DE1668851B2 - AMIDINE AND THE METHOD OF MANUFACTURING THEM - Google Patents

Description

R '

OR "

or acid addition salts thereof, in which R and R 'are identical n-alkyl radicals each having 5, 6 or 8 carbon atoms are and R "is an n-alkyl radical with

a) represents 5 or 6 carbon atoms when R or R 'has 5 carbon atoms.

b) represents 7 carbon atoms if R or R 'has 6 carbon atoms,

el represents 6 carbon atoms when R or R 'has 8 carbon atoms.

2. Process for the preparation of an amidine de; general formJ

HN -— C-

./ \ A Γ ir Ί

vy

OR '

R '

where R and R 'are identical n-alkyl radicals each having 5, 6 or 8 carbon atoms and R ″ is one n-alkyl radical with

a) represents 5 or 6 carbon atoms when R or R 'has 5 carbon atoms.

b) represents 7 carbon atoms when R or R 'has 6 carbon atoms.

c) represents 6 carbon atoms when R or R 'has 8 carbon atoms

or an acid addition salt thereof, characterized in that a nitrile of the general formula

CN

OR '

described, wherein R and R 'are alkyl groups. which together contain from 4 to 10 carbon atoms and R "contains a lower alkyl group N ¹ which contains from 1 to 4 carbon atoms, with the exception of an ethyl group, and in which R and R 'are not n-butyl. Means methyl radical.

in British patent specification 679 140 amidines of the formula

R.
/

HN = C-N '

OC ₂ H ₅

in which R and R 'are identical or different alkyl groups which together have 4 to IOC atoms, as Local anesthetics described.

It has now been found that new, higher homologs of these amidines according to the formula below 1 are effective against different types of tapeworm infestation in mammals. For example has It turned out that the new amidines against the infestation by the tapeworm (cestodes) Hymenoleois nana in mice and Taenia pisiformis in dogs and certain of these compounds against Dipy'idium caninum and Echinococcus granulosus in dogs, Monieza expansa in sheep and Oochoristica symmetrica are effective in mice. The new amidines are also essentially free of pb.rmaclogicals and toxic effects when given to the host in therapeutic Doses to be administered orally.

The novel compounds forming an object of the present invention are those of the general formula

OR "

with a halomagnesium derivative of a secondary amine of the general formula RR'NH and the reaction product obtained is hydrolyzed, where the radicals R. R 'and R' have the same meaning as above have.

The present invention relates to amidines and processes for their preparation.

HN = C-N

R '

OR '

or an acid addition salt thereof, in which R and R 'are identical n-alkyl radicals each having 5. 6 or 8 carbon atoms and R "is an n-alkyl radical ..lit

a) 5 or 6 carbon atoms
R 'has 5 carbon atoms.

l. if R resp.

668

hi represents 7 carbon atoms when R or R '

(i has carbon atoms.
ei i) represents carbon atoms if R or R '

S possesses carbon aioms.

Are amidines of the formula I in which R, R ¹ and R 'is n-alkyl and between them / wipe 16 and I ¹ J carbon atoms have including ueuenük · Jem more resistant tapeworm Üöchoristica symnicirica are effective in mice.', ₀

! -! .. ndworm infestation. which simply with a Λ: ι idin der For ... I or acid addition salt thereof K! can be mdelt, includes, for example, Echin ..ecus granulosus in dogs. Diphyllobothrium η. ,, ϋΜίηι or üiphyllobothrium erinaed in dogs. K / s or pigs. Monieza expansa b.-i sheep üi ■ I cattle. Davainea proglouina at Genüuel. R.iillielina tci'-agona. Raillietina echinobothrida " ii '.- lhigel. Taenia taeniafonnis in cats. Taenia I ..! Aiiuena or Taenia pisiformis in dogs.

Jic anihelmintische effectiveness of Amidinsäure-; i ■ uionssalze is hm Amidinteil of the molecule. ιΐϋ, Ι the acid can be any acid which starts with υ-. · \ Midinbase reacts to form a therapeur ι. compatible acid addition salt. e.g. Embo-1:. ·· -. llydrochloride-. Hydrobromio-. Lactal, citrate. S 'Ipliat-. Succinate, oxalate, p-toluene sulphonate. : Hydroxy - 3 - naphthoate or ρ - chlorobenzene; ■>: '. Mionate acidic addilion salts.

^:) Ie amidines of the formula i are relatively Si: ke bases having a jH in the range of 11 to 12 I; '- i therefore represent in their Sa zen the cationic component is, if in the form of the free bases they \ c.. : are followed, it is to be expected that they will be converted into salts by the stomach acid. Since the salts are very stable over the less stable free bases, the amidines of the formula I are in practice treated, stored and administered as acid addition salts.

The preparation of an amidine of formula 1 by reacting a halomagnesium dialkylamine of formula RR'NMgX (where X is halogen) with the appropriate 4-alkoxy-u-naphthonitrile and then Hydrolysis of the product is that described in British Patent 619,659 Procedure similar.

The halomagnesium residue is produced by the Grigr.ard reagent and the appropriate secondary amine. Any Grignard reagent can be used as the Grignard hydrocarbon radical acts as an inert hydrocarbon in the formation of the i'alomagnesium secondary amine is eliminated. The halogen can be chlorine. Be bromine or iodine, however bromine is preferred; Has ethyl magnesium bromide proved to be a good reagent to use.

The Halomagncsiiim-dialkylamine can with a 4-n-alkoxy-ri-naphthonitrile under reflux in one inert oiganischen solvents, such as. B. ether, over a period of time that depends on the nature of the alkyl and alkoxy groups in the reactants is. to be implemented: in some cases there is a period of up to 2 days to complete the Reaction required; however, 1 to 4 hours are usually sufficient.

The first reaction product is the flalomagnesium derivative of amidine. This is z. B. by an ice-cold aqueous solution of ammonium chloride hydrolyzed and so the halomagnesium residue is replaced by water stolT to release Jes Amidins. Usually the hydrolysis product is contaminated with secondary amine, which is produced by distillation removed in vacuo or by other conventional methods (such as crystallization of the salts).

The invention also relates to a process for the preparation of an amidine in general formula

HN - == C-N

OR

where R and R 'are identical n-alkyl radicals with in each case 5. 6 or 8 carbon atoms and R "is an n-alkyl radical with

a) represents 5 or 6 carbon atoms when R or R 'has 5 carbon atoms.

b) represents 7 carbon atoms if R or R 'has 6 carbon atoms,

c) represents 6 carbon atoms when R or R 'S has carbon atoms

or an acid addition salt thereof, characterized in that a nitrile of the general formula

CN

OR "

with a halomagnesium derivative of a secondary amine of the general formula RR'NH and hydrolyzing the reaction product obtained, where the radicals R, R 'and R "have the same meaning as above have.

The higher activity of the compounds of the present invention against infections by Hymenolepis nana in the mouse via the well-known and established taeniacid arecoline hydrobromide (synonym ; Methyl - N - methyltetrahydronicotinate hydrobromide; see "The Merck Index", 7th edition, p. 98) and male fern extract (synonym: oleoresm of Aspidium; see "The Merck Index". 7th edition. S. IOS and 753) is determined by the following experiment, the results of which are given in Table 1, explained.

Sexually mature worms are carefully squeezed in a mortar to free the eggs. These are suspended in tap water and large pieces of worm tissue are removed. After counting the Eggs in three aliquot volumes of 0.1 ml each made the total volume of the suspension 500 eggs

668 851

set per milliliter. Each mouse receives a Gavage 0.2 ml of the suspension containing approximately 100 eggs. 14 to 15 days after infection occurred eggs in the faeces. A solution of a compound of the invention was made in distilled water as such or as an emulsion by grinding for 24 hours with gum tragacanth in a Wilz mill manufactured. The dose volume was finally adjusted to a value of 0. ImIOg body weight. On the P. or the 18th day after the infection, each mouse received a solution of a compound with a single dose vcMi 200 mg of the hydrogen chloride salt of a compound, based on the base per kilogram Mouse body weight.

Wu later expressed three days ^r to the contents of the small intestines intact under water in a large petri dish and tested against a black background. Particular care has been taken to find and enumerate all tapeworm heads. The appendix and rectum were opened and checked for whole worms or limbs shortly beforehand removed by peristalsis. The evaluation of the activity was based on a comparison of the number of mice in the test group which were completely free from any infection and the number of mice which were not completely free.

ίο In 'labelIe 1, R, R' and R "have the same Meaning as in general formula 1. The column "Number of surviving mills" gives the Number of mice still alive at necropsy and the column “Number of infections free mice «indicates the number of surviving mice which, after necropsy, were found to be completely free of any infection were found.

Tabel example

R (- ■ = R)

n-amyl j n-hexyloxy
Male fern extract
Arecoline hydrobromide

Number of Maum:
with dose volume

10

number of
The mouse borrowed

5 4th

Number of \ on
Infections
Free mouse

5 (= 100 "« I
2 (50 "uI

2 (50 "ο I

In practice an amidine can be used for treatment a tapeworm infestation in the form of an orally-imchable pharmaceutical preparation, which an amidine or a salt thereof together with a therapeutically acceptable carriers therefor. The amidine or a salt thereof may advantageously be in the form of tablets. Capsules. Oblai.cn, each with a predetermined amount the connection contains, advertise presented. It can also come as a powder or as granules, as a Solution or suspension in a non-aqueous or emulsified liquid are presented.

The novel amidines described herein can also be used as a component of the host's diet a tape heat transfer device and those described Preparations include feed additives in which an amidine is present as an active ingredient and which is suitable as an additive to the feed either directly or after dissolving or mixing.

The preparations can be prepared by any method of pharmacy, which Tableting by compression or compression molding. Granulating, grinding, stirring, coating. Grind and rolling includes. Carriers that can be contained in a preparation are diluents, dissolved substances, buffers, taste-improving agents. Binding, dispensing and surface-active. Thickening, Lubricants and coating materials, preservatives, antioxidants, animal feed and bacteriostatics and any other compatible ingredients.

The preferred preparation for the treatment of tapeworm infestation are tablets and granules, comprising an amidine of the invention or a salt thereof.

The following examples illustrate the invention. All temperatures are given in degrees Celsius.

The mass values of 16. 20 and 100 correspond the opening sizes of 1130, 965 or 100;

example 1

Production of
N, N-Di-n-amy! -4-n-hexyloxy - (- nap'haniidin

A Grignard solution was made from magnesium turnings (5 g) and ethyl bromide (22 g. 0.2 mol) in absolute ether (200ml) in a stirrer. Reflux condenser and dropping funnel-equipped flasks were prepared. Di-n-utnylamine (32 g) was added to this mixture in such an amount that that this was held at a gentle reflux and after the addition was complete. the solution was refluxed for a further hour. To the refluxed solution became an ethereal solution of 4-n-Hexyloxya-naphthonitrile (38 g, 0.15MoI) for a period added for 30 minutes. After the addition was completed, the reaction mixture became Refluxed for 24 hours, chilled and poured with an ice cold solution of acidic acid hydrolyzed. A substantial amount of solid separated and was filtered off. The filtrate was extracted with * ether, the extract discarded, the aqueous layer treated with a base and treated with Ether extracted. The essential extract formed extract I.

The solid originally obtained by filtration was dissolved in warm water, the solution then basified and extracted with benzene to give Extract II. Extract I and Il were then separately over a steam bath and optionally using vacuum for removal the last traces of di-amylamine evaporated. The two basic residues were then in dissolved with absolute ethanol and with ethanolic

7 8 U

Made hydrogen chloride acidic. Absolute ether posed. The melting points of the salts are with was added until it became cloudy and then the crystallization of the amidine hydrochloride was brought about by rubbing. The resulting salt had an N, N-di-n-amyl-4-n-amyloxy

Melting point from 217 to 218 °. 5 "-naphthamidine 220 to 221

. . N.N-Di-n-hexyl-4-n-heptyloxy-

Example 2 "-naphthamidine 197 to 198

The hydrochloride salts of the following amidines were-! ^, N-n-DioctyM-n-hcxyloxy-

in the manner described in Example 1 her-a-naphthamidin 190 to 191

Claims (1)

Palent claims: 1. Common formula amidines In British patent specification 679 119 are substituted Amidines with local anesthetic properties of the following formula HN - "CN