depot effect, and also salts for changing the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and other therapeutically active substances.
Other therapeutically active substances of this type are, for example: ~-receptor blockers such as, for example, propranolol, pindolol, metoprolol; vasodilators such as, for example, carbochromen; sedatives such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics such as, for example, chlorothiazide;
agents which increase cardiac tone such as, for example digitalis preparations; hypotensive agents such as, for example, hydralazine, dihydralazine, prazosine, clonidine, rauwolfia alkaloids; agents which lower the fatty acid level in the blood such as, for example, benzafibrate, fenofibrate; and agents for thrombosis prophylaxis such as, for example, phenprocoumon.
The compounds of the formula I, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula I or their pharmacologically acceptable acid addition salts as active compounds may be used in humans in the control or prophylaxis of disorders of the cardiovascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, and in the control or prophylaxis of angina __ 14 pectoris etc. The dosage may vary within wide limits and is to be adjusted to the individual condition in each individual case. In general, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is suitable on oral administration. Even with other administration forms the daily dose, on account of the good absorption of the active compound, lies in similar dose ranges, i.e. in general also at 0.5 to 100 mg/human. The daily dose is normally divided into a number of, for example 2 to 4, part administrations.
The pharmacological action of the compounds of the formula I was determined by a modified method of Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl.) 35 to 49, 1972) and of Schüman et al (Naunyn-Schmiedeberg's Arch. Pharmacol.
289, 409 to 418, 1975). In this connection, spiral strips of the pulmonal artery of the guinea pig are depolarized using 40 mmol/l of potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmol/l of CaCl2 then induces a contraction. The relaxant effect of the test substance is determined by cumulative addition in 1/2 log 10 graduated concentrations. The concentration of the test substance which inhibits the contraction by 50% (=IC50, mol/l) is determined from the concentration-effect curve (abscissa: -log mol.l of test substance, ordinate: % inhibition of the maximum contraction, average value of 4 to 6 vessel strips). The IC50 values thus obtained are indicated in the following table. As the comparison with the IC50 value 3.10-4 for the known compound molsidomin (N-ethoxycarbonyl-3-morpholino-sydnone imine), ~ 9 8 9 23233-236 compare DE-B-1,695,897, shows, the values for the compounds of the formula I are considerably more favourable.
IC50values in mol/l a) 3-~3,3-Dimethylmorpholin-4-yl)-sydnone imine hydrochloride 1.10 6 b) 3-(2,2-Dimethylpiperidin-1-yl)-sydnone imine hydrochloride 1.10 6 c) 3-~4-Isopropyl-2,2-dimethyl-piperazin-1-yl)-sydnone imine dihydrochloride 1.10 6 d) N-Ethoxycarbonyl-3-morpholino-sydnone imine 3.10 4 a to c: Compounds according to the invention d: Comparison compound molsidomin Example 1 3-(3,3-Dimethylmorpholin-4-yl)-sydnone imine hydrochloride a) 4-Nitroso-3,3-dimethylmorpholine A solution of 17 g of sodium nitrite is added dropwise at 0 to a mixture of 23 g of 3,3-dimethylmorpholine and 20 g of conc. hydrochloric acid in 30 ml of water and the reaction mixture is stirred for 15 hours. The product is extracted by shaking with diethyl ether. After drying over sodium sulphate and concentrating, a yellow oil remains.
Yield: 21.9 g The 3,3-dimethylmorpholine required as starting material can be prepared according to J. Org. Chem. 11, 288 (46).
X
133~989 ..
b) 4-Amino-3,3-dimethylmorpholine 21.6 g of the nitroso compound obtained in step a are dissolved in 150 ml of tetrahydrofuran and 6.3 g of lithium alanate are added in portions. An exothermic reaction occurs after addition of 1/3 of the reducing agent. The temperature is kept under 50C and the mixture is subsequently stirred at room temperature for 15 hours after completion of the addition. The flask is then cooled with ice and ice water is cautiously added dropwise for just as long as hydrogen is still evolved.
Precipitated aluminium hydroxide is filtered off with suction and the filtrate is extracted three times by shaking with diethyl ether. The aluminium hydroxide is suspended using diethyl ether and filtered off with suction, and the organic phases are combined, washed with saturated sodium chloride solution, then dried over sodium sulphate and distilled.
A colourless oil is thus obtained.
Yield: 14.6 g c) N-Nitroso-N-3,3-dimethYl-morpholin-4-yl-amino-acetonitrile 14.4 g of the 4-amino-3,3-dimethylmorpholine obtained in step b are dissolved in 70 ml of water, 11 g of conc. hydro-chloric acid are added and the mixture is cooled to 0-5 C. A
solution of 8.6 g of potassium cyanide in 25 ml of water and then 11 g of 39% strength aqueous formalin solution are then added dropwise with stirring. This mixture is subsequently stirred for 4 hours, cooled to 5C and adjusted to pH = 1 by addition of conc. hydrochloric acid, and a solution of 7.6 g of sodium nitrite in 20 ml of water is added dropwise. The reaction is complete after 1 hour. The product is extracted by 133~989 shaking with ethyl acetate, and the ethyl acetate solution is dried and concentrated. A red-brown oil remains.
Yield: 15 g d) 3-(3,3-Dimethyl-morpholin-4-yl)-sydnone imine hYdrochloride The nitroso compound from step c is dissolved in 70 ml of ethanol, and hydrogen chloride is introduced into this solution with ice cooling until it is saturated. After 1 day, the precipitate is filtered off with suction and the filtrate is concentrated. The remaining oil is stirred with ethyl acetate, and the solid is filtered off with suction and recrystallized from isopropanol.
Yield: 5.2 g m.p.: 155C (Decomposition) The following sydnone imines can be prepared in an analogous manner:
Example 2 3-(2,2-Dimethylpiperidin-1-yl)-sydnone imine hydrochloride Yield: 45% of theory m.p.: 168C (Decomposition) The preparation of the 2,2-dimethylpiperidine required as starting material is described in J. Org. Chem. 27, 1290 (1962).
Example 3 3-(2~2-Dimethyl-pyrrolidin-1-yl)-sydnone imine hydrochloride Yield: 41% of theory m.p.: 177C (Decomposition) The preparation of the 2,2-dimethylpyrrolidine required as starting material is described in Org. Synthesis Coll. Vol. IV, 354.
l33~989 Example 4 3-(4-Isopropyl-2~2-dimethyl-piperazin-1-yl)-sydnone imine dihydrochloride Yield: 38% of theory m.p.: 152C ~Decomposition) Example 5 N-(4-Chlorobenzoyl)-3-(2,2-dimethylpiperidin-1-yl)-sydnone imine A solution of 1.6 g of 4-chlorobenzoyl chloride in 20 ml of methylene chloride is added at 0C to a solution of 2.1 g of 3-(2,2-dimethylpiperidin-1-yl)-sydnone imine hydrochloride and 1.5 g of sodium bicarbonate in 15 ml of water. The mixture is stirred at room temperature for 15 hours, and the methylene chloride phase is separated off, dried and concentrated. The residue is recrystallized from diisopropyl ether.
Yield: 1.4 g m.p.: 138-141C
Example 6 N-Acetyl-3-(2,2-dimethylpiperidin-1-yl)-sYdnone imine The preparation is carried out analogously to Example 5, acetic anhydride being used instead of 4-chlorobenzoyl chloride.
Yield: 73% of theory m.p.: 83-84C
ExamPle 7 N-Ethoxycarbonyl-3-(2,2-dimethylpiperidin-1-yl)-sydnone imine The preparation is carried out analogously to Example 5, ethyl chloroformate being used instead of 4-chlorobenzoyl chloride.
Yield: 65% of theory m.p.: 70-75C
18a Example 8 N-Cyclohexylcarbonyl-3-(3,3-dimethylmorpholin-4-yl)-sydnone imine The preparation is carried out analogously to Example 5, cyclohexanecarbonyl chloride and 3-(3,3-dimethylmorpholin-4-yl)-sydnone imine hydrochloride being employed.
Yield: 68% of theory m.p.: 91-93 C
Example 9 N-Isobutyroyl-3-(2,2-dimethyl-4-isoproPyl-piperazin-1-yl)-sydnone imine The preparation is carried out analogously to Example 5, isobutyroyl chloride and 3-(2,2-dimethyl-4-isopropyl-piperazin-1-yl)-sydnone imine dihydrochloride being employed.
Yield: 61% of theory m.p.: 71-73C
Pharmaceutical preparations are described in the following Examples A to F.
Example A
Soft gelatin capsules containing 5 mg of active compound per capsule:
per capsule Active compound 5 mg Fractionated triglyceride mixture from coconut fat 150 mg Capsule content 155 mg Example B
Injection solution containing 1 mg of active compound per ml:
per ml Active compound 1.0 mg Polyethylene glycol 400 0.3 ml 18b Sodium chloride 2.7 mg Water for injection purposes to 1 ml Example C
Emulsion containing 3 mg of active compound per 5 ml per 100 ml of emulsion Active compound 0.06 g Neutral oil q.s.
Sodium carboxymethyl cellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2.0 g Flavouring q.s.
Water (demineralized or distilled)to 100 ml Example D
Rectal medicament containing 4 mg of active compound per suppository per suPpository Active compound 4 mg Suppository foundation to 2 g Example E
20 Tablets containing 2 mg of active compound per tablet per tablet Active compound 2 mg Lactose 60 mg Maize starch 30 mg Soluble starch 4 mg Magnesium stearate 4 mq 100 mg 18c Example F
Coated tablets containing 1 mg of active compound per coated tablet per coated tablet Active compound 1 mg Maize starch 100 mg Lactose 60 mg Sec. calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silica 4 mg 200 mg 18d
Claims (13)
1. A substituted 3-aminosydnone imine of the general formula I
(I) or a pharmacologically acceptable acid addition salt, in which A denotes the radical -CH2-, -O-, -S(O)n-, -N(R4)- or a direct bond;
R1 denotes hydrogen or the radical -COR5;
R2, R3 denote alkyl having 1 to 4 C atoms;
R4 denotes alkyl having 1 to 4 C atoms; hydroxyalkyl having 2 to 4 C atoms; phenylalkyl having 1 to 4 C atoms in the alkyl radical;
R5 denotes an aliphatic radical having 1 to 4 C atoms which may also be substituted by alkoxy having 1 to 3 C atoms;
a cycloaliphatic radical having 5 to 7 C atoms; a bicyclo-aliphatic radical having 7 to 14 C atoms; a tricycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by a radical or radicals selected from the group consisting of 1 to 3 halogen atoms, 1 to 3 alkyl radicals having 1 to 3 C atoms, 1 to 3 alkoxy radicals having 1 to 3 C atoms, 1 or 2 nitro groups and any combination thereof; and n denotes the number 0, 1 or 2.
(I) or a pharmacologically acceptable acid addition salt, in which A denotes the radical -CH2-, -O-, -S(O)n-, -N(R4)- or a direct bond;
R1 denotes hydrogen or the radical -COR5;
R2, R3 denote alkyl having 1 to 4 C atoms;
R4 denotes alkyl having 1 to 4 C atoms; hydroxyalkyl having 2 to 4 C atoms; phenylalkyl having 1 to 4 C atoms in the alkyl radical;
R5 denotes an aliphatic radical having 1 to 4 C atoms which may also be substituted by alkoxy having 1 to 3 C atoms;
a cycloaliphatic radical having 5 to 7 C atoms; a bicyclo-aliphatic radical having 7 to 14 C atoms; a tricycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by a radical or radicals selected from the group consisting of 1 to 3 halogen atoms, 1 to 3 alkyl radicals having 1 to 3 C atoms, 1 to 3 alkoxy radicals having 1 to 3 C atoms, 1 or 2 nitro groups and any combination thereof; and n denotes the number 0, 1 or 2.
2. A substituted 3-aminosydnone imine according to claim 1, wherein R2 and R3 denote methyl.
3. A substituted 3-aminosydnone imine according to claim 1 or 2, wherein R1 denotes hydrogen.
4. A substituted 3-aminosydnone imine according to claim 1 or 2, wherein R1 denotes -COR5 and R5 denotes methyl, ethyl, isopropyl, tert.-butyl, methoxy, ethoxy, isopropoxy, cyclohexyl, phenyl, 4-chlorophenyl.
5. A substituted 3-aminosydnone imine according to claim 1 or 2, wherein A denotes -CH2-, -O- or -N(R4)-.
6. 3-(3,3-Dimethylmorpholin-4-yl)-sydnone imine or a pharmacologically acceptable acid addition salt thereof.
7. 3-(2,2-Dimethylpiperidin-1-yl)-sydnone imine or a pharmacologically acceptable acid addition salt thereof.
8. 3-(4-Isopropyl-2,2-dimethyl-piperazin-1-yl)-sydnone imine or a pharmacologically acceptable acid addition salt thereof.
9. A process for preparing a compound of formula I accord-ing to claim 1, which process comprises cyclizing a compound of general formula II
(II) in which A, R2 and R3 have the meanings indicated in claim 1, to give a compound of formula Ia (Ia) or an acid addition salt thereof, and if required, isolating the free compound from the acid addition salt, and, to prepare a compound of formula I in which R1 = -COR5 acylating the compound of the formula Ia or an acid addition salt thereof with an acylating agent to introduce the radical -COR5 and then if required, converting the compound obtained into an acid addition salt.
(II) in which A, R2 and R3 have the meanings indicated in claim 1, to give a compound of formula Ia (Ia) or an acid addition salt thereof, and if required, isolating the free compound from the acid addition salt, and, to prepare a compound of formula I in which R1 = -COR5 acylating the compound of the formula Ia or an acid addition salt thereof with an acylating agent to introduce the radical -COR5 and then if required, converting the compound obtained into an acid addition salt.
10. A process according to claim 9, wherein cyclization is carried out in a solvent, dispersant or diluent at a temperature of -10 to 40°C with the aid of a cyclizing agent which establishes a pH below 3 in aqueous solution.
11. A process according to claim 9, wherein cyclization is carried out in a solvent, dispersant or diluent at a temperature of 0 to 20°C with the aid of a cyclizing agent which establishes a pH below 3 in aqueous solution.
12. 3-Amino-sydnone imine according to any one of claims 1, 2, 6, 7 and 8, as a pharmacological active compound for use in the control and prophylaxis of a cardiovascular disorder.
13. A pharmaceutical preparation, comprising a compound according to any one of claims 1, 2, 6, 7 and 8, or an acid addition salt thereof as active compound together with a pharma-ceutically acceptable excipient or additive and, if required, one or more other pharmacological active compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3820210A DE3820210A1 (en) | 1988-06-14 | 1988-06-14 | SUBSTITUTED 3-AMINO-DYNONOMINES, PROCESS FOR THEIR PREPARATION AND THEIR USE |
| DEP3820210.7 | 1988-06-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1335989C true CA1335989C (en) | 1995-06-20 |
Family
ID=6356514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000602645A Expired - Fee Related CA1335989C (en) | 1988-06-14 | 1989-06-13 | Substituted 3-aminosydnone imines, a process for their preparation and their use |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0346694B1 (en) |
| JP (1) | JP2898302B2 (en) |
| KR (1) | KR910000719A (en) |
| AT (1) | ATE85054T1 (en) |
| CA (1) | CA1335989C (en) |
| DE (2) | DE3820210A1 (en) |
| DK (1) | DK247389A (en) |
| ES (1) | ES2053868T3 (en) |
| GR (1) | GR3007514T3 (en) |
| HU (1) | HUT55389A (en) |
| IE (1) | IE891900L (en) |
| PT (1) | PT90840B (en) |
| ZA (1) | ZA894470B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4015236A1 (en) * | 1990-05-13 | 1991-11-14 | Cassella Ag | SUBSTITUTED 3-AMINO-DYNONOMINES, PROCESS FOR THEIR PREPARATION AND THEIR USE |
| DE59001784D1 (en) * | 1989-11-30 | 1993-07-22 | Cassella Ag | SUBSTITUTED 3-AMINOSYDNONIMINE, METHOD FOR THE PRODUCTION AND USE THEREOF. |
| DE4031373A1 (en) * | 1990-10-04 | 1992-04-09 | Cassella Ag | 3-PIPERAZINO-SYDNONIMINE, METHOD FOR THE PRODUCTION AND THEIR USE |
| FR2703047B1 (en) * | 1993-03-25 | 1995-06-09 | Hoechst Lab | NITERATED DERIVATIVES OF SYDNONIMINE, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS A MEDICAMENT. |
| DE4337335A1 (en) * | 1993-11-02 | 1995-05-04 | Cassella Ag | Process for the preparation of Sydnoniminium hydrogen sulfate |
| JPH08321345A (en) * | 1995-05-24 | 1996-12-03 | Yazaki Corp | Connector housing |
| WO1998047896A1 (en) * | 1997-04-22 | 1998-10-29 | Chugai Seiyaku Kabushiki Kaisha | Sydononimine derivatives |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1695897C3 (en) * | 1966-07-04 | 1979-02-15 | Takeda Chemical Industries Ltd | N-acyl-sydnonimines, their salts, processes for their preparation and medicaments containing these compounds |
| JPS5836922B2 (en) * | 1976-07-02 | 1983-08-12 | 株式会社クボタ | reaping harvester |
| DE2930736A1 (en) * | 1979-07-28 | 1981-02-12 | Cassella Ag | PHARMACOLOGICALLY ACTIVE, SUBSTITUTED 3-AMINO-SYDNONIMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| JPS5859977A (en) * | 1981-10-06 | 1983-04-09 | Banyu Pharmaceut Co Ltd | Novel n-acylsydnoneimine derivative and its preparation |
| JPS5998076A (en) * | 1982-11-26 | 1984-06-06 | Hiroyoshi Hidaka | Novel sydnoneimine compound and its preparation |
| DE3522191A1 (en) * | 1985-06-21 | 1987-01-15 | Cassella Ag | PHOTOSTABILIZATION OF SYDNONIMINES |
| DE3526068A1 (en) * | 1985-07-20 | 1987-01-22 | Cassella Ag | SUBSTITUTED 3-AMINO-SYDNONIMINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
| DE3702083A1 (en) * | 1987-01-24 | 1988-08-04 | Cassella Ag | ALLYLMERCAPTOACETYL SYDNONIMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
-
1988
- 1988-06-14 DE DE3820210A patent/DE3820210A1/en not_active Withdrawn
-
1989
- 1989-05-22 DK DK247389A patent/DK247389A/en not_active Application Discontinuation
- 1989-06-01 EP EP89109930A patent/EP0346694B1/en not_active Expired - Lifetime
- 1989-06-01 DE DE8989109930T patent/DE58903385D1/en not_active Expired - Fee Related
- 1989-06-01 AT AT89109930T patent/ATE85054T1/en not_active IP Right Cessation
- 1989-06-01 ES ES89109930T patent/ES2053868T3/en not_active Expired - Lifetime
- 1989-06-13 IE IE891900A patent/IE891900L/en unknown
- 1989-06-13 JP JP1148535A patent/JP2898302B2/en not_active Expired - Lifetime
- 1989-06-13 HU HU893064A patent/HUT55389A/en unknown
- 1989-06-13 ZA ZA894470A patent/ZA894470B/en unknown
- 1989-06-13 CA CA000602645A patent/CA1335989C/en not_active Expired - Fee Related
- 1989-06-13 KR KR1019890008084A patent/KR910000719A/en active IP Right Grant
- 1989-06-14 PT PT90840A patent/PT90840B/en not_active IP Right Cessation
-
1993
- 1993-03-31 GR GR930400205T patent/GR3007514T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0346694A1 (en) | 1989-12-20 |
| IE891900L (en) | 1989-12-14 |
| DK247389D0 (en) | 1989-05-22 |
| DE3820210A1 (en) | 1989-12-21 |
| PT90840B (en) | 1994-11-30 |
| GR3007514T3 (en) | 1993-08-31 |
| JPH0236180A (en) | 1990-02-06 |
| KR910000719A (en) | 1991-01-30 |
| JP2898302B2 (en) | 1999-05-31 |
| DE58903385D1 (en) | 1993-03-11 |
| EP0346694B1 (en) | 1993-01-27 |
| PT90840A (en) | 1989-12-29 |
| ES2053868T3 (en) | 1994-08-01 |
| HUT55389A (en) | 1991-05-28 |
| DK247389A (en) | 1989-12-15 |
| ATE85054T1 (en) | 1993-02-15 |
| ZA894470B (en) | 1990-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1335989C (en) | Substituted 3-aminosydnone imines, a process for their preparation and their use | |
| CA1327362C (en) | Substituted 3-aminosydnonimines, process for the preparation thereof, and the use thereof | |
| CA1309408C (en) | Allylmercaptoacetylsydnonimines, processes for their preparation, and their use | |
| US4937244A (en) | Substituted 3-aminosydnonimines, processes for their preparation and their use | |
| US5179206A (en) | Substituted 3-aminosydnone imines | |
| US5120732A (en) | Substituted 3-aminosyndone imines, a process for their preparation and their use | |
| US5155109A (en) | 3-piperazinosydnone imines, process for their preparation and their use | |
| US5006540A (en) | Substituted 3-aminosydnonimines, processes for their preparation and their use | |
| IE920223A1 (en) | Substituted 3-aminosydnone imines, process for the¹preparation therefore and the use thereof | |
| US5079244A (en) | Substituted 3-aminosydnone imines, pharmaceutical compositions containing same, and process for administering same | |
| US5166166A (en) | 3-dicyclohexylaminosydnone imines, process for their preparation and their use | |
| HU201535B (en) | Process for producing substituted 3-aminosydnone imines and pharmaceutical compositions comprising such compounds as active ingredient | |
| US5221680A (en) | Substituted 3-aminosydnonimines | |
| CA2019811A1 (en) | Substituted 3-aminosydnone imines, processes for their preparation and their use | |
| CA2042321A1 (en) | Substituted 3-aminosydnone imines, processes for their preparation and their use | |
| US5091398A (en) | Substituted 1,2,3,4-oxatriazolium-5-olates, a process for their preparation and their use | |
| US5204475A (en) | Substituted 3-aminosydnone imines and salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |