DE2065333A1 - N-SUBSTITUTED 3,4-DIHYDRO-3-OXO-2H1,2-BENZOTHIAZINE-S-DIOXYDE DERIVATIVES, THEIR USE AND METHOD FOR PREPARING THE SAME - Google Patents

Description

DR. STEPHAN G. BESZEDES
PATENT ADVOCATE

DACHAU at MÖNCHEN

BOX 1168

AM HEIDEWEG 2

TEtEPHONt DACHAU 437f

Postal checking account Munich 136871 Bank account no. 90 637 at the district and city savings bank Dachau-Indersdorf

P 534

Eliminated from P 20 22 69 ^ .2-44

the filing date is the

May 8, 1970

description

for patent application

RECOEDATI S.A. CHEMICAL AND PHARMACEUTICAL COMPANY

Lugano, Switzerland

concerning

N-substituted 3,4-dihydro-5-oxo-2H-1,2- -benzothiazine-S-dioxide derivatives, their use and process for the preparation thereof

The invention relates to new 3-oxodihydrobenzothiazine-S-dioxyde, their use as medicaments, in particular as hypnotics or sleeping pills and anti-spasmodics, and methods of making the same.

3 0 9812/1215

The invention relates to N-substituted 3,4 ~ Dihydro-3-oxo-2H-1,2-benzothiazine-S-dioxide derivatives of general formula.

where R is an alkyl radical with 1 to 4 carbon atoms, an allyl radical or a radical of the formula

O
Il

-C-C-N

Ho

II

CH,

stands.

The compounds of the formula I have valuable therapeutic properties. Most of all, they have an effect on the central nervous system and are particularly suitable as hypnotics, sleeping pills or narcotics and anticonvulsants.

Therefore, according to the invention, medicaments are also which 1 or more of the above compounds as an active ingredient or ingredients contain or of such or consist of such, provided.

309812 / 12.15

- 3 - BAO ORSGiNAL

_. 3 -

In the following Table I are the results of the pharmacological Experiments with compounds according to the invention as well the one for their excellent hypnotic or sleep-inducing and sedative or calming effect known comparative substance 2 ~ methyl-3-o-tolyl-4- (3H) -quinazolinone (Metaqualon) and the comparison substance phenylethylbarbituric acid, which is known for its excellent anti-spasmodic effectiveness (Phenobarbital) compiled. To determine the toxicity, the substances were used in white MiRI mice administered intraperitoneally and used to determine the hypnotic The substances in white HMRI mice showed sleep-promoting and anti-spasmodic effects, respectively entered orally. The fatal doses at 50% (LDcQ values) were determined 48 hours after administration of the substances. For the hypnotic or sleep-demanding doses at 50% (HD, -Q scores) the hypnosis was respectively Sleep promotion is considered to coincide with the disappearance of the righting reflex. To determine the The animals became antispasmodic 30 minutes after administration of the substances subjected to an electric shock. The anticonvulsant dose is that given to 50% of the animals protects. All doses are given in mg / kg body weight.

Table I.

link - R LD ₅₀ value HDcQ value antispasmodic dose formula - CH ₃ 1,000 100 I. - ° 2 ^H 5 650 - 130 I. - 11 - C ^ H, -, 1,000. - 200 I. - ⁿ - Vg 2,400 5OO 3OO I. -

3 0 9 8 1 2/1 2 1

Table I continued

link - R LD _O value HD ^ value
■ yd Anti-spasmodic
dose formula H
I.
-CC = CH ₀
H ₂ ² 800 800 160 'I - O ^ CH,
Il - /. 3
- C - C - N
H ₂ -. \
CH _x • 840 400 120 I. 2-methyl-5-o -t ο lyl-4- <50-
-quinazolinone
(Comparison substance) 605 159 PhenylethyIb works with acid
(Comparison substance) 250

It should also be noted that the compounds according to the invention, which are compounds belonging to a new body class with effects on the central nervous system, show a new, i.e. different mechanism of action than that of the prior art.

For the preparation of the compounds of general formula I, there are various synthesis options, from which the most advantageous by the following equation are shown.

3 0 9812/1215

Force1 V

Formula I.

Formula X

Formula XlI
M * hydrogen or

Alkali atom

C-C-OH

Formula XI

M ■ hydrogen or
Alkali atom

For: .el VIII

cn ω co

One of the methods of the formula scheme above is Cyclizing an o-sulfamylphenylacetic acid (formula IV), zxtfeckweise in the presence of a dehydration or Dehydrating agents, for example phosphorus pentachloride, thionyl chloride, polyphosphoric acid or a mixture of glacial acetic acid and anhydrous sodium acetate, optionally with the addition of acetic anhydride. The ones in the above Process used as starting materials compounds of formula IV by hydrolysis of either the corresponding Carboxamides (formula VI) or the corresponding nitrile (formula IX) can be obtained.

According to an advantageous embodiment of the invention is thus a process for the preparation of the compounds of the formula I, in which a compound of the formula IV in itself known manner with the escape of 1 molecule of water or a compound of the formula VI in a manner known per se with escape of 1 molecule - a compound of the formula R - NHp, wherein R is as defined above, is cyclized, provided.

According to another advantageous embodiment of the invention is a process for the preparation of the compounds • of the formula I, in which an amine of the formula R r NHp, wherein R is as defined above, in a manner known per se with an acid of the formula

-SO H

III

'G-C-OH

H _? II

^ά 0

309812/1215 _ η _

or a functional derivative thereof is condensed _v preferably the chloride of formula X, is provided.

According to a further advantageous embodiment of the Invention is a process for making the compounds of the formula I, in which a compound of the formula V is hydrolyzed in a manner known per se, is provided.

In the case of the compounds of the formula I in which R represents hydrogen, it is possible to replace this by a group in such a way that a compound of the formula I in which R is different from hydrogen is obtained. Μ to this end, the classical methods of alkylation and acylation can be used by imido groups. Therefore, according to a further advantageous embodiment of the invention, a process for the preparation of compounds of the formula I in which R is different from hydrogen, in which process a compound of the formula

Ia C = O

in a manner known per se with one to replace the hydrogen by the desired group R on the nitrogen atom capable connection is implemented.

It is also possible to create a group R by extending it an already existing chain of atoms on the stick

30981271215 - ⁸ -

substance atom of 3,4 — dihydro-3-oxo-2H-% 2-ben2othiazine-S- -dioxydes to form.

This is the case according to a further advantageous embodiment of the invention a process for the preparation of compounds of formula I, in which. R for a group of the * formula

Il

C-C-

II

in which latter R ₂ and Rz are as defined above, in which process is a compound of the formula

/
H - N, where R2 "and R ^ are as defined above, in

known per se with a carboxylic acid of the formula

Il

C-C

H ₂

VII

or a functional derivative thereof, preferably the chloride is condensed. For example, a group can have the formula

Ii

C-C-N

II

R-

9812/1215

where R ^ and R ^ are defined as above, by condensation of the 3i4-diydro-3-oxo-2H-1 ^ -benzothiazine-S-dioxide ^ -ylacetyl-

chlorides with an amine of the formula H-N, wherein R ^ and

R ₃ . as defined above.

The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

example 1

o (- (3,4-Dihydro-3-oxo-2H-1,2-benzothiazine-S- -dioxyd-2-yl) -Έ , N- (dimethyI) acetamide

Il

Pormel I with R = - G - C - N

H _P

There were 3.15 g (0.016 mol) of 3,4 ~ dihydro-3-oxo-2H- -1,2-benzothiazine-S-dioxide (I formula I with R = H) in 25 cm · ^ anhydrous acetone 2.1 g (0.01 mol) of K, N-dimethyl-c <-chloroacetamide in 10 cm ^ anhydrous acetone, 1.43 g (0.017 moles) sodium bicarbonate and a little potassium iodide admitted. It was stirred for 24 hours respectively Shake and low reflux heated to boiling. The solvent was evaporated, the residue was washed with Chloroform and water treated and the chloroform phase was separated, with 5 ^ -1SeI * sodium bicarbonate solution and with Washed water, dried and evaporated. By crystallizing the residue from a Mixture of ethanol and water / water were mixed with 3 S product

- 10 309812/1215

a melting point of 162 to 164 ⁰ C obtained.

The 3,4-dihydro- used as starting material above -3-OXO-2H-1,2-benzothiazine-S-dioxide (formula I with R = H) using one of the following procedures, j

a) It was a mixture of 1962 g (0.1 mol) 3,4-Dihydro-3-imino-2H-1,2-benzothiazine-S-dioxide (Formula V with R = H), 900 cm ^ water and 100 cm ^ a 0.1 η sodium hydroxide solution heated to boiling under reflux for 4 hours. After that it was decolorized ', filtered, cooled and acidified in the cold with concentrated hydrochloric acid. After this Left standing, 14 g of product with a melting point of 198 to 200 ° C were recovered. A analogous result was obtained by boiling the imino derivative for 8 hours (formula V with R = H) with the molar equivalent of Na ^ CO ^ in 0.1 molar Get solution.

b) There were 2.15 g (0.01 mol) of o-sulfamy! phenylacetic acid (formula IV with R = H) in portions in polyphosphoric acid (10 enr 85% H ^ PO ^, + 15 S Pp ^ ', - ) and then ^{heated to 10O 0} G for 1 hour. After cooling, the reaction mixture was poured into ice and allowed to stand in the cold, whereby

1.3 g of product with a melting point of

198 to 201 ⁰ G eliminated. Melting point after recrystallization from aqueous ethanol: 202 to 204 ° C.

In the above procedure a) as a starting material used 3,4-dihydro-3-imino-2H-1,2-benzothiazine-S- -dioxide (formula V with R = H) was obtained as follows:

There were 10 g (0.051 mol) of o-gyanmethylbenzenesulfonamide

309812/1215 - 11 -

(Formula IX with R = H) introduced in portions into 100 cm * concentrated sulfuric acid. The resulting solution was left to stand for 16 hours. After that, it was poured into ice, and the solid was collected and washed. Yield: 7.3 g. Melting point: 270 to 275 ° G; Melting point after recrystallization from aqueous ethanol: 280 to 283 ° CV

Analysis:
For GgHgN ₂ O ₂ S

calculated: N = 14.28%, S = 16.34%; found: N = 14.43%, S = 16.32%

In the above procedure b) as the starting material o ~ sulfamic acetic acid used (formula IV with R = H) was obtained as follows:

5 »5 g (0.028 mol) of o-gyanmethylbenzenesulfamide (formula IX with R = H) were refluxed for 3 hours in 85% sodium hydroxide solution. It was decolorized, filtered and acidified with concentrated hydrochloric acid. The product crystallized on standing in a refrigerator overnight. Yield: 4.7 g · Melting point: 175 to 180 ⁰ C. melting point after recrystallization from water: 185 his 187 ° C.

The o-gyanmethylbenzenesulfonamide (formula IX with R = H) used above as starting material was obtained as follows:

It was stirred or shaken in a

Solution of 18.1 g (0.12 mol) of o-gyanomethylbenzenesulfochloride

-χ
(Formula VIII) was introduced into 260 cnr benzene for 0.5 hour ammonia, with cooling by means of a water bath and ice. A suspension was obtained which

309812/1215 - 12 -

was filtered. The 6 ^{Θ88ι) Μηίϊ} 1 ^ ⁶ solid substance was stirred into a paste in water and finally recovered and washed again. Yield: 14 g. Melting point: 158 to 160 ° C.

The ο-cyanine used above as starting material t hy I-benzenesulfochloride (Formula VIII) was obtained as follows:

There were 28.7 β (0.17 mol) ^{o-aminophenylacetonitrile hydrochloride suspended in 115 cm 5 of} concentrated hydrochloric acid (prepared according to V. Rousseau and HG Lindwall, J. Am. Chem. Ooc. £ 2, 3 047 [1950]) 5 ° C with 11.8 g (0.17 mol) of sodium nitrate dissolved in 25 cnr VJaaser. At the end of the reaction, it was filtered quickly and the whole thing slowly poured into 170 cm of a 20% strength solution of SOp in acetic acid containing 1.5 _{U Cu 2} Clg. It was stirred or shaken for 1 hour at room temperature, poured into 450 cm * of water and the precipitated solid was recovered; this was dissolved in benzene and the organic solution was washed with water, dried and evaporated. The residue was collected and washed with slightly cold ligroin. Crude yield: 23 R. Melting Point: 107 to 109 ⁰ Cj melting point after recrystallization from a Hischung from ligroin and benzene: 109 to 111 ° C.

Analysis: C. .55% H = 2 , 88%, H = 16 , 24%, Cl = 6 , 49 For C ₈ II ₆ ClKO ₂ U C. , 58%, H α 3 , 16%, 16 Cl = 6 .65 * calculated: found: * 44 »44

- 13 309812/1215

COPY

Example 2

2-Allyl-3,4 ~ dihydro-3-oxo-2H-1,2-benzothiazine -

-S-dioxide

(Formula I with E = -CC = CH ₀ )

. ^H 2

A mixture of 7 »06 g (0.03 Hol) of the potassium salt of 3i ^z > -dihydro-3-oxo-2H-1,2-benzothiazine-S-dioxide (formula I with R = K), 3 , 63 g (0.03 mole) allyl bromide

3 ο

and 3 ° C. dimethylformamide at 65 to 70 ° C. for 6 hours and -p heated to 100 ° C for hour. The reaction mix was cooled, treated with a saturated solution of Na-CO-, extracted with chloroform, dried and the organic phase was evaporated. What was left as a cuckoo Oil was purified by fractional distillation under vacuum. Yield: 5 * 2 g. Boiling point: 157 to 160 ° C / 0.9 mm / Hg.

The potassium salt of 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-S-dioxide (formula I with R = K) used as starting material above was obtained by dissolving 3> 4 ~ dihydro- -3-OXO -2H-1,2-benzothiazine-S-dioxide (formula I with R = H) in methyl alcohol, addition of the equivalent of methanolic potassium carbonate solution, concentration to a small volume and recovery of the solid, which was dried at 100 ° C under vacuum , obtain. Melting point: 303 to 306 ⁰ C;

The 3 ^ -dihydro- used as starting material above -3-OXO-2H-1,2-benzothiazine-S-dioxide (formula I with H = H) was obtained as described in Example 1.

- 14 309812/1215

_ _ΑΛ copy

BAD Q

Example 3

2-ethyl-3,4-dihydro- 3-oxo-2H-1,2-benzothiazine-S -

-dioxide

(Formula I with R = - CpH ₅ )

A mixture of 2.43 g (0.01 mol) of o-ethyl

sulfamylphenylacetic acid (Formula IV with R = - CpH ₁ -), 4.5 g

7. <- y anhydrous sodium acetate and 40 cm glacial acetic acid heated to boiling for 7 hours. The reaction mixture was cooled and poured into ice, and the precipitated white solid was collected and washed. The latter was digested in aqueous bicarbonate solution and then recovered and dried. Yield: 1.5 S of crude product. Melting point 62 ° to 63 ° C, after recrystallization from petroleum ether 64 to 66 ⁰ C.

The o-ethylsulfamylphenylacetic acid used above as starting material (formula IV with R = - C ₂ H ₅ ) was obtained as follows:

-D '

There were added to 6.05 g (0.027 Hol) o-ethylsulfamylphenylacetonitrile (formula IX rait R = - C ₂ H ₅ ) 27O cm ^ of a 0.2 η sodium hydroxide solution and it was refluxed for 7 hours. It was decolorized with charcoal, filtered, cooled, acidified with concentrated hydrochloric acid, and the whole was left to stand in a refrigerator overnight. The solid was collected, washed with ice water, redissolved in aqueous sodium bicarbonate solution, filtered and reprecipitated with concentrated hydrochloric acid. Yield: 5.1 B- Melting point: 143-145 ° C

The o-ethylsulfamylphenylacetonitrile (formula IX with R = - CpH ₅ ) used above as starting material was

3098 17/1215 - 15 -

BATH ORIGINAL

copy

obtained as follows:

There were added to 18.1 cnr * (0.12 Hol) in 50 cm * chloroform suspended 30% igera (expressed as weight in Vclumkonzentration) aqueous ethylamine with stirring or shaking and maintaining a temperature of 20 to 30 ° C 12.07 g (0.056 mol) of o-cyanomethylbenzenesulfochloride (formula VIII) dissolved in 110 cnr * chloroform were added. After the addition had ended, stirring or shaking was continued for 3 hours, it was evaporated to dryness and the residue was taken up again in 150 cm- * of an η sodium hydroxide solution. It was treated with charcoal, filtered, cooled in ice and acidified with concentrated hydrochloric acid, whereby 10 g of product with a melting point of 63 to 66 ^° C. were obtained.

example

2 ~ Pror> yl ~ 3.4-dihydro-3-oxo-2H-1.2-benzothiazine- -S-dioxide

(Formula I with R = - η - CjHr,)

A mixture of 9.86 g (0.05 mol) 3, ^/ 4-dihydro--3-oxo-2H-1,2-benzothinzine-S-dioxide (formula I with H = H), 5.46 g (0.065 koi) Hatriumbicorbonat, 8 g (0.065 mol) of 1-Brorapropan and 120 cnr dimethylformamide eight hours heated to 7O ⁰ C for. The dimethylformamide was then evaporated off under reduced pressure, the residue was treated with a 7 ton aqueous sodium bicarbonate solution and with chloroform, and the organic phase was separated off, extracted with a 5 'sodium bicarbonate solution and with Wosser, dried and dried Dim- u3u Hücl:! -. t.;. nd νι.τ-remaining oil was reduced by fractional distillation

309817/1715

COPY BAD ORIGINAL

16 -

Vacuum cleaned. Yield: 5 g «boiling point; I50 to 155 ° C / O, 8 mm Hg. The residue in the still became solid on treatment with isopropyl ether; the firm one Fabric was obtained and crystallized from a mixture of hexane and benzene, with carbon decolorization, 1.1 g of the isomer J-propyloxy - ^ - H-i, 2-benzothiazine- -S-dioxide in the form of yellow melting at 95 to 97 ° C Get crystals.

The 3,4-dihydro- used as starting material above -3-OXO-2H-1,2-benzothiazine-S-dioxide (formula I with E = H) was obtained as described in Example 1 «,

Data of identification of end products of the formula I and of intermediates of Formulas I, IV and IX which have been produced according to the described in the preceding examples traversing enswe isen are summarized in the following Tables II to V.

- 17 30981? / 1215

- 17 Table II

N -

G = O

(X.
cc - E. Melting point in ⁰ C
respectively
Boiling point jn ° C / min Hg To the Kristalli
sation ver
turned lo
solvent Gross formula analysis H N S. % found C. H N S. κ, - CH _x 89 to 91 Ligroin C ₉ H ₉ NO ₃ S % calculated 4.29 15.18 51.47 4.41 4.91 κ -C ₂ H ₅ 64 to 66 Petroleum ether C ₁₀ H ₁₁ NO ₃ S C. 4.92 53.28 5.17 C " - η - G ₅ H ₇ 150 to 153 / 0.8 C ₁₁ II ₁₃ NO ₃ S 51.17 5.4-7 55.14- 5.62 - iso - C ₂ H _n
0 ( 90 to 91 Hexane G ₁₁ H ₁₃ NO ₃ S. 53.32 5f7 5.85
ι 13, ^ 0 54-, 88 5.14- 5.93 13.67 - η - C ^ H ₉ 43 to 44
158 to 159 / 0.9 Hexane / benzene C ₁₂ H ₁₅ NO ₃ S 55.21 5.97 56.96 SfO 55.21 56.89

σ> cn co co co

Continuation; of Table II

- R Melting point in ⁰ g
respectively
Boiling point in ° C / in Hg To the Kri
stalli
sation
use
detes
Solution
middle Gross formula analysis C. H N S. % found C. H 10.12 S. H
i
- C - C = CH ₀
H ₂ . 2 157 to 160 / 0.9 G ₁₁ H ₁₁ NO ₅ S. % calculated 55.68 4.67 55.71 ^ 5 C.
U
α Si ζ ⁰ "*
- C - C - II
H ₂ \
^ 'CF 162 to 164 Ethanol /
/Water _
51.05 5PO 9.92 51.22 5.14 N
■ Μ
N

co ο co co

- 19 Table III

C =

- R Melting point in ⁰ C To the Kristalli Gross formula analysis H Ή % found H N ■ use sation
detes solution
middle % calculated 3.58 7.10 'C 3,4-2 6.99 - H 202 to 204 Ethanol / water C ₀ H _n KO _x S
8 7 3 C. 48.03 48.72

(Ji cn

Ca) U)

co ο co eo

• - 20 -

Table IV

IX

—J
S3 - R. - H Melting point in ⁰ C
respectively
Boiling point in,
° C / mm Hg ■. To the Kri
stalli
sation
use
detes
Solution
middle Gross formula analysis H N S. % found N S. ■ "« «1
ro
cn - ^C 2 ^H 5 161 to 163 Ethanol /
/Water C ₈ H ₈ N ₂ O ₂ S % calculated 4.11 14.28 16.34 'C H 14.31 16.54 - iso - C ^ Hr ₇ 65 to 66 Benzene / Pe-
-trolether C ₁₀ H ₁₂ N ₂ O ₂ S C. 5.39 12.49 43.73 4.31 12.76 155 to 158 / 0.1 O ₁₁ H ₁₄ N ₂ O ₂ S 48.96 5.92 11.76 13.45 55.71 5.40 11.70 13.14 53.56 55.36 6.14 55.44

-

- 21 Table V

IV

Ϊ-5
"♦>, ■
• A - H - H Melting point
in ⁰ C Ztir Kri
stalli
sation
use
tes lo
solvent Gross formula G calculated H 21st N 51 analysis C. 63 Ό found τ [ 50 S. tv » 185 to 187 water G ₈ H ₉ NO ₄ S 44, 38 6, 76 44, 24 H 6th 06 - iso -i G _x H _n
5 7 144 to 146 water C ₁₀ E ₁₅ NO ₄ S. 64 5, 88 5, 44 S. 4-9, 30th 4.41 6th , 40 115.5 to 117 VJ ater C ₁₁ H ₁₅ NO ₄ S 51, 37 5, 5, 51, 5.11 5 12.53 54 6.06 12.46

Claims

Claims (1)

Claims N-substituted 3,4-dihydro-3-oxo-2H-1,2-benzothiazine-S-dioxide derivatives the general formula - R = O where R is an alkyl radical with 1 to 4 carbon atoms, an allyl radical or a radical of the formula .0 Il CC H ₂ .CH, II CH, stands. 2.) Medicines consisting of "compounds according to claim 1 and customary auxiliaries and carriers. 3 ·) Process for the preparation of the compounds according to claim 1, characterized in that an amine of the formula R - NH ₂ , in which R is as defined in claim, in a manner known per se with an acid of the formula 303812/1215 - 23 ORIGINAL BATHROOM III C-C-OH ^ 0 or a functional derivative thereof, preferably the chloride, condenses. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the formula wherein R is as defined in claim 1 per se known manner with the escape of 1 molecule of water or a compound of the formula 309817/1215 . - 24 - 5.) - 24- - wherein R is as defined in claim 1 per se "known method with leakage of 1 molecule of a Compound of the formula R - Iffi ^, in which R is as in Aisprudi 1 is fixed, cyclized. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the formula in the wherein R is as defined in claim 1, in itself hydrolyzed in a known manner. 6.) Process for the preparation of compounds according to claim 1, in which R is different from hydrogen is, characterized in that a compound of the formula HO Yes in a manner known per se with a replacement for the 3G981? / 1? Ir ~ 25 - Hydrogen through the desired group E am Reacts nitrogen atom capable compound. 7 ·) Process for the preparation of compounds according to claim 1, in which R is a group of the formula Ji C-G- II wherein R2 and R * are as defined in claim 1, stands, characterized in that one bond of the formula H-N, where R2 and R * as defined in claim 1, in a manner known per se with a carboxylic acid of the formula - C = O - OH VII or a functional derivative thereof, preferably the chloride, condensed. tr = i;