DE2512510A1 - NEW ORGANIC COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION - Google Patents

Description

SAN! DQZ - PATE NT-GMBH Case 600-6638

7850 Loerracn

New organic compounds and processes for their

Manufacturing

The invention relates to new 5-amino-7-phenyl-2,3-dihydro lH-l _/ 4-diazepines of the formula I,

R-

wherein either R. for hydrogen, an alkyl group with

1-6 carbon atoms or an amino group, and R _{2 represents} hydrogen or an alkyl group

1-6 carbon atoms, with the proviso that (1) R ₁ and R are not t-alkyl groups at the same time, and (2)

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if R- is an amino group, R is hydrogen,

or R ₁ and R- together for the groups

^CH 2 ~ ^CK 2 ^CH 2 ~ ^CH 2

stand,

_{and R 1} , R and R 1. independently represent hydrogen, an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, fluorine, chlorine or bromine, or two of the substituents R, R. and R, which are on adjacent carbon atoms, represent one Methylenedioxy group stand, as well as processes for their preparation.

The compounds of the formula I can occur in the form of free bases and in the form of acid addition salts.

The compounds of the formula I can likewise occur in the form of their tautomers of the formula I 'and, if R _{2 is} hydrogen , of the formula I ″.

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I "

The tautomeric forms are subject to a counter->. lateral conversion in the presence of acid. For the sake of simplicity, however, the following only refers to the form of the formula I or its chemical designation is referred to, but the subject matter of the invention is not intended be limited to this tautomeric form alone.

According to the invention one arrives

a) to compounds of the formula I by adding compounds of the formula II,

II

where R_, R. and R have the above meaning,

and R ^{1 represents} a primary or secondary alkyl group

with 1-4 carbon atoms, preferably methyl or ethyl

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with amines of the formula III,

Mtip TJ TTT

JNtIK. Xv_ XXJ.

wherein R ₁ and. R _{2 have the} above meaning, b) to compounds of the formula Ia,

Yes

and R ₁ 'for an alkyl group with 1-6 carbon

where R_, R. and Rj. have the above meaning, for an alkyl
atoms stands,

by adding compounds "of the formula IV,

where R ', R, R. and R have the above meaning, under strongly acidic conditions in the presence of an inert organic solvent and in an inert atmosphere cyclized,

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c) to compounds of the formula Ib,

Ib

wherein R_, R. and R ₁ . have the above meaning,

by heating compounds of the formula Ia in which R ₁ " ^{1 is} t-butyl in the presence of free acid. or

d) to compounds of the formula Ic,

NHKH,

Ic

where R, R and R_ have the above meaning,

by reacting compounds of the formula Ia or Ib with hydrazine in an inert atmosphere.

Process a) can be carried out in the presence of an inert solvent, in which case 1.05 to 10 moles of the compound of the formula III are used per mole of the compound of the formula II. Preferably, however, serves a large excess of the amine of the formula III, for example

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wise from 2 to 1000 moles per mole of the compound of formula II as a solvent. If ammonia or a volatile amine with a boiling point below 60 ° C. is used , the reaction is preferably carried out in a sealed reaction vessel. Suitable reaction temperatures are 20 to 115 ° C, preferably 60 to
115 ° C. If the compound of the formula III boils in the last-mentioned range, it is expedient to work with
Reflux temperature of the reaction mixture and preferably in an inert atmosphere, for example nitrogen. The reaction times are between 5 minutes and 3 hours, preferably 10 minutes to 2 hours.

Suitable solvents in process b) are low
Alkanols, for example ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and isobutanol, are preferred
Ethanol, n-propanol or isopropanol, halogenated
lower alkanes, for example 1,1,2-trichloroethane or 1,2-dichloroethane, cyclic ethers such as p-dioxane, acyclic ethers, preferably with 5-10 carbon atoms, and formic acid amides, for example formamide and its mono- or di-lower alkyl -Derivatives, for example
N-ethylformamide, Ν, Ν-dimethyl or diethyl formamide
or N-ethyl-N-methylformamide. The preferred solvents are lower alkanols. The acids used in process b) include strong mineral acids, for example perchloric acid, hydrobromic acid, hydrochloric acid or sulfuric acid, and strong organic acids such as

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Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. The acid is conveniently as a concentrated aqueous solution, as a solution in an organic solvent, for example a lower alkanol, such as ethanol, n-propanol or iscpropanol, or in undiluted form. For example, the perchloric acid is expedient as a 70% aqueous solution, hydrochloric acid and hydrobromic acid as saturated solutions of gaseous hydrogen chloride or hydrogen bromide in a lower alkanol, the sulfuric acid as a concentrated solution and the sulfonic acids conveniently used as solids. So much acid is used that the pH of the medium is 0.6 to 6, preferably 1 to 4, in particular 2 to 3. Appropriately, nitrogen is used as the inert atmosphere. That The process is expediently carried out at temperatures of 45 to 120.degree. C., preferably 55 to 100.degree. The reaction times are expediently 30 to 180 minutes, preferably 60 to 120 minutes.

In process c), the compounds of the formula Ia in which R ^ ^{1 is} t-butyl are expediently heated above their melting points in the presence of free acid until the evolution of gas bubbles has ceased. The use of acid addition salts, the anions of which tend to decompose at elevated temperatures, should be avoided. Preferably the connection is in shape

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of the methanesulfonate acid addition salt. The acid addition salt can be used as such or in situ from the free base by adding at least some more than one equivalent, for example 1.01 to 5 equivalents, of an acid are produced. Suitable Reaction temperatures are from 150 to 210 ° C, and suitable reaction times are between 5 and 45 minutes. The reaction is preferably carried out without a solvent. If desired, however, can high-boiling, inert organic solvents can be used.

In process d) the hydrazine is preferably used in anhydrous form. An excess of the hydrazine, for example a 10 to 1000-fold excess _r, which serves as the solvent, is preferably used. Suitable reaction temperatures are between 80 ° C. and the reflux temperature of the hydrazine The reaction can, if desired, also be carried out in the presence of an inert organic solvent, the boiling point of which is above 80 ° C. In this case, 1 to 2 moles of hydrazine are expediently used per mole of the compounds of the formula Ia or Ib are used. Suitable reaction times are between 20 and 180 minutes, preferably 30 to 60 minutes. The reaction is carried out in an inert atmosphere, for example nitrogen.

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The compounds of the formula I obtained according to the invention can be isolated and purified in a manner known per se. The compounds of formula I can in per se are converted into their acid addition salts in a known manner and vice versa.

The compounds of the formula II used as starting compounds in process a) can be obtained by Compounds of formula V,

wherein R ~, R ₄ and R, - have the above meaning, with trialkyloxonium tetrafluoroborate in an inert organic solvent. Of the tetrafluoroborates, the trimethyloxonium and triethyloxonium are. tetrafluoroborate preferred. Halogenated lower alkanes, preferably methylene dichloride, are suitable as inert organic solvents. The reaction can be carried out at temperatures from 0 ° to 30 ° C, preferably at 20 to 25 ° C. The reaction time is expediently 25 to 120 minutes. The reaction is preferably carried out in an inert atmosphere, for example nitrogen. The compounds of the formula II can be isolated and purified in a manner known per se.

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The compounds of the formula IV used as starting compounds in process b) can be prepared by using compounds of the formula VI,

VI

where R ', R-, R. and R_ have the above meaning, and A® means an anion that is not involved in the reaction,

with ethylenediamine in an inert organic solvent implements.

Suitable anions A ~ are perchlorate tetrafluoroborate, Methyl sulfate, ethyl sulfate, bisulfate, chloride, bromide and iodide. Halogenated alkanes, for example methylene dichloride, are suitable as inert organic solvents Ethers, for example p-dioxane; lower alkyl nitriles, for example acetonitrile and substituted Amides, for example Ν, Ν-dimethylformamide, are preferred Methylene dichloride. The molar ratio of ethylenediamine to the compound of the formula VI is preferably at least 1.5: 1, but in particular a large molar excess, for example from 2 to 10 mol Ethylenediamine is used per mole of the compound of the formula VI.

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The reaction is conveniently carried out at temperatures from -10 to + 40 ° C, preferably +10 to + 35 ° C, for a time between 20 and 120 minutes, preferably The reaction is preferably carried out in an inert atmosphere, for example nitrogen carried out.

The compounds of the formula IV can be isolated and purified in a manner known per se, but they can processed further without isolation according to method b).

The compounds of the formulas V and VI are either known or can be prepared in a manner known per se.

The compounds of formula I are characterized by pharmacodynamic Properties. They are particularly effective against obesity and have an anti-diabetic effect, so that they are suitable for the treatment of obesity and diabetes.

The daily dose to be administered is between 75 and 2000 mg, conveniently administered in several partial amounts between about 20 and 1000 mg, 2-4 times a day or in sustained release form.

The compounds of the formula I can be in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts are used, the salts being of the order of magnitude have the same effectiveness as the corresponding free bases. Suitable acid addition salts

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are the perchlorates, hydrochlorides, methanesulfonates and tetrafluoroborates.

The compounds of the formula I can be mixed with customary, pharmaceutically acceptable diluents or carriers mixed and administered in the form of tablets or capsules.

In the compounds of the formula I, the following substituents R ₁ to Rj. Are preferred:

R. = hydrogen, or alkyl, especially t-butyl; R ₂ = hydrogen;

R_ = hydrogen, p-methyl, p-methoxy, p-ethyl or p-ethoxy; especially hydrogen, p-methyl or p-methoxyf

R. = hydrogen or m-methyl;
Rj. = Hydrogen.

Of the compounds of the formula I, preference is given to those in which R 1 to R _{5 have} the meanings mentioned above as being preferred. 5-Amino-7-phenyl-2,3-dihydro-1H-1,4-diazepine is particularly preferred, very particularly as methanesulfonate.

The invention is illustrated in more detail by means of the following examples.

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Example 1: 5-methylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (VII)

A) S-Aethox ^ -T-ghenYl-g ^ S-dihYdro-lH-l ^^ - diazegin

10.0 g (53.0 mmol) of 7-phenyl-1,2,3,4-tetrahydro-1,4-diazepin-5-one are suspended under nitrogen in 100 ml of dry methylene chloride. Become the stirred suspension 10.1 g (53.0 mmol) of triethyloxonium tetrafluoroborate were added over the course of 20 minutes so that the reaction mixture remains at a temperature of 20 to 25 ° C (the reaction is slightly exothermic). After the addition is complete the reaction mixture for a further 30 minutes at room temperature touched. The mixture is then evaporated to give 16.6 g of oily crystals. By rubbing of the solid in ethyl acetate and recrystallization from chloroform gives 5-ethoxy-7-phenyl-2,3-dihydrolH-1,4-diazepine as a tetrafluoroborate of m.p. 157.5-158.5 ° C

B) 5-MethYlamino37-2henYl-2 ^ 3-dihYdro-1H-l _x 4-diaze2in (VII)

3.20 g of 5-ethoxy-7-pheny1-2,3-dihydro-IH-I, 4-diazepine tetrafluoroborate and 15 to 20 ml of methylamine are placed in an autoclave and left to stand for 1 1/2 hours. The reaction mixture is then heated to 40 to 50 ° C. for 1 1/4 hours to complete the reaction. The excess methylamine is evaporated, the oil obtained is dissolved in chloroform, the solution is filtered and evaporated. The residue is crystallized from isopropanol / ether, then in 5%

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Dissolved methanol / chloroform, filtered through silica gel and recrystallized from isopropanol / ether, whereby one to 5-methylamino-7-pheny1-2,3-dihydro-IH-1,4-diazepine tetrafluoroborate of m.p. 121.5-12 3 ° C.

Example 2: 5-n-Butylamino-7-pheny1-2,3-dihydro-IH-1,4-diazepine (VIII) [method a)]

2 g (6, Ό7 mmol) of the compound obtained in Example 1 A) and 10.0 ml of n-butylamine are heated to boiling (reflux) under nitrogen for 5 minutes and that excess n-butylamine evaporated under reduced pressure. The oil obtained in this way is dissolved in 50 ml of chloroform dissolved, the solution washed with 50 ml of water and treated with 50 ml of cold 2N aqueous sodium hydroxide solution. The chloroform solution is dried with anhydrous magnesium sulfate and with a 70% perchloric acid solution acidified in isopropanol. The solvent is evaporated. Trituration with water (1.8 g) gives By-product crystals. The mother liquor becomes too. evaporated with an oil and triturated with ether while cooling, the 5-n-butylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine perchlorate is obtained from m.p. 59-64 ° C.

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Example 3; 5-dimethylamino-7-phenyl-2,3-dihydro-lH-l _f 4-diazepine (IX) [method a)]

Analogously to Example 1 B) and using appropriate starting compounds, which are heated to 100 ° C. for 20 After heating for minutes in an autoclave, 5-dimethylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine tetrafluoroborate is obtained of m.p. 126.5-128.5 ° C.

Example 4; 5-pyrrolidino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (X) [method a)]

3.8 g of the compound obtained in Example 1 A) are dissolved in 10 ml of pyrrolidine and the solution under nitrogen heated to boiling (reflux) for 10 minutes. The excess pyrrolidine is evaporated and the oil obtained dissolved in about 10 ml of isopropanol. About 20 ml of dry ether are added to the solution and the crystals obtained are added recrystallized from isopropanol, resulting in 5-pyrrolidino-7-phenyl-2,3-dihydro-1H-1, 4-diazepine tetraf luoro * - borate of m.p. 139.5-140.5 ° C.

Example 5: 5- (N'-2-HydroxyäthyIpiperazino) -7-pheny1-2 , 3-dihydro-1H-1,4-diazepine (XI) [method a)]

3.1 g of the compound obtained in Example 1 A) and 2.1 g of freshly distilled N- (2-hydroxyethyl) piperazine are during Heated to 100 ° C for 1 hour. After cooling, the reaction product is applied to 100 ml of silica gel using various Methanol / chloroform mixtures as eluents

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chromatographed. The one containing the reaction product Fraction is recrystallized from isopropanol, giving 5- (N'-2-Hydroxyäthylpiperazino) -7 ~ phenyl-2,3-dihydrolH-1,4-diazepine tetrafluoroborate of m.p. 120-121.5 ° C reached.

Example 6: 5-t-Butylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (XII) [method b)]

A) ß- (2-Aminoäthy_lamino) -ß- (1, _l-diittethy_läthYlamino) viny_l-

i) To a stirred solution of 50.0 ml (750 mmol) Ethylenediamine in 700 ml of methylene chloride are during 20 minutes 30.0 g (100 mmol) of solid 2-t-butyl-5-phenylisoxazolium perchlorate [J. Org. Chem. _31, 2039 (1966)] in small portions. The temperature the reaction mixture is kept at 20.degree. to 30.degree. C. by cooling. When the addition is complete, stir continued for an hour. The reaction mixture is diluted to 1 liter by adding methylene chloride, then washed twice with 300 ml of water each time and dried with anhydrous magnesium sulfate. That Methylene chloride is evaporated under reduced pressure to give an oil. The OeI is anhydrous in 300 ml Dissolved ether and filtered off white solids. The white solids are mixed with a washed a small amount of anhydrous ether,

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the wash water combined with the filtrate, evaporated under reduced pressure, whereby the ß- (2-Aminoäthylamino) -ß- (1,1-dimethylethylamino) vinyl phenyl ketone obtained as a colorless OeI.

ii) To a vigorously stirred solution of 150 ml of ethylenediamine IUU g of 2-t-butyl-5-phenylisoxazolium perchlorate are added to 2 liters of methylene chloride under nitrogen. the The temperature of the reaction mixture is increased by appropriate metering of the addition and by cooling Maintained 20 to 25 ° C. After the addition has ended, stirring is continued for 1 hour. Then it will be the reaction mixture extracted twice with 1 liter of water each time and dried with anhydrous magnesium sulfate. The methylene chloride is stripped off under reduced pressure and the oil obtained is dissolved in 1 liter of ether. The solids obtained are removed by filtration, the ether under reduced pressure evaporated, whereby the ß- (2-Aminoäthylamino) -ß- (1,1-dimethylethylamino) vinyl phenyl ketone received as OeI.

The compound can be converted into its dihydrochloride with a melting point of 175 ^° C. (decomposition) by adding gaseous hydrogen chloride to its solution.

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(XII)

i) A solution of 24.0 g (92.0 mol) of β- (2-aminoethylamino) -β- (1,1-dimethy! ethylamino) vinylpheny! ketone in 200 ml of absolute ethanol is brought to a pH of about 1 with 70% perchloric acid and below Nitrogen heated to boiling (reflux) for 1 hour. Thereafter, the mixture is cooled to room temperature treated with 500 ml of anhydrous ether, the 5-t-butylamino-7-pheny1-2,3-dihydro-IH-1,4-diazepine perchlorate as white crystals obtained after recrystallization from ethanol / ether have a melting point of 169 ° -171 ° C (decomposition).

ii) The procedure described above is repeated with the following changes. The reaction mixture is acidified to a pH of 1 to 2 and heated to boiling (reflux) for 40 minutes. The reaction product is crystallized out by adding 500 ml of anhydrous ether and cooling. The mother liquor is evaporated to a volume of 200 ml under reduced pressure, heated to boiling (reflux) under nitrogen for 11/2 hours and evaporated to a volume of 50 ml under reduced pressure. By adding 100 ml of water, additional crystals are obtained which are combined with the previously obtained crystals and recrystallized from absolute ethanol / ether , the 5-p-butylamino-7-pheny1-2,3-dihydro-IH-I, 4 diazepine perchlorate with a melting point of 169-171 ° C (decomposition).

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Example 7: 5-t-Butylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (XII) [method b)]

A solution of 2.5 g (9.5 mmol) of β- (2-aminoethylamino) -β- (1,1-dimethylethylamino) vinyl phenyl ketone in 50 ml of absolute ethanol with 1.0 g (10.0 mmol) of methanesulfonic acid added and the reaction mixture heated to boiling (reflux) for 20 minutes. After the mixture has cooled down the ethanol is removed under reduced pressure. The oil obtained is triturated with anhydrous ether and the resulting crystals are recrystallized from isopropanol / ether, 5-t-butylamino-7-pheny1-2,3-dihydro-IH-1,4-diazepine methanesulfonate of m.p. 159-162 ° C obtained.

10.0 g (29.5 mmol) of the above-mentioned compound are dissolved in 50 ml of water, and the solution is cooled in ice water and 50 ml of aqueous 2N sodium hydroxide solution are added. The mixture is twice with 150 ml of chloroform extracted, the chloroform extracts combined and dried with anhydrous magnesium sulfate. The chloroform will evaporated under reduced pressure, whereby one. OeI receives. Adding 50 ml of anhydrous ether is possible most of the oil in solution, leaving behind some white solids which are filtered off. That The filtrate is evaporated to the smallest volume under reduced pressure. By slowly adding heptane and cooling gives 5-t-butylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine of melting point 102-103.5 ° C. in the form of the free base. More free base. of m.p. 93-97 ° C was also obtained.

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Example 8: S-t-Butylamino-V- (4'-methoxyphenyl) -2,3-

dihydro-1H-1,4-diazepine (XIII) [method b)]

4 ^ -methoxy_gheny_lketone

Analogously to Example 6 A) ii) and using 6.64 g (20.0 mmol) 2-t-Butyl-5- (4'-methoxyphenyl) isoxazolium perchlorate and 10 ml of ethylenediamine are obtained ß ~ (2-amino ethylamino) -ß- (1,1-dimethylethylamino) vinyl-4'-methoxyphenyl ketone in the form of an OeI.

The oily product of Example 8 A) is dissolved in 100 ml of absolute ethanol and the solution by adding a hydrogen chloride solution in absolute ethanol made slightly acidic (pH about 5). The solution will be heated to boiling (reflux) under nitrogen for 1 1/2 hours and then the ethanol under reduced pressure Pressure removed. The oil obtained is dissolved in 150 ml of water and treated with aqueous 2N sodium hydroxide solution neutralized. The free base is extracted twice with 150 ml of chloroform each time, and the combined extracts with dried anhydrous magnesium sulfate and evaporated under reduced pressure to an oil. By adding 5-t-butylamino ~ 7- (4'-methoxyphenyl) is obtained from isopropanol and 70% perchloric acid solution in isopropanol -2,3-dihydro-IH-1,4-diazepine perchlorate, which according to ^ .crystallization from isopropanol at 151-152.5 ° C melts.

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Example 9: [method b)]

Analogous to Example 6 and using suitable starting materials The following compounds of the formula I are obtained in approximately equivalent amounts:

a) 5-t-Butylamino-7- (4'-methoxyphenyl) -2,3-dihydro-1H-1,4-diazepine perchlorate of m.p. 151-152.5 ° C (XIII),

b) 5-methylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine perchlorate (VII),

c) [ using a hydrogen chloride solution in ethanol instead of perchloric acid] 5-t-butylamino-7- (2'-chlorophenyl) -2,3-dihydro-1H-1,4-diazepine hydrochloride with a melting point of 152- 155 ° C (XIV).

Example 10; [Method b)]

Analogously to Example 7 and using suitable starting materials in approximately equivalent amounts, about the corresponding compounds of formula iv the following compounds of formula I:

a) S-t-Butylamino-7- (4-methylphenyl) -2,3-dihydro-1H-1,4-diazepine methanesulfonate, mp 174-177 ° C (Decomposition) (XV),

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b) 5-t-Butylamino-7- (3 ·, 4'-dimethylphenyl) -2,3-dihydrolH-1,4-diazepine methanesulphonate with a melting point of 200-202 ° C (decomposition) (XVI),

c) 5-ethylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine methanesulphonate (XVII).

Example 11 .: 5- Amino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (XVIII) [method c)]

2 g of 5-t-butylamino-7-phenyl-2,3-dihydro-1H-1,4-diazepine methanesulphonate are heated to 160-165 ° C. in an oil bath for 15 minutes with a drop of methanesulphonic acid. After the melt no longer forms bubbles, the hot residue is dissolved in the smallest amount of isopropanol and the '5-amino-7-phenyl-2,3-dihydro-1H-1,4-diazepine methanesulfonate with a melting point of 176 is precipitated -177.5 ° C caused by the addition of ether . The free base can be obtained analogously to Example 7 .

Example 12: [method c)]

Analogously to Example 11 and using suitable starting compounds in approximately equivalent amounts to the following compounds of formula I:

a) S-Amino-7- (4'-methylphenyl) -2,3-dihydro-lH-1,4-diazepine - methane sulfonate of melting point 200-210 ° C (XIX)

b) 5-Amino-7- (3 ', 4'-dimethylphenyl) -2,3-dihydro-IH-1,4-diazepine methanesulphonate, m.p. 180-181.5 ° C (XX).

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Example 13; 5-hydrazino-7-phenyl-2,3-dihydro-1H-1,4-diazepine (XXI) [method d)]

25 ml of anhydrous hydrazine are mixed with 5.0 g of 5-t-butylamino-7-pheny1-2,3-dihydro-IH-1,4-diazepine methanesulfonate added and the mixture heated to boiling (reflux) under nitrogen for 30 minutes. The superfluous hydrazine is evaporated under reduced pressure. The oil obtained is mixed with 50 ml of isopropanol and then with 50 ml anhydrous ether is added, crystals having a melting point of 139.5-141.5 ° C. which are obtained with isopropanol / ether (1: 1) can be washed. The washing water is combined with the mother liquor and the mixture is evaporated to an oil, that on 125 ml of silica gel using chloroform, 2% methanol solution in chloroform, 10% Methanol solution in chloroform and 50% methanol solution is chromatographed in chloroform as the eluent. The 50% methanol / chloroform fraction is under evaporated under reduced pressure to an oil which, after trituration in dry ether, gives 5-hydrazino-7-phenyl-2,3-dihydro-lH-1,4-diazepine crystallized in the form of the free base with a melting point of 85-88 ° C.

The free base is converted into the methanesulfonate salt, by making a solution of about 1.3 g of the crude free base in 25 ml of isopropanol while cooling with 0.5 g of methanesulf added onic acid in 10 ml of isopropanol. After some

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Within minutes, crystals form and 50 ml of anhydrous ether are added. The crystals are filtered off, washed with ether and recrystallized from absolute ethanol / ether, adding 1.4 g of 5-hydrazino-7-phenyl-2,3-dihydro-lH-1,4-diazepine methanesulfonate from m.p. 190.5-191.5 ° C arrives in the form of white crystals.

Example 14;

The table below shows the spectroscopic data of compounds of the formula I in which R_ is hydrogen. The UV spectra were recorded in methanol; the media for the IR and NMR spectra are given in the table. All NMR spectra were recorded at room temperature with a 60 MHz NMR spectrometer, the chemical shifts are measured in ppm (<?) Compared to tetramethylsilane. If a single S value is given for a non-singlet in the table, it refers to its central point. The numbers in brackets after the ^ values indicate the number of protons in the spade; s = singlet, d = doublet, m = multiplet, χ = interchangeable with D ₂ O, b = broad.

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Connect
manure SaIz-
for At-
spat! - IR (ClU- ¹ ) - (Nujol) UV ε NMR
(&) 3400 -Smax (um) (CD _3, SO.CD ₃ ) VII 1 (NUjOl)
3380 3340 13,600 2.8 (3, d, s
after exchange) 1595 1630 233 26,300 3.45 (4, s) 1545 1585 297 4.7 (l, s) 1310 1550 7.0-8.0 (8, 3x) VIII CiO 2 (KBr) 1325 13,300 (CDCl ₃ ) 3230 1210 235 26,200 0.7-1.9 (7, m) 1590 1030 298 3.0-3.8 (6, m) 1535 5.15 (l, s) 1110 - 5.45 (l, b, x) 5.95 (2, x) 7. 2-7; 7 (5, ir.) XII ClO " 6th 14,900 (CD _3, SO.CD ₃ ) 238 22,100 1.3 (9, s) 315 3.5 (4, m) 4.8 (l, s) ' 7.4-8.2 (8, m, 3x) •

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Connect
manure - XIV SaIz-
forrr. At-
spat! IR (Cm " ¹ ) UV Smax (πιμ ε - NMR
(&) XII CH ₃ SO ₃ 7th - - (CD _3, SO.CD ₃ ) 1.4 (9, s) 2.3 (3, s) 3.6 (4, m) 5.0 (l, s) 13,200 7.4-8.4 (8, m, 3x) XII free
base. 7th (Nujol)
1620 234 19,300 (CD _3, SO.CD ₃ )
1.3 (9, s) 1580 318 3.6 (4, m) 1315 4.65 (l, s) 1260 7.3 (7, m, 2x) 1240 > XIII C1O ~ 8, 9a (Nujol) 8,750 I.
(CD _3, SO.CD ₃ ) 3400 214 1.3 (9, s) .3350 9,650 1620 258 3.5 (4, m) 1575 23.200 1540 318 3.8 (3, s) 1515
1505 4.9 (l, s) 1080 6.9-8.3 (7, m, 3x) Cl " 9c (Nujol) 6,200 (CD .80.CD ₃ ) 3200 232 17,000 1.35 (9, s) 1620 306 3.6 (4, m) • 1550 4.65 (l, s) 1320 7.5 (4, m) 1275 8.05 (l, m) 1240 8.45 (2. m)

509840/1075

600-6638

Connect
manure SaIz-
shape at
game IR (cm ¹ J 3020 3280 3310 3195 uv • 245 t • - NMR
(δ) XV CH ₃ SO ₃ 10a (CHCl ₃ )
3460 3320 1550 2990 1650 1635 Amax (inu) 319 15,300 (CDCl ₃ )
1.4 (9, s) 3180 1450 1550 1580 1535 243 23,400 2.3 (3, bs) 1620 1340 1450 1180 1170 318 2.6 (3, s) 1490 1055 1375 1110 3.3-3.8 (4, m) 1380 (CHCl ₃ ) 1235 (Nujol) 4.9 (l, bs) 1180 3430 1045 3300 7.0-8.4 (7 _r m, 3x) XVI CH ₃ SO ₃ 10b 3150 (Nujol) 1660 (CDCl ₃ ) 1625 3400 1570 237 12,300 1.4 19, s) 1490 3190 1210 313 21,400 2.25 (6, bs) 1405 1590 1050 2.6 (3, s) 1335 1230 3.2-3.8 (4, m) 1175 1165 4.9 (l, bs) 7.0-7.5 (4, in, Ix) 244 7.6-8.5 (2, In ₇ 2x) XVIII CH ₃ SO ₃ " 11 314 (CD _3, SO.CD ₃ ) Έ 15,100 2.3 (3, s) 18,600 3.2-3.8 {4, m) 4.85 (l, bs) 7.2-7.85 (7, m, 2x) - 8.2-8.8 (2, in, 2x) XIX CH ₂ SO " 12a (CD _3, SO.CD ₃ ) 12,150 2.36 (3, s) 16,900 2.43 (3, s) Ü9JUO / 1075 ■ 3.50 (4 in) 4.90 (l, s) 7.40 (6, m, 2x) 8.50 (2, bd, 2x) XXI free
base 13th (CDCl ₃ )
2.6-3.4 (4, m) 4.8 (4, b, 4x) 5.8 (l, s) 7.0-7.8 (5, m)

Claims (3)

- 28 - 600-5638 Claims; . Process for the preparation of new 5-amino-7-phenyl-2,3-dihydro-1H-l, 4-diazepines of the formula I, wherein either R. for hydrogen, an alkyl group with 1-6 carbon atoms or an amino group,
and Rp represents hydrogen or an alkyl group with 1-6 carbon atoms stand, with the proviso that (1) R. and R "do not mean t-alkyl groups at the same time, and (2) if R, stands for an amino group, R_ 1 ~ - Hydrogen means
or R ₁ and R 2 together for the groups / CH ₂ -CH _ — CH
2 S09840 / 107S - 29 - 600-6638 stand, and R ₃ , R. and R_ independently represent hydrogen, an alkyl group with 1-4 carbon atoms, an Al.koxy group with 1-4 carbon atoms, fluorine, chlorine or bromine, or two of the substituents R_, R. and R ₅ , which are on neighboring • carbon atoms stand for a methylenedioxy group, characterized in that one a) for the preparation of compounds of the formula I, compounds of the formula II, II where R_, R ₄ and R have the above meaning, and R ^{1 represents} a primary or secondary alkyl group with 1-4 carbon atoms, preferably methyl or ethyl S09840 / 107S - 30 - € -00-6538 with amines of the formula III, NHR R ₂ III wherein R, and R _{2 have the} above meaning, converts, b) for the preparation of compounds of the formula Ia, Yes wherein R-, R ₄ and R have the above meaning, and R ₁ ¹ is an alky! group having 1-6 carbon atoms, Compounds of formula IV, IV where R -, '/ R ^ / R ₄ and R_ have the above meaning, cyclized under strongly acidic conditions in the presence of an inert organic solvent and in an inert atmosphere » 509340/1075 - 31 - 600-6638 c). for the preparation of compounds of the formula Ib, Ib where R-, R. and R_ have the above meaning, Compounds of the formula Ia in which R ₁ 'is t-butyl, heated in the presence of free acid, or d) for the preparation of compounds of the formula Ic, Ic NHNH ₂ where R_, R. and R _{5 have the} above meaning, Compounds of formula Ia or Ib with hydrazine in inert Atmosphere. 503840/1075 - 32 - bOO-6638 Germany 2. New 5-amino-7-pheny1-2,3-dihydro-IH-1,4-diazepines of formula I, wherein either R. for hydrogen, an alkyl group with 1-6 carbon atoms or an amino group,
and R _{2 represents} hydrogen or an alkyl group with 1-6 carbon atoms, with the proviso that (1) R. and R are not simultaneously mean t-Alky! groups, and (2) if R. is an amino group, R _{0 is} hydrogen, or R, and R ~ together for the groups N-CH ₉ CH ₀ OH S09S40 / 107S - 33 - bOO-6638 Germany stand, and R ₃ , R. and R ₅ independently of one another represent hydrogen, an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, fluorine, chlorine or bromine, or two of the substituents R-, R. and R, the are on adjacent carbon atoms, represent a methylenedioxy group. 3. Medicines, characterized by the content of compounds of the formula I. 37OO / IG / SE SANDOZ-PATENT-GMBH ORIGINAL INSPECTED S0984Ö / 107S