DE1098950B - Process for the preparation of hydrazine compounds effective as amino oxidase inhibitors - Google Patents

Description

GERMAN

PATENT OFFICE

KL.12q 13

INTERNAT. KL. C 07 C

L28403IVb7l2q

REGISTRATION DATE (Y: 20. A ü G U S T 1957

NOTICE
LOGIN
AND ISSUE OF THE
EDITORIAL: FEBRUARY 9, 1961

The invention relates to a process for the preparation of hydrazine compounds which are effective as amino oxidase inhibitors of the general formula II

Method of manufacture
of as amino oxidase inhibitors
effective hydrazine compounds

(CH ₂ ), * - CH- Ν

II

that consists in that a) compounds of the formula I

.R ₂

ι
R ₃

- (CH ₂ ) ^ - C = N - N:

reduced or that b) compounds of the formula VI

X \.

(CH ₂ ) ^ - CH-N-NO

R ₅

VI

Applicant:

Lakeside Laboratories, Inc.,
Milwaukee, Wis. (V. St. A.)

Representative: Dr.-Ing. H. Ruschke, Berlin-Friedenau,

and Dipl.-Ing. K. Grentzenberg,
Munich 27, Pienzenauer Str. 2, patent attorneys

Claimed priority:
V. St. v. America 23 August 1956

John H. Biel, Milwaukee, Wis. (V. St. A.),
has been named as the inventor

in which R _{1 is} an alkyl group, to compounds of the formula VII

- (CH ₂ ) ^ - CH-N-NH ₂

VII

reduced and that these compounds of formula VII are treated with an aldehyde and a reducing agent, where % is an integer from 1 to 10, R _{1 is} hydrogen or a lower alkyl group, but is only hydrogen if at least one of the groups R ₂ , R ₃ , R ₄ and R _{5 are} not hydrogen, with R ₂ and R _{3 also being} hydrogen, a lower alkyl group or a monocyclic aralkyl group with a low molecular weight alkylene radical, R _{4 being} hydrogen, halogen, a hydroxyl, lower alkoxy, lower alkyl or low molecular weight Alkylenedioxy group and R ₅ denotes hydrogen or a low molecular weight alkyl group, and that, if appropriate, the resulting compounds of the above formula II are finally converted into their non-toxic acid addition salts or quaternary ammonium salts.

The phenylalkylhydrazones of the formula (I) to be used as starting compounds are obtained from Reaction of phenylalkyl-alkyl ketones of the formula (III) with Ν, Ν-disubstituted hydrazines of the formula (IV).

(CH ₂ ) _ra - C - R ₅ + H ₂ N - N:

XX

III

IV

3 4

Phenylalkyl-alkyl ketones, such as benzyl methyl ketone and < Diajlyl-N '- (^ * (p-methylphenyl) -isopropylidene) -hydrazine,

Phenäthyhnethylketon, also ring-substituted derivatives, N-Ethyl-N '- (4-phenyl-butylidene-2) -hydrazine and N-Ben-

such as p-oxybenzyl methyl ketone, o-methylbenzylmethyl-zyl-N '- (5-phenyl-amylidene-3) hydrazine.

ketone, p-chlorobenzyne ethyl acetone, m-propoxybenzyl- The hydrazones obtained in this way are

methyl ketone, körinen as starting compounds - 5 responsive hydrazines converted by reduction,

be turned. "A catalytic hydrogenation can expediently with

Furthermore, hydrazine can be used as starting compounds with the aid of a catalyst made from platinum or from platinum oxide

as well as N, N-disubstituted hydrazines, e.g. B. N, N-Di- or a reducing agent such as lithium aluminum

methylhydrazine, Ν, Ν-diethylhydrazine, Ν, Ν-dibenzylhydride. This catalytic reduction can

hydrazine, N, N-I) iphenäthy ^ hydrazine, .N-Methyl-N-äthyl- io can be effected by the fact that the hydrazone in one

hydrazine and Ν, Ν-diallylhydrazine, as well as N-mono-inert solvents, such as a lower alcohol, the

substituted hydrazines, such as N-methylhydrazine and containing a small amount of acid, dissolves. Good result

N-benzylhydrazine, in question. nits are generated at room temperature and a hydrogen

The reaction between the phenylalkyl-alkyl ketone pressure up to 7.0 kg / cm ^{2 is} achieved. Reductions with and hydrazine can be accomplished by contacting the aluminum thium hydride will be in inert solution reactants in a suitable solvent such as anhydrous ether, dioxane and tetrahydro. Appropriate liquid reaction furan executed. Elevated temperatures, such as reflux media are lower alcohols, especially in the mixture temperature, increase the conversion. With those only with water. Although the reaction takes place at temperatures that are elevated to room temperature, sufficient for the reaction to proceed, it is nevertheless desirable to keep the temperature for 1 to 5 hours. When the implementation is complete, the ratur of the mixture can increase somewhat, such as. B. be decomposed to excess lithium aluminum hydride by water 50 ° C to a faster completion of the reaction. The product is now known to bring about. Upon completion of the reaction, proceedings can be won.

the hydrazone obtained by conventional methods hydrazines of the formula (II) in which R _{1 is} a lower

will. 25 alkyl and both R ₂ and R _{3 are} hydrogen, can also

Hydrazones obtainable in this way are N-methyl- ■ can be prepared by using a corresponding

N '- (/ S-phenyl-isopropylidene) hydrazine, N, N-dimethyl-N-alkyl-N- (phenylalkyl) -amine (formula V) with nitrous

N '- (j8- (p-chlorophenyl) -isopropylidene) -hydrazine, Ν, Ν-di-acid to the N-nitroso-N-alkyl-N- (phenylalkyl) -amine

benzyl-N '- (/? - (o-hydroxyphenyl) -isopropyHden) -hydrazine, (formula VI) and the latter to hydrazine

N, N-diethyl-N '- (^ - phenyl-isopropyHden) -hydrazine, N, N- 30 (formula VII) reduced.

- (CH ₂ ) ^ - CH-NH-R ₁ + HNO ₂

A- (CH ₂ ) _B -CH-N-N0 _{mAV +} - ν ι ι (reduction)

(CH ₂ ) ^ - CH - N - NO

(CH ₂ ) "- CH-N-NH ₂

VL

In the formulas (V), (VI) and (VII), R _{1 is} a lower propylamine, N-amino-N-ethyl-p-hydroxyphenylisopropyl-alkyl, and n, R ₄ and R ₅ have the meaning given. pylamine, N-Anmo-N-propyl-3,4-methylene & oxyphenyl-

The isopropylamine, N-amino-N-methyl-N- (2-phenylbutyl) -available N-alkyl-N- (phenylalkyl) amines are, for example, used in the process according to the invention. B. 50 amine and N-amino-N-ethyl-N- (3-phenylamyl) amine.
N-methylphenylisopropylamine, N-ethyl-p-hydroxyphe- These compounds in which R _{1 of} the formula II is a

nylisopropylamine, N-PropyJ-3,4-methylenedioxyphenyl- lower alkyl and R ₂ and R _{3 are} hydrogen, which isopropylamine, N-butyl-o-methoxyphenylisopropylamine, can be regarded as primary amines, can be N-ethyl-N- (3-phenylbutyl) -amine and N-propyl-N- (2-phe- easily converts into the compounds in which R ₂ and R _{3 are} alkylnylamyl) -amine. 55 and aralkyl groups, by reductive alkylation

The nitrosation can be carried out by using a suitable aldehyde and Redukdas N-alkyl-N- (phenylalkyl) -amine and nitrous acid converting agent. Thus forms through Umunter aqueous conditions at room temperature or setting of N-amino-N-methylphenylisopropylamine with brings together with weak cooling. With extra formaldehyde in the presence of formic acid at moderate hern the reaction mixture with a temperature increased with water 60 N, N-dimethyl-N'-methyl-N '- (3-phenicht miscible solvents and then abnyl-2-propyl) hydrazine. By similar reductive alkyd evaporation this solvent can produce the nitrosolations as with acetaldehyde and hydrogen as an intermediate product be won. It can be obtained by using a nickel catalyst, N, N-diethyl fractionated Clean distillation. N'-methyl-N '- (3-phenyl-2-propyl) hydrazine can be obtained

The reduction of the nitrosoyl bond to that end. Similarly, N, N-diphenethyl-N'-ethyl-N '- (3-p-speaking Hydrazine can expediently be based on hydroxyphenyl-2-propyl) hydrazine and N, N-dipropyl known chemical or catalytic methods N'-propyl-N '- (3-p-phenyl-2-propyl) hydrazine produced carry out. To be typified in this way.

see compounds include N-Amino-methylphenyliso- The hydrazines according to the invention form acid

propylamine, N-amino-N-methyl-p-methoxyphenyliso-addition salts as well as quaternary ammonium salts.

ι u »o you

Acid addition salts are prepared by treating the hydrazines with a suitable acid such as Mineral acid, e.g. B. sulfuric acid or hydrochloric acid, or organic acids such as formic acid, citric acid, Maleic acid, fumaric acid, and penicillin.

Quaternary ammonium salts are easily obtained by mixing the hydrazines with alkyl and aralkyl esters of mineral and organic acids, preferably in the presence of an organic solvent, Examples of such compounds which can be reacted with the hydrazines are dimethyl sulfate and Haloalkyls such as methyl chloride, ethyl bromide and methyl iodide.

The compounds of the formula (II) to be taken orally have a long-lasting vasoconstrictor effect on. The compounds are useful for nervous shocks as they keep blood pressure up to the desired level Increase level. They also work against inflammatory hyperemia in the nose. In contrast to 1-phenyl-2-aminopropane Such compounds do not lose their effectiveness even after repeated administration and do not have analeptic properties like that, but rather a lasting duration of action. In addition it also comes that they, especially in the form of their acid addition salts, are effective inhibitors of enzyme amino oxidase are taking this enzyme for the destruction of the metabolism of therapeutically valuable hormones, such as Adrenaline, norepinephrine, and 5-hydroxytryptamine (serotonin), is responsible.

Non-toxic hydrazine salts are the preferred dosage form. Such salts can be in conventional Applied pharmaceutical forms including tablets, capsules, powders and solutions will.

example 1

N - (/ 3-phenyl-isopropyl) hydrazine

ΙΓ

CH ₂ CH (CH ₃₎ NH-NH ₂

VIII

To 106 g of 85 ° / ₀ aqueous hydrazine hydrate (1.8 moles) in 500 cm ³ of methanol was added 120.8 g (0.90 moles) of phenylacetone with stirring and cooling and keeping the temperature between 15 and 20 ° C. This mixture was stirred at room temperature for 4 hours. The methanol was distilled off and the residue was dissolved in 400 cm ^{3 of} ether. The ether solution was dried with potassium bicarbonate and the ether was distilled off. 100 g of the residue were ^{dissolved in 300 cm 8 of} ethanol and hydrogenated in the presence of 40 g of acetic acid and 1.0 g of platinum oxide at a hydrogen pressure of 4.20 kg / cm ² . The solution was clarified by filtration, the solvent was distilled off, the residue was dissolved in water, the aqueous solution was saturated with potassium hydroxide and the alkaline mixture was repeatedly extracted with ether. The product was collected by distillation at 7O ⁰ C (0.02 mm); n% ° = 1.5373; Yield: 53 g (46%).

Analysis for C ₈ H ₁₄ N ₂ : '"' ^: '

Calculated N 18.66;

found N 18.54.

When handling ethereal hydrochloric acid in a 1: 1 ether-isopropyl alcohol solution, N - (/? - phenylisopropyl) hydrazine hydrochloride is obtained. 115 to 116 ° C.
Analysis for C ₉ H ₁₅ ClN ₂ :

Calculated Cl 19.03;

found CI 19.00.

Example 2
a) N-methyl-N '- (/ 3-phenyl-isopropylidene) hydrazine

V- CH ₂ C = N - NH - CH.

CH _a

To 48 g of monomethylhydrazine sulfate in 325 cm ^{3 of} water

ίο were 40.1 g 28 / optionally ° _o sodium ammonium hydroxide and then 40.2 g of methyl benzyl ketone in 300 cm ³ of methanol while maintaining the temperature at 30 to 35 ° C. The _pH value of the reaction mixture was adjusted with acetic acid. 6 The methanol was distilled off, the residue was dissolved in water, the aqueous solution was saturated with solid potassium hydroxide, the alkaline mixture was extracted with ether and the extracts were dried with potassium carbonate. The product was collected at 83 ° C (1.0 mm). The yield was 21 g (430 1/2). _n " ₌ 1.5442.

Analysis for C ₁₀ H ₁₄ N ₂ :

Calculated N 17.26;

found N 16.98.

b) N-methyl-N '- (jS-phenyl-isopropyl) -hydrazine
and its hydrochloride

■ CH ₂ CH (CH ₃ ) -NH-NHCH ₃

A mixture of 20.5 g of the isopropylene derivative, 7.5 g of glacial acetic acid, 75 ecm of ethanol and 0.3 g of platinum oxide were subjected to hydrogenation at 4.20 kg / cm ² and at room temperature. The catalyst was filtered off, the solvent was distilled off and the residue was dissolved in water. A saturated aqueous potassium hydroxide solution was added to this residue, and the mixture was extracted with ether. The ether extracts were dried with potassium carbonate and the product collected by distillation. B.p. 78 ° C (1 mm), yield: 14.9 g (71%), nf = 1.5205.

Analysis for C ₁₀ H ₁₆ N ₂ :

Calculated N 17.06;

found N 16.86.

An ether-isopropyl alcohol solution was added to 1.8 g of the free base given essential hydrochloric acid. The precipitate was collected by filtration. Yield: 1.6 g. 115 to 117 ° C.

Analysis for C ₁₀ H ₁₇ ClN ₂ :

Calculated Cl 17.66;

found Cl 17.99.

Example 3
a) N, N-dimethyl-N '- (/ 3-phenylisopropylidene) hydrazine

y CH ₂ - C = N- N (CH _{3) 2}

CH ₃

To 108 g Ν, Ν-dimethylhydrazine, dissolved in 500 cm ³

Methanol, 120.8 g of methyl benzyl ketone were added at 15 to 20 ° C. After 20 hours of standing of the reaction

mixture at room temperature, the methanol was

ί 098960

distilled and the product collected at 67 ° C (0.15 mm). n% ° = 1.5185, yield: 144g (91%). Analysis for C ₁₁ H ₁₆ N ₂ :

Calculated · N 15.90;

found N 15.86.

b) N, N-dimethyl-N '- (^ phenyh'sopropyl) hydrazine' ^ ^ - CH ₂ CH (CH ₃ ) - NH-N (CH ₃ ) ₂

The isopropylidene derivative was prepared according to the method in Example 2 specified method. Yield: 73%.

Bp. 60 ° C (0.35 mm), n ^s _D ° = 1.5185,

Analysis for C ₁₁ H ₁₈ N ₂ :

Calculated N 15.72;

found = .., N 15.78.

Hydrochloride: This compound was prepared in a mixture of isopropyl alcohol and ether. M.p. 128 ° C. Analysis for C ₁₁ H _{19 ClN 2} :

Calculated Cl 16, Sl;

found Cl 16.52.

Example 4 a) N-Nitroso-N- (jS-phenylisopropyl) -methylamine

To 29.5 g (0.50 mol) of an 85% strength hydrazine hydrate in ISO cm ³ methanol were added 44.5 g (0.25 mol) of 3,4-methylenedioxydphettylacetone at 5 to 10 ° C. over the course of 1 hour. The solution was stirred for 2.5 hours and the methanol was distilled off. ^{150 cm 3 of} absolute ethyl alcohol and 500 mg of platinum oxide were added to the residue ^{and the mixture was then hydrogenated at 4.20 kg / cm 2 of} hydrogen and at room temperature. The catalyst was filtered off and the product was recovered by fractional distillation. Yield: 31.9 g (66%); Bp 130 ° C / 0.6 mm.
Analysis for C ₁₀ H ₁₄ N ₂ O ₂ :

Calculated N 7.22;

found .- N 6.84,

Example 6
N ^ '- Bis' ^ phenylisopropylJ-hydrazine

CH ₂ -CH (CH ₃ ) -NH-NH-CH-CH ₂

CH,

XVII

, -CH ₂ CH (CH ₃ ) N (CH ₃ ) NO

XIV

92.8 g (0.44 mol) of N-Methylphenylisopropylaminhydrochlorid in 100 cm ³ of water and 26 ^cm3 (0.54 mol) of concentrated hydrochloric acid, cooled to 5 to 10 ° C, was slowly added a solution of 85 g (1 2 mol) of sodium nitrite in water so that the reaction was carried out at 5 to 10 ° C. After the reaction mixture had been extracted with ether and the solvent had been removed, the product was fractionated. Bp 115-116 ° C (0.8 mm), yield: 77.3 g (87%).

b) N-amino-N-methylphenyhsopropylamine [N-methyl-N- (j5-phenylisopropyl) hydrazine]

As to 106 g (1.8 mol) of 85% hydrazine hydrate in 50 cm ^{3 of} methanol, 120.6 g of phenylacetate were added with stirring. After stirring for 1 hour at room temperature, the solution was refluxed for 15 minutes. After the methanol had been distilled off, the residue was extracted with ether. After its Abdestillatiön the residue was dissolved in 15Ö cm ³ of ethanol and hydrogenated in the presence of 600 mg of platinum oxide at 4.20 kg / cm ^ä hydrogen and at Räumtemperatür. After filtering off the catalyst, the.

Product collected at 140 ° C (0.02 mm). Yield: 43.0 g (35.6%).
Analysis for C ₁₈ H ₂₄ N ₂ :

Calculated, titratable N 5.22;

found titratable N 5.26.

Example 7

N - (/? - phenylisopropyl) -N ', N'-trimethylhydrazinium bromide

• CH ₂ CH (CH ₃ ) - N (CH ₃ ) - NH ₂

45

XV

CH ₂ CH (CH ₃ ) NH-N (CHs) ₃ + Br "

XVIII

35.7 g (0.20 mol) of the nitroso compound were added to 10.6 g (0.28 mol) of lithium aluminum hydride in 500 cm ^{3 of anhydrous ether.} The mixture was refluxed for 6 hours and then ^{treated with 82 cm 3 of} 40% strength potassium hydroxide solution. After decanting the ethereal layer, the solids were washed repeatedly with ether. The essential extracts were dried with potassium carbonate and the product collected by fractional distillation. B.p. 68 to 71 ° C (0.45 to 0.60 mm), yield: 27.2 g (83%). Analysis for C ₁₀ H ₁₆ N ₂ :

Calculated N 8.53;

found N 8.35.

Example 5
3,4-methylenedioxyphenyl isopropyl hydrazine

"y CH ₂ CH (CH _{3) 2} NH- NH

H, c:

XVI

^6o

65

70 3.6 g of N, N-dimethyl-N '- (/? - phenyHsopropyl) hydrazine from Example 3 were added to 2.85 g of methyl bromide in 25 cm ^{3 of acetonitrile.} After the addition of ether, an oil which crystallized on standing precipitated out. This crystalline precipitate was filtered off. Yield: 3.8 g. F. 152 to 154 ° C.
Analysis for C ₁₂ H ₂₁ BrN ₂ :

Calculated 29.25;

found, 29.54.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of hydrazine compounds which are effective as amino oxidase inhibitors general formula (II) R ₅ , Y- _(CH2) "- N-CH- n characterized in that a) compounds of the formula (I) (CH ₂ ) "- c = ν - ν: reduced or that b) compounds of the formula (VI) ₇₁ - CH- N - NO in which R _{1 is} an alkyl group, to compounds of the formula (VII) as follows I - (CH ₂ ) _ra - CH - N - NH ₂
R * R ₁ and that these compounds of the formula (VII) are treated with an aldehyde and a reducing agent, where η is an integer from 1 to 10, R _{1 is} hydrogen or a lower alkyl group, but is only hydrogen if at least one of the groups R ₂ , R ₃ , R ₄ and R _{5 are} not hydrogen, where furthermore R ₂ and R _{3 are} hydrogen, a lower alkyl group or a monocyclic aralkyl group with a low molecular weight alkylene radical, R _{4 is} hydrogen, halogen, a hydroxyl, lower alkoxy, lower alkyl or low molecular weight Alkylenedioxy group and R ₅ denotes hydrogen or a low molecular weight alkyl group, and that, if appropriate, the resulting compounds of the above formula (II) are finally converted into their non-toxic acid addition salts or quaternary ammonium salts. 2. The method according to claim 1, characterized in that such compounds of the general Formula (I) used as starting compounds, which can be obtained by reacting compounds of general formula (III) (CH ₂ ) »- C - R ₅ with compounds of the general formula (IV) H ₂ N- -N X ₁ have been received. 3. The method according to claim 1, characterized in that such compounds of the general Formula (VI) used as starting compounds by reacting compounds of the general formula (V) 1- (CH ₂ ) J ₁ -CH-NH-R ₁ R ₅ with nitrous acid. © 109 509/569 1.61