CA1159840A - 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention provides 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione derivatives of the following Formula II

II

wherein R3 and R4 independently of one another are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio or one of R3 and R4 are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, trifluoro-methyl or nitro and the other is hydrogen, with the proviso that R3 is not bromine when R4 is methyl, which are intermediates in the preparation of 3-amino-1-benzoxepin-5(2H)-one derivatives corresponding to the Formula I:

I

wherein: R1 and R2 independently of one another are hydrogen, C1-C5 alkyl, C1-C5 alkyl substituted with a terminal phenyl, or a phenyl containing one or two halogens, methyl or methoxy groups, a 3,4-methylenedioxy or a 3,4-ethylenedioxy group, C2-C5 alkyl, C2-C5 alkyl substituted with terminal hydroxy or methoxy or C3-C4 alkenyl; or one of R1 and R2 are hydrogen or a C1-C5 alkyl and the other is a C2-C5 alkyl substituted with a terminal NR5R6; R5 and R6 independently of one another are hydrogen or C1-C5 alkyl;
or R5 and R6 are together a 5 to 7 member ring, or R5 and R6 are together a 5 to 7 member ring having heterogeneous oxygen, sulfur or nitrogen; R1 and R2 are together a 5 to 7 member ring, or R1 and R2 are together a 5 to 7 member ring having heterogeneous oxy-gen, sulfur or NR7; R7 is hydrogen, methyl, benzyl or phenyl; and R3 and R4 are as above; and pharmaceutically acceptable acid addi-tion salts thereof, which are useful in the treatment of spasms of the stomach-intestinal tract.

Description

1 159~0 The present inven-tion relates to intermediates for use in the preparation of l-benzoxepin-5(2H)-one derivatives and their pharmaceutically acceptable salts thereof, as well as met-hods of their production. Copending application No. 357,544 from which this applieation is a divisional application discloses and claims certain pharmaceutieally aetive l-benzoxepin-5(2H)-one derivatives, their pharmaeeutieally aeceptable acid addition salts as well as to the proeess of producing these pharmaceutically ac-tive derivatives and pharmaceutically aceeptive aeid addition salts and the pharmaeeutieal eompositions themselves as well as to a method of using sueh compositions in therapy and more particu-larly, for the treatment of certain gastrointenstinal disorders and diseases.

It is known that a considerable number of gastroentero-logical complalnts are caused by functional disturbances. Disor-ders of the motility, more particularly of the stomach and its sphineters, have been reeognized more and more as the cause of various diseases and disorders of the gastrointestinal tract.
See, for instance, "Leber, Magen, Darm" (liver, stomach, intes-tines), Vol. 8, (1978), No. 4, pages 177 to 182 and pages 184 to 190, or, respectively, "Internist", Vol. 20, 1979, pages 10 to 17.

.~

I 1~9~40 More particularly, a pylorus incompetence which is made respon-sible for the duodeno-gastric reflux, is discussed extensively in connection with a search for the pathologic-physiological causes of various disturbances and disorders of the gastrointes-tinal tract. See, for instance, "Digestive Diseases", Vol 21, 1976, No. 2, pages 165 to 173. According to these discussions and publications, the reflux gastritis, the ulcus ventricu]i and duo-deni, as well as the sense of fullness, nausea, and epigastric pain without anatomically recognizable reasons are caused, or are complicated in their course by disorders of the gastric passage.

Heretofore, no satisfactory pharmaceutical agent for treating disorders of the gastrointestinal motility was known.

In said copending application No . 357,544, there is provided l-benzoxepin-5(2H)-one derivatives and their pharmaceu-tically acceptable acid addition salts as well as simple and ad-vantageous process of producing such 1-benzoxepin-5(2H)-one deri-vatives and their pharmaceutically acceptable acid addition salts.

The present invention provides intermediate compounds for the production of the pharmacologically active l-benzoxepin-5(2H)-one derivatives.

9~0 In principle, the invention of copending application provides the medical profession with 3-amino-1-benzoxepin-5(2H)-one derivatives having valuable pharmacological and therapeutic propexties.
Surprisingly, it was found that the compounds have a favorable effect upon gastric motility.

Thus, the invention of the copending application comprises 3-amino-1-benzoxepin-5(2H)-one derivatives of the following Formula I:
/

~ ~ o / ~ (I) R4 Rl wherein Rl and R2 independently of one another are hydrogen, Cl-C5 alkyl, Cl-C5 alkyl substituted with a terminal phenyl, or a phenyl containing one or two halogens, methyl or me-thoxy groups, a 3,4-methylenedioxy or a 3,4-ethylenedioxy group, C2-C5 alkyl, C2-C5 alkyl substituted with terminal hydroxy or methoxy or, C3-C4 alkenyl; or one or Rl and R2 are hydrogen or a Cl-C5 alkyl and the other is a C2-C5 alkyl substituted with a terminal NR5R6;

r ~ 3 -1 ~5~8~0 - f J

R5 and R6 independently of one another are hydrogen or Cl-C5 alkyl; or R5 and R6 are together a 5 to 7 member ring, or R5 and R6 are together a 5 to 7 member ring having heterogeneous oxygen, sulfur or nitrogen Rl and R2 are together a 5 to 7 member ring, or Rl and R2 are together a 5 to 7 member ring having heterogeneous oxygen, sulfur or NR7i R7 is hydrogen, methyl, benzyl or phenyl;
R3 and R4 independently of one another are hydrogen, halogen, Cl-C4 alkyl, Cl-C4 alkoxy or Cl-C4 alkylthio; or one of R3 and R4 is trifluoromethyl or nitro and the other is hydr~ge~
loJ,a~ n~c~ C~/~ ~C /~
15 and th~ acid ad~ition salts thereof.
Suitable lower alkyl groups and grouos comprislng the Rl and R2 moieties include both straight chain and branched chain lower alkyl groups of one to five carbon atoms. For example, methyl, ethyl, propyl, 20 isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, allyl, 2-butenyl, 3-butenyl and the like. Preferred are the compounds in which only one of the Rl and R2 groups is a substituted alkyl and the other is a hydrogen or Cl-C5 alkyl.
The above-mentioned specific alkyl groups containins one to five carbon atoms are also applicable for R5 and R6.
As examples of substitutions wherein alkyl groups are joined through a nitrogen atom, either 30 directly or-through a hetero atom are the following:
pyrrolidine, piperidine, azacycloheptane, m.oroholine, thiomorpholine, piperazine and homo-piperazine wherein it is possible to substitute the nitrogen with methyl, benzyl or phenyl. Preferred are the alkyl groups 35 joined in the form of five and six membered rings.

1 159~40 Substituents R3 and R4 on the phenyl ring may comprise the halogen atoms fluorine, chlorine, bromine and iodine. Especially preferred are fluorine, chlorine and bromine. The Cl-C~ alkyl portion of the lakyl, alkoxy or alkylthio groups can be s~raight chain or branched wherein the methyl groups are especially preferred with multi sub-StitUtiGns on the phenyl ring. Thus, methyl, methoxy, methylthio or methylenedioxy are preferred. Of one of the substituents is nitro or trifluoromethyl monosubstitution is preferred.

With substitution of the respective piperazine or homopiperazine and alkyl-NR5R6, the free bases isolated from the reaction mixture can be converted to their phy-siologically compatible acid addition salts by treatmentwith an inorganic or organic acid in the conventional manner.
As suitable acids for producing the acid addition salts, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, o-phosphoric acid, maleic acid, cyclohexylamino sulfonic acid, amido sulfonic acid or _-toluene sulfonic acid, are preferred.

The invention of the copending application also provides the method of producing the 3-amino-1-benzoxepine-5(2H)-one derivatives of Formula I:
R3;~ ~ / 2 wherein Rl, R2, R3, R4 are defined as above as well as the pharmaceutically acceptable salts. The method comprises reacting in an inert solvent the compound of the Formula II:

1 159~0 R ~ II

wherein R3 and R4 are defined as above, a) with an amine of the Formula III

Rl wherein Rl and R2 are defined as above, or b) reacting the 2,3,4,5-tetrahydro-1-benzoxepin-3,5-di-one derivative of Formula II with an acid halidë in an inert solvent to form the compound o~
Formula IV R

. 10 R ~ IV

wherein R3 and R4 are defined as above and X is chlorine or bromine, converting these by way of transposition with an amine of the Formula III into the compounds of Formula I, isolating the free base and, as desired, convert-ing to the acid addition salts or isolating the free base fror the acid addition salts.

The transformation of a compound of Formula II
or Formula IV with the amine of Formula III is conducted in a conventional manner. For example, the transposition of 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione derivative of Formula II with the amine of Formula III can preferably be achieved by the addition of catalytic quantity of inorganic and organic acids such as hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or formic acid. As suitable inert solvents chloroform, dichloromethane, benzene and toluene are mentioned. The reaction can be conducted in a temper-ature range of from 0 to 150C. The transposition can be carried out in an improvement by removal of the water formed during the reaction in the conventional manner.
Use of the compounds of Formula IV in the transposition reaction with the amine of Formula III can be effected in an inert solvent such as chloroform, dichloromethane, dimethyl-formamide dioxane and tetrahydrofuran at temperatures between -70C and ~50C. The reaction in this instance is conducted in the presence of an organic base such as tri-ethylamine or in excess quantities of the amine compound.

The new compounds of Formula IV can be producedby conventional techniques such that the 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dione derivative of Fnrmula II is reacted with a suitable acid halide. These acid halides may be, for example, a phosphor oxide halide, a phosphoric trihalide, thionyl chloride or especially, oxalylchloride. In the pxesence of an inert solvent, for example, dichloromethane ox dimethylformamide the transposition can be carried out in a temperature range of -20 to 80C. The reaction pro-duct which has been freed from excess acid halide and solvent can be employed for the reaction with the amine of the formula III.

35The present invention provides the 2,3,4,5-tetra-hydro-l-benzoxepin-3,5-dione derivatives of Formula II:

1 159~4~

3 ~ /

wherein R3 and R4 are defined as above which can be produced by a process comprising reacting the compound of Formula 10 V: O

3 ~ ~ ~ ~ CH3 V
R4 ~ ~ ~ ~ o-cH2-cooR8 wherein R3 and R4 are defined as above and R8 is straight chain or branched chain lower molecular alkyl group, pre-ferably a methyl group, in a strong base selected from the group consisting of lithium hydride, sodium hydride, lithium-tert.-butylate and potassium-tert.-butylate in the presence of an inert solvent at a temperature between -70C and the boiling point of the solvent. Suitable solvents are, for example, dimethylformamide and tetrahydrofuran.
Ice water can be mixed with the reaction mixture for subsequent treatment permitting the separation of the precipitated compounds of Formula II. The compounds of Formula II can also be separated from the by-products by precipitation from alkali salts, especially lithium salts, with an unpolar solvent, for example, toluene or petroleum ether. The free compounds can be recovered from the salts by means of an inorganic or organic acid, for example, a .

1 ~59~4~

water solution of hydrochloric acid, sulfuric acid or acetic acid.
It is surprising that with the use of the above-mentioned bases, for example, sodium hydride and 5 lithium-tert.-butylate, the compounds of ~ormulG II
can be obtained by closing of the ring structure of the compounds of Formula V. Only benzofuran derivatives can beobtained by cyclization of the 2'-acetylphenoxy-acetate wiff~ the conventionally used sodium ethylates 10 (see Journal of Organic Chemistry, Vol. 42, 1977, page 4265 as ~ell as Tetrahedron Letters No. 41, 1966, page 4995, paragraph 1). Only the 7-bromo-8-methyl substituted compound is known and the unsubstituted

2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione which has ; 15 been isolated, inter alia, upon hydrolysis of 2,3-dihydro-5-hydroxy-3-oxo-1-ber.zoxepin-4-carboxaldehyde (see Syn~hesis (1977) page 61 to 63). The substituted 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones of Formula II are, therefore valuable, ne~,~ intermediate products 20 and constitute part of the instant invention. For the production of 2,3,4,5-tetrahydro-1-ber.zoxepin-3,5-dione derivatives of Formula II, necessary 2'-acetyl-phenoxyacetates can be obtained from 2-hydroxyaceto-phenones in good yields such that in a simple manner 25 the manufacture of the pharmacologically interesting

3-amino-1-benzoxepin- 5(2H )-one derivatives of Formula I is achieved.

DESCRIPTION OF T~E P~EEERRED E`~BODIMENTS

The following examples are to illustrate the present invention. More particularly, the examples illustrate the processes of producing the novel 3-amino-1-benzoxepin-5(2H)-one derivatives of Formula I. These examples are given without in any manner limiting the inventionO

Example 1 A solution of 88 g (0.5 mole) 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dione and a spatula tip of p-toluene 10 sulfonic acid in 750 ml toluene are mixed while stirring with 44 g (0.5 mole) N,N-dimethylethylene-diamine and subsequently stirred to the end of the reaction at room temperature. After concentration of the solution, a product is obtained by filtering 15 off the solution under suction and subsequently recrystallizingfrom benzene/ligroin. 108 g (88% of the theoretical yield) of 3-(B-dimethylamino-ethylamino)-l-benzoxepin-5(2H)-one are obtained.
The melting point of this derivative is 100 to 101C.

20 Example 2 A solution of 17.6 g (0.1 mole) 2,3,4,5-tetra-hydro-l-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 200 ml dichloromethane are mixed while stirring with 6 g (0.1 mole) iso-25 propylamine and subsequently stirred to tne end ofthe reaction at room temperature. After concentration of the solution a product is obtained by filtering off under suction and by recrystallizing from butyl-acetate. 13.5 g (62~ of the theoretical yield) of 30 3-isopropylamino-1-benzoxepin-5(2H)-one are obtained.

`` 1 ~5~g40 ~11~

Example 3 Dimethylamine is introduced while stirring into a boiling solution of 52.8 g (0.3 mole) 2,3,4,5-tetra-hydro-l-benzoxepin 3,5-dione and a spatula tip of ~-toluene sulfonic acid in 225 ml toluene. The water of reaction is separated by a water separator.
After the reaction has ended, the solution is con-centrated, the remaining residue is filtered under suction and recrystallized from chloroform/ether.
42 g (69~ of the theoretical yield) of 3-dimethylamino~
l-benzoxepin-5(2H)-one are obtained. This compound displays a melting point of 136-136C.

Example 4 .~ethylamine is added with stirring to a boiling solution of 160 g (0.9 mole) 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dione and 1 ~1 formic acid in 500 ml dichloromethane. The water of reaction is removed by a water separator. After the enl of the reaction the solution is cooled with ice, the 3-methylamino-1-benzoxepin-5(2~)-one is filtered under suction and recrystallized from methanol. 140 g (81% of the theoretical yield) of this compound is obtained having a melting point of 176-178C.

Example 5 Ammonia is introduced with stirring to a boiling solution of 70.4 g (0.4 mole) 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dione in 400 ml chloroform. The water of reaction is separated in a water separator.
After completion of the reaction, the solution is cooled, the 3-amino-1-benzoxepin-5(2H)-one is 'iltered under suction and recrystallized. 60.5 g of the product (86% of the theoretical yield) is obtained. The product displays a melting point of 196-200C from chloroform.

`` 1 159~

Exam~le 6 -38.1 g (0.3 mole) oxalychloride is added to a solution of 35.2 g (0.2 mole) 2,3,4,5-tetrahydro-1-~enzoxepin-3,5-dione in 200 ml dichloromethane.
After fourteen hours at room temperature the solvent is removed and the remaining residual oil is dis-tilled. The distillation fraction obtained at 150-170C/3 m bar contains as the main product, 3-chloro-1-benzoxepin-5(2H)-one. This is recovered in 100 ml of chloroform. The resulting solltion is cooled with ice and mixed by dropwise addition under cooling with an excess of piperidine dissolved in dichloromethane. lhe solution is stirred to the com?letion of the reaction at 0C and subsequently cooled with ice followed by separation of the organic phase. Thereafter, the organic phase is washed with water, dried and evaporated. The 3-piperidino-l-benzoxepin-5(2H)-one is recrystzllized from ether.
19.3 g (40% of the theoretical yield, drawn from 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione) of the 3-piperidino-1-benzoxepine-5(2~)-one is obtained.
The compound displays a melting point 101-103C.

Example 7 According to the procedure of Examples 1 through 2S 6, the following compounds can be obtained in similar yields from 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and B,B-dimethyl-y-dimethylaminopropylamine, n-butylamine, benzylamine, morpholine, y-dimethylamino-propylamine, phenethylamine, diethylamine, pyrrolidine, B-methoxyethylamine, N-benzylpiperazine or tert.-butylamine derivatives of the l-benzoxepin-3,5-dione:

~ 159~

Melting Point C
3-(B,B-dimethyl-y-dimethylamino-propylamino)-l-benzoxepin-5(2H)-one ~ 113 3-(n-butylamino)-1-benzoxepin-5(2H)-one 120-122 3-benzylamino-1-benzoxepin-5(2H)-one 157-160 3-morpholino-1-benzoxepin-5(2H)-one 126-129 3-(y-dimethylamino-propylamino)-l-benzoxepin-5(2~)-one 118-120 10 3-phenethylamino-1-benzoxepin-5(2H)-one 180-182 3-diethylamino-1-benzoxepin-5(2H)-one 95- 96 3-pyrrolidino-1-benzoxepin-5(2H)-one 118-122 3-(B-methoxyethlamino)-l-benzoxepin-5(2H)-one108-110 3-(N-benzylpiperazino)-l-benzoxepin-5(2H)-one132-135 15 3-(tert.-butylamino)-1-benzoxepin-5(2H)-one oil IR (CH2C12) 1605 cm 1 1 ~598~

Exæmple 8 According to the procedures of the foregoing examples and by known techniques the following:
2,3,4,5-tetrahydro-7-fluoro-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7-nitro 1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7,8-dichloro-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7,8-dimethyl-1-benzoxe?in-3,5-dione, 2,3,4,5-tetrahydro-7-bromo-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7-methoxy-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-8-methoxy-l-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7-chloro-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-8-chloro-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7-methyl-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-7-ethyl-1-benzoxepin-3,5-dione, 2~3~4~5-tetrahydro-8-methyl-l-benzoxepin-3l5-dione~
2,3,4,5-tetrahydro-7-chloro-8-methyl-1-benzoxepin-3,5-dione, 2,3,4,5-tetrahydro-8-tert.-butyl-1-benzoxepin-3,5-dione, and me.~hylamine, dimethylamine or Y-dimethylamino~ropyl-amine derivatives of these compounds are employed to produce the following compounds Meltinq ~oint C

3-methylamino-7-fluoro-1-benzoxepin-5(2H)-one ~ 0.25 H2O) 216-219 3-methylamino-7-nitro-1-benzoxepin-5(2H)-one 200 3-methylamino-7,8-dichloro-1-benzoxepin-5(2H)-one 238-241 3-methylamino-7,8-dimethyl-1-benzoxepin-5(2H)-one 218-222 3-methylamino-7-bromo-l-benzoxepin-5(2H)-one 200-202 3-methylamino-7-methoxy-1-benzoxepin-5(2H)-one 169-172 3-methylamino-8-methoxy-1-benzoxepin-5(2H)-one 211-214 1 15~'1V

3-methylamino-7-chloro-1-benzoxe~in-5(2~)-one 136-198 3-methylamino-8-chloro-1-benzoxepin-5(2H)-one 204-208 3-methylamino-7-methyl-1-benzoxepin-5(2~)-one 178-180 3-methylamino-7-ethyl-1-benzoxepin-5(2H)-one 181-183 3-dimethylamino-8-chloro-1-benzoxepin-5(2~)-one 126-129 3-(y-dimethylamino-propylamino)-7-chloro-l-benzoxepin-5(2~)-one hydrochloride 206-208 3-methylamino-7-chloro-8 methyl-l-benzoxepin-5(2H)-one 229-234 3-methylamino-8-methyl-1-benzoxepin-5(2~)-one 182-184 3-methylamino-8-tert.-butyl-1-benzoxe~in-5(2H)-one 195-196 xample 9 30.1 g (1 mole) of sodium hydride (80% in oil) is added at -20~ in small portions to a cooled solu-tion of 242 g (1 mole) (2'-acetyl-4'-chloro) phenoxyacetic acid-methyl ether in 300 ~1 dimethyl-formamide. The addition proceeds such that the temperature is not allowed to rlse above -10C.
Subsequently, after stir-ing for 45 minutes at -15C, the solution is care~ully poured into ice water and extracted with toluene. After acidification or the water pnase, the precipi~ated product is filtered under suction and recrystallized from cyclohexane/
toluene. 126 g of 2,3,4,5-tetrahydro-7-chloro-1-benzoxepin-3,5-dione are obtained. This compound displays a melting point of 131-134C. The yield is 60~ of the theoretical yield.

Example 10 8.8 g ~0.11 mole )lithium-tert.-butylate in 50 ~.1 dry tetrahydrofuran under cooling is added to a solution of 28.7 g (0.1 mole~ (2'-acetyl-4'-bromo) phenoxyacetic acid methyl ester in 150 ml dry tetra-hydrofuran. The addition proceeds so that the temperature ~ 159~0 is maintained between 25 to 35C. Subsequently, the suspen-sion is poured into 400 ml petrolether and the precipitated lithium salt of 2,3,4,5-tetrahydro-7-~romo-1-benzoxepin-3,5-dione is filtered under suction. These salts are poured into a mixture of 150 ml of water and 11 ml of hydrochloric acid (32%). The'precipitated product is filtered under suction, dissolved in dichloromethane, washed in a saturated sodium chIoride solution, dried over sodium sulfate, eva-porated and recrystallized from cyclohexane. 11.7 g (46 of thé theoretical yield~ of 2,3,4,5-tetrahydro-7-bromo-l-be'nzoxepin-3,5-dione are obtained. The compound displays a melting point of 110-112C.

Ex'ample 11 According to the procedure defined in Examples 9 and 10, the following compound can be subjected to treat-ment with sodium hydride and lithium-tert.-butylate respec-tively:

t2'-acetyl-4'-methyl)-phenoxyacetaic acid-methylester, (2'-acetyl-5'-methyl)-phenoxyacetic acid-methylester, (2'-acetyl-5'-chloro)-phenoxyacetic acid-methylester, (2l-acetyl-4'-fluoro)-phenoxyacetic acid-methylester, t2'-acetyl-4'-methoxy)-phenoxyacetic acid-methylester, t2'-acetyl-5'-methoxy)-phenoxyacetic acid-methylester, (2'-acetyl-4',5'-dichloro)-phenoxyacetic acid-methylester, t2'-acetyl-4'-chloro-5'-methyl)-phenoxyacetic acid-methylester, t2'-acetyl-4',5'-dimethyl)-phenoxyacetic acid-methylester, 3Q t2l-acetyl-5'-tert.-butyl~-phenoxyacetic acid-methylester, t2'-acetyl-4'-ethyl)-phenoxyacetic acid-methylester, 2'-acetyl-phenoxyacetic acid-methylester, 59~V

Upon such treat~ent, the lollowing compounds are obtained in yields similar to that of Examples 9 and 1 0 :
l~elting oint C
2,3,~,5-tetrahydro-7-methyl-1-benzoxepin-3,5-dione 124-127 2,3,4,5-tetrahydro-8-methyl-1-benzoxepin-3,5-dione 97~ 98 10 2,3,4,5-tetrahydro-8-chloro-1-benzoxepin-3,5-dione 152-154 2,3,4,5-tetrahydro-7-fluoro-1-benzoxepin-3,5-dione 138-140 2,3,4,5-tetrahydro-7-methoxy-1-benzoxepin-3,5-dione 101-102 2,3,4,5-tetrahydro-8-~ethoxy-1-benzoxepin-3,5-dione 125-127 2,3,4,5-tetrahydro-7,8-dichloro-1-benzoxepin-3,5-dione 168-170 20 2,3,4,5-tetrahydro-7-chloro-8-methyl-1-benzoxepin-3,5-dione 172-174 2,3,4,5-tetrahydro-7,8-dimethyl-1-benzoxepin-3,5-dione 117-118 2,3,4,5-tetrahydro-8-tert.-butyl-1-benzoxepin-3,5-dione oil IR(CH2C12):1676, 1738 cm 2,3,4,5 tetrahydro-7-ethyl-1-benzoxepin-3,5-dione 74~75 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione 83-86 30 2,3,4,5-tetrahydro-7-nitro-1-benzoxepin-3,5-dione 138-139 1 1~98~0 UTILITY P~D TESTS
As stated above, it is an important feature of the present invention .o provide the medi-cal profession with novel and highly effective therapeu~ic agents for restoring physiological motility and unimpeded passage of food through the stomach.
The new compounds and their acid addition salts provide these results. All of them show the retarding and regulating effect with spasms of the smooth 10 musculature in the stomach intestinal canal.
Painful abdominal sicknesses are frequently brought about by spasms in the gastrointestinal canal musculature. The treatment of these spasms are, therefore, the objectives of the numerous spasmolytic 15 working medicaments. Above all, the parasympathicolytica have applied already for many years. The unsatisfactory selectivity of their activity makes their application only suitable within narrow parameters. Above all, undesirable side effects such as dryness of the mouth, 20 impairment of vision and fluid retention prohibit the application of the previously known medicaments in sufficiently high doses.
It has now been surprislngly found that the 3-amino-1-benzoxepin-5(2H)-one derivatives of Formula 25 I produce a specific desired retarding and regulating effect ~lithout the chemical or pharmacolosical dis-advantages of the above-mentioned side effects.

3escription of the Pharmacological Test Methods:
1. Determination of Acute Toxicity The acute seven-day toxicity is determined by intraperitoneal administration OL a single dose of the respective compound to a fasting white ~Jl~I mouse.
The LD50-values are calculated via electronic data processing by a probit analysis as described in the boo~

1 1 5 ~ 8 Ll (~

"Grundbegriffe der Biometrie" (Basic ~iometrical ~efinitions) by L. Cavalli-Sforza, page 153 et seq., published by Gustav Fischer Verlag, Stuttgart, 1964.
2. Testing of the Gastric Peristalsis To determine the functioning of the gastric peristalsis, rats weighing about 200 g are narcotized by means of ketamine hydrochloride and xylazine. A
catheter is introduced into the Vena jugul~ris of the narcotized rats and a tracheal catheter into ~he trachea. A stomach probe is inserted into their stomach and tied thereto. The probe is connected via a three-way cock with a Statham pressure imparting device (P 23 DB). The stomach is sealed off by a ligature at the pylorus and at the cardia. The stomach ls filled with 3 ml of a 0.9% aqueous sodium chloride solution. The pressure waves oroduced by the stomach are continuously registered by a suit-able recording device such by a ~Jatanabe rlulticorder (MC 641).
In conducting the test, a control value is obtained by inducing a stimulation of the stomach through a lengthy intravenous infusion of 50 mg/kg/h of bariumchloride and the amplitude and frequency of resultant pressure waves are measured. Subse~uently, in order to determine the pharmacological effects, the compounds to be tested are dissolved in ohysiologica~
sodium chloride solution or are suspended in Tylose MH7 50 solution. The solutions or suspensions are then administered intraoeritoneally to the rats in a dose of 20 mg/kg. The amplitudes and frequencies of the pressure wave-like move~ents of the stomach as they occur with the test solution and after administration of the compound to be tested, are compared.

1 1~98~
.

Shortly after administration of the compounds according to the present invention evaluation of the test resul~s shows that the perist~ltic move-ments of the stomach are reduced, ~hich is manifes~ed by a significant reduction in the amplitudes.
The frequency is varied only in small .
e~ as shown in the table which follows. The low toxicity of the substances ensure a good compatibility of the same. A further advantage is the observed 10 rapid onset of activity produced by the novel substances.
The following 3-amino-1-benzoxepin-5(2H)-one compounds ~ere tested according to thesemetho~s:
A) 3-methylamino-1-benzoxepin-5(2H)-one B) 3-methylamino-8-chloro-1-benzoxepin-5(2H)-one C) 3-isopropylar.lino-1-benzoxepin-5(2Y)-one D) 3-amino-1-benzoxepin-5(2H)-one E) 3-(n-butylamino)-1-benzoxepin-5(2H)-one F) 3-phenethylamino-1-benzoxepin-5(2H)-one G) 3-(N-benzylpiperazino)-l-benzoxepin-5(2H)-one H) 3-morpholino-1-benzoxepin-5(2H)-one I) 3-(~-methoxyethylamino)-1-benzoxepin-5(2H)-one ~) 3-methylamino-8-methyl-1-benzoxepin-5(2H)-one L) 3-~ethylamino-7-methyl-1-benzoxepin-5(2Hj-one ~1) 3-methylamino-3-tert.-butyl-1-benzoxe~in-5(2H)-one N) 3-methylamino-7-chloro-1-benzoxepin-5(2H)-one o) 3-methylamino-7-fluoro-1-benzoxepin-5(2H)-one 1 159~

T A B L E

~EASUREMENT OP THE GASmRIC PRESSU~E

. _ . . . .. _ . .
Compound Decrease in Amplitude Frequenc~ LD 0 i.p.
Tested % Change(~g/k5) *
in %
.

E 26 ~36 442 P 29 - 7 n.b G 31 +10 634 H 12 +1? 650 I 46 +11 n.b X 55 + 4 n.b L - 75 +15 n.b M 72 +10 n.b N 46 - 1 n.b 0 37 + 1 n.b n.b. indicates test results are not known.

1 1598~0 The pharmacologically observed eCfects clearly indicate tnat the compounds according to the Eresent invention provide a favorable influence over the various spastic conditions in the stoma_h-intestinal canal as well as the other components of the digestive system.
Suitable pharmaceutical preparations according to the present invention contain, as ef.ective agents, the ~-amino~ enzoxepin-5(2H)-one derivatives of Formula I or their pharmacologlcally compatible acid addition salts in combination with conventional pharmaceutically acceptable excipients, such as carrier materials and/or diluents. The resulting pharmaceutical preparations can be administered orally or parenterally. Suitable preoarations are in the form of tablets, capsules, lozenges, sirups, dry powders, injectable or infusible solutions or suspensions. They can also be prepared and adr:linistered in the form.
of suppositories. The preferred preparations are those which can be orally administered.
The dosage to be administered of the pharmaceutical compounds according to the present inven,ion is de-pendent on various ac~ors, such as the kind and the seriousness of the disease or the compound to be administered. In general asingle dose of between 1 mg and 50 mg and preferably between 2 mg and 20 mg, administered orally, is sufficient to achieve satis-factory results.
The following example illustrates the preparatior.
of an orally administrable composition without, however, being limited thereto.
Exam~le 12 -Capsules containing 3-methyl amino-1-benzoxepin-5-(2H)-one as the active compound.

~ 15g~'10 Each capsule contains an intimate mixture of the following ingredients:
Pharmacologically Active Compound 1~ mg Lactose 65 mg Dried Corn S~arch 40 mg Soluble Starch 4 ~g ~agnesium stearate 1 ma Total Content of Each Capsule 120 mg Production Method:
The pharmacologically active compound is mixed with the lactose and dried corn starch. The resultant mixture is thoroughly wetted with a 15% aqueous solu-tion of the soluble starch and granulated. The damp mass is passed through a 1.6 mm sieve, dried at 40C and finally passed through a 1.0 mm sieve. The resulting mixture is encapsuled in amounts of 120 mg after the mixing of the granulates with magnesium stearate. In this fashion, each capsule contains 10 mg of the pharmacologically active compound.
23 Of course, many changes and variations in the process of producing the compound of Formula I
according to the present invention and of their acid addition salts, in the reactants and solvents used, in the reac~ion conditions, temperature, pressure and duration, in the manner of working up the reaction mixture and of isolating and purifying the resulting reaction products, in the preparation of pharmaceutical compositions containing said 3-amino-1-benzoxepin-5(2H)-one derivatives and their acid addition salts, in the method of administering said pharmaceutical compositions for the treatment of motility disorders of the gastrointestinal tract, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione derivatives of the following Formula II

II

wherein:
R3 and R4 independently of one another are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkylthio; or one of R3 and R4 is trifluoromethyl or nitro and the other is hydrogen;
which comprises the step of converting a compound of the Formula V

V

wherein R3 and R4 are defined as above and R8 is a straight chain or branched lower molecular alkyl with a strong base selected from the group con-sisting of lithiumhydride, sodiumhydride, lithium-tert.-butylate in the presence of an inert solvent at a temperature of between -70°C and the boiling point of the solvent to produce the 2,3,4,5-tetra-hydro-1-benzoxepin-3,5-dione derivative of Formula II.

2. The process of Claim 1, wherein R8 is methyl.

3. A process for preparing 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione derivatives of the following Formula II

II

wherein R3 and R4 independently of one another are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio or one of R3 and R4 are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, trifluoromethyl or nitro and the other is hydrogen, with the proviso that R3 is not bromine when R4 is methyl, which comprises the step of converting a compound of the Formula V

V

wherein R3 and R4 are defined as above and R8 is a straight chain or branched lower molecular alkyl with a strong base selected from the group con-sisting of lithiumhydride, sodiumhydride, lithium-tert.-butylate in the presence of an inert solvent at a temperature of between -70°C and the boiling point of the solvent to produce the 2,3,4,5-tetra-hydro-1-benzoxepin-3,5-dione derivative of Formula II.

4. 2,3,4,5-tetrahydro-1-benzoxe-pin-3,5-dione derivatives of the following Formula II

II

wherein R3 and R4 independently of one another are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio or one of R3 and R4 are halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, trifluoromethyl or nitro and the other is hydrogen, with the proviso that R3 is not bromine when R4 is methyl, whenever prepared by the process of Claim 1, 2 or 3.