DE1620511A1 - Process for the production of new basic substituted pseudoindoles - Google Patents

Description

Dr.F. To be in · Dr. Ε.Αίΐιτ, αηη .Λ. , C ~ / 71) U

Dr. R. Koonigibergor ^ HM ^ / ^ύ '

Dipl. Phys. R. Holzbauer Ι c ο Π C Ι Η Patent attorney «I Di Ub I 1

2, Bräuhaussira ^ 4 // ff '

Case 5/304 ".

50 / eg new complete registration documents

Dr. Karl Ihoinae GmbH, Biberach an der Riss

Process for the production of new basic substituted

Pseudoindoles

SSSSSSSSSSSSSKSSS

Addition to patent application iß 26 315 ITd / i2p (Case 5/272)

In the German patent specification. ... ... (patent application Ϊ 26 315 IVd / i2p) is a process for producing new Basically substituted pseudoindoles of the general formula

in the R. a methyl group or a phenyl radical, R ₂ ; . Hydrogen or halogen atom, a lower alkyl or AlIcosygruppGv R ₅ a lower ACyl group or a phenyl radical, which may be substituted by halogen or lower alkyl or alkoxy groups, R < a lower alkyl

BATH ORIGINAL

rest. Rc is a lower alkyl Ir eat or an aralkyl red or together with R, and the nitrogen atom also a saturated lioterocyolisolien Riag, which can optionally be interrupted by 'another' heteroatom and / or substituted by a lower alkyl * radical, and A is a straight chain or [branched divalent aliphatic hydrocarbon radicals Mt mean 2-4 carbon atoms, as well as their acid »addition salts. zait physiologically compatible inorganic or organic acids by cyclization of a phenylhyd *. : the Pormel

in which R ^ - 2U and Λ have the meanings given in the presence of an anwa ^ n j fl ? ^ T > ffpa1 t ^{|> w} g- effecting condensation means described. These new compounds have valuable therapeutic properties, in particular an analgesic effectiveness.

Bs has now been found that the same procedure more new basically substituted Pseudoindole ι be produced Oer general Pormol "I, also up a very good analgetisohe effectiveness, but in addition also a antiphlogistischd, hastens tillende and spasmolytisohe effect

009818/1898 bad original

- 3 -

Y / cison, if one starts from those phenylhydraaones of the above formula II in which the radicals R ₁ to R ₇ and A have the meanings mentioned at the beginning, R. a lower alkyl or alkenyl radical and R ~ a by a cycloalkyl radical with 3- 8 carbon atoms, which in turn can optionally be substituted by lower alkyl or alkoxy radicals, substituted alkyl radical, a straight-chain or branched, optionally halogen-substituted alkenyl rust or consisting of R ^ and the nitrogen atom by a phenylree-fc, which is optionally lower by halogen atoms, hydroxyl groups Alkyl or Alkoiyreete can be substituted, mean substituted piperidino or tetrahydropyridine radical.

The cyclization; This pheny! hydrazones au compounds of the above general formula I ₉ in which the radicals R ₁ to R 1 and A have the _{meanings mentioned at the beginning and R 5 have} the meanings given above in the definition of the phenyl hydrazones, takes place as described in the main patent, at temperatures between 00 and 180 ⁰ O ₉ vorsttgoweioe at temperatures between 80 and 160 ⁰ O ₉ by means of a condensation agent causing amaonial splitting, possibly in the presence of an organic solvent , or heavy metal halides, vie copper (I) chloride, fifickel chloride or bis (II) chloride

009Ö18 / 1888 '

Questioned · As losux ^ smilttel are preferred polar © Üösungs-> agents such as alcohols, such as methanol, · Α ^# THANOL, butanol

or glycols or lower fatty acids, such as acetic acid, .ein- ' puts.

F * _m _

The Phonylhydrasone from Forrael II used as starting materials

'can v / io those of the main pateat according to known methods, with-! for example, according to Eouben Weyl -! Methods of the Organic Giiezaie Volume YII, Seil I, page 461 f £ (1954) - from the corresponding

Aoinoketones of the formula.

1? ? 3 R - C - CH - Δ -

in which R ^, R-, R ^, R ^ and A have the meanings given to the aase, are obtained by reaction with a phenylhydrasine. The amino ketones of the formula III have not yet been described in the literature; .. \ l Wilson J. Chem 1952, page 6-9 "are prepared beiepiols- mii'den by ά η & methods given therein, the following ketones and get their Pnenylhydrasone..:

1) 1- (4-Phen7lpiperidino) -3-phenyl-pentafon- (4); Kp. 170 -? 73 ⁰ C / O, O2 & 33 Hg, obtained by condensation of phenylacetone with 1- (2-chloroethyl) -4-j henylpiperidin in the presence of Katriumamid.
The phonylhydrasone melts at 121 ⁰ C (& ue

eS18 / 18Sl8 BAD

2) 1- {4 ~ Pfeex3 ^ ll _f 2.5 »6-tetrohy ^

Bp 16O-75 ° O / O, O4 mi Eg, obtained from bienylacetone τζζ-α l »(; 2-Cliio3: ä1; hyl) -4-p3iejayl-1,2 ₉ 5 _t 6-" CQtrQliyd3: opyj7idia In Gegenwartvoii ffatriuaaradcl · ^; '

The £ henylhydr &"on schmilst at 119 -121 ⁰ C (from ethanol).

The henylhyclra £ one dor iolßeiiden aminolcofcones were as high products implemented further.

3) 1-iAllyl - Köthyl-ßailno) -3- "phenyl-PEN1" AON (4) "bp 89-91 ⁰ O / 0.2 sun

4) 1- {3j3-

Bp 172 -173 ° C / 11 ma Hg.

5) 1-. Kp 170 - ΐ71 ^Ο β / ΐ1 ΕΕ3 Hg.

The new VerbiKclimgen der 3Omel I Icöimea geuünscntQJSifalls in their iSäureedditionsealae iaii; physioü.ogisch Ye.T-fcrSslicb.en aacrganischen or orgaxd.sche: -a acids are converted. Come as Saiarsa "For example Salsaäwra, Broiawaöseratof:? 0äurep Heavy?"! -.

Ü-iire, ilalonic acid, maleic acid,

Nensäure or Vieinsäu ^ Q into consideration · The Säu.? eadditi <m38 & lze veiscn öDGnso like the bases on the aforementioned effects.

The following Baispiele serve ZVOS aähßren explained ί lärfindungs.

SiI 8 / 18.SI.

example 1

2-methyl-3-phenyl-3- / 2- (allyl-methyl-amino) -ethylj-pseudoindole

55, Og crude phenylhydrazone of 1- (allyl-methyl-amino) -3-phenylpentanone- (4) are refluxed with 25 ecm of ethanol and 55.0 g of anhydrous zinc chloride for 5 hours. Has cooled • the reaction mixture is first with 1Q0 ecm benzene and then with ice cooling with concentrated ammonia until the al-. kaiischen reaction. The benzene layer is diluted with 100 ecm - ether and separated from the aqueous layer, then washed several times with water and dried with potassium carbonate. After the solvent has evaporated, the residue is distilled in vacuo. This gives 20.0 g of the desired compound} Kp 142-143 ⁰ C / 0.08 mm Hg hydrochloride. F. 21O ⁰ C (Essigester / methanol).

Example 2

2-methyl-3-phenyl-3- / 2- (3,3-dimethylallyl-methyl-amino) -ethyl7-

pseudoindole

Obtained from the phenylhydrazone of 1- (3,3-dimethylallyl-methylamimo) -3-phenyl-pentanone- (4) by cyclization in the manner described in Example 1. Bp 151-152 ° C / 0.2 mm Hg hydrogen maleate: F. 141 ⁰ C (ethyl acetate)..

Example 3

2-methyl-3-phenyl-3- / 2- (cyclopropylmethyl-methyl-amino) -ethyl7-

pseudoindole

Obtained from the phenylhydrazone of 1- (cyclopropylmethyl-methylamino) -3-phenyl-pentanone- (4) by cyclization in the manner described in Example 1. Bp 147 - 148 ⁰ C / 0.04 mm Hg. I Hydrochloride: F. 235 - 236 ⁰ C (ethyl acetate / methanol)

Example 4
2-methyl-3-phenyl-3- / 2 '- (4-phenylpiperidino) -ethyl7-pseudoindole

A mixture of 100 ecm of ethanol and 180 g of anhydrous zinc chloride are with 100 g of 1- (4-phenylpiperidino) -3-phenyl-pentanqn-

009818/1898

BATH ORIGINAL

(4) phenylhydrazone was added and 6 hours at an inner temperature of 110 - 115 ⁰ C heated. After cooling, concentrated aqueous ammonia is added until an alkaline reaction occurs, the crude product separating out in an oily form with the development of heat. It is taken up in benzene, the benzene layer is dried with potassium carbonate and the solvent is distilled off. The residue is distilled in vacuo to give 60 g of the desired compound, bp 210-220 ⁰ C / 0.05 mm Hg is obtained..

Hydrochloride: mp 188-190 ⁰ C (methanol) methanesulfonate: F. 235-236 ⁰ C (Essigester / methanol) mandelate: F. 194 ° C
Hydrogen malonate: m.p. 141 ^° C
Hydrogen maleate: F. 169 - 17O ⁰ C.

Example 5

2-methyl-3-phenyl-3-i £? - (4-phenyl-r, 2,5,6-tetrahydropyridino) -

ethyl7-pseudoindole

25.0g of the phenylhydrazone of 1- (4-phenyl-1,2,5,6-tetrahydropyridino) -3-phenyl-pentanone- (4) are reacted with 45.0 g of zinc chloride and 25 ecm of ethanol according to Example 4 and worked up. 12 g of the pseudoindole with a boiling point of 220-24O ⁰ C / 0.04 mm Hg, hydrochloride: M. 216-217 ⁰ G (ethyl acetate / methanol) are obtained.

Example 6

2-methyl-3-phenyl-3 - ^ - (4-p-tolyl-piperidino-1)

CH ₂ CH ₂ - ΝΛ- ^ Λ- CH ₃

09818 / 18S8 BAD

was prepared as described in the same manner in Example 4, from 1- (4-p-tolyl-piperidino-1) -3-phenyl-pentanone (4) phenylhydrazone obtained, melting at 12O ⁰ C. The base distills at 23.0-232 ° C / 0.02 mm.

The following salts were prepared in a conventional manner: hydrochloride, mp = 218 ⁰ C (Essigester / methanol) hydrogen maleate, mp = 181-102 ⁰ C (Essigester / methanol) methanesulfonate, mp = 214 ° C (Essigester / methanol) oxalate from F .. = 229 - 231 ⁰ C (methanol) ß-naphthalene sulfonate from F = 152 ⁰ C (ethanol / water).

Example 7

2-methyl-3-phenyl-3- (ß-diallylamino-ethyl) -pseudoindole

In the same manner as described in Example 1, this compound was prepared from the crude phenylhydrazone of the 1-diallylamino-3-phenyl-pentanone (4), bp 0.02 100 ⁰ C. The base distilled at 150-154 ⁰ C / 0.05 mm, the hydrochloride melts at 165-166 ⁰ C, the methanesulfonate melts at 118 ° C.

BAD 009818/1898

In. the glolchon V / olso ₉ \ ilo in the Boispiol 4 booohriobcn, was dicno connection aiw dom PHonylhydrason dea 1 «(4-p-Moth05cyphonyl-pipori · 'dlno) -3« pixonyl-pentanoÄ- (4) from? · 84 - 85 ⁰ O received · That

dor base ßohmilst at 213 ⁰ O (from methanol)

98-10 / 18 i'i "'" BATH

I 1

* t

Beie-piol 9 ■ '.

psoudoindole

jKi & ^

To a slurry of 16 g ITatrlunanid In 150 ml of absolute benzene are added dropwise 54 g Phenylaeeton stirring · Hach heondigter addition er \ irUrmt man "at 6O ⁰ C for 30 minutes and then crosslinked tropfenweioe mit.45 β H ^ -Butonyl-LT mcthyl-S-chlorüthylanin, wolohes AU3 the Byärochlorid Schaolsspunkt from 104 ⁰ C released v / orden _t was under stirring and heated for 3-4 hours under Rückfluas · Hach the cooling, it is decomposed with Wanoor, dio Lösunssnittelsehioht separates and extracts the layer waOoriße The combined solution of ether is then ochüttolt nan with dilute hydrochloric acid, makes the acidic solution alkaline with caustic soda and absorbs the abochiodono oil with ether ⁰ C and 0.01 na over,

^) ^ r / ffriffr ^ BttJiggy ^

46 g of l- (lT-2-butenyl-H-nothyl-amino) -3-phenyl-4-pcntanone 113et nan in 200 nl of loluene, gives 20 g of phonylhydrazine and 1 g of p-soluolaulphone säuro zu «heats up 2 hours under RUokfluoo on the W

and then removes the solvent from the solvent. The phenylhydrasone formed is then reacted without further purification. The co erhaltono raw hydrazone is heated in 60 ml of absolute ethanol with 120 β zinc chloride 4 S tuna on in an oil bath of HO ⁰ C without stirring. ITaoh dom cooling, zorootat you by adding cono. Arnaonioli up to the alkaline reaction, ninat the ab ^ eocliiedono oil in ether up. The solution with Y / aocer and dryness cio · Sor near the foraging of the ether verbloibondo residue is distilled off. You get A3 g dos obon ßon & nnton? Ceudoindolo ^voa ^ 0.1 m ^W - ¹⁵² ° ^C -

Its hydrochloride eolinilat after dor. Umkriotallioation. the end

boi 180 * 181 ⁰ O, -.

10

2-! Iotliyl-3- [ß- / i7- (2-iaothyl-2-proponyl) «H-notliyl-anino7-ethyl} -3 · -

phenyl-p3oudoinäol

* 3

a) 1- / Π- (2 ~ Ι · ΐ2 ^ γ1-2-ρΓοροηγΐ) ~] Τ-ηο ^ ν1-ρ ^ ίηο7 ~ 3 ^

! lan works in the same Vioise x / ie in the previous example bocchriüben, jodooh untor the use of ^ - (2-Kothyl-2-propenyl) -K-uGtliyl7-2-chloraotliyla2iiii and phenylaoetone. and get that

Aninocoton of Kp ^ 164 - 166 ⁰ C *

0 0 9818/1838 ΒΛΟ

lrigrZ? ^^

Works nan v / io in previous oa Boispiol t>oaohrlol> on ₉ oo ephillt nan aua l - ^ - (2-Kothyl-2-ijropßnyl) -17-nothyl '<uiinji ^ir -3-plionyl-4-pcntiinpn through, üaootsnanß nit Plicnylliydrazin dao eiitoproohoade PlionyUiydrcicon, which in doroolLon Woiao v / io in vorh.or £ ohondcn üoicpiol oyclioiort v / ird. 2a cnfcotoht daboi dao οLcn calledο pocudoindole from Kp _{0 Q} v ^ _n 154 - 155 ⁰ C ^ üq na on llydrociilorid

dor üolcriatallioation, from ilotlianol / Eaoicoctor at 225 ⁰ O cohnilst #

BATH ORIGINAL 009818/1899

Claims (7)

Claims -— »- -» -. ι ι 1.) Process for the production of new "basic substituted Pseudoindoles of the general formula at: as well as from their acid addition salts according to DBP (Patent application T 26 315 IVd / i2p), characterized in that that one is a phenylhydrazone of the formula | 3 CSI -A-N H W in which R _{1 is} a methyl group or a phenyl radical, R _{2 is} a hydrogen or halogen atom, a lower alkyl or alkoxy group, R ~ is a lower alkyl group or a phenyl radical which can optionally be substituted by halogen atoms or lower alkyl or alkoxy groups, R, a lower alkyl or alkenyl radical, Rc an alkyl radical substituted by a cycloalkyl radical with 3-8 carbon atoms, which may optionally contain lower alkyl or alkoxy radical, an optionally halogen-substituted straight-chain or branched alkenyl radical or together with R ^ and the nitrogen atom one by one Phenyl radical, which can optionally be substituted by halogen atoms, hydroxyl groups, lower alkyl or alkoxy radicals, substituted piperidino or tetrahydropyridino radical and A is a straight-chain or 009818/1898: BAD OR1G «NAL branched divalent aliphatic hydrocarbon radical with 2-4 carbon atoms "in the presence of a condensing agent which causes ammonia elimination, cyclized and the compound obtained, if desired ■ by known methods in an acid addition salt with a physiologically compatible inorganic or organic Acid transferred. 2.) The method according to claim 1, characterized in that the condensing agent boron trifluoride, sulfuric acid, hydrogen chloride acid, polyphosphoric acid, polyphosphate ester, Zinc chloride or a heavy metal halide is used. 3.) As new compounds, basic substituted pseudoindoles of the general formula I. 4.) 2-Methyl-3-phenyl-3 - / ^ - (methyl-allylamino) -ethyl-7-pseudoindole and its salts, especially its hydrochloride. 5.) 2-Methyl-3- {ß - ^ - (2-methyl-2-propenyl) -N-methyl-amino7-ethy]} -3-phenyl-pseudoindole and its salts, especially its hydrochloride. 6.) 3- ^ ß "- (N-2-butenyl-N-methyl-amino) -ethyl7-2-methyl-3-phenylpseudoindole and its salts, especially its hydrochloride. 7.) 2-Methyl-3-phenyl-3- / iJ- (4-phenylpiperidino) -ethy ^ -pseudoindole and its salts, especially its methanesulfonate. S. ) 2-Methyl-3-phenyl-3- / B ~ - (4 'ip-methoxypheny ^} -piperidino) ethyl7-pseudoindole and its salts, especially its methanesulfonate. SAD 009818/1898