CA1221702A - Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use - Google Patents
Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their useInfo
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- phenylsulphonyl
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Abstract
Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use Abstract The compounds of the formula (I), in which R represents the radical of the formula
Description
~2~1L7~
4 14375/=
Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use _ _ . . .
The present invention relates to iminosulphon-asides and processes for the manufacture thereof, pharmaceutical preparations containing such amino-sulfonamides, and the use of these iminosulphonamides as pharmacologically active compounds.
The invention relates especially to 1-~4-~2-(acylamino)-ethyl1-phenylsulphonyl~-3-cyclohexyl-22-imino-imidazolidine compounds of the formula
4 14375/=
Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use _ _ . . .
The present invention relates to iminosulphon-asides and processes for the manufacture thereof, pharmaceutical preparations containing such amino-sulfonamides, and the use of these iminosulphonamides as pharmacologically active compounds.
The invention relates especially to 1-~4-~2-(acylamino)-ethyl1-phenylsulphonyl~-3-cyclohexyl-22-imino-imidazolidine compounds of the formula
2 SHEA SO -I f 2 NH
(I) in which R represents the radical of the formula ~`~
R1 \ 13 COCK (It) in which R1 represents lower alkyd and each of R2 and R3, independently of the other, repro-sinks hydrogen or lower alkyd, and salts of such compounds Lower alkyd has preferably up to and including 3 carbon atoms, lower alkyd groups I and R3 representing especially methyl, whilst R1 may represent, for example, methyl, ethyl, n-propyl or isopropyl.
With regard to R1 and the carbonyl group, the compounds of the formula I may have the Swiss but preferably have the trans-configuration.
The novel compounds may be in the form of acid addition salts, especially in the form of foremost-gaily acceptable, non-toxic acid addition salts.
Suitable salts are, for example, those with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic caxboxylic or sulphonic acids, for example formic acid, acetic acid, prop ionic acid, succinic acid, glycolic acid, lactic acid, mafia acid, tartaric acid, citric acid, malefic acid, hydroxymaleic acid, pyruvic acid, fumaric acid, benzoic acid, 4-amino-benzoic acid, anthranilic acid, ~-hydroxybenzoic acid, salicylic acid, ~mbonic acid, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ''' ~Z~7~2 ethylenesulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid, or with other acidic organic compounds, such as ascorbic acid.
The present invention relates especially to compounds of the formula I in which R represents the radical of the formula Ian and R1 represents alkyd having up to and including 3 carbon atoms, R2 repro-sets preferably hydrogen, and also methyl, and R3 represents hydrogen or methyl, it being possible for these compounds to have the Claus- off preferably the trans-configuration with regard to the radical Al and the carbonyl group, and especially to 3-cyclohexyl-2-imino-1-~4-~2-(crotonylamino)-ethyll-phenylsulphonNoel-imidazolidine (trays), and salts, especially forum-ceutically acceptable salts thereof The novel compounds of the present invention can be obtained in a manner known so, for example (a) by reacting a compound of the formula H C - I
H INCH -OH SO -N N \.
2 2 2 \ _ / 2 \ C / \
NH
IT
or a derivative thereof with an acid of the formula R-C(=O)-OH (III) or a reactive derivative, and, if desired, converting a salt obtainable according to the invention into the free compound or into a different salt, and/or converting a free compound obtainable according to the invention into a salt and/or, it desired, separating a mixture of isomers into the individual isomers.
I
A derivative of the starting material of the formula II may be, or example, a sill derivative, such as a troweler alkylsilyl, such as -trim ethyl-sill, derivative, and also an acid addition salt, such as a salt with one of the acids mentioned herein before A reactive derivative of an acid of thy formula III is especially an android, including an assume-metric android, such as, inter alias an android with a strong inorganic acid, such as a hydraulic acid, especially the corresponding acid chloride, or with a carbonic acid semester, such as a carbonic acid lower alkyd semester, for example carbonic acid isopropyl semester, or an internal android, that is to say the corresponding kitten compound. Suitable reactive acid derivatives are also esters, such as a lower alkyd ester, for example methyl or ethyl ester, and especially, however, activated esters of acids of the formula III, such as suitably substituted phenol esters, for example 4-nitrophenyl ester or pentachlorophenyl ester, or suitably substituted methyl esters, for example cyanomethyl ester.
The reaction can be carried out in a manner known so, if necessary in the presence of a condensation agent, for example a carbodiimide, such as Dow-cyclohexyl-carbodiimide, these being employed espy-Shelley when a free acid of the formula III is used, or an acid-binding agent, such as, for example, an inorganic base or salt, such as an alkali metal hydroxide, alkali metal bicarbonate, alkali metal carbonate or alkali metal phosphate, such as the corresponding sodium or potassium compound. It is also possible to use an organic base, for example pardon, trimethylamine, triethylamine, N,N-di-isopropylethylamine or colliding, which, when added in excess, can be used at the same time also as Lo solvent. The reaction is usually carried out in the presence of a solvent, preferably an inert organic solvent which may or may not be miscible with water, in the presence or absence of water. Suitable inert organic solvents are, for example, hydrocarbons, such as Bunsen, Tulane or zillion, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydra-carbons, such as ethylene chloride, or lower kittens, such as acetone or methyl ethyl kitten. The reaction may, if necessary, be carried out while cooling or heating, under elevated pressure and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formulae II and III
are known, those of the formula II can be obtained for example, by treating an acid addition salt, such as the hydrochloride of 4-(2-aminoalkyl)-phenylsul-phonamide, with ~-(2-chloroethyl)-N-cyclohexyl-cyan-aside in the presence of an alkali metal hydroxide, for example potassium hydroxide.
The novel compounds of the formula I can also be obtained if (b) a reactive derivative of a sulphonic acid of the formula o If H . _ .
2 SHEA . /. S03H (IV) . _ --is reacted with a compound of the formula H-N N V) I \._ NH
or a derivative thereof, and, if desired, the add-tonal process steps are carried out.
Reactive derivatives of sulphonic acids of the formula IV are especially the androids thereof, especially mixed androids with strong acids, such as hairlike acids, especially the corresponding chlorides, and also the corresponding symmetric an-hydrides.
A derivative of a compound of the formula V may be, for example, a sill derivative, such as a in-lower alkylsilyl, such as trimethylsilyl, derivative, and also an acid addition salt, such as a salt with one of the acids mentioned herein before.
The reaction can be carried out in a manner known per so, if necessary in the presence of an acid-bind-in agent, such as, for example, an inorganic base or salt, such as an alkali metal hydroxide, alkali metal bicarbonate, alkali metal carbonate or alkali metal phosphate, such as the corresponding sodium or poles-slum compound. It is also possible to use an organic base, for example pardon, trimethylamine, triethyl-amine, N,~-diisopropylethylamine or colliding, which, when added in excess, can be used at the same time also as solvent. The reaction is usually carried out in the presence of a solvent, preferably an inert organic solvent which may or may not be miscible with water, in the absence or presence of water. Suitable inert organic solvents are, for example, hydrocarbons, Lo such as Bunsen, Tulane or zillion, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydrocarbons, such as ethylene chloride, or lower kittens, such as acetone or methyl ethyl kitten. The reaction may, if necessary, be carried out while cool-in or heating, under elevated pressure and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials are known or can be menu-lectured in a manner known per so, it being possible to obtain, for example, halides of acid compounds of the formula IV, for example by treating a NO
2-phenylethylamine with a halosulphonic acid, especially chlorosulphonic acid.
The novel compounds of the formula I can also be obtained by (c) cyclising a compound of the formula R-C~N-CH2-CH2-~ ox I N-./ /. (VI) X Y
in which one of the radicals X and Y represents cyan and the other represents hydrogen, and, if desired, carrying out the additional process steps.
The cyclisation mentioned above can be carried out under reaction conditions that are known per sex In so doing, the starting material of the formula VI is usually formed in situ and, without being isolated, is converted directly into a compound of the formula I.
Thus, for example (cay) a compound of the formula ~2C--CH2 Ho SHEA -SNOW / \ (Via in which Ye represents hydrogen or a radical that can be removed under the reaction conditions can be reacted with a reactive derivative of cynic acid, in this manner, it is possible to obtain a compound of the formula I directly without isolating an inter-mediate of the formula VI.
In a starting material of the formula Via for example a radical that can be removed undoer the reaction conditions, that is to say upon reaction with the cynic acid derivative, is a methyl group which is : optionally moo-, dip or tri-substituted, for example by an aureole group, such as phenol optionally substituted, for example, by lower alkyd, such as methyl, lower alkoxy, such as methoxy, or halogen, such as chlorine, or a methyl group which is optionally substituted by lower alkenyl, such as vinyl, that is unsaturated at the linking carbon atom.
A reactive derivative of cynic acid is, for example, a halide, such as cyanogen chloride or cyanogen bromide, or an ester, such as a lower alkyd ester or, especially a phenol ester thereof The reaction can be carried out in a manner known En so, if necessary in the presence of an acid-bind-in agent, such as an inorganic base, for example an alkali metal hydroxide, bicarbonate, carbonate or phosphate, such as the corresponding sodium or potassium compound. Calcium carbonate, and also - ' ~L~V~3L7~
g calcium phosphate or magnesium carbonate may also be used.
The reaction is effecter in the absence, but preferably in the presence, of an inert, usually organic solvent, if desired in the presence of water.
Suitable solvents are, for example, hydrocarbons, such as Bunsen, Tulane or zillion, lower alkanols, such as methanol or ethanol, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydra-carbons, such as ethylene chloride, lower kittens, such as acetone or methyl ethyl kitten, carboxylic acid esters, such as ethyl acetate, carboxylic acid nitrites, such as acetonitrile, or sulphones, such as tetrahydrothiophene 1,1-dioxide. The reaction is carried out, if necessary, while cooling or heating, under elevated pressure and/or in an inert gas atoms-phone, such as a nitrogen atmosphere.
A starting material of the formula Via can be obtained, for example, by treating a 4-~2-~R-carbonyl-amino)-ethyll-benzenesulphonyl chloride with aziridine and reacting the resulting N- ~-r2~(R-carbonylamino)-ethyll-phenylsulphonyl~ aziridine with a N-Ya-cyclo-hexylamine.
It is also possible (cub) to react a compound of the formula Of H2C SHEA
R-C-N-CH2-CE2-~ S02 I b (VIb3 in which Pa represents hydrogen and Ye represents a -reactive esterified hydroxy group, or in which Pa and Ye together form a bond, with N-cyclohexyl-cyanamide or a derivative thereof, in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
A reactive esterified hydroxy group Ye is hydroxy esterified by a strong inorganic or organic acid, such as a hydraulic acid, for example hydrochloric acid or hydrobromic acid, or an organic sulphonic acid, such as ~-toluenesulphonic acid or methanesulphonic acid.
A derivative of N-cyclohexyl-cyanamide is especially a metal derivative, such as an alkali metal, for example lithium, sodium or potassium, derivative, or an alkaline earth metal, for example calcium, derivative. Such a derivative is used especially in the reaction with a starting material of the formula Jib in which Pa and Ye together form a bond.
The reaction can be carried out in a manner known per so and, when using starting materials of the formula Vim in which Pa represents hydrogen and Ye represents a reactive esterified hydroxy group, pro-fireball in the presence of acid-binding agents, such as inorganic or organic bases, for example alkali metal or alkaline earth metal hydroxides, such as sodium or potassium hydroxide. If necessary or desired, the reaction is carried out in the presence of a solvent, such as an ether, for example deathly ether, twitter-hydrofuran, dioxin, anisole or ethylene glycol dim ethyl ether, or a lower alkanol, for example buttonhole, a carboxylic acid aside, such as dimethylformamide, or a sulphoxide, such as dim ethyl sulphoxide, while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formula Vim can be obtained, for example, if a 4-~2~ carbonylamino)-ethyl~-benzenesulphonyl chloride is reacted with 3L7~
aziridine or with an acid addition salt of a 2-Yb-ethyl amine in which Ye represents a reactive esterifi~d hydroxy group, preferably in the presence of a base, such as an alkali metal, for example sodium or poles-slum, hydroxide.
It is also possible (cc) to react a compound of the formula o R--C-~-CH2-CH2--</ I- S02 NH2 (Vim) with a reactive esterified N-cyclohexyl-N-(2-hydroxy-ethyl cyanamide or a derivative thereof, in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
In a reactive ester of N-(2-hydroxyethyl)-cyanamide, the hydroxy group is esterified by a strong inorganic or organic acid, such as a hydraulic acid, for example hydrochloric acid or hydrobromic acid, or an organic sulphonic acid, such as ~-toluenesulphonic acid or methanesulphonic acid.
A derivative of the cyanamide starting material is, for example, an acid addition salt, for example with a mineral acid, such as a hydraulic acid, for example hydrochloric acid.
The reaction is carried out in a manner known so, advantageously in the presence of an acid-binding agent, such as an inorganic base for example an alkali metal hydroxide, bicarbonate, carbonate or phosphate, such as sodium or potassium hydroxide, bicarbonate, carbonate or phosphate, or also an organic base, such as a tertiary amine, for example NUN-diisopropylethylamine~ If necessary or desired, the reaction is carried out in the presence of a suitable solvent, optionally in the presence of water, such as a lower alkanol, for example buttonhole, an ether, for example dioxin or diethylene glycol monomethyl ether, a carboxylic acid aside, for example ~,N-dimethyl-formamide, or a sulphoxide, for example dim ethyl sulphoxide, while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formula Vim can be obtained in a manner known per so, for example by aminolysis of a 4-[2-(R-carbonylamino)-ethyll-benzene-sulphonyl chloride or by treating l-cyclohexylaziri-dine with a reactive derivative of cynic acid, such as a cyanogen halide, for example cyanogen bromide.
A further process variant consists in cud cyclising an addition salt compound of the formula YC-CH~-CH2 R-CO-N~CH2-CH2-o~ /. S02 I H _ /
CM
(Void) in which Ye represents a reactive esterified hydroxy group: in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
A reactive esterified hydroxy group Ye is espy-Shelley halogen, especially bromide, and also chlorine, I
but may also be an organic sulphonyloxy group, such as methylsulphonyloxy or 4-methylphenylsulphonyloxy.
The reaction is carried out in a manner known per so, preferably while heating and, if necessary or desired, in the presence of a solvent, especially one of high boiling point, such as an ether, for example diethylene glycol dim ethyl ether, or a carboxylic acid aside, for example N,N-dimethylformamide, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
The starting material of the formula Void can be obtained, for example, if a 4-~2-(R-carbonylamino)-ethyl1-benzenesulphonyl chloride is reacted, for example by being treated with disodium cyanamide in water, to form a sodium derivative of the correspond-in N-cyanobenzenesulphonamide and this is treated with a N~(2-Yc-ethyl)-cyclohexylamine.
The novel compounds of the formula I can also be obtained if (d) a compound of the formula o Ha OH
Ro-c-~-cH2-cH2--~ SNOW / N _ o/
(VII) in which R represents a radical of the formula R1 lo CHUM Ida I
I
in which R1 represents a 1-lower alkenyl radical, or a derivative thereof is isomerised and, if desired, the additional process steps are carried out.
A derivative of a compound of the formula VII is especially an acid addition salt, such as a salt with a mineral acid, such as a hydraulic acid The isomerisation reaction usually occurs spun-tonsil, that is to say in situ in connection with the manufacture of the starting materials of the formula VII, if necessary or desired while heating and in the presence of a suitable solvent, in a closed vessel and/or in an inert gas atmosphere, or example a nitrogen atmosphere.
The starting materials can be obtained in a manner known per so, for example by treating a compound of the formula II with an acid of the formula R-C~=O~-OH (VIII) or a suitable derivative, for example an android, such as a halide, for example the chloride, thereof, if necessary in the presence of a condensation agent or an acid-binding agent. As mentioned above, the starting material of the formula VII may isomerism spontaneously to a compound of the formula I.
Salts that asp obtainable in accordance with the process can be converted in a manner known so, for example by treatment with a suitable base, into the free compounds, or, for example by salt-exchange with a suitable salt, into a different salt.
Free compounds of the formula I that are obtain-able according to the invention may, if desired, be converted into their acid addition salts, for example by reaction with an acid in a suitable solvent Mixtures of isomers that are obtainable according to the invention can be separated into the individual isomers in a manner known per so, for example by means ox physico-chemical separating methods, with preferably the more active isomer being isolated.
~2Z~7~%
The invention relates also to those forms ox the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a derivative, for example a salt, and/or in the form of an isomer or mixture of isomers, or, as demonstrated above, is wormed under the reaction conditions.
In the process of the present invention, the starting materials used are preferably those which result in the compounds mentioned at the beginning as being especially valuable. The present invention relates also to novel starting materials and to pro-cusses for the manufacture thereof.
The compounds of the present invention have pharmacological and especially, pronounced blood sugar-reducing, properties which can be demonstrated both in normal and in diabetic experimental animals.
The blood sugar-reducing action in normal experimental animals is determined in normal female rats (Tip: RAIN (SPY)? weighing from 170 to 200 g whose food was withdrawn 6.5 hours before the beginning of the test. After taxing a first blood sample (starting value), the test preparation is administered orally (by means of a pharyngeal probe) in the Norm of a suspension in a 0.5 % aqueous solution of methyl-cellulose and in a volume of 5 ml/kg body weight.
Further samples of blood are taken after 2, 4.5 and 7.5 hours, at least 5 experimental animals being used per dose, The blood sample is taken retro-orbitally (Riley, Proc~Soc.Exptl. Blot. Med., vol. 104, page 751 (1960)) under light anesthetic (oxygen/carbon dioxide 1:1, 45 seconds, Green, Animal Handbooks 8, London Laboratory Animals Ltd., page 154 (1979)).
The blood sugar is determined according to the envy-matte GOD method (Werner et aloe Z. anal. Chum., -~223L~
vol. 252, page 224 (1970)) on an autoanalyser.
In this test procedure, the compounds of the present invention exhibit the following blood sugar-reducing actions:
_ _ . .
compound maximum blood sugar reduction (as % of the (Example) starting value) in the doses indicated (in mg/kg pro.) ._ _ . _ .. _. .,. _ _ _.
l 80 76 41 17 4 MU _ The blood sugar-reducing action in diabetic experimental animals is determined in streptozotocin-diabetic rats, the streptozotocin-diabetes being induced by a single injection of streptozotocin (55 mg/kg) into the causal vein in male rats (Tip:
RAIN (SPY)) weighing from 140 to 200 g whose food is withdrawn 16 to 24 hours before the beginning of the test. Experimental animals having blood sugar values of between 300 and 700 moper cent (approximately 17 to 39 milliliter) are used for the tests 3 to 4 weeks, at the earliest, after this treatment.
The blood sugar is determined 3 to 6 hours after the oral administration of the test preparation (see above for normal rats) to animals that have been fed.
Since the blood sugar in diabetic rats, in contrast to normal rats, decreases as a rule by 5 Tao % during the Lo test period, the spontaneous blood sugar reduction (as % of the starting value) of a simultaneously investigated control group is deducted from the blood sugar reduction of the test group. At least 5 animals per group are used.
In this test procedure, the compound of Example 1, for example, exhibits, at a dosage of 100 mg/kg, a maximum blood sugar reduction (as % of the starting value) of 29 % and, at a dosage of 30 mg/kg, one of 10 %.
In addition, the compounds of the present invention have a low toxicity in comparison with the strong anti-diabetic actions. Thus, for example, the LD50 dose for the compound of example 1 is 600 gig pro. (rat).
The compounds of the present invention can there-fore be used for reducing the blood sugar level in diabetes, being suitable, by virtue of the rapid onset of action and the remarkably short duration of action (the maximum action is achieved, for example at a dosage of 2 mug of the compound of Example 1, after 1 hour and the action can no longer be detected after 5 hours), especially for the periprandial treat-mint of diabetes of old age.
The invention relates also to the use of the compounds of the formula I or of pharmaceutically acceptable salts of such compounds having salt-form-in properties, especially as pharmacologically active, particularly as flood sugar-reducing, compounds.
They can be used, preferably in the form ox forum-ceutical preparations, in a method for the trophy-lactic and/or therapeutic treatment of the animal or human body, especially for the treatment of diabetes.
The dosage of the active ingredient which is ad minis-toned on its own or together with the customary carrier and adjunct depend on the species to be treated, the age and individual condition thereof and also on the mode of administration. The daily dosages for mammals weighing approximately 70 kg is, depending on the type of diabetes, individual condition and age, preferably approximately from 50 to 500 my.
The invention relates further to pharmaceutical preparations containing as active ingredients compounds of the formula I or pharmaceutically acceptable salts thereof, and to processes for the manufacture thereof.
The pharmaceutlc~l preparations according to the invention are for entirely, such as per oral or rectal, and for sublingual administration and also for parenteral administration to warm-blooded animals.
Corresponding unit dosage forms, especially for per oral and/or sublingual administration, for example drapes tablet or capsules, contain preferably from approxi-mutely 50 to approximately 250 my, especially from approximately 50 to approximately 150 my, of a come pound of the formula I or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers.
Suitable carriers are especially fillers, such as sugars, for example lactose, succors, minutely or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth or methyl-cellulose, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinylpyrrolidone, ajar, alginic acid or a salt thereof, such as sodium align-ate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, Starkey acid or salts thereof, such as magnesium or calcium Stewart, and/or polyethylene glycol.
Drug cores can be provided with suitable coatings that may be resistant to gastric juice, there being used, inter alias concentrated sugar solutions which may contain gum Arabic talc, polyvinylpyrroli-done, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings that are resistant to gastric juice, solutions of suitable cellulose preparations, such as acutely-cellulose phthalate or hydroxypropylmethylcellulose phthalate.
Dyes or pigments can be added to the tablets or drug coatings, for example for identification pun-poses or to indicate different doses of active inure-dint.
Other orally administrable pharmaceutical pro-portions are dry-filled capsules made from gelatin, and also soft, sealed capsules made from gelatin and a plasticizer, such as glycerine or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium Stewart and, optionally, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as oils, paraffin oil or liquid polyethylene glycols, it being possible also to add stabilizers.
As rectally administrable pharmaceutical pro-portions there come into consideration, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or sync Thetis triglycerides, paraffin hydrocarbons, polyp ethylene glycols or higher alkanols. Gelatin rectal capsules which contain a combination of the active ingredient with a base may also be used, as bases I
there come into consideration, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons Especially suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble Norm, for example solutions of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, with suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl owlet, or trimly derides being used, or aqueous injection suspensions containing substances that increase the viscosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilizers.
The pharmaceutical preparations of the present invention can be produced in a manner known per so, for example by means of conventional mixing, granulate in, confectioning, dissolving or lyophilising pro-cusses. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture and, if desired or necessary after the addition of suitable adjuncts, processing the mixture or granulate to form tablets or drug cores.
The following Examples illustrate the invention described above without limiting the scope thereof in any way. Temperatures are given in degrees Centigrade.
51 ml of triethylamine and 34 ml of chloroformic acid ethyl ester are added drops in succession, at -10, to a solution of 30 g of crotonic acid in 1500 ml of ethylene chloride. After 20 minutes, there is added at this temperature a suspension of 153 g of 1-~4-(2-aminoethyl)-phenylsulphonyl~-2-imino-3-cyclohexyllmidazolidine dihydxochloride in 1500 ml of ethylene chloride and, at 0, a solution of 107 ml of triethylamine in 500 ml of ethylene chloride is added drops The whole is stirred for a further 3 hours at 0 and for 12 hours at room -temperature, the solution becoming clear. It is washed in succession with 500 ml each of water, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. The resulting 1-~4-~2-(crotonylamino)-ethyl1-phenylsulphonyl~-3--cyclohexyl-2-imino-~dazolidine (trays) is recrystallized from ethyl acetate and melts at 157 to 158.
Example:
A solution of 1.5 g of crotonic acid android in 5 ml of absolute dioxin is added drops at 0 to a solution of 3.5 g of 1-~4-(2-aminoethyl)-phenylsul-phonyll-2-imino-3-cyclohexylimidazolidine in 100 ml ox absolute dioxin, After stirring for 12 hours at room temperature, the dioxin is distilled off, the residue is dissolved in 300 ml of ethylene chloride, and the solution is washed in succession with 50 ml each of water, 0.5N aqueous sodium hydroxide and water. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. There is thus obtained I 2-(crotonylamino)-ethyl~-phenylsulphonyl~-3-cyclohexZulu-2-iminc-Dmidazolidine trueness) which, when recrystallized from ethyl acetate melts at 157 to 158~, Example 3:
2.7 g of triethylamine, 2.7 g of chloroformic acid I
ethyl ester and a solution of 7.4 g of Amman-ethyl)-phenylsulphonyll-2-imino-3-cyclohexylimida--zolidine in 100 ml of ethylene chloride are added in succession, at -10, to a solution of 2.2 g of vinyl-acetic acid. After stirring for 3 hours at 0, the reaction mixture is left to stand overnight and is then washed in succession with water, saturated aqueous sodium bicarbonate solution and water. After recrystallization from ethyl acetate, cry-tonylamino)-ethyl1-phenylsulphonyl~ 3-cyclohexyl-2-imino-imidazolidine (trays), mop. 157 to 158, is obtained.
Example 4:
20.4 g of 1-cyclohexyl-2-imino-~midazolidine hydrochloride are added to 8.5 g of sodium hydroxide in 85 ml of water. There is added to the resulting solution 28.8 g of 4-(2-crotonylaminoethyl)-benzene-sulphonyl chloride dissolved in 100 ml of acetone, the reaction mixture becoming warm. It is heated at 90 for half an hour and then concentrated by evapora-lion under reduced pressure. The residue is wrecker-stylized from ethyl acetate, and 1-~4~2-(crotonyl-amino~-ethyl1-phenylsulphonyl~-3-cyclohexyl-2-iminno-imidazolidine (trays) which melts at 157 to 158 is obtained.
The starting material can be manufactured as follows:
18.9 g of N-(2-phenethyl)-crotonic acid aside are added in portions, while stirring, to vow g of sheller-sulphonic acid. The mixture is then stirred for 3 hours at 60, whereupon it is poured onto ice. The crystals are filtered with suction, washed with water and dried under reduced pressure. The resulting _.
4-(2-crotonylaminoethyl)-benzenesulphonyl chloride is further processed in the form of the crude product.
Example S
A mixture of 28 ml of ON aqueous sodium hydroxide solution and 4.3 g of ethyleneimine is cooled to -10.
A suspension of OWE g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride in 100 ml of acetone is then added while stirring and cooling, so that the tempera-lure does not exceed 0. When the drops addition is complete, stirring is continued for 30 minutes at 0. The cooling bath is then removed and there is added to the solution of the resulting 1-[4-(2-crotonylaminoethyl)-phenylsulphonyl~-aziridine 100 ml of cyclohexylamine. The temperature increases to 40 -50. The reaction mixture is stirred for a further hour and the excess amine is then distilled off in a rotary evaporator. The resulting crystal mass which contains, in addition to sodium chloride, the desired 1-~4-(2-crotonylaminoethyl)-phenylsulphonyl1-2 hexylethylenediamine is dissolved in 56 ml of ON
aqueous sodium hydroxide, and 10.6 g of cyano~en Ramada are added thereto in portions while stirring, the temperature not being allowed to exceed 40.
After one hour, extraction is carried out with methyl tone chloride, and the organic solution is washed with 20 ml of ON aqueous sodium hydroxide and twice with 100 ml of water. after drying the ethylene chloride solution and concentrating it by evaporation under reduced pressure, the residue is recrystallized from ethyl acetate and yields 1-~4-~2-(crotonylamino~-ethyll-phenylsulphonyl~-3-cyclohexyl-2-imino-imidaa-zolidine (trays) of melting point 157 to 158.
__ ~L~2~7~%
A solution of 19.8 g of cyclohexylamine in 400 ml of absolute deathly ether is added drops at -5 to a solution of 10.6 g of Swenson bromide in 100 ml of absolute deathly ether. When the addition is complete, the whole is stirred for 30 minutes, the cyclohexyl-nine hydrobromida which has precipitated is filtered of and, at -5 with the exclusion of moisture, 503 g of a 50 % suspan~ion ox Swede hydrlde in mineral oil are introduced in portions into the filtrate. When the addition it complete, the mixture is stirred for a further 30 minutes at -5 and the temperature it then allowed to increase to 20 . There is then added drop-wise to the resulting suspension of sodium cyclohexyl-cyanamide, in the course of 15 minutes, a solution of 33.1 g of N-(2-chloroethyl)-4~(2 crotonylaminoethyl)-benzene~ulphonamide in 100 ml of iota and the resulting suspension is stirred for 15 hours at room temperature and then reflexed for 5 hours. After cooling to room temperature, 100 ml of water are added thereto and the whole is concentrated to dryness by evaporation under reduced pressure. The residue is partitioned between water and chloroform, the insoluble portion is filtered off, and the two phases are spear-axed. The chloroform phase is extracted with ON
hydrochloric acid, and 9 while cooling, the aqueous-acidic extract it rendered alkaline with concentrated aqueous sodium hydroxide and extracted with ethylene chloride. The ethylene chloride extract it dried with sodium ~ulphate and the ethylene chloride it distilled off ale residue it recrystallized from ethyl acetate and yields I 2--(crotonyl~nino)~ethyl~-phanyl-sulphonyl~-3--cyc.l.ohexyl 2-~nino~imidazolidine (trays which melt at 157 to 158.
I
Example 7:
A solution of 28.8 g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride in 100 ml of acetone is added drops to a solution ox 8~0 g of sodium hydroxide and 4.3 g of ethyleneimine in 60 ml of water, the temperature of the mixture king maintained between 0 and ~10 by cooling When the addition is complete, stirring is carried out for one hour at room temperature and then the acetone is evaporated off under reduced pressure. Crude ~-C4-(2-crotonylaminoethyl)-phenyl-sulphonyl]~ethyleneimine separates from the remaining aqueous solution in the fox of an oil. It is extracted with ethylene chloride) the extract is dried with sodium sulfite and the ethylene chloride is evapora-ted off under reduced pressure 4-(2-crotonyl-aminoethyl)-phenylsulphonyl]-ethyleneimine remains behind as a crystalline residue A solution of 10.6 g of cyanogen bromide in 100 ml of absolute deathly ether is added drops, while stirring at -5, to a solution of 19.8 g of cycle-hexylamine in 400 ml of absolute deathly ether. After 30 minutes, the cyclohexylamine hydrobromide whir has precipitated is filtered off, and 503 g o a sodium hydride-mineral oil suspension (50 % strength) are added in portions, at I to the filtrate. Stirring is continued for a further 30 minutes at -5 and the temperature is then allowed to increase to approxi-mutely 20 . Into the resulting, white suspension of sodium cyclohexyl-cyanamide there is then introduced, while stirring, a solution of the N-~4-(2-crotonyl-aminoethyl)-phenyl~ulphonyl] ethyleneimine prepared according to the above process, in 150 ml of Dixon The resulting suspension is stirred for 15 hours at room temperature and then reflexed for 5 hour.
After cooling to room temperature, So ml of water are added drops thereto and the whole is concentrated to ~2~L7~3~
dryness by evaporation under reduced pressure. The residue is partitioned between chloroform and concern-treated aqueous sodium hydroxide. The chloroform phase is decanted from the insoluble resins, extracted with ON hydrochloric acid, and the extract is rendered alkaline with concentrated aqueous sodium hydroxide and extracted with ethylene chloride. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. The 1-~4-~2-(crotonylamino)-ethyll-phenyl-sulphonyl~-3-cyclohexyl-2-imino-lmidazolidine (trays) which remains is recrystallized from ethyl acetate and melts at 157 to 158.
Example 8:
26.8 g of 4-(2-crotonylaminoethyl)-benzenesul-phonamide and 18.7 g of N-(2-chloroethyl)-N-cyclo-hexyl-cyanamide are added to a mixture of 4 g of sodium hydroxide, 15 ml of water and 300 ml of dip methyl sulphoxide. The resulting solution is heated for 1 hour at a bath temperature of 110. The dip methyl sulphoxide is distilled off under reduced pressure and the residue, a brown oil, is taken up in ethylene chloride. The organic phase is washed three times with water, dried and filtered and yields, after concentration by evaporation under reduced pressure, a brown crystalline residue. After no-crystallization from ethyl acetate, 1-~4-~2-(crotonyl-amino)-ethyll-phenylsulphonyl~-3-cyclohexyl-2-iminno-imidazolidine (trays) of melting point 157 to 158 is obtained.
Example 9:
To a solution of 9.0 g of disodium cyanamide in 50 ml of water there are added, first of all, 15 ml of Lo acetone and then, in portions, in the course of 15 minutes, 29.8 g of 4 (2-crotonylaminoethyl)-benzene-sulphonyl chloride. Thereupon, 19.8 g of sheller-ethylcyclohexylamine hydrochloride are added and the whole is concentrated to dryness by evaporation. The paste like residue is extracted with a mixture of 150 ml of ethanol and 150 ml of isopropanol. The extract is concentrated to dryness by evaporation under reduced pressure, the residue is taken up in 200 ml of acetone, the solution is filtered and the filtrate is again concentrated by evaporation. The remaining, clear, yellow oil is heated for lo hours at 1~5. The vitreous residue which is left behind after cooling is taken up in water and acidified with ON hydrochloric acid, and the solution is washed with chloroform. The aqueous phase is then rendered alkaline with concern-treated aqueous sodium hydroxide while cooling, during which an oil separates which is taken up in ethylene chloride. The resulting ethylene chloride solution is washed with water, dried over sodium sulfite and then concentrated to dryness by evaporation under reduced pressure. Upon subsequently chromatographing the residue over silica gel there is eluded with sheller-form containing 2.5 % methanol 1-~-~2-(crotonylamino)-ethyll-phenylsulphonyl~-3-cyclohexyl-2-imino-1mldaazalea-dine (trays) which crystallizes after evaporating the solvent and, after being recrystallized from ethyl acetate, melts at 157 to 158.
Example 10:
2 g of isocrotonic acid are dissolved in lo ml of ethylene chloride. At -10, 3.4 ml of triethyl-amine, I ml of chloroformic acid ethyl ester and, after 20 minutes, a solution of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyll-2 imino-3-cyclohexyl-~2~7~2 imidazolidine in 100 ml of ethylene chloride are added drops. The reaction mixture is left for 3 hours at 0 and for 12 hours at room temperature, then diluted with ethylene chloride and washed in succession with water, a saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfite, filtered and concentrated by evaporation under reduced pressure. The oil which remain is crystallized with petroleum ether and the resulting
(I) in which R represents the radical of the formula ~`~
R1 \ 13 COCK (It) in which R1 represents lower alkyd and each of R2 and R3, independently of the other, repro-sinks hydrogen or lower alkyd, and salts of such compounds Lower alkyd has preferably up to and including 3 carbon atoms, lower alkyd groups I and R3 representing especially methyl, whilst R1 may represent, for example, methyl, ethyl, n-propyl or isopropyl.
With regard to R1 and the carbonyl group, the compounds of the formula I may have the Swiss but preferably have the trans-configuration.
The novel compounds may be in the form of acid addition salts, especially in the form of foremost-gaily acceptable, non-toxic acid addition salts.
Suitable salts are, for example, those with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic caxboxylic or sulphonic acids, for example formic acid, acetic acid, prop ionic acid, succinic acid, glycolic acid, lactic acid, mafia acid, tartaric acid, citric acid, malefic acid, hydroxymaleic acid, pyruvic acid, fumaric acid, benzoic acid, 4-amino-benzoic acid, anthranilic acid, ~-hydroxybenzoic acid, salicylic acid, ~mbonic acid, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, ''' ~Z~7~2 ethylenesulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid, or with other acidic organic compounds, such as ascorbic acid.
The present invention relates especially to compounds of the formula I in which R represents the radical of the formula Ian and R1 represents alkyd having up to and including 3 carbon atoms, R2 repro-sets preferably hydrogen, and also methyl, and R3 represents hydrogen or methyl, it being possible for these compounds to have the Claus- off preferably the trans-configuration with regard to the radical Al and the carbonyl group, and especially to 3-cyclohexyl-2-imino-1-~4-~2-(crotonylamino)-ethyll-phenylsulphonNoel-imidazolidine (trays), and salts, especially forum-ceutically acceptable salts thereof The novel compounds of the present invention can be obtained in a manner known so, for example (a) by reacting a compound of the formula H C - I
H INCH -OH SO -N N \.
2 2 2 \ _ / 2 \ C / \
NH
IT
or a derivative thereof with an acid of the formula R-C(=O)-OH (III) or a reactive derivative, and, if desired, converting a salt obtainable according to the invention into the free compound or into a different salt, and/or converting a free compound obtainable according to the invention into a salt and/or, it desired, separating a mixture of isomers into the individual isomers.
I
A derivative of the starting material of the formula II may be, or example, a sill derivative, such as a troweler alkylsilyl, such as -trim ethyl-sill, derivative, and also an acid addition salt, such as a salt with one of the acids mentioned herein before A reactive derivative of an acid of thy formula III is especially an android, including an assume-metric android, such as, inter alias an android with a strong inorganic acid, such as a hydraulic acid, especially the corresponding acid chloride, or with a carbonic acid semester, such as a carbonic acid lower alkyd semester, for example carbonic acid isopropyl semester, or an internal android, that is to say the corresponding kitten compound. Suitable reactive acid derivatives are also esters, such as a lower alkyd ester, for example methyl or ethyl ester, and especially, however, activated esters of acids of the formula III, such as suitably substituted phenol esters, for example 4-nitrophenyl ester or pentachlorophenyl ester, or suitably substituted methyl esters, for example cyanomethyl ester.
The reaction can be carried out in a manner known so, if necessary in the presence of a condensation agent, for example a carbodiimide, such as Dow-cyclohexyl-carbodiimide, these being employed espy-Shelley when a free acid of the formula III is used, or an acid-binding agent, such as, for example, an inorganic base or salt, such as an alkali metal hydroxide, alkali metal bicarbonate, alkali metal carbonate or alkali metal phosphate, such as the corresponding sodium or potassium compound. It is also possible to use an organic base, for example pardon, trimethylamine, triethylamine, N,N-di-isopropylethylamine or colliding, which, when added in excess, can be used at the same time also as Lo solvent. The reaction is usually carried out in the presence of a solvent, preferably an inert organic solvent which may or may not be miscible with water, in the presence or absence of water. Suitable inert organic solvents are, for example, hydrocarbons, such as Bunsen, Tulane or zillion, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydra-carbons, such as ethylene chloride, or lower kittens, such as acetone or methyl ethyl kitten. The reaction may, if necessary, be carried out while cooling or heating, under elevated pressure and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formulae II and III
are known, those of the formula II can be obtained for example, by treating an acid addition salt, such as the hydrochloride of 4-(2-aminoalkyl)-phenylsul-phonamide, with ~-(2-chloroethyl)-N-cyclohexyl-cyan-aside in the presence of an alkali metal hydroxide, for example potassium hydroxide.
The novel compounds of the formula I can also be obtained if (b) a reactive derivative of a sulphonic acid of the formula o If H . _ .
2 SHEA . /. S03H (IV) . _ --is reacted with a compound of the formula H-N N V) I \._ NH
or a derivative thereof, and, if desired, the add-tonal process steps are carried out.
Reactive derivatives of sulphonic acids of the formula IV are especially the androids thereof, especially mixed androids with strong acids, such as hairlike acids, especially the corresponding chlorides, and also the corresponding symmetric an-hydrides.
A derivative of a compound of the formula V may be, for example, a sill derivative, such as a in-lower alkylsilyl, such as trimethylsilyl, derivative, and also an acid addition salt, such as a salt with one of the acids mentioned herein before.
The reaction can be carried out in a manner known per so, if necessary in the presence of an acid-bind-in agent, such as, for example, an inorganic base or salt, such as an alkali metal hydroxide, alkali metal bicarbonate, alkali metal carbonate or alkali metal phosphate, such as the corresponding sodium or poles-slum compound. It is also possible to use an organic base, for example pardon, trimethylamine, triethyl-amine, N,~-diisopropylethylamine or colliding, which, when added in excess, can be used at the same time also as solvent. The reaction is usually carried out in the presence of a solvent, preferably an inert organic solvent which may or may not be miscible with water, in the absence or presence of water. Suitable inert organic solvents are, for example, hydrocarbons, Lo such as Bunsen, Tulane or zillion, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydrocarbons, such as ethylene chloride, or lower kittens, such as acetone or methyl ethyl kitten. The reaction may, if necessary, be carried out while cool-in or heating, under elevated pressure and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials are known or can be menu-lectured in a manner known per so, it being possible to obtain, for example, halides of acid compounds of the formula IV, for example by treating a NO
2-phenylethylamine with a halosulphonic acid, especially chlorosulphonic acid.
The novel compounds of the formula I can also be obtained by (c) cyclising a compound of the formula R-C~N-CH2-CH2-~ ox I N-./ /. (VI) X Y
in which one of the radicals X and Y represents cyan and the other represents hydrogen, and, if desired, carrying out the additional process steps.
The cyclisation mentioned above can be carried out under reaction conditions that are known per sex In so doing, the starting material of the formula VI is usually formed in situ and, without being isolated, is converted directly into a compound of the formula I.
Thus, for example (cay) a compound of the formula ~2C--CH2 Ho SHEA -SNOW / \ (Via in which Ye represents hydrogen or a radical that can be removed under the reaction conditions can be reacted with a reactive derivative of cynic acid, in this manner, it is possible to obtain a compound of the formula I directly without isolating an inter-mediate of the formula VI.
In a starting material of the formula Via for example a radical that can be removed undoer the reaction conditions, that is to say upon reaction with the cynic acid derivative, is a methyl group which is : optionally moo-, dip or tri-substituted, for example by an aureole group, such as phenol optionally substituted, for example, by lower alkyd, such as methyl, lower alkoxy, such as methoxy, or halogen, such as chlorine, or a methyl group which is optionally substituted by lower alkenyl, such as vinyl, that is unsaturated at the linking carbon atom.
A reactive derivative of cynic acid is, for example, a halide, such as cyanogen chloride or cyanogen bromide, or an ester, such as a lower alkyd ester or, especially a phenol ester thereof The reaction can be carried out in a manner known En so, if necessary in the presence of an acid-bind-in agent, such as an inorganic base, for example an alkali metal hydroxide, bicarbonate, carbonate or phosphate, such as the corresponding sodium or potassium compound. Calcium carbonate, and also - ' ~L~V~3L7~
g calcium phosphate or magnesium carbonate may also be used.
The reaction is effecter in the absence, but preferably in the presence, of an inert, usually organic solvent, if desired in the presence of water.
Suitable solvents are, for example, hydrocarbons, such as Bunsen, Tulane or zillion, lower alkanols, such as methanol or ethanol, ethers, such as deathly ether, dioxin or tetrahydrofuran, halogenated hydra-carbons, such as ethylene chloride, lower kittens, such as acetone or methyl ethyl kitten, carboxylic acid esters, such as ethyl acetate, carboxylic acid nitrites, such as acetonitrile, or sulphones, such as tetrahydrothiophene 1,1-dioxide. The reaction is carried out, if necessary, while cooling or heating, under elevated pressure and/or in an inert gas atoms-phone, such as a nitrogen atmosphere.
A starting material of the formula Via can be obtained, for example, by treating a 4-~2-~R-carbonyl-amino)-ethyll-benzenesulphonyl chloride with aziridine and reacting the resulting N- ~-r2~(R-carbonylamino)-ethyll-phenylsulphonyl~ aziridine with a N-Ya-cyclo-hexylamine.
It is also possible (cub) to react a compound of the formula Of H2C SHEA
R-C-N-CH2-CE2-~ S02 I b (VIb3 in which Pa represents hydrogen and Ye represents a -reactive esterified hydroxy group, or in which Pa and Ye together form a bond, with N-cyclohexyl-cyanamide or a derivative thereof, in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
A reactive esterified hydroxy group Ye is hydroxy esterified by a strong inorganic or organic acid, such as a hydraulic acid, for example hydrochloric acid or hydrobromic acid, or an organic sulphonic acid, such as ~-toluenesulphonic acid or methanesulphonic acid.
A derivative of N-cyclohexyl-cyanamide is especially a metal derivative, such as an alkali metal, for example lithium, sodium or potassium, derivative, or an alkaline earth metal, for example calcium, derivative. Such a derivative is used especially in the reaction with a starting material of the formula Jib in which Pa and Ye together form a bond.
The reaction can be carried out in a manner known per so and, when using starting materials of the formula Vim in which Pa represents hydrogen and Ye represents a reactive esterified hydroxy group, pro-fireball in the presence of acid-binding agents, such as inorganic or organic bases, for example alkali metal or alkaline earth metal hydroxides, such as sodium or potassium hydroxide. If necessary or desired, the reaction is carried out in the presence of a solvent, such as an ether, for example deathly ether, twitter-hydrofuran, dioxin, anisole or ethylene glycol dim ethyl ether, or a lower alkanol, for example buttonhole, a carboxylic acid aside, such as dimethylformamide, or a sulphoxide, such as dim ethyl sulphoxide, while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formula Vim can be obtained, for example, if a 4-~2~ carbonylamino)-ethyl~-benzenesulphonyl chloride is reacted with 3L7~
aziridine or with an acid addition salt of a 2-Yb-ethyl amine in which Ye represents a reactive esterifi~d hydroxy group, preferably in the presence of a base, such as an alkali metal, for example sodium or poles-slum, hydroxide.
It is also possible (cc) to react a compound of the formula o R--C-~-CH2-CH2--</ I- S02 NH2 (Vim) with a reactive esterified N-cyclohexyl-N-(2-hydroxy-ethyl cyanamide or a derivative thereof, in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
In a reactive ester of N-(2-hydroxyethyl)-cyanamide, the hydroxy group is esterified by a strong inorganic or organic acid, such as a hydraulic acid, for example hydrochloric acid or hydrobromic acid, or an organic sulphonic acid, such as ~-toluenesulphonic acid or methanesulphonic acid.
A derivative of the cyanamide starting material is, for example, an acid addition salt, for example with a mineral acid, such as a hydraulic acid, for example hydrochloric acid.
The reaction is carried out in a manner known so, advantageously in the presence of an acid-binding agent, such as an inorganic base for example an alkali metal hydroxide, bicarbonate, carbonate or phosphate, such as sodium or potassium hydroxide, bicarbonate, carbonate or phosphate, or also an organic base, such as a tertiary amine, for example NUN-diisopropylethylamine~ If necessary or desired, the reaction is carried out in the presence of a suitable solvent, optionally in the presence of water, such as a lower alkanol, for example buttonhole, an ether, for example dioxin or diethylene glycol monomethyl ether, a carboxylic acid aside, for example ~,N-dimethyl-formamide, or a sulphoxide, for example dim ethyl sulphoxide, while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, such as a nitrogen atmosphere.
The starting materials of the formula Vim can be obtained in a manner known per so, for example by aminolysis of a 4-[2-(R-carbonylamino)-ethyll-benzene-sulphonyl chloride or by treating l-cyclohexylaziri-dine with a reactive derivative of cynic acid, such as a cyanogen halide, for example cyanogen bromide.
A further process variant consists in cud cyclising an addition salt compound of the formula YC-CH~-CH2 R-CO-N~CH2-CH2-o~ /. S02 I H _ /
CM
(Void) in which Ye represents a reactive esterified hydroxy group: in this manner, compounds of the formula I can be obtained directly without isolating an intermediate of the formula VI.
A reactive esterified hydroxy group Ye is espy-Shelley halogen, especially bromide, and also chlorine, I
but may also be an organic sulphonyloxy group, such as methylsulphonyloxy or 4-methylphenylsulphonyloxy.
The reaction is carried out in a manner known per so, preferably while heating and, if necessary or desired, in the presence of a solvent, especially one of high boiling point, such as an ether, for example diethylene glycol dim ethyl ether, or a carboxylic acid aside, for example N,N-dimethylformamide, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
The starting material of the formula Void can be obtained, for example, if a 4-~2-(R-carbonylamino)-ethyl1-benzenesulphonyl chloride is reacted, for example by being treated with disodium cyanamide in water, to form a sodium derivative of the correspond-in N-cyanobenzenesulphonamide and this is treated with a N~(2-Yc-ethyl)-cyclohexylamine.
The novel compounds of the formula I can also be obtained if (d) a compound of the formula o Ha OH
Ro-c-~-cH2-cH2--~ SNOW / N _ o/
(VII) in which R represents a radical of the formula R1 lo CHUM Ida I
I
in which R1 represents a 1-lower alkenyl radical, or a derivative thereof is isomerised and, if desired, the additional process steps are carried out.
A derivative of a compound of the formula VII is especially an acid addition salt, such as a salt with a mineral acid, such as a hydraulic acid The isomerisation reaction usually occurs spun-tonsil, that is to say in situ in connection with the manufacture of the starting materials of the formula VII, if necessary or desired while heating and in the presence of a suitable solvent, in a closed vessel and/or in an inert gas atmosphere, or example a nitrogen atmosphere.
The starting materials can be obtained in a manner known per so, for example by treating a compound of the formula II with an acid of the formula R-C~=O~-OH (VIII) or a suitable derivative, for example an android, such as a halide, for example the chloride, thereof, if necessary in the presence of a condensation agent or an acid-binding agent. As mentioned above, the starting material of the formula VII may isomerism spontaneously to a compound of the formula I.
Salts that asp obtainable in accordance with the process can be converted in a manner known so, for example by treatment with a suitable base, into the free compounds, or, for example by salt-exchange with a suitable salt, into a different salt.
Free compounds of the formula I that are obtain-able according to the invention may, if desired, be converted into their acid addition salts, for example by reaction with an acid in a suitable solvent Mixtures of isomers that are obtainable according to the invention can be separated into the individual isomers in a manner known per so, for example by means ox physico-chemical separating methods, with preferably the more active isomer being isolated.
~2Z~7~%
The invention relates also to those forms ox the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a derivative, for example a salt, and/or in the form of an isomer or mixture of isomers, or, as demonstrated above, is wormed under the reaction conditions.
In the process of the present invention, the starting materials used are preferably those which result in the compounds mentioned at the beginning as being especially valuable. The present invention relates also to novel starting materials and to pro-cusses for the manufacture thereof.
The compounds of the present invention have pharmacological and especially, pronounced blood sugar-reducing, properties which can be demonstrated both in normal and in diabetic experimental animals.
The blood sugar-reducing action in normal experimental animals is determined in normal female rats (Tip: RAIN (SPY)? weighing from 170 to 200 g whose food was withdrawn 6.5 hours before the beginning of the test. After taxing a first blood sample (starting value), the test preparation is administered orally (by means of a pharyngeal probe) in the Norm of a suspension in a 0.5 % aqueous solution of methyl-cellulose and in a volume of 5 ml/kg body weight.
Further samples of blood are taken after 2, 4.5 and 7.5 hours, at least 5 experimental animals being used per dose, The blood sample is taken retro-orbitally (Riley, Proc~Soc.Exptl. Blot. Med., vol. 104, page 751 (1960)) under light anesthetic (oxygen/carbon dioxide 1:1, 45 seconds, Green, Animal Handbooks 8, London Laboratory Animals Ltd., page 154 (1979)).
The blood sugar is determined according to the envy-matte GOD method (Werner et aloe Z. anal. Chum., -~223L~
vol. 252, page 224 (1970)) on an autoanalyser.
In this test procedure, the compounds of the present invention exhibit the following blood sugar-reducing actions:
_ _ . .
compound maximum blood sugar reduction (as % of the (Example) starting value) in the doses indicated (in mg/kg pro.) ._ _ . _ .. _. .,. _ _ _.
l 80 76 41 17 4 MU _ The blood sugar-reducing action in diabetic experimental animals is determined in streptozotocin-diabetic rats, the streptozotocin-diabetes being induced by a single injection of streptozotocin (55 mg/kg) into the causal vein in male rats (Tip:
RAIN (SPY)) weighing from 140 to 200 g whose food is withdrawn 16 to 24 hours before the beginning of the test. Experimental animals having blood sugar values of between 300 and 700 moper cent (approximately 17 to 39 milliliter) are used for the tests 3 to 4 weeks, at the earliest, after this treatment.
The blood sugar is determined 3 to 6 hours after the oral administration of the test preparation (see above for normal rats) to animals that have been fed.
Since the blood sugar in diabetic rats, in contrast to normal rats, decreases as a rule by 5 Tao % during the Lo test period, the spontaneous blood sugar reduction (as % of the starting value) of a simultaneously investigated control group is deducted from the blood sugar reduction of the test group. At least 5 animals per group are used.
In this test procedure, the compound of Example 1, for example, exhibits, at a dosage of 100 mg/kg, a maximum blood sugar reduction (as % of the starting value) of 29 % and, at a dosage of 30 mg/kg, one of 10 %.
In addition, the compounds of the present invention have a low toxicity in comparison with the strong anti-diabetic actions. Thus, for example, the LD50 dose for the compound of example 1 is 600 gig pro. (rat).
The compounds of the present invention can there-fore be used for reducing the blood sugar level in diabetes, being suitable, by virtue of the rapid onset of action and the remarkably short duration of action (the maximum action is achieved, for example at a dosage of 2 mug of the compound of Example 1, after 1 hour and the action can no longer be detected after 5 hours), especially for the periprandial treat-mint of diabetes of old age.
The invention relates also to the use of the compounds of the formula I or of pharmaceutically acceptable salts of such compounds having salt-form-in properties, especially as pharmacologically active, particularly as flood sugar-reducing, compounds.
They can be used, preferably in the form ox forum-ceutical preparations, in a method for the trophy-lactic and/or therapeutic treatment of the animal or human body, especially for the treatment of diabetes.
The dosage of the active ingredient which is ad minis-toned on its own or together with the customary carrier and adjunct depend on the species to be treated, the age and individual condition thereof and also on the mode of administration. The daily dosages for mammals weighing approximately 70 kg is, depending on the type of diabetes, individual condition and age, preferably approximately from 50 to 500 my.
The invention relates further to pharmaceutical preparations containing as active ingredients compounds of the formula I or pharmaceutically acceptable salts thereof, and to processes for the manufacture thereof.
The pharmaceutlc~l preparations according to the invention are for entirely, such as per oral or rectal, and for sublingual administration and also for parenteral administration to warm-blooded animals.
Corresponding unit dosage forms, especially for per oral and/or sublingual administration, for example drapes tablet or capsules, contain preferably from approxi-mutely 50 to approximately 250 my, especially from approximately 50 to approximately 150 my, of a come pound of the formula I or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers.
Suitable carriers are especially fillers, such as sugars, for example lactose, succors, minutely or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth or methyl-cellulose, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinylpyrrolidone, ajar, alginic acid or a salt thereof, such as sodium align-ate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, Starkey acid or salts thereof, such as magnesium or calcium Stewart, and/or polyethylene glycol.
Drug cores can be provided with suitable coatings that may be resistant to gastric juice, there being used, inter alias concentrated sugar solutions which may contain gum Arabic talc, polyvinylpyrroli-done, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings that are resistant to gastric juice, solutions of suitable cellulose preparations, such as acutely-cellulose phthalate or hydroxypropylmethylcellulose phthalate.
Dyes or pigments can be added to the tablets or drug coatings, for example for identification pun-poses or to indicate different doses of active inure-dint.
Other orally administrable pharmaceutical pro-portions are dry-filled capsules made from gelatin, and also soft, sealed capsules made from gelatin and a plasticizer, such as glycerine or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium Stewart and, optionally, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as oils, paraffin oil or liquid polyethylene glycols, it being possible also to add stabilizers.
As rectally administrable pharmaceutical pro-portions there come into consideration, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or sync Thetis triglycerides, paraffin hydrocarbons, polyp ethylene glycols or higher alkanols. Gelatin rectal capsules which contain a combination of the active ingredient with a base may also be used, as bases I
there come into consideration, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons Especially suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble Norm, for example solutions of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, with suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl owlet, or trimly derides being used, or aqueous injection suspensions containing substances that increase the viscosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilizers.
The pharmaceutical preparations of the present invention can be produced in a manner known per so, for example by means of conventional mixing, granulate in, confectioning, dissolving or lyophilising pro-cusses. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture and, if desired or necessary after the addition of suitable adjuncts, processing the mixture or granulate to form tablets or drug cores.
The following Examples illustrate the invention described above without limiting the scope thereof in any way. Temperatures are given in degrees Centigrade.
51 ml of triethylamine and 34 ml of chloroformic acid ethyl ester are added drops in succession, at -10, to a solution of 30 g of crotonic acid in 1500 ml of ethylene chloride. After 20 minutes, there is added at this temperature a suspension of 153 g of 1-~4-(2-aminoethyl)-phenylsulphonyl~-2-imino-3-cyclohexyllmidazolidine dihydxochloride in 1500 ml of ethylene chloride and, at 0, a solution of 107 ml of triethylamine in 500 ml of ethylene chloride is added drops The whole is stirred for a further 3 hours at 0 and for 12 hours at room -temperature, the solution becoming clear. It is washed in succession with 500 ml each of water, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. The resulting 1-~4-~2-(crotonylamino)-ethyl1-phenylsulphonyl~-3--cyclohexyl-2-imino-~dazolidine (trays) is recrystallized from ethyl acetate and melts at 157 to 158.
Example:
A solution of 1.5 g of crotonic acid android in 5 ml of absolute dioxin is added drops at 0 to a solution of 3.5 g of 1-~4-(2-aminoethyl)-phenylsul-phonyll-2-imino-3-cyclohexylimidazolidine in 100 ml ox absolute dioxin, After stirring for 12 hours at room temperature, the dioxin is distilled off, the residue is dissolved in 300 ml of ethylene chloride, and the solution is washed in succession with 50 ml each of water, 0.5N aqueous sodium hydroxide and water. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. There is thus obtained I 2-(crotonylamino)-ethyl~-phenylsulphonyl~-3-cyclohexZulu-2-iminc-Dmidazolidine trueness) which, when recrystallized from ethyl acetate melts at 157 to 158~, Example 3:
2.7 g of triethylamine, 2.7 g of chloroformic acid I
ethyl ester and a solution of 7.4 g of Amman-ethyl)-phenylsulphonyll-2-imino-3-cyclohexylimida--zolidine in 100 ml of ethylene chloride are added in succession, at -10, to a solution of 2.2 g of vinyl-acetic acid. After stirring for 3 hours at 0, the reaction mixture is left to stand overnight and is then washed in succession with water, saturated aqueous sodium bicarbonate solution and water. After recrystallization from ethyl acetate, cry-tonylamino)-ethyl1-phenylsulphonyl~ 3-cyclohexyl-2-imino-imidazolidine (trays), mop. 157 to 158, is obtained.
Example 4:
20.4 g of 1-cyclohexyl-2-imino-~midazolidine hydrochloride are added to 8.5 g of sodium hydroxide in 85 ml of water. There is added to the resulting solution 28.8 g of 4-(2-crotonylaminoethyl)-benzene-sulphonyl chloride dissolved in 100 ml of acetone, the reaction mixture becoming warm. It is heated at 90 for half an hour and then concentrated by evapora-lion under reduced pressure. The residue is wrecker-stylized from ethyl acetate, and 1-~4~2-(crotonyl-amino~-ethyl1-phenylsulphonyl~-3-cyclohexyl-2-iminno-imidazolidine (trays) which melts at 157 to 158 is obtained.
The starting material can be manufactured as follows:
18.9 g of N-(2-phenethyl)-crotonic acid aside are added in portions, while stirring, to vow g of sheller-sulphonic acid. The mixture is then stirred for 3 hours at 60, whereupon it is poured onto ice. The crystals are filtered with suction, washed with water and dried under reduced pressure. The resulting _.
4-(2-crotonylaminoethyl)-benzenesulphonyl chloride is further processed in the form of the crude product.
Example S
A mixture of 28 ml of ON aqueous sodium hydroxide solution and 4.3 g of ethyleneimine is cooled to -10.
A suspension of OWE g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride in 100 ml of acetone is then added while stirring and cooling, so that the tempera-lure does not exceed 0. When the drops addition is complete, stirring is continued for 30 minutes at 0. The cooling bath is then removed and there is added to the solution of the resulting 1-[4-(2-crotonylaminoethyl)-phenylsulphonyl~-aziridine 100 ml of cyclohexylamine. The temperature increases to 40 -50. The reaction mixture is stirred for a further hour and the excess amine is then distilled off in a rotary evaporator. The resulting crystal mass which contains, in addition to sodium chloride, the desired 1-~4-(2-crotonylaminoethyl)-phenylsulphonyl1-2 hexylethylenediamine is dissolved in 56 ml of ON
aqueous sodium hydroxide, and 10.6 g of cyano~en Ramada are added thereto in portions while stirring, the temperature not being allowed to exceed 40.
After one hour, extraction is carried out with methyl tone chloride, and the organic solution is washed with 20 ml of ON aqueous sodium hydroxide and twice with 100 ml of water. after drying the ethylene chloride solution and concentrating it by evaporation under reduced pressure, the residue is recrystallized from ethyl acetate and yields 1-~4-~2-(crotonylamino~-ethyll-phenylsulphonyl~-3-cyclohexyl-2-imino-imidaa-zolidine (trays) of melting point 157 to 158.
__ ~L~2~7~%
A solution of 19.8 g of cyclohexylamine in 400 ml of absolute deathly ether is added drops at -5 to a solution of 10.6 g of Swenson bromide in 100 ml of absolute deathly ether. When the addition is complete, the whole is stirred for 30 minutes, the cyclohexyl-nine hydrobromida which has precipitated is filtered of and, at -5 with the exclusion of moisture, 503 g of a 50 % suspan~ion ox Swede hydrlde in mineral oil are introduced in portions into the filtrate. When the addition it complete, the mixture is stirred for a further 30 minutes at -5 and the temperature it then allowed to increase to 20 . There is then added drop-wise to the resulting suspension of sodium cyclohexyl-cyanamide, in the course of 15 minutes, a solution of 33.1 g of N-(2-chloroethyl)-4~(2 crotonylaminoethyl)-benzene~ulphonamide in 100 ml of iota and the resulting suspension is stirred for 15 hours at room temperature and then reflexed for 5 hours. After cooling to room temperature, 100 ml of water are added thereto and the whole is concentrated to dryness by evaporation under reduced pressure. The residue is partitioned between water and chloroform, the insoluble portion is filtered off, and the two phases are spear-axed. The chloroform phase is extracted with ON
hydrochloric acid, and 9 while cooling, the aqueous-acidic extract it rendered alkaline with concentrated aqueous sodium hydroxide and extracted with ethylene chloride. The ethylene chloride extract it dried with sodium ~ulphate and the ethylene chloride it distilled off ale residue it recrystallized from ethyl acetate and yields I 2--(crotonyl~nino)~ethyl~-phanyl-sulphonyl~-3--cyc.l.ohexyl 2-~nino~imidazolidine (trays which melt at 157 to 158.
I
Example 7:
A solution of 28.8 g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride in 100 ml of acetone is added drops to a solution ox 8~0 g of sodium hydroxide and 4.3 g of ethyleneimine in 60 ml of water, the temperature of the mixture king maintained between 0 and ~10 by cooling When the addition is complete, stirring is carried out for one hour at room temperature and then the acetone is evaporated off under reduced pressure. Crude ~-C4-(2-crotonylaminoethyl)-phenyl-sulphonyl]~ethyleneimine separates from the remaining aqueous solution in the fox of an oil. It is extracted with ethylene chloride) the extract is dried with sodium sulfite and the ethylene chloride is evapora-ted off under reduced pressure 4-(2-crotonyl-aminoethyl)-phenylsulphonyl]-ethyleneimine remains behind as a crystalline residue A solution of 10.6 g of cyanogen bromide in 100 ml of absolute deathly ether is added drops, while stirring at -5, to a solution of 19.8 g of cycle-hexylamine in 400 ml of absolute deathly ether. After 30 minutes, the cyclohexylamine hydrobromide whir has precipitated is filtered off, and 503 g o a sodium hydride-mineral oil suspension (50 % strength) are added in portions, at I to the filtrate. Stirring is continued for a further 30 minutes at -5 and the temperature is then allowed to increase to approxi-mutely 20 . Into the resulting, white suspension of sodium cyclohexyl-cyanamide there is then introduced, while stirring, a solution of the N-~4-(2-crotonyl-aminoethyl)-phenyl~ulphonyl] ethyleneimine prepared according to the above process, in 150 ml of Dixon The resulting suspension is stirred for 15 hours at room temperature and then reflexed for 5 hour.
After cooling to room temperature, So ml of water are added drops thereto and the whole is concentrated to ~2~L7~3~
dryness by evaporation under reduced pressure. The residue is partitioned between chloroform and concern-treated aqueous sodium hydroxide. The chloroform phase is decanted from the insoluble resins, extracted with ON hydrochloric acid, and the extract is rendered alkaline with concentrated aqueous sodium hydroxide and extracted with ethylene chloride. The organic phase is dried over sodium sulfite, filtered and concentrated to dryness by evaporation under reduced pressure. The 1-~4-~2-(crotonylamino)-ethyll-phenyl-sulphonyl~-3-cyclohexyl-2-imino-lmidazolidine (trays) which remains is recrystallized from ethyl acetate and melts at 157 to 158.
Example 8:
26.8 g of 4-(2-crotonylaminoethyl)-benzenesul-phonamide and 18.7 g of N-(2-chloroethyl)-N-cyclo-hexyl-cyanamide are added to a mixture of 4 g of sodium hydroxide, 15 ml of water and 300 ml of dip methyl sulphoxide. The resulting solution is heated for 1 hour at a bath temperature of 110. The dip methyl sulphoxide is distilled off under reduced pressure and the residue, a brown oil, is taken up in ethylene chloride. The organic phase is washed three times with water, dried and filtered and yields, after concentration by evaporation under reduced pressure, a brown crystalline residue. After no-crystallization from ethyl acetate, 1-~4-~2-(crotonyl-amino)-ethyll-phenylsulphonyl~-3-cyclohexyl-2-iminno-imidazolidine (trays) of melting point 157 to 158 is obtained.
Example 9:
To a solution of 9.0 g of disodium cyanamide in 50 ml of water there are added, first of all, 15 ml of Lo acetone and then, in portions, in the course of 15 minutes, 29.8 g of 4 (2-crotonylaminoethyl)-benzene-sulphonyl chloride. Thereupon, 19.8 g of sheller-ethylcyclohexylamine hydrochloride are added and the whole is concentrated to dryness by evaporation. The paste like residue is extracted with a mixture of 150 ml of ethanol and 150 ml of isopropanol. The extract is concentrated to dryness by evaporation under reduced pressure, the residue is taken up in 200 ml of acetone, the solution is filtered and the filtrate is again concentrated by evaporation. The remaining, clear, yellow oil is heated for lo hours at 1~5. The vitreous residue which is left behind after cooling is taken up in water and acidified with ON hydrochloric acid, and the solution is washed with chloroform. The aqueous phase is then rendered alkaline with concern-treated aqueous sodium hydroxide while cooling, during which an oil separates which is taken up in ethylene chloride. The resulting ethylene chloride solution is washed with water, dried over sodium sulfite and then concentrated to dryness by evaporation under reduced pressure. Upon subsequently chromatographing the residue over silica gel there is eluded with sheller-form containing 2.5 % methanol 1-~-~2-(crotonylamino)-ethyll-phenylsulphonyl~-3-cyclohexyl-2-imino-1mldaazalea-dine (trays) which crystallizes after evaporating the solvent and, after being recrystallized from ethyl acetate, melts at 157 to 158.
Example 10:
2 g of isocrotonic acid are dissolved in lo ml of ethylene chloride. At -10, 3.4 ml of triethyl-amine, I ml of chloroformic acid ethyl ester and, after 20 minutes, a solution of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyll-2 imino-3-cyclohexyl-~2~7~2 imidazolidine in 100 ml of ethylene chloride are added drops. The reaction mixture is left for 3 hours at 0 and for 12 hours at room temperature, then diluted with ethylene chloride and washed in succession with water, a saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfite, filtered and concentrated by evaporation under reduced pressure. The oil which remain is crystallized with petroleum ether and the resulting
3~cyclohexyl-2-imino-1-~4-~2-(isocrotonylamino3-etthy]-phenylsulphonyl~-imidazolidine (is) is recrystallized from ethyl acetate. Mop. 93 to 94.
Example 11:
3~4 ml ox triethylamine, I ml of chloroformic acid ethyl ester, a suspension of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyl]-2-Imino-3-cyclohexyl--imidazolidine dihydrochloride in 100 ml of ethylene chloride and again 7 ml of triethylamine in 100 ml of ethylene chloride are added drops in succession, at -10, to a solution of 2.4 g of tiglic acid in 100 ml ox ethylene chloride. The reaction mixture is allowed to warm up slowly to room temperature and is stirred for a further 12 hours The reaction mixture is then washed with water, a saturated aqueous sodium bit carbonate solution and water. After drying the organic phase over sodium sulfite, concentration by evapora-lion under reduced pressure is carried out and the oil which remains is recrystallized from ethyl acetate.
There is thus obtained 3-cyclohexyl-2-imino~ 4-C2-(2,3-dimethylacrylamino)-ethyl~-phenylsulphonyl~-imidazolidine of melting point 140 to owe Example 12:
I ml of triethylamine and 2.4 ml of chloroformic ~L22~71D2 acid ethyl ester are added drops, at -10, to a solution of 2.8 g of trays 4-methyl 2-pentenoic acid in 100 ml of ethylene chloride and, after 30 minutes, a solution of 8.4 g of 1-~4-(2-aminoethyl)-phenyl-sulphonyll-2~imino-3-cyclohexylimidazolidine in lo ml of ethylene chloride is added drops and the whole is stirred for 3 hours at 0 and for 12 hours at room temperature. After filtration, the filtrate is washed with 50 ml each of water, a saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfite, filtered again and concentrated by evaporation under reduced pressure. The resulting 3-cyclohexyl-2-imino-1- r4-[2-~4-methyl-2-pentenoyl-amino)-ethyll-phenylsulphonyl~-2-imino-3-cyclohexyye-imidazolidine (trounces recrystallized from ethyl acetate. Mop. 160 to 162 .
Example 13:
3.4 ml of triethylamine and 2.4 ml of chloroformic acid ethyl ester are added drops at -10 to a solution of 2.7 g of trans-2~hexenoic acid in 100 ml of ethylene chloride. after 20 minutes, a suspension of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyl7-2-imino-3-cyclohexylimidazolidine dihydrochloride in 100 ml of ethylene chloride and a solution of 5 g of triethyl-amine in 100 ml of ethylene chloride are added drop-wise at 0. The whole is left to react for 3 hours at 0 and for 12 hours at room temperature, and the reaction mixture is washed with water, dried over magnesium sulfite, filtered and concentrated by evaporation under reduced pressure. The white, crystalline residue is recrystallized from ethyl acetate. The 3-cyclohexyl-2-imino-1 ~4-~2-(2-hexenoyl-amino)-ethyl~-phenylsulphonyl~ imidazolidine (trays) obtainable in this manner then melts at 153 to 156, ~Z2~%
Example lo:
Tablets, each containing 100 my of 1-~4-~2-(crotonylamino)-ethyll~phenylsulphony~ -3-cyclohexyl-2-imino~imidazolidine (trays), can be prepared as phallus:
Composition (for 10,000 tablets):
1-~4-~2-~crotonylamino)~ethyl1-phenyl-sulphonyl~-3-cyclohexyl-2-imino-imidazoli-dine trueness) Lowe g lactose 500 0 g potato starch 330.0 g gelatin 8.0 g talc 60.0 g magnesium Stewart Lowe g silica (colloidal) 20.0 g water I.
The I 2-(crotonylamino)-ethyll-phenylsul-phenol cyclohexyl-2-imino~Lmidazolidine (trays) is mixed with the lactose and 270.0 g of the potato starch, the mixture is moistened with an aqueous solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium Stewart and the colloidal silica are mixed in and the mixture is pressed to form tablets weighing 200 my which may, if desired, be provided with dividing notches for finer adjustment of the dosage.
Example 15:
Drug each containing 100 my of 1-~4-~2-(crotonylamino)-ethyll-phenylsulphonyl~ -3-cyclohexyl-2-imino-im~dazolidine (trays), can be prepared as I
follows:
Composition (for 10,000 drapes 1-~4-~2-(crotonylamino)-ethyll-phenyl-sulphonyl~-3-cyclohexyl-2-imino-imidazoli-dine (trays) Lowe g lactose 500.0 g silica (colloidal) 290.0 g talc 290.0 g potato starch 40.0 g magnesium Stewart 5.0 g succors (cyst.) 533.0 g shellac 20.0 g gum Arabic 75.0 g dye 1.5 g water us The 1 I r 2-(crotonylamino)-ethyll-phenylsulphonyl~ -3-cyclohexyl-2-imino-imidazolidine (trays) is mixed with the lactose and 270.0 g of the silica, 40~0 g of the talc, the potato starch and the magnesium Stewart and pressed to form drug cores. These are thin coated with a concentrated aqueous syrup consisting of the succors, shellac, gum Arabic the remainder of the talc and silica and the dye and dried. The resulting drapes have a weight of 240 my.
Example 11:
3~4 ml ox triethylamine, I ml of chloroformic acid ethyl ester, a suspension of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyl]-2-Imino-3-cyclohexyl--imidazolidine dihydrochloride in 100 ml of ethylene chloride and again 7 ml of triethylamine in 100 ml of ethylene chloride are added drops in succession, at -10, to a solution of 2.4 g of tiglic acid in 100 ml ox ethylene chloride. The reaction mixture is allowed to warm up slowly to room temperature and is stirred for a further 12 hours The reaction mixture is then washed with water, a saturated aqueous sodium bit carbonate solution and water. After drying the organic phase over sodium sulfite, concentration by evapora-lion under reduced pressure is carried out and the oil which remains is recrystallized from ethyl acetate.
There is thus obtained 3-cyclohexyl-2-imino~ 4-C2-(2,3-dimethylacrylamino)-ethyl~-phenylsulphonyl~-imidazolidine of melting point 140 to owe Example 12:
I ml of triethylamine and 2.4 ml of chloroformic ~L22~71D2 acid ethyl ester are added drops, at -10, to a solution of 2.8 g of trays 4-methyl 2-pentenoic acid in 100 ml of ethylene chloride and, after 30 minutes, a solution of 8.4 g of 1-~4-(2-aminoethyl)-phenyl-sulphonyll-2~imino-3-cyclohexylimidazolidine in lo ml of ethylene chloride is added drops and the whole is stirred for 3 hours at 0 and for 12 hours at room temperature. After filtration, the filtrate is washed with 50 ml each of water, a saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfite, filtered again and concentrated by evaporation under reduced pressure. The resulting 3-cyclohexyl-2-imino-1- r4-[2-~4-methyl-2-pentenoyl-amino)-ethyll-phenylsulphonyl~-2-imino-3-cyclohexyye-imidazolidine (trounces recrystallized from ethyl acetate. Mop. 160 to 162 .
Example 13:
3.4 ml of triethylamine and 2.4 ml of chloroformic acid ethyl ester are added drops at -10 to a solution of 2.7 g of trans-2~hexenoic acid in 100 ml of ethylene chloride. after 20 minutes, a suspension of 10.2 g of 1-~4-(2-aminoethyl)-phenylsulphonyl7-2-imino-3-cyclohexylimidazolidine dihydrochloride in 100 ml of ethylene chloride and a solution of 5 g of triethyl-amine in 100 ml of ethylene chloride are added drop-wise at 0. The whole is left to react for 3 hours at 0 and for 12 hours at room temperature, and the reaction mixture is washed with water, dried over magnesium sulfite, filtered and concentrated by evaporation under reduced pressure. The white, crystalline residue is recrystallized from ethyl acetate. The 3-cyclohexyl-2-imino-1 ~4-~2-(2-hexenoyl-amino)-ethyl~-phenylsulphonyl~ imidazolidine (trays) obtainable in this manner then melts at 153 to 156, ~Z2~%
Example lo:
Tablets, each containing 100 my of 1-~4-~2-(crotonylamino)-ethyll~phenylsulphony~ -3-cyclohexyl-2-imino~imidazolidine (trays), can be prepared as phallus:
Composition (for 10,000 tablets):
1-~4-~2-~crotonylamino)~ethyl1-phenyl-sulphonyl~-3-cyclohexyl-2-imino-imidazoli-dine trueness) Lowe g lactose 500 0 g potato starch 330.0 g gelatin 8.0 g talc 60.0 g magnesium Stewart Lowe g silica (colloidal) 20.0 g water I.
The I 2-(crotonylamino)-ethyll-phenylsul-phenol cyclohexyl-2-imino~Lmidazolidine (trays) is mixed with the lactose and 270.0 g of the potato starch, the mixture is moistened with an aqueous solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium Stewart and the colloidal silica are mixed in and the mixture is pressed to form tablets weighing 200 my which may, if desired, be provided with dividing notches for finer adjustment of the dosage.
Example 15:
Drug each containing 100 my of 1-~4-~2-(crotonylamino)-ethyll-phenylsulphonyl~ -3-cyclohexyl-2-imino-im~dazolidine (trays), can be prepared as I
follows:
Composition (for 10,000 drapes 1-~4-~2-(crotonylamino)-ethyll-phenyl-sulphonyl~-3-cyclohexyl-2-imino-imidazoli-dine (trays) Lowe g lactose 500.0 g silica (colloidal) 290.0 g talc 290.0 g potato starch 40.0 g magnesium Stewart 5.0 g succors (cyst.) 533.0 g shellac 20.0 g gum Arabic 75.0 g dye 1.5 g water us The 1 I r 2-(crotonylamino)-ethyll-phenylsulphonyl~ -3-cyclohexyl-2-imino-imidazolidine (trays) is mixed with the lactose and 270.0 g of the silica, 40~0 g of the talc, the potato starch and the magnesium Stewart and pressed to form drug cores. These are thin coated with a concentrated aqueous syrup consisting of the succors, shellac, gum Arabic the remainder of the talc and silica and the dye and dried. The resulting drapes have a weight of 240 my.
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of compounds of the formula I, and the pharmaceutically acceptable salts thereof, (I), in which R represents the radical of the formula (Ia) in which Rl represents lower alkyl and each of R2 and R3, independently of the other, represents hydrogen or lower alkyl, and salts of such compounds, characterised in that a) a compound of the formula (II) NH
or derivative thereof is reacted with an acid of the formula R-C(=O)-OH (III) or an anhydride or ester thereof, or b) a anhydride of a sulphonic acid of the formula (IV) is reacted with a compound of the formula (V) or a silyl derivative or an acid addition salt thereof, or c) a compound of the formula (VI), in which one of the radicals X and Y represents cyano and the other represents hydrogen, is cyclised, or d) a compound of the formula (VII) in which R° represents a radical of the formula (VIIa) in which R1° represents a 1-lower alkenyl radical, or a derivative thereof is isomerised, and, if desired, a salt obtainable according to the invention is converted into the free compound or into a different salt, and/or a free compound obtainable according to the invention is converted into a salt and/or, if desired, a mixture of isomers is separated into the individual isomers.
or derivative thereof is reacted with an acid of the formula R-C(=O)-OH (III) or an anhydride or ester thereof, or b) a anhydride of a sulphonic acid of the formula (IV) is reacted with a compound of the formula (V) or a silyl derivative or an acid addition salt thereof, or c) a compound of the formula (VI), in which one of the radicals X and Y represents cyano and the other represents hydrogen, is cyclised, or d) a compound of the formula (VII) in which R° represents a radical of the formula (VIIa) in which R1° represents a 1-lower alkenyl radical, or a derivative thereof is isomerised, and, if desired, a salt obtainable according to the invention is converted into the free compound or into a different salt, and/or a free compound obtainable according to the invention is converted into a salt and/or, if desired, a mixture of isomers is separated into the individual isomers.
2. Process according to claim 1, characterised in that the starting material of the formula VI according to process variant (c) is formed in situ by ca) reacting a compound of the formula (VIa), in which Ya represents hydrogen or an unsubstituted or substituted methyl group with a halide of cyanic acid, or cb) reacting a compound of the formula (VIb), in which Xa represents hydrogen and Yb represents a hydroxy group esterified with a strong inorganic or organic acid, or in which Xa and Yb together form a bond, with N-cyclohexyl-cyanamide or a derivative there-of, or cc) reacting a compound of the formula (VIc) with a N-cyclohexyl-N-(2-hydroxyethyl)-cyanamide esteri-fied with a strong inorganic or organic acid, or an acid addition salt thereof, or cd) cyclising an addition salt compound of the formula (VId), in which Yc represents halogen or an organic sulphonyl-oxy group.
3. Proeess according to claim 1 for the manufacture of compounds of the formula I in which R
represents the radical of the formula Ia, and R1 re-presents alkyl having up to and including 3 carbon atoms, R2 and R3 represent hydrogen or methyl, or salts thereof.
represents the radical of the formula Ia, and R1 re-presents alkyl having up to and including 3 carbon atoms, R2 and R3 represent hydrogen or methyl, or salts thereof.
4. A process according to claim 1, which comprises preparing 1-{4-[2-(crotonylamino)-ethyl]-phenylsul-phonyl}-3-cyclohexyl-2-imino-imidazoline, by reaeting 1-[4-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclo-hexylimidazolidine dihydrochloride with crotonic acid.
5. A process according to claim 1, which comprises preparing 3-cyclohexyl-2-imino-1-{4-[2-(isocrotonyl-amino)-ethyl]-phenylsulphonyl}-imidazolidine, by reacting 1-[4-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclonexylimidazolidine with isocrotonic acid.
6. A process according to claim 1, which comprises preparing 3-cyclohexyl-2-imino-1-{4-[2-(2,3-dimethyl-acrylamino)-ethyl]-phenylsulphonyl}-imidazoline (trans), having a melting point of 140 to 142°, by reacting 1-[4-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclo-hexylimidazolidine dihydrochloride with tiglic acid.
7. A process according to claim 1, which comprises preparing 3-cyclohexyl-2-imino-1-{4-[2-(4-methyl-2-pentenoylamino)-ethyl]-phenylsulphonyl}-2-imino-3-cyclohexylimidazolidine (trans), having a melting point of 160 to 162°, by reacting 1-[4-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclohexylimidazolidine with trans 4-methyl-2-pentenoic acid.
8. A process according to claim 1, which comprises preparing 3-cyclohexyl-2-imino-1-{4-[2-(2-hexenoyl-amino)-ethyl]-phenylsulphonyl}-imidazolidine (trans), having a melting point of 153-156°, by reacting 1-[4-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclo-hexylimidazolidine dihydrochloride with trans-2-hexenoic acid.
9. compound of formula I, (I), in which R represents the radical of the formula (Ia) in which R1 represents lower alkyl and each of R2 and R3, independently of the other, represents hydrogen or lower alkyl, and pharmaceutically acceptable salts of such compounds, whenever prepared by a process as claimed in claim 1, or by an obvious chemical equivalent thereof.
10. A compound of formula I in which R represents the radical of the formula Ia, and R1 represents alkyl having up to and including 3 carbon atoms, R2 and R3 represent hydrogen or methyl, or salts thereof, whenever prepared by a process as claimed in claim 3, or by an obvious chemical equivalent thereof.
11. 1-{4-[2-(crotonylamino)-ethyl]-phenylsulphonyl}-3-cyclohexyl-2-imino-imidazoline and whenever prepared by a process as claimed in claim 4 or by an obvious chemical equivalent thereof.
12. 3-cyclohexyl-2-imino-1-{4-[2-(isocrotonylamino)-ethyl]-phenylsulphonyl}-imidazolidine and whenever prepared by a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
13. 3-cyclohexyl-2-imino-1-{4-[2-(2,3-dimethylacryl-amino)-ethyl]-phenylsulphonyl}-imidazoline (trans), having a melting point of 140° to 142°, whenever prepared by a process as claimed in claim 6 or by an obvious chemical equivalent thereof.
14. 3-cyclohexyl-2-imino-1-{4-[2-(4-methyl-2-pentenoylamino)-ethyl]-phenylsulphonyl}-2-imino-3-cyclohexylimidazolidine (trans), having a melting point of 160 to 162°, whenever prepared by a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
15. 3-cyclohexyl-2-imino-1-{4-[2-(hexenoylamino)-ethyl]-phenylsulphonyl}-imidazolidine (trans), having a melting point of 153-156°, whenever prepared by a process as claimed in claim 8 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000451063A CA1221702A (en) | 1984-04-02 | 1984-04-02 | Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000451063A CA1221702A (en) | 1984-04-02 | 1984-04-02 | Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221702A true CA1221702A (en) | 1987-05-12 |
Family
ID=4127556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000451063A Expired CA1221702A (en) | 1984-04-02 | 1984-04-02 | Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1221702A (en) |
-
1984
- 1984-04-02 CA CA000451063A patent/CA1221702A/en not_active Expired
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