DE2263130A1 - ACNES CONTAINING GUANIDES - Google Patents

Description

The invention relates to the use of certain guanidines as an anti-acne agent and pharmaceutical preparations that contain such guanidine as an active ingredient. .

Even if the etiology of acne vulgaris is not complete is cleared up, the clinical picture is well known. Lipases of bacterial origin. lead to the formation of fatty acids, which in some way produce the characteristic 'comedones. Certain bacteria are always present with this disease, and unsightly skin damage often occurs sometimes leaving permanent scars.

To combat acne have long been used topically Funds used; to date, however, no satisfactory results have been achieved with it. Phenolic compounds (such as

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Phenol, hexachlorophene, dichlorometaxylenole, p-chlorometaxylenol) are inactivated by organic material and in some cases by soap. From these and others Reasons they are ineffective for fighting acne. Quaternary ammonium surfactants are made by protein, soap and hard water inactivated. They too have proven to be ineffective in fighting acne.

The anti-acne agents according to the invention consist of ⁱ Alkylguaniden, biguanides and especially bis-biguariiden having precisely those properties that are required for the control of acne. They have a broad spectrum of anti-acne activity and are highly effective against Corynebacterium acne and against Staphylococcus epidermis, ie those microbes that are most frequently found in acne pustules. They are strong nouns against the skin, penetrate the skin, are compatible with considerable amounts of soap and organic material, and are bactericidal in low concentrations.

Have examinations that extended over a long period of time showed that these compounds do not lead to the emergence of resistant strains and that they are effective against strains that target tetracycline, a common acne drug, have developed resistance, are active. In addition, continued research has shown that the anti-acne agents according to the invention are effective Are lipase inhibitors.

The bis-biguanides according to the invention, which have anti-acne activity, are 1,1'-bridges-to-tS-higher-alkyl-biguariide] and their pharmaceutically acceptable salts of the general formula:

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14 399

Formula I.

In which the two-valued bridge A

(a) Alkylene having 2 to 12 carbon atoms, in which the free Valences belonging to different carbon atoms or

(b) - (CH ₀ ) - Y -

CZ ill

-, where m and η are integers

₀ ) Y (CHp)

CZ. ill £ - XX

are from 2 to 6 and. Y is O or S, or

CH

-CH ₂ -CH

CH-CH ₂ -

or

CH

Z ¹ -

⁵ Λ_ /

in which each of the substituents Z and Z ^{1 is} alkylene of 1 to J carbon atoms, or

wherein Q is the group -O-, -S-, -SO- or -SO ₂ -, or

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Χ * 399

(f)

CH = CH

is, R

»Ι

(a) alkyl of 6 to 16 carbon atoms, or

(b) Alkyl-Y-alkylene, in which Y has the meaning given above Has,

is,

R ^{1 is} H or lower alkyl and

X is 2.

The preferred anti-acne agents according to the invention are Bis-biguanide:

1,1'-hexamethylene bis [5- (n-heptyl) biguanide] 1,1'-hexamethylene bis [5- (n-octyl) biguanide] 1,1'-hexamethyleribis-tS-CS-ethylhexyl) - biguanide] 1,1 ^f -hexamethylene bis [5-nony! biguanide] 1,1'-hexamethylene bis-13-hexylguanide] 1,1'-hexamethylene bis-t ^ -octylguanide] 1,1'-hexamethylene bis [5- ( 3-ethoxyethyl) biguanide] 1,1'-hexamethylene bis [5- (3-isobutoxypropyl) biguanide] 1,1 '- (2-chloro-p-xylylene) -bis- [5-octylbiguanide]

Further anti-acne agents according to the invention are: 1,1'-hexamethylene bis [5-hexy! Biguanide]

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1,1'-Hexamethylene bis [5- (l, 1, j3,3-tetramethylbutyl) biguanide] 1,1'-hexamethylene bis [5- (2-ethylhexyl) biguanide] cobalt complex 1,1 '-hexamethylene bis - [5-dodeeylbiguanide] 1.1 ^! -Hexamethylenbis- [5-decylbiguanid] 1,1 ^t -hexamethylenbis- [^ - decylguanid] 1,1'-Hexamethylenbis-iS - ^ - isopropylmercaptopropyl) -biguanid] 1,1'-Hexamethylenbis-E ^ -Cö-methylmercaptohexyl) -biguanide] 1,1'-hexamethylene bis [5- (7-methylmercaptoheptyl) -biguanide] 1,1 * -hexair.ethylene bis- [5- ( ⁱ l -pentylmercaptobutyl) -biguanide] 1,1 ^ hexamethylene bis-tS -CS-methylmercaptooGtyl) -biguanid] 1,1 ^χ -hexamethylene bis- [5- (2-hexyloxy-1-methylethyl) -biguanide] 1,1'-hexamethylene bis- [5- (2-propyloxy-l-methylethyl) - biguanide] 1,1'-hexamethylene bis [5- (4-propyloxy-1-methylbutyl) biguanide] 1,1'-hexamethylene bis [5- (7-methoxyheptyl) biguanide] 1,1'-hexamethylene bis [ 5- (3-isopropoxypropyl) -biguanide], 1,1'-hexamethylenebis [5- (3-propoxypropyl) -biguanide], 1,1'-hexamethylenebis [5-hexadeeylbiguanid] 1, I ¹ -Hexamethylenbis- [5- tetradecy! biguanid] 1,1'-hexamethylene bis-Es-C ^ S, 12-trimethyltridecyl) biguanide] l, l '- (2-methyl-1,4-butylene) -bis- [5-heptylbiguanide] 1, 1 '- (p-xylylene) -bis-C5- (2-ethylhexyl) -biguanide] l _i l ^l - (2.3 _J 5 _J 6-Tetra chloro-p-xylylene) -bis - {; 5- (2-ethylhexyl) -

biguanid] ^:.

1,1'-octamethylene bis [5-hexyl-5-methylbiguanide] 1,1 '- (2,5,5 ^ 6-tetramethyl-p-xylylene) -bis- [5- (2-ethylbexyl) -

biguanid]

1,1 '"[p-phenylenebis (ethylene) i-bis- [5-octylbiguanide] 1,1' - [oxybis - (p -phenylene)] -bis - [5-octy! Biguanide]!, L-oxybis-propylene lb
mercaptobutyl) biguanide]

l, l'-oxybis [propylene] bis [5-methyl-5- (l-ethyl-2-methylmercaptopropyl) biguanide]

1,1'-Oxybis-Cpropylenj-bis-Es-ethyl-S-hexylbiguanid] -1 , 1 '- (2,5-dimethyl) -p-phenylenebis-' (ethylene) -bis- [5-hexyl-

biguanid]

1,1 '- [Phenylenbis- (l-methylethylene)] - bis- [5-hexylbiguanide] IjV - [I, ^ - cyclohexanebis-Cmethylene)] - bls- [5-hexylbiguanid] l, l ^f -Thiobis- [ p-phenylene] bis [5-octyl biguanide]

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1 * 399 _χ 226 3 Ί

1.1 * -SuIf inylbis- [p-phenylene] bis [5-octylbiguanid] 1.1 * -Sulfonylbis- [p-phenylene] bis [5-octylbiguanid] l, l ^t - (^, 4 * -Stilbene) -bis- [5-octylbiguanide] l _J l ^l - (1,3-xylylene) -bis- [5-octylbiguanide] 1,1 * - (1,2-xylylene) -bis- [5- octyl biguanide] l ^ ^f thiobis [ethylene] bis- [5-octyl biguanide] 1,1'-thiobis-tpropylene] -bis- [5-octylblguanide] 1,1'-oxybis-tbutylen1-bis-Cs-octylbiguanide ]

The bis-biguanide be administered topically, and are in the pharmaceutical preparations in an amount of about 0.01 to 0.5 wt .- #, preferably about 0.02 to 0.1 wt -.%, Contained. Such pharmaceutical preparations are effective agents for treating acne in humans.

The dosage for a given patient will of course depend on various factors, including activity the compound used, age, body weight, general health, gender, diet, time of administration, Extent of excretion, drug combination as well as the degree of disease and the part of the body to be treated.

The pharmaceutical preparations according to the invention can be any form suitable for topical administration. Examples of such preparations are lotions, refreshments, Creams, ointments, jellies, pastes and emulsions. They can be produced by known processes. You can up to $ 99.99 of the total weight of the product on one or several miscible non-toxic surfactants, Solvents and / or emollients: contain. Examples these are alkanols, such as methanol, ethanol, isopropyl alcohol and the like, 2-octyldodecanol, methylpyrrolidone, squalene, Squalane, isopar "M" (coparaffinate), isopropyl myristate, Acetulan (acetylated lanolin alcohol), polyethylene glycol, diethyl phthalate, polysorbate 8o, Ceraphyl 2 ^ 0 (diisopropyl adipate), Mineral oil, propylene glycol, water, glycerin, salicylic

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Perfume, coloring agent, watery Buffers, benzyl alcohol, bipropylene glycol and

! · The pharmaceutically acceptable salt © de · · above "bisbiguanides can, in accordance Antiaknemittela de, his rent hold examples of solch® salts are dl © or di-hydrQha.lQgenide> 3xklf amate :, SaeGharine * Tartrate, Acetates, sulfates. ,, Phthalates · ,, succinates, citrates, lae / tate and nitrates.

The compounds used according to the invention are from of US-PS 2,468,898 and are there as antit> akterielle Means described.

The following examples illustrate the preparation; various acne inhibitor agents according to the invention;

example %

Acne Lotion wt .- ^

Ethyl alcohol ", 4: 5

Salicylic acid 0> 5

l, l ^t -hexamethylene bis-l5- (2-..

ethylhexyl) biguanide] -2HCl 0.1

Water 54> Λ

Perfumes and coloring agents,
sufficient amount

The ethyl alcohol will be l, l. ^t -Hexamethylenbis- {5- (2-ethylhexyl) ■ biguanid] '2HCl, salicylic acid, water and, if necessary, perfume and coloring agents were added.

If other compounds of the above general formula I, for example 1,1'-hexamethylene bis-tS-Cn-heptyl) -biguanid}.? 1,1 '-hexamethylene bis [5- (n-octyl) biguanide] j 1,1 ^r ' -hexamethylene bis [5-nonyl biguanide] j X _x I ^f -hexamethylene bis - [. J5 ~ hexylguanide]; 1,1'-hexamethylene bis-t ^ -octylgyanidl J 1> V ->

- 7 "3Q9 826 / T

Hexamethylene bis-£ 5- (2-ethoxyethy 1) biguanide]; iji 'tetethylene bis [5- (5-isobutoxypropyl) biguanide! or JU1 * · (2-chloro-p-xylylene) bis [5-octylbiguanid] * instead of Λ _{'Λ Ϊ} *' -Hexamethylenbis- [5 - (2-a * thylhexyl} -biguanidJ used; be "so the corresponding product is obtained.

Example 2 ■ · wt. . ^ Acne face serf freshening agent 29.9 Isopropyl alcohol 0.1 l ₁ l ^l -hexamethylene bis-i5- (2-
at hy1hexy1) -biguanid] · 2HC1 70.0 Aqueous citrate-phosphate buffer
up to pH = 5.5

Perfumes and coloring agents,
sufficient amount

^{A mixture of 1.1 f} -hexametinylent> i $ -15 - "(2-ethyIhexy1) -biguanide] · 2HC1 and isopropyl alcohol is added to an aqueous citrate-phosphate buffer solution of pH 5.5 while stirring. If desired, fragrances and coloring agents are added.

If other compounds of the general formula I, for example 1,1 * -hexamethylene bis-ES-Cn-heptyl) -biguanide? J 1,1'-hexamethylene bis [5- (n-octyl) i-biguanide]; 1,1'-hexamethylene bis-IS-nonyl biguanide]; 1,1'-hexamethylene bis [3-hexylguanide]; 1,1-hexamethylene bis [3-octylguanide]; 1,1'-hexamethylene bs-fS- (2-ethoxyethyl>biguanide]; 1 ,, l ^f -hexamethylene bs [5- (3-isobutoxypropyl) biguanide] or 1,1 ^f - (2-chloro-p-xylylene ) -bis-15-octylbiguanide] are used instead of 1,1 ^r -hexamethylene bis- [5- (2-äth3rlhexyl) -biguanid], the corresponding product is obtained.

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Example 3

Feuc nt1gke it s-Lot i on wt. -%

Isopropyl alcohol '"25.00

Propylene glycol. 10.00

l, l ^f -hexamethylene bis-E5- (2-

ethylhexyl) biguanide] 2HCl 0.05

Water 64.95

Perfumes and coloring agents,

sufficient amount .

Be a solution of isopropyl alcohol and propylene glycol with stirring 1,1 * -hexametnylenbis- [5- (2-ethylhexyl) -biguanide] • 2HC1, water, perfume and coloring agents added.

If other compounds of the general formula. I, for example 1.1 ^l ^ hexaniethylenebis [5- (n-heptyl) biguanide]; 1,1'-hexamethylene bis [5- (n-octyl) biguanide]; 1.1 ^f -hexamethylene bis [5-nonyl biguanide] ; 1,1 * -hexamethylene bis-Ej-hexylguanide] J 1 * 1 * - hexamethylene bis - [^ - octylguanide3; 1.1 ^f -hexamethylene bis [5- (2-ethoxyethyl) biguanide]; 1,1 * -hexamethylene bis [5- (3-isobutoxypropyl) biguanide] or 1,1 '- (2-chloro-p-xylylene) -bis- [5-octyibiguanide] instead of the 1.1 ^t -hexamethylene bis- [5- (2-äthyIhexyl) -biguanid] are used, the corresponding product is obtained.

Example 4 .

Moisture lotion Gevr. -%

Isopropyl alcohol '25.00

Glycerin. 10.00

l, l'-hexamethylene bis [5- (2-

ethylhexyl) biguanide] '2HCl 0.05

Water 64.95

Perfumes and coloring agents,
sufficient amount

- 9 -309 8 26/1 167

The 1,1'-hexamethylene bis [5- (2-ethylhexyl) biguanide] 2HCl ₁ glycerine, water, perfume and coloring agents are added to the isopropyl alcohol with stirring.

If other compounds of the general formula I, for example 1,1 ^f -hexamethylene bis- [5- (n-heptyl) -biguanide]; 1,1'-hexamethylene bis [5- (n-octyl) biguanide]; 1,1'-hexamethylene bis [5- (nonyl biguanide]; 1,1'-hexamethyleribis [3-hexylguanide] | 1,1'-hexamethylene bis [3-octylguanide]; 1,1'-hexamethylene bis [5- (2-ethoxyethyl) biguanide]; 1,1'-hexamethylene bis [5 - (^ - isobutoxypropyl) biguanide] or 1,1 '- (2-chloro-p-xylylene) -bis ^ [5-oetylbiguanide] instead of 1,1'-hexamethylenebis [5- (2-ethylhexyl) biguanide] are used, the corresponding product is obtained.

Example 5

Acne lotion, emulsion wt. -%

1,1 · -hexamethylene bls- [5- (2-

ethylhexyl) biguanide] '2HCl 0.1

Propylene glycol 2.5

Ethoxylated Lanolin Alcohols * 3 * 2

Mineral oil 3.8

Cetyl alcohol 1.1

Glycerol monostearate 4.0

Water, to make up to 100.0

Perfumes and coloring agents,
sufficient amount

A mixture of the mineral oil, the cetyl alcohol, the glycerol monostearate and ethoxylated lanolin at 80 ⁰ C, a solution of 1,1'-hexamethylenebis [5- (2-ethylhexyl) -biguanide] '2HCl, the propylene glycol and water were added. The resulting mixture is then cooled to room temperature with stirring.

If other compounds of the general formula I, for example

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wise \ Λ ^f -hexamethylenebi: s-l5 ^ n - heptyl) -biguanide .,%,% * ~ Hexa. ·? - metl ^ lenbis ^ 5- (n ~ octy-l) -biguanid]? 1 A ^x -Hexemethytembis- £ e> _: ~ nony! BiguanidJ * %. , 1 * -hex-amethylene bis / -

guanidj staitefc des, 1 * 1 * -Hexaroefe ^ lj ^^ guanJd) are used, one obtains the eating% speaking product,

Example-1 6 _ ■ .-. ■ .-: ''. ■. / -

Aqueous citrate-phosphate buffer

up to pH ^ 5.5.

Perfume \ md coloring agents

sufficient amount .

An aqueous citrate-phosphate buffer solution from; pH 33 ^, with stirring. Gemiseh des t ^ l ^ -Kexamethyle ^ bis-IS-CS: "™ äthylhexyl) -biguanid]; * 2HCl and isopropyl alcohol added .. If desired, fragrances; and coloring agents ^: can be added.

If other compounds of the above general formula 1, for example 1 , t * '-Hexamethy lenbis - [^ - (n-heptyl) -biguanid] jr 1,1 ^t -hexamethylene bis'-C5 - (n-octyl): - biguanid | il ^ t ^ -hexamethylene bis - [5-nony! biguanid}; 1,. 1 * -hexamethylene bis-ijhexylguanid] :; 1.1 ^? -Hexamethyienbls-13-Qetylguaniä:}; 1,1'-Iiexamethylenbis-E5- (2-ethoxyethyl> -biguaRidl | i I,.% ^L -Kexamethylenbls- [5-O-isobutQxypropy 1} -biguanidl or % Λ * - (2-chloro-p-xylylene) -bis-t5-QQtylbiguanid] '$%. a &% des: 1, i ¹ -HeXamethylenebis-t5- (2-ethylhexyl) .- biguanidJ can be used, so the corresponding product is obtained,

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Claims (1)

Patent answer back 1. Pharmaceutical agent in meterable form for a topical Administration to achieve an anti-acne effect, characterized in that there is an inert pharmaceutical carrier per unit dose and an effective non-toxic amount of at least one Compound of the general formula in which the divalent bridge A (a) Alkylene with 2 to 12 carbon atoms, its valence bonds belong to different carbon atoms, or (b) - (CH ₂ ) _m - Y - (CH ₂ ) _n -, in which m and η are integers from 2 to 6 and Y is 0 or S, or (c) -CH ₂ -CH CH; CH; CH-CH ^ - or wherein each of the substituents Z and Z ^{1 is} alkylene of 1 to J5 carbon atoms, or - 12 - 309826/1167 399 (e) Wherein Q is -0-, -S-, -SO- or -SO ₀ -, or (f) CH = CH is, R either (a) alkyl of 6 to 16 carbon atoms or (b) Alkyl-Y-alkylene, in which -Y has the meaning given above Has, R ^{1 is} H or lower alkyl and X is 2. 2. Means according to claim 1, "dadurc IV characterized in that A is alkylene, R is alkyl and R ^{1 is} hydrogen. J. Agent according to claim 2, characterized in that that it as an active ingredient of general , Formula of claim 1 1,1'-hexamethylene bis [5- (n-heptyl) biguanide]; 1,1'-hexamethylene bis [5- (n -oetyl-biguanide] j -! "3 - 30 9826/1167 ff 1,1 * -hexamethylene bis [5- (2-ethylhexyl) biguanide]; 1,1'-hexamethylene bis [5- (nonyl) biguanide]; 1,1'-hexamethylene bis [3- (hexyl) guanide]; l _J l ^f -hexamethylene bis [3 ~ (octyl) guanide]; 1,1 * -hexamethylene bis [5- (hexyl) biguanide]; !, l'-hexamethylene bis-ß-fljlj ^ -tetramethylbutyl) biguanide]; 1,1 '- (2-methyl-1,4-butylene) bis [5- (heptyl) biguanide]; or 1,1'-hexamethylene bis [5- (decyl) biguanide] contains. 4. Means according to claim 3 »characterized that the active ingredient is 1,1'-hexamethylene bis [5- (n-heptyl) biguanide] contains. 5. Agent according to claim 3> characterized in that it is 1,1'-hexamethylene bis [5- (n-octyl) biguanide] as active ingredient contains. 6. Means according to claim 3> characterized in that that it contains 1,1'-hexamethylene bis - [5- (2-ethylhexyl) biguanide] as active ingredient. - 14 -309826/1167