DE1802394A1 - Aminoguanidines, process for their preparation and their use - Google Patents

Description

! Dft. BERQ DIPU-INa. STAW

PATENTANWÄLTE • MÜNOHKN ft HiLBUWTRAS · «··

10, Oct.

Attorney file 17 738 Be / Sch

American Home Products Corporation 685 Ihird Avenue, New York 17 O.S.A.

"Aminoguanidines, process for their preparation and their use * ¹

This invention relates to new aminoguanidines, a method for their manufacture and pharmaceutical use »Virkaaiaer aminoguanidines as or in medicaments for suckers, including PÄeneohen.

Eo are a number of benzylidene aminoguanidines found in the Benaol ring are monosubstituted, known, for example

AHP-4220-f -2-

909819/1249

ORIGINAL INSPECTED

weis © by the, German © i> atentsefarift 958832 «» in the The same patent is also (3 »4 - Diehlorbenzyliden) aminoguanidine described the antibacterial © and. fungicide, but has no strong hypotensive activity.

British Patent 1,019,120 (bhell) are Aminoguanidines of the general formula

OH-N

and acid addition and quaternary ammonium salts are described, where in the formula 1 © in halogenated or a hydroxy, alkoxy or Äöylo3 £ j group ₉ m a

1 * gansie Sahl from 1 to 5? R eia hydrogen atom or a Is hydrocarbyl group, and hydrocarbyl group sai

1 ? can with the restriction that the remainders U wati K

"Raefl can form a heterocyclic ring system" The hydrocarbyl groups can be substituted "for example by one or more amino ₉ imines" _a Alkylaiiao and DialkylaainogruppQa and © in © such, group, vjie for example in the compound N-CSse-JDicnlorbenzylidaa} Ii '- Araidinohydrazine is an Araidinohydrazine group. Sh2.11 found that the compounds of the above formula have herbicidal activity and furthermore in the patent specification herbicidal preparation-i .:

909819/1249 ' ^?

containing such compounds.

It has now surprisingly been found that some of the Compounds of the above general formula indicated by Shell have pharmacological activity, v / ie this is specified in detail below.

The present invention provides a pharmaceutical one Preparation containing a compound of the general formula

X-O = N-KH * ö -N (I)

or an acidic addition salt thereof (where X is an immediate Bond or a methylene, ii.tb.ylen- or

1 2

Is vinylene residue? R _t H and Y are identical or different and each is a halogen atom or a nitro, amino, lower · © :: · alkyl, lower alkoxy, substituted or unsubstituted benzyloxy, hydroxy · "or trifluoromethyl radical _t cx.d η = O ₉ i _¥ 2 or 3, or η = 1 X3t and ϊ and R additions form a methylenedioxyx'ess? H ^ hydrogen, cycloalkyl of 3 to 5 carbon atoms, lower alkyl ₉ iithynyl, allyl or ßenayl is j the grids R ^ and Rt- each a hydrogen e / eos od sr * a lower alkyl rent, or H. and B _{E t} ztujrr-.iynoii with nitrogen atoms, with which they are connected, ' ^: one Imidasaolin ring form

909819/1249

BAD ORfQfNAL

CD

the; and Rg is hydrogen or lower alkyl with the proviso that when R ^ and Hc together form an iridazoline ring, R _{6 is} hydrogen, "lower alkyl" and "lower alkoxy" denote radicals containing up to 6 carbon atoms and one pharmaceutically acceptable Comprises carrier, the preparation being presented in a standard customary form for eyes, including humans. For example, the preparations should be suitable for oral or parenteral administration to humans. The invention therefore does not include herbicidal preparations which contain compounds of the general formula (I) *

Where there are more than two substituents in the insol ring (i.e. ₀ η >> 1, 2 or 3) _t . ϊ as a precaution © in Halogenated. A particularly preferred group of connections of the above general formula are solcae in which η »= O and R is in the 6-position. This preferred group of compounds corresponds to the general formula.

- O «. MHC - N

CO Y-W IB

CD OO

CO

^ uni of the acid addition salts the same-n ^, in which the radicals ί ^ and Eg equal and hemogenous atoms ^ Nitroresto, lower alkyl

~ jf

traveled or lower A LkO yyi ^ sje tindj and X, R ^, R> R- * and

BADQiJGfNAL

H have the meanings explained above.

Examples of R and R ² radicals are fluorine, chlorine, bromine, nitro, unsubstituted or substituted amino (for example dimethylamines), lower alkyl preferably with 1 to 4 carbon atoms (for example methyl or ethyl), lower alkoxy, preferably with 1 to 4 carbon atoms (for example foethoxy or ethoxy), substituted or unsubstituted benzyloxy (for example "benzyloxy or p-halobenzyloxy) and trifluoromethyl Y is preferably halogen, alkoxy or alkyl, for example fluorine, bromine, chlorine, l-iethoxy or frethyl · optionally Y and / ^

H triiien Kethylendioxyrest, for example to the 5- and Form 4 positions of the benzene ring. Examples of ir are hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, methyl,

4 5 Ethyl, Propyl, Ethynyl, Allyl und Benzyl i The iteste B ", E ^ | and R are preferably altogether hydrogen, although they can also be, for example, methyl, ethyl, propyl or butyl. R and R ^ can optionally form an imidazoline ring if R 'is hydrogen.

In the compounds of the present invention, when "X" forms a direct bond between the substituted benaol ring and the -C * carbon atom, dio

Ix

Compounds as subjtextuierte Phowothylidenaminoguani-

90 98 1 9 / 12A9

-6-

~ 6 -

dine denotes; when "X" is "ethylene", the compounds are called 3-substituted propylidene aminoguanidines and when "X" is "vinylene", substituted cinnamylidene aminoguanidines. Typical examples of these are ^ 2,6-dichlorobenzylidene) -amine £ 7-guanidine acetate, £ j ^ 2 , 6 ~ dichloro ~ phen & thylidene) -aminoT-guanidine,
propyliden7-a5iino) -guanidine and
den) -aminoT-guanidine.

The compounds of the formula I generally have one or more of the following pharmacological activities, namely hypotensive activity, antibacterial activity, activity against you. Jäenteales Hex: w; isysteBi (sura example antireserpine, iVatifflorphin- ₄ antioxytreroorin-, depressor- or nsydriatic effectiveness), anaigetic, diuretic, liyperglyeeaiseh ©, anti-inflammatory and /i^poti "are generally Hypotensive activity particularly valuable, especially the hypotensively active compounds with substituents in the 2- and 6-positions of the benzene ring, and some compounds with substituents in the 5- ^ 1 position (see Example 2'-hydroxy-3,5-dichloro ^ ~ and 2 ₉ 5-Dimeth03 £ ybenzylidene), compounds having substantially a bacterial activity but little or no hypotensive iVirksamkeit generally include 2,3-dihalo, 2,4-dinitro- and 2,4 ~ Diehlorben2ylidene. Other * by The compounds created by the invention include powerful stimulants or psyches, energy-stimulating means, calming

909819/1249

Medicines and drugs against Parkinson's disease * see disease.

For the production of pharmaceutical preparations from the pharmacologically active compounds of the general formula I, pharmaceutically acceptable carriers can be in solid or liquid form. The preparations in solid form include powders, tablets, capsules, cachets and suppositories containing appropriate dosage units. As the solid carrier, one or more substances can be used for the preparation of the aforementioned preparations, further wherein dieee as extenders, or diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders CDER _t al3 disintegration of the tablets könnenj act favoring agent, the carrier may further can be used as a capillary material. In the case of powders, the carrier is a finely divided solid that is mixed with the finely divided compound and is then made up in proportions. In the tablet the compound is mixed (ger with a Trä-, having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99 $ of active ingredient. Suitable solid carriers are ISagneaiumcarbonat, magnesium stearate , Talc, sugar, milk sugar, pectin, dextrin, starch, gelatin, tragacanth, methylcd cellulose, sodium carboxymethylcellulose, a low

- * melting wax and cocoa butter. Capsules can go through ro

^ Enveloping the compound (with or without others

Carrier) are produced by means of a carrier.

-8th-

BADOPLIGlNAt

Liquid preparations contain sterile solutions, Suspensions and JSmulsions · As an example, you can Water — propylene glycol solutions for parenteral injection mentioned v / erden “Liquid preparations can continue to be used Solution presented in aqueous polyethylene glycol solutions will. Aqueous suspensions for oral use are suitable, can by .Dispersing the finely divided compound in sterile water with viscous material, ^ natural or synthetic slimes, resins, for ßei-. play gum arabic, ions from rather resins, faethyleellulose, Sodium carboxy methyl cellulose and other known ones . ^ dispensing means are produced.

Preferably, the pharmaceutical preparation has a unit dosage form, in such a form the preparation becomes; "divided Sinheitsdosen \ foengen the appropriate connection" in containing, wherein the Einheitisdosierüngsform can be a packaged preparation, the package as such w- discrete quantities, the 'preparation, for example packetiei. ¹ · te -'powder "of Plaschcliexr 'or ampoules contains <,

The unit dosage form may be a capsule, or tablet, © as such, or it may be any suitable number :? of these forms in "Ford packaged. The amount of compound in a single dose of the preparation can be adjusted from 1 mg to 10G-QIg ₉ according to the particular application and potency of the" iJirkstoifsy, "

BATH O ^

T802394

In the phartnacological evaluation of the invention Connections were among other things the following investigations used.

(a). To examine the bypotensive and antihypertensive Effectiveness, the following procedures were carried out:

(1) Female "Sprague ^ Dawley" rats were made hypertensive by the application of a] igur-8 ligature to the left kidney and contralateral nephrectomy, as in Grollraan, in Proe, ooc, rütptl, Biol, Med. 57, 102 and Baum, and Shropshire, in Am · J. Physiol «212, 1020 (1957). Systolic blood pressure was indirectly detected on swan using a Umiiüllung and a bottling sleeve as the "deck-Caudal plethysmograph" ,, produced by "Decker Corp." B-ala-Cynvjyd, Pa, '% of the Voluraveränäerung of 8ch ^T /; an3i3, if they occur with every blow of Horas * The! plague compounds were administered orally with various con2-ent /? at? ion-3.i by means of a gastric sonäe -and the pressures were: vo: -y the dose delivery and 1 , 5? '·· * ^ nd sometimes detected 24 hours later «

The inventions of the reduced GJestvorfahrsn, specified in · dei ^ οι · 311. if you ox'al at a bc .- 'oich. from 'about 1 seg to about 70 mg / k ^: Köi not administered ^ r' - / urdcn, in general the blood pressure. i: a r-average -iam 20 to 60 ram Hg · «" In this point yur.i

90981 9 / 1-249 '

BAD ORHÄINAU

Particularly effective results by / T2 ₉ 6 ~ dichlorobenzylidene) -amino7-guanidine and _J ^ T2-chloro-6-fluorobenzylidene) ~ amino7 ~ guanidine nitrate, as shown in the following table "aufgeseigt obtained, this indicates © the maximum pressure changes in Batten, which occur at any of the three observation times regardless of the time of occurrence, although these peaks were usually observed at 1.5 hours.

^ abelleJL

Connection dose number d, blood pressure (mm Hg)

Control change

dose
(ing / kg) Number d.
Rats 1 12th 2 11th 3 11th 4th 8th 7.5 4th 10 4th

174 -29 eenzylids) -

aiBino7-guanidine- 2 11 183-34 acoteit

185

183 -43

/ jfe-chloro-e- 7.5 4 194 -39 £ luorbenzylidene) -

J "_ 178

nitrate

(2) Hypertension was assessed in Plunden through a three-step process generated, where each under Psntobarbitai · - Anesthesia (35 rag / kg) was performed. The carotid artery bifurcations were exposed by two sciinittees and the sine by stripping off the 'Ad' / entitia in the Area entnez ^ / to di © right kieren artery was through Flank cut exposed and secured by a silver-gold leaf clamp susaarae-pressed. Finally the left kidney was removed * The systolic / diasoolic blood pressure was indirect

909819/1249

BATH

voin tail with a condenser microphone according to that in Prioli and Winbury, in J. Appl. Physical. 15: 523 (i960). yfT2,6-J) was ichlorbenzyli guanidine -amino7-den) intraperitoneally 5 '1.0 and 2 »5 rag / kg in four groups of hypertensive dogs with doses of O _e and orally ing with 5 / kg applied and de? Blood pressure would be determined after one and four hours. The results are set out in table B below:

909819 / t249 "^ - ^ 2-

BATHROOM 0RH3INAU

Table B.

link

benssyli & en} -aminoj-gtiani
dinacetate

- .0.5

Handling number d. Blood pressure (mm Hg).! Us dogs control change

i.p

204/131 -28 / -21 ± 8/6. ± 11/9 Hers speed (beats / M Control change

102 ± 6

-50 ± 12

2.5

i.p.

i.p.

204/137 .- ± 10/9 ± 6/8

• 190/135 -31 / -32 ± 7/8. ± 5/9 111-10

orally

202/127 -26 / -34 ± 9/5 ± 9/11

103 * 7

In the study given above, all doses of / T2,6-dichlorobenzylidene) -atnino7-guanidine acetate decrease significantly blood pressure and heart rate, whether administered intraperitoneally or orally.

(b) To study the effectiveness on the central In the nervous system, the following procedures were performed. ·

(1) The connections are initially classified as follows: the compound was administered orally to three mice at each of the following doses: 400, 12? » 4-0 and 12.7 mg / kg administered.

The relationships were observed for at least two hours. During this time there were signs of general stiffness (ie, increased spontaneous motor activity, hyperactivity with palpable stimulation, twitching or convulsions), general depression (ie reduced spontaneous motor activity, reduced Respiration) and autonomic activity (i.e., iMiosis, mydriasis, diarrhea) are observed. The animals are examined for reflex changes (ie flexor extensor) and assessed for the presence of iedationsafcaxia using a climbing pole and a sewn overhead.

i) as ^{: 1} Sddy Hot "Plate Method" (Nathan 3. EiLdy and Porothj Leitabacb, J. Pharmacol, iixpsr. 'i'herap, 107: 385 * 1953) v used to test the analgesia.

909819/1249

by giving each animal a maximum electric shock subjected to the test of anticonvulsant activity

'(2) The antimetrazole effectiveness was measured as follows: Connections with a number of Dosaiv: were at Administered to groups of six mice. i & lne hour later (or half an hour later, if the compound was administered intrafe peritonally) the animals were given metrazol 125 mg / kg intraperitoneally tested for response. Entering clonic and tonic convulsions and death were observed for half an hour. The protection against convulsions and iodine was determined by comparison with concurrently running controls determined. Kine BD ^ q opposite Convulsions and / or death was determined statistically from the probability of the deviation from the mean

of dose diagrams (probit-log doae curves).

(3) Antagonism to ßeserpinptosis was after

I Rubin et al. JPS ¹ JJ. VoI 120 page 125 (1957) geroessen.

(4) Antitremor effectiveness was determined according to & @ m method of iJverett et al., Science Gol "124 öeite 29 (1956) measured"

(5) Ataxia was determined by the method of Dunham and Heya, J ₉ Am ». Phartn. Assoc Scientific ed. VoI * 46 beite 206 (1957).

C6) Antiioorphine effectiveness was determined according to the Uoltent © st _s

"Acta Pharmacol et iPoxicol" Vol 13 deite 113 (1957) ge>^; _ö; 909 819/1249

measured·

(7) Protection against maximum Klektroechoek was after the method of Swinyard et al., J. Phermacol, Vol.106 öeite 319 (1952V determined.

(e) The hypoglycanic potency was measured as follows:

Male rats weighing 170 to 200 g were left you sober overnight, after which a control blood sample " taken from the swan and a test dose of 60 mg / kg Was given by gastric tube * Following were Blood samples taken every hour at five hour intervals. In general, a connection was considered active viewed, v / erm lowering blood sugar by about 2Q # during at least three of the five hour test dates was observed,

(d) The Antient was zundungsvjirksamkeit according to the method of Buttle, inter alia, _o, Mature Vol. 159 page 629 (1957) and Winter u _o a., Proc. Joe, Expo ßiol _e Hed, Vol. 111 oeite 544 (1962) measured "

(e) The diuretisiche V / was irksarakeit by the method of Lipschita _s u al., J "Pharmacol 79" 9? (19 ^?) Measured.

(f) The antibacterial effectiveness was measured as follows:

90 9819/1249

Staramlösungen with 10,000 ug / ml were prepared in suitable carriers · Zweifaehverdünnungen »1 ml. Volume were made with sterile water were _t of each dilution in 9 ral placed in sterile petri dishes of agar solution. The cured surface was seeded with test organisms and incubated for 18 hours at 55 ⁰ C, wherein the check against various standard ~ Mikroorganissnen was performed and the minimum inhibitory concentration (HIQ) was measured.

When used therapeutically as medicinal agents, the compounds according to the invention are usually administered daily with an initial dose of 0.1 mg to 10 mg per kg. However, the dosages may change depending on the needs of the patient. In particular, / C2 can be used in warm-blooded animals in the range of 0.1 bit 10 mg per kg per day _s 5-Dichlorbensyliden) amine was £ 7 * _i guanidine of the found that it "has ness" excellent hypo-intensive effect although changes can be made · However, a dose level in the bar of 0.05 rag to 2.5 rag per kg live weight per kg is used, which is worth seeing _? ubi effective © to achieve results,

With this in mind, there are new © and useful preparations created by having the active ingredient of this invention mixed with a feed. Suitable feedstuffs are at F.B. Morrison "Feeds and Feeding", New York (1946)

described,

819/1249

When (a) Hr is cycloalkyl of 5 to 5 carbon atoms, lower alkyl or benzyl and the remaining variables (the radicals HV R ² , ß ⁴ »R ⁵ * H ⁶ , X, Ϊ and n) have the same meaning v / ie above or (b) R ^ is hydrogen and -R, R and Y nitro, amino, lower alkyl, substituted or unsubstituted bensyloxy or trifluoromethyl

are, where η »is 1, 2 or 3, or R and Y together form a methylenedioxy radical, where η = * 1, are the Compounds of the general formula (I) new compounds f and the invention further provides such compounds and their acid addition saline »

The compounds of the general formula (I) can be prepared if you sin aldehyde or ketone of the general formula

(ID

with an aminoguanidine of the general formula

1IH - 0 - M ^- "

or a salt θ-or same -uiasotzt, where in the Fo the hosts © R ¹ , R ² , R ⁵ , R ⁴ , R ^ ₅ H ^& , Y ₅ q and X are the ax of the general formula (I) specified meaning

909819/1249

18-

ίο -

* Preferably when connecting the all « common formula (III) η «O and R in the 6-position, i.e. e3 is a compound of the general formula

R ¹ -

X-C = O

I ₅

/ 1 P 2

p in which the radicals R, · ^ν Κ, Ir and X have the meanings given in connection with the general formula (II).

Di © reaction is usually carried j £ rhitsen of the aldehyde or ketone ₉ in solution in an organic solvent, _{y 9} (for example, ethanol) with an acidic aqueous solution of a soluble Säureadditicnssalaes of Arainoguanidin as the Kitrat CDER acetate performed _ö The Srhits @ nv / It is generally carried out on a steam bath for reaction B-sides from a few minutes (in the example ΊΟ minutes) to a few hours (for example 16 hours) ₉ whereby the time depends on the particular connection intended to be made presence of an inorganic or organic acid (sum as nitric acid, acetic acid, lactic acid, glycolic acid, trifluoroacetic acid, formic acid or gluconic acid) is liährend eggs Reektion recommended wGbei in this Fallo the ifeodukt as obtained ßäürc- addition salt may »the free base thereof _e if desired , by neutralizing with a suitable one

909819/1249; ■ ν BAD LOCAL GINAL

Base can be obtained.

Many of the substituted phenylcarbonyl starting materials of general formula (III) are commercially available, and they and others can also be _{prepared by any conventional method as described in 0, A 0} 62 _t 995Ί · £ and 57, 136780 · The herein as Alkyl-substituted aminoguanidines used in the reaction can be prepared by the process described in J. Med. Chenu 6, 28 $ (1963), while (2-Iffiidazolin-2-yl) -fe-fdrasin according to the method described in J. Org , Ohem. 18, 790 (1953) described sn method can be prepared.

The compounds of the general formula (I) can further * produced by other methods known to the person skilled in the art for example when the radicals R, JK and E Hydrogen, by overheating the corresponding thio-

of the aldehyde or ketone of the formula (III) with k od @ r by reacting a corresponding hydrazone d.o £ 5 aldehyde or ketone of the general formula (III) with O ^ / anaoid *

Sic Skureadditionssals © can be prepared by treating the free B. H3 with an acid. Suitable © Säureacxliwionfssalze the inventive compounds beinhal-:; on u _fr a-. Inorganic acids such as hydrohalic acids (miraculous hydrochloric and hydrobromic acids, for example), sulfuric acid, nitric acid and phosphoric acid, and organic acids

909819/1249

- -20-

LOCAL BATHROOM

Acids such as lactic acid, fumaric acid, malic acid »citric acid, Formic acid, acidic acid, glycolic acid, succinic acid, Gluconic acid, glutaric acid and maleic acid

The following non-limiting examples explain the preparation of the compounds of the general formula (I) and pharmaceutical preparations containing such compounds

/ C2,6-dichlorobenzylidene) amine £ 7-guanidine acetate

A solution of 4.5 g of 2,6-dichloro-naldehyde in 20 ml of iitha is added to a solution of 3.5 g of aminoguanidine bicarbonate in 4-0 ml of water and 2.5% of acetic acid. which gradually dissolves, the solution is heated steam wcmn on spine. After a ötun | jL ©, the solution is filtered and concentrated on half a töiumen in a © inir crystal dish with the formation of 5.5 β

inacetat ai with an equilibrium point of 192.5 ⁰ O with decay "

J ^ calculates for -GgBgOIgKj ^ %% Ög

^ 41 0 ää 01, 19 »25 N"

19.01 S »

Similarly, we use the same procedure as in 1, but an andsto-organic or an-acid "instead of Ss3igaMurs" is used

90801 S / iI ^: 49 oi

BAD ORJQINAL

the corresponding acid addition salt obtained.

/ r2-0hlor-6-fluorobenzylidene) -aB »ino7-guanidine nitrate

Is Following the procedure of Example 1, but SetAt 2-0hlor-6-fluorbenzylaldehyd in place of 2,6-Dtohlorbenzaldehyd and nitric acid in place of acetic acid, eo _J / r2-chloro-6-fluorobenzylidene) -amino7-guanidine nitrate a with a melting point of 222 to 223 ° O (decay) obtained *

Analysis: Calculated for CgHgOlFN ^ ENT ,:

%% 34.61 G ₁ 3.27 H, 25.23 N, 12.77 Gl

Example 3
^ j2,6-Dibromo- »a-'Biethylbenzylidene) -amino7-guanidine acetate

Oan follows the procedure of Example 1, but uses 2.6-dibromoacetophenone in the place of 2,6-dichlorobenzaldehyde, the result is 2X2 "6-dibromo-a-nethylbenzyliden) -ainino7-guanidine.

Example 4

_J ^ T2,6 «Mfluoro-a-ethylb6nzylidene) - aroino7-guanidine acetate

Follows the procedure of Example 1 but uses 2,6-difluoropropiophenone instead of 2,6-dichlorobenzaldehyde, one obtains ^ T2,6-difluoro-a-ethylbenzylidene) -amino7-guanidinao budget·

909819/1249

—22—

~ 22 ~

Example 5

^ Γ216 - Di chloro-a ~ benzylidene) -amine ^ -guanidinac etat

The procedure of Example 1 is followed, but 2,6-bichloro-a-phenylaeetophenone is used instead of 2,6-dichlorobenzaldehyde, this gives ^ 2,6-Diehlor-a-phenylbenzylidene) -. 5imin27-suanidinaeetat after a long period of heating.

£ ( 2,6-Diehlor-α-allylbenzylidene) -ainino7 ^; -Suanidinaeötat

If the procedure of Example 1 is followed, but 2 _P 6-dichloro-a-vinylacetophenone is substituted for 2,6-pichlorobenzaldehyde, then one obtains ^ j2,6 "dichloro-a-allylbenzylidene)

example

Following the procedure of Example 1, but uses 2.6-Dichlorpropiolophenon to slide instead of 2,6-Dichiorbens "aldehyde so obtained?, You ^ J ^ jo-Diclilor-a-ath ^ ylbenzyliden)» aaino7-guanidinae < 3 fact »

Example 8

/ Jfe 16 "dichloro-a-propylbsn2sylid © a) -aiaino7-guanidine acetate

If one follows the procedure of Example 1, but substitutes 2,6-Diohlorbutyrophenon to the © Stell © of 2,6-Dichlorbönzaldeijyd »then we get m & n ^ T2 ₉ 6 ~ Diehlor-e -« 'propylbonzyliden)

nuanidinacotat ♦ 909819/1249

«AD ORfGiNAL

«23

Example 9

ßfe , ö-dichloro-oc-cyclopropy (benzylidene) ~ amino7-guanidine-

acötat

Following the procedure of Example 1, but using 2,6-dichlorocyclopropiophene in place of 2 »6-dichlorobenzaldebyd * This gives / C2,6-dichloro-a-cyclopropylbenzylidene amine £ 7-euanidinaoetat.

Example 10 i

hy4rochlori &

If the procedure of Example 1 is followed, but substituting 2 _t 6 -dicethylcyclobutyrophenoa in place of 2,6-dichlorobensaldehyde and salesturo in place of acetic acid, one obtains "2 _t 6 -dioethyl-a-cyclobutylbeneylidene) -amine ~ Gusnidine hydrochloride

Example 11

^ J2, 6 * Diffiet hoxy-a- * cye lopentylb enzy liden) -ajuinoT-guanidine-

eulfate

If the procedure of Example 1 is followed, but 2,6-dicsothoxycyclopeutiopaenone is substituted for 2,6-dichlorobenzaldehyde and sulphuric acid is substituted for acetic acid, then benzene is obtained
doa) -ßiBino7-'3uanidinsulfat,

908819/1249

If the procedure of the preceding examples is repeated with suitable reactants, the acid addition salt © of compounds corresponding to the following formula was obtained
"1

X - 0 st N - NH - C - N

wherein in each compound the substituent di © follows gend © mean:

H ¹
■ MfcXMfW R ²
-ηώ: ** » £ ή £ £ X (a) F. F. H H H H (b) CH ₅ GH ₅ Η " H H Ce) Gl Gl ■ H H H OH ₅ Co) G ₂ H ₅ G ₂ H ₅ PI CE 5 - ^0H 3 OH ₅ Ce) Cl Gl H H H H OH = Cf) ' Br W "■ GH ₅ ' O ₂ ] B ^. H O ₂ H ₅ (B) no ₂ - uo ₂ i- H H C ₅ H ₇ E. «Do Ch) O ₃ B ₇ 0 ₃ H _? ^; H OE 5 H. OH ₅ U) σι - ■■ · · 'Ή' "" - ■ H H H OH ₂ CD) . O ₂ H ₅ Q- ^: ' ^f ° 2 ^H 5 ^: H E. (k) Br ' Br ^f - ' H H H - CD OH ₅ O GH ₃ O ' :, _¥ -: ..-. ". S ₇ - "■ H Η ¹ Cm) Gl 01 II H H H Cn) 01 Bs? H H H H Co) Br - F - ■ - - "- Ή ■ H H H ■■ '■ _ ■■

0 9 819/1249

-25 -

Example %

Following the procedure of Example 1, but is 2- (2-lEjida25olin-2-yl) -liydrazinhydrochlo3? Id in the place of aminoguanidine and hydrochloric acid in place of acetic acid, one obtains 2 ₉ 6 ~ dichlorobenzaldehyde, (2 ~ iTnidazolin ~ 2-yl) ~

bydrazon *

The following connections manufactured:

2,6-Dibrombenaaldehyde, (2-iisidasolin ~ 2-yl) «» hydr8zone; 2,6-dimethylbenzaldehyde, (2-imidazolin42-yl) -hydra3one; and 2j6 ~ BiEietho: xybenzaldehyde, (2-iiaida3olin-'2 ~ yl) -hydrazone.

If the procedure of Example 1 is repeated, the the following connections established:

, G-Dimethyl-B-cyclopropylphene.tbyliden) amine £ 7-guanidine;

, 6-Dibroniphene obhyliden ) - ^ Άίζ ±

, 6-diethylphenyl) -T ~ inethylpropyliden7-amino) -6uanidine;

- (2 _J e-Dibroiophenyl) -propyliden7-aniino) ~ g ^v uanidine; / t2 _? 6-Diiaethoxycinnarayliden) '- a5nin ^? ^l -'giianidin and / r2 _t 6 ~ DiffiGthylcinnamyliden) -amino7-gu & nidin,

2r example 15

4? * / X ?. j »4 ~ dichlorob'ena3rlid0n) -aHiino7 ~ guanidin0al2e

CO "-

(a) Its solution of 9 g of 2 _s 4 * diolarbene-aldehyde in 25 ml

co -

Ethanol was added to a solution of iron 7 g of aminoguani & inbiearboiiat, dissolved in 60 ml of water and 3 ₃ 2 ml of concentrated nitric acid, to which 60 ml of ethanol were added. The solution was heated on the steam bath and after 10 minutes a precipitation began, * gradually assuming up to 1 hour to separate "The solid was collected on filter © INEM and V / ater and washed ethanol * He weighed 15 S and had a melting point of 24-5 to 246 ⁰ O imter decay.
Analysis: Calculated for OgHrtOlgHcO ^;

#: 32.67 0.39 H ₉ 24.11 01, 23.84 N Found: % ·. 32.71 0.2 * 82 H, 24.2 01, 23.6 H.

(b) Put © in 5 ^ 5 b »1 lactic acid © in the place of nitric acid in example 15 (a) »this is how the lactate is obtained · yield 11 g, melting point 187 to 188 ° 0,

Analysis: Calculated for ^^

%: 41.14 0, 4.39 H, 22.08 Cl, 1? ₉ 45 N Found #: 41.37 G, 4 _S 44 H, 21.7 01, 17 ₉ 7 N

(c) 4.5 to SetAt S Glykolsäur © in place of the Sälpetersäure of Example 15 (a), then the obtained glycolate "Yield 10 g, mp 215-216 ⁰ O.

Analysis: Calculated for O ₈ HqCI ₂ N ^ ^β 0 ₂ Η ^ 0χ:

&: 39.10 0, 3.9 ^ • H, 23.09 01, 18.24 N Found % t 38 ^ 70 0 »3» 76 H, 23.0 01, 18.3 N

(d) 3.5 g of 2,4-dichlorobenzaldehyde are added to 10 ml of ethanol

909819/1249

2.0 g of trifluoroacetic acid, dissolved in 30 ml of water and 2.7 g of aminoguanidine bicarbonate, filtered the solution and concentrated it in an evaporation dish and obtained 4 g of trifluoroacetate with a melting point of 163 to 164 ^° C.

Analysis: Calculated for OgHgCIgN ^ * ΟΡ, ΟΟΟΗ:

#: 34.79 O, 2.62 H, 20.55 01, 16.52 F Found % t 34.46 O, 2.62 H, 16.2 N, 20.4 01, 16.4 F.

(e) Adding 2.3 ml of formic acid to a suspension

of 3.5 g arrainoguanidine bicarbonate in 30 ml water gives a® solution, to which 4.3 g 2,4-dichlorobenzaldehyde in 30 ml ethanol was added. An oil was separated off which gradually dissolved as the mixture did After an hour the oil was gone and the solution was filtered into an evaporation dish and concentrated to half volume, whereby small white rosettes began to form (were collected on a filter to give 4.5 g, melting point 245 to 246 ⁰ G with disintegration.

Analyst: Calculated for ÖqH ^ qCXjIS ^^:

#: 39.01 0, 3.64 H, 25.59 01, 20.22 H Found % i.38.62 0, 3.64 H, 25.8 01, 20.13 H

(f) A solution of 9 g of 2 _t 4-dichlorobenzaldehyde in 30 ml of ethanol was added to 7 g of aminoguanidine bicarbonate, dissolved in 1 o ml of vI water, with 9 g of gluconic acid @ aiahydride and

909819/1249 , -28-

the mixture was heated on the steam bath overnight. The syrupy The solution was concentrated to dryness on a steam bath, the gluconate remaining as a glassy solid, which after pulverization took up an electrical charge and was very easily dispersed as an aerosol. That Powder had a melting point of 82.4 0 »

Analysis? Calculated for C ^^ H ^ gGlgN ^ Ög;

SlS: 38.11 C ₉ 4.11 H ₈ 16.07 Cl * 12.70 K P Found $ i 58.45 C ₉ 4 ₉ 56 H ₉ 16.6 Cl, 13.06 N

(g) A solution of 9 g of 2,4-dichlorobenzaldehyde in 50 ml Ethanol was mixed with a solution of 7 β aainogutuiidin bicarbonate in 80 ml of water, heated with 4 ml of acetic acid on the steam bath for 2 hours and filtered » After cooling, 15 g of white © platelets of Acetat® were stored

* ft

starting with a melting point at 18? up to 188 C with decay «, _

Analysis: Calculated for Ciq ^H 12 ^C1 2% ° 2 ^s

#: 41.25 0.4 _f 16-H, 24.36 Cl _f 19.25 H "'Found £: 41.19 Gt 3 _S 8% H, 24 _S 4 Cl ₉

^ Ί [2 _? 4-dichloro «Hx-iBet-hylbenz yliden) -

A © solution of 10 g of 2 ', 4-dichloroacetophenone in 40 "ml of ethanol became a solution of 7 S aminogiaenidine bicarboEat generally 40 ml of water and 4 ml of acetic acid stated <* This ergaifo a mixture of oil and supernatant head ii / ÄBpiger solution that three-day "was ridden on a steam bath-, whereby- © in little

909819/1249

'"! ■ ¹ P" SF ι ^";';

29 *

Oil was still present. After cooling, 2 g of white solid, melting point 170 to 171 ⁰ O, were slowly separated off.

Analysis: Calculated for C ^ H ^ Gl ^ KfgO ^:

56: 43.29 0, 4.62 H, 23.24 01, 18.36 IT Found #: 43.32 0, 4.86 H, 22.8 Cl ₈ 18.37 »

Example 1?

A solution of 10 g of 3 _{tons of} 5-dichlorosalicylaldehyde in 25% of ethanol was added to a solution of 7 g of amino-guanidine carbonate in 30 ml of water and 4 ml of acetic acid. After heating the resulting solution on a steam bath for two hours, 11 g of a pale yellow powder, melting point 249 to 250 ⁰ O, separated after cooling »

Analysis: Calculated for

56: 38.88 0, 3.26 H, 28.70 Cl, 22.68 H Found % i 39 * 08 C, 3.19 H, 28 ₉ 7 01, 22 _t 94 N

Example 18

"/ T2 j 5 * 3i ör oni-a» ätbylb anayliden} -aKinpJT ^ guaiiidin nitrate

3u 220 g * 1,4-Dibrombensol and 180 g'wasserfreiem Aluminiu> schlorid 80 g Eropionsäureanhydrid under .Rühren su ~ gogeban αηά overnight b © i 80 ⁰ C © 3 * hitEt "\ That mixture wu3? De then üboz * Poured ice and absorbed the lower open layer in chloroform, with iJassejr gewaechon χαχά distillierh Dan pale yellow Px'oduld; (2,5- ^ ibiOiapropiophonQn) hatto one-

9 0 9 819/1249. ^ ₀ ..

BATH ORIGINAL

Boiling point at 165 to 170 ° C / 15 ram and weighed 130

Analysis: Calculated for CgHgBroQ:

%>. 37.03 0, 2.76 H, 54.76 * Found £: 36.06 C, 2.32 H, 55 ₉ O Br

A solution of 15 g ^2,5-t Dibrompr ^r opiophenon in 30 ^ l ethanol vrard © was added to a solution of 10 g of aminoguanidine bicarbonate in 50 aal water and 4 ml of nitric acid and the mixture heated overnight on the steam bath * After cooling parted 9 g of white crystals of the compound listed in the heading from _T melting point 173 to Z with disintegration

Analysis: Errsehnot for

% z 29.22 C, 3 * 19 H, 38,, S8 Br ₉ 17 * 04 Found #: 29.62 C ₃ 5.24 H _s 38 ^ 8 Br, 17.36

Sine solution of 7 S Sjö-dichloro-S-hydrosybenzaldehyd in 50 ml of ethanol solution of 5 au einor S aminoguanidine bicarbonate in 30 si water and 4 ml of formic acid was added and the mixture Uacht on mandrel steam © rhitat "msrden, Hach cooling. 7 ^ 3 S white © crystals, melting point 196 to 197 ° ö »collected«

Analysis: Ecrechnet for ÖqU ^ qGI ^ S ^ Ö ^ i

Si: 36.88 O ₉ 3.43 H, 24.19 ^C1 » ¹ 9.12 N 6 © footd © n $ \ 36.84 O ₉ 3.43 H ₅ 24.6 oil, 19.32 N

909819/124 9

-31 «

1§02394

Example 20

f oriniat.

A © solution of 12 g 2,4,6-TrichlorHMiydroxybenzaldehyd, melting point 144 · 14-5 to ⁰ C, in 50 ml of alcohol was added to a solution of? g arrainoguanidine bicarbonate in 30 ml HgO and 4 ml formic acid are added, and the mixture is heated on the steam bath for 30 minutes. After cooling, a layer of the yellow solid was separated and slowly transferred into a thick mass of white needles which on a filter had a melting point of about 320 ⁰ G after collection, where they Seih at 260 ° 0 wurdenο

Analysis: Calculated for

$ i 33.00 C, 2.77 H, 32.4-7 Gl ₉ 17.10 N Found #: 33.25 C, 3.05 H, 32.9 01, 17.33 N

Example 21

5-öibrom-K-iaethylb @ n25yliden) '- ai2ino7-guanidinf ormiat

8 g of aminoguanidine carbonate dissolved in tu were added to a solution of 14 g of 2.5 l) ibromoacetophenone in 30 ml of ethanol. Vlasser and 5 ral formic acid (850) eye give · The check resulting mixture was left overnight on a steam bath to © give in © clear solution from which one 4 x g at cooling, white platelets, mp 216-217 ⁰ O ₁

Analysis:. Calculated for

#; 31.60 0.3 * 13 H _v 4-3.03 Br, 14.75 N

Found #: 31, -99.0, 2.88 H ₅ 4-3 _r 2 Br, 14.30 N

9 09819/1249

BAD ORDINAL

- 52 -

Example 22

After heating a mixture of a solution of 10 s of 2,5-dichloropropiophenone in 50 ml of ethanol and a solution of 7 g of aminoguanidine bicarbonate in 80 ml of water and 5 ml of acetic acid on the steam bath for three days, crystals of the compounds named in the title were obtained after cooling.

example

while heating a Lößung of 5 g S> bansalde hyd at 15 Bl ethanol Jait Pedal © r Löfung of 5 g guapidinbicarbonat 4-n 15 PJL water and $ ml i ^ sigsäure ü Nashfc on? Daiiipfbad _? 2.5 g of the alcoholic fillet of the compound referred to above were obtained after cooling off.

· Analysis? ^? rephnet for O ^ & ^ Glgi ^ OzS

% 0, μ-, 39 Η, 22.08 01

^^ «© uanidinf ^

cp '■. ■ - ■ '"·."

^ By every hour I5rhits0n its solution of 15 g broia ~ 2-methoxybenzaldehyde in 50 ml of ethanol with a solution from ? s Affiinoguanidinbicarbpnat in 30 isal water and 5 ml Acetic acid on a steam bath, vücden lirißtsill © in the

** 33 -

Prescribed compound received after cooling.

Example 25

By heating a solution of 15 S 2 _? 4,6 ~ iCrichlox'-S'-niethoxybenzaldehyde in 50 ml of ethanol with a solution of 7 S araguanidine bicarbonate in 30 ml of water and 5 ml of formic acid on the steam bath, / crystals of the compound named in the title were obtained after cooling

Example .. 26

/ Γ2 ₅ 6-Diohlor-5-ät hoxyb enzylidea) -aoin ^ -suanidini oriaiat

! If they laugh at 50 ml ethanolic Lösimg of Ί0 g 2.6 * dichloro-3 - ätho3ybensaldehyd (prepared by treating _2-T 6 DiGhlor ~ 3 '' hydroxyboni3ald © hyd _1> dissolved in a solution of excess potassium carbonate rait Diäthylßulfat stirred unjirdo ) with a solution of 7 liters of arainoguanidiribicarbonate in 30 ml of water and 5 wl of formic acid "added to a steam bath," the crystals of the compound named in the heading are obtained after cooling "

Example 27 '

Han eraitst oine hour © © in © 50 al ethanolic solution of 1-5 6 2 ₇ '! - _J , 6 ~ T ??:'. Chlor «3" -äthosybeazaldeayd, (manufactures Cnvoh from 2j ^ -; 6 «» 'I ¹ richlor- "3-h _x ydr-ox3rbensaldehydj der iü 909819/1249

“AD ORIGINAL

a solution of potassium carbonate in excess with bio-ethyl » sulfate is stirred) with a solution of 7 S Aminoguani «· Din bicarbonate in 50 ml of water and 5 nl of formic acid the steam room, and receives after. Cooling crystals of in Yerbin & usg.

/ X3 »5 ~ dichloro-2 ~ ethoxyben-kylidene) -aiaino7-guanidinf ormiat

Bureh for two hours heating a 50% oleic acid solution of 10 s 5j5 "-I ^| chloro-2-ethoxyben2; aldehyde prepared by treating a quenched solution of 3 _$ 5-oleylsalicyclaldehyde in excess aqueous potassium carbonate Diethyl sulfate) si with a solution of 7 g of aminoguanidine carbonate in 30 ml of water and 5 ial of formic acid on the steam bath, and after cooling it gives crystals of the compound named in the title,

IIino solution of 10 g of 2.5 ^e- chlorobutyrophonone (obtained by treating a body of 1,4-dichloro-benzol butyric anhydride with a mixture of aluminum chloride) in 30% of ethanol and 30% of butanol, is mixed with a solution of 7 g of aminoguanidiabica ^ bonat mixed in 30 ail water silt 5 al acetic acid; and aiii the Baöpfbad three days orhitat, whereby crystals of the in the

Connection designated under the heading.

909819/1249

bath

- 35, - ■■ ■. ■■■:

Example go

A solution of 10 g of 2,4-diethoxyaeetophenone in 50 ml Ethanol was added to a solution of 7 S aminoguanidine bicarbonate in 30 ml of water and 5 ^ l of acetic acid and over Heated overnight on the steam bath, which after cooling down di © in the heading receives the connection «

ßl2. , 5- ^ chloro * ß.-methylben2ylidin) ~ ainino7-guanidine

This compound was prepared from 2 _{tons of} 5-dichloroacetophenone (10 g), aminoguanidine bicarbonate (7 g) and acetic acid according to the method of Example 1j. Yield 6 g, melting point 182 to 18 ° C (Zorfall).

This compound was prepared from 4- GhXor ~ 2-nitro- { benzaldehyde (5 g)? Aainoguanidiubic carbonate (4 g) and acetic acid according to the method of Example 1, yield 5 * 5%, very releasable point 255 to 256 ° C (disintegration),

Example 33

This connection was made from bonsaldohyä_ (10 g), aminoguanidine bicarbonate (7 s) and

909819 / 12A9

BATH ORIGINAL

acid © following the procedure of Example 1 "Yield 13 g" Melting point 175 to 176 ° C.

example

^ 5 ~ chloro-2-nitrobenzylidine) -amino7-guanidine

This compound was prepared from 5-chloro-2- nitrobenzaldehyde (9 ₉ 3 g) aminoguanidine carbonate (7 g) and acetic acid by the method of Example 1, yield 10 g, melting point 205 ° 6 ° C. (decomposition).

This compound was prepared from 1.5 nitrobene aldehyde (11 g), aöinoguanidinbicarbonat (7 g) and acetic acid according to the method of Example 1 * Yield 11.5 6 »melting point 250 ⁰ G (decomposition),

I example 3

This © connection vjui-d © made from 2, M - Dinitrobens aldöüyd ('-! · G) _s Auiinoguanidinbioarbonat (3 g) and Üssi ^ after dom. Procedure of Example 1 * Yield 3 g of ₅ pualrb 227 b ± s 228 ° 0 ('expiration). '

Example 37 ■

This connection vjurdo established exiss

909819/1249

SM) ORIGINAL

Benzaldehyde (9 g), aminoguanidine bicarbonate (7 g) and Jissig acid according to the method of Example 1 · Yield 15 * 5 6 * Melting point 210 ⁰ O (disintegration).

Example 58

ßZ _f 5-dimethoxy-a-ffi © thylb0nzylidin) ~ araino7-guanidiri

This compound was prepared from 2,5-dimethoxyacetophenone (9 g), aminoguanidine carbonate (7 g) and acetic acid following the procedure of Example 1. Yield 2.5 g? ßchmelapunkt 15 * to i55 ° ö (decay).

Example 39

This compound was prepared from 2,6-dihydroxyacetophenone (8 g) _Λ aminoguanidine bicarbonate (7 g) and nitric acid by the method of Example 1. Yield 7 g "melting point 1-0-9 to 15O ⁰ O.

This compound was prepared from 2 ~ hydroxy-5-nitrr> bonsaldehyd (5 g) i Aminoguanidiabioarbonat (5 »5 δ) ¹ ^ Dd acetic acid according to the V © 2? G fahx ^s sn of Example 1 * yield 7, 31- öchfflelspunkt 5 ⁰ O (decay),

909819/1249

1802334

- 38 - -

Example 41

This compound was prepared from 2,3-Dimetho3qrbenz al & efayd (8 g), aminoguanidine bicarbonate (7 g) and acetic acid by the procedure of Example 1 »Yield? ₉ Melting point 163 to 164 ^° G (disintegration).

This prebindimg was made from 2 _¥ 5 ~ diBsethylaceto ~ phenone (7g)? Arainoguanidine carbonate (7 g) and nitric acid according to the method of Example 1, yield 7 g »melting point 187 to 188 ⁰ O ⁵ (disintegration).

Example / ta, 2 j ^ h- ¹ JDr inset hylbenzylidiö) «

This compound was produced from 2,4-disaethylaceto »pbenone (7 g) _t -asinoguanidine carbonate (7 g) and S

acid according to the method of Example 1, yield ^{9-5 melting point 204 to 205 0} G (Serfall) «

example

Diose compound feorgestel.lt 2, .6 »dichloro-3-n-itrobeEi; s' aldöhyd (10 g), aminoguanidine bicarbonate (7 g) gave after uad Saur © dosj ancestors of Example 1 _S fa

909819/12 A9

Crystals that were difficult to purify »These were converted to the kitrate by adding 2.5 ml of nitric acid · Yield 7 g _Y melting point 225 ⁰ O (decay).

Example

This compound was prepared from 2,5-diethoxyacetophenone (10 g), arrainoguanidine b carbonate (7 g) and nitric acid according to the method of Example 1 »Yield 9g» Schjaelspuakt 163 to °

example

■ ΤίΓ-ΙιιΤΓίΓιι ι IiHi Il ι tIHI ^ 2,3 ₅ ^ _t 5,6-Pentafluorob © nzylidin) -aKin £ 7-suanidin

This compound was prepared from 2 _t 3 _i ^z i-s5 £ luorbGnaa3.dehyde (5 s) i aminoguanidine bicarbonate (3 g) and acetic acid according to the procedure of Example 4-2 * Yield 0.6 g, temperature point 262-253 ° C (decay)

Example 47

<! ■> ti Il IVl Il <ι '.aj ■ < WfiliiMf —Ο ΊΙ «

This compound was made from 2 ~ öhlor ~ 3, loriä-iox ^ bensaldehyde (10 g) ;. A'iiirLOg ^ ianidine bicarbonate (? G) and. L'ssigsä-ar-e according to the procedure of example 1. Yield 11 g. Melting point 211 to 212 ° G (Sörfa.ll) *

example

Yox * bindv.ng was made from 2 ₅ 4 «DimG-bhoxyb © nz-. 909819/1249 bad

aldehyde (9 g), aminoguanidine bicarbonate (7 g) and

acid following the procedure of Example 1. Yield 12 g _f

Melting point 209 to 210 ° 0 (disintegration).

Example 49

This compound was prepared from 2,6 ~ dichloro-3-methoxybenzaldehyde (1g), aminoguanidine bicarbonate (1g), and nitric acid by following the procedure of Example 1, yield 1.2 g, melting point 265 ° 0 (disintegration).

Example 50
^ Γα> «2 _f 4,5-ietramethylbenzylidine) -aniine £ 7-guanidine

This compound was prepared from 2,4,5-trimethylacetophenone (10 g), aminoguanidine bicarbonate (7 g) and nitric acid by the procedure of Example 1 with the addition of n-butanol and heating for 48 hours. Yield 12g. Melting point 17 * to 175 ⁰ C (disintegration) »

Example 51

ß £ _r 5-diet ho3 £ ya-ethylbenzylidine) -aminjoZ-guanidine

This compound was prepared from 2 "S-Diäthoacypropiophenon (10 g), aminoguanidine bicarbonate (7 g) and nitric acid according to the procedures of Example 1. Yield 12 g _f melting point 132-133 ° O.

909819/1249

Example 52 / C2-ßenzyloxy-5-brorabenzylidine) -arainoi7-guanidine

This compound was prepared from 2-benzyloxy-5-bromobenzaldehyde (10 g), arrainoguanidine bicarbonate (8 s) ^and acetic acid by the method of Example 44, with the addition of nitric acid. Yield 14 g, melting point 169 to 170 ⁰ G (disintegration).

Example 53

(£ 5-bromo-2- (p- chlorobenzyloxy) -b enss; y 1 idin7-araino) -guanidine

This compound was prepared from 5- ^ romr * 2- (p-chlorobenzyloxy) -benesaldehyde (10 g), aminoguanidine bicarbonate (8 g) and acetic acid by the method of Example 1. Yield 11 g »melting point 249 to 250 ⁰ O ( Decay) "

~ meth ₍ f lcinnamylidin) -amino7-guaiiidin

This compound was made from 2,4-i3ichlarstyryl-

(10 g), iminoguanidine bicarbonate (7 g) and vinegar , subsequently duvch Baipitric acid after the process

from Example 44. Removed 1.5 g * Sehmel point 235 to 236 ⁰ G (disintegration).

Example 55

.Kino sinity liquid dose preparation that is suitable for oral or parenteral administration _? will

t by mixing 1 g of 909819/1249

amino7-guanidine acetate in sufficiently sterile distilled Water containing 0.5% by weight of carboxymethyl cellulose, wherein is made up to 1CO ml. This mixture can then be flavored for oral use or aseptic are filled into sterile ampoules, which are then melted, sterilized and stored under refrigeration, bi3 they are intended for use.

Similarly, oral and parenteral become liquids Preparations of the following hypotensive agents are made:

_J ^ r2,6-dibromobenzylidene) -amino / -guanidine} ß ^ 2 , 6-difluorobenzylidene) -ainino7-guanidine; / C2-chloro- & (fluorobenzylidene) amine £ 7-guanidine nitrate; _J ^ r2-chloro-6-bromobenzylidene) amine £ 7-guanidine; and _; / r2-bromo-'6-fluorobenzylidene) -amino7-guanidine »

example

Tablets and capsules for oral administration are used according to the following recipes h

Component © milligram 10 15th I.
25th 50 100 / Γ2,6-Dichlorb®nsylidine) -
amino7 ~ giianidinac etat 1 28? 282 2? 2 24? 197 Milk sugar ¹ * 296 3 3 3 3 " 3 Magnesium stearate 3 500 500 500 300 300 300

Ia similar fc'öis® are tablets and capsules a & r

909819/1249

_ 4-3 -

the following hypotensive agents:

1 ^ 2. , 6-dibrorabenzylidene) amino7-guanidine; / Γ2JB-difluorobenzylidene) -amino7-6uanidine; _j / T2 ^ 6-chloro "> 6-fluorobenzylidene) aniine £ 7-suanidine nitrate; / COE ⁱ 0hlor ~ 5-bromobenzylidene) ~ amino7-guanidine ·; and / r2-bromo-6-fluorobenzylidene) amine £ 7-guanidine.

Example 57

By repeating the procedures of Examples 55 and 56, you can Capsules, tablets and liquid preparations of hypotensive agents are used as such in the Examples 3 to 5 ^ are described.

9 098 19/1249

Claims (4)

Patent claims: 1 · Use of a guanidine of the general formula W or acid addition salt thereof, in which X is a © direct bond or a methylene, ethylene or vinylene radical Ί P is, the radicals R and R and Y are identical or different and each is a halogen atom or a nitro · -, amino-, lower Alkyl, lower alkoxy, substituted or unsubstituted Benzyloxy, hydroxy or irifluoromethyl radical '", and ■ 2 η = 0, 1, 2 or 3, or η »1 and Y and R together form a methylenedioxy radical, the radical R * is a water atom or a cyclo (lower) alkyl from J to f> Koh-κ lenefroffatomen, lower alkyl, athynyl- * allyl- or ßenzylrest, the radicals R and R- * ^ eder is a hydrogen atom or a lower alkyl radical, or the radicals R and R- ⁷ , sjdaanir.pn with the nitrogen atoms, whichever they are connected to form an imidazoline ring to 6 ■ ο form, and R is a hydrogen atom or lower alkyl CD - '. "- ■ O ^ rait the restriction that if the radicals R and R ^ arengenoimnen form an iridazoline ring, R ^{6 is} hydrogen, ν »the drawings" lower alkyl "and" lower alkoxy "φ mean radicals which contain up to G carbon atoms “In arsenal for singers, including people. BAD ORtGlNAL - ' 2. Use according to claim 1, characterized in that the compound [(2,6-dichlorobenzylidene) amino] guanidine or an acid addition salt thereof, a reduction in hypertension being achieved. 3 »Use according to claim 1, characterized in that the compound t (2-chloro-6-fluorobenzylidene) -amino] -guanidine or an acid addition salt thereof, whereby a reduction in hypertension is achieved. f 4. Compound of the general formula -p-7 X - 0 * NNHC - N or an acid addition salt thereof, where in the formula the radicals X, R ⁴ , R ^ and R have the meanings given in claim 1 and either (a) R ^ is hydrogen and 12th R, H and Ϊ are the same or different and are each one Represents nitro, amino, lower alkyl, substituted or unsubstituted benayloxy or trifluoromethyl radical, η & 0, 1, 2 or 3 or Y and R together form a methylenedioxy radical and η = 1 or -46- 909819/1249 (B) R, R, ϊ and η have the meanings given in claim 1 and Br is cycloalkyl, of 3 to 5 carbon atoms, lower alkyl, ethynyl, allyl or benzyl. 5. Process for the preparation of compounds according to claim 1 characterized in that (a) an aldehyde or ketone of the general formula X-G-Q with an aminoguanidine of the general formula NR ⁴ _B 5 H ₂ N - NH - G - N or an acid addition salt thereof (in which R, R, R, R ', R- ^, H, X, η and X have the meanings given in claim 4, or (b) ammonia with a thiosemicarbazide of an aldehyde or ketone of the above given general formula, or (c) cyanamide with a hydrazone of an aldehyde or ketone of the general formula given above, and, if desired _} converts the compound formed to an acid addition salt thereof. 909819/1249