PROCEDURE FOR THE PRODUCTION OF NEW INDOLINYL GUANIDIN DERIVATIVES

The invention concerns a procedure for the production of new Indolinylguanidin derivatives of the formula R5 q S. R NR 1 --C (I] IO where R hydrogen, alkyl with i to 4 carbon atoms or if necessary in the Phenyltell by fluorine, chlorine or bromine, alkyl with 1 to 4 carbon atoms and/or Alkoxy with i to 4 carbon atoms of more monooder disubstituiertes Phenylalkyl with 7 to 9 carbon atoms meant, R2 hydrogen, alkyl with 1 to 4 carbon atoms, if necessary err, Phenylteil by fluorine, chlorine or bromine with 1 to 4 carbon atoms and/or Alkoxy with i to 4 carbon atoms of more monooder disubstituiertes Phenylalkyl with 7 to 9 carbon atoms, alkenyl or Alkinyl with 3 to 5 carbon atoms, whereby the honour specialized connection does not stand for Hydroxy in A, 8-Stellung to the nitrogen atom, to which the remainder is bound, Cycloalkyl with 3 to 7 carbon atoms, by Cycloalkyl with 3 to 7 carbon atoms monosubstituted alkyl with 1 to 4 carbon atoms, if necessary in the Phenylteil by fluorine, chlorine or bromine, alkyl with 1 to 4 carbon atoms and/or Alkoxy with 1 to 4 carbon atoms of more monooder disubstituiertes Phenoxyalkyl with 8 to II Konlenstoffatomen, whereby the oxygen atom is separate by at least 2 carbon atoms from the nitrogen atom, to which the remainder is bound, by alkyl with 1 to 4 carbon atoms of disubstituiertes Aminoalkyl with 2 to 5 carbon atoms, whereby the nitrogen atom is separate from the nitrogen atom by at least 2 carbon atoms, to which the remainder is bound, or a group of OR 7 - (CH2) n-chlorine 8 meant, whereby n for a whole number from I to 5 stands and Rù and RA ven either alkyl with 1 to 4 carbon atoms or together an alkyl chain 2 or 3 carbon flavours mean, R 3 and R independently hydrogen or alkyl with i to 4 carbon atoms mean and independently hydrogen, fluorine, chlorine or bromine or an alkyl, a Alkoxyoder Alkylthiogruppe with 1 to 4 carbon atoms means R-S and R6. Possible Alkyloder alkoxy groups in the connections of the formula (I) contained preferably 1 or 2, in particular 1 carbon atom; however if R2 stands for alkyl, then it means preferably branched alkyl, in particular Isopropyl. Possible halogen substituents in the connections of the formula (I) stand preferably for chlorine, possible Phenylalkylgruppen preferably for Phenäthyl or benzyle, a possible Phenoxyalkylgruppe, preferably for Phenoxyäthy! , a possible Alkenyloder Alkinylgruppe, preferably for allyl or 2-Propinyl, a possible Cycloi alkyl group, preferably for Cycloalkyl with 3 to ö carbon atoms, in particular for Cyclopropyl, a possible by Cycloalkyl monosubstituted alkyl group, preferably for one by Cycloalkyl with 3 to 6 carbon atoms monosubstituted group of methyls, in particular for Cyclopropylmethyl, a possible Aminoalkylgruppe, preferably for one by alkyl disubstituierte Amlnoäthylgruppe, a possible Alkylthiogruppe, preferably for Methylthio, disubstituierte by alkyl. n stands in particular for a whole number from i to 3, preferably for I or 2. Preferably stand Bi, R3, B and R0 for hydrogen, R2 for hydrogen, Hydroxy, Cycloalkyl, unsubstituiertes Phenylalkyl or, the Aminoalkylgruppe disubstituierte defined above by alkyl, R5 for hydrogen or halogen, preferably chlorine, and Bù and B8 for alkyl. I0 R-S and/or B0 stand preferably in 5, 0oder 7, in particular in 5-Stellung of the Indolingerüstes. One arrives according to invention at the new connections of the formula (I), by one an ISO thiourea derivative of the formula R R0/“N! H C/N-R -- SR, (II) where R, Bù, Bs and R6 above meaning possess and low alkyl means R9, with an amine of the formula HN! B2 (! II) where R2 and R3 possess, convert above meaning. R9 preferably contains 1 or 2, in particular of i carbon atom. The conversion according to invention knows more nnter for the production of similar Guanidine admitted reaction conditions to be accomplished. Appropriately the conversion to presence of a mineral acid takes place such as hydrogen chloride, bromwasserstoff, Jodwasserstoffoder sulfuric acid. Preferably one works in presence of at least an equivalent mineral acid, related to the connections of the formula (II), however 2S the connections of the formula (II) become or (III) appropriately begun into partial of unprotonierter form. The conversion kanu e.g. in solvents inert under the Beaktionsbedingungen or in the melt to be accomplished. The connections of the formula (I) can be present in form of the free base or in the form of addition salts with acids. Of the free bases for example Aeetate or Hydrogenmaleinate can be made and in reverse into well-known way acid addition salts. If R2 contains a group of acetals, then calculation must be carried with the conversion according to invention and/or the isolation as acid addition salt of the acid instability of the Aeetalgruppe by work with mild conditions. The connections of the formula (II) are new. They can be won similarly to well-known methods. One receives it e.g. by conversion from connections of the formula R5 B --R NH-B IO NHS (IV) where B i, H R-S and R6 possess above meaning, with an alkyl halide of the formula B9 Hal, (V) where R9 above meaning possesses and for halogen, preferably iodine stands for Hal. Connections of the formula [IV), where B, hydrogen means, receives one by conversion from connections of the formula R-S (VI) RST where R, B s and possesses H 6 above meaning, with Benzoylisothiocyanat and splitting off of the Benzoylgruppe from in such a way received l-Benzoylthioharnstoff-connection. , Where B, above meaning possesses, however not for hydrogen, can one by conversion of the connections of the formula (VI) with a connection of the formula R stands for connections of the formula (IV) - N=C=S, (VIl) where R', the meaning with the exception of hydrogen, indicated for R, possesses, receive. The conversions to the connections of the formula (IV) can be accomplished likewise similarly to well-known methods. As far as the production of the necessary raw materials is not described, are these admits or in well-known procedures and/or similarly to described the here or similarly to that procedures actually admitted producible. The connections of the formula (I) in free form or in form of their physiologically vertr acid addition salts, in the following as erfinduugsgemäße substances designation, resembled possess interesting pharmacodynamic characteristics. They can be used from there as cures. They possess themselves in particular salidiuretische activity, like in animal experiments, for example at the rat (method of E. Flückiger et al., Switzerland. med. Wochenschr. 93 1232-1237) q] it doses from approximately 0.1 to 100 mg/kg by OS shows. Due to their salidiuretischen effects the new substances can be used as Salidiuretika. Those to using doses vary naturally depending upon kind of the substance, the administration and the condition which can be treated. Generally however satisfying results with a daily dose are received from approximately 1 to approximately 50 mg; this dose can be given if necessary in 2 to 4 portions or also as Hetardform. For oral applications the partial doses contain about 0.25 to approximately 25 mg of the new substances apart from firm or liquid supports. In addition they possess venentonisierende characteristics; at the rat with destroyed brain and back Mark (Brit. J. Pharmac. Chemother. 30 78-87) causes it in a dose connected from approximately 0.02 to approximately 50 pg/kg i.v. a long lasting pressorischen effect with a blood pressure increase. Due to these characteristics the connections can as venentonisierende means e.g. for the Propyhlaxe and treatment of vascular headache such as migraine or of orthostatischen disturbances like orthostatischer Hypotonie and their symptoms, as apply, to the swindle. Those to using doses vary naturally depending upon kind of the substance, the administration and the condition which can be treated. Generally however satisfying results l0 with a daily dose are received from approximately 0.0025 to approximately 1 mg. This dose can be given if necessary in 2 to 4 portions or also as Retardform. Thus the partial doses contain about 0.0005 to 0.5 mg of the connections apart from firm or liquid supports e.g. for oral applications. For above application the connections of the formula w R-S are particularly suitable -- NH I/NH - C (lw) where Rw hydrogen, Hydroxy, Cycloalkyl with S to 6 carbon atoms, Phenylalkyl with 7 to 9 carbon atoms or by alkyl with 1 to 2 carbon atoms of disubstituiertes Aminoalkyl with 2 to S carbon atoms, whereby the nitrogen atom is separate from the Sticksteffatom by at least 2 carbon atoms, to which the remainder is bound and RTM hydrogen or halogen with an ordinal number from 9 to 35 mean, and their acid addition salts. The connections of the formula (1) can be given alone or in suitable dosage form. The medicine forms, e.g. a tablet, can be manufactured similarly to well-known methods. In the following examples, which describe the invention more near, all temperature specifications in centigrades, without corrections take place. Example 1: l (5-Chlorindolin-l-yl) - 2-oyclopropylguanidin 12 g l (5-Chlorindolin-l-yl) - 2-methylisoLhioharnstoff-hydrochlorid are solved in 60 ml methanol and heated up with 15 ml Cyclopropylamin in autoclaves 5 h on 100°C. The Beaktionslösung one evaporates to dry ones and vibrates the Eindampfrückstand between ethyl acetates and more diluted SO sodium hydroxide solution out. With the evaporation of the ethyl acetate solution dried over magnesium sulfate, received raw l (5-Chlorindolin-l-yl) - 2-cyelopropylguanidin one crystallizes from ethyl acetate and points a stop. from 146 to 149° up. The l (5-Chlorindolin-l-yl), used as raw material - one receives 2-methylisothioharnstoff-hydrochlorid e.g. as follows: By conversion sodium hydroxide solution under return flow during 15 min, diluted by 1-Amino-5-chlorindolin with Benzoylisothiocyauat in simmering tetrahydrofurane and following soaping with, one receives 1 (5-Chlorindolin-l-yl) - thiourea (stop. 199 to 2000 from ethyl acetate/petroleum ether). This thiourea is transferred by cooking during 1 h with methyl iodide in methanol into the 1 (5-Chlorindolin-l-yl] - 2-methylisothioharnstoff-hydrojodfd. By FreisetT.en of the base with aqueous sodium hydroxide solution and following addition of 2N äthanolischer hydrochloric acid one receives the hydrochloride from the l (5-Chlorlndolin-l-yl) - to -2-methylisothioharnstoff (stop. 178 to 179°, from ethanol/ether). Nr.358062 example 2: l-Hydroxy-2 (indolln l yl) guanidin g l (Indolin l yl) - 2-methylisothioharnstoff-hydrochlorid and ii, 4 g hydroxyl amine hydrochloride are suspended in 240 ml ethanol and heated up after addition by 6,9 g Kaliualäthylat I h for simmering. After the cooling one sucks Kaliumchlorid and surplus hydroxyl amine hydrochloride off and evaporates the filtrate to dry ones. The Eindampfrückstand becomes between konz. aqueous ammonia solution and dichloromethane out-vibrated. One evaporates the dichloromethane solution dried over magnesium sulfate to dry ones. The l-Hydroxy-2 (indolin l yl), received as Eindampfrückstand, guanidin crystallized after addition of acetic acid as acetate from ethanol ether and points a stop. from 155 to 1580 up. i0 example 3: i (5-Chlorindolin-l-yl) - 2 - (2,2-diäthoxyäthyl} gu anidin 6 g l (5-Chlorindolin-l-yl) - 2-methylisethioharnstoff-hydrochlorid and I0 ml Aminoacetaldehyddiäthylacetal are heated up 1 n on 120o bath temperature. Surplus Aminoacetaldehyddiäthylacetal is evaporated at the vacuum and the Eindampfrückstand between ethyl acetates and IN sodium hydroxide solution is out-vibrated. One evaporates the ethyl acetate phase dried over magnesium sulfate to dry ones. The l (5-Chlorindolin-l-yl), received as Eindampfrückstand - 2 (2,2-diäthoxyäthyl) guanidin crystallizes as Naphthalin l, 5-disulfonat and ethanol/ether with a stop. from 163 to 165°. in ana] oger way one receives, on the basis of the appropriate connections of the formula (IL), in which R9 methyl means, by conversion with the appropriate connections of the formula (III), the following connections of the formula (1): Example similar to No. ex. No. 4 I 1 6 i 7 1 8 1 g i 1 11 I 12 I 13 1 14 2 3 RST 3 17 1 18 1 industrial union 1 1 RI H H H H H H H H H H H H H H Isopropyl H H RZ R3 R4 R-S R-S stop. H H H H R H Cyclepropyl H H H Cyclopropyl H isopropyl H Isopropyl H Cyc [ohexyl H OimethylH aminoäthyl OH H benzyle H (2,6-OichlorH phenoxy) ethyl H H H H H H H H 5-CI H H 6-CI H 6-CI H H 7-Br H H 7-Br H H H H H 5-C1 N H 5-CI H H H H H 5-C1 H H 5-C1 H H H H Federal Intelligence Service 17k-175° 153-155o 127-12ge TC 173-175° hF 233-23& ° 153-156o hf 102-105° hf 11B-120° 186-188o bhm 154-156° hcl 164-155o 151-1530 hf 184-IB6° hf ZI7° (Zers.) hf 102-1050 hcl 188-1900 hf 102-i05° Cyclopropyl H H 4-C1 H H Isopropyl H H H 8eisplel similar to g 1 r, to ex. No. 21 1 22 1 23 1 24 1 1 28 1 27 1 28 1 2g 1 1 31 1 32 1 33 1 34 1 1 R2 H H Isopropyl H H H H H H Cyclopropyl benzyle H H methyl methyl H H 3,4-Oimetho×y” henäLhy! 3,4-0£ H meLhoxyphenäthyl H methyl H 4-Chlorbenzyl 4-ChlorH benzyle H 4-ChlorphenäLhyl 4-ChlorH phenäthyl 38 1 H 37 I methyl 38 1 H 39 1 4-Methylphenäthy] i methyl 41 1 methyl 42 i methyl 7 R-S H H H Isopropyl H H H H H methyl H H methyl methyl methyl H 4-MethylH phenäLhyl H H HeLhyl H methyl methyl methyl H R R-S R6 H 5-G1 H 5-C1 H H 6-F H H 5-C1 H H 6-F H H 6-CI H 2-Methyl H H 2-Methyl H H 2-Methyl H H 2-Methyl H H 3-Methyl H H 3-Methyl H H 3-Methyl H H H 4-Methyl H H 4-Methyl H H 4-Methoxy H H 4-Methoxy H i H 4-Methyl H H 4-Methyl H 2-Methyl H H 2-Methyl H H H 7-Methyl H Smp, 7-CI hf 204-2050 hf 118-1200 hcl 181-1830 hF 118-1200 TC 179-181° 151-1530 196-1980 196-198o 108-1100 108-1100 86-870 135-1360 135-136a 147-148o 147-148° hj 241-2420 hj 210-2120 122-1230 122-1230 125-1250 box 144-1450 131-1320 Nr.358062 bhm = to hydrogenmalelnaL; hcl = Hydrochlorld; hf = Hydrogenfu arat; TC = Hydrogenmaleinat; Federal Intelligence Service = HydrogennaphLhalin-1,5-disulfonat; HC [= hydrochloride; hf = HydrogenfumaraL; hn = hydrogenmaleinaL; hj = hydraulic iodide; hox = hydraulic towards oxalate