DE1620523A1 - Process for the preparation of new 11H-pyrido [2,3-b] [1,5] benzodiazepine-5 (6H) -ones which are substituted in the 11-position - Google Patents

Description

Process for the preparation of new ones substituted in the 11-position

-one

The invention relates to a method for the production of new 11H substituted in 11-lactation 5 (6H) -ones c ·? ^ General formula

as well as their salts with physiologically compatible anor = ganic or organic acids.

In the above ponael, the radicals R ₁ and R ₂ mean hydrogen atoms or lower alkyl radicals © »R ^ a straight-chain or

309881/1693 ■ bad original

branched alkyl radical with 1-5 carbon atoms, an alkenyl radical with 3-5 carbon atoms, a cycloalkyl radical with 5-7 carbon atoms or an aryl radical, R * hydrogen, a straight-chain or branched alkyl radical with 1-5 carbon atoms, an alkenyl radical with 5-5 Carbon atoms or a cycloalkyl radical with 5-7 carbon atoms or together with the nitrogen atom and R. a saturated heterocyclic radical with 5-7 carbon atoms, which can optionally be substituted by lower alkyl radicals and / or interrupted by a further hetero atom, the latter if it is a nitrogen atom, which in turn can be substituted by a lower alkyl, aralkyl, hydroxyalkyl or acetoxyalkyl radical.

You new compounds are obtained according to the invention by that a 11H = -pyrido / ?, 3- | 7 / T, jgrbenzodiazepin-5 (6H) -one of the formula

in which R ₁ and Rg have the meanings mentioned at the outset, by customary methods with a compound of the formula

Bai »- CO - OH ₂ - Hai III,

909881/1693. BAD ORIG.NAL

00-O

iffiä IMX the ai

l · Best ■ ■ ■ - - ' ::

auagetiiuecht becomes "

They produce the compounds required as starting materials the Toicel II can, for example, according to the ia DBF. ...... (Patentareelduisg f 25 723 IVd / 12p) are carried out · lall the bensol ring of this Verbißduagen an alkyl radical all elements contain »germinated in some cases the position of which has not yet been precisely determined» what in the off » fetamgebebeispielan is still -venrleeen.

S03881 / 1B93 bad-original

The reaction of the compounds of the formula II with the halogen-acetic acid halides of the formula III is preferably carried out in an inert solvent in the presence of a hydrogen halide-binding agent at elevated temperatures, preferably at the boiling point of the solvent used. Aromatic hydrocarbons such as benzene, toluene or xylene, ither such as bioethyl ether, bipropyl ether or, preferably, cyclic ethers such as dioxane can be used as solvents; tertiary organic bases such as triethylamine, pyridine and the like or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates are suitable as nalogenwaoo first off-binding agents. The reaction mixture is worked up in the customary manner; the yields are up to 80 ^% theoretical. The halogenoacetyl compounds of the formula IV formed are mostly substances which can be crystallized easily and which can also be used as crude products for the further reaction without further purification.

The conversion of the halogenoacetyl compounds of the formula IV to compounds of the formula I is carried out by reaction with an amine general formula

mr v,

in which R ^ and R ^ have the meanings given. she

BAD ORIGINAL 909881/1693

esa J ** - "'-" * "■ · - ι

Implementation takes place advantageously in an indifferent »! Db'euügöffii-utel, advantageous in the presence of an acid-binding agent for him " elevated temperatures, preferably at the boiling point of ver applied solvent. The solvents used are preferably ethanol or acetone, but aromatic solvents can also be used Hydrocarbons such as benzene or toluene or chlorinated hydrocarbons such as methylene chloride are used Aiiiin of the formula Y used in a sufficient excess to to bind the released hydrogen halide, but you can also use other hydrogen halide binding agents such as pyridine, diethylaniline, Add alkali carbonates or alkali hydrogen carbonates. If volatile amines are used, work may be carried out in a closed vessel.

To shorten the reaction time and lower the reaction temperature, it is in some cases advisable to start from compounds of the formula XT in which shark denotes an iodine atom. These iodoacetyl compounds can most conveniently be obtained in such a way that the corresponding chloroacetyl compounds are first prepared in the manner described and then converted by customary methods with sodium iodide in acetone.

The workup and purification of the end products of the formula X is done in the usual manner, it will be up to 85 1> theory achieved yields of umkristallisiartem pure product.

The buildings obtained can be achieved by implementing them with physiologically compatible inorganic or organic Acids are converted into their acid addition salts by known methods leads to be. Examples of acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, succinic acid, oxalic acid and the like have been found suitable.

They make new compounds and their salts have valuable therapeutic properties Properties, in particular, they possess one very good hating effect with low toxicity, whereby many of the new compounds are as effective as or more potent than codeine.

The following examples serve to provide a more detailed explanation Invention:

a) II ^ O bJ.oracetyl -IIH-p ^ nrido / ^^ ^ bT / T.sTb engodiageiJin-eiSH) on 21 g (0.1 mol) 11H ° Py £ 'ido _i ^, 5-b7 / T , _< g7benzodiazepia-6i5H) -one who dissolved in 300 ml of absolute moxan with warming. An LH solution of 15.3 g (0.14 mol) of chloroacetyl chloride, dissolved in 40 ml of absolute dioxane, and at the same time a solution of ron are added dropwise to the boiling solution within 50 minutes. 14.4 β (Q ₃ H mol) triethylaein, dissolved in 50 ml of absolute dioxa, too. 2facii

_ΛΛΑΛΛ ~ _ίΛ BADORiGiNAL

909881/1693 *

Aofctatündigen Irhitien under reflux is filtered hot. The filtSftt vizd In vacuum evaporated _s the Rückßt & nd vfird from Ibopaeopanol or ati · acetonitrile uBlcrie tall is ated. Ϊ. «229 - 225 ⁰ O with decomposition. O ₁₄ H ^ ₀ CW ₅ O ₂ (287.7)

Ber.l 0 58.45 * H 3.51 + H 14.61 * Cl -12 »32 # Qmt.t 58.50 Ji 3.59 * 14.67 5ί 12.12 ^

The following compounds of the formula IT get

b) 8- (or

▲ ve 8- (or

on and chloroacetyl chloride

T. «215 ⁰ C with decomposition (also methanol).

C ₁₅ H ₁₂ OU ₃ O ₂ (301.7)

Ber.t Cl 11.78 ^

t - 11.50 1> '. ■ ....-, ..

c) 8,9-Dlaetbyl-1 1-chloroacetyl-i 1H ° pyrido ^, 3-bjT / T, ^ b

Aua 8.9 "BiMethyl-1 IH ^ pyrido / ^^^ TZ ^ tÄ ^ eniodimeepin- 6 (5H) -on

1, m 242 "t45 ° C umter seraetmm" (from Ieopropanbl or Acetoel

and chloroacetyl chloride J. «2

909881/1693 ^ÖAD

.s oil 11 _f 2 $ $ «ftf ·! - ■ 11 »25

g C ^

Scm! Deep

I. ■

Ber.s C 6S Gef.8 §6

iia

1-Ohloraee-

3 _S 65 g

m SS © si absolute ethanol ge - BSto & flttfi eeoitst · The Flltsnt i® Takttins are filtered in and

J6 I 17.2? 17i51

g ₉ 9 g of iii

1η- £ Ί

1 a} '■' «

In eiaoß 500 s echrittenea 1 i

5 (6H) ~ ors.® la 200 al abisolitem ethanol depended, tu 5th dr mi

O ⁰ C cooled S ^ iapeiafiioii gives construction 1C «al DiEietlKfla'niö mJ ·: r

closes the AutGldaroi «fen eswümt 1Γ, ytundun ani 70 - 80 ^c ': - _f

cools down wnä the obtained steams

3; β

yak

ü-v-r

The ticket stand will also be «? Iu «> propaacl mc] i-zde-ba37 l ^ J-sr / r»

BATH ORIGINAL 9 0 9 8 8 1/1 B 9 3

Calc .: C 64 * 85 t H 5.44 f H 18.91 $ Qtet.ι 64.90 $ 5.62 # 18.68 §6

According to the same method, the In the Table asageftthrtesi terbisiduBgen dermal I.

At-
3game CHg-GHg-CH ₅
^ Si CHp-OH ^ -CH ₅ T 8-CH ₅ 9-GH ₅ L. - Melting point Molecular formula Mole weight analysis
ber. C = 66.40
B "6.13
N = 17.45 4th 9-GH ₅ P. = 235-236 ⁰ G
from acetonitrile S ₈ H ₂₀ V ₂ 324.4 C = 66.65
H = 6.2a /
N = 17.27 C = 68.40
H = 6.92
N = 16.30 90988t / t 5 .CH ₂ - (OFg) ₂ -CH ₅
-Sl
"*** C ₀ - (CH ₀ ) ,, - GH, H H P. = 199-200 ⁰ C.
from isopropanol O ₂₀ H ₂ AO ₂ 352.4 C = 68.16 '
H = 6.86
N = 15.90 C = 66.20
H = 6.94
N = 15.75 CD
CO 6th Ij JTjL _ WMB 1 Ijfl J «a« IjH
" ^{h /} oh η oh 8-CH ₅ 9-CH ₅ P. = 171-172 ⁰ C.
from isopropanol
ether λ 20 24 4 2 352.4 0 = 68.16
H = 6.86
N = 15.90 G = 69.30
H = 7.54
i '= 14.95. 'm 7th H H P. = 151-153 ⁰ C.
from isopropanol C ₂₂ H ₂₈ N ₄ O ₂ 380.5 C = 69.45
H = 7.42
N = 14.72 C = 69 * 75
H = * Ί 47 D.
O
3D
O
3?
r * 8th 8-GH ₅
or
H H
he
9-CH2 P. = 153-154 ⁰ C.
from 50 ^ ethanol G ₂₂ H ₂₈ N ₄ O, 380.5 C = 69.45
H = 7.4?
N = 14.72 C = 69.80
H = 7.78
N = 14.00 9 P. = 162-163 ⁰ C.
from CH ₅ OHZH ₂ O C ₂₅ H ₅₀ N ₄ O ₂ 394.5 C = 70.02
H = 7.66
N = 14.20

OCM cn

Ό CQQO

OCMC

VO T-

I! Il Il OWl

IACMCM

cnc- * ν © τ-

ovo cn

VOCQC-

• fc * * * *

OC-C-C- τ-.

VOO T-

IA σ »C-

M Jl Jl

OK \ O VOOC-

ocotn

c- τ-ιι I! Il

OWSZS

ν © ο

τ

o c-in ω crtoo

co in in vo * -

Ii Ii η

IA C-

it Ji Ji

en
iSH!

13 Θ

Si as Pi «3

I m

■ = 53-

ο ö

© it

O ρ

ν- U

B ö

63

VS

a ^

!! ® ο S3

fs? O

8 © Ea

Ci3 ES

O el '

ο ©

O!

cn

read

CM

CM

CM O

CV

1 ° ι -

OS

CV!

O 8 ο

CM

CVJ

CM

ο S cn

CV!

o -

O S CU

f- * t

CM

ν! Λ

. 9 ρ 9 ε

example

16

18th

19th

-N

-O

-O

-O

Melting point

F. = 243 ethanol

O ₁ pH., <JS

Ä
4th

r «. ι "besv,

ji sf & ο

F ₈ = 257 O 2 @ rs,

ans A "than © 1

P. = 217-218 ° G from isopropanol

P. = 219-220 ⁰ C from acetonitrile

350.4

Os ($ 7 ₉ 84
Ie 16 ^ 65

, 33
15.99

C = 68.55

H = 6.53
Η "» 15.99

Cfe 63.79

0 »68 ,, H« 6i33

I = 15 »B5

Ο «63.40 Η« 6.37 I ^ 16.10

20th

P. = 216-218 ° E from isopropanol

351.4

C = 64.94
H = 6.02
N = 19.93

0 = 64.70 H = 6.19 N = 19.83

-iQi-OH,

8-CH.

or

9-CH,

P. = 222 ° C

Acetonitrile /

Ethanol

365.4

C = 65.74
Η »6.34
N = 19.16

C = 65.40 H = 6.31 N = 19.33

-N H-CH,

8-CH

9-CH,

P. = 230-231 C from acetonitrile

C ₂₁ H ₂₅ N ₅ O ₂

379.5

C = 66.47
H = - 6.64
N = 18.45

C = 66.40 H = 6.67 U ^- = 18.65

example

Melting point

Suminenf ο rme 1

Mol-G-ew,

Analysis "calc. _(Found.

J?. = 213-215 0 from isopropanol / H ₂ O.

427.5

C = 70.24 H = 5.89 N = 16.38

C = 70.50 H = 6.14 N = 16.57

Pv = 200-201 ^U C from isopropanol /

Dihydrochloride

3 ?. » 215-216 ⁰ C (dec.)

381.4

454.3

C = 62.98 H = 6.08 N = 18.36

Eq = 15.61

C = 62.60 H = 6.04 N = 18.63

01 = 16.00

! ■ 0 /

P. = 232-234 C from isopropanol

409.5

C = 64.53 H = 6.65 N = 17.10

3 = 64-, 70 ι

= * 6.84

ti = 17.33 *

Hydrochloride ¹ , = 105-106 ⁰ C (decomp.) From isopropanol

380.8

C = 63.07 H = 4.50

N = 14.71 Cl = 9.3201 =

D = 62.80 S = 4.53 BT = 14.55 ' 9.44

P. 179-181 = ^u 0 of acetonitrile

^G 21 ^H 24 ^F 4 ° 2

364.5

C = 69.21 H = 6.64 N = 15.37

C = 69.40 H = 6.75 N = 15.25

ÖAD ORlGiWAL

«- 14 °»

The compounds obtainable according to the invention can be incorporated into the customary pharmaceutical preparations are incorporated. The average single dose of the substances is 5 - 50 mg. .litt the following are some pharmaceutical preparations described in more detail:

1st drop ψ Watch etzj Wg *

100 ral drip solution contain: 8,9-Diiaethyl-11 - /? - (2

2 _F 5 g

Tartaric acid 1.0 g Polyethylene glycol 600 10.0 g Saccharin Hatriua 0.2 g Sorbic acid 0.1 g Herrenliköreseens (HBarm. & Reimer) I ₁ Og

Xthanol 50.0 g

Bed, water ad 100.0 ral Manufacturing process;

In ethanol 13et sow successively tartaric acid, _t Polyätiiylenglykol the WirkeubBt & nB and the Iiiköreseene (iöeung A). In deat. Saccharin fiber and sorbic acid are dissolved in water and solution A is mixed. The drip solution is filtered. 1 tablespoon of drip solution contains 25 ag of active substance

9 QS 8 81/1 6 9 3 " ^ÖAD original

$ S

O ₉ 5 O ₀ 4

Water wl ^ ssmf 80 C © ew1sb% vmä ü & sin sm asäer Benzoeoäur®, Amraoni ^ Mchlorid, Eltromexsanres at the active ingredient, the dye and sugar dissolved, in the solution, cooled at low temperature, give men a raspberry flavor while stirring and ethanol and filtered dnrc \\ a ß & filter. 5 nl of syrup contain 25 mg of active substance

t dragle core contains «

- / 5.3

, jJ7-benaodlaeepiE-5 C6H> «on ί 5.0 rag

909 881/1 6.9.3

bad ORiG> NAt

Calcium phosphate sec. anhydrous 80.0 mg »

'Corn starch 30.0 mg

Gelatin. 4.0 mg Magnesium stearate 1.0 mg

140.0 mg

Manufacturing process ^

The mixture of the substance with calcium phosphate, and corn starch is granulated with a 10bigen aqueous gelatin solution through sieve 1.5 mm, at 45 ⁰ C and dried again rubbed di ^ ch a sieve with 1 mm Maechenweite. The granulate obtained in this way is mixed with magnesium stearate and compressed to form slag cores. Core weight 140 mg, stamp 7 mm domed.

The tablet cores produced in this way are coated with a shell using a known method, which essentially: the end Consists of sugar and talc. The finished coated tablets are included Polished with the help of beeswax. Dragee weight: 18o mg

4. Children's soup itories

1 suppository contains:

1 i-DipropylamlaoaeetTfi-1IH- ^ pyrido «/ ?,

Suppository cheamasse (e.g., Wi <-fipso3 ¥ 45} $ 2'Vi m-κ

909881 / 169.1 _BAD0 R, _S1 NAL

Manufacturing process ^

Ia die.gescfcmolaene and cooled to 4O ⁰ C Zäpfcheamasse is stirred by means of a Eintauehhomogenisators the feinpulve riaierte substance. The mass is cooled to 35 ° and poured into slightly pre-cooled molds. Suppository weight 1.0 g

5. Dragees 1 Dragfeekern contains:

11-Dipropylaminoacetyl ~ 1 IH-pyrido · »/ ?, / T ", gM> eneodiacepin" 5 (6H) -one

! • Cyclohexyl-K-methyl- (2-amino-3,5'-dibromobenzyl} =

ammonium chloride lactose Potato starch polyvinylpyrrolidone magnesium stearate

Manufacturing process. - *

The Hischung of the active substances with Kilohzuoker «nd potato" starch is treated with a solution 10xigen on Polyvinj3 yrrolid ^ © © ns in 5OS6ige ethanol by aieb 1.5 mm »granulated dried at 45 ° C and rubbed through sieve 1 mm, which ao obtained Granules are mixed with magnesium stearate and pressed into dragfee kernels.

iernfewAelit? 120 »g; ■ .- ■■: .- Stenpel; T mti arched.

The so obtained. Dragee cores are coated in a known process with a mille, which consists essentially of sugar and talc. I) The finished coated tablets are polished with the help of beeswax »
Dragee weight: 200 mg /

6. Syrup

100 ml of syrup contain:

11 ^ Dipropylaminoacetyl »11 H-pyr ido · = - / ?, 3-b7 =» ZTt £ 7-bens! Odiacepin «5 (6H) -on.

1-C3 "5 * dihydro-phenyl) -2-isopropyl-aminoethanol"

... sulfate

Citric acid Aaeonium chloride Benzoic acid

sugar

Xngweressens

tobenspitteigelb Kr. 2

Lebeneaittelblau Mr. 3

Ethanol

Dist. Water ad

0.5 S. 8th 0.2 ε IBl 0.5 S. 0.4 G 0.2 S. 65 * 0 Λ * 0.0015 g 0.005 S 10.0 100.0

D "etilli" rt "e ¥ * saer wir4 to 80 ^p 0" rwärjit und dari "• nier leaifowilure" ieeoniuachlorid, citric acid, d

909881 / 1692- BADORiGtNAL

«19 -

Active substance * the dyes as well as the sucker dissolved · Man
cools to building temperature as and, dissolves 1- {3 _V 5-diydroiyphenyl) ' g-ieopropylaainoethanol sulfate · The mixture of ethanol with ginger essence is stirred into the syrup, ifen filtered duroli • in a suitable filter. 5 ■! Syrup contain 25 ing active substance.

BATH

909 88 1/1 6 9 3

Claims (7)

Claims 1. Process for the preparation of new 11H-l ^ ido / ?,> - b7i! T »57 ^{l) eni5odiaze} P ⁱⁿ ~ 5 (6H) - ones of the formula I, in which R ₁ and Rg are carbon atoms or lower alkyl radicals, R «is a straight-chain or blackened alkali radical with 1-5 carbon atoms, an alkenyl radical with 3 " 5 carbon atoms, a cycloalkyl radical with 5-7 carbon atoms or an aryl radical, R * hydrogen, a straight-chain or branched alkyl radical with 1-5 carbon atoms, an alkenyl radical with 3-5 carbon atoms, or a cyclic radical with 5-7 carbon atoms or, together with R.sup.1 and three nitrogen atoms, a 5-7-membered saturated heterocyclic crack ₉ which is optionally substituted by alkyl radicals and / or interrupted by a further heteroatom 00iß kana, where letsrtex'ee _t BATH provided it a. Is nitrogen atom, optionally by a lower alkyl, hydroxyalkyl, ethoxyalkyl or aralkyl « reet can be eubstituted, mean, as well as their acid addition saleen with physiologically compatible inorganic or organic acids, characterized in that an 11H «pyrido / 2,3-b7 / T, j7fcenzodiacepin-5 (6H) ~ one the lOnnel II, in which R ₁ and R _{2 have the} ^meanings mentioned at the outset, by customary methods with a compound of the formula Shark »- OO - OH ₂ - shark III, in the shark and shark ', which can be the same or different, Mean chlorine, bromine or iodine atoms, converted and in the resulting haloacetyl compound of the formula OO-CHg-Hal 909881/1693 in which B ^, Rg and Hal have the meanings given, the Balogen atom according to the usual methods against the order -H is exchanged and optionally the base obtained in this way Usual methods bit a physiologically compatible inorganic or organic acid in their acid addition salse over » will lead. 2. Veue 11H-pyrido / ?, 3 ~ b7 / T, j57 bensodiasepin «> 5 (6H) -ones of the orme3jl, in which B ₁ and B ₂ hydrogen atoms or lower alkyl radicals, B ^ a straight-chain or carbonized alkyl radical with 1-5 carbon atoms, an alkenyl radical with 3-5 carbon atoms, a cycloalkyl radical with 5-7 carbon atoms or an arylate, e.g. hydrogen, a straight-chain or branched alkyl radical with 1-5 carbon atoms, an ilkenyl radical with 5- 5 lohlenstoffatomen, a Cycio "alkyl group having 5-7 carbon atoms or susamen with B and the nitrogen atom, form a 5 - through 7-membered heterocyclic gesXttigten brat, &'r, where appropriate. Alkyl radicals can be substituted and / or interrupted by a further heteroatom, the latter, provided that it is a nitrogen atom, can optionally be substituted by a lower alkyl, hydroxyalkyl, acetoxyalkyl or afelkyl radical, BAD ORlG'NAt-909881/16? »^. as well as their acid additlouasalsö with physiologically vt ν'τ & ι ¹ XI 'inorganic or organic acids » 3. 8,9-bimethyl-11 "- / f- (2" hyd3: oxyall · 3rI) -pipe2? Aέ5l} .oacetyl / "1" 4. 11 ^ Dipropylami3ioacetyl * 11H-p ^ rido ^, 3-b7 / T _f J ^ 7lje3i5scdieaQ ;! in 5 (6H) -one. 5 · 11 «^ - (2 '- ^ faroaqratsliyl) pi9iäraiii3ioac © ty 3 ^ 11H-pypieto / 2 _r '; -» / 6. 11-Diissobutylaminoacetyl "11H ~ 3gyrido ^, 3 ~ ί7 / ϊ", 5 (6H) «one. 7. 3, «-5 (6H) -one