Note: Descriptions are shown in the official language in which they were submitted.
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 --
~'
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
1335989
- - 23233-236
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,
13 3 7 9 8 9 23233-236
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
/
CH2--C
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
R2 R3
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
133S989
^ 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.
1335989
23233-236
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~
- 23233-236
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
23233-236
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
2 2
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
CH2 - CH2
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 '.
1335989
~ 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 )
CH 2 CH 2
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 K N C O A N--C O - N H 2
\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)
R3
R2-C=CH -A-CH =CH-CH (X)
R3
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
X 12
1335989 23233-236
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
1 3 3 5 9 8 9 23233-236
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
IC50
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
16
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..
23233-236
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
17
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- 23233-236
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
23233-236
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
- 1 3 3 5 9 8 9 23233-236
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
1335989 23233-236
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
1335989 23233-236
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
