DE2401446A1 - PHARMACEUTICAL PREPARATIONS FOR THE RELIEF OF SKIN PROLIFERATIONAL DISEASES - Google Patents

Description

LAWYERS

dr. IUR. DiPL-CHEM.Walter beil 2401446 11 Jan 1974

ALFRED HOEPPENER -τι ..

üR. JUR. DIPL.-CHEM. H.-J. WOLFF

ÜR. JUR. HANS CKR. BEIL · '

FRANKFURTAM MAIN-HdCHSt

ADELONSTSASSiM

Our no.19 091. Ec / br

John James Voorhees Ann Arbor, Michigan, V.St.A.

Pharmaceutical preparations for the relief of skin proliferation diseases. · -.--

The present invention relates to pharmaceutical preparations for the relief of skin proliferation diseases such as psoriasis, atopic dermatitis and the like, in humans or pets .. The preparations according to the invention, which are topical and / or systemic can be administered, contain a pharmaceutical carrier and at least one active ingredient from the groups the substituted alkyl xanthines, tricyclic antidepressants, organic mitrates, anti-hypertensive remedies, asthma remedies, and sedatives for the central nervous system.

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The preparations according to the invention can be administered topically or by injection, so that the Preparation enters the bloodstream, or it can be administered intralesionally, intradermally, subcutaneously, or orally will. Treatment can be therapeutic or prophylactic.

Skin proliferation diseases are far in the world spreads and infects millions of people and their pets. The invention relates to pharmaceutical preparations, which are suitable for the relief of these diseases. The term "skin proliferation diseases" used here means benign and malignant rampant (proliferating) skin diseases that are accelerated by Cell division in the epidermis, skin, or skin appendages, along with incomplete tissue differentiation Marked are. These diseases include: psoriasis, atopic dermatitis, non-specific Dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and flaky cell carcinoma of the skin, lamellar ichthyosis, epidermolytic Hyperkeratosis, precancerous sun-induced keratosis, non-cancerous keratosis, acne and seborrheic Dermatitis in humans and atopic dermatitis and mange in pets.

To date, skin proliferation disorders have generally been considered by mankind to be a persistent evil accepted that in different degrees of strength, which over time, with the inherited skin properties and external factors fluctuate, occurs, whereby these diseases however always as disfiguring, painful and were considered pathological. In human

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Countless drugs and treatments have been suggested, tried, with varying degrees of success and applied. However, there was no previously devised treatment or pharmaceutical composition applied in the wide spectrum-specific diseases, which are expressed by the expression diseases of the skin proliferation can be circumscribed, quite successfully.

The current treatments are commercial in nature, which are prescribed for the treatment of skin proliferative diseases and applied include three ways:

(1) topical applications: coal tar derivatives, 5-pluoruracil, Vitamin Α acid, glucocorticoids in high doses (which form an impermissible concentration), Bath oils and non-specific emollients being creams and ointments;

(2) systemic administration: glucocorticoids and classic anti-cancer agents such as methothrexate, hydroxyurea, Azaribine and cyclophosphamide;

(3) physical treatment types: ultraviolet light, X-rays and, in serious cases, surgery.

While these treatments do result in some relief from the original symptoms in certain cases, every treatment suffers from a certain deficiency, e.g. a temporary and incomplete alleviation of Symptoms, rapid recurrence of the disease, when the mitigation ends aSb, a serious one and sometimes irreversible damage (atrophy) resulting from topical application during extended periods Periods of glucocorticoids, an acute inhibition of bone marrow formation and cirrhosis of the liver, which results from prolonged use of methothrexate,

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can lead to the death of the patient, and the
Cancer formation as a result of the use of anti-cancer drugs,
X-rays or, ultraviolet rays.

It has now been found that diseases of skin proliferation are alleviated, that is to say that the symptoms of the disease are noticeably weakened or even undetectable
when treating the patient affected by the disease or the sick animal with one or more of the pharmaceutical compositions according to the invention,
v; which are described in more detail below.

For the purposes of the present invention, a skin proliferation disease is referred to as alleviated if, when touching, a noticeable decrease in the thickness of a pathological change, with or without residual reddening,
remaining slightly dilated blood vessels or one
residual hyper- or hypopigmentation noted
will. In this sense, psoriasis is referred to as alleviated if a pathological change due to dandruff-free psoriasis is noticeably reduced in thickness or noticeably but incompletely cleaned
(cleared) or completely cleaned.

The preparations according to the invention can be topical
or administered by injection so that the preparation enters the bloodstream, or they can
administered intradermally, intra- or perilesional or subcutaneously.

The term "topical" as used in the present refers to the application of the active ingredient, which is incorporated into a suitable pharmaceutical carrier, and to the site of the diseases for the exercise of a
local effect is applied. Accordingly, the-

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like topical compositions those pharmaceutical forms in which the compound is applied externally by direct Applied in contact with the skin surface to be treated will. Conventional pharmaceutical forms for this purpose ■ include ointments, lotions, pastes, jellies, sprays, aerosols, Bath oils and the like.

The term "ointment" includes formulations (including creams) with oily, absorptive, water-soluble and emulsion-like base materials such as Vaseline, lanolin, polyethylene glycols and their mixtures. It it has been found that topical administration with occlusion of an area larger than that to be treated Area, compared to a non-okiuded topical application brings better results, and the former is consequently the preferred method of topical treatment with the preparations according to the invention.

Some of the pharmaceutical preparations according to the invention can advantageously contain auxiliaries that penetrate the skin, such as dimethyl sulfoxide, dimethylacetamide and the like ..

A "intradermal injection ¹¹ is the introduction of the formulation of the invention into the dermis (high dermis) understood by injection with the needle or by injection of air under high pressure.

"Intra- or perilesional" injection is the introduction of the preparation according to the invention into the diseased change or understood in the tissue adjacent to the diseased change.

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The preparations according to the invention can be injected so that they intramuscularly, subcutaneously, through suppositories rectal, sublingual, intravenous, oraj by inhalation or by application to non-diseased skin.

The best mode of administration of the compounds according to the invention is such a treatment of the diseased animal or human that a continued release of the active ingredient at the diseased site or sites occurs at a selected, controlled rate which is maintained for an extended period of time, for example, epinephrine becomes continuous released and provides an epinephrine activity which is maintained for 9 to 10 hours if one uses an aqueous suspension of crystalline epinephrine in a ratio of 1: 200 in a sterile solution, which contains 0.5 % phenol, 0.5 % sodium thioglycolate, Contains 1 % sodium ascorbate and 25 % glycerine in water. This suspension can be administered subcutaneously in a dosage of 0.1 to 0.3 cm of the suspension. Epinephrine activity is obtained essentially immediately from the epinephrine in solution and continued release results from the crystalline epinephrine in suspension. Various modifications to the components of the suspension which are compatible with the particular active ingredient selected for injection can be made in order to obtain the desired, continued and sustained activity of the active ingredient at the site to be treated. Furthermore, the above-mentioned components of the suspension can conveniently be replaced by the selected active ingredient

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For topical or systemic administration to the sick Adapt to patients, and similarly improved results will be obtained from such applications, Isei where the active ingredient is released over an extended period of time.

The compositions of the invention comprise a pharmaceutical carrier and from about 0.1 to about 15 wt -.% / Vol. from at least one of the following connection groups:

1. Xanthines of the general formula

wherein R and R. hydrogen atoms, alkyl or hydroxyalkyl groups with 1 to 7 carbon atoms, cycloalkyl groups with 3 to 7 carbon atoms or aralkyl groups, the alkyl part of which contains 1 to 7 carbon atoms, R _{2 is} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or represents a complex with ethylenediamine and Y represents a hydrogen atom or a thiol radical;

2. Thioxanthines of the general formula

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- ö

24Q1446

wherein R ₁ denotes the methyl, ethyl or propyl group or the group -CH ₂ -CH = CH ₂ , R ₂ denotes the methyl, ethyl or propyl group, the group -CH ₂ CH = CH ₂ , the isopropyl or isobutyl group , the group CH ₂ CCH = CH ₂ , the pentyl, 3-methoxy-propyl, 2-methyl-butyl, hexyl, benzyl, phenyl, phenethyl or furfuryl group and R, a hydrogen atom, the methyl - or represents the ethyl group;

3. a compound of the formula

R ₃ -N-

in which R. denotes a lower alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, the phenyl group or the group (RJ -phenyl. or (Rjj) -phenyl- _{lower alkyl, in which R 1} , a hydrogen atom, a lower alkyl group according to the definition above,

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a halogen atom or a lower hydroxyalkyl group, whose carbon chain contains 1 to 3 carbon atoms; and η denotes the number 1 or 2, Rp denotes a hydrogen atom or represents a lower alkyl group as defined above and R-. a hydrogen atom or a lower one Means an alkyl group as defined above, as well as the physiologically acceptable acid addition salts thereof Links;

4. a compound of the general formula

COOR

'\ 0

wherein R and R are hydrogen atoms or lower alkyl groups with 1 to 3 carbon atoms mean Rp and R, hydrogen atoms, lower alkyl groups with 1 to 4 carbon atoms, phenyl, benzyl, phenethyl, dialkylaminoalkyl groups with 1 to 3 carbon atoms in the alkyl radical or R_ and R_ together form a heterocyclic ring, such as »the pyrrolidino, piperazino, piperidino, methylaziridino, 2,3-dimethylaziridineq or the 4-Hydroxyäthylpiperazinorest form, as well as the pharmaceutical compatible acid addition salts of these compounds;

5. a compound of the general formula

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-Ιΰ-

2A0U46

(I)

■ (II)

wherein R and R. are each hydrogen atoms, lower alkyl groups with 1 bds 8 carbon atoms, represent benzyl or phenethyl groups, R_ is a hydrogen atom, one means lower alkyl group having 1 to 8 carbon atoms or a phenyl group, R, a hydrogen atom, a lower alkyl group as defined above or a lower alkanoyl group, its acyl radical. 1 to 8 carbon atoms contains, means, where only one of the substituents R is a phenyl-containing substituent, and physiological compatible acid addition salts of these compounds;

6. a compound of the general formula

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2401U6

wherein R and R are hydrogen atoms or lower alkyl groups represent with 1 to 3 carbon atoms, Rp and R-, Hydrogen atoms, lower alkyl groups with 1 to 4 Carbon atoms, phenyl, benzyl, phenethyl or dialkylaminoalkyl groups, with 1 to 3 carbon atoms represent in the alkyl radical or R ^ and R, together one form heterocyclic ring, such as the pyrrolidino, piperazino, piperidino, methylaziridino, 2,3-dimethylaziridino or the 4-Hydroxyäthylpiperazinorest, as well as the pharmacologically acceptable acid addition salts of these compounds;

7. a compound of the general formula

= 0

wherein R 1 is a lower alkyl group of 1 to 7 carbon atoms or represents a phenyl, benzyl or phenethyl group and R_ represents a hydrogen atom or a lower one Denotes an alkyl group as defined above;

8. a compound of the general formula

COOR

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2A0U46

where R is a hydrogen atom or an alkyl group with up to 12 carbon atoms, R. is a hydrogen atom, a lower alkyl group as defined above, or a meta- or para-R _i ., R _c . ~ benzoyl-, -phenyl-, -benzyl - or • -phenäthylrest means, Rp is a hydrogen atom, a lower alkyl group according to the above definition, a phenyl, benzyl or phenethyl radical, R means a lower alkyl group according to the above definition, a benzyl or phenethyl radical, and Rj, and R ₁ - in each case V / aster material atoms, halogen atoms, methyl or methoxy groups, as well as physiologically acceptable acid addition salts of these compounds;

3. a compound of the general formula

wherein R denotes a halogen or hydrogen atom, a lower alkyl or a lower alkoxy group, Rp, R, and R ^ independently of one another _{denote hydrogen atoms, lower alkoxy or lower hydroxyalkoxy groups, where of the independent substituents R 2} , R, and Rj. at least one is an oxygen-containing substituent, or R, Rp, R, and Ru as an adjacent pair represent a methylenedxoxy group, or the optical antipodes of these compounds:

10. a compound of the general formula

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C-O-R

vrorin R represents a hydrogen atom or the group -CH ₂₂ , X represents a lower alkyl group with 1 to 8 carbon atoms, a lower alkoxy group with 1 to 8 carbon atoms, a chlorine or bromine atom, or the group -CH, CF, or N0 _p , Y represents a chlorine or bromine atom, the group CP 1, -CH, or NO 2 or a lower alkyl group having 1 to 8 carbon atoms and Z represents a hydrogen or halogen atom, the group CF, or a lower alkyl group having 1 to 8 carbon atoms ;

11. a compound of the general formula

wherein R _{1 is} a hydroxyl group and R _{2 is} the group

" ^ΝΗ Λ \ //"^CH;

or

or R. and R_ together represent the group

- Ö ■ = CH-C 0 or = CH-C-CH ₃

represent;

12. a compound of the general formula

wherein R ₁ '. a hydrogen atom or the methoxy group, R_ the group

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_ -t r _

CH ₃ S

-CS-CH ₃ S

Π H. _{-CH 3} -CNN = Cv.

-C-CH;

-I- / Vcι

or'! -CH ₂ -CH ₂ -N ^

R, a hydrogen atom, the methyl or phenyl group or the group S-CH ₃

and R |. a hydrogen atom, the hydroxyl group, or the group

S.

Ii / —ν ü ^H

-CN 0; -CM-CH ₂ CH ₂ -OH

CN or -C = C- (SCHa) ₂

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mean;

13. a compound of the general formula

wherein X is either the group NR. wherein R _{1 represents} the

Group y 2

means in which η is the number 1 to 3 and R _? and R are hydrogen atoms or methyl groups; or wherein X represents the group C = R ^, wherein Rj. represents the group

H ^ ₅
= C- (CH ₂ ) _n -M ^, in which η is the number 1 to 3,

^R 6

and R [- and Rg represent hydrogen atoms or methyl groups;

14. and at least one compound from the following Group:

Pentylenetetrazole "

Methylphenidate

Bunamidine

Pyrvinium pamoate

Meprobamate

Phenacemide

Dipyridamole

Indomethacin

Chlordiazopoxide

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Nicotinamide Diazepam Disodium Chromium Glycate Levamisole Diazoxide Aldosterone Nitroglycerin AmyInitrat Sodium Nitrate Isosorbide Dinitrate Nicotinic Acid Cyclandelate Erythritol Tetranitrat Pentaerythritol TetranitFat Minoxidil and Quazodine,

wherein the active ingredient is in one for the relief of a skin proliferation disease effective concentration.

The preparations. according to the invention can be used in conjunction with glucocorticoids. Under the The term "glucocorticoids" is used as a naturally occurring one Product of the adrenal cortex or its synthetic analogue understood, which is an anti-inflammatory Effectiveness and has minimal or no mineralcorticoid or sex steroid effectiveness. Of the natural glucocorticoids can be used, for example, hydrocortisone or synthetic glucocorticoids such as e.g.

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Methylprednisolone acetate (prednisone) for oral administration or triamcinolone for topical therapy turn around. The glucocorticoids should be used in small amounts or an "acceptable dose". Under the term "permissible dosage" for glucocorticoids is understood to mean an amount which is the natural output of adrenal cortex glucocorticoids minimally supplemented in a normal person and which in a single person Administration has no noticeable effect on skin proliferation disorders.

The amount of the active ingredient to be used in the preparations according to the invention for topical, parenteral or systemic administration is in the case of topical administration from about O ₃ I % to about 15% by weight, in the case of parenteral administration from about 0.1 to about 10% w / v. and for oral dosage forms, the percentage of active ingredient will be determined by the physical properties of the carrier in terms of manufacturing requirements and elegance.

The preparations according to the invention are for systemic administration to humans and animals in Dosage unit forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions and oral solutions or suspensions such as oil-water emulsions containing a suitable one Amount of one or more of the aforementioned active ingredients made available.

Both solid and liquid unit dosage forms can be prepared for oral administration. To the

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Preparation of solid compositions, such as tablets, becomes the main active ingredient with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate j calcium sulfate, starch, lactose, Akazlenguimai, Methyl cellulose or functionally similar substances as pharmaceutical excipients or carriers mixed. The tablets can be coated or composed in other ways to make one dosage form to give which benefit of a prolonged or delayed effect or a predetermined one to offer successive effects of the included medication. For example, a tablet can have an inner Dosage component and an outer dosage component, the latter in the form of an envelope of the former is present.

However, a 2-component system can also be used for production of tablets that contain 2 or more incompatible active ingredients are used - wafers made in the same way as tablets; they differ only in form and inclusion of sucrose or other sweeteners and / or flavorings. In the simplest embodiment Capsules, like tablets, are made by using the active ingredient or active ingredients with an inert pharmaceutical Mixing extender and filling the mixture into a hard gelatin capsule of suitable size. at In another embodiment, capsules are produced, by making hard gelatine capsules with the active ingredient or the active ingredients containing beads, which with polymers Acids are coated, fills. Soft gelatin capsules are made by machine encapsulation of a slurry of the active ingredient or ingredients in one

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compatible vegetable oil, liquid paraffin oil or a other inert oil produced.

Liquid dosage unit forms for oral administration, such as syrups, elixirs and suspensions can also be produced. The water-soluble forms can in an aqueous vehicle along with sugar, aromatic flavors and preservatives be dissolved to form a syrup. An elixir is made by making an aqueous-alcoholic one (Ethanol) Vehicle with suitable sweeteners, such as sugar and saccharin, used together with an aromatic flavor.

Suspensions can be prepared from the insoluble forms with a syrupy vehicle using a suspending agent, such as acacia, tragacanth, methyl cellulose and the like.

By dispersing the active ingredient (s) in ' a suitable ointment base, such as vaseline, lanolin, polyethylene glycol or their mixtures, topical ointments can be made. Advantageously, the active ingredient or the active ingredients are with Using a colloid mill using paraffin oil as a triturating agent prior to dispersion in the ointment base finely divided. Topical creams and lotions are made by adding the active ingredient or the Active ingredients in the oil phase before emulsifying them in V / water dispersed.

The dosage forms are used for parenteral administration made by adding the active ingredient or the

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_ 21 _

Active ingredients and a sterile vehicle, with water being preferred is used. The connection can, depending on Form and concentration used, either suspended or dissolved in the vehicle. In the preparation of From solutions, a water-soluble form of the compound can be dissolved in water for injection and passed through a filter sterilized before filling into a suitable vial or ampoule and its closure. In the vehicle, the auxiliaries, such as local anesthetics, preservatives and Buffer to be dissolved. To increase the stability, the composition can be filled into the. Vial frozen and the water can be removed under vacuum. The freeze-dried powder is then placed in the vial and a dedicated vial of water for injection may be supplied to restore fluid prior to use. Parenteral suspensions are used made in essentially the same way with with the exception that the compound is suspended in the vehicle rather than dissolved and that there is no sterilization can be achieved by filtration. The compound can be sterilized by placing it in suspension exposes ethylene oxide in the sterile vehicle. Advantageously, a surfactant or a Wetting agents included in the composition to to facilitate an even distribution.

For parenteral or systemic administration of the compositions according to the invention, the usual Dosages of the selected active ingredient or the selected active ingredients are used .. The invention Compositions can include one or more of the aforementioned active ingredients in a single composition

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contain; a variety of compositions, each containing a single or multiple active ingredient, can be administered. In some cases, the administration of compositions which contain a single active ingredient or a mixture of active ingredients can be considered in a variety of these administration forms, such as, for example, a combination of oral administration and / or injection and / or topical administration and the like ..

In other cases it is advantageous to use the dosage forms combined in a time-spaced sequence, for example by systemic administration of one or more of the compositions applies for a period of time, and then one or more compositions administered topically or by injection while systemic administration continues, and the like.

The following examples explain the invention in more detail; they are examples of compositions which typical for the combination of selected active ingredients with a pharmaceutical carrier / are used for treatment of diseases of the skin proliferation can be used in the aforementioned manner.

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The preparations of Examples 1 to 19 can still be improved in their effect if one at the same time or in between 2 χ 20 mg oral prednisone per week administered.

example 1

Capsules

1,000 two-piece hard gelatin capsules for oral use, each of which contains 200 mg of 1-methyl-3-isobutyl-xanthine were made from the following materials:

1-methyl-3-isobutyl-xanthine 50 g

Cornstarch. 250 g

Talc 75 g Magnesium stearate 2 _S 5 g

The fabrics were carefully mixed and then put on encapsulated in the usual way.

The aforementioned capsules are useful for the systemic treatment of psoriasis in adults by using a capsule administered every 6 hours.

In a similar manner, capsules containing 25 ₃ .75 or 100 mg of active ingredient were produced according to the above process by using corresponding amounts of this active ingredient instead of 50 g of l-methyl-3-isobutylxanthine,

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Example 2
Capsules

1,000 two-part hard gelatin capsules for oral use, each of which contains 100 mg of 1-methyl-3-isobutyl-xanthine were made from the following ingredients

1-methyl-3-isobutyl-xanthine 100 g

Corn starch 25Og

Talc 75 g Magnesium stearate 2.5 g

The ingredients were mixed thoroughly and then encapsulated in the usual manner.

The capsules so produced are useful for the systemic treatment of psoriasis in adults; it is administered orally per day h times a capsule.

Example 3

Tablets

1,000 tablets for oral use, each containing 50 mg of 1-methyl-3-isobutyl-xanthine, were taken out the following components:

1-methyl-3-isobutyl-xanthine 50 g

Lactose / 125 g

Corn starch 65 g

Magnesium stearate 7.5 g

Paraffin oil 3 g

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The ingredients were carefully mixed and extruded. The blanks were crushed by taking them Drifted through a sieve with a mesh size of 0.99 mm (No. 16 screen). The granules obtained were then compressed into tablets, each tablet 50 mg l-methyl-3-isobutyl-xanthine.

The tablets so produced are useful for the systemic treatment of psoriasis in adults; one tablet is given orally every 6 hours.

Example ¹ J Oral syrup

1000 cmr of an aqueous suspension for oral use, with a dose of 5 cm 100 mg of l-methyl-3-isobutyl-xanthine were made from the following components:

l-methyl-3-isobutyl-xanthine citric acid

Benzoic acid

Sucrose

Tragacanth

Lime oil

Deionized water

The citric acid, benzoic acid, sucrose, tragacanth and lime oil were dispersed in so much water that a solution of 85O cirr was obtained. In the syrup the l-methyl-3-isobutyl-xanthine was stirred in until it was evenly distributed. So much water was admitted that 1000 cnr were obtained.

ε 2 ε 1 ε 700 ε 5
2 ε
cm ad 1 000 CITK

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The composition so prepared is for systemic Treatment of psoriasis in adults, at a dose of one teaspoon full 4 times a day, is useful.

Example 5

50 G if ε 2, 5 g O, 17 g 1000

Parenteral solution

A sterile aqueous solution for intramuscular use which contains 50 mg of l-methyl-3-isobutylxanthine in a citk was made from the following ingredients:

1-methyl-3-isobutyl-xanthine Lxdocaine hydrochloride methyl paraben propyl paraben

Water for injection ad

The ingredients were dissolved in the water, and the solution was sterilized by filtration. The sterile Solution was filled into vials and the vials sealed.

The preparation is useful for the systemic treatment of psoriasis, being administered intramuscularly at a dose of 1 cm k times a day.

Example 6 Parenteral solution

A sterile aqueous solution for intradermal use, polygamy in one cm 15 mg of l-methyl-3-isobutyl-xanthine

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was made from the following ingredients:

1-methyl-3-isobutyl-xanthine 15 g

10 $ sodium chloride solution q.s.

Injection water ad 1000 cm

The l-methyl-3-isobutyl-xanthine was added to the water and enough sodium chloride was added to that an isotonic solution was formed and the solution was sterilized by filtration.

The sterile solution is given intradereally by high pressure injection for the treatment of psoriasis.

Example 7

Topical ointment

1,000 g of a 10% ointment were made from the following ingredients manufactured:

1-methyl-3-isobutyl-xanthine. 100 g

heavy paraffin oil 250 g

Wool fat 200 g

Vaseline ad 1 000 g

The petroleum jelly and wool grease were melted and 100 g of the paraffin oil was added. To the rest Paraffin oil, the 1-methyl-3-isobutyl-xanthine was added, and the mixture was ground until the Powder was finely divided and evenly distributed.

The powder mixture was stirred into the petroleum jelly mixture and stirring was continued until the ointment froze.

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The ointment made in this way is used to treat mange suitable * when applied topically to the animal skin.

Example 8

1,000 g of a topical cream was made from the following ingredients:

1-methyl-3-isobutyl-xanthine 50 g self-emulsifying glyceryl monostearate
("Tegacid Regular", commercial product of
Goldschmidt Chemical Corporation,

New York, N.Y.) 150 g

Cetin 100 g

Propylene glycol 50 g

Polysorbate 80 5g

Methyl paraben 1 g deionized water to 1 000 g

The glyceryl monostearate and cetin were melted together at a temperature of 70 to 80 ^° C. The methyl paraben was dissolved in about 500 g water and the propylene glycol, polysorbate 80 and l-methyl-3-isobutylxanthine were added in turn, maintaining a temperature maintained vrurde of 75 to 80 ⁰ C. The methyl paraben mixture was slowly added to the melt of the glyceryl monostearate and the cetine with constant stirring. The addition was continued for at least 30 minutes with continued stirring until the temperature dropped to 40 to 15 ° C. By adding 2.5 g of citric acid and 0.2 g of dibasic dissolved in about 50 g of water
Sodium phosphate became the pH of the final cream

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set to 3j5. Eventually there was so much water added to bring the final weight to 1,000 g and the formulation was made to maintain stirred for homogeneity until it cools and solidifies

The preparation thus obtained is useful for treating psoriasis by applying it to the pathological ones Applying changes with an occlusion bandage.

Example 9
cream

1-methyl-3-isobutyl-xanthine 1,000 g

Cetyl alcohol. 600 g.

Stearyl alcohol "600 g

Aerosol OT, 150 g

Vaseline '3,000 g

Propylene Glycol 1 O00 ml

distilled water to 10,000 g

The l-methyl-3-isobutyl-xanthine was mixed with the petrolatum and poured into a melt of the alcohols and des Stir in propylene glycol. The aerosol OT was dissolved in 5,000 cm of water and it was mixed with the vaseline mixture an emulsion was formed by adding enough water to make 10,000 g.

The cream is applied to the areas pathologically changed by psoriasis with an occlusion bandage twice a day upset.

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A composition which · better penetration of the active ingredient in the skin was optionally produced according to the above procedure, with 2,000 g of water were replaced with 2,000 g of dimethylacetamide.

Example 10

Chapels

1,000 two-part hard gelatin capsules for oral use, each ^{containing 25 mg of 1} } (3-butoxy-3-methoxybenzyl) -2-imidazolidinone, were made from the following substances:

4 (3 ~ butoxy-3 ~ niethoxybenzyl) -

2-imidazolidinone 25 g

Corn starch 250 g

Talc · '75 g

Magnesium stearate 2.5 g

The materials were mixed thoroughly and then encapsulated in the usual manner.

The aforementioned capsules are useful for the systemic treatment of psoriasis in adults by administering 1 capsule every k hours.

According to the above procedure, capsules containing 5, 10 and 100 mg of active ingredient were prepared by instead of the 25 g used above. * J (3-butoxy-3-methoxybenzyl) -2-imidazolidinone equivalent Amounts of this active ingredient used.

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Example 11

Capsules

1,000 two-part hard gelatine capsules for oral use, each of which contained 25 mg of 4 (3-butoxy-3-methoxybenzyl) · 2-imidazolidinone were made up of the following ingredients manufactured:

4 (3-butoxy-3-methoxybenzyl) -

2-imidazolidinone 25 g

Corn starch 250 g

Talc 75 g

Magnesium stearate 2.5 g

The ingredients were mixed thoroughly and then encapsulated in the usual manner.

The capsules so produced are useful for the systemic treatment of psoriasis in adults; 1 capsule is administered orally twice a day.

Example 12

Tablets

1,000 tablets for oral use, each of which contains 10 mg of 4 (3-butoxy-3-methoxybenzyl) -2-imidazolidinone were made from the following components:

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4 (3-butoxy-3- methoxybenzyl) ~

2-iniidazolidinone 50 g

Lactose 125 g

Corn starch 65 g Magnesium stearate 7 »5 g

Paraffin oil 3 g

The components were carefully mixed and extruded. The blanks were comminuted by forcing them through a sieve with a mesh size of 0.99 mm (Mr.16 screen). The obtained granules were then compressed into tablets, each tablet 10 mg ⁱ i- (3-butoxy-3-methoxybenzene) -2-imidazolidinone contained.

The tablets so produced are useful for the systemic treatment of psoriasis in adults; 1 tablet is given orally every 4 hours.

Example 13 Oral syrup

1,000 cm * of an aqueous suspension for oral use, each dose of 5 cm containing 25 mg of 4 (3-butoxy-3-methoxybenzyl) -2-imidazolidinone, were made from the following components:

¹ I (3-But oxy-3-methoxybenzy 1) 2-imidazolidinone

citric acid

Benzoic acid

Sucrose

Tragacanth

Lime oil

Deionized water ad

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5 ε 2 G 1 G 700 ε 5 G 2 cm 1,000 cm

The citric acid, benzoic acid, sucrose, tragacanth and lime oil were dispersed in enough water that a solution of 85O cnr was obtained. The ^ (3-butoxy-3-niethoxybenzyl) -2-imidazolidinone was in the syrup stirred in until it was evenly distributed. So much v / ater was added that 1,000 cnr were obtained.

The so hergesbellte preparation is for the systemic treatment of psoriasis in adults at a dose of 1 teaspoon H χ daily usable.

Example 1 * 1 Parenteral solution

A sterile aqueous solution for intramuscular use containing 5 mg of ¹ l- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone in 1 cm was prepared from the following ingredients:

4- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone

Lidocaine hydrochloride methyl paraben propyl paraben

Water for injection ad

The ingredients were dissolved in the water, and the solution was sterilized by filtration. the sterile solution was filled into ampoules and the ampoules were sealed.

5 G G 2 , 5 g O , 17 g i 000 cm ^

409830/1096

- 3k -

The preparation is useful for the systemic treatment of psoriasis, it being administered intramuscularly in a dosage of 1 cm h daily

Example 15 Parenteral solution

A sterile aqueous solution for intradermal use, which contained 1 cm ^ 5 mg ⁱ t- (3 ~ butoxy-3-methoxybenzyl) -2-imidazolidinone, was prepared from the following ingredients:

4- (3-butoxy-3-methoxybenzyl) -2-

iraidazolidinone 5 g

10% sodium chloride solution q.s.

Injection water ad 1 000 cm

The 4- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone was added to the water and it became sufficient Sodium chloride was added to form an isotonic solution and the solution was purified by filtration sterilized.

The sterile solution is given intradermally by high pressure injection for the treatment of psoriasis.

Example 16 Topical ointment

1,000 g of a 10 # ointment was made up of the following ingredients manufactured:

409830/1096

240U46

ⁱ i- (3-butoxy-3-methoxybenzyl) -2-

imidazolidinone 100 g

Heavy paraffin oil 250 g

Wool fat 150 g

Vaseline ad 1 000 g

The petroleum jelly and the wool fat melt and 100 g of the paraffin oil are added. M- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone was added to the remaining paraffin oil added, and the mixture was ground until the powder was finely divided and uniform distributed.

The powder mixture was stirred into the petroleum jelly mixture and stirring was continued until the ointment froze.

The ointment produced in this way is suitable for the treatment of mange if it is applied topically to the animal skin.

Example 17

1,000 g of a topical cream are made from the following ingredients:

^ - (3-Butoxy-3-methoxybenzyl) -2-

imidazolidinone 50 g.

Self-emulsifying glyceryl monostearate ("Tegacid Regular"), commercial product of Goldschmidt Chemical Corp., Mew Yorl $ N.Y.) 150 g

Cetin 100 g

Propylene glycol 50 g

Polysorbate 80 5 g.

409830 / "1096

Methyl paraben "Ig

Deionized water ad 1 000 g

The glyceryl monostearate and cetin were melted together at a temperature of 70 to 80 ° C. That Methyl paraben was dissolved in about 500 grams of water, and the propylene glycol, polysorbate 80 and 4- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone were in turn added, maintaining a temperature of 75 to 80 ° C became. The methyl paraben mixture slowly became the melt of the glyceryl monostearate and the cetin added with constant stirring. The addition was carried out over a period of at least 30 minutes while continuing Stir, continuing stirring until the temperature dropped to 40-45 ° C. By Add 2.5 g citric acid and 0.2 g in about 50 g With sodium dibasic phosphate dissolved in water, the pH of the final cream was adjusted to 3 * 5. Finally enough water was added to bring the final weight to 1000 g, and the preparation was stirred to maintain homogeneity until it had cooled and solidified.

The preparation thus obtained is useful for treating psoriasis by applying it to the pathological ones Applying changes with an occlusion bandage.

Example 18
cream

4- (3-butoxy-3-methoxybenzyl) -2-

imidazolidinone 1,000 g

Cetyl alcohol 600 g

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240U46

Stearyl alcohol - 600 g

Aerosol OT 150 g

Vaseline 3,000 g

Propylene glycol 1 000 ml

distilled water to 10,000 g

The ^I i- (3-butoxy-3-methoxybenzyl) -2-imidazolidinone was mixed with the petrolatum and stirred into a melt of the alcohols and propylene glycol. The aerosol OT was dissolved in 5,000 cm of water, and an emulsion was formed with the petroleum jelly mixture by adding enough water to obtain 10,000 g.

The cream is applied 2 daily to the areas pathologically changed by psoriasis with an occlusal bandage upset. '

A composition that provides better penetration of the active ingredient in the skin, was optionally produced according to the above procedure, with 2,000 g of water being replaced by 2,000 g of dimethylacetamide.

Example 19

Following the procedure of Examples 1 to 8 above, preparations were made which are suitable for the treatment of psoriasis by employing a therapeutic dosage amount of the following substances: 1-methyl-3-isobutyl-xanthine, 6-thio-theophylline 1,6- Dimethyl-1,6-dihydro-dipyrazolo (3, Ü ~ b : 3 ', 4 ^! -D) pyridin-3-one, 4-dimethylamino-5-niethoxyearbonyl-3-iiiethylisoxa-

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240U46

yolo- (5, 4-b) -pyridine, S-ethoxycarbonyl- ^ - (2-tert-butylhydrazino) -3-methylisoxayolo- (5 _s 4-b) -pyridine, 5-ethyl-iJ-piperazino ⁱ -3-niethylisoxayolo - (5 j ¹ Hb) -pyridine, 5,6,8-trimethyldipyriazolo- (3, ² ib: 3 ', ¹ I ^! -D) -pyridin-3 (2H) -one, 4-ethoxy-1-ethyl -3-methy1-lH-pyrazolo - (^, 3-c) -pyridine-T-carboxylic acid ethyl ester, 4- / 3- (n-butoxy) -4-raβthoxybenzy3.7-2-imidazolidinone, glyeeryl-2- (2,6-dimethylanilino) nicotinate, l-oxo-2-acetonylidene benzo (b) thiophene, N- _> / T- (pyrollidino) -iithyl7-2-phenyl-5-methoxyindole, or imipramine.

A09830 / 1096

Claims (1)

Claim: wherein R and R. are hydrogen atoms, alkyl or hydroxyalkyl groups having 1 to 7 carbon atoms, Cycloalky! groups, R ₂ represents a hydrogen atom, an alkyl group having 1 to k having 3 to 7 carbon atoms, or aralkyl groups whose alkyl moiety contains 1 to 7 carbon atoms, Represents carbon atoms or a complex with ethylenediamine and Y represents a hydrogen atom or a thiol radical; 2. Thioxanthines of the general formula 409830/1096 2AQH46 where R denotes the methyl, ethyl or propyl group or the group -CHp-CH = CH ₂ , R ₂ denotes the methyl, ethyl or propyl group, the group -CHpCH = CH ₂₃ denotes the isopropyl or isobutyl group, the group CH ₂ CCH = CHp, the pentyl, 3-methoxy-propyl, 2-methyl-butyl, hexyl, benzyl, phenyl, phenethyl or furfuryl group and R., a hydrogen atom, the methyl or the Represents ethyl group; 3. a compound of the formula R ₃ -N- v / orin R. a lower alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, the phenyl group or the group (Rj -phenyl, or (Rh) -Phenyl-lower alkyl means in which R ^ is a Vfassstoff atom, a lower alkyl group as defined above ^ A09830 / 1096 - kl - a halogen atom or a lower hydroxyalkyl group ₃ whose carbon chain contains 1 to 3 carbon atoms, and η denotes the number 1 or 2, R “denotes a hydrogen atom or a lower alkyl group as defined above. and R-, a hydrogen atom or a lower alkyl group as defined above, and the physiologically acceptable acid addition salts of these compounds; k. a compound of the general formula R ₂ R ₃ ■■■■ "'■■■;: N - ^ ·., ■ ·. (T COOR where R and R. are hydrogen atoms or lower alkyl groups with 1 to 3 carbon atoms, R ^ and R-, hydrogen atoms ₃ lower alkyl groups with 1 to 4 carbon atoms, phenyl, benzyl, phenethyl, dialkylaminoalkyl groups with 1 to 3 carbon atoms, in the alkyl radical or Rp and R together form a heterocyclic ring, such as, for example, the pyrrolidino, piperazino, piperidino, methylaziridino, 2,3-dimethylaziridino or 4-hydroxyethylpiperazino radical, as well as the pharmaceutically acceptable acid addition salts of these compounds; 5. a combination of the general formula ■ 409830/1096 0OR ₁ (I) 240H46 NH-N = C-Y 00R ₁ (M) wherein R and R ^. each represent hydrogen atoms, lower alkyl groups with 1 to 3 carbon atoms, benzyl or phenethyl groups, R _p denotes a hydrogen atom, a lower alkyl group with 1 to 8 carbon atoms or a phenyl group, R denotes a hydrogen atom, a lower alkyl group as defined above or a lower alkanoyl group whose acyl radical contains 1 to 8 carbon atoms, only one of the substituents R being a phenyl-containing substituent, and physiologically acceptable acid addition salts of these compounds; 6. a compound of the general formula. NO 409830/1096 240U46 vrorin R and R _{1 represent} hydrogen atoms or lower alkyl groups with 1 to 3 carbon atoms, Rp and R., hydrogen atoms, lower alkyl groups with 1 to 4 carbon atoms, phenyl, benzyl, phenethyl or dialkylaminoalkyl groups with 1 to 3 carbon atoms Represent an alkyl radical or Rp and R ^ together form a heterocyclic ring, such as, for example, the pyrrolidino, piperazino, piperidino, _a methylaziridino, 2 ₉ 3-dimethylaziridino or the 4-hydroxyethylpiperazino radical, and the pharmacologically acceptable acid addition salts of these compounds; 7. a compound of the general formula = 0 H ₃ wherein R 1 is a lower alkyl group having 1 to 7 carbon atoms or represents a phenyl, benzyl or phenethyl group and R_ represents a hydrogen atom or a lower one Alky! Group according to the above definition means; 8. a compound of the general formula COOR 409830/1096 -Hk- 2A0U46 where R denotes a hydrogen atom or an alkyl group with up to 12 carbon atoms, R. denotes a hydrogen atom., a lower alkyl group as defined above, or a meta- or para-R _i pR _c . -benzoyl-, -phenyl-, -benzyl - or. -phenäthylrest means, R _{2 is} a hydrogen atom, a lower alkyl group according to the above definition, a phenyl, benzyl or phenethyl radical, R ^ a lower alkyl group according to the above definition, a benzyl or phenethyl radical, and R. and Rj - each denotes hydrogen atoms, halogen atoms, methyl or methoxy groups, and physiologically acceptable acid addition salts of these compounds; 9. a compound of the general formula wherein R is a halogen or hydrogen atom, a lower alkyl or a lower alkoxy group, R, R and Rk are independently hydrogen atoms, lower alkoxy or lower hydroxyalkoxy groups, where of the independent substituents R ₂ , R-. and R ^ is at least one an oxygen-containing substituent, or R, Rp, R ^. and R ^ as an adjacent pair represent a methylenedioxy group, or the optical antipodes of these compounds 10. a connection of the general Porinsl 409330/1096 wherein R represents a hydrogen atom or the group -CBLCHOHCHpOH, X represents a lower alkyl group with 1 to 8 carbon atoms, a lower alkoxy group with 1 to 8 carbon atoms, a chlorine or bromine atom, or the group -CH ,, CF- or NO ₂ , Y represents a chlorine or bromine atom, the group CF ,, ^CH ^ or NO ,, or a lower alkyl group having 1 to 8 carbon atoms and. Z represents a hydrogen or halogen atom, the group CP, or a lower alkyl group having 1 to 8 carbon atoms; 11. A compound of the general formula wherein R _{1 is} a hydroxyl group and R "is the group -CH ₃ or 409830/1096 - lib - or R ₁ and R together represent the group - O! = CH-C or O = CH-C-CH _; represent; 12. a compound of the general formula wherein R ₁ .. is a X-fiber atom or the methoxy group, R_ the group 40983 0/1096 -CH ₃ S -CS-CH ₃ S. - (1-N-CH ₂ -CH ₃ -C-N-N = C- J. CH ₃ (t Vc ι or! -CH ₂ -CH ₂ -ii R is a hydrogen atom, the methyl or "phenyl group or the group S-CH ₃ ■ and Rj _{1 is} a hydrogen atom, ₃ the hydroxyl group, or the group S Ο Il y — ν U ^H " -C-N Ο; -C-N- ( -CH ₂ CH ₂ -OH CN -CC- (SCHa) ₂ 409830/1096 mean; 13. a compound of the general formula wherein X is either the group NR _-1 , wherein R ^ the R group / ~ < ^C Vn < means in which η is the number 1 to 3 and B and R-. Are hydrogen atoms or methyl groups; or wherein X represents the group C = R ^, wherein Ru represents the group H
= C- (CH ₂ ) _n -N means in which η is the number 1 to 3, and R ₁ - and Rg represent hydrogen atoms or methyl groups; lh. . at least one compound from the following group: Pentylenetetrazole methylphenidate bunamidine Pyrvinium pamoate meprobamate Phenacemid dipyridamole Indomethacin chlordiazopoxide 409830/1096 Nicotinamide Diazepam Disodium Chromium Glycate Levamisole Diazoxide. - Aldosterone nitroglycerin Amyl nitrate Sodium nitrate Isosorbide dinitrate Nicotinic acid Cyclandelate '.. Erythritol tetranitrate Pentaerythritol TetranitBat Minoxidil and Quazodine, wherein the active ingredient is in one for the relief of a skin proliferation disease effective concentration For: John James Voorhees Ann Arbor, Michigan, V.St.A. Dr H.J. Wolff Lawyer 409830/1096