DE2435383A1 - PYRIMIDOBENZOXADIAZEPINE AND PYRIMIDOBENZOXADIAZOCINE, METHOD FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

"Pyriraidobenzoxadiazepine and Pyrimidobenzoxadiazocine, Ver ■>

drive to their manufacture and medicines " Priority: July 26, 1973, V.St.A., No. 382 803

The invention relates to that characterized in the claims

Object.

The pyrimidinium compounds of the general formula IV used in the process and the imino compounds of the general formula V are prepared from 2-aminopyrimidines of the general formula II and o-bromophenoxyalkylene halides of the general formula III in which X is a chlorine or bromine atom. This reaction is carried out in a solvent or solvent mixture, can be solved in which the reactants and having a boiling point of at least about 100 ⁰ C. Typical examples of such solvents are aromatic hydrocarbons, ethers, aliphatic alcohols and aryl-substituted aliphatic alcohols, such as toluene, xylene, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether,

^L "509807/1134

1 ethylene glycol monomethyl ether, ethylene glycol dimethyl ether,

■ n-amyl alcohol and benzyl alcohol. The compounds of the general formulas II and III are heated to temperatures of about 100 to 140.degree. C. for a few hours, generally about 3 to 24 hours, in one of the solvents described above or a mixture thereof. The resulting pyrimidinium compounds of the general formula IV are converted into the imino compounds of the general formula V by reaction with an alkali metal alkoxide having 1 to 3 carbon atoms or an alkali metal carbonate in a water-miscible alcohol. This reaction takes place at room temperature for a period of about 1 to 4 hours. The compounds of general formula V may be prepared by heating to temperatures of 60 to 120 ⁰ C in a water-miscible alcohol with an alkali metal alkoxide having 1 to 3 carbon atoms, and in the presence of copper while "4 to 10 days, generally 6 to 8 days, into the end products of the general formula I. The compounds of the general formula IV can also be prepared directly by heating to temperatures of about 60 to 120 ^° C. for about 4 to 10 days, generally for about 6 to 8 days, in the presence of potassium carbonate and copper are transferred into a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene or diethylbenzene in the compounds of general formula I '. Vorzugsv / else but the compounds of the general formula IV can be directly on to the compounds of general formula I by heating Temperatures of about 60 to 120 ^° C. for about 4 to 10 days, generally for e about 6 to 8 days, in the presence of an alkali metal hydroxide, carbonate, phosphate, metaborate or ^

509807/1134

-tetraborate in a mixture of water and a water-miscible alcohol and in the presence of copper. Specific examples of suitable condensing agents are LiOH, NaOH, KOH, RbOH, CsOH, Na ₂ CO ₃ , K ₂ CO ₃ , Rb ₂ CO ₃ , Cs ₂ CO ₃ , Na ₃ PO ₄ , K ₃ PO ₄ , Rb ₃ PO ₄ , Cs ₃ PO ₄ , Na ₂ B ₂ O ₄ , Na ₂ B ₄ O ₇ , K ₂ B ₂ O _4, and K ₂ B ₄ O ₇ . Water and water-miscible alcohol are used in proportions such that a homogeneous, single phase is obtained.

If m has the value 1 and if the radical R is only in the 5-position of the compounds of the general formula II, only one isomer of a compound of the general formula I / If m has the value * 1 and the radical R is formed is in the 4-position of the compounds of the general formula Ha and R ^{1 is} in the 5-position of the compounds of the general formula III, two isomers of the general formulas Ia and Vb are formed via the intermediates of the general formula IVa or Va and IVb and Vb Ib. If m is ¹ and 2 and the two radicals R are in the 4- and 5-positions, two isomers of the general formula Ic and Id are formed. These isomers can all be separated from one another in the usual way, for example by fractional recrystallization or column chromatography . This process is illustrated by the following reaction scheme:

509807/1134

pi

O'M

IN

61

θ S3 - /

Pi-U

η |

<Ν

CQ

> l

Pi— ¹

509807/1134

Pi-

Pi.

(M

O ^

= S4 Pi-O

(N

= W Pi-O

■ Λ

ο>

Ρί

Ml

_Γ 2Α35383Π

The compounds of the general formulas IV and V and the process for their preparation and their use are also a subject of the invention. Specific examples for these intermediates are:

2-Amino-1 - / ^ (o-bromophenoxy) methyl / pyrimidinium chloride, 1- (o-bromophenoxymethyl) -1,2-dihydro-2-iminopyrimidine, 2-Amino-1 - / (2-bromo-A-chlorophenoxy) -methyl / -pyrimidinium chloride, 2-amino-1 - / 2 '- (o-bromophenoxy-1' -methylethyl) _ / - 5-phenylpyrimidinium chloride and

1- / 2 '- (o-Bromophenoxy-1' -methylethyl) _7-1,2-dihydro-2-imino-5-phenylpyrimidine.

The intermediates of the general formula III, in which η den Has value O, by converting approximately equimolar amounts of a 1,1-dibromoalkane or a 1-bromo-1-chloroalkane with 1 to 4 carbon atoms of the general formula VI with one saturated Sodium sulfite solution can be prepared over a period of about 40 to 120 hours and reflux. That resulting 1-bromoalkane-i-sodium sulfonate of the general formula VII is then used with approximately equimolar amounts of an o-bromophenol of the general formula VIII heated in the presence of aqueous alkali. The resulting sodium o-bromophenoxyalkylene sulfonate of the general formula IX is used with phosphorus pentachlo- * rid or phosphorus pentabroraid at room temperature to the corresponding ο-bromophenoxyalkyl chloride or bromide of the general formula mel X implemented. This procedure is followed by the following reaction scheme explained:

509807/1134

- 8th - ρ 2435383 R "
Br-CH-X Na ₃ SO ₃ R "
Br-CH-SO ₃ Na X = Cl or Br (VI) (VII)

R "I

NaO ₃ S-CHO ^ -

R "
-CH-O

PXr

Br

X = Cl or Br

(IX)

The intermediates of the general formula III, in which η den Has a value of 1 can be prepared by using a 1-bromo-2-chloroalkane of the general formula XI with approximately equimolar Amounts of a compound of the general formula VIII in the presence of aqueous alkali to the compound of the general Formula XII implements. These compounds can also be prepared by reacting an ο-bromophenoxyalkanol of the general formula XIII be made with phosphorus pentachloride or phosphorus pentabromide. These procedures are followed by the following reaction scheme explained:

509807/1134

R "Cl-CH-CH ₂ -Br

(XI)

'Toi

Br ^ \ ^

(VIII)

PCl ₃ or PBr "

R "

^Rl X-CHCH ₀ -O

R ¹

(XII)

R "HO-CHCH ₂ -O

The compounds of the general formula VIII, in which R ¹ denotes a fluorine atom, a trifluoromethyl, alkylsulfonyl or dialkylamidosulfonyl group, can be prepared according to the following reaction scheme:

ENT.

H ₂ SO ₄

> R

Heat

All processes are carried out in a manner known per se. O-Broinphenols can also be made from phenols with bromine and iron powder are prepared according to the following reaction scheme:

509807/1134

R ¹ denotes a fluorine atom, a trifluoromethyl or alkyl mer

captogroup.

The salts of the compounds of the general formula I can be derived from inorganic or organic acids, for example the hydrohalic acids, such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid, maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, 2-acetoxybenzoic acid, salicyl · ^. . acid, succinic acid, p-aminobenzoic acid, p-acetamidobenzoic acid and methanesulfonic acid as well as theophylline, 8-chlorotheophylline. .

The compounds of general formula I and their salts are valuable medicinal substances that have a stimulating effect on the Central nervous system and have a muscle-relaxing effect. For the manufacture of drugs \ / ground the connections of the general formula I in the usual way, e.g. formulated into tablets, injection preparations, as a syrup or capsule preparation.

The pyrimidinium compounds of the general formula IV are valuable bactericides. The minimal inhibitory concentration of some compounds of the general formula IV was found in Staphylococcus aureus (1), Streptococcus pyogenes (2), Salmonella schottmuelle-

509807/1134

ri (3), Salmonella gallinarum (4), Pseudomonas aeruginosa (5), Proteus vulgaris (6), Escherichia coli (7), Pasteurella multocida (8) and Mycobacterium tuberculosis (9). The results are summarized below.

Minimum inhibitory concentration, y / ml

Test organization example link from Example 11 nism 3.13. 1 example 4 Example 5 6.25 12.5 12.5 6.25 25.0 1 . 12.5 50.0 50.0 12.5 2 6.25 50.0 12.5 12.5 3 12.5 25.0 12.5 25.0 4th * 12.5 25.0 25.0 25.0 5 3.13 25.0 25.0 6.25 6th 6.25 25.0 12.5 12.5 7th 0.39 12.5 25.0 0.78 8th 6.25 1.57 9

The compounds of the invention can be administered orally, intraperitoneally, administered subcutaneously, intramuscularly, or intravenously.

The examples illustrate the invention. 20th

example 1

6H-pyrimido / i, 2-c7 3 _t 3, S / benzoxadiazepine hydrochloride A) sodium bromomethanesulphonate

A mixture of 372.0 g of dibromomethane and a saturated solution Solution of 261.0 g of sodium sulfite in 750 ml of water is 80 hours heated under reflux and stirred. Then 600 ml of V / water are distilled off from the reaction mixture. The residue solidifies on standing and is recrystallized from 200 ml of water, lized. Yield 380.0 g of the Tite] compound from F. 277 bis

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281 ⁰ C.

B) (o-Bromphenoxv) methanesulfonic acid, sodium salt 68.0 g of sodium bromomethanesulfonate are added to a solution of 61 ", 3 g of o-bromophenol in sodium hydroxide solution (15.5 g of sodium hydroxide in 61 ml of water) ^{slowly heated to 150 °} C. in an oil bath with stirring, and at the same time water is distilled off. 61 ml of water are distilled off over the course of about 3 hours. The residue solidifies and is ^{heated to 200 °} C. for a further 2 1/2 hours 800 ml of warm water are dissolved, the solution is filtered, the filtrate is adjusted to pH 5 and washed twice with 200 ml of ether each time. The aqueous phase is then evaporated to 600 ml and cooled are filtered off and dried under reduced pressure. Yield 63.3 g of the title compound After recrystallization from 600 ml of 90 percent aqueous ethanol, 57.5 g of the title compound with a melting point of 282 ° to 284 ° C. are obtained.

20 C) o-bromine - (- chloroanisole

A mixture of 29.0 g of (o-bromophenoxy) methanesulfonic acid sodium salt and 50.0 g of phosphorus pentachloride is mixed thoroughly in a mortar. After about 10 minutes of mixing, the mixture partially melts, a violent reaction sets in and the total mixture liquefies. The mixture is left to stand for 15 minutes with occasional stirring, then 700 ml of diethyl ether are added, a white solid separating out, and then poured into 750 g of crushed ice. The Ätherlö- _L is sung j verminder-separated, washed, dried and

509807/1 134

evaporated under pressure. There remain 21.0 g of a liquid residue which is distilled under reduced pressure. Yield 19.5 g of colorless liquid, bp 74-75 ⁰ C / 2 Torr.

njf ' ³ 1.5799. "· 5

D) 2-Amino-1 - / (o-bromophenoxv) -methyl7-Pvrimidiniumchlorid A solution of 7.1 g of 2-aminopyrimidine in 35 ml of xylene is added dropwise with a solution of 11.1 g of o-bromo-a-chloroanisole in 45 ml of xylene are added. The mixture is heated to 50 ° C. for 5 minutes and stirred at room temperature for 40 hours. The originated. which crystals are filtered off and dried. Yield; 16.0 g of the title compound. After recrystallization from isopropanol, 14.0 g of the title compound are obtained.

15 E) 6H-pyrimido / i, 2-ς_7 / ί, 3-, 57benzoxadiazepine

A mixture of 9.5 g of 2-amino-1- / ~ (o-bromophenoxy) -methyl7-pyrimidinium chloride, 8.3 g of potassium carbonate and 0.4 g of copper bronze in 150 ml of n-propanol are refluxed under nitrogen for 7 days heated and stirred. The reaction mixture is filtered while it is still hot and the deep yellow colored filtrate evaporated to dryness. The residue is dissolved in 400 ml of diethyl ether, and the ether solution is washed, dried and evaporated. It left behind. ben 6.4 g of the title compound as a yellow-colored solid. To • Recrystallization from cyclohexane gives 3.6 g of the title compound

25 received. .

509807/1134

^Γ -14- 2Α35383 ^Π

1 F) 6H-Pvrimido / i.2-ο7 / ΐ, 3.5 / benzoxadiazepine hydrochloride

A solution of 1.0 g of 6H-pyrimido / i, 2-c // i, 3.5, / benzoxadiazepine in 20 ml of isopropanol is mixed with 5.0 ml of a 4.2 μm solution of hydrogen chloride in isopropanol. Anhydrous diethyl ether is added to the clear solution obtained, and turbidity forms. The mixture is then left to stand. The resulting light yellow crystals are filtered off and recrystallized from acetonitrile. Yield 1.0 g of the title compound.
10

Example2,

6H-pyrimido / i, 2-0 .// Ϊ, 3, 57benzoxadiazepine

A) 1- (o-Bromophenoxymethyl) -1,2-dihydro-2-iminopyrimidine

A suspension of 7.0 g of the product from Example 1D, 5.6 g of finely powdered anhydrous potassium carbonate and 175 ml anhydrous n-propanol is heated under reflux and stirred for 8 hours, filtered while hot and the Piltrat under reduced Pressure evaporated to dryness. The residue is dissolved in 150 ml of diethyl ether, the ether solution with V / water and saturated Washed brine, dried and evaporated. The title compound remains, which is recrystallized from pentane will. Yield 5.8 g of pure compound.

B) 6H-Pvrimido / i, 2-c7 / i. _t 3,5_7benzoxadiazepine

A solution of 4.65 g of the product of (A) in 150 ml of n-propanol is made with 0.20 g copper bronze and 5.6 g finely powdered anhydrous potassium carbonate is added and the mixture is heated under reflux and stirred for 10 hours. After working up according to the example 1 (E), 2.78 g of the title compound are obtained. _j

509807/1134

1 Examples 3 to 13

According to Example 1 (D), but using the substituted pyrimidines listed below, the corresponding substituted compounds of the general formula IV, IVa, IVb, IVc or IVd, in which R ¹ and R "are hydrogen atoms and η has the value 0, are obtained These compounds are then converted according to Example 2A into the corresponding substituted compounds of the general formula V, Va, Vb, Vc and Vd, which according to Example 2 (B) are converted into the corresponding substituted compounds of the general formula I, Ia, Ib, Ic and Id be convicted »

L -J

509807/1134

to

(Λ

example

_r1 © .CH-

_els

NH B:

Ol O (O OO O

Br

^B1 W ^H2

■ sr

CH ₂ O.

'X NO 4> LJ Cn CO CX) CO

CN Si

CN W

η W U

CN

pT

BB KK

υ — υ — υ — u

CN

fO (N CNJ

ta 'a w w υ — u — υ — u

ro

⁰ CN

\ i

CN

ro cn cn

BBBB

CN

H. • Η · Η

ω ρ

CN

θ S3- <

'Oa

'CN

B U

ro B U

J-

B U

ro B O CN

WWBW UU-U-U

509807/1

CM

fj

(N

K L)

Vf

ffi

/ \ W

(D

• H -H:

ω ρ
CQ ω

00

509807/1134

• Η P CO • Η ω m

509807/1

2U5383

H C) • Η P

ω • η G)

ro

509807/1 134

^Γ - 21 - 2Α35383 " ¹

1 Examples 14 to 23

Same as Example 1 (A) to 1 (D) but using the following Substituted pyrimidines listed are the correspondingly substituted compounds of the general formula IV obtained according to Example 1 (E) to the appropriately substituted Compounds of general formula I are implemented.

509807/1134

CJ Mr

CM

vT υ

CM

CJ

CM

H Φ • Η P CQ • Η (D

ιη

509807/1134

r-1 (D • Η Γ-i ω • Η

S CO

η ^ - '

(N

⁵² K

ta υ

η W U

CO

5 0 9 8 0 7/1134

S3

example

CD CO 00 CD

^19th

CH ₃ CHCH ₂

3 Ö

CH-

CH ₃ CHCH ₂

CH,

CH ₃ CH ₃ CHCH ₂

Br

.θ

, CH ₂ O.

CH.

I , CH

CH ^ CHCH

CH ^ CHCH-ι 2

CH ₂ O

20,

'CH ₃ CH

CH

ητι ms

CH.

CH ₀ CH,

Br

CH ₃ CH ₂

CH

CH-

CH-CH

to

example

21.

CH

r ^ N ^ ²

IO ι | O

: h ₂ . NH ₂ Br

NH

• N

: η

.CH,

IV) VJl

2 ?.

(CH.

JSL

) ₂ CH

Φ CH ₀ O

, Θ

(CH ₃ ) ₂ CH

K3®

te

CM

• r-l P ω • Η

ta 'ο

do

- 26 -

509807/1134

-27- 2Α35383 ^Π

Example 24

i, 2-c _ // i, 3.57 benzoxadiazepine hydrochloride

A) 2-Bromo-4-chlorophenoxvmethanesulphonic acid, sodium salt A solution of 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is mixed with 16.0 g of sodium hydroxide and 100g of sodium bromoethanesulphonic acid and reacted according to Example 1 (B) . Yield 74.5 g of the title compound from F. ⁰

B) 2-bromo-4-chlorophenylchloromethyl ether

A mixture of 71.0 g of the product of Ca) and 110.0 g of phosphorus pentachloride is reacted according to Example 1 (C). Yield. "· ■ 55.7 g of the title compound, melting at 56.0 to 57.5 ⁰ C.

C) 2-Amino-1 - / "^ - bromo ^ -chlorophenoxy) methyl / pyrimidinium chloride ■

A solution of 14.1 g of 2-aminopyrimidine in 180 ml of warm anhydrous xylene is mixed with 25.6 g of the product from (B) in 70 ml of anhydrous xylene, and the mixture is stirred at room temperature for 4 hours and then at 100 ° C. for 2 hours . After working up ^"n 33.0 of the title compound g.

D) 2-chloro-6H-pyrimido / i. 2-c7 / i, -3, 57benzoxadiazepine hydrochloride A mixture of 14.0 g of the product from (B), 11.1 g of finely powdered anhydrous potassium carbonate, 0.4 g of copper bronze and

350 ml of anhydrous n-propanol is refluxed for 8 hours * and stirred, then filtered while still hot and the deep yellow colored filtrate evaporated to dryness under reduced pressure. After work-up, 6.8 g of the title compound are grounded L_alf5 free base obtained. _J

509807/1134

2.0 g of the free base in 50 ml of warm isopropanol are mixed with 5.0 ml of a 4.8 η solution of hydrogen chloride in isopropanol are added. After cooling, the resulting crystals become filtered off. Yield 2.2 g of the title compound. After recrystallization from a mixture of acetonitrile and anhydrous Ethanol, 1.9 g of the title compound are obtained from a melting point of 303 to 305.degree (Decomposition) obtained.

Examples 25 to 40

10 As in Example 24, but using the following in Substituted 2-bromophenols listed in column I are ·>

finally obtained the 'compounds of the general formula listed below in which R' occupies the position indicated in column II.
15th

Example 25, 26, 27, 28, 29, 30, 31, 32:33, 34.

2,5-dibromophenol 2-bromo-5-iodophenol

2-bromo-5-methylphenol

2-bromo-5-ethylphenol

2-bromo-5-chlorophenol

2-bromo-5-n-butylphenol

2-bromo-5-isobutylphenol

2-bromo-5-fluorophenol

6-bromo-α, α, α-trifluoro-m-cresol

2-bromo-5-sulfamoylphenol

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II

3-bromo 3-iodine

3-methyl

3-ethyl 3-chloro 3-n-butyl 3-isobutyl 3-fluoro 3-trifluoromethyl 3-sulfamoyl

Example.

35.

36.

37. 38. 39. 40.

- 29 -

2-bromo-5-dimethylaridosulfonylphenol

2-bromo-4-dibutylamidosulfonylphenol

2-bromo-5- (methylsulfonyl) phenol 2-bromo-5- (η-butylsulfonyl) phenol 2-Bromo-5-ethylsulfonylphenol 2-Bromo-5-propylsulfonylphenol

II

3-dimethylamidosulfonyl

2-dibutylamidosulfonyl

5-methylsulfonyl 5-n-butylsulfonyl 2-ethylsulfonyl 2-propylsulfonyl

Examples 41 to

According to Example 1, but using the following in Compounds listed in column I, the compounds of the general formula given below are obtained in which R " has the meaning given in column II.

20 at
game I. 41. 1,1-dibromoethane 42. 1,1-dibromoisobutane 25 43. 1,1-dibromopropane 44. 1,1-dibromopentane 45. " 1,1-dibromobutane 46. 1,1-dibromoisopentane

II

-CH-

-CH ₂ CH ₃

-CH ₂ CH ₂ CH ₃
-CH ₂ CH (CH ₃ ) CH ₃

509807/1134

1 Example 47

' 6 _? 7-dihydro-7-methyl-1O-phenylpvrimido / ϊ, 2-dJ // \ _f 4. 67-benzoxadiazocine

A) o-Bromphenvl ^ chloropropyl ether

A solution of 23.0 g of sodium in 500 ml of anhydrous ethanol is mixed within about 30 minutes with a solution of 173.0 g of o-bromophenol in 250 ml of anhydrous ethanol. The mixture is heated and stirred under reflux for 30 minutes, then ^{cooled to 0} ° C. and 157.5 g of i-bromo-2-chloropropane are added dropwise over the course of about 1 hour. The mixture is ^{then stirred for 2 hours at 0} ° C., then slowly heated to reflux temperature over the course of 2 hours and refluxed for a further 2 hours. The sodium bromide which has crystallized out is then filtered off and the filtrate is evaporated at 40 ° C. under reduced pressure. 204.2 g of the title compound remain as an easily mobile, colorless liquid.

B) 2-Amino-1- / 2 '- (o-bromophenoxy-1 ^f -methylethyl) / - 5-phenylpvrimi dinium chloride

A solution of 29.4 g of 2-amino-5-phenylpyrimidine and 50.0 g of des Product of (A) in 200 ml of anhydrous toluene is refluxed for 6 hours and then cooled. The resulting Crystals are filtered off. Yield 60.2 g of the colorless crystalline title compound.

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C) i - ^ '- Co-Bromphenoxv-i'-methvläthyl) 7 ^ 1.2-dihydro-2-imino-

^ -phenvlpyrimidine

A solution of 8.5 g of the product from (B) in 100 ml of anhydrous n-propanol is pulverized with 2.8 g of anhydrous Potassium carbonate is added and the mixture is heated under reflux and stirred for 1 hour. The suspension is filtered while hot and the filtrate evaporated. A pale yellow solid remains which is recrystallized from cyclohexane. Yield 5.8g of the title compound in light yellow crystals. 10

D) 6,7-dihydro-7-methyl-10-phenylpyrimido-Zi, 2-dJß , 4,67benzoxa ~ <-

diazocin *

3.39 g of the product from (C), '50 ml of anhydrous n-propanol, 2.8 g of anhydrous finely powdered potassium carbonate and 0.25 g of copper bronze are refluxed and stirred for 6 hours. The mixture is filtered while hot and the deep yellow colored filtrate ^{evaporated to dryness at ^ 0 0} C under reduced pressure. The deep yellow colored solid residue is recrystallized from ligroin. Yield 2.22 g of the title compound.

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1 · Example 48

Manufacture of a capsule preparation Ingredients mg / capsule

6H-pyrimido / i, 2-cJβ ', 3,5 / benzoxadiazepine-400

hydrochiorid

5 strength 80

Magnesium stearate 5

The drug, the starch and the magnesium stearate are combined with one another mixed. The mixture is filled into hard gelatin capsules in an amount of 485 mg.

Example 49
Manufacture of tablets
• Ingredients mg / tablet

15 2-chloro-6H-pyrimido / i, 2-ς7 / ΐ, 3, §7benzoxa-

diazepine hydrochloride 300

Lactose 200

Corn starch (to mix) 50

Corn starch (for paste) 50

Magnesium stearate 6

The drug, lactose and corn starch for mixing are mixed together. The corn starch for the paste is suspended in water in an amount of 10 g corn starch per 80 ml water and heated with stirring. The resulting paste is used to granulate the powder mixture. The moist granulate is sieved and dried at 5O ⁰ C. The dry granules are sieved again and the mixture is mixed with magnesium stearate and compressed into tablets. Each tablet contains

509807/1134

1,300 mg of drug.

Example 50
Making a syrup
Components . lot

/ i, 2-d // i, 4,6 / benzodiazocin ^ 00 ^m &

Sorbitol solution (70 percent US pharmacopoeia). 40 ml

Sodium benzoate 150 mg

Sucaryl 90 mg

Saccharin 10 mg

red dye (F.D. & Co. No. 2) 10 mg

Cherry flavor · '50 mg

distilled water to 100 ml.

40 ml of distilled water are mixed with the sorbitol solution. The drug is then suspended in the solution. This is followed by the sucaryl, saccharin, sodium benzoate, cherry flavor and red dye added and dissolved. The volume is adjusted to 100 ml with distilled v / ater.

Other components can replace the aforementioned components. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethyl cellulose or methyl cellulose be used. Phosphates,. “Citrate or Tartrates can be added. As a preservative, p-hydroxybenzoic acid ester or sorbic acid, and instead of the Cherry flavor and red color, other flavors and colors can be used.

509807/1134

Claims (1)

Patent claims . 1. Pyriraidobenzoxadiazepines and pyrimidobenzoxadiazocines of the general formula I
5 in which m has the fourth 1 or 2, if m has the value 1, R entwe-10 which is in the 4- or 5-position of the 2-aminopyrimidine used, if R is a halogen atom, this is only in the 5-position if m has the value 2, both radicals R are in the 4- and 5-position of the aminopyriniidine used, but only one of the two radicals R can be a halogen atom in the 15th 5-position, R is a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical with 1 to 4 carbon atoms, a benzyl group or a fluorine, chlorine, Bromine or iodine atom, an alkyl or alkoxy radical with 1 to 4 carbon atoms or a trifluoromethyl group substitute-20 - te phenyl group means, R 'a hydrogen ™, fluorine, chlorine, Bromine or iodine atom, an alkyl or alkylsulfonyl radical with 1 up to 4 carbon atoms, a dialkylamidosulfonyl group having 1 to 4 carbon atoms in each alkyl group, or a trifluoromethyl group and R "is a hydrogen atom or an alkyl radical with 25 Represents 1 to 4 carbon atoms and η has the value 0 or 1, and their salts with acids. 509807 / 113A ■ ³⁵ - 243538a 1 2. 6H-pyrimido / 1,2-c // i, 3,5 / benzoxadiazepine, 3. 2-chloro-6H-pyrimido / i, 2 - <^ / i, 3,5 / benzoxadiazepine. 4. 6,7-Dihydro-7-methyl-10-phenylpyrimido / i, 2-d // i, 4,6 / benzoxadiazocine. 5. Process for the preparation of the compounds according to Claim 1 _K, characterized in that a compound of the general formula IV or V is used 15 or (V) in which R, R ', R "., m and η have the meaning given in claim 1 and X represents a chlorine or bromine atom, in the presence a copper catalyst and an alkali metal hydroxide, carbonate, alkoxide, phosphate, metaborate or tetraborate heated and optionally converted the compound obtained into a salt with an acid. 6. Medicament containing a compound according to claim 1 and over! cozy Trä gerstof-Fe and / or diluents and / or auxiliary substances s. - ¹ 509807/1 134