DE1214674B - Process for the production of guanidine derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

Number:
File number:
Registration date:
Display day:

C 07c

German class: 12 ο-25

1214674
E27090IVb / 12o
May 22, 1964
April 21, 1966

The present invention relates to a process for the preparation of guanidine derivatives of the general formula

Ri NR ₃ R ₄

R-NH-C-CH ₂ -NH-CN I

R ₂

R ₅

and their physiologically acceptable salts with acids, where R is optionally with low molecular weight -Alkyl groups-substituted cycloalkyl group with 5 to 7 carbon atoms, Ri to Rs an alkyl group with 1 to 4 carbon atoms or Ri, R3, Rä, R5 hydrogen and R5 additionally denote an amino or an acyl group having 1 to 4 carbon atoms.

According to the invention, a 2-aminoalkylamine of the general formula is now used in a manner known per se

Ri

R - NH - C - CH ₂ -NH ₂ R ₂

II

a) with a thiourea derivative of the general ^formula NR ₃

R ₆ -SC III

NR ₅

R ₄

wherein R _{5 is} a hydrogen atom, an amino group or an alkyl group having 1 to 4 carbon atoms, R _{6 is} an alkyl or aralkyl group and Ri, R ₂ , R3 and R4 have the meaning given above, or

b) with cyanamide or

c) with a cyanogen halide and then with ammonia or an amine or

d) with N-nitrosoguanidine or an N-alkyl-N-nitrosoguanidine

implemented or is a thiourea of the general formula

K.1

Process for the production of guanidine derivatives

Applicant:

"Evans Medical Limited, Liverpool, Lancashire
(Great Britain)

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:
Wilfred James Cecil Dyke,
Uptom-by-Chester, Cheshire (UK)

Claimed priority:

Great Britain December 13, 1963 (49 408)

R-NH-C-CH ₂ -NH-CS-NH ₂ IV

R ₂
with mercury (II) oxide and ammonia or one

Amine reacted, the reaction products are optionally alkylated or acylated and optionally converted into the physiologically compatible salts.

The guanidine compounds obtainable according to the invention have a particularly favorable hypotensive activity, in particular against renal and neurogenic hypertension. In addition, they have a particularly expedient duration of action in practice, since this is neither impractically short nor undesirably long and starts practically immediately. In contrast to a number of previously proposed guanidine hypotensives, the compounds obtainable according to the invention can be safely administered both by injection and orally. Very advantageous is ¹ also that the compounds according to the invention obtainable from readily available starting materials can be prepared.

In the above formula I, the substituents Ri and R2 can be, for example, straight-chain or branched-chain alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl groups. Preferably R _{2 is} a methyl group and Ri is hydrogen or a methyl

609 559/426

group. The substituents R3, R4 and Rg are preferred all hydrogen atoms.

The compounds in which Rl and R2 are two or Having multiple carbon atoms are of particular interest as they are virtually instantaneous Cause lowering of blood pressure; the compound in which Ri and R2 represent a methyl group, R is a cyclohexyl group and R3, R4 and Rg are hydrogen atoms, is special in this regard remarkable. The compound in which Ri is a methyl group, R2 is a hydrogen atom, R is a Cyclohexyl group and R3, R4 and Rs represent hydrogen atoms, is especially for oral administration suitable as it is in contrast to some previously proposed guanidine hypotensives this way gives a regular effect.

If R5 represents an acyl radical with 1 to 4 carbon atoms, this consists, for example, of an acetyl, propionyl or acrylyl group. The acyl radical can also be substituted, so that R ₅ can mean, for example, a trichloroacetyl or hydroxypropionyl group. If R3, R4 and / or Rg consist of an aliphatic group with 1 to 4 carbon atoms, this can be straight-chain or branched.

If the groups Ri and R _{2 are} different, the compounds obtainable according to the invention are present as optical isomers and racemic mixtures. 2- (Cyclohexylamino) propylguanidine can thus be present, for example, in the form of the d- and 1-isomers and as a racemic d, l mixture.

The group R is preferably a cyclohexyl group.

Since the bases obtainable according to the invention generally contain two basic groups, can they "are converted into their physiologically acceptable mono- and diacid addition salts.

The implementation of a 2-aminoalkylamine of the general formula II carried out according to the invention with a thiourea derivative of the general formula III, as described above under a), can be carried out both in the presence and in the absence of a solvent, water and water-miscible organic solvents such as water-miscible alcohols, ethers, ketones, or acids such as methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, Acetic acid, suitable solvents are. The reaction temperature is not particularly critical. Even if normal temperature is generally sufficient, higher temperatures can also be used, for example up to the boiling point of the medium.

The amines of the general formula II used in the above process can be easily used by reducing the corresponding nitriles of the following general formula:

R ₁ .
R - NH - C - CN

R ₂

These nitriles can be produced by condensation of an amine RNH ₂ with an aldehyde or ketone Ri - CO - R ₂ and subsequent treatment with a cyanide. The aldehyde or ketone is preferably used in the form of its bisulfite adduct, e.g. B, sodium acetaldehyde bisulfite, sodium acetone bisulfite. The cycloalkylamine is advantageously added dropwise to a solution of the bisulfite adduct in an aqueous solvent, for example in water. The cyanide is preferably an alkali metal cyanide, e.g. B. sodium cyanide or potassium eyanide. The reduction of the propionitrile is preferably carried out with a metal hydride as the reducing agent, e.g. B. lithium aluminum hydride, in a solvent such as ether or tetrahydrofuran.

The amines of the formula II can also be obtained by condensation of a cycloalkanone with a diamine

Ri
H ₂ NC-CH ₂ -NH ₂

R ₂

and subsequent reduction of the Schiff base obtained.

If the manufacturing process leads to an unsubstituted guanidine group, can if appropriate, then introduce the substituents R3, Ri and Rg, for example by alkylation using conventional methods such as reaction with an alkyl halide or sulfate. Of the Substituent R5 can then also by acylation, for example using a functional derivative of a carboxylic acid, such as the acid halide or anhydride, are introduced.

The manufacturing processes given here for the new compounds generally lead to the Compounds in the form of their salts. The free base can be obtained from the salt by treatment with a strong anion exchange resin or by treatment with caustic alkali or with silver oxide getting produced. Other salts can be formed from the free base thus obtained. Possibly can the anion of an acid addition salt using conventional ion exchange processes, for example using anion exchange resins, replaced by a different anion will.

No protection is sought for the manufacture of the raw materials.

The following examples serve to further illustrate the invention without limiting it.

example 1

15.6 g of 2- (cyclohexylamino) propylamine were added to a solution of 15.4 g of S-methylisothiourea sulfate in 50 ml of water. The mixture was allowed to stand at room temperature overnight, during which time methyl mercaptan was evolved, and then the reaction was terminated by heating on a boiling water bath for 1 hour. On cooling, crystals separated out from the solution which, after filtering off and drying, weighed 22.6 g and had a melting point of 198 ^° C. These were recrystallized from water, as a result of which 2 - (cyclohexylamine) propylguanidine sulfate, mp = 206 ° C. (corrected), was obtained.

5 6

The 44 g of the 2-cyclohexylamino-2-methyl-

applied 2 - (Cyclohexylamine) - propylamine was propionitrils in 75 ml dry ether was all-

prepared in the following way: 364 g sodium acetate- gradually to a suspension of 13 g lithium-

Aldehyde bisulfite was dissolved in 800 ml of water, and aluminum hydride in 600 ml of ether was added. That

and 198 g of cyclohexylamine 5 were added to the solution.

Refluxed dropwise at room temperature over 3 hours and then

Added for 30 minutes with mechanical stirring. left to stand overnight. Carefully 10 ml

The mixture was then added to water for an additional hour and finally 13 ml of 20% strength

left to stand, followed by a solution of sodium hydroxide. After cooling, the fil-

108 g of sodium cyanide in 200 ml of water treated io trated solution dried over sodium sulfate. Of the

became. Ether formed on standing in a separatory funnel was evaporated and the remaining oil

the reaction mixture two layers. The nitrile fractionates, with 24 g of 2-CycIohexylamino-

was separated as the upper layer. The lower 2-methyl-propylamine gave; Kp.is mm == 112 to

Layer was extracted twice with 500 ml of ether, 114 ⁰ C; n% = 1.4721.
and the ether extracts became the top nitrile 15

shift admitted. Example 3 obtained in this way
entire ethereal solution was left to stand over

dried anhydrous sodium sulfate. After Ab- It was a solution of sodium propionaldehyde

distillation of the ether, the remaining oil bisulfite was produced by pre-

by distillation under reduced pressure fractionally 58 g of propionaldehyde to 300 ml of a 37% strength

tioned, and 240 g of 2- (cyclohexyl aqueous sodium bisulfite solution was added)

amino) - propionitrile; Kp.11 mm = 106 ⁰ C; n% den. 9.9 g of cyclohexylamine were added to the solution

= 1.4688. A solution of 176 g of 2- (cyclo- dropwise over 30 minutes at room

hexylamino) propionitrile in 300 ml of dry ether temperature added with mechanical stirring,

became a suspension of 58 g lithium aluminum, whereupon the stirring continued for a further 60 minutes.

nium hydride in 200 ml of dry ether while driving. A solution of 100 g of sodium

1 hour added. The mixture was then cyanide in 200 ml of water was then added and

Heated under reflux for 3 hours and cooled again. the resulting mixture was stirred for a further 3 hours

50 ml of water were then carefully added slowly and then left to stand overnight. That on this

added and then 60 ml of a 20% strength 30 way formed 2-cyclohexylamino-n-butyronitrile

Sodium hydroxide solution and finally others were extracted with ether and the ether extract

140 ml of water. After filtering, it was dried over anhydrous sodium sulfate. To

ethereal solution over anhydrous sodium sulfate removal of the ether was the nitrile by

dried. The ether was evaporated and the distillation purified; Bp 12 mm = 106 to 108 ^° C;

Product, 2- (cyclohexylamino) propylamine, at 35 "m = 1.437.

distilled under reduced pressure; Kp.is mm = 105 to A solution of 35.2 g of the thus obtained 2-CycIo-

107 ⁰ C; Bp 26mm = 120 to 121 ° C; ng = 1.4742; hexyl-n-butyronitrile in 100 ml dry ether

Yield 122g. slowly became a suspension of 10 g

Example 2 Lithium aluminum hydride in 500 ml of dry ether

40 added and the mixture at reflux for 3 hours

A mixture of 15.8 g of S-methylisothiourea heated. After cooling it was careful with

sulfate, 16.6 g of 2-cyclohexylamino-2-methyl ~ propyl- 8 ml of water and then treated with 10 ml

amine and 50 ml of water was overnight with a 25% caustic soda solution and finally with

Let stand room temperature. Developing 24 ml of water. After the filtration, the ethereal

the methyl mercaptan was dried by heating the solution over anhydrous sodium sulfate.

Solution on a water bath during a further After removal of the ether, the 2-cyclo-

Hour ended. After cooling, the hexylamino-η-butylamine were distilled off; 15 mm

separate crystals of 2-cyclohexylamino- = HO ⁰ C; n ° _{0 to} 1.476; Yield 22.3g.

2-methyl-propylguanidine-sulfate from a mixture A mixture of 17 g of 2-cyclohexylamino-n-butyl-

recrystallized from alcohol and water; F. = 203 50 amines, 15.4 g S-methylisothiourea sulfate and

to 206 ⁰ C; Yield IS g. 50 ml of water was added to the boiling water bath

The required 2-cyclohexylamino-2-methyI- heated for 2 hours. Developed during this time

propylamine was made in the following way: methyl mercaptan, and a solid

A solution of 120 g of acetone sodium bisulfite in fabric. After cooling it became solid

400 ml of water was slowly mixed with 66 g of cyclohexyl 55 product, 2-cyclohexylamino-n-butylguanidine sulfate,

amine treated. After standing for 1 hour this was filtered off and it showed off after recrystallization

Mixture with 36 g of sodium cyanide dissolved in 70 ml of 150 ml of 33% aqueous alcohol

Water, treated. The upper layer of 2-Cyclo- F. = 125 ° C; Yield 19.7g.
hexylamino-2-methyl-propionitrile that formed

had, was removed and the lower layer 60 B eis ρ ie 1 4
extracted three times with ether. The ether extracts

were combined and added to the original top 7.8 g of 2 - (cyclohexylamine) propylamine, 11 g

Layer of nitrile added. The thus obtained ether - S - ethyl - N - methylisothiuronium - sulfate and 5 ml

solution was poured over anhydrous sodium sulfate. Alcohol were mixed and placed on a water bath

dries. After removal of the ether, the 65 was heated for 1 hour, with ethyl mercaptan

Distilled residue under reduced pressure and developed. The oily residue obtained became

resulted in 47 g of the pure nitrile, which in the. stirred with ethyl acetate and was after

"Itehen solidified; F. = 52 ⁰ C. A solution dissolved from the separation in 200 ml of water The aqueous.

Claims (1)

Solution was passed through a chromatography column made of De-Acidite FF (OH ~ form) and the Liquid concentrated to a small volume under reduced pressure. This then became neutralized with 5 η-sulfuric acid and treated with acetone. The gummy solid that forms was recovered and solidified by trituration with fresh acetone. In this way · became the l-P-CyclohexylaminopropyO-S-methylguanidine - obtained sulfate as a white solid; M.p. = 236 ° C (decomposition). Test report Two compounds prepared in accordance with the invention, 2-cyclohexylamine-2,2-dimethylethylguanidine sulfate (referred to as M 313) and 2-cyclohexylaminopropylguanidine (referred to as EM 311) are treated with 2 - heptamethyleneiminoethylguanidine sulfate (called guanethidine) and in one case with N-o-bromobenzyl-N-ethyl-N ^ -dimethylammonium p-tosylate (called Bretyllium) in terms of their hypotensive effects. There will be the following Test method used: 25 1. Nictitating skin test in cats Such attempts are based on the fact that conscious cats have the nictitating membrane is hardly visible, however, by processes or substances that affect the normal activity of the sympathetic Interrupting nerves, slackening them and making them easily visible. Because a humiliation of the blood pressure is also caused by disturbance of the sympathetic nerve tone, shows the Relaxation of the nictitating membrane by a drug indicates an effect of that drug on blood pressure. the Speed of onset and the duration of the effect on the nictitating membrane also shows how fast and how long the drug is likely to work for. Table 1 shows that at doses of 50 mg / kg subcutaneous administration EM 313 shows a faster effect than guanethidine, but that the The effect of EM 313 is slightly shorter than that of guanethidine. Table 2 shows that at doses of 5 mg / kg EM 313 shows a very good effect that lasts neither too long nor too short while Guanethidine shows no effect. 2. Blood pressure test in anesthetized cats The anesthesia is induced with nitrous oxide, oxygen and ether and with 70 mg / kg chloralose maintain. The right femoral artery is cannulated and fitted with a mercury manometer tied together. The movements of the mercury column are recorded on a kymograph. The left femoral vein is cannulated to introduce the drugs. The drugs are only injected ^ when blood pressure and carotid occlusion response were constant for 30 minutes. The carotid occlusion causes a reflex increase in blood pressure and allows the effects of the drugs too check while blood pressure is temporarily elevated. The occlusion is achieved by clamping both carotid arteries achieved. F i g. Figure 1 shows that EM 311 and EM 313 increase blood pressure in anesthetized cats without an initial Increases decrease while guanethidine and bretyllium cause an initial increase in blood pressure demonstrate. This initial increase is particularly pronounced in guanethidine and is a well-known one This is a disadvantage of this much used remedy. Tabel Effect of subcutaneous injections at doses of 50 mg / kg body weight on the nictitating membrane of conscious cats 2 hours 24 2 > 3 Degree of relaxation 4th H the nictitating membrane 5 6th + + 7th + 8th + + 9 -i Days H O + + + + + + + + + + + H - + + to + to + + Claim: + O to + Guane O + to + + + + + to + + - + + H + + · until O thidin + + - ++++ + + + + + + + + + + - + to + + + O EM 311 f Tabel : + + EM 313 + Effect of subcutaneous injections at doses of 5 mg / kg body weight on the nictitating membrane of conscious cats Degree of relaxation of the nictitating membrane 48 O O O 72 96 1 I 24 hours + + ^ -r- 1- O O Guanethidine O O EM 313 ......... 55 60 65 Process for the preparation of guanidine derivatives of the general formula Ri NR ₃ Ri R-NH-C-CH ₂ -NH-CN I R ₂ R ₅ and their physiologically acceptable salts with .Acids, where R is an optionally with low molecular weight Alkyl groups substituted cycloalkyl group with 5 to 7 carbon atoms, Ri to Rs is an alkyl group with 1 to 4 carbon R ₆ -SC III 10 atoms or Ri, R ₃ , R4, Rs hydrogen and R5 additionally denote an amino or an acyl group with 1 to 4 carbon atoms, characterized in that a 2-aminoalkylamine of the general formula is used in a manner known per se Ri R-NH-C-CH ₂ -NH ₂ II R ₂ a) with a thiourea derivative of the general formula NR ₃ NR ₅ R ₄ wherein R5 is a hydrogen atom, an amino group or an alkyl group having 1 to 4 carbon atoms, Re is an alkyl or aralkyl group and Ri, R ₂ , R3 and R4 have the meaning given above, or b) with cyanamide or c) with a cyanogen halide and then with ammonia or an amine or d) with N-nitrosoguanidine or an N-alkyl-N-nitrosoguanidine converts or a thiourea of the general formula Ri R - NH - C - CH ₂ - NH - CS - NH ₂ IV R ₂ reacts with mercury (II) oxide and ammonia or an amine, the reaction products optionally alkylated or acylated and they optionally converted into the physiologically acceptable Salts transferred. 609 559/426 4.66 © Bundesdruckerei Berlin