DE1206902B - Process for the preparation of piperidinoalkylguanidine derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

Number:
File number:
Registration date:
Display day:

C07d

German class: 12 ρ-1/01

1206 902
F36495IVd / 12p April 7, 1962 December 16, 1965

It has been found that long-lasting antihypertensive compounds can be obtained when compounds of the general types are used according to methods which are customary per se and are described in detail below formula

R'-f ^ N-Alk-NH-1

R "

V /

NH
NH ₂

in which Alk is an alkylene group with 2 to 5 carbon atoms and R, R 'and R "represent hydrogen atoms, a methyl or an ethyl group, where R or R' represents at least one methyl or ethyl group.
One proceeds in such a way that one either

a) Amines of the general formula
R.

N-AIk-NH ₂

wherein R, R 'and R "are hydrogen, methyl or ethyl and where at least R or R' is methyl or represent an ethyl group and Alk represents an alkylene group having 2 to 5 carbon atoms, in in a manner known per se with cyanamide, with a .vs Halocyanamide and then with ammonia, with alkylisothiourea salts or with isourea ethers or with salts or reactive derivatives of guanidine or that one

b) amines of the general formula

N -Alk -X

Process for the preparation of piperidinoalkylguanidine derivatives

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen

Named as inventor:

Dr. Hartmund Wollweber,

Dr. Rudolf Hiltmann, Wuppertal-Elberfeld; Dr. Hugo Wilms, Leverkusen; Dr. Hans-Günther Kroneberg, Wuppertal-Elberfeld;

Dr. Kurt Stoepel, Wuppertal-Vohwinkel

c) piperidines of the general formula R.

in which R, R 'and R "" have the meaning given above, with reactive derivatives of guanidino alcohols the general formula

HO -Alk -NH

in the alk has the meaning given above, or that one

d) guanidine derivatives of the general formula R.

N-Z-Alk'-Z-NH-C

: NH

NH ₂

in the Alk 'is a direct bond or an alkylene group having 1 to 3 carbon atoms and Z is a

wherein X denotes the remainder of a reactive ester group 50 CH ₂ , CO or CS group, but denotes that it is present with guanidine, its salts or at least one CO or CS group in the molecule capable of being converted or that one is present must, with complex metal hydrides

509 75Ϊ / 425

treated, and the bases obtained, optionally with inorganic or organic pharmacologically neutral acids converted into salts.

Reactive derivatives of the guanidino alcohols mentioned which are suitable for the implementation are, for. B. their halides, sulfuric acid, alkyl or aryl sulfonic acid esters. On the other hand, X in the formula under b) means e.g. B. a halogen atom or the group OSO ₃ H, OSOs-alkyl and OSO ₂ -aryl. The implementation under a) can, for. B. be made with 1-guanidino-3,5-dimethylpyrazole nitrate as a reactive derivative of guanidine.

Compared to the corresponding saturated guanidino-alkyl-substituted piperidine derivatives, the products obtainable according to the invention are several times superior with regard to the duration and intensity of the antihypertensive effect. The toxicity of the piperidinoalkylguanidines is also significantly lower than that of the piperidinoalkylguanidines. This results in a pharmacological and toxicological investigation of N- (2'-guanidinoethyl) -4-methyl-J ³ -piperidein monosulfate and N- (2'-guanidinoethyl) -3,4-dimethyl-J ³ -piperideinmonosulfat in comparison to N - (2'-guanidinoethyl) -3,4-dimethyl-piperidine monosulfate and N- (2'-guanidinoethyl-2,2,6,6-tetramethyl-piperidine monosulfate.

D? Strong bases prepared in accordance with rfii -. 'iänc form stable monobasic or dibasic salts which crystallize well _{with ano: tet mix or organic acids.}

example 1

7.1 g of N- (2 ^/ -aminoethyl) -4-methyl-J ³ -piperidein and 6.8 g of S-methylisothiourea sulfate in 50 ml of alcohol and 10 ml of water are heated under reflux for 3 hours. After the reaction has ended, the mixture is concentrated in vacuo, filtered off and the N - (2 '- guanidinoethyl) - 4 - methyl ^{- I 3} - piperidein monosulfate is recrystallized from alcohol and ethyl acetate. F. 185 to 1S6 ^: C (turning brown). Yield 9 g.

When another equivalent of sulfuric acid is added to this salt in alcohol-water, the neutral sulfate crystallizes out. C ₉ Hi ₈ N ₄ · H ₂ SO ₄ · 2 H ₂ O loses the water of crystallization in vacuo at 10O ⁰ C and then melts at 232.5 ° C (decomposition). The basic sulphate with a temperature of 185 to 186 ° C cannot be kept in the air. The neutral sulphate, mp 232.5 ⁰ C is virtually indefinitely in the air.

The N- (2'-aminoethyl) -4-methyl-J ³ -piperidein used as starting material. Bp.12 84 to 86 ° C., is obtained by reacting 4-methyl-J ³ -piperidein with glycolonitrile to give N-cyanomethyl-4-methyl-J ³ -piperidein, b.p.12 96 ^D C, and subsequent reduction with lithium aluminum hydride .

Example 2

Equivalent amounts of monosodium cyanamide and N- (2'-aminoethyl) -4-methyl-J ³ -piperidein monosulfate are refluxed in water for 8 hours. The mixture is treated with one equivalent of sulfuric acid, concentrated by evaporation in vacuo, filtered after addition of alcohol, and crystallizing the N- (2'-Guanidinoäthyl) - 4-methyl - J ³ - piperideine - monosulfate order from alcohol Essigester.

Example 3

20 g of N - (2 '- aminoethyl) - 4 - methyl - ^{I 3} - piperidein are heated to 120 to 140 ° C. with 15 g of guanidine thiocyanate for 3 hours. When the reaction is complete, it is taken up in methanol and a little water, sent over a strongly basic ion exchanger and the free base thus obtained is converted into N- (2'-guanidinoethyl) -4-methyl-I ^{3 -piperidein monosulfate with dilute sulfuric acid.}

Example 4

A solution of 15.7 g of guanidinoethyl chloride hydrochloride in 200 ml of alcohol is slowly added dropwise to a solution of 29 g of 4-methyl-I ^{3 -piperidein in 200 ml of alcohol;} it is stirred for 2 hours at 20 ^° C. and heated for 4 hours on the water bath. Then alcoholic hydrochloric acid is added until the reaction is weakly acidic, the mixture is concentrated in vacuo, 100 ml of ethyl acetate are added and the dihydrochloride which precipitates is filtered off. After recrystallization from alcohol-ethyl acetate, the N- (2'-guanidinoethyl) - 4 - methyl - J ³ - piperidein dihydrochloride has a melting point of 195 to 196 ° C.

Example 5

^{A solution of 31.6 g of N- (2'-chloroethyl) -4-methyl-I 3} -piperidein in 100 ml of toluene is slowly added dropwise at reflux temperature to a solution of 11.8 g of guanidine in 150 ml of alcohol. The mixture is heated under reflux for 1 hour, then concentrated in vacuo, alcoholic hydrochloric acid is added until the reaction is weakly acidic and, after the addition of ethyl acetate, the precipitated N- (2'-guanidinoethyl) -4-methyl-I ³ -piperidein dihydrochloride is filtered off .

The N- (2'-chloroethyl) -4-methyl-J ³ -piperidein used as starting material, boiling point 0.3 60 to 65 ^C C,

is obtained by reacting 4-methyl-J ³ -piperidein with ethylene oxide to give N- (2'-hydroxyethyl) -4-methyl-J ³ -piperidein, b.p. 12 90 to 95 ° C, and its subsequent chlorination with thionyl chloride .

Example 6

29.1 g of 4-methyl-J ³ -piperidein are refluxed with 40 g of chloroacetylguanidine in 300 ml of ether for 2 hours. A suspension of 18 g of lithium aluminum hydride is then gradually added, the mixture is heated under reflux for 12 hours, decomposed with 35 ml of 20% strength sodium hydroxide solution, filtered and the residue is extracted by boiling twice with 100 ml of benzene. After the benzene extracts and the ether filtrate have combined, one equivalent of sulfuric acid is added and N - (2 '- guanidinoethyl) - 4 - methyl ^{- I 3} - piperidein monosulfate is obtained.

Example 7

20 g of N- (2'-aminoethyl) -3,4-dimethyI- J ³ -piperidein are refluxed with 18 g of S-methyl isothiourea sulfate in 100 ml of alcohol and 10 ml of water for 4 hours. The reaction product is concentrated in vacuo and the N- (2'-guanidinoethyl) -3,4-dimethyl-J ³ -piperidein monosulfate obtained is recrystallized from alcohol-ethyl acetate. F. 260 ^° C. (decomposition, brown coloration beginning ^{at 210 ° C.).}

Example 8

According to the method described in Example 1, N- (2'-aminoethyl) -4-ethyl-J ³ -piperidein and S-methylisothiourea sulfate are obtained

basic sulphate with a melting point of 177 to 179 ° C. Neutral sulfate Mp 212 ° C.

The N- (2'-aminoethyl) -4-ethyl-I ³ -piperidein used as starting material, boiling point 102 to 104 ° C., is obtained by partial reduction of N- (2'-hydroxyethyl) -4-ethyl-pyridinium chloride with sodium borohydride to give N- (2'-hydroxyethyl) -4-ethyl-I ³ -piperidein, bp 118 to 124 ° C, chlorination with thionyl chloride to give N- (2'-chloroethyl) -4-ethyl-I ³ - piperidein, b.p. 20 120 ⁰ C, and subsequent reaction with liquid ammonia obtained.

According to the method described in Example 1, the N- (2'-guanidinoethyl) -3-methyl-zl ³ -piperidein is obtained from N- (2'-aminoethyl) -3-methyl-J ^{3 -piperidein and S-methylisothiourea sulfate} is basic sulfate of F. 208 ⁰ C.

The N- (2'-aminoethyl) -3-methyl-J ³ -piperidein used as starting material, boiling point 15 90 ° C., is obtained by partial reduction of N- (2'-hydroxyethyl) -3-methyl-pyridinium chloride with sodium borohydride to N - (2 '- hydroxyethyl) - 3 - methyl - A ³ - piperidein, bp. i4 109 to Hl ⁰ C, chlorination with thionyl chloride to N - (T - chloroethyl) - 3 - methyl - Δ ³ - piperidein, b.p. .6 78 ⁰ C, and subsequent reaction with liquid ammonia obtained.

According to the method described in Example 1, N- (2'-aminoethyl) -3,5-dimethylpiperidein and S - methylisothiourea sulfate give N - (T - guanidinoethyl) - 3,5 - dimethyl - Λ ³ - piperidein as a basic sulfate from 221 to 224 ° C (decomposition).

The N- (2'-aminoethyl) -3,5-dimethyl-J ³ -piperidein used as starting material, boiling point 1296 ° C., is obtained by partial reduction of N- (2'-hydroxyethyl) -3,5-dimethyl pyridinium chloride with sodium borohydride to give N- (2'-HydroxyäthyI) ^{-3,5-dimethyl-3-piperidine} zl, Kp.13 117 to 120 ⁰ C, chlorination with thionyl chloride to give N- (2'-ChloräthyI) -3,5 -dimethyl-J ³ -piperidein, bp 67 ° C, and subsequent reaction with ammonia produced.

The production of the starting materials is not part of the subject matter of the invention.

Claims (1)

Claim: Process for the preparation of piperideinoalkylguanidine derivatives, characterized in that that one either a) Amines of the general formula N-AIk-NH ₂ wherein R, R 'and R "are hydrogen, methyl or ethyl and at least R or R' is methyl or denotes an ethyl group and Alk denotes an alkylene group having 2 to 5 carbon atoms represents, in a known manner with cyanamide, with a halocyanamide and then with ammonia, with alkyl isothiourea salts or with isourea ethers or with Reacts salts or reactive derivatives of guanidine or that one b) amines of the general formula N -Alk -X wherein X denotes the residue of a reactive ester group with guanidine, its salts or reactive derivatives, or that one
c) Piperideine of the general formula NH in which R to R "have the meaning given above, with reactive derivatives of Guanidino alcohols of the general formula HO - Alk - NH- C: <NH ^ NH ₂ in the alk has the meaning given above, or that one
d) guanidine derivatives of the general formula R " N-Z-Alk'-Z ^ NH ^ NH ₂ in which R, R 'and R "have the meaning given above, Alk' is a direct bond or an alkylene group having 1 to 3 carbon atoms and Z is a CH ₂ , CO or CS group, but at least one CO or CS group must be present in the molecule, treated with complex metal hydrides and the bases obtained, if necessary, converted into salts with inorganic or organic, pharmacologically inert acids. When announcing the application, three tables, a figure and a page are explanatory Text has been interpreted. 509 758/425 12.65 © Bundesdruckerei Berlin