DE1795559A1 - New heterocyclic compounds - Google Patents

Description

New, complete ones intended for the printing of the Offenlegurgsschrift Registration documents

File number: P 17 95 559.8-44. - U. Sign: 21 728-BR / H ^! ^^ AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Case 5560 / lVÖ Germany

New heterocyclic compounds

The invention relates to new amidines. It is known that compounds of the type

-CH = C-He t

109885/2000

Jeue Uriterb ^ r .1. · ■:, ;. .: · ·.,. '·. ·

l. V. 4.

wherein Het is a heterocyclic radical and IU hydrogen or a lower alkyl radical, is an antibacterial and antiparasitic activity (cf., for example, the Belgian Patent Nos 638'22O und.638 * 221;.. Further, the French Patent Specification No. I ¹ 359'503. Belgian patents 630 * 163 and 639'955, Japanese patent publications Nos. 13 740/64, 19 452/64, 19 643/64, 19 653/64, 19 654/64 and 21 527/64, and J.pharm .soc. Japan. 81, I357 (196I); ££., 771, 778 and 1129 (1963)). . \

It has now been found that the replacement of the amino group in the compounds mentioned by an aniidine group also results in anti-parasitic and antibacterial compounds, which are also better in the form of their salts are water-soluble than the salts of the corresponding amines,

Furthermore, the aqueous solutions of the salts of the amidines according to the invention are less acidic than those of the Salts of the known heterocyclic amines mentioned above.

The present invention therefore relates to compounds of the formula

OJh

, 4
-CH = C-Het-N = CR

109885/2000

BAO ORfQlNAt

wherein Het is an optionally substituted heterocyclic radical containing at least one ring nitrogen atom Character means in which the arcidine grouping of the formula -N = O-R with a ring carbon atom and the Nitrofurfurylidenmethylrest is linked to another ring carbon atom in a position which activates a methyl radical, R an optionally by aliphatic hydrocarbon

radicals, which can also be interrupted by oxygen, sulfur or nitrogen atoms, means substituted amino groups, R for an aliphatic radical or a hydrogen atom and Rk for hydrogen or a lower alkyl residue stands, but with the exception of the N- [5- (5-K: Ltrofurfurylidenmethyl) -6-pyridazinyl] "- N ', N' -dimethylformamidine.

In the new compounds, the heterocyclic radical Het is a mononuclear or polynuclear radical of aromatic character, the at least one heterocyclic ring having at least one ring nitrogen atom .aromatic character · contains ters as an ingredient. Such radicals are, for example, radicals consisting of 6-membered rings which contain a nitrogen atom have, such as pyridine or quinoline radicals, radicals consisting of six- and / or five-membered rings which have two nitrogen atoms, e.g. diazine residues, such as pyridazine, pyrimidine or pyrazine residues or diazole residues, such as pyrazole, imidazole or benzimidazole radicals, radicals consisting of five- and optionally six-membered rings, the one nitrogen atom and one oxygen, or sulfur atom

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* A "b ORIGINAL.

have, such as oxazole, thiazole, benzoxazole or benzothiazole residues, radicals consisting of five-membered rings, the two nitrogen atoms and one oxygen or sulfur atom have, such as thiadiazole or oxadiazole radicals, or radicals consisting of five or six-membered rings with three Nitrogen atoms, such as triazine or triazole residues,. ...

Substituents on carbon atoms of said heterocyclic radical are in particular lower ones Alkyl radicals, such as methyl, ethyl, propyl or isopropyl radicals, straight or branched, connected in any position Butyl, pentyl or hexyl radicals, lower alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy groups, Halogen atoms, such as chlorine, bromine or iodine atoms, trifluoro. methyl groups or nitro groups in Betraohb.

In heterocyclic radicals that carry a hydrogen atom on a ring nitrogen atom, this can also be done through lower alkyl radicals or acyl radicals, in particular benzoyl radicals or especially lower alkanoyl radicals, e.g. acetyl radicals be. The 5-nitrofurfurylidenemethyl radical stands in particular in the α-position or optionally in the 7-position to a ring nitrogen atom. · · '. j

In the amino group R there are aliphatic hydrocarbon radicals, which can also be interrupted by sulfur, nitrogen or oxygen atoms, for example Alkyl radicals, e.g. the above-mentioned alkenyl radicals,

such as lower alkenyl, allyl or .how Methallylreste. ^§ 109885/2000

GA8

Alkylene radicals, oxa, aza or thiaalkylene radicals, such as, for example / optionally lower alkylene radicals interrupted by the heteroatoms mentioned, such as butylene- (l, ') ■) -.> Pentylene- (l, 5) -j hexylene- (l , 5) -, hexylene- (l, 6) -, hexylene- (2.5) -., Heptylene- (l, 7) ~, -heptylene- (2.7) -, heptylene- (2.6) -, 3 ~ 0 ^{χ £} > - or azapentylene-

(1,5), 3-oxa or azahexylene (1,6) radicals are possible.

In addition to a hydrogen atom, the radical R is preferably a lower alkyl radical, for example one of the abovementioned ones.

The new compounds have valuable pharmaceutical ecological, especially anti-parasitic and antibacterial properties. Above all, they show an effect against Bacteria in vitro and in vivo. For example, on infected animals, for example on mice, they are against gram-negative and gram-positive bacteria, e.g. Salmonella typhi, such as Salmonella typhi murium, Coli bacilli, such as E.coli, staphylococci, such as Staph.aureus, and Pasteurella avicida effective. The new compounds also have an effect, such as when they are tested shows on hamsters against amoeba and, e.g. on mice and sheep, against schistosomes. The new connections can therefore be used as anti-parasitic and antibacterial agents. In particular, they are suitable for handling development of the diseases caused by the pathogens mentioned. The new compounds are also valuable intermediates for the manufacture of other useful substances, especially pharmacologically active compounds.

Particularly noteworthy are the following ^! · ■ - ■ · ■ - '·: c. u 109885/2000

8AÖ ORKsMNAL

led heterocyclic compounds, where Nfm in each case for the 5-nitrofurfurylidenemethyl radical of the formula

R,

I ⁴

-CH = C-

O ₂ N-

stands in which R ^, a lower alkyl radical or in particular represents a hydrogen atom and A represents the remainder of the formula

R,

I ³

-N = C-N

represents where R, and R _? stand for hydrogen or, in particular, lower alkyl radicals or R, and R _p together with the nitrogen atom form a pyrrolidino, piperidino, piperazino, morpholine or thiamorpholino radical, and R-. mean a NiederalkyIrest or in particular a hydrogen atom. .

a) A-4-Nfm-quinolines attached to ring carbon atoms lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted, but are preferably unsubstituted, especially corresponding 2-A-4-Nfm-quinolines;

b) A-2-Nfm-quinolines attached to ring carbon atoms lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted,

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BAO OBlGiNAL

but are preferably unsubstituted, as corresponding 4-A-2-Nfm-quinolines or corresponding 8-A-2-Nfm-quinolines or especially corresponding 5-A-2-Nfrn-quinolines and corresponding β-Α-2-Nfm quinolines;

c) A-4-Nfm-pyridines, the atoms through to ring carbon lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted, but are preferably unsubstituted, especially corresponding ones 2-A-4-Nfm pyridines; '

d) A-2-Nfm pyridines attached to ring carbon atoms lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted, but are preferably unsubstituted, especially corresponding 5-A-2-Nfm pyridines or corresponding 6 ~ A-2-Nfm-

• pyridines; . - · _ ■■ _ ■■■ '

e) A-3-Nfm-pyridazines attached to ring carbon atoms lower alkyl radicals or preferably by lower alkoxy groups or in particular by halogen atoms and / or Trifluoromethyl groups can be substituted, preferably, but are unsubstituted, especially corresponding ones β-Α-3-Nfm-pyridazines; . ''

f) A-4-Nfm-pyridazines attached to ring carbon atoms by lower alkyl radicals or preferably by lower alkoxy groups or in particular by halogen atoms and / or. Trifl ".omethyl groups can be substituted, preferably . · .. .. .. · 109885/2000

but are wise unsubstituted, especially corresponding J) Th- ¹ I -Nfm-pyridazines or corresponding 6 ~ A-4 ~ Nfrn-pyridazines; '. .

g) Ä-2-Nfm-pyrimidines, which on ring carbon atoms by, lower alkyl radicals, lower alkoxy groups, halogenators and / or trifluoromethyl groups can be substituted, but are preferably unsubstituted, especially corresponding ones H-A-2 ~ Nfm pyrimidines;

h) A- ² {--Nfm ~ pyrimidines which can be substituted on ring carbon atoms by lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups, but are preferably unsubstituted, especially corresponding 2-A-4-Nfm-pyrimidines ; - ■ - ■: '. v>

i) A ~ 2-Nfm-Pyra2ine, which on ring carbon atoms through lower alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted, but are preferably unsubstituted, especially corresponding ones 5-A-2-Nfm-pyrazines or corresponding β-Α-2-Nfm-pyrazines; -. '. ·. . . '·' ··

k) A-2-Nfm-imidazble, the lower alkyl radicals, lower Alkoxy groups, halogen atoms or trifluoromethyl groups can be ring-O-substituted, preferably " but are unsubstituted and which are unsubstituted on the ring nitrogen atoms or in the second place on ''

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ORfGfNAl

a ring nitrogen atom through a lower alkyl radical may be substituted, especially corresponding 4-A-2-Nfm-imidazoles; . . .. ■ '

l) A-3-Nfm-pyrazoles, through lower alkyl radicals, lower Alkoxy groups, halogen atoms or trifluoromethyl groups may be ring-C— substituted, but preferably are unsubstituted and which are unsubstituted on the ring nitrogen atoms or, secondarily, on a ring nitrogen atom can be substituted by a lower alkyl radical, especially corresponding 5-A - 3-Nfm- '' ■ Pyrazolej .- · - ··. .

m) A-2 ~ Nfm-benzimidazoles attached to ring carbon atoms Throughout all of the alkyl radicals, lower alkoxy groups, halogen atoms and / or trifluoromethy groups may be substituted -. " but are preferably unsubstituted .. and those at the ring nitrogen atoms are unsubstituted or in the second Line on a ring nitrogen atom through a low- ren alkyl radical or a Niederälkanoyl- or Benzoylresfc ■ can be substituted, especially corresponding S-Ärä- ■ Nfm-BenzimidazolesJ ". · · ·

n) A-2-Nfm-oxazoles, through lower alkyl radicals, lower Alkoxy groups, halogen atoms or trifluoromethyl groups can be ring-C - substituted, preferably - ■.,. · ' but are unsubstituted, especially the corresponding 4-A-2.-

IQ3335 / 20 00

ORIGINAL BATHROOM

-Nfm-Oxazole ;. ... -, .. ·: ■. .... ·. ■

ο) A-2-Nfm-thiazoles, the lower alkyl radicals, lower Alkoxy groups, halogen atoms or trifluoromethyl groups' Ring-C - can be substituted, preferably, but are substituted, especially corresponding 4-A-2-Nf.m-thiazoles; . "".

p) A-2-Nfm-Benzoxazole, which at Ringkohlenstoffatowen by lower .Alkylreste, lower Alkpxygrüppen, halogen atoms and / or trifluoromethyl groups can be substituted, ■ but are preferably unsubstituted, especially corresponding 5-A-2-Nfm-benzoxazolo;

q) A-2-Nfm-benzothiazoles attached to ring carbon atoms be substituted by "lower alkyl radicals," lower alkoxy groups, halogen · atoms "and / or trifluoromethyl groups. can, but are preferably unsubstituted, especially corresponding 5-A-2-Nfm-Benzthiazolej ·:. ■

r) 5-A-2-Nfm-1,3,4-Oxadiazole j. ·. -. . . s) S-A-a-Nfm-l ^^ - thiadiazoles; .. - '·. ■ ·

t) A-6-Nfm-l, 2,4-triazines, which by lower alkyl radicals, lower alkoxy groups ,. Halogenatorae or trifluoromethyl groups can be ring-C— substituted, preferably but are unsubstituted, especially corresponding 3-A-6-Nfni-1,2,4-triazines; '' · \. *

no .gas

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original

u) h-'5-H £ ml, 2 _t 4-triazines, which can be ring-C-substituted by lower alkyl radicals, lower alkoxy groups, halogen atoms or trifluoromethyl groups, but are preferably unsubstituted, especially corresponding 6-A-3- Nfm-l, 2,4-triazines;

v) 4-A-2v-Nfm-1,3,5-triazines, which by lower alkyl radicals, lower alkoxy groups, halogen atoms or trifluoromethyl groups May be ring-C-substituted, but are preferably unsubstituted; ■. ·

w) 5-A-3-Nfm-l, 2,4-triazoles.

The 6-A-2-Nfm-pyridaziria and above all the 6-A-2-Nfm-quinolines, especially the N- [2- (5-nitrofurfurylidene-methyl) -6-quinolyl] -N ^r , are particularly valuable, N'-dirnethylformamidine.

The new connections v.o-ra: ~, v; enn man in a manner known per se either

a) a compound of the formula

R R

-CH = 0 - Het -N = C-X

wherein Het, R, and R _{2 have} the meanings given and X is an etherified or esterified hydroxyl group or a free or etherified mercapto group, with

109885/2000

BAD ORiGtNAL

Ammonia or an amine containing at least one hydrogen atom or reacts

b) a compound of the formula

I ⁴

-CH - G - Het - NH

wherein Het and R ^ have the meanings given, or a Salt thereof with a nitrile, a thioamide or a thioimino ether or with an enol ether (imino ether), enol ester (imino ester) or acetal of an aliphatic carboxamide or a salt thereof or with an addition product of a Lewis acid with an aliphatic carboxamide implements, or

c) a compound of the formula

f ⁴ ? ³

H ₃ C - Het - N = C - R,

wherein Rk, Het, R and R- have the meanings given, with 5 ~ nitrofurfural or a reactive derivative thereof implements or.

d) a compound of the formula

-CH =

I ⁴

C - Het

-N = C-R

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BATH ORIGINAL

wherein Het, R, PL · and R ^, have the meanings given, nitrated in the 5-position of the Purfurylidenrests, and, if desired, compounds obtained in which the amino group R has at least one hydrogen atom, alkylated or compounds obtained in which the amino group R is disubstituted, reacted with ammonia or a primary amine and / or free compounds obtained are converted into their salts or _# obtained salts are converted into the free compounds.

In procedure a) an etherified hydroxyl group is in particular one through an aliphatic or araliphatic hydrocarbon radical substituted hydroxyl group such as an alkoxy group, e.g., a lower one Alkoxy group, such as an 'ethoxy group or methoxy group, or an optionally substituted aralkoxy group such as a benzyloxy group. An etherified mercapto group is e.g. an etherified mercapto group corresponding to the etherified hydroxyl groups mentioned above.

Esterified hydroxy groups are, for example, with a carboxylic acid such as an aliphatic carboxylic acid such as chloroformic acid or chlorocarbonylformic acid, or an arcw matic carboxylic acid, such as a benzoic acid, esterified hydroxyl groups or preferably with a strong inorganic one or organic acid esterified hydroxy groups, such as with a hydrohalic acid, e.g., chlorine or bromine. hydrofluoric acid, a sulfonic acid, e.g. an aryl sulfonic acid, such as benzene or toluenesulphonic acid, chlorosulphonic acid

109885/2000

or chlorosulfinic acid, or a halogenated acid of the phos- • phosphorus, such as dichlorophosphorous acid, dichlorophosphoric acid or tetrachlorophosphoric acid, or optionally corresponding Bromine compounds esterified hydroxyl groups.

In procedure b), enol cups are used. especially those which, as described above for X, contain aliphatic or aromatic hydrocarbon radicals. Particularly suitable enol esters are those the one. Acid residue of one of the acids described for X above such as imide chlorides or amide chlorides. ' Particularly suitable acetals are those in which the Alcohol component, a lower alkanol or alkanediol, such as dimethylformamide-t-film ethyl acetal and as a Lewis acid boron trifluoride is to be mentioned in particular.

In procedure c), the reactive derivatives of 5-nitrofurfural used are above all acetals and thioacetals or acylates or bisulfite compounds. One goes. from an acylate, di-acetate is preferably used.

The reaction is carried out in a customary manner, if appropriate in the presence of preferably acidic condensing agents or catalysts, e.g. depending on the nature of the carbonyl component in the presence of water, alcohol or acid splitting agents Means, carried out at ordinary or advantageously elevated temperature, for example the not

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desired reaction products, such as water or alcohols, can be withdrawn continuously from the reaction mixture.

In procedure d), the nitration takes place in a manner known per se, of course under conditions in which the amidine grouping is not attacked, such as by reaction with the mixed anhydride of Nitric acid and a carboxylic acid such as acetic acid.

Compounds obtained in which the N ¹ nitrogen atom bears at least one hydrogen atom can be alkylated. The alkylation is carried out in a manner known per se, for example by reaction with reactive esters of alcohols, such as lower alkanols or aralkanols, such as lower alkyl or aralkyl halides, sulfates, or corresponding esters of sulfonic acids, such as methyl, ethyl, n- or i Propyl or benzyl chloride, bromide or iodide, dimethyl or diethyl sulphate, methane, ethane or p-toluenesulphonic acid methyl or ethyl ester.

In compounds obtained in which the N- ¹ nitrogen atom is disubstituted, the N ', N'-disubstituted amino group can be converted into an N ¹ mono- or unsubstituted amino group. This conversion takes place in the usual

109885/2000

Way, e.g. by reaction with ammonia or a primary aniine. .. ■.

^ '' ■ .. The reactions mentioned are carried out in the usual way carried out. ..'... * ·. . . \. . ■

'' Depending on the process conditions and starting materials the end products are obtained in free form or in the

"Form of their salts also included in the invention ·. ·. · So, for example, basic, neutral, acidic or ge. \ mixed salts, possibly also hemi-, mono-, sesqul- ·. or polyhydrates thereof can be obtained. The salts of the final .. · substances can be used in a manner known per se. e.g. be converted into the free bases with alkalis or ion exchangers the. Of the latter, by reaction with organic or inorganic acids, in particular those, '-. ■ ■, which are suitable for the formation of therapeutically usable salts, "win salts. Such acids are, for example: Hydrogen halides, sulfuric acids, phosphorus: '··· .. acids, nitric acid, perchloric acid; ^ aliphatic, alicyc-,. ··

. lic, aromatic or heterocyclic carbon or sulfone ·

acids such as formic, acetic, propionic, succinic, glycols, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenylacetic -, 'Benzoe- ,. ■ '·> ■ p-aminobenzoic, anthranil, p-hydroxy-benzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or SuI-

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... · '.. BADORiGlNAL

fanilsUure; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, for example the picrates, can also serve for purification of the bases obtained, by converting the bases into salts, separating free and -these ~ from the salts again the ^bases. power. As a result of the close relationships between the bases in free fovra and in the form of their salts, in the foregoing and in the following, the free bases are to be understood as meaning the appropriate salts and, if appropriate, also the corresponding salts. . "■ .- '■.' -.

The invention also relates to those embodiments of the method, after which one on

■ ·

at any stage of the process as an intermediate product. borrowed compound, for example a compound of the formula

CH -. OH - Het - N «0 - R,

where Het, R, R and Rk have the meanings given "and Y is a '; ^! " radical which can be split off with formation of a double bond, such as, for example, a hydroxyl group, and "the missing process steps; such as, for example, the introduction of the double bond elimination of the radical Y, for example, in - ... ''. · case specified under water spin-off / makes, ^or. '·' ...

the process is terminated at any stage, or in which the starting materials optionally in the form of salts used and / or formed under the reaction conditions.

For example, the enol ethers and Enol esters of the carboxamides or the condensation products form with Lewis acids under the reaction conditions. For example, the acid amide in question can be mixed with the corresponding Amine in the presence of an acid halide of the specified Acids, or a Lewis acid.

For the reactions according to the invention, those starting materials are primarily used which are those mentioned above give preferred compounds.

The starting materials are known or can be obtained by methods known per se.

The new compounds can be used as medicaments in the form of pharmaceutical preparations which contain the new compounds in free form or in the form of their salts together with pharmaceutical, organic or inorganic, solid or liquid excipients which are suitable for enteral, for example oral, parenteral or topical Application are included. For the formation of the same substances come into question that do not react with the new compound, such as water, gelatin,

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Lactose, starch, magnesium stearate, talc, vegetable Oils, benzyl alcohols, gums, polyalkylene glycols, petrolatum, cholesterol or other known excipients. the Pharmaceutical preparations can e.g. as tablets, coated tablets, capsules, creams, ointments or in liquid form in the form of solutions, suspensions or emulsions. The creams or ointments can contain 0.1 - 2 ^ of the active ingredient, preferably contain 0.25-1 # thereof. If necessary, they are sterilized and / or contained Auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic Pressure or buffer. They can also contain other therapeutically valuable substances. The connection can but can also be used in the usual way, e.g. together with the usual carriers, as disinfectants.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified.

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example 1

4.0 g of H-C5-I

.nolin, 5 * Og dimethylformamide diethylacetai and 4.0 ml dimethylformamide are heated to 100 ° for 2 hours; A precipitate separates out on cooling and is recrystallized from dimethylformamamide-methanol. This gives the N- [2- (5- "··· nitrofurfurylidene-methyl) -6-quinolyl] -N!, N ¹ -dimethylformamide d in the formula ■ .. '·.., · ·"".

= CfH-N (OH ) ₂

in crystals of P. 190 °. ! '■' ■. '''..' · ■ ·. ·· '· The methanesulphonate is obtained by dissolving the base in dimethylformamide and adding one equivalent of methanesulphonic acid. When alcohol is added, the methanesulfonate precipitates from P. 265 ° '. · '·. ·· ': ..''. ·.

The 2- (5-nitrofurfurylden-methyl) -6-amino-quinoline used as starting material can be obtained as follows

A solution of 7.4 g of 2-methyl-6-amino-quinoline and 6 g of 5-nitro-furfural in 75 ml of acetic anhydride is heated to 10 ^{0 for} 2 hours. The precipitate which has separated out is filtered off with suction and removed Recrystallized dimethylformamide alcohol. The 2 ~ (5-nitrofurfurylidene-methyl) -6-acetamido- "

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8ÄD

quinoline in crystals with a temperature of 284 - 286 °. . ■

12 g of 2- (5-Nltrofurfuryliden-methyl) -6-acetamido- · quinoline are mixed with 120 ml of 2-n. Hydrochloric acid in 120 ml of methanol cooked for 3 hours. The precipitated precipitation ' it is filtered off and the same is boiled with 50 ml of dimethylformamide and sucks-the sparingly soluble 2- (5-nitrofurfurylidene-- methyl) -6-amino-quinoline hydrochloride. The connection melts above 300

• The free base melts at 197-200 °.

Example 2:

7.0 g of N - ^ - methyl-δ-quinolyl) -N ^ N ¹ -dimethylformamidine are heated to 100 with 7.0 g of 5-nitrofurfural in 75 ml of acetic anhydride for 2 hours. The precipitate is filtered off with suction and the piltrate is evaporated in vacuo. "The residue is saponified with alcohol and the undissolved portion is recrystallized from dimethylformamide-methanol. N- [2- (5rNitrofurfurylidene-methyl) -6-quinolyl] -N is obtained , which is' N ^l dimethylformamidine to that described in example I ¹ product identical. ■ ".

The N- (2-methyl-6-QuinOIyI) -N ¹ JN'-dimethylformamidine used as starting material can be obtained by condensation of 20 g of dimethylformamide diethyl acetal with 10 g of 2-methyl-6-amino-quinoline in 20 ml of dimethylformamide at 100 ° getting produced. The compound melts after recrystallization

Isopropanol at 114-115 · · ·. . ;

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Example 5

To a suspension of 1.1 g of 3-amino-6 ~ (5-nitrofurfurylidenemethyl) -l, 2,4-triazine in 22 ml of dimethylformamide, 1.0 g of dimethylformamide-dimethylaeetal is added and heats the mixture. At 120 ° the crystals dissolve so that a clear solution is formed. Leave for 2 hours this temperature react, filtered and allowed to cool. This gives crude N- [6- (5-nitrofurfurylidenemethyl) -1, 2,4-triazinyl- (5) J-N ', N'-dimethylformaiaidin of the formula

I 1

OJT-J

CH ₃ CH - / ^ S - h = CH - N

after recrystallization from dimethylformamide, a red-brown powder of cerium. 259-260 ° C.

Example 4

1.2 ml of phosphorus oxychloride are added dropwise at 25-50 ° C. to a mixture of 1.0 ml of dimethylformamide and 50 ml of dioxane. The mixture warms up slightly and becomes slowly, cloudy. The mixture still is maintained for one hour at this temperature and then added 1.7 g of 5-Araino-6- (5-nitrofurfurylidenmethyl) -l, 2% - triazine in small

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Servings too. The reaction starts with development of heat. A clear, dark brown solution is obtained lets react for another 1.5 hours at 50-55 and then in Pour 75 ml of water. The insolubles are filtered off, neutralized with aqueous ammonium hydroxide solution and retained so the N- [6- (5-nitrofurfurylidenemethyl) -1, 2,4-triazinyl- (5) J-N ', N'-dimethylformamidine as orange-red crystals from dec. 259-260 ° (from dimethylformamide). The connection is identical to that obtained in Example 5.

Example 5

1.2 g of 5-AminQ-r6- (5-nitrofurfurylidenemethyl) -1,2,4-triazine are in 24 ml of a mixture of equal parts by volume Dioxane and dimethylformamide suspended. 1 * 75 g of pyrrolidinodiethoxymethane are added and the mixture is heated to 70-80 °. The crystals dissolve to form a dark red solution, which can be kept for 90 minutes at the same temperature holds. On cooling, brown crystals of N- [6- (5-Nitrofurfurylidenmethyl) -l, 2,4-triazinyl- {5) l-N * separate , N'-tetramethylene fortnamidine of the formula

CH = CH - </% - N = CH - N

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17if§§§

which after recrystallization from dimethylformamide show an orange color and a decomposition point of 257-258 °.

Example 6

1.6 g of 3-amino-O- (5-nitrofurfurylj-denmethyl) -1,2,% - triazine ml of dimethylformamide are suspended in 64 and _Ä 2.55 S Piperidinodiäthoxymethan added. The mixture is heated to reflux, forming a dark red solution. On cooling, the N- [6- (5-nitrofurfurylidenemethyl) -1, 2,4-triazinyl- (3)] - N ^f , N'-pentamethylene form amide of the formula precipitates

I I

CE = CH - Cf V - N = CH - N

which, after recrystallization as dimethylformamide, forms red-orange needles with a decomposition point of 2J> 6 ~ 2J> B.

Example 7

To a suspension 2.6 g of 3-amino-6- (5-nitrofurfurylidenemethyl) -1,2,4-triazine in 40 ml of dioxane is added> 65 g Diethylformamide diethylacetal and heated to reflux. the

109885/2000 Ä ^: BAD

Crystals dissolve , so that a clear solution is created. After 2 hours, the mixture is filtered hot and allowed to cool. This gives the N- [6- (5-nitrofurfurylidenemethyl) -l, 2,4-triazinyl- (3)] - N ^! , N'-diethylformamidine of the formula

O ₂ If-

- CH = GH

N-CH-N

QJi / 25

O ₂ H ₅

as yellow-brown crystals that after recrystallize from dioxane show flaky shape and a decomposition point from

-191 have.

Example 8

1.2 g of i-amino-δ- (5-ni trof urylidenemethyl) -1,2,4-triazine are suspended in 18 ml of dimethylformamide, 2.6 g of morpholinodiethoxyethylene are added and the mixture is heated. At a temperature of 100 ° the reaction starts and the crystals dissolve. The reaction is allowed to continue for a further 90 minutes and kühlt.ab, whereupon the N- [6- (5-Nitrofurfurylidenmethyl) -1, 2,4-triazinyl- (5) 1-N ', N ¹ -3-oxapentamethyleneformamidh of the formula

O ₂ N-

GH = s CH - </

N = GH - N

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SAO

fails. Obtained by diluting the mother liquor with water one more product. The combined yields are recrystallized from dimethylformamide and give red-orange needles from decomposition point 25 ^ -256.

Example 9

3.0 ml of phosphorus oxychloride are added dropwise at 25 ~> Q ^O to a mixture of l8 ml of dioxane and 2.5 ml dimethylformamide, and further stirred for an hour. " 3.6 g of 2-amino-5- (5-nitrofurfurylidenemethyl} -1, ^ - oxadiazole are added and the mixture is heated at 50-55 ° for three hours Aqueous Aisffioniaic.This gives the N- [5 - (- 5-nitrofurfurylidenemethyl5-1 # 5 * ^ - oxadiazolyl- (2)] - N ', N' ~ dimethylformamidine of the formula

N = CH - M (OHj ₉

after recrystallization from ethylene glycol monomethyl ether forms red-orange needles from P. 204-207 °. .

109885/2000. .

^ O ν »λ · - '' BAD OftiGtNAl

" ^ar " 1795551

Example 10

1.0 ml of phosphorus oxychloride was added to a mixture of 6 ml of dioxanes and 1.12 ml of diethylformamide and the mixture was stirred vigorously for 90 minutes at 25-50 °. 1.2 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1,?, 4-oxadiazole are added and the mixture is stirred for a further 5 hours at 50-55. The crystals formed are filtered off, suspended in water and neutralized with aqueous ammonia. Yellow crystals of N- [5- (5-nitrofurfurylidenemethyl) -1, 3,4-oxadiazolyl- (2) 3-N ', N ^f -diethylformamidine of the formula are obtained in this way

I I

OJi-I

-Ci-

CH = CH - k " J - N = CH

By adding water to the mother liquor, additional material is obtained as the hydrochloride, which is added to the as above. free base can be converted. After recrystallization from ethylene monomethyl ether, the base forms yellow-brown flaky crystals with a temperature of 204-205 °.

Example 11

1.25 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1, 3,4-oxadiazole suspended in 12.5 ml of dimethylformamide and 1.9 g of dimethylformamide diethyl acetal at room temperature . 109885/2000

.0

The mixture is slowly warmed to 60-65 in order to dissolve the crystals, held at this temperature for a further 2 hours and filtered. When standing, orange-red needle-like crystals of N- [5- (5-nitrofurfurylidenemethyl) -1,3,4-oxadiazolyl- (2) J-N ', N ^f -dimethylformamidine separate, which after recrystallization from ethylene glycol monomethyl ether give the F. 20 ^ -207 have. Further substance can be obtained from the mother liquor by adding water. The product is identical to that obtained according to Example 9.

Example 12 -

1.29 g of diethylformamide diethyl acetal and 0.7 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1, J, 4-oxadiazole in 7 ml of diethylformamide are slowly heated to 65 and 2 Held at this temperature for hours. On cooling one receives N- [5- (5-nitrofurfurylidenemethyl) -1,3,4-oxadiazolyl- (2)] - N ', N'-diethylformamidine, which after recrystallization from ethylene glycol monomethyl ether yellow-brown flake-like Forms crystals of P. 204-205 °.

The product is identical to that obtained according to Example 10.

109885/2 000

Example 15 17S5559

1 * 75 S 2-amino-5- (5-nitrofurfurylidene.tiethyl) -1,5,4-oxadiazole are suspended in a mixture of 8.8 ml of dimethylformamide and 8.8 ml of dioxane and 2.0 g of pyrrolidinodiäthoxymethan admitted. When heated to 80-90, a red-brown solution results, which can be kept at this temperature for 2 hours and then let it cool down. The N- [5- (5-nitrofurfurylidenemethyl) -1, 5,4-oxadiazolyl- (2) J-N ', N'-tetramethyleneformamides are obtained in this way of the formula r

OJH

ί — Ν

as yellow-orange, needle-like crystals from Zersp. 215-215 (dimethylformamide).

Example 14

1.76 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1,5,4-oxadiazole are suspended in 7 × 8 ml of dimethylformamide and 2 g of piperidino diethoxymethane are added. The resulting mixture reacts immediately and forms a red-brown solution. The reaction is allowed to continue for a further two hours at 40-50 °. On cooling, yellow-brown crystals of N- [5- (5-nitrofurfurylidenemethyl) -l, 5,4-oxadia2; olyl- (2) J-N ', N'-penta-

10988 5/20 00 ORIGINAL BATHROOM

methylenformamidine of the formula

OJH

I I

/ -CH = CH

which "after recrystallization from dimethylformamide form yellow-orange needles of P. 197-199 °. From the mother liquor further product can be obtained by diluting it with water. . · *.

Example 15

0.78 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1,>, 4-oxadiazole are suspended in 7 * 8 ml of dimethylformamide and 1.0 g of morpholinodiethoxymethane is added. When heated to 60-70 °, solution occurs first, then crystals separate out. The mixture is kept at 70-80 ° for two hours, then allowed to cool and the N- [5- (5-nitrofurfurylidenemethyl) -li3i ^ -oxadiazolyl- (2)] - N ', N ¹ -3-oxapentamethyleneformamine of the formula is obtained . ·

I I

, ₀ / -CH = CH- ^ / - _N = CH-N O as yellow-orange crystals with a melting point of 205-207 ° (dimethylformamide).

109885/2000

BADORlGtNAL

Delspiel16:

10.0 g of 2- (5-nitrofurfurylidene-methyl) -6-acetamidoquinoline are mixed with a solution of 10 g of triethyloxonium · fluoborate in 100 ml of methylene chloride while stirring Heated to 50 ° for hours. The insoluble part is fil- ' trJ.ert and the filtrate is evaporated in vacuo Crude imino ether is slowly added with cooling with a solution of 5, Og n-butylamine in 100 ml of ethanol After 2 hours it is evaporated in vacuo. The residue is mixed with methanol, filtered and crystallized from dimethylformamide-methanol. The Ν ~ [2 ·· (5-Hitrofurfuryliden-methyl) -6-quinolyl] -N'-butyl-acetamidine is obtained the formula. ■ -

CH,

-CH = CH

in crystals from F. 215 - 220 ♦

The 2- (5-nitrofurfurylidene-methyl) -6-acetamido-quinoline used as starting material can be obtained as follows:. ·

A solution of 7.4 g of 2-methyl-6-amino-quinoline and 6 g of 5-nitro-furfural in 75 ml of acetic anhydride are heated

1 0 9 BB ^r . / 2 Q 0 Π

ORIGINAL

it

2 hours on I30. The deposited precipitate is filtered off with suction and recrystallized from dimethylformamide alcohol. The 2- (5-nitrofurfurylidene-methyl) -6-acetamido ~ quinoline is obtained in crystals with a melting point of 284 ° -286 °.

BATH ORIGINAL

■,. 109885/2000

Example 17

2.3 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1,3,4-oxadiazole are suspended in 25 ml of dimethylformamide and 2.1 g of N-methylformamide diethylacetal are added. One warms up to 70 °, whereupon a reddish, clear solution forms. It is held at 70-80 ° for a further 2 hours, then left to cool and diluted with water, whereupon yellow crystals of N- [5- (5-nitrofurfurylidenemethyl) -1,3,4-oxadiazolyl- (2)] - N'-methylformamidine the formula

OJS

-N _{2 -X 0} / GH = CH-1 [ ₀ JJ-N = GH-NH-GH

deposit which, after recrystallization from toluene, have a temperature of 162-164 °.

109885/2000 ^BAD ORIGINAL

Example 18

A mixture of 18 ml of dioxane and 1.65 ml of dimethylformamide 2.2 g of phosphorus pentachloride are added while cooling with ice. The mixture is kept at 20-25 ° for 2 hours and is set then in Heine portions 2.18 g of 2-amino-5- (5-nifc * ofurfuryli- & nmethyl) -1, 3,4-thiadiazole to, whereby the mixture heats up. The reaction mixture becomes clear and yellow crystals are cancelled. The mixture is left to stand at room temperature for 1 hour and at 50 for 2 hours. The reaction mixture is poured into Water and neutralized with ammonia. Red crystals of N- [5- (5-nitrofurfurylidenemethyl) -1, 5, ^ - thiadiazolyl- (2)] - N ', N'-dimethylformamidine separate the formula -

Il Il / ⁵

-CH = CH-Λ q / - ® = CH-H

from, which after recrystallization from ethylene glycol monomethyl ether have the P. 215-217 ° (decomp.). '

109 8 8 5/2000 BAD ORIGINAL

3S

Example 19

2.0 g of dimethylaeetamide are dissolved in 21 ml of dioxane and a solution of is added dropwise while cooling with ice 2.4 g of phosgene in 13 ml of dioxane, with white crystals separating out. The mixture is stirred for a further hour and then added at room temperature 2.57 g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1,3 * 4-oxadiazole to. The mixture is heated and at 40 two layers are formed. When the temperature reaches around 50, Crystals separate from the lower layer. The reaction mixture is kept at 50-55 for a further 3 hours and filtered then. The precipitate is dissolved in about 100 ml of water and the solution is neutralized with aqueous ammonia. It part N- [5- (5-nitrofurfurylidenemethyl) -1, 3,4-oxadiazolyl- (2) J-N ', N'-dimethylaeetamidine the formula

O ₂ N-

pil

-CH

Il Il '-

= GH-U _Λ y -N = G-N

in the form of red-orange crystals that after recrystallize from aqueous dimethylformamide have the F. 196-197.

109885/2000

Example 20

A mixture of 7 ml of dimethylformamide and 5j5 ml of dioxane is mixed with 0.66 g of 2-amino-5- (5-riitrofurfurylidenemethyl) -l, 3,4-thiadiazole and 0.8 g of dimethylformamide diethyl acetal is slowly added dropwise. The mixture is heated to 55-60 for 5 hours, then allowed to cool and the precipitated red crystals are filtered off, which consist of N- [5- (5-nitrofurfurylidenemethyl) -1, 3,4-thiadiazolyl- (2)] - N ^! , N'-dimethylformamidine from P. 216-217 ° (decomp.) And are identical to the product obtained according to Example 18.

10 9 8 85/2000 BAD ORKSlNAL

37

Example 21

A mixture of 18 ml of dioxane and 1.65 ml of diethylformamide we.rden with 2.2 g of phosphorus pentachloride while cooling with ice offset. The mixture is kept at 20-25 for 2 hours and then 2.2J g of 2-amino-5- (5-nitrofurfurylidenemethyl) -1, 3,4-thiadiazole are added in small pores to, whereby the mixture heats up. The reaction mixture becomes clear and yellow crystals are cancelled. The mixture is left to stand at room temperature for 1 hour and at 50 ° for 2 hours. The reaction mixture is poured into Water and neutralized with ammonia. Red-orange crystals of N- [5- (5-nitrofurfurylidenemethyl) -1,3,4-thiadiazolyl- (2)] - N ', N'-diethylformamidine separate the formula

OJI

-CH

NN
= CH-H _q Ji-N = CH-N

cjh

from, which after recrystallization from ethylene glycol monomethyl ether have the P. 163.

*: 5

109885/2000

Example 22

In a manner analogous to that described in Examples 1-21, N- [6- (5-Nitrofurfurylidenemethyl) -1, 2,4-triazinyl- (5) J-N'-methylformamidine can also be used from Zersp. 225-224 ° can be obtained.

109885/2000

Example 25

In the usual way, use a cream as follows Composition ago:

N- [2- (5-nitrofurfurylidene-methyl) -

6-ehinolyl] -N ¹ _} Ii '-dimethyl formamidine'

Vaseline oil. * ·. 2

Vaseline 97

109885/2000

BAD ORfGfNAL

Claims (1)

Claims 1 · Compounds of the formula χ —GH = G - Het - N a G - R, O wherein Het is an optionally substituted, at least one Ring nitrogen atom containing heterocyclic radical aromatic Character means .in which the amidine grouping of the Formula -N = C-R with a ring carbon atom and the nitrofur- ' furylidenemethyl radical is linked to another ring carbon atom in a position which activates a methyl radical, R is an optionally'by aliphatic hydrocarbon radicals, which can also be interrupted by oxygen, sulfur or nitrogen atoms, denotes substituted amino groups, R-, for an aliphatic radical or a hydrogen atom and R. for hydrogen or a lower alkyl radical stands, but with the exception of N- [> - (5-Nitrofurfurylidenmethyl) -6-pyridazinyl] -N ', N'-dimethylformamidine, and their salts. 2. ö-Aa-Nfm-quinolines, where A has the radical -N = CN ^. means in which R, and R 'are hydrogen or, in particular, lower alkyl radicals or R ₁ and R together with the nitrogen atom form a pyrrolidino, piperidino, piperazino, BATH ORIGINAL Morpholine or thiamorpholino form, and R .. a. Mean lower alkyl radical or, in particular, a hydrogen atom and Nfm for the 5-Nltrofurfurylidenmethylrest of the formula CH = C- is in which Rw is a lower alkyl radical or in particular means a hydrogen atom, and their salts. 6-A-3 "Nfm-pyridazines, in which A denotes the radical -N = CN, in which R ₁ and R- represent hydrogen or, in particular, lower alkyl radicals, or R ₁ and R ₀ together with the nitrogen atom are a pyrrolidino, Form piperidino, piperazino, morpholino or thiamorpholino radical, and R a lower alkyl radical or in particular a hydrogen atom 'and Nfm for the 5-nitrofurfurylidenemethyl radical of the formula -CH ^ C- stands in which R _{2 is} a lower alkyl radical or, in particular, a hydrogen atom, but with the exception of N- [5- (5-Nitrofurfuryliden-methyl) -6-pyridazinyl] -N ', N' -dimethylformamidine, and their salts. 109885/2000 BATH ORIGINAL 4. N- [2- (5-Nitrofurfurylidenemethyl) -6-quinolyl] -N ', N ^f dimethylformamidine and its salts. h / ^R i 5. 5-A-6-Nfm-l, 2,4-triazines, in which A denotes the radical -N = CN, in which R and R represent hydrogen or, in particular, lower alkyl radicals, or R and R _p together with the nitrogen atom form one Form pyrrolidino, piperidino, piperazino, morpholino or thiamorpholino radical, and R is a lower alkyl radical or, in particular, a hydrogen atom and Nfm is the 5-nitrofurfurylidenemethyl radical of the formula I ⁴ ₀ / -CH = C- is in which R ^ is a lower alkyl radical or in particular means a hydrogen atom, and their salts. 6. 2-A-5-Nfm-l, 5,4-oxadiazoles, in which A denotes the radical -N = CN, in which R ₁ and Rp represent hydrogen or, in particular, lower alkyl radicals, or R and R_ together with the nitrogen atom form one Form pyrrolidino, piperidino, piperazino, morpholino or thiamorpholino radical, and R, a lower alkyl radical or in particular a hydrogen atom and Nfm for the 5-nitrofurfurylidenemethyl radical of the formula R. OJS- '2 " ^x 0 109885/2000 CH = C- BADORtQINAU is in which R ^ is a lower alkyl radical or in particular means a hydrogen atom, and their salts. 7. 2-A-5-Nfm-l, 5,4-thiadiazoles, in which A denotes the radical -N = CN, in which R _{1 and R 2 represent} hydrogen or, in particular, lower alkyl radicals, or R and R together with the nitrogen atom form a pyrrolidino, piperidino, piperazino, morpholino or thiamorpholino radical, and R represents a lower alkyl radical or, in particular, a hydrogen atom and Nfm represents the 5-nitrofurfurylidenemethyl radical of the formula OJi- -CH = C- is in which R. is a lower alkyl radical or in particular Means hydrogen atom and its salts. 8. Pharmaceutical preparations characterized by a content of one of the claims 1-7 named compounds. 9. Process for the preparation of compounds of the formula R ₁
I. H = 0 - Het - N = C ~ R 109885/2000 BAD LOCATION. wherein Het is an optionally substituted heterocyclic radical having at least one ring nitrogen atom of aromatic character means in which the amidine grouping of the formula -N = C-R with a ring carbon atom and the Nitrofurfurylidenmethylrest linked to another ring carbon atom in a position activating a methyl radical is, R is an optionally by aliphatic hydrocarbon radicals, which can also be interrupted by oxygen, sulfur or nitrogen atoms, substituted amino group means, R-, for an aliphatic radical or a hydrogen atom and R ^ for hydrogen or a lower one Alkyl radical, but with the exception of N- [3- (5-nitrofurfurylidene-methyl) -6-pyridazinylJ-N ', N'-dimethylformamidine, characterized in that in a known manner ■ either a) a compound of the formula. R. ΕΙ ⁴ I ³ -CH = C - Het - N = C - in which Het, R and R _{4 have} the meanings given and X is an etherified or esterified hydroxyl group or a free or etherified mercapto group, with ammonia or an amine containing at least one hydrogen atom implements or ;:; '^ 109885/2000 HS b) a compound of the formula -GH = G - Het - NH, wherein Het and R ^ have the meanings given., or a Salt thereof with a nitrile, a thioamide or a thioimino ether or with an enol ether (imino ether), enol ester (imino ester) or acetal of an aliphatic carboxamide or a salt thereof or with an addition product of a Lewis acid with an aliphatic carboxamide implements or. '· c) a compound of the formula H ₀ G - Het - If = C - R 2 wherein R ₂ ,, Het, R and R have the meanings given, reacts with 5-nitrofurfural or a reactive derivative thereof or d) a compound of the formula ¹ H = I ⁴ G - Het -N = G-R 109885/2000 BAD ORtGfNAL wherein Het, R, R .. and R. have the meanings given, nitrated in position 5 of the furfurylidene radical, and, if desired, compounds obtained in which the Arainogruppo R has at least one hydrogen atom, alkylated or compounds obtained in which the amino group R is disubstituted is, reacted with ammonia or a primary amine and / or obtained free compounds in their salts or obtained Salts converted into the free compounds. 10 9885/20 00, BATH ORIGINAL