DE2259160A1 - NEW SUBSTITUTED 2-PHENYLAMINOIMIDAZOLINE, THEIR ACID-ADDITIONAL SALTS AND METHOD FOR MANUFACTURING THE SAME AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents

Description

Dr.Cr/sk 22 59 130

CH. BOEHRINGER SOHN, INGELHEIM AM RHEIN

New substituted 2-phenylamino-imidazolines, their acid addition salts and processes for producing the same as well their use as medicines

The invention relates to new substituted 2-phenylamino-imidazoline- (2) the general formula

^R 3

as well as their physiologically compatible acid addition salts with valuable therapeutic properties.

In formula I, R-., Rp and R ,, mean the same or different can be a hydrogen or fluorine, chlorine or ■ bromine atom, or a methyl, ethyl, methoxy, hydroxy, Tr i fluorine thyl or cyano group.

409823/1084

R ^ and R ^, which can be the same or different, represent a hydrogen atom or a straight or branched alkyl chain with up to 12 carbon atoms. R> and R _c cannot be hydrogen at the same time.

The compounds of the formula I are prepared by:

a) Implementation of a 2-phenylamino-imidazoline (2) of the general formula

II

in which R ₁ , R ₂ and R, have the abovementioned meaning with a halide of the general formula

III

where Hai is a chlorine, bromine or iodine atom and R ^ has the above meaning, but not hydrogen, and optionally subsequent reaction of the formed Phenylamino-imidazolines- (2) of the general formula V

^R 2 At / I

I «4 ^N

R ^H

R ₃

IV

in which R ₁ , R ₂ , R and R ^ have the abovementioned meaning (R ^ is not hydrogen), in the second reaction stage with a halide of the general formula Hal-R ₅ , in which Hal is chlorine, bromine or iodine -

/ »09823/1084

atom means and P, - has the above meaning, but not Means hydrogen; or

b) Implementation of a 2-phenylamino-imidazoline (2) of the general formula

ψ / Η ^R 3

O.

VI

in the R- ,, R2, R- * and R- the. above meaning be · » sit, but R- does not mean hydrogen, with a halide of the formula III, in which Hal means a chlorine, bromine or iodine atom and R ^ has the above meaning, not but means hydrogen; or

c) Implementation of metal salts of 2-phenylamino-imidazoline- (2) the general formula

Marg

Me

VII

wherein R 1 to R ^ are defined as given above, Me ^ a metal cation, preferably an alkali cation, with a halide of the general formula IV.

d) Implementation of a compound of the general formula

VIII

in the

through R are as defined above and A 409823/1084

a cyano group or the remainder

^ Y

means,

where Y is an alkoxy or alkylthio group with up to k

Carbon atoms or a sulfhydryl or amino group and R ^ a hydrogen atom or a straight or branched one

Represents an alkyl chain of up to 12 carbon atoms with a diamine of the formula

H ₂ N-CH ₂ -CH ₂ -NH-R ₅ IX

wherein R _{5 has} the meaning given above, or its acid addition salts.
or
e) Implementation of compounds of the general formula

in which R-, to R, have the meaning given above and X and Y, which can be the same or different, a halogen atom, preferably chlorine, a sulfhydryl group, represent an amino group, an alkoxy group or an alkylthio group.

The respective position of the substituents can be excluded set by the synthesis also by the NMR spectroscopy [cf. H. Stähle and K.H. Pook, Liebigs Ann. Chem. 751, 159 ff (1971)].

The reaction according to processes a) and b) is expediently carried out by heating the reactants - preferably in the presence of polar or non-polar organic

409823/1084

Solvent - ■ to temperatures of about 50-15O ⁰ C. The specific reaction conditions depend to a large extent on the reactivity of the reaction participants. It is advisable to use a slight excess of the halide in the alkylation and to carry out the reaction in the presence of an acid-binding agent.

In the process d), it is necessary to work at elevated temperature between 60 and .180 ⁰ C. Solvents are not required. It is advantageous to use the diamine or its reactant used as a reactant; Acid addition salt, to be used in excess .

The reaction according to e) takes place at temperatures between

and 180 ⁰ C depending on the radicals X and Y.

As a solvent also come depending on the Residues X and Y are polar, non-polar or polar-aprotic in

Question.

If one of the radicals X or Y is a halogen atom, it is advisable to use an acid-binding agent in the reaction to use. The reaction time depends on the reactivity of the components used and varies between a few minutes and several hours.

In the process according to c), it is best to work in a non-polar organic solvent, such as, for example, tetrahydrofuran, at an elevated temperature (up to 150 ^° C.). The reaction time is usually 1-3 hours.

In the alkylation of Z-Arylamino.-imidazoline-Ca) the Formula II, the substitution takes place first on the bridge nitrogen atom. Depending on the reaction time and the applied amount of the alkylating agent can also have a second substituent on one of the two imidazoline N atoms occur, so that at the same time 2 new imidazoline derivatives can arise, which must be separated from each other. Fractionated ones are particularly suitable for separation

409823- / 108 4

Extraction at different pH values or column chromatography.

The preparation of starting compounds of the formula II

is for example in Belgian patents 623 305, 6? 3 933,

687 657 and 687 656.

These compounds of the formula II can be inert metalate anhydrous solvents, e.g. with Met? !! - · hydrides or metal alkyls, such as sodium hydride or but; lithium, whereby starting compounds of the formula VIl zußüwj; · be borrowed.

Starting compounds of the formula VI, which are simultaneously according to the invention Compounds of formula I in which R 1 is a hydrogen atom are by the process e) accessible.

, ι

Urea and thioureas of the formula VIII can by

Implementation of anilines of the formula

XI

with cyanic acid or thiocyanic acid according to Wöhler, which convert into corresponding alkylisoureas or alkylisothioureas by alkylation. Cyanamides of the formula VIII can be obtained from the aforementioned thioureas by splitting off H ₂ S by means of lead or mercury oxide. Guanidines can be produced by adding ammonia to cyanamides.

409823/108

Compounds of formula X are in the German Offenle £ ungsschrift 1,670,162. By reacting the phenyl isocyanide dihalides described there with hydrogen sulfide or mercaptans or alcohols, compounds are obtained of the formula X, in which X or Y is a sulfhydryl, alkylthio or alkoxy group. Phenylisocyaniddichloride der Formula X can also be used with ammonia to correspond Cyanamides are implemented, which are convertible into corresponding guaridines upon further addition of ammonia. ·.

The new imidazolidine derivatives according to the invention of yours Formula I can be converted into their physiologically acceptable acid addition salts in the customary manner. To the Acids suitable for salt formation are, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, Hydrofluoric acid, sulfuric acid, phosphoric acid, Nitric acid or organic acids such as acetic acid, Propionic acid, butyric acid, valeric acid, caproic acid, capric acid, Oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, Malic acid, gluconic acid, benzoic acid, p-hydroxybenzoic acid, Steel acid, cinnamic acid, salicylic acid, ascorbic acid, 8-chlorotheophylline methanesulfonic acid, Ethanephosphonic acid and the like.

The compounds of the general formula I according to the invention and their acid addition salts have valuable antihypertensive, sedative, anti-secretion and analgesic properties and can be used accordingly in treatment of high blood pressure or the various manifestations of painful conditions, such as migraines, application Find.

The compounds of general formula I and their acid addition salts can be used enterally or parenterally. The dosage for oral use is included 0.1 to 80, preferably 1 to 30 mg. The connections

409823/1084 _ft , _n ■

BATH ORIGINAL

of the formula I or their acid addition salts can in addition with other types of active ingredients, e.g. antispasmodics, sedative tranquilizers, analgesics and the like auto ISineatz reach. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, LOiuuieti, Emulsions or powders? this can lead to their production the commonly used galenic aid »» ÜÜffäger-Spreng- or lubricants or substances are acceptable a depot effect can be applied. The manufacture of such galenic dosage forms are carried out in the conventional way Way according to the known manufacturing methods *

The following examples illustrate the invention, but never to restrictι

4Ö9823 / TÖI4

_ 9 A production examples. 2 no.5 9 Ί 6 O

example 1 2- [N- (2,6-dichlorophenyl) -N- (n-hexyl) -amino1-2-imidazoline

6.9 g (0.03 mol) of 2- (2,6-dichlorophenylamino) -2-imidazoline are mixed with 6.2 g (125%) of n-hexyl bromide and 9.5 ml of triethylamine in 50 ml of absolute toluene with stirring Heated to reflux for 6 hours. After cooling, the reaction mixture is mixed with dilute approx. 1 η hydrochloric acid and extracted several times with ether (ether extracts are discarded). Subsequently, at increasing pH values, extraction is carried out in a fractionated manner with ether (blunting or alkalinization with dilute NaOH). The ether fractions, which are uniform on the basis of the thin-layer chromatogram, are combined, dried over MgSO ^ and evaporated to dryness in vacuo. The new imidazoline derivative remains in a yield of 2.95 g, corresponding to 31.3 % of theory; Mp j 123-125 ⁰ C.

Example 2

1-n-Octyl-2- [N- (2-methyl-5-fluorophenyl) -N- (n-octyl) -amino] -2-imidazoline (A) and 2- [N- (2-methyl-5 -fluorophenyl) -N- (n-octyl) -aminoi-2-imidazoline (B)

3.86 g (0.02 moles). 2- (2-Methyl-5-fluorophenylamino) -2-imidazoline are refluxed for 3 hours with stirring together with 4.25 g (HO%) n-octyl bromide and 4 g soda in 40 ml butanol. The inorganic salts are then filtered off with suction and the filtrate is concentrated to dryness in vacuo. The oil remaining as residue is dissolved in dilute hydrochloric acid and the solution is extracted several times with ether to remove impurities (ether extracts are discarded). It is then extracted with ether at different pH values (blunted using dilute sodium hydroxide solution) and the two new imidazoline derivatives are separated from one another in this way. The fractions which contain the two imidazolines in pure form (control by thin-layer chromatogram) are

409823/1084

each united and concentrated. The yields are 0.55 g, corresponding to 6.6 % of theory for substance A and

4.0 g corresponding to 65 _f 6 % of theory for substance B. Both substances are oily and are characterized by the following Rf values

characterizes:

RF _A = 0.9, RF _B = 0.3

Mobile phase for thin-layer chromatograms Benzene: Dioxane: Ethanol: Concentrated ammonia:

50 40 5 5 Carrier: silica gel G, pre-fabricated Merck plates Detection: Schüttler's reagent (potassium iodoplatinate)

Example 3

l-n-Hexyl-2- (2-chloro-3-methylphenyl-amino) -2-imi.dazp3.in

6.3 g (0.03 mol) of 2- (2-chloro-3-methylphenyl-amino) -2 ~ imidazoline are given together with 1.3 g of sodium hydride dispersion (55 percent) in 50 ml of absolute tetrahydrofuran and 2 hours stirred for a long time at room temperature. The thin suspension is then 4.95 g (0.03 mol) of n-hexyl bromide in 10 ml of absolute Tetrahydrofuran was added dropwise and the reaction mixture was then refluxed for 3 hours. After this Time is concentrated to dryness in vacuo and the oil remaining as residue is taken up in dilute hydrochloric acid. After shaking out several times with ether (ether extracts are discarded), the acidic solution is treated with activated charcoal and brought to different pH values with dilute sodium hydroxide solution, each of which is extracted with ether. Of the total of 11 ether fractions obtained, 8 fractions contain the new imidazoline derivative in pure form (by thin-layer chromatogram control). They are combined, dried over MgSO ^ and in vacuo constricted.

Yield: 3.1 g corresponding to 35.296 of theory. The compound does not crystallize and is an oil of medium consistency.

409823/1084

RF = 0.85>.

Eluent for thin-film automatic gram:

Benzene: dioxane: ethanol: conc. Ammonia: = 50 40 5 " Carrier: silica gel G, pre-fabricated Merck plates. Detection: potassium iodoplatinate

The imidazoline derivatives of structure I listed in the table can be prepared analogously to Examples 1-3 will:

409823/1084

3 game No. ^R l R ₂ ^R 3 ^R 4 ^R 5 Fp .: yield 4th 2-CL 6-CL a CH ₃ H 106-108 ° 13.9% I.
5 2-CL 6-CL H C ₂ H ₅ H 120-121 ° - 6th
> 2-CL 6-CL H nC ₄ H _g H 130-132 ° 27.8% r · »
/ 2-CL 6-CL H HC ₈ H ₁₇ H 73-75 ° 22.4% 'β. 2-Cl 6-CL H H 74-76 ° 19.2% υ 9 2-Cl 6-CL H H 75-77 ° 20.7% ' 10 2-CL 6-CL H UC ₅ H ₁₁ 128.5-130.5 ° 32.2% 11 2-CL 6-CL H HC ₇ H ₁₅ ftf 109-112 ° ΙΪ-iA '% ■■ - ΝΛ
Ni 12th 2-Cl 6-CL H H ^η - ° 10 ^Η 21 oil οι 13th 2-CF ₃ H H H CH ₃ Nitrate: 183-183 ° VJ )
43.5 % ^Ο

example
".. ,, Kr ,. ,, ■ .. "*1 —- -: - ~ ί
^Β 2 r - -?
■ ^R 4 ^R 5 Fp ,: *
yield 14th 2-CL 6-CL H H CH ₃ Nitrate: 226 ° 13.1% 15th
r ' 2-CH ₃ H " H C ₂ H ₅ H oil. 9.0% « _Η 2-CL 6-CL H HC ₁₁ H ₂₃ - H , 76.5-72.5% 23.4% 17th 2-CL 6-CL H , . ^nK: 3 ^H 7- H 15'4-156 ° 17.8% 18th 2-CL 6-CL H ^η - ° 5 ^Η 1ΐ " ^η - ° 5 ^Η 11 oil 12.1%, 19th 2-CL 6-GL H HC ₁₂ H ₂₅ - ⁿ " ^C 12 ^H 25- oil ■ ■ 6 * 8% yj »
< - 20, · ^: 2-CL 6-CL H HC ₁₂ H ₂₅ - .H .61-6 3 °
j 21.8% 21st 2-CL r 6, -C ₁ L H. - \ CH ₃ ^; CH ₃ 9 ^ _ ₉₄ o 8.3% ro 22nd 2-CL. 6-CH ₃ H HC ₅ H ₁₁ - · j H 12.6-128 ° ■■ - ■ cn
.29.8% CO ZX 2-CL ^; 4-Br I-CL ⁿ ^ 5 ^H ll- H 106-108 ° CD
36.9% O

Example no ^R l ^R 2 ^R 3 ^R 4 ^R 5 Fp .: yield 24 2-F 4-F H ^η - ° 6 ^Η ΐ3 ~ H 52-54 ° 20.3% 2> 2-CF ₃ j H H Ti-C ₆ H ₁₃ - H 75-77 ° 40.6% 26th 2-C ₂ H ₅ - J ₆ -C ₂ H ₅ - H HC ₅ H ₁₁ - H oil 50.5% 27 H H H HC ₇ H ₁₅ - HC ₇ H ₁₅ - oil 8.4% 28 H H H HC ₇ H ₁₅ - H oil _ 58.0% 5e.
I. 29 4-CN. H H IX-C ₄ H ₉ - HC ₄ H ₉ - oil 6.0% 30 .. 4.-CM. H M. HC ₄ H ₉ H 122-125 ° 38.0% 31 5-OCH ₃ H ^η ^ 7 ^Η 15 " H oil 50.2% Ki 32 2-CL : 3-CH,
- '- *. * - *: _ --r * .. " ■ _-, ■■, - = · ■ li H 4 "5Λ. ^Η 17". ^{η- <:} 8 ^Η 17 ~ oil cn
8.0% CO 33 2-CL 3-CH ₃ H: ^A HC ₈ H ₁₇ H 68-70 ° ■ 54-, 4. %., _: . _{? r} .,. O

Λ09823 / 1084

{Example no.
I. ^R i , R ₂ - ^R 3j -V ■ ^R 5 FP · ,: yield 2-CL 4-CH ₃ H ^ 6 "U- - H oil 47.6% <I.
j 55 2-CL 6-CH ₃ H H ^η "° 7 ^Η 15" oil' 29.3% ι
j 36 5-F H H HC ₅ H ₁₁ - oil 30.4% : ■■ ₃₇ 2-CH3 5-F H HC ₅ H ₁₁ - H 54-56 ° 6.3% i ^; ■
38- 2-CL 4-CH ₃ H ' H HC ₄ H ₉ - 85-88 °. '■ 24.5%
4th , .j.,, 39. 2-CL 6-CL H H n-CgH> ₇ - oil 34.1% 5;
« ! 40
... -Λ
ί 2-CL 6-CL H H HC ₆ Hp- oil 37.4% ! ^Α1 · 2-CL 6-CL H H oil 36.6% κ) : ^Λ2 2-hCL 6-CL H H HC ₇ H ₁₅ - oil cn
31.5% CD j 43-. 2-CL 6 ^ CL H H - nC _g H ₁₉ - oil oV
31.8% CD

409823/10 & 4

I.
example ^R l R, R ₃ ^R 4 / ^H 3
^ CH ₃ ^H 3 ^R 5 Fp .: yield K) 1 2-CL 6-CL H H ^nC ll ^H 23 " oil 32.2% 591 * _t 45 2-CL 6-CL H H "" ^ ΐΣ ^ δ " oil 35.2% CO ■ 46 2-CL 6-CL H H oil 33.8% 47 2-CL 6-CL H H HC ₃ H ₇ oil 31.8% 48 2-CL 6-CL H H C ₂ H ₅ 33-35 ° 36.2% 49 2-C _A 6-C ₂ H ₅ H CH ₃ H oil 31.2% 50 2-CL 6-CL H ^ H ₂ . H 122-123 ° 20.1% 51 2-CL 6-CL H - (CH ₂ ) H
< 114-115 ° 33.3%

Example no.

Fp .:

yield

52

2-Cl

6-Cl

-CH ^C 2 ^H 5

oil

C ₂ H ₅

12.5 %

53

2-OH

5-OH

Bromide:
- 72 °

49.2 %

54

2-Cl

6-Cl

-CH ₂ -CH ₂ -CH CH,

oil

U 0 9823/1084 34.4 %

5 mg 65 mg 120 mg 40 mg 3 ms ®t: 5 2 * 5

B formulation examples; Example A.

Tablets

2- [N- (2,6-dichlorophenyl) -N- (n-hexyl) τ-amino] -2-

imidazoline lactose corn starch secondary calcium phosphate soluble starch Magnesium stearate colloidal silica

Manufacturing:

The active ingredient is mixed with some of the excipients intensively with an aqueous solution of the soluble starch kneaded and granulated in the usual way using a sieve. The granules will be with the rest of the excipients mixed and pressed into tablets weighing 245 mg each. The same process can be used to produce tablet cores, which can then be coated in the usual way with the help of sugar, talc and gum arabic.

Example B ampoules

2- [N- (2,6-dichlorophenyl) -N- (η-butyl) -amino] -2-imidazoline 2 mg

Sodium chloride 18 mg

distilled water ad. 2.0 ml

The active ingredient and the sodium chloride are dissolved in water. The solution is sterile and filtered under nitrogen in glass ampoules bottled.

409823/1 0 8

Example C drops

2- [N- (2,6-dichlorophenyl) -N- (n-hexyl) -amino] -2-imidazoline. 0.02 g

methyl p-hydroxybenzoic acid 0.07 g

Propyl p-hydroxybenzoate 0.03 g

demineralized water ad. 100 ml

4 09823 / 1,0.8,4-

Claims (1)

- 20 claims 2759160 1 / New substituted 2-phenylamino-imidazolines of the general formula in which R, R ₂ and R ,, which can be identical or different, represent a hydrogen or fluorine, chlorine or ßromatom, or a methyl, ethyl, methoxy, hydroxy, triiluomethyl or cyano group and R ^ and Rr, which can both be identical or different but not simultaneously hydrogen, denote a hydrogen atom or a straight or branched alkyl chain with up to 12 carbon atoms, as well as their acid addition salts. 2, process for the preparation of compounds of general Formula I according to claim 1, characterized in that one a) a 2-phenylimidazoline (2) of the general formula II wherein R ₁ , R2 and R, have the abovementioned meaning, with a halide of the general formula HaI-R ₄ III where Hal is a chlorine, bromine or iodine atom and R _{4 has} the above meaning, but is not hydrogen, reacts and optionally then the formed 409823/1084 2-Phenylamino-imidazoline (2.) of the general formula fl R ₄ HR ₃ wherein R- ,, Rp, R- * and R ^ the above own, in the second reaction stage with a Halide of the general formula HaI-R ₅ IV in which Hal denotes a chlorine, bromine or iodine atom and Rc has the above meaning but does not represent hydrogen;
or b) a 2-phenylamino-imidazoline (2) of the general formula ^R l in which R ₁ , R ₂ , R- * and R ^ have the abovementioned meaning, but Rc is not hydrogen, is reacted with a halide of the formula III; or c) a metal salt of 2-phenylamiho-imidazoline (2) of the general formula BATH 409823/1084 -O He ® VII which may have R ^ above nngftKebftn · ^def ined are, Me ^{l ()} oin metallation, before / uK "w" lne "in Alknl lknt lon, means a HeJogunJ'J the" I l _R "m € inen Formally implements;
or d) a compound of the general formula ^R l VIII in which R ₁ to R are defined as indicated above and A is a cyano group or the remainder -C means Y is an alkoxy or alkylthio group up to carbon atoms or a sulfhydryl or aeino group and R 1 is a hydrogen atom or a straight or branched alkyl chain with up to 12 carbon atoms, with a diamond of the formula H ₂ N-CH ₂ -CH ₂ -NH-R ₅ IX wherein R _{5 has} the meaning given above, or its Acid addition salts, converted;
or 409823/1084 BAD ORiGiNAL e) a compound of the general formula in which R- to R- have the meaning given above and and Y, which can be identical or different, represent a halogen atom, preferably chlorine, a sulfhydryl group *, an amino group, an alkoxy group or an alkylthio group, with a thiamine of the formula IX implements; and that the end product obtained is optionally converted into an acid addition salt. 3. Pharmaceutical preparations, characterized in that they contain one or more compounds of the as active ingredients general formula I according to claim "I or their acid addition salts contain. 4. Process for the preparation of medicaments according to claim 3, characterized in that one or more compounds of the general formula I or their acid addition salts with customary pharmaceutical auxiliaries, carriers, Disintegrants or lubricants or substances to achieve a depot effect on tablets, capsules, suppositories, Formulated solutions or powders. 5. Method of combating ^ hypertension ^ e'mix compounds of the general formula I or their physplogi-gch compatible acid addition salts. ¹ ^ ¹ ^ 409823 / Ί08a