FI113168B - A process for the preparation of bicyclic amidinohydrazones and an intermediate useful in the process - Google Patents

Description

. 113168

The present invention relates to a novel process for the preparation of pharmaceutically active bicyclic amidine-substituted amidinohydrazones, which are carried out on novel bicyclic hydroxyamidine and in the preparation of amide substituted amidinohydrazones, whereby intermediates and end-products for which various tautomeric forms are possible may also exist as tautomers and / or, in the case of salt-forming groups, salts.

Methods for the preparation of pharmaceutically active amidinohydrazones are disclosed in European Patent Application EP 0 456 133 (published November 13, 1991). It provides, for example, three synthetic methods of formula Va; ·; HN Nh 2; 25: f Xl <Va>

ϊ X A

; ; ; ^ NH ^ NH2 30 2 1 / · »! V, 4-amidino-1-indanone-2'-amidinohydrazone and certain salts thereof.

First synthesis according to EP 0 456 133

* · 'Make formula B

't t »

I I

2 113168

OF

III

c 5 ^ o

4-cyano-1-indanone which is reacted in pyridine and in the presence of triethylamine at about 40 ° C with hydrogen sulfide of formula C

Οφ

O

4-thiocarbamoyl-1-indanone. 4-Thiocarbamoyl-20-yl-1-indanone is then reacted with triethyloxonium tetrafluoroborate in absolute methanol under argon at room temperature.

the remaining formula D

25 C ^ 3 S NH

; : \ ηΓ V

- 6? 30 ° ♦ »ethyl thioimino ether which is then reacted in absolute ethanol with ammonium chloride.

with din at reflux, whereby chroma; Template 35 on adsorbate resin yields formula E

4-amidino-1-indanone as the hydrochloride salt of η 3,316,168 h 2 N 2 - (2H) -1 - (E) 5 - Sr. This is then reacted with aminoguanidine-bicarbonate-10 in aqueous methanol under reflux, in the presence of hydrochloric acid, to give the compound of formula Va, which is obtained as the dihydrochloride.

Another synthesis also proceeds from 4-cyano-1-indanone which is reacted with hydrogen sulfide to form a compound of formula C as described above. This is now heated directly with amidinoguanidine hydrogencarbonate in ethanolic hydrochloric acid under reflux to give formula F

20 δ <ϊ: ^ 55ϊ / 'ΝΗ2 s Cp »h

m: · 25 jC JL

^ nh ^ nh2

• I

4-thiocarbamoyl-1-indanone-2'-amidinohydrazone as the hydrochloride salt. This is then reacted with; v, triethyloxonium tetrafluoroborate to form methylene

chloride and argon at room temperature to give the corresponding formula G

«T 1 i: 35» 4 113168

LII-I

5 l85 # 1I \ J NH

Ethyl thioimino ether of α 1 -NH 2 NH 2, which is obtained as the dihydrochloride salt, which is then reacted with ammonium chloride in absolute ethanol to give, after chromatographic purification in the adsorbate resin, the compound of formula Va as the dihydrochloride.

15

It would be advantageous to find a process for the preparation of a compound of formula Va which does not require reaction with toxic gaseous hydrogen sulfide and in which all intermediates and end products are obtained directly in the crystalline form after the reaction without the need for any chromatographic separation steps.

Y 'The third process according to EP 0 456 133 originates from 4' 4 '' '', likewise from 4-cyano-1-indanone, which is first reacted with aminoguanidine-bicarbonate in an aqueous solution.

Refluxing in methanolic hydrochloric acid for 4 days to give formula H

OF

k ciy »,

N J

4-Cyano-1-indanone-2'-amidinohydrazone of NH 4 NH 2 which is obtained as the hydrochloride and subsequently reacted with absolute sodium methoxide in absolute methanol and then treated with ammonium chloride to give the compound of formula Va 5 te as the dihydrochloride salt.

It would be advantageous to find a process which, unlike the latter method, can be carried out without prolonged reactions, such as a 4-day reaction to the compound of formula H under reflux conditions.

Surprisingly, a process has now been found which is carried out through novel types of intermediates in which the N-hydroxy-15-hydroxyamino group of 4- (N-hydroxyamidino)] -1-indanone-2'-amidinohydrazones is catalytically surprisingly hydrogenated and has the above-mentioned preferred properties.

The process of the invention for the preparation of pharmaceutically active bicyclic amide substituted amidinohydrazones is a process of formula V

HN

: · 'Rir 25 00 a Γ6 00! Ml IL for the preparation of a compound of R 5 NH 4 -? 4 R 3 30 or a tautomer or salt thereof, wherein R x and R 2 independently of one another are hydrogen or lower alkyl and are bonded to the same carbon atom or different carbon atom of the central bicycle. provided that when both Rx and R2 are:, ·, 35 bonded to the 2-position of the central bicycle, either R1 and R2 are both hydrogen or one of Rx and R2 is hydrogen and the other is methyl or ethyl, 113168 6 A is - (CH 2) n - wherein n is 1 or 2 and R 3, R 4, R 5 and R 5 independently of one another are hydrogen or lower alkyl, which process is characterized in that

5 qH of formula I

/ N <N / NH2 - IJQ (l)

OF

l 15

or a salt thereof wherein Rx, R2 and A have the meanings given in the definitions of the compounds of formula V and Rx and R2 are bonded to the same carbon atom or different carbon atoms of the central bicycle are reacted with formula III

The aminoguanidine or tautomer thereof or its (i)

with a salt wherein R 3, R 4, R 5 and R 6 independently of one another are hydrogen or lower alkyl, wherein ··. 30 is obtained by formula IV

t t I I i

OH

V /

Nv. NH 2 R 1 (i ': 1 /> il': 35 IL) Hydroxyamidino compound according to NRe (IV) IR <113168 7 or a tautomer thereof or a salt thereof wherein Rx, R2, R3, R4, R5, R5 and A has the meanings given for the compounds of formula I and R x 5 and R 2 are bonded to the same carbon atom or different carbon atoms of the central bicycle.

In another process step, the hydroxyamidino compound of formula IV or a tautomer thereof is selectively hydrogenated in the presence of a catalyst in the presence of a free form or a salt thereof to give a compound of formula V wherein the residues have the meanings given above or a tautomer thereof.

15

If desired, the salt of the resulting compound of formula V or its tautomer is converted into the free form or another salt and / or the resulting isomeric mixture of the compound of formula V or its tautomer or salt is separated into individual isomers and / or the compound of formula V or its tautomer is converted into V or its pathogen

* f I

'. ': To me.

»» · »* · •» »ϊ> j ϊ 25 In this section it should be noted that the above formula

The compound of formula Va is one of the compounds of formula V; thus, the compound of formula Va is thus a prefix ♦ * of the compounds of formula V.

Preferably, the preparation of a compound of formula I according to the invention is carried out such that

i »

OF

, V Hl ii "

O

113168 8

wherein Rx, R2 and A have the meanings given for formula V, and R1 and R2 are bonded to the same carbon atom or different carbon atoms of the central bicycle, is reacted with hydroxylamine or a salt thereof to give formula I

OH

/ n ^ nh2

10 T R R

Azz;

cv ·

OF

Compounds of the formula I or salts thereof wherein R1; R2 and A have the meanings given for the compounds of formula V and R2 and R2 are bonded to the same carbon atom or different carbon atoms of the central bicycle.

The compounds of the invention which are useful as novel types of intermediates of the amidino-

, * 25 for the preparation of the hydrazones are of formula I above

Or the salts thereof with Rx and R2; : independently of one another hydrogen or lower alkyl, provided that when both Rx and R2 are attached at the 2-position of the central bicycle, either: v. 30 Rx and R2 represent hydrogen or one of the residues, ··>. Rx and R2 represent hydrogen and the other methyl or ethyl, * and A represent - (CH2) n-, where n is 1 or 2.

I * I I)

I t I

*, .. · Particularly preferred are compounds of formula I or salts thereof wherein only 2 hydrogen atoms are attached to the 2-position of the central bicycle.

113168 9

The compounds of the formula I are valuable intermediates in organic synthesis, in particular for the preparation of active ingredients of drugs. In particular, they serve as intermediates for the preparation of pharmaceutically active bicyclic hydroxyamidine-substituted amidinohydrazones of formula IV as defined above, and in particular for the preparation of bicyclic amidino-substituted amidinohydrazones of formula V and thus as an inhibitor of the growth of both eukaryotic and prokaryotic cells. Due to this inhibitory effect, the compounds of formula V are of interest, e.g. as tumor therapeutic agents and in the treatment of protozoal infections.

Another surprising feature of the present invention is also interesting: Catalytic hydrogenation of amidoxime salts to amidine salts is already known (DE OS 1 586 144, where reduction is described only in non-aqueous media). However, there are indications in the literature that hydrogenation of oximes is possible under similar conditions as hydrogenation of hydrazones. For example, both *, * acetone oxime and butyraldehyde phenylhydrazone hyd-, '' are traced in the presence of nickel catalysts for 1-2 hours in non-aqueous solvents (Winans, C.).

F. and Adkins, H., J. Am. Chem. Soc. 55, 2051 (1933)). Acetone oxime then forms isopropylamine, butyraldehyde phenylhydrazone n-butylamine, di-n- v, butylamine and aniline. Thus, the N-N bond of the hydrazones is also cleaved. Thus, it is surprising that the catalytic hydrogenation of the compound of formula IV is carried out selectively in the V. amidoxime group without simultaneous cleavage or reduction of the group = N-NR3- (C = NRS) -NR4R5.

Use of novel bicyclic hydroxyamidines according to the invention as intermediates in the preparation of a pharmaceutical. Relates to the use of a compound of formula I for the preparation of a compound of formula V, or a tautomer thereof, or a salt thereof, wherein the use is characterized in that:

a compound of Formula I, or a salt thereof, wherein R 1f R 2 and A have the meanings given, are used to react it with a compound of Formula III

10 NR6 H2N-n ^ X 5 (ΠΙ) k 15

with an aminoguanidine or tautomer thereof or a salt thereof, wherein R 3, R 4, R 5 and R 6 independently of one another are hydrogen or lower alkyl to give the formula IV

20

OH

\: N ^^ Nh2 25 (Tl nr6 ™ ^ Νίί # ίιι 11 r5 v: | R4 r3 30) a hydroxyamidine compound or a tautomer thereof or a salt thereof, wherein R1, R2 and A have the formula: Means for the compounds of formula I, with the residues: 35 R3, R4, R5 and R6 have the meanings indicated for the compounds of formula III and Rx and R2 are bonded to the same carbon atom or different carbon atoms of the central bicycle;

11316 P

then the compound of formula IV or a tautomer thereof is selectively hydrogenated in the presence of a catalyst either using the free form in the presence of an acid or using a salt thereof to give a compound of formula V having the meanings above or a salt thereof if desired converting a salt of a compound of formula V or a tautomer thereof into a free form or one of its other salts and / or separating the resulting isomeric mixture of a compound of formula V or its tautomer or salt into one of the isomers and / or converting a compound of formula or a tautomer thereof.

15

In the context of this application, the general terms used hereinabove and hereinafter have the following meanings in particular: Depending on the structural conditions, the compounds of formula I, II, III, IV and / or V may exist in the form of isomeric mixtures or pure isomers. If, for example, Rx '' and / or R2 represent a non-hydrogen substituent, then the corresponding compounds of formula I may present

',,, · 25 as racemates or pure enantiomers. The formula I

* * I

| ' * and IV, the hydroxyamino group may exist in the E and / or Z configuration [Formula (E) or the like. (Z)], in addition, a tautomeric form (T) is conceivable:

30 OH

, ··, N ^ NHo / MU

HO'-► n ^ / NH2 :, x (E) (z) y

^ "Oh

I; ·, 35 ^ HN ^^ NH

i CD

113168 12 (where the X represents the formula

Y

wherein Y represents a bivalent group of 10 = NOH (in formula I) or NR6

15 I

K3 (in formula IV), and wherein A, Rx, R2, R3, R4, R5 and R5 have the meanings given).

The Z configuration is particularly preferred, however, the presence of Form E (E) or tautomer (T) in solution or solid form cannot be ruled out. * quantities, especially the presence of small quantities of V '. Therefore, in the case of compounds of formula I, all isomers and / or tautomers present in equal amounts are thus always included.

* l '. In the compounds of the formula I, the hydroxyimino group may be present at the 1-position of the bicycle in the syn or anti-configuration or both.

• »

The prefix "lower" denotes a residue having a maximum of 7 and especially a maximum of 4 carbon atoms.

: 35 Generally, Rx and R2 are on the central bicycle (or its precursors) so that they are bonded to the hydrogen atoms present on this bicycle.

/ 113168 13

Whenever a compound, its tautomer or its salt or compounds, tautomers or salts are mentioned, this is always to be taken to mean "one or more" unless otherwise stated. As used herein, "compounds" also means the individual compounds, salt or salts, where salt-forming groups, isomers or isomers are present, and / or tautomers or tautomers, if tautomeric, are possible.

Lower alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, in particular ethyl or methyl.

Cycloalkyl is primarily C3-C8 and especially C5-C6 cycloalkyl, meaning that it contains 3-8 or equivalent. 5 or 6 ring carbon atoms. However, it may also be substituted by lower alkyl. Cycloalkyl is especially cyclopentyl or cyclohexyl.

20

Aryl lower alkyl is primarily phenyl or naphthyl, such as 1- or 2-naphthyl, which is preferably attached at the terminus to lower alkyl, as defined above.

The phenyl or naphthyl residues may be unsubstituted or substituted, especially as set forth in the following phenyl linkage. Aryl is preferably phenyl which is unsubstituted or substituted with one or more substituents, in particular one or two substituents, lower alkyl, lower alkoxy, e.g. methoxy or ethoxy, lower alkanoyloxy, e.g. formyloxy, '. or pivaloyloxy, nitro, 'halogen, trifluoromethyl, lower alkoxycarbonyl, e.g., tert-butoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-dialempalkylcarbamoyl, cyano ,; Lower alkanoyl, e.g., formyl, acetyl, propionyl or pivaloyl, arylcarbonyl, e.g. Ν-dialempialkyylisulfamo-yl. Preferably, aryl means phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, and above all phenyl. Aryl lower alkyl is especially phenyl lower alkyl, especially benzyl.

10 Halogen means especially chlorine and bromine, but it can also mean fluorine or iodine.

Tautomers may be present, for example, when R3, R4 and / or R5 in the compounds of formulas III, IV or V represent hydrogen: The corresponding guanyl radical represented by the formulas III, IV and V as -N (R3) -C ( = NR6) -NR4R5, then may also exist in tautomeric forms -N = C (-NR6H) -NR4R5, -N (R3) -C (-NR6H) = NR5 or -N (R3) -C (-NR6H) = nr4 .

The presence of such or similar tautomers is known to those skilled in the art. The compounds of general formulas I, III, IV and V include all the corresponding tautomers.

If A represents - (CH 2) n - and R x and R 2 are different from hydrogen then the substituent j V corresponding to R 3 and / or R 2 may also be attached to the carbon atom of - (CH 2) n .

* · I

• · I f The residue A represents a bivalent linear group of the formula - (CH 2) n where n is 1 or 2, especially 1.

IV. The salts of the compounds of the formula V are primarily »pharmaceutically acceptable, non-toxic acid addition salts formed with an acid [PA] which is a mono- or poly-protonic acid, which is an unsubstituted or unsubstituted or singly or multiply substituted alkenic acid, unsubstituted or substituted, cycloalkylcarboxylic acid, arylcarboxylic acid or aryl-lower alkylcarboxylic acid, wherein substituted, aryl-lower alkenylcarboxylic acid, heterocyclylcarboxylic acid, alkanesulfonic acid 5 unsubstituted or substituted, arylsulfonic acid (aryl-SO 2 -), alkyl sulfuric acid, N-substituted sulfamic acid, non-acidic, non-organic, or an inorganic acid such as carbonic acid, halogen hydrocarbon such as hydrochloric acid, sulfuric acid, phosphoric acid or pyrophosphoric acid.

The following definitions apply to acids [PA] ([PA] is "protic acid"): The alkanoic acids are primarily C 1 -C 7 alkanoic acids, in particular C 1 -C 7 alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid. , pentanoic acid, hexanoic acid or heptanoic acid, or further octanoic acid, decanoic acid or dodecanoic acid, in particular acetic acid, propionic acid or octanoic acid, wherein these acids are unsubstituted or substituted one or more times, especially one to six times, , either once, such as in glycolic acid, · lactic acid or 2-hydroxybutyric acid, or several times, e.g. up to five times, such as in gluconic acid: or glucose monocarboxylic acid (“glucoheptanoic acid”), with carboxylic acid, e.g. C 1 -C 4 alkanoic acids, in particular C 1 -C 4 alkanoic acids such as succinic acid, or further adipic acid, pimelic acid, aliphatic acid or azelaic acid, hydroxy and carboxylic acid; x, such as malic acid, tartaric acid, citric acid, glucaric acid or galactaric acid, amino or amino: zero and carboxy and / or one or two mercapto: methylmercapto, hydroxy, phenyl, 4-: [35] hydroxyphenyl, naphthyl, cyclohexyl, imi! with an amino substituted with aazolyl or indolyl, such as amino acids, especially glutamic acid or aspartic acid, in (D), (113) 186 (L) or (D, L), in particular (D) or (L) form; substituted amino and carboxy and / or one or two mercaptans (also in oxidized form as the corresponding two disulfide of the corresponding mercaptan), methylmercaptol, hydroxy, phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl or imidazolyl , such as amino acids, e.g. N-mono- or N, N-dia preferable alkyl amino acids such as N-methylglycine, 10 or N-lower alkanoylamino acids such as acetylaminoacetic acid (N-acetylglycine), N-acetyl aspartin or N-acetyl oxo, such as pyruvic acid or acetic acetic acid, fosto and amino, such as phosphoserine, or phospho and hydroxy, such as 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, Glu. in sucrose-1-phosphoric acid or fructose-1,6-bis-phosphoric acid. Amino acids are primarily α-amino acids which may exist in the (D), (L) or (D, L) form, especially in the (L) or (D) form, and when other centers of asymmetry exist, as other isomers , e.g., Glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine (H- * · · '·' 1 Leu-OH), isoleucine (H-Ile-OH), norleucine (α-amino-hexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (α-amino-γ-hydroxybutyric acid), threonine (H-Thr-OH), methyl: thionine (H-Met-OH), cysteine (H-Cys-OH) (which may also exist in oxidized form as cystine), phenyl * lialanine (H-Phe -OH), tyrosine (H-Tyr-OH), β-phenylserine (β-hydroxyphenylalanine), phenylglycine, α-30 naphthylalanine (H-Nal-OH), cyclohexylalanine (H-

Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), * »aspartic acid (H-Asp-OH), aspartic acid (H-Asn-OH), amino malonic acid, glutamic acid (H-Glu-OH), glutamine (H-lithium Gln-OH), histidine (H-His-OH), δ-hydroxylysine, ornic:, ·, 35-tin (α, δ-diaminovaleric acid), α, γ-diaminobutyric acid, α, β-diaminopropionic acid , arginine (H-Arg-OH) and lysine (H-Lys-OH). Particularly preferred amino acids are glycine,? serine, cystine, aspartic acid and glutamic acid, most notably aspartic acid and glutamic acid.

Alkenic acids include, for example, C2-C10 alkenedioic acids which are unsubstituted, such as maleic acid or fumaric acid, or substituted, in particular, with hydroxy, such as hydroxy-malic acid (tautomer: oxalacetic acid), or lower alkyl, e.g.

10

Cycloalkylcarboxylic acids include in particular C4-C12cycloalkylcarboxylic acids in which the cycloalkyl residue is bi- or tricyclic, in particular monocyclic or tricyclic, e.g.

For example, aryl carboxylic acids in the aryl radical have from 20 to 20, in particular 6 to 14, carbon atoms and are e.g. phenyl, 1- or 2-naphthyl or indane and are unsubstituted as in benzoic acid or substituted, in particular 1-3 *. lower alkyl such as methyl, halogen such as V ', fluorine, chlorine or bromine, hydroxy, lower alkoxy, eg, methoxy, phenoxy, lower alkanoyl | solutions such as Acetoxy, amino or carboxy such as salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-amino-30 acylic acid or phthalic acid.

In aryl lower alkyl carboxylic acids, aryl is as defined above with respect to the aryl carboxylic acids and unsubstituted or as above: substituted, and lower alkyl is especially methyl or! ethyl, wherein lower alkyl is unsubstituted, such as in phenylacetic acid, or substituted, e.g., hydroxyl- / 11316818a, such as mandelic acid.

In aryl lower alkenylcarboxylic acids, aryl is the same as defined above for arylcarboxylic acids, and the lower alkenyl especially contains 2-4 C atoms, as in Kane fatty acid.

Heterocyclylcarboxylic acids include, for example, a heterocyclyl consisting of one to three rings, in particular one or two rings, and saturated or partially or completely unsaturated, especially saturated or unsaturated, containing 5-12 ring atoms, in particular 5-7 ring atoms having carbon and up to three heteroatoms, in particular one to two heteroatoms, particularly oxygen, nitrogen and / or sulfur, preferably oxygen and nitrogen, wherein heterocyclyl represents e.g. pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl or a fully or partially saturated derivative or pyranyl or furanyl of these residues, and is unsubstituted as in nicotinic acid or isonicotinic acid, or mono- to five-fold substituted, especially hyd. hydroxy or hydroxymethyl such as glucuronic acid or galacto-lacturonic acid.

The alkanesulfonic acids are, in particular, C 1 -C 6 al-cyanosulfonic acids, especially lower alkanesulfonic acids, such as methanesulfonic acid or ethanesulfonic acid, which are unsubstituted or substituted, in particular by one or two hydroxy or sulfo, such as 2 , * in roxethanesulfonic acid or alkane disulfonic acid, e.g. lower alkanesulfonic acid such as ethane-1,2-di-3 'sulfonic acid.

1 'J; t

For example, aryl in arylsulfonic acids is as defined for 113,168,19 and is unsubstituted, such as in benzenesulfonic acid or 2-naphthalenesulfonic acid, or as substituted with arylcarboxylic acids, in particular lower alkyl, e.g. -phonic acid, or another sulfonyl residue such as 1,3-benzenedisulfonic acid or naphthalene-1,5-disulfonic acid, especially 1,5-naphthalenedisulfonic acid.

10

The alkyl sulfuric acids are primarily C 1 -C 20 alkyl sulfuric acids, especially lower alkyl sulfuric acids such as methyl sulfuric acid or ethyl sulfuric acid, or dodecyl sulfuric acid.

N-substituted sulfamic acids include, for example, N-cycloalkylsulfamic acids in which the cycloalkyl is especially C4-C12cycloalkyl and the cycloalkyl residue is mono-, bi- or tricyclic, such as in cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, N-cyclohexylsulfamic acid, or N-alkylsulfamic acids, especially N-lower alkylsulfamic acid such as methyl, ethyl or propylsulfamic acid.

Organic acids which do not contain carboxy, sulpho, sulphate, phate or phosphorus include, for example, acidic acids; · ': Hydroxy groups such as ascorbic acid.

* Important acids are hydrochloric acid, sulfuric acid, carbonic acid, 30 acetic acid, propionic acid, octanoic acid, decanoic acid, ···, dodecanoic acid, fumaric acid, glycolic acid, lactic acid,

* I

2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid ,; ·. 35 citric acid, glucaric acid, galactaric acid, glutamides, ti; nic acid, aspartic acid, N-methylglycine, acetyl * -aminoacetic acid, N-acetyl-aspartic acid, N-acetylcystyl / 11316820n, pyruvic acid, acetic acid, phosphoserine, 2-or 3-glycerophosphoric acid, glucose phosphoric acid, fructose-1,6-bisphosphoric acid, maleic acid, hydroxy maleic acid, methyl maleic acid, 5-cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-or 3-hydroxynaphthoxy, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-amino-salic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4-15 methylbenzenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodec yl sulfuric acid, N-cyclohexylsulfamic acid, methyl, ethyl or propylsulfamic acid, or ascorbic acid.

Very important acids are hydrochloric acid, sulfuric acid, acetic acid, octanoic acid, fumaric acid, succinic acid,,, adipic acid, lactic acid, salicylic acid, methanesulphonic acid; 'Phonic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid or N-cyclohexylsulfamic acid, especially hydrochloric, lactic, acetic, methanesulfonic acid t · e | V or benzenesulfonic acid.

* · * * ·> • ·

* I

: The acids mentioned, especially if they contain more than one acidic group of different acidity, which can dissociate protons, may also exist as mixed-salt lithium cations, for example alkali metal ions such as sodium or potassium ions. , v .: such as magnesium salts or zinc salts, wherein said mixed salts contain, or may have, at least one further disulfide proton in the acid component, in a form in which not all protons are liberated, but at least however / 113168 21 one proton is shifted to the respective base of formula V in question. Thus, for example, carbonic acid may be used as a bicarbonate salt such as sodium or bicarbonate tin.

5

Acid addition salts formed with an acid [PA] of a base of formula V may also exist as hydrates. The crystals may also contain other solvents used for crystallization.

10

Depending on the structural conditions, the acid addition salts of this invention may also exist in the form of isomeric mixtures or pure isomers. If, for example, R2 represents a substituent other than hydrogen, then the corresponding acid addition salts of formula V may exist as racemic salts or enantiomerically pure salts or also as diastereomeric salts, e.g., asymmetric center acids [PA] such as said amino acids or lactic acids.

20

According to compounds of formula V, compounds of formula I, III, IV and V and other reagents may be present in the synthesis of compounds of formula V for compounds of formula V in the form of said salts and optionally in the form of hydrates or crystalline forms; containing solvent. Non-pharmaceutically acceptable salts, e.g. picrates or perchlorates, may also be used for isolation and purification. Only the pharmaceutically usable, non-toxic salts of the compounds of formula V, which are therefore preferred, will come into therapeutic use.

* t * '/,' Transformation of Compounds of Formula II according to the Invention:: The compounds of formula I occur as such; 35 under normal conditions carbonyl and cyano groups! reaction with nitrogen bases, whereby simultaneous conversion of the carbonyl and cyano groups in one of the 113168 22 batches is particularly preferred, but the reaction may also be carried out sequentially by first reacting one group and then another, especially if a methyl or ethyl residue 5 is attached Rx. The reaction utilizes hydroxylamine, which is preferably present in a double molar amount or excess, especially up to ten times more, especially in a double to triple molar amount, or a salt thereof, especially the hydroxylamine salt of any one of with an acid, in particular a salt formed with an inorganic acid, e.g., hydrochloric acid, such as hydrofluoric, hydrochloric, hydrobromic or iodine, preferably hydrochloric, sulfuric, or hydrogen sulfate such as alkali metal hydrogen sulfate, phosphoric acid, phosphoric acid or a dihydrogen phosphate, e.g. an alkali metal hydrogen phosphate or a dihydrogen phosphate such as sodium hydrogen phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen phosphate, or a salt formed with an organic acid, e.g. in the lower alkyl residue '* * a lower alkanecarboxylic acid, e. g. acetic acid, chloroacetic, unsubstituted or especially substituted by a halogen such as V · fluorine, chlorine or iodine | •: Potassium, dichloroacetic acid or trifluoro or trichloroacetic acid, or sulfonic acid such as lower alkane sulphate | ; 'I'; with a phonic acid, e.g. prepared in situ, for example, from an alcoholic solution of nitric oxide and thiol (II) salt, such as Sn (II) Cl 2; In the presence of Cu salts or N, O-bis- [trimethylsilyl] -! hydroxylamine potassium salt (prepared from (H3C) 3Si-NH-O-Si (CH3) 3 and potassium hydride in tetrahydrofuran, followed by liberating the potassium salt of the compound of formula I with an acid, e.g. ammonium chloride) and reacting with water (in the presence of without them), in an aqueous solvent mixture, in mixtures of water and one or more alcohols, e.g. such as dimethylsulfoxide, dialkylalkyl loweralkanoylamides such as dimethylformamide, or sufficiently inert solvents such as acetonitrile, a mixture of such organic solvents, or liquid ammonia, especially an aqueous alcoholic solution such as methanol / water or ethanol. was / water at -78 ° C to the reflux temperature of the corresponding reaction mixture, preferably -30 to 100 ° C, especially 5 to 90 ° C, e.g. about 75 to 80 ° C for about 1 to At pressures of 10,000 bar, in particular by using hydroxylamine salts of hydroxy at normal pressure, in the absence of a base, or especially acid salts of hydroxylamines, by neutralizing the acid with a base, particularly an '·' hydroxide such as an alkali metal hydroxide, e.g.

v 'with sodium or potassium hydroxide, carbonate or hydrogen carbonate, in particular with an alkali or alkaline earth metal carbonate or hydrogen carbonate, for example sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, With an alkali metal or alkaline earth metal salt of succinic acid such as sodium acetate or potassium acetate, organic nitrogenous bases, in particular secondary or tertiary. An aromatic amine, e.g., a cyclic 5- or 6-membered secondary or tertiary amine, such as:,, 35, pyrrolidine or pyridine, or alcoholates; e.g., alkali metal lower alkyl alcoholates such as sodium or potassium methylate, ethylate or tert-butylate, or an anion exchanger, e.g. Amberlite IR-4B, with the presence of an alkali metal carbonate being particularly preferred; a compound of formula I, in particular in the crystalline form, and after recrystallization from solvents or mixtures of solvents, in particular alcohols such as methanol or ethanol, or esters such as lower alkyl lower alkanoic acid esters, for example acetic acid ethyl ester or mixtures thereof; .

When reacted sequentially, unless otherwise noted, the reaction conditions mentioned above for the simultaneous reaction, which are also specifically taken into account, are preferably first reacted with a keto group at the central 1-position on the hydroxyamine, for example for a simultaneous reaction under said reaction conditions. , with a single-double double molar excess of hydroxylamine relative to the compound of formula II, preferably in the absence of a base. In particular, a salt of hydroxylamine, preferably a salt of a hydrohalic acid such as the HCl salt in said organic solvents, preferably an alcohol such as methanol or ethanol, is reacted at said temperatures, especially at about 75-80 ° C, yielding the corresponding cyano * 1-oxime, which can be further purified or directly used. This is then converted to a two-to-three-fold molar ratio of the acid salt of hydroxylamine; v. 30, in particular a salt of a hydrohalic acid such as HCl, ·· *, a salt in one of the organic solvents mentioned, especially alcohol such as methanol, ethanol or *. 'Tert-butanol in the presence of alkaline earth metal alcoholates such as lithium, sodium or in the presence of potassium methylate, ethylate or: 35-tert-butanolate, or further in said solvent or mixture of solvents with one of the above bases, in particular alkali metal hydroxides, sodium or potassium hydroxide, or alkali metal carbonates, or for simultaneous reaction with di-potassium carbonate at said temperatures, in particular between 0 ° C and reflux temperature, whereby the cyano group reacts to the corresponding compound of formula I.

Reaction for preparing compounds of formula V from compounds of formula I or salts thereof and / or when using compounds of formula I for preparing compounds of formula V by reacting a compound of formula I with an aminoguanidine of formula III, preferably used in an approximately equimolar amount or more 15 molar to the molar amount of the compound of the formula I, in particular 1 to 2-fold, to give the hydroxyamidino compound of the formula IV, per se under ordinary conditions for reacting carbonyl groups with nitrogen bases, especially under conditions conventional for oxime with a nitrogen base, the compound of formula III is used to react with an acid, e.g., a hydrohalic acid such as hydrofluoric, hydrochloric, hydrobromic or iodine, especially hydrochloric, sulfuric, or hydrogen sulfate. I alkalimetallivetysulfaatin, e.g., sodium hydrogen. phosphate, phosphoric acid, hydrogen phosphate or dihydrogen phosphate, e.g., alkalimetallivetyfosfaatin or -divetyfosfaatin, such as sodium hydrogen phosphate, disodium hydrogen phosphate ka-V or a salt or dipotassium hydrogen phosphate, 30 an organic acid, especially a carboxylic acid, such as alem-pialkyylitähteessä or unsubstituted. especially lower alkanecarboxylic acid substituted with a halogen such as fluorine, chlorine or iodine, e.g. acetic acid, chloroacetic acid, dichloroacetic acid or trifluoro or trichloroacetic acid, lactic acid or sulfonic acid such as | a salt of lower alkanesulfonic acid, e.g. a weak acid such as acetic acid, or more particularly carbonic acid or bicarbonate, by removal of the weak acid, and or in the absence thereof), in an aqueous solvent mixture such as a mixture of water and one or more alcohols, e.g. methanol, ethanol or isopropanol, dialkylalkyl sulfoxides such as dimethyl sulfoxide, or dialem-15alkyl lower alkanoylamides, such as dimethylformamide. such as in one or more alcohols, e.g. in a solution such as methanol, ethanol or especially isopropanol, preferably at -20 ° C to the reflux temperature of the reaction mixture in the presence of a solvent, for the melts up to 220 ° C, preferably; at room temperature to the reflux temperature of the reaction mixture in the presence of solvent. 30, in particular approximately refluxing in a heat, ··· state to obtain the compound of formula IV directly in free form or, above all, as a salt, in particular: ·, · as a salt of the acid present in the reaction, a compound of formula IV may be obtained; In free form, for example by reaction with a base, especially a hydroxide, e.g. an alkali metal hydroxide such as potassium or sodium hydroxide, in the presence of the most recently defined organic solvents, or in particular in the absence thereof, with an anion exchanger in the form of -20 to 80 ° C, in particular 0 to 40 ° C, e.g. e.g. a mixture of water and organic solvents e.g. alcohols such as methanol or especially ethanol.

For the selective hydrogenation of a hydroxyamidino compound of formula IV, which may be used as a salt or also as a free base, the catalysts used in the presence of a catalyst and an acid of formula V are primarily cobalt, and especially nickel, particularly in its finely divided on pumice, alumina, silica gel or activated carbon, and the acid used is, above all, the acids mentioned above in the definition of salts, in particular the acids [PA], in particular the acids mentioned above, in particular molar amounts of formula I or in excess, in particular stoichiometrically necessary to form a salt of both basic centers of the compound of formula IV, e.g., equimolar • (especially in the case of divalent acids), in double molar quantities (especially in the case of monovalent acids) or in excess (especially in the case of weak acids having a pKs> 4, such as a lower alkane). -30 acids, e.g. acetic acid), wherein the solvent is organic solvents such as reaction-inert alcohols, e.g. methanol, ethanol:: or isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran. or anisole, esters, such as ethyl acetic acid, or if the acid [PA] is'; organic liquid acid under reaction conditions, this acid itself, acetic acid, mixtures of these solvents, 113168 28 water-soluble organic solvents such as the above-mentioned alcohols or liquid organic acid-water mixtures, or water itself, in particular water is preferred; Between C and the reaction mixture, particularly at 10 to 70 ° C, e.g. between room temperature and about 50 ° C, and the reaction is carried out at slightly reduced pressure, normal pressure or slightly elevated pressure, particularly 0.5 to 10 bar, especially at atmospheric pressure, by passing 10 hydrogen, especially until the calculated amount of hydrogen is received, especially until the hydrogen uptake ceases spontaneously under the reaction conditions, and the compound of formula V is obtained especially by direct filtration of the catalyst, e.g. .

15 and, if necessary, evaporating the filtrate as a salt of the acid used in crystalline form, optionally further crystallizing, e.g. from organic solvents such as alcohols, e.g. methanol or ethanol, or ethers such as diethyl ether, dioxane or tetrahydrofuran. solvent mixtures, e.g. ethanol / ether ethers.

Hydrogenation may also be carried out continuously so that: solutions of the compound of formula IV are allowed to drain; *; on solid catalysts and contacting with hydrogen at the above conditions upstream or downstream.

. The advantage of this hydrogenation is that it is possible in aqueous solution or in polar organic solvents as opposed to, for example, amidoximes; V: reaction with iron pentacarbonyl (Dondoni, A., J.

Chem. Soc. 1975, 761-2). Since the hydrogenation starting materials are more soluble in water or in aqueous solvents; rather than pure organic solvents, the reaction can be carried out under conditions of optimum solubility also with ore 113168 29 organic solvents for less soluble compounds, especially in less than 16 hours and especially without heating to reflux.

All intermediates are preferably obtained in crystalline form, so that no purification by chromatography is required in any case.

EXTRAORDINARY METHODOLOGICAL MEASURES

If desired, the salt of the resulting compound of formula V or its tautomer may be converted into the free form or into another salt and / or the resulting iso-15 mixture of the compound of formula V or its tautomer or salt may be separated into isomers and / or

or a tautomer thereof may be converted to another compound of formula V or a tautomer thereof.

The conversion of a salt of a compound of formula V or a tautomer thereof into another salt, in particular the salt of the above-mentioned acid [PA], occurs, for example, in solvents, especially organic solvents, in particular polar. In solvents, preferably esters, e.g.

!, · * 25 in lower alkanoyl lower alkyl esters, such as acetic acid, in ethyl amides, e.g., N, N-dialkylalkyl; *; lower alkanoylamides such as dimethylformamide,. alcohols, e.g. hydroxy lower alkanes such as methanol, ethanol, ethylene glycol or glycerol, or aryl alcohols such as phenols or dimethylsulfoxide, in the absence or presence of water, particularly in the presence of water or water itself. It is particularly preferred to carry out the reaction on alcohols such as the latter hydroxy lower alkanes, mixtures of such alcohols with water, or on the water itself.

The reaction occurs, for example, in free solution, but may also occur in chromatographic columns, e.g., by gel filtration, ion exchangers, or through semi-permeable membranes, by osmotic events, e.g., dialysis.

5

The reaction takes place at temperatures between the freezing point and the boiling point of the solutions in question, in particular 0 to 50 ° C, especially 20 to 40 ° C, e.g. at room temperature, under an atmosphere of a shielding gas, e.g. nitrogen or argon.

10

Compounds of formula V and acids [PA] are used in appropriate molar ratios, or acid [PA] is used in excess. Preferably, the individual components are used in a molar ratio that corresponds to the molar ratio of base V to acid [PA] in the resulting salts.

For example, the formed salts precipitate spontaneously, possibly only after cooling, or they are precipitated by the addition of solvents, in particular non-polar solvents, eg ethers such as diethyl ether or water, and / or recovered by partial or total evaporation.

·. ' The reaction may also be carried out via the free v-bases of formula V prepared, for example, by converting the acid salt used as the starting material for the base of formula V into the free base with an acid other than 1 '·': , an alkali metal hydroxide such as an NaOH or KOH in an aqueous solution in the presence or absence of an organic solvent as defined above. The subsequent conversion of the free base occurs, for example, as described above.

The preparation of the free bases of the compounds of formula V or their tautomers is carried out in particular in the above brochure! by further chromatography, e.g., gel filtration or ion exchangers.

3i 113168

Instead of the compounds of formula V, the above-mentioned salt modifications of salts and free compounds may also be carried out with intermediates, in particular with intermediates of formula IV.

5

Mixtures of isomers obtained according to the invention can be separated into individual isomers in a manner known per se, for example by racemization of salts with optically pure salt-forming reagents and separation of the resulting diastereomeric mixture, e.g. by fractional crystallization or chromatography on optically active column materials.

The free form compound of formula V or its tautomer or salt thereof can be converted to another compound of formula V.

For example, in a compound of formula V wherein one, more or all of R 3, R 4, R 5 or R 5 is hydrogen, one, more or all of the hydrogen atoms can be converted to one of the lower alkyl residues mentioned above by alkylation, for example, lower alkyl halides, bromides or iodides by attaching a lower alkyl residue. The reaction proceeds to alkylation under standard conditions and takes place in ** solvents, especially organic solvents, preferably in polar solvents, preferably esters, e.g. lower alkanoyl lower alkyl esters such as acetic acid ethyl ester, e.g. , N-; ·> · ι 3 0 in dialempalkyl-lower alkanoyl amides such as dimethylformamide, alcohols, e.g. hydroxy-lower alkanyl; -, such as methanol, ethanol, ethylene glycol <', v or glycerol, or aryl alcohols such as phenol: water, e.g., phenol, or dimethylsulfoxide; \ 35 in the absence or presence, especially in the absence of water! At temperatures between -80 ° C and the reflux temperature of the reaction mixture, especially at 20-100 ° C.

"113168 '32

Particularly preferred is the above process for the preparation of a compound of formula V or a tautomer or salt thereof wherein Rx and R2 are independently hydrogen or lower alkyl, especially hydrogen, methyl 5 or ethyl, provided that when both R3 and R2 are bonded to the central bicyclic ring 2 position, either R 1, R 2 and R 2 are both hydrogen or one of R 3 and R 2 is hydrogen and the other is methyl or ethyl, and A is - (CH 2) n -, where n is 1 or 2, and R 3, R 4, R 5 and R 8 represent hydrogen, compounds of formula I characterized in that in the compound of formula I or a salt thereof and in the compounds of formula III and IV or their tautomers or salts thereof R 3 and R 2 independently represent hydrogen; or lower alkyl, especially hydrogen, methyl or ethyl, provided that when both Rx and R2 are bonded at the 2-position of the central bicycle, either Rx and R2 are both hydrogen or one of Rx and R2 is hydrogen and the other is methyl or ethyl, and A is - (CH2) n- wherein n is 1 or 2 and that In the compound of formula III or a tautomer or salt thereof, each of R 3, R 4, R 5 and R 5 represents hydrogen.

Especially preferred is the compound of formula I or. the use of a salt thereof as defined above for the preparation of a compound of formula V, a tautomer thereof or a salt thereof; wherein R 3 and R 2 independently represent hydrogen and lower alkyl, especially hydrogen, methyl and ethyl, provided that if both R 3 and R 2 are attached at the 2-position of the central bicycle, then both R x and R 2 represent hydrogen or one of the radicals *. ·. * R 3 and R 2 represents hydrogen and the other represents methyl or ethyl (i) wherein compounds having two hydrogen atoms at position 2 of the central bicycle are particularly preferred, and? denotes a group - (CH 2) n - wherein n is 1 or 2 and wherein each of R 3, R 4, R 5 and R 5 represents hydrogen, the use of which i 113168 33 is characterized in that a compound of formula I or a salt thereof and In the compounds of the formula IV or in their tautomers or salts thereof, the radicals R 3 and R 2 independently of one another are hydrogen or lower alkyl, especially hydrogen, methyl or ethyl, provided that if both R 3 and R 2 are bonded to the 2-position of the central bicycle, either Rx and R2 are both hydrogen or one of the radicals Rx and R2 is hydrogen and the other is methyl or ethyl, in particular compounds having 2 hydrogen atoms in the central bicycle are preferred; A is - (CH 2) n -, wherein n is 1 or 2, and in the compound of formula III, or a tautomer or salt thereof, each of R 3, R 4, R 5 and R 6 represents hydrogen.

Even more preferred is the above process for the preparation of a compound of formula V or a tautomer or salt thereof wherein each of R 3 and R 2 is hydrogen, A is - (CH 2) n - and each of R 3, R 4, R 5 and R 6 is hydrogen. characterized in that the compound of formula I or a salt thereof and the compounds of formula III and IV or their tautomers or their

:, j,: 25 in salts, both R 3 and R 2 represent hydrogen and A

is -CH 2 - and that in the compound of formula III or its tautomer or salt thereof, each of R 3, R 4, R 5 and R 5 represents hydrogen, in particular to form salts of the compound of formula V, in particular salts; hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, dode-

f I

'Y uric acid, fumaric acid, glycolic acid, lactic acid, 2-

Vt '· hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, succinic acid, adipic acid, pimelic acid,' t 35 suberic acid, azelaic acid, malic acid,! citric acid, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acetyl 113168 34 aminoacetic acid, N-acetyl aspartic acid, N-acetylcystine, phosphoric acid, 2-acetic acid, 2-acetic acid, , glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, 5 maleic acid, hydroxy maleic acid, methyl maleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-or 3-carboxylic acid, 1-or 3-carboxylic acid, , 5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-10 aminosalicylic acid, phthalic acid, phenylacetic acid, cinnamic acid, nicotinic acid, methonic acid, glucuronic acid, 1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalene-sulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4-methylbenzenesulfone with acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, N-cyclohexylsulfamic acid, methyl, ethyl or propyl sulfinic acid, or ascorbic acid, in particular salts formed with hydrochloric, sulfuric, acetic, lactic, acetic, succinic acid, adipic acid, salicylic acid, methanesulfonic acid, • benzenesulfonic acid, 1,5-naphthalenedisulfonic acid or • N-cyclohexylsulfamic acid, especially with hydrochloric acid, acetic acid, lactic acid, methanesulfonic acid.

Also particularly preferred is the use of a compound of formula I or a salt thereof as hereinbefore defined for the preparation of a compound of formula V, a tautomer thereof or a salt thereof, wherein each of Rx and R2 is hydrogen, A is - (CH2) n- and each is R 3, R 4, R 5 and R 6 represent hydrogen, the use of which is characterized in that the compound of formula I or a salt thereof and the compounds of formula III and 35 IV or their tautomers or; in their salts, both Rx and R2 represent hydrogen and A is -CH2-, and that in the compound of formula III or its tautomers or salts thereof, each of R3 / R4 / R5 and R5 represents hydrogen, to give in particular formula V salts of the compound of the invention, in particular salts formed with hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, gluconic acid, gluconic acid, , pimelinic acid, suberic acid, azelaic acid, malic acid, vii-nitric acid, citric acid, glucaric acid, galactic acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-methylglycine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, maleic acid, hydroxymaleic acid, methyl maleic acid, cyclohexanecarboxylic acid, adamantanicarboxylic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxy-2-benzoic acid, 4-Aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, methanesulfuric acid, 1,2-sulfonic acid, ethanesulfonic acid, 2-ethoxysulfonic acid, benzenesulfonic acid, 2 '- / naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2, 3': 3- or 4-methylbenzenesulfonic acid, methyl sulfuric acid, ethyl sulfonic acid, dodecyl sulfonic acid, N-cyclohexyl sulfamic acid, with nitric acid, or ascorbic acid, especially salts,. formed with hydrogen chloride, sulfuric acid, acetic acid,

(I

pony, lactic acid, octanoic acid, fumaric acid, succinic acid, adipic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid or 35 N-cyclohexylsulfamic acid, especially hydrochloric acid, mayonic acid, ethanedioic acid,

36 11316 °

Particularly preferred is a process for the preparation of a compound of formula V or a tautomer thereof or a salt thereof wherein R3 and R2 independently represent hydrogen and lower alkyl, especially hydrogen, methyl and ethyl, provided that when both Rx and R2 are bound at the 2-position of the central bicycle, either R 3 and R 2 each represent hydrogen or one of R x and R 2 represents hydrogen and the other represents methyl or ethyl, with compounds having two hydrogen atoms at position 2 of the central bicycle being particularly preferred a group - (CH 2) n - where n is 1 or 2, and wherein each of R 3, R 4, R 5 and R 5 represents hydrogen, a compound of formula II characterized by a process of reacting a compound of formula II with a compound of formula or a salt thereof, and the compounds of formula III and IV or their tautomers or salts thereof have the radicals Rx and R2 independently of one another hydrogen or lower alkyl, in particular hydrogen, methyl or ethyl, provided that if both Rx and R2 are bonded to the 2-position of the central bicycle, then either R3 and R2 are hydrogen or one of R3 and R2 is hydrogen and the other 'is methyl or ethyl, and A is - (CH 2) n -, wherein n is 1 or 2 µ and each of R 3, R 4, R 5 and R 6 in a compound of formula III or a tautomer or salt thereof; 1 stands for hydrogen.

Very preferred is a process for the preparation of a compound of formula V, or a tautomer or salt thereof, wherein R 3 and R 2 are each hydrogen, A is - (CH 2) n - and each of R 3, R 4, R 5 and R 6 is > hydrogen, from a compound of formula II, for which the process is characterized in that a compound of formula II, a compound of formula I, or a salt thereof, and a compound of formula III and IV or their! in tautomers or their salts, both R3 and R3

R 2 is hydrogen and A is -CH 2 -, and that in formula III

113168 37 or its tautomers or salts thereof, each of R3, R4, R5 and R6 represents hydrogen to give salts, in particular salts of the compound of formula V, in particular salts of sulfuric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid. p, octanoic acid, decanoic acid, dodecanoic acid, fumaric acid, glycolic acid, 2-hydroxybutyric acid, glucose monocarboxylic acid, succinic acid, , glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetyl aspartic acid, N-acetylcystine, pyruvic acid, acetic acid, phosphoseronic acid, 2 or 3-glycerophosphoric acid, , fructose-1,6-bisphosphoric acid, maleic acid, hydroxymaleic acid, methyl maleic acid, cyclohexanecarboxylic acid, Adamant acetic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, cinnamic acid,? 'nicotinic acid, isonicotinic acid, glucuronic acid,? -lacturonic acid, methanesulfonic acid, ethanesulfonic acid,? -? With 2-, 3- or 4-methylbenzenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, N-cyclohexylsulfamic acid, methyl, ethyl or propylsulfamic acid, or with ascorbic acid,

I I

ft · dyn, sulfuric acid, acetic acid, lactic acid, octanoic acid, fumaric acid, succinic acid, adipic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid or N-cyclohexylsulfonic acid! with hydrochloric acid, acetic acid, lactic acid, methanesulfonic acid or benzenesulfonic acid.

The reaction conditions in the above methods and uses are preferably selected as follows, whereby the more general definitions may be replaced by the more specific and preferred definitions described above in connection with the respective process steps:

The reaction of the compounds of the formula II with the compounds of the formula I is effected in particular by the simultaneous reaction of a carbonyl and cyano group with a hydroxide of inorganic acid, a carboxylic acid or a sulfonic acid, especially with a double to triple molar amount in water, dialkylalkyl loweralkanoylamides such as dimethylformamide, or a mixture of water and one or more alcohols at temperatures of -30 to 100 ° C, particularly 5 to 90 ° C, e.g. 80 ° C: at normal pressure by neutralizing the acid with hydroxide, carbonate or bicarbonate, a salt of a weak organic acid, or a secondary '·' 'or a tertiary amine to give · · * · preferably directly in crystalline · 25 form and optionally by recrystallization e.g.

i ·: alcohols such as methanol or ethanol, or esters such as lower alkyl lower alkanoic acid ester, l * e.g. acetic acid ethyl ester.

Alternatively, the reaction may also be carried out stepwise by first reacting the 1-keto group and then the cyano group. In the sequential reaction, the keto group at position 1 of the central bicyclic is first reacted with hydroxylamine, using a single, two-fold excess of hydroxylamine · 35 alone in the compound of formula II. distillate, especially without base. In particular, the hydroxylamine is reacted as a salt of a hydrohalic acid, 113168 39 as the HCl salt, in an alcohol such as methanol or ethanol, especially at about 75-80 ° C to give the corresponding cyano-1-oxime which can be further purified or directly used ·. This is then converted into two-molar molar amounts of hydroxylamine in the form of a salt of the hydrochloric acid, such as the HCl salt, in an alcohol such as methanol, ethanol or tert-butanol, in the presence of alkaline earth metal alcoholates such as lithium, sodium or potassium. in the presence of methylate, ethylate or 10-tert-butylate, whereupon the alkali metal cation salt with the halide anion of the hydroxylamine salt precipitates at room temperature at 60 ° C and reflux temperature, if necessary, at a temperature lower than that required for the reaction of the cyano group. the cyano group reacts to the corresponding compound of formula I.

The reaction of the compounds of the formula I with the compounds of the formula IV is preferably carried out in a molar amount of the aminoguanidine of the formula III of 1 to 2 times the molar amount of the compound of the formula I, wherein the aminoguanidine of the formula III is used with hydrogen chloride, sulfuric acid or hydrogen sulfate. ,: as a salt of phosphoric acid, hydrogen phosphate or dihydrogen phosphate, carboxylic acid or sulfonic acid, or in particular is prepared first in situ as a readily volatile weak acid, i '·'; such as the corresponding salt of carbonic acid or bicarbonate by addition of a strong acid such as sulfuric acid or, in particular, a hydrohalic acid such as hydrochloric acid or methanesulfonic acid, water and one or more alcohols such as! > \,! in a mixture of methanol, ethanol or isopropanol, or in an alcohol such as methanol, ethanol or iso-propanol at room temperature to the reflux temperature of the corresponding reaction mixture, whereby the compound of formula IV is directly obtained. or in the form of a salt, in particular a salt of an acid present in the reaction, in particular crystalline form, which can give the compound of formula IV in free form, for example by reacting a base, in particular a hydroxide, e.g. with sodium hydroxide in water-5 solution in the presence or absence of the latter-defined organic solvents at -20 to 80 ° C, especially 0 to 40 ° C, e.g. at room temperature, or further with an anion exchanger in the? by recrystallization, e.g. from a mixture of water and organic solvents, e.g. alcohols such as methanol or especially ethanol.

The selective hydrogenation of the hydroxyamidino compound of formula IV, especially in free form, to the compound of formula 15V occurs particularly in the presence of catalyst nickel which is used in finely divided form, e.g., Raney nickel or further on carriers such as clay, pumice, alumina, as activated carbon, in the presence of an acid used to form a salt with both basic centers of a compound of formula V in a stoichiometric amount, * e.g. equimolar amount (especially for divalent, · ·) acids, double molar: 25 (in the case of monohydric acids) or in excess (especially in the case of weak acids having a pKg> 4, as in the case of lower alkanoic acids, e.g. acetic acid), in particular the acids defined above n (PA), above all; V (30 hydrochloric, sulfuric, carbonic, acetic, propionic, octanoic, decanoic, dodecanoic, fumaric, glycolic, lactic, 2-hydroxybutyric, gluconic, ; kahaponic acid, adipic acid, pimelinic acid, suberic acid, 35 azelaic acid, malic acid, tartaric acid, citric acid,! Glucaric Acid, Galactaric Acid, Glutamic Acid, Aspartic Acid, N-Methyl Glycine, Acetylaminoacetic Acid, N-Acetyl Asparagine, N-Acetyl Cystine, Paloric Acid, Acetic Acid, Phosphoric Acid, Phosphoseric Acid, Phosphoric Acid , glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, maleic acid, 5-hydroxy-maleic acid, methyl-maleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, 1-salicylic acid, , 5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicyl acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotonic acid, gluconic acid, glucuronic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, Me sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, N-cyclohexyl sulfamic acid, methyl, ethyl or propyl sulfamic acid, or ascorbic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, lactic acid, octanoic acid, , benzenesulfonic acid, 1,5-naphthalene-disulfonic acid or N-cyclohexylsulfamic acid; especially in the presence of hydrogen chloride, acetic acid, lactic acid, methanesulfonic acid or benzenesulfonic acid: water-soluble organic solvents such as alcohols, e.g. methanol, ethanol or isopropanol and water. in the mixture, or especially in the water itself, at 0 ° C to the reflux temperature of the corresponding solvent, especially at room temperature to about 50 ° C, by passing hydrogen until the calculated amount of hydrogen is taken up, especially until the hydrogen uptake stops! by itself, whereby the compound of formula V is obtained after the catalyst has been filtered off, e.g. with marshmallow datin paper or with a filter aid, e.g., diatomaceous earth; or a cellulose-based adjuvant, directly in crystalline form as the salt of the acid used, optionally recrystallized from an organic solvent such as an alcohol such as methanol or ethanol, or an ether such as diethyl ether, tetrahydrofuran or anisole, or a solvent mixture, e.g.

5 of ethanol / ether.

Particularly preferred compounds of formula I are those wherein Rx and R2 are independently hydrogen or lower alkyl, especially hydrogen, methyl or ethyl, provided that when both Rx and R2 are attached at the 2-position of the central bicycle, then both Rx and R2 R 2 represents hydrogen or one of the radicals R x and R 2 represents hydrogen and the other represents methyl or ethyl, in particular compounds having two hydrogen atoms at position 2 of the central bicycle are preferred, and A represents - (CH 2) n - wherein n is 1 or 2, or salts of these compounds.

Particularly preferred is the compound of formula I or a salt thereof according to claim 10, wherein Rx and R2 are hydrogen and A is -CH2-.

'' For the preparation of compounds of the formula I and their salts wherein Rx and R2 are independently of one another; · 25 matt hydrogen or lower alkyl, especially hydrogen, methyl; *: or ethyl, provided that if both Rx and · "·: R2 are bonded to the 2-position of the central bicycle, either Rx and R2 are hydrogen or one of Rx and R2 is hydrogen and the other is methyl or; Ethyl, in particular those compounds wherein the position of the central bicycle is 2; t is two hydrogen atoms, and A is - (CH 2) n -, wherein n is 1 or 2, or a salt thereof. is especially preferred a process for the preparation of a compound of formula I as hereinbefore defined wherein the reaction is carried out using a compound of formula II wherein Rx and R2 are independently hydrogen; or lower alkyl, provided that when both R 2 and R 2 are bonded at the 2-position of the central bicycle, then both R 2 and R 2 are hydrogen or one of R 1 and R 2 is hydrogen and the other methyl or ethyl, with particular preference being given to those compounds having two hydrogen atoms at position 2 of the central bicycle and A being - (CH 2) n - wherein n is 1 or 2.

10

For the preparation of compounds of formula I and salts thereof wherein Rx and R2 are hydrogen and A is -CH2-, a particularly preferred process for the preparation of a compound of formula I as defined above is characterized in that the reaction is carried out using a compound of formula II wherein R1 and R2 are hydrogen and A is -CH2-.

With respect to the preferred process conditions, the reaction conditions described above are applicable in this reaction.

The present invention also relates to such embodiments of the processes and / or the use of the compounds of formula I, starting from a process and / or reaction step V which is of importance for use; and carrying out the remainder; '·': the reaction steps of the process or the like. This is particularly true of the reactions set forth in the Examples.

; v, 30 In most cases, the methods of formula I are preferred.

I I

compounds and their uses as explained in the Examples.

> t »

\ '' Ί STARTING COMPOUNDS

35 | The starting compounds of formulas II and III as defined above and the hydroxylamine and its salts are commercially available, known and / or can be prepared according to known methods. Particularly preferred are the conditions disclosed in EP 0 456 133.

Compounds of formula II may be prepared, e.g., by intramolecular acylation according to Friedel-Crafts, of formula VI.

Ω-phenyl-lower alkanoic acids or their acid derivatives, such as acid chlorides or acid anhydrides according to WR, m - --0 "Λ o, wherein W in the formula W represents cyano or cyano precursor and the other residues have the meanings indicated. and in the case of acid chlorides or anhydrides e.g. AlCl 3.

20

Preferably, this reaction uses compounds of formula VI wherein W is not cyano but cyanoacetate, e.g. halogen, especially bromine, or protected V * amino, e.g. acetylamino. After the cyclization step ij! The cyano precursors can then be converted into a cyano, such as bromine, in a manner known per se, by reaction with copper (I) cyanide or acetylamino, cleavage of the acetyl protecting group, diazotization and reaction with copper (I) cyanide.

30 ♦>. t

The compounds of formula II may be further prepared, e.g., by oxidation, e.g., chromium trioxide (Cr

35 t t - * 45 11316ε

Rl W / / * 2

Js / - * Y I (VII) 5

H H

wherein W represents a cyano or cyano precursor as defined above and the other 10 residues have the meanings as defined above. If a cyano precursor is used, this must in turn be converted to a cyano, e.g., as described above after oxidation.

Another possibility for the preparation of compounds of formula II is by starting from compounds of formula II wherein hydrogen is substituted for the cyano group and attaching the cyano group, for example, by reaction sequence according to Example 10 of U.S. Patent 3,956,363 (nitrosation, reduction of nitro to amino, diazotization and then reacting copper (I) with cyanide (Sandmeyer reaction)).

v: Aminoguanidines of formula III wherein the residues have the meanings given above may be prepared, e.g. with an amine of formula NHR4R530.

t I

Said thiosemicarbazides (precursors of compounds of formula III) are prepared, for example, by reacting hydrazides of formula H2N-NHR3 in which R335 has the meaning as defined above, e.g.

RsN = C = S with isothiocyanate or thiocarbamoyl chloride of formula R6NH-CSC1, or by reacting one of said hydrazines with an acyl isothiocyanate, e.g. acetyl isothiocyanate, followed by acidic hydrolysis.

Hydroxylamine or its salts may be obtained, for example, from commercial hydroxylamine hydrochloride by release from bases, e.g., alkali metal alcoholates such as sodium ethoxide or sodium butoxide, alkali metal carbonates such as .

The following examples illustrate the invention without limiting its scope. Temperatures are shown in degrees Celsius (° C). Nuclear Magnetic Resonance (NMR) values are expressed as δ values relative to tetramethylsilane.

The following abbreviations are used: 20 ether diethyl ether DMF dimethylformamide '·' NMR nuclear magnetic resonance spectroscopy V · m.p. m.p. v ': 25:' Example 1: 4- (N-hydroxyamidino) -1-indanone oxy

Variation 1:

A mixture of 20.43 g (0.13 mol) of 4-cyano-1-indano- v. 30 nia [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)], 18.07 g (0.26 moles) of hydroxylamine hydrochloride, * → '), 13.46 g (0.127 moles) of sodium carbonate and 650 ml of 50% aqueous ethanol are mixed. At 80 ° C for 3.5 hours. Then 35 9.035 g (0.13 moles) of hydroxylamine hydrochloride and 6.73 g (0.0635 moles) of sodium carbonate are added once more, the reaction mixture is stirred for a further 5 hours at 80 ° C and then allowed to cool slowly over 113 hours. temperature. The reaction mixture is then cooled to 10 °, filtered and the precipitated product is washed with 20 ml of 50% aqueous ethanol and a little ether. The crystallization is then added to 900 ml of methanol, stirred for 1 hour at room temperature, filtered from insoluble components and the filtrate evaporated in vacuo to about 150 ml. Cool to 5 ° to precipitate the product which is filtered, washed with a little methanol and ether and dried.

The title compound thus obtained melts at 192-194 ° (dec).

Variation 2:

To a solution of 7.86 g (50 mmol) of 4-cyano-1-indan-15-one [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] in 75 ml of Ν, Ν-dimethylformamide, add 10.4 g (150 mmol) of hydroxylamine hydrochloride and 37.5 ml of 2M Na 2 CO 3 solution with stirring and heat at 75 ° for 3.75 hours: in. The still warm reaction mixture is diluted with 25 mL of water and filtered while warm. 88 ml of water are now added to the filtrate with stirring and cooled to 0-5 °. The crystallized product is suctioned off, washed with DMF / water (1: 3) and finally with EtOH, dried and recrystallized from 3 times the amount of DMF. This gives the title compound, · 25 dots, which melts at 192-194 ° (dec). MS (FAB): (MH) = 206, 2H NMR (DMSO): δ = 10.87 (s, 1H), 9.64 (s, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.30 (t, 1H), 5.76 (s, 2H), 3.15 (t, 2H), 2.74 (t, 2H).

; ·. t 3 0 Variation 3:

A mixture of 157 mg (1.0 mmol) of 4-cyano-1-indanone v. '[Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] and 139: mg (2.0 mmol) of hydroxylamine hydrochloride in 4 ml of ethanol are stirred for 1.5 hours at 80 ° C and cooled. here in the ice bath. The crystallized product is suctioned off, washed with cold ethanol and ether and dried. How about 11316? 48 yields the intermediate 4-cyano-1-indanone oxime, which melts at 200-202 ° (dec). 1 H-NMR (DMSO): δ = 11.22 (s, 1H), 7.84 (d, 1H), 7.81 (d, 1H), 7.45 (t, 1H), 3.15 (t , 2H) / 2.84 (t, 2H).

5

To a mixture of 360 mg (2.06 mmol) of the intermediate 4-cyano-1-indanone oxime and 355 mg (5.1 mmol) of hydroxylamine hydrochloride in 10 mL of methanol are added 920 mg (5.1 mmol). sodium methylate and it-10 is stirred for 10 minutes at room temperature. The reaction mixture is filtered and the filtrate is boiled under reflux for 2 hours. After cooling, the precipitated product is filtered off, washed with a little methanol and dried. This gives the title compound, which melts at 192-194 ° (dec). 1 H-NMR (DMSO): δ = 10.87 (s, 1H), 9.64 (S, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.30 (t , 1H), 5.76 (S, 2H), 3.15 (t, 2H), 2.74 (t, 2H).

According to the above example, 20 a) 5-cyano-1-tetralone is converted to 5- (N-hydroxyamidino) -1-tetralone oxime, 1 H-NMR (DMSO): δ = 10.75 (s, 1H), 8.23 (q, 1H), 7.84 (q, 1H), 7.40 (t, 1H), 5.6 (s, 2H), 3.26 (t, 2H), 2.75 (t , 2H), 2.21 (m, 2H), 1 H, 25: b) 4-Cyano-2-methyl-1-indanone to 4- (N-hydroxyamidino) -2-methyl-1-indanone oxime.

> »

According to the above example (variation 3), the mixture of: Of 0.85 g (5.0 mmol) of 4-cyano-2-methyl-1-indanone and 0.52 g (7.5 mmol) of hydroxylamine hydrochloride in 20 ml of ethanol, is stirred for 1.5 hours at 80 °. After cooling, the reaction mixture is evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with dilute saline solution! 1A, dried over magnesium sulfate, filtered and evaporated. This gives a mixture of intermediates, syn / anti-4- 113168 49 cyano-2-methyl-1-indanone oximes, which melts at 136-9 °. 1 H-NMR (DMSO): δ = 11.39 and 11.16 (2s, 1H), 8.56 and 7.81 and 7.46 (d and 2m, 3H), 2.5-3.46 (m , 3H), 1.23 (2d, 3H). 180 mg (1 mmol) of this intermediate is dissolved in 4 mL of DMF, added 140 mg (2 mmol) of hydroxylamine hydrochloride and 0.5 mL of 2M Na 2 CO 3 and heated at 80 ° C for 1.5 h. :in. After cooling, 20 ml of water are added to the reaction mixture. The crystallized product is sucked off, washed with water and dried. This affords the title compound as a mixture of oximes. 1 H-NMR (DMSO): δ = 11.05 and 10.81 (2s, 1H), 9.6 and 9.63 ((2s, 1H), 8.33-7.28 (m, 3H), δ , 73 (s, 2H), 2.5-3.46 (m, 3H), 1.20 (2d, 3H).

C) 4-Cyano-2-ethyl-1-indanone to 4- (N-hydroxyamidino) -2-ethyl-1-indanone oxime, 1 H-NMR (DMSO): δ = 10.83 (Is, 1H), 9.65 (S, 1H), 7.85-7.23 (m, 3H +), 5.8 (s, 2H), 3.55-2.5 (m, 3H), 1.95-1. 3 (m, 2H), 0.9 (m, 3H).

D) 4-Cyano-3-methyl-1-indanone to 4- (N-hydroxyamidino) -3-methyl-1-indanone oxime, 1 H-NMR (DMSO): δ = 10.69 (s, 1H), 7.95 (m, 2H), 7.55 (t, 1H), 5.71 (s, 2H), 3.71: (m, 1H), 3.06 (q, 1H), 2.45 ( q, 1H), 1.57 (d, 3H).

E) 4-cyano-6-methyl-1-indanone to 4- (N-hydroxyamidino) -6-: methyl-1-indanone oxime; and / or f) 4-cyano-6,7-dimethyl- 1-Indanone to 4- (N-hydroxyamidino) -6,7-dimethyl-1-indanone oxime.

. · 30 »· f •«

The products of Examples 1 and 1a) - f) can be used as follows: * »*» »*» «113168 50

Example 2: 4- (N-Hydroxyamidino) -1-indanone-2'-amidino-hydrazone

To a mixture of 14.22 g (69.3 mmol) of 4- (N-hydroxy-5 amidino) -1-indanone oxime, 10.37 g (76.2 mmol) of aminoguanidine bicarbonate and 170 ml of isopropanol , add 15.4 ml of concentrated hydrochloric acid with stirring and then reflux for 75 minutes. The reaction mixture is then cooled to 10 °, filtered and the filtrate residue is washed with isopropanol and a small amount of ether. The title compound, dried at 100 ° C, crude dihydrochloride melts at 269-271 ° (dec) / 1 H-NMR (DMSO): δ = 8.03 (d, 1H), 7.67 (d, 1H). , 7.52 (t, 1H), 3.29 (m, 2H), 2.91 (m, 2H).

15

For the conversion to the free base, a mixture of 20.63 g (about 64.6 mmol) of 4- (N-hydroxyamidino) -1-indanone-2'-amidino-hydrazone dihydrochloride, used as a crude product, and 136 ml of IN sodium hydroxide, stir for 30 minutes at room temperature. Filter and wash the filter residue with a little water, ethanol and ether and then recrystallize the crude product from water / ethanol. This gives the title compound in the form of v · dihydrate, m.p. 208 ° (dec.). If water / ethanol ',, instead of * 25 recrystallization is performed slurry 5-. . . 10 times ethanol for 15 minutes * · *: 80 °, cooled, suctioned off and dried in vacuo at 50 ° for 6 hours to give the title compound as an anhydrous product, m.p. 235 ° C (dec.).

30 * · ♦

According to the above example, a · v: a) is converted to 5- (N-hydroxyamidino) -1-tetralone oxime into 5- (N-hydroxyamidino) -1-tetralone-21-amidinohydrazone, b) 4- (N -hydroxyamidino) -2-methyl-1-indanone oxime 4- (N-hydroxyamidino) -2-methyl-1-indanone-2'-amidinohyde. 35

11316P

C) to 4- (N-hydroxyamidino) -2-ethyl-1-indanone oxime 4- (N-hydroxyamidino) -2-ethyl-1-indanone-2'-amidinohydrazone, d) 4- (N-hydroxyamidino) -3-methyl-1-indanone-1-oxime to 4- (N-hydroxyamidino) -3-methyl-1-indanone-2'-amidinohydrazone, 10e) 4- (N-hydroxyamidino) -6-methyl-1-indanone oxime to 4- (N-hydroxyamidino) -6-methyl-1-indanone-2'-amidinohydrazone and / or 15 f) 4- (N-hydroxyamidino) -6,7- dimethyl-1-indanone oxime to 4- (N-hydroxyamidino) -6,7-dimethyl-1-indanone-21-amidinohydrazone.

The products of Examples 2 and 2a) - f) can be further used as follows:

Example 3: a) 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride: To a solution of 4.0 g (14.17 mmol) of 4- (N-hydroxy-J: siamidino) -1 -indanone-21-amidinohydrazone dihydrate:; In 240 ml water and 14.3 ml 2N hydrochloric acid, add 1.3; g of Raney nickel and hydrogenate at room temperature when hydrogen uptake is complete. The reaction mixture is warmed to 55 °, filtered through ®Hyflo Super Cel (diatomaceous earth filter aid, Fluka, Switzerland) and the filtrate evaporated to about 150 ml. The product obtained by evaporation of the filtrate is redissolved by heating The solution is then cooled to 10 °, filtered and the resulting crystallization is washed with a little water, ethanol and ether After drying at 100 ° C, the title compound is obtained, with a water content of 6.26%, m.p. Evaporation of the mother liquor to about 50 ml and subsequent completion of the final steps gives a second batch of the title compound having a water content of 5.98%, mp> 280 °.

For conversion to the free base, a solution of 9.63 g (30 mmol) of 4-amidino-indanone-1-amidinohydrazone dihydrochloride in 900 mL of distilled water is added dropwise at 10-20 to 30 mL of 2N sodium hydroxide. The separated product is sucked off, washed with a small amount of ice water and dried. The title compound is obtained in the form of the free base, m.p. 250 ° (dec.).

Example 4: 4-Amidino-1-indanone-21-amidinohydrazone-dimethanesulfonate

To a solution of 4.0 g (14.17 mmol) of 4- (N-hydroxyamidino) -1-indanone-21-amidinohydrazone dihydrate in 160 ml of water and 28.34 ml of 1N methanesulfonic acid are added 1.2 g Raney nickel and hydrogenate at room temperature until hydrogen uptake is complete. It is then filtered through ®Hyflo Super Cel (Fluka, Switzerland), the filtrate is evaporated in vacuo and the residue is recrystallized from methanol. The title compound thus obtained has a water content of 3.68% and melts at 263-265 ° (dec). Evaporation of the 25 L mother liquor gives a second batch of 4.5% water, m.p. 261-263 ° (dec.).

For conversion to the free base, a solution of 5.93 g (25 mmol) of 4-amidinoindanone-1-amidino-, 30-hydrazone-dimethanesulfonate hydrate in 37 ml of distilled water is added dropwise with stirring at 10-20 ° C. in 13 ml of 2N sodium hydroxide. The separated product is sucked off, washed with a little ice water and ethanol and dried. 4-amidino-1-indanone-2'-amidinohydrazone is obtained, m.p. 250 ° (dec.).

11316F

53

Alternative Preparation 4-Amidino-1-indanone-21-amidinohydrazone-dimethanesulfonate monohydrate

To a solution of 15.04 g (0.043 mol) of 4- (N-hydroxyamidino) -1-indanone-2'-amidinohydrazone-dimethanesulfonate in 43 ml of water is added 3.0 g of Raney nickel and hydrogenated at room temperature until hydrogen uptake is complete. It is then filtered through ®Hyflo Super Cell. The filtrate is brought to pH 3.5 with dilute methanesulfonic acid, evaporated in a rotary evaporator until crystallization begins, and twice with ethanol. The crystallized product is suctioned off, washed with ethanol-15 and dried. The title compound thus obtained has a water content of 4.34% and melts at 263-265 ° (dec).

The starting compound of the alternative process is prepared as follows: a) 4- (N-Hydroxyamidino) -1-indanone-2'-axnidinohydrazone-dimethanesulfonate > To a suspension of 40.2 g (0.163 mol) of anhydrous 4- (N-hydroxyamidino) -1-indanone-2'-amidinohydrazone (Example 2) in 96 ml of water is added with stirring 31.4 g ( 21.2 moles) of methanesulfonic acid. A temporarily clear solution is obtained which crystallizes the title compound. The crystal suspension is diluted with 127 mL of ethanol and filtered. The removed product is washed with water / EtOH (1: 1) and dried in vacuo to constant weight, m.p. 237-9 ° (dec.).

t I

·: 1 H NMR (D 2 O): δ = 8.04 (d, 1H), 7.67 (d, 1H), 7.53 (t, * V, 1H), 3.27 (m , 2H), 2.95 (m, 2H), 2.77 (s, 6H).

11316? 54

Example 5: 4-Amidino-1-indanone-21-amidinohydrazone dihydrochloride

To a solution of 4.0 g (14.17 mmol) of 4- (N-hydroxy-5-amidino) -1-indanone-2'-amidinohydrazone dihydrate in 60 ml of water and 28.34 ml of 1N methanesulfonic acid is added 1 ml, 2 g Raney nickel and hydrogenate at room temperature until hydrogen uptake is complete. It is then filtered through ®Hyflo Super Cel (Fluka, Switzerland) and 14.17 ml 2N hydrochloric acid is added to the 10 ° C cooled filtrate.

The crystallized product is suctioned off, washed with a little water, ethanol and ether and dried. The water content of the title compound thus obtained is 7.1%, m.p. > 280 °.

Example 6: 4-Amidino-1-indanone-21-amidinohydrazone diacetate

A solution of 980 mg (4 mmol) of 4- (N-hydroxyamidino) -1-indanone-21-amidinohydrazone in 30 ml of 10% acetic acid is hydrogenated using 0.3 g of Raney nickel at normal pressure and 50 ° C. After receiving a theoretical calculated amount of hydrogen and filtering the catalyst '* as in Example 5, the filtrate is evaporated. The residue is crystallized from ethanol / ether to give the α- / pork compound as a hemihydrate, m.p. 218-20 ° (dec.).

I * »« * f • ·

Example 7: 4-Amidino-1-indanone-2'-amidinohydrazone-dibenzenesulfonate, A solution of 980 mg (4 mmol) of 4- (N-hydroxyamidino) -1,11-indanone-2'-amidinohydrazone and 1, 26 g (8 mmol) of T-benzenesulfonic acid in 50 ml of methanol are hydrogenated *, using 0.3 g of Raney nickel at normal pressure and 50 °. After receiving a theoretical calculated amount of hydrogen: 35 and after filtering the catalyst, Example 5, The filtrate is evaporated. The residue is crystallized from an ethane list. This gives the title compound, m.p. > 250 ° (dec.). 113- 11316? 55 NMR (D 2 O): δ = 7.38-7.95 (m, 16H), 3.21 (m, 2H), 2.78 (m, 2H).

Example 8: 5

According to the above examples, the dihydrate of 4- (N-hydroxyamidino) -1-indanone-21-amidinohydrazone is converted using salicylic acid, succinic acid, adipic acid, lactic acid, 1,5-naphthalenedisulfonic acid or 1,2-ethanedisulfonic acid into either of these. a) 4-amidino-1-indanone-21-amidinohydrazone disalcate, b) 4-amidino-1-indanone-2'-amidinohydrazone succinate, c) 4-amidino-1-indanone-2'- amidinohydrazone adipate, d) 4-amidino-1-indanone-21-amidinohydrazone dilactate, e) 4-amidino-1-indanone-21-amidinohydrazone-1,5-naphthalenedisulfonate and / or f) 4-amidino -l-indanone-21-amidinohydratsoni etaanidisul-sulfonate.

Example 9: 25 According to the above examples, a) 5- (N-hydroxyamidino) -1-tetralone-21-amidinohydrazone is converted to 5-amidino-1-tetralone-2'-amidinohydrazone, b) 4- (N-hydroxyamidino) -2 -methyl-1-indanone-2'-amidino-hydrazone to 4-amidino-2-methyl-1-indanone-21-amidinohydrazone, »»! c) 4- (N-Hydroxyamidino) -2-ethyl-1-indanone-21-amidino-1'-hydrazone to 4-amidino-2-ethyl-1-indanone-2'-amidinohydro-4-racone, 35 d ) 4- (N-Hydroxyamidino) -3-methyl-1-indanone-2'-amidino-! hydrazone to 4-amidino-3-methyl-1-indanone-2'-amidinohydrazone, 113168 56 e) 4- (N-hydroxyamidino) -6-methyl-1-indanone-2'-amidino-hydrazone; and / or f) 4- (N-Hydroxyamidino) -6,7-dimethyl-1-indanone-2'-amidinohydrazone to 4-amidino-6,7-dimethyl-1-indanone-2'-amidino hydrazone. The products are deposited in this case acids in the presence directly in the form of salts (dihydrochloride presence of hydrochloric acid, methanesulfonate methane-sulfonic acid in the presence of diacetate in acetic acid in the presence of dilaktaattina of lactic acid in the presence of -dibenz-10 benzene sulfonate benzenesulfonic acid in the presence of disalisylaattina salicylic acid in the presence of sukkinaat-tin succinic acid in the presence of adipate adipiiniha-acid in the presence of 1,5-naphthalenedisulfonate in the presence of 1,5-naphthalenedisulfonic acid or ethane disulfonate-15 tin in the presence of ethane disulfonic acid).

t> * * »I i · (* 4 * · *% * 1)

Claims (10)

113168 57 1. Method of formula V Process according to Claim 1, characterized in that the reaction of the compounds of the formula I with the compounds of the formula IV is carried out at a molar amount of aminoguanidine of the formula III in a ratio of 1 to 2 times molar amount. -15 hours as the salt of hydrochloric acid, sulfuric acid or hydrogen sulfate, phosphoric acid, hydrogen phosphate or dihydrogen phosphate, carboxylic acid or sulfonic acid or prepared in situ from the corresponding salt of a readily volatile weak acid by the addition of and that selective hydrogenation to react the hydroxyamidino compound of formula IV. * the conversion of the compound of formula V takes place by the use of nickel as a catalyst which is used as a fine; ': in the form or applied to carriers, in the presence of an acid used to form a salt of both basic centers of the compound of formula IV in a stoichiometric amount or excess (in the case of weak acids having a pKs> 4), in a mixture of solvent and water '! * or in the water itself at temperatures between 0 ° C and the reflux temperature of the corresponding solvent by passing: hydrogen until the calculated amount of hydrogen has been received, whereby the compound of formula V in crystalline form is obtained. as a salt of the acid used. 11316? 60 A process according to claim 1 for the preparation of a compound of formula V or a tautomer or salt thereof as claimed in claim 1, wherein R 1f R 2, R 3, R 4, R 5, R 9 have the meanings set forth in claim 15, characterized in that A compound according to A / A ixp 15 wherein R 2 and R 2 independently represent hydrogen or lower alkyl and R x and R 2 are bonded to the same carbon atom or different carbon atoms of the central bicycle provided that if both Rx and R position, either R3 and R2 are both hydrogen or one of the radicals Rx and R2 is hydrogen and the other is methyl or # ♦ »V: ethyl, A is - (CH2) n- where n is 1 or 2, '• I '. Is reacted with hydroxylamine or a salt thereof to give a compound of formula I or a salt thereof according to claim 1, wherein the residues, * r. R1f R2 and A have the meanings set forth in claim 1, and then the resulting compound of formula I, or a salt thereof, is reacted with an aminoguanidine of formula III or a tautomer thereof, or an i * I 'thereof. '* with a salt wherein R 3, R 4, R 5 and R 6 independently of one another represent 113168 61 hydrogen or lower alkyl to give the formula IV HO - N NH 2 V R 1 A process for the preparation of a compound of formula V as claimed in claim 1 or 3, which is 4-amidino-1-indanone-2'-amidinohydrazone or a salt thereof, characterized in that correspondingly substituted starting materials are used. A process according to claim 3, characterized in that the reaction of the compounds of formula II with the compounds of formula I is carried out by reacting a carbonyl and cyano group simultaneously with an inorganic acid, carboxylic acid or sulfonic acid salt of a hydroxylamine or a hydroxylamine. with a double to ten-fold molar amount of the compound in water, dialkylalkyl lower alkanoylamide, or a mixture of water and one or more alcohols at -30 to 100 ° C at normal pressure by neutralizing the acid with hydroxide, carbonate or bicarbonate, with an amine, the reaction of the compounds of formula I with the compounds of formula IV occurs with a 1 to 2-fold molar amount of the aminoguanidine of formula III in the ratio of the molar amount of the compound of formula en, wherein the aminoguanidine of formula III is used as a salt of hydrochloric acid, sulfuric acid or hydrogen sulfate, phosphoric acid, hydrogen phosphate or dihydrogen phosphate, carboxylic acid or sulfonic acid or prepared in situ *. from the corresponding salt of the volatile weak acid by adding a strong acid, in a mixture of water and one or more alcohols, at room temperature and the like; at reflux temperature of the mixture, and that the selective hydrogenation to react the hydroxy: siamidine compound of formula IV to the compound of formula V occurs in the presence of a nickel catalyst used in fine form or in bulk; which is used to form the salt of both basic centers of the compound of formula IV in a stoichiometric amount or excess (in the case of weak acids having a pKg value> 4), water-11316? 63 in a mixture of a soluble organic solvent and water, or in water itself, at a reflux temperature of 0 ° C and the corresponding solvent, by passing hydrogen until a calculated amount of hydrogen is received to give a compound of formula V as a salt of the acid in crystalline form. A hydroxyamidine compound or tautomer thereof or a salt thereof according to Formula II ((V) N1R4R310) wherein R 1f R 2, R 3, R 4, R 5, R 5 and A have the meanings indicated for compounds of formula V and R 3 and R 2 are bonded to the same carbon atom or different carbon atoms of the central bicycle 15, and then the hydroxyamidino compound of formula IV or a tautomer thereof is selectively hydrogenated in the presence of a catalyst using either the free form or an acid salt to give a compound of formula V or a tautomer thereof in the form of a salt, 'and, if desired, converting the salt of the compound of formula V or of its tautomer into the free form or into another salt and / or one of the compounds of formula V'; the resulting isomeric mixture of the distillate or a tautomer thereof or a salt thereof is resolved into the isomers and / or the compound of formula V or its tautomer is converted into another compound of formula V or its tautomer. 30 * 1 5 HN NH 2 R, 1 / 'r 2 Cv 2 r w 10. For the preparation of a compound of formula X * 4 R 3 or a tautomer or salt thereof wherein R x and R 2 are independently hydrogen or lower alkyl and are bonded to the same carbon atom or different carbon atoms of the central bicycle provided that both R 2 and R 2 are bonded to the 2-position of the central bicycle, either Rx and R2 are both hydrogen or one of the radicals R1 and R2 is hydrogen and the other is methyl or ethyl, A is - (CH2) n- where n is 1 or 2 and R3 , R 4, R 5 and R 5 independently of one another are hydrogen or lower alkyl, '' characterized in that: 25 • ': OH V: / N 1 / NH 2 30, y 2: ·' ··: (1) VAC 2 11; A 35 L compound or salt thereof wherein R1 (R2 and 11316? 58 A have the meanings given for compounds of Formula V and R3 and R2 are bonded to the same carbon atom or different carbon atoms of the central bicycle is reacted with NR6 H2N-nAnCR5 ) R 4 with an amidoguanidine of R 3 10 or a tautomer thereof or a salt thereof, wherein R 3, R 4, R 5 and R 6 independently of one another are hydrogen or lower alkyl to give OH A hydroxyamidine compound or tautomer thereof or a salt thereof having R 1; R 2, R 3, R 4, R 5, R 5 and A have the meanings given for the compounds of formula V and R 3> 'j'. and R 2 are bonded to the same carbon atom or different carbon atoms of the central bicycle, and then 30 * ..! a hydroxyamino compound of formula IV or a tautomer thereof; * the hydrogen is selectively hydrogenated in the presence of a catalyst; '·. either by using the free form in the presence of an acid, or using a salt thereof to give a compound of formula V, mvv 35 having the meanings above, or a tautomer thereof in the form of a salt 113168 59 and, if desired, the resulting formula V converting a salt of a compound of formula V or a tautomer thereof into a free form or another salt and / or separating the resulting isomeric mixture of a compound of formula V or a tautomer or salt thereof into isomers and / or converting a compound of formula V or a tautomer thereof into another compound of formula V or its tautomer. A compound of formula I OH 10 / n ^ .nh 2 I (l) 15 Ίι N 1 or a salt thereof wherein R x and R 2 are independently hydrogen or lower alkyl and are bonded to the same carbon atom or different carbon atoms of the central bicycle provided that if both Rx and R2 are bonded to the 2-position of the central bicycle, either Rx and R2 are both hydrogen * or one of Rx and R2 is hydrogen and the other; methyl or ethyl, A represents - (CH 2) n -, wherein n 1 is 1 or 2. The compound of formula I according to claim 6, which is: 4- (N-hydroxyamidino) -1-indanone oxime or a salt thereof. »113168 64