DE3407861A1 - PHENETHANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS - Google Patents

Description

PROF. DR. DR. J. REITSföTTeR "DR". WERNER KINZEBACH DR. ING. WOLFRAM BUNTE

DEAD. KINZEBACH Bl PARTNER PATENT LAWYERS

ACH 7-0. DBOOO MÜNCHEN 43 APPROVED REPRESENTATIVES AT

EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE: (Ο8Θ) 2 71 6B 83 CABLES: PATMOND1AL MUNICH

TELEX: OS21B2OB ISAR D TELEKOP: (Ο8β) 271 βθ 83 (GR. II + III) BAUERSTRASSE 22. D-SOOO MUNICH

March 2, 1984

OUR FILES: M / 25 027

OUR REF:

BRISTOL-MYERS COMPANY
Park Avenue

New York, NY10154
United States

Phenethanolamines, process for their preparation and

pharmaceutical agents

POSTAL ADDRESS: D-BOOO MÜNCHEN 43. POST BOX 7ΘΟ

ohU / ob I Μ / 25 027 Λ. '

The invention relates to anti-inflammatory, nonsteroidal, pharmaceutical compositions for topical administration. In particular, these agents contain one as an active ingredient or several βg-adrenergic agonists.

The invention also relates to heterocyclic carbon compounds the indole series with an amino substituent and methods of making these compounds. The compounds according to the invention have a biological one Effect and are useful for treating the body.

Although hundreds (if not thousands) of β ₂ agonists are known, topical anti-inflammatory effects have only been described for salbutamol. At the present time it is assumed that no structure-activity relationship is known for predicting a topical, anti-inflammatory effect, on the contrary, such an effect can hardly be predicted.

Most skin diseases are associated with inflammation. The variety of inflammatory skin diseases and Skin conditions (including those chronic and acute types) has a constant search for anti-inflammatory Medicinal products.

The introduction of steroids provides the dermatologist with a class of anti-inflammatory agents, those against a wide range of inflammatory diseases Skin diseases is therapeutically effective. For many inflammatory conditions, especially chronic ones Conditions, however, the steroids are only palliative and require extensive use. the

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1

However, long-term use of steroids has adverse consequences such as skin atrophy, stria, telangiectasia, steroid acne and adrenal suppression, especially in children. In addition, termination of steroid therapy in various chronic, inflammatory skin diseases to a recurrence of symptoms inflammatorisehen _f sometimes even with increased intensity out. In view of the disadvantages of steroid use, many nonsteroidal anti-inflammatory agents (ie, NSAIA) have been developed over the past 20 years for use in various diseases, including rheumatic diseases. These compounds appear generally free from the adverse side effects of the Steroids, especially of tissue atrophy, adrenal suppression and other less severe side effects.

One class of compound that belongs to the NSAIA group is a group of compounds called prostaglandin synthetase inhibitors represent. These materials are generally effective in reducing UV-induced erythema (i.e., erythema induced by ultraviolet light) in guinea pigs. However, these materials are at other dermatitis tests »including the one in the Examples of croton oil and oxazolone ear edema assays, only weakly effective or even inactive. The creation of other non-steroidal classes of compounds with topical anti-inflammatory activity is therefore of great interest.

ß-adrenergic agonists (including the S ₁ - and ß ₂ agonists) are compounds, _{ie © 9} as for example by RJBrittain et al. in Adv.Drug R © s. £, 197, 1970,

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described, act by stimulating adenylate cyclase, which leads to a conversion of adenosine triphosphate (ATP) into cyclic 3 ^f , S'-adenosine monophosphate (C-AMP). The walls of substantially fully nucleated mammalian cells contain the enzyme adenylate cyclase, which is stimulated by various compounds including prostaglandin E and β-adrenal drugs.

Adenylate cyclase activity has been reported to be present in the epidermis of humans and animals. Disruptions in adenylate cyclase activity and in the C-AMP level have been reported in proliferative skin diseases such as Eczema, psoriasis, and epidermolytic hyperkeratosis lamellar ichthyosis, reported.

In short, ß-agonists are a class of compounds which is the adrenergic system of the human Body stimulates.

Materials classified as ß.j agonists are ß-agonists, which are selective with the ß ^ -receptors react and induce cardiac stimulation.

Materials classified as β ₂ agonists react selectively with the β ₂ receptors that are present in the smooth muscles of the blood vessels and bronchi. These materials cause bronchodilation and vasodilation.

GB-PS 4,323,575 discloses disubstituted catecholamines (which can be ß2 agonists) with topical, anti-inflammatory Effect described.

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1

US Pat. No. 3,341,584 describes sulfonanilides of the general formula I.

(I)

Those sulfonanilides of the formula I in which Z is CHOH are pharmacologically active phenethanolamines with a Effect corresponding to either the effects of the adrenal medular hormones or the adrenergic neurotransmitter resembles or runs counter to these effects. Phenalkanolamines, which are alkyl- and aryl-sulfonamido-substituted on the core have useful pharmacological effects, on the basis of which they act in various ways as vasopressors, vasodepressors, analgesics, bronchodilators, α-receptor stimulants, ß-receptor stimulants, a-receptor blockers, 3-receptor blockers, papaverln-like depressants from smooth Muscles or anti-inflammatory © agents which are used for Control or prevention of anaphylaxis are useful.

Anaphylaxis is listed in the McGraw-Hill Dictionary of Scientific and Technical Terms, 2nd Edition, 1978, as hypersensitivity defined following a parenteral injection of an antigen, with a local or systemic, allergenic reaction occurs »when the antigen has passed administered again over a period of time. Topical application is called "local application or intended for local application "and is used in the context of the present invention in this sense. Because now anaphylaxis and topical inflammation

H ti m * m

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1

are different physiological conditions, a drug is useful for treating the one condition is, in general, not useful for the treatment of the other condition.

In US Pat. No. 3,801,631, the 2-hydroxy-5 · - [1-hydroxy-2- (2-methyl-1-phenyl-2-propylamino) -ethyl] methanesulfonanilide called Zinterol is used described {this compound also falls within the scope of the US-PS 3,341,584 described sulfonic acid amides). Zinterol is described as a potent anorexigenic agent, an orally active bronchodilator, and an analgesic.

In the article, "Adrenergic SuIfonanilides, 4th Centrally Active β-Adrenergic Agonists ", D.L. Temple et al., Journal of Medicinal Chemistry, Volume 19, No. 5, pp 626-633 (1976), Zinterol (Compound No. 43) is described as a potent anorexant and as a narcotic antagonist.

Other uses are shown in U.S. Patents 3,919,424 and 3,993,776 indicated by Zinterol.

Salbutamol is a β ₂ agonist. This connection is described in R. Seely et al., Proc.Soc.Exp.Biol.Med. 1% 2, 223 (1978), described as a useful topical anti-inflammatory agent.

The synthesis of salbutaraol is in Drugs of the Future IV, 629 (1979). Salbutamol is used there as a useful anti-inflammatory when administered locally Means mentioned. In addition, it is stated that salbutamol when administered orally is the control

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of asthma related drugs is superior. A mechanism for the action of salbutamol is proposed? beat (see page 631 of the above publication).

In the publication by Saiichirou Seo et al., "Inhibition of Adjuvant Arthritis by Salbutamol and Aminophylline ", European J. of Pharmacology, 63, 267-274, 1980 is the Inhibition of swelling on mouse paws after injections of salbutamol and aminophylline combinations described.

Have other materials that structural similarities to Zinterol and topical, antiinflammatorisohe effect are described in US Patent No. 4,323,575. These materials can be β agonists; whether they are, however, could only be determined by experiment.

Further ' ^R ' agonists which have anti-inflammatory effects are described in US Pat. No. 4,088,756.

As will be explained _{below, it is not possible to predict with sufficient certainty which β 2} agonists are effective, topical, anti-inflammatory agents. After many experiments it has now been found that almost all β-agonosts tested for such an effect were either ineffective or highly toxic or both.

Despite the known connections, there is therefore a constant need for non-sterile, anti-inflammatory drugs that are good anti-inflammatory Have activity and are non-toxic.

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The state of the art for ß-adrenergic agonists The basis of phenethanolamine compounds of the catechol type is extraordinarily extensive.

In the above-mentioned US Pat. No. 3,341,584, phenethanolamines of the catechol type are broadly described, one of the hydroxyl groups on the phenyl ring being replaced by a sulfonic acid amido group. This gets one compounds with ß-adrenergic, biological activity.

In US Pat. No. 2,908,691, hydroxyphenalkylaminoalkyl indoles are in broad form which have different effects on the central nervous system and act as antisecretory agents to reduce stomach acidity. The most important connection seems 3- (2- [2-Hydroxy-2- (3,4-dihydroxyphenyl) ethylamino] propyl] indole tartrate the preparation of which is described in Example 7.

The object of the invention was therefore to create a material which, in a suitable carrier, provides a means which when administered topically reduces topical inflammation in mammals.

The object of the invention was also to provide a pharmaceutical agent in the form of an ointment, cream, lotion or a to create another formulation that, when applied topically to mammals, reduces skin inflammation or prevented.

These objects are achieved by the invention pharmaceutical means that

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(a) One to achieve a topical, anti-inflammatory Effect effective amount of at least one compound of the general formula II

^ ^ - CH-CH ₉ NH-ACB-CH ₉ -M (II)

OH
10

wherein

1 2

R and R independently of one another denote a hydrogen atom or a lower alkyl group, where R and R ² cannot simultaneously denote a hydrogen atom;

M is a phenyl group or an indole group of the formula (a)

Η

or represents a hydrogen atom;

A is the group (-CH ₂ -) _n , where η is 0, 1 or 2;

B denotes the group (- ^c H ₂ -) _m , where m denotes Q, 1 or 2; where _n and m are integers,

R ^{3 is} -OH or -OCO- (O) -CH; and

R ^{4 is} -NH-SO ₂ -CH ₅ or -OCO- (O) -CH ₃ ,
or a. pharmaceutically acceptable salt or sol-vate thereof, and

(b) a compatible, topically acceptable
Carrier included.

"1

R and R are preferred in the above formula (II) for methyl groups and m and η for 0. The is preferred

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Compound of the formula (II), in which η and m are 0, 1 2

R and R stand for -CEU, M stands for a phenyl group,

R ^{5 is} -OH and R ^{4 is} -NH-SO ₂ -CH ₃ . This compound is known as Zinterol (hereinafter referred to as Compound III).

Another preferred compound for use in the agents according to the invention is the compound of general formula (II), in which η and ra stand for 0,

1 2

R is a methyl group and R is a hydrogen atom

■ 55 a

M means an indole group, R- 'for -OH and R for -NH-SO ₂ -CH. This compound is referred to below as compound IV.

Another preferred compound for use in the agents according to the invention is the compound of the general formula (II), in which η and m are 0, 1 ρ
R and R stand for -GHU, M stands for an indole group,

R ^{5 is} -OH and R ^{4 is} -NH-SO ₂ -CH ₃ . This compound is referred to below as compound V or azazinterol.

Another preferred compound for use in the agents according to the invention is the compound of general formula (II), in which η and m are 0,

1 2
R and R represent a methyl group, M represents a hydrogen atom and R · ⁵ and R represent -OCO- ^ Ö ^ -GH ^. This compound is hereinafter referred to as Bitolterol and is commercially available * It is used to treat allergies, but it was not previously known that it could also be used to treat topical inflammation.

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The treatment of topical inflammations in mammals, including humans, is carried out by topically administering a compound of the general formula (II) to the mammal so that localized (as opposed to systemic) activity against topical inflammations is established.

In addition, the invention relates to a topically administered pharmaceutical agent for reducing topical inflammations in mammals, which comprises at least one compound of the general formula (II) in a non-toxic but sufficient amount to reduce the inflammation in a pharmaceutically acceptable carrier material or carrier materials, wherein A, B, R ¹ , R ² , R have meanings.

where A, B, R, R, R, R and M are those given above

Another preferred embodiment relates to a pharmaceutical agent to be administered topically, the at least one compound selected from Zinterol, Compound IV, Compound V and Bltolterol, in a non-toxic, but to reduce the inf! animation in a sufficient amount and in a pharmaceutically acceptable carrier.

The expression "used in the present invention topically ¹¹ represents local application or intended for local administration to a local effect, preferably without an accompanying systemic effect to cause. The next in the inventive compositions for use compounds can be therefore administered in a variety of but they cannot be injected or swallowed.

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cutaneous, nasal, vaginal, rectal, otic and buccal administered. They are administered in conjunction with a dermatologically acceptable carrier, which is preferably is selected so as to prevent or reduce systemic absorption of the active ingredient.

The invention also relates to antiasthmatic agents which are bronchodilators and potent but selective Are inhibitors of smooth muscle contraction. The effectiveness and selectivity of these agents in the Inhibition of smooth muscle contraction by antigen-induced release of chemical mediators caused by pharmacological tests using immunized guinea pig tracheal rings shown. These agents include compounds IV and V and their pharmaceutically acceptable ones Solvates and salts. The invention also includes its use as antiasthmatic agents.

The compound (s) to be incorporated into a carrier to provide agents suitable for topical use as anti-inflammatory preparation (s) in mammals, including humans, are the compounds of the general formula above (II) (or their pharmaceutically acceptable salts and solvates). In this formula, M denotes a phenyl or indole group or a hydrogen atom, A denotes - (CH ₂ -) _n , where η denotes 9, 1 or 2; B is (-CH ₂ ) _m -, where m is 0, 1 or 2; R ¹ and R ² independently of one another represent a hydrogen atom or

1 2

a lower alkyl group, where R and R cannot be a hydrogen atom at the same time; R * stands for -OH or -OCO- (O) -CH,; and R ^ is -NH-SO ₂ -CH ₃ or -OCO- (O) -CH ₃ .

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In the context of the present invention, a lower alkyl group means a straight-chain or branched one Hydrocarbon radical having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms.

Many β ₂ -adrenergic agonists (all of which are Zinterol analogs) were tested. Of about. 45 such compounds showed a strong topical, anti-inflammatory activity with no toxic effect in only 4 in the tests described below in the examples. The remaining compounds, when administered topically to the test animals, were either toxic, ineffective and / or of inconsistent anti-inflammatory activity, or both.

The creation of a pharmaceutical agent that can be used as an anti-inflammatory preparation for topical use Useful in mammals, compound (s) to be incorporated into a carrier are as follows Way made.

The preparation of Zinterol is detailed in US Pat. No. 3,801,631 "2 ^L -hydroxy-5 '- [i-hydroxy-2- (2-aethyl-1-phenyl-2-propylamino) -ethyl] -methanesulfonanilide and its Salts ". This patent is hereby incorporated by reference.

In the context of the present invention, Me means a Methyl group. A detailed description of the preparation of the compounds (IV) and (V) is given below specified '. You can choose between two general procedures choose. The making of the connections of the Formula II according to claim 1 is carried out analogously.

M / 25 027 ¹ Procedure 1

(b)

340786I

OH

NHSO ₂ CH ₃

(VIII)

10

■> Connection IV

15 20 25

catalyst

One synthetic method involves the reductive amination of an indolyl carbonyl compound with an appropriate one Phenethanolamine. The choice of reagents and the reaction conditions for reductive aminations are known to the person skilled in the art. In general, the reaction is carried out by adding a solution of a suitable Carbonyl compound and a phenolic amine in a solvent such as a lower alkanol, e.g. methanol, in the presence of a hydrogenation catalyst such as a noble metal catalyst such as platinum oxide in a hydrogen atmosphere shakes. Alternatively, the reaction can also be carried out in stages by first applying the Carbonyl compound and the phenolic amine is converted to the corresponding condensation product and then the hydrogenation is carried out as a separate process stage.

A variation of Synthetic Method 1 is a nucleophilic substitution on an indolylalkyl halide or an equivalent thereof by the phenolic amine. This procedure is hereinafter referred to as procedure 1A reproduced.

M / 25 027 1 Procedure 1A

+ (VIII)

(c)

Compound IV (when R = H) or

Connection V (if R = Me)

In the general formula (c), X represents a common one Leaving group, such as a halide, tosylate or the like. Here too, the choice of reaction conditions is important and the reagents for the nucleophilic substitution reaction known to those skilled in the art.

The second, for the preparation of compounds (IV) and (V) useful procedures are shown in General Synthesis Procedure 2 below. This general procedure can also be used to prepare the compound (V).

Procedure 2

OH

(X)

NHSO ₂ CH,

reduction

Compound IV (when R = H)

or

Connection V (if R = Me)

This process involves the alkylation of an indolylalkylamine by a corresponding phenolic bromoketone. The carbonyl group is then reduced to a secondary alcohol group. In practice it will the phenolic OH group during the nucleophilic sub-

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institution protected. This is necessary in order to prevent the phenolic group from being attacked nucleophilically and thus undesirable ether by-products are formed. In general, a benzyl group serves as a protective group, which is then removed by catalytic reduction.

These general synthetic procedures were incorporated into the synthetic schemes used to prepare Compounds IV and V. accepted. These schemes are given below.

Scheme A t preparation of compound IV

CHCl ^

^C 6 ^H 12 ^N 4 -

Ο Br JJ.

NHSOpCH

(IX)

OH

HCl

θ Br

^C 6 ^H 12 ^N 4

NHSO ₂ CH ₅

HCl

Pd / C EtOH

(VIII)

H ₂ PtO,

NHSO ₂ CH ₃

OH

EtOH HCl

NHSO ₂ CH ₃

(XI)

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t6

KHSO ₂ CH ₃

IV

SO ₂ CH ₃

OCH ₂ Ph

XII, R = H

l) acetonitrile

2) NaBH,

NHSO ₂ CH ₃

OCH Ph 2

X, R = H IX »

Scheme A shows the preparation of the compound IV. Two reaction paths are shown, both of which start from one of the bromo ketones IX and IX ¹ . In the upper reaction route, compound IX is treated with hexamethylenetetramine. (CgH ₁₂ N ^) converted to a quaternary salt, which is converted into the aminoketone XI and then by catalytic hydrogenation into the phenethanolamine VIII. The reductive alkylation of 3-indolyacetone with VIII gives the title compound IV. The second and preferred reaction route leads via a nucleophilic reaction of the indolylamine X and IX ¹ (the O-benzyl analog of IX) and subsequent borohydride reduction to the intermediate product with benzyl -blocked phenolic group (XII: R = H). This intermediate product is then catalytically reduced to the desired end product.

4 ■ · «

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Scheme B; Establishing the connection V

"OCH ₂ Ph

X; R = Me

IX ¹

2) NaBH ^ EtOH

10

(XII: R = Me)

MeOH.

20th

OH

NX ₁ ^ -UW ₂ W ₃

| WJ-

NHSO ^ CH,

Compound V

Scheme B illustrates the preparation of compound V, using essentially the same reaction route as in second part of scheme A is taken. In scheme B, the corresponding indolylamine is reacted with IX ' and the resulting adduct is then reduced to the protected phenolic compound (XII: R = Me) with borohydride. This is then converted into the desired compound V by catalytic hydrogenation.

These two synthesis schemes will be explained in more detail. The interconnections used for this purpose are

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either commercially available, such as 3-indolylacetone, or they are in the chemical literature as cited in B in the discussion of the prior art Publications.

The production of bitolterol is described in US Pat. No. 4,138,581, which are hereby incorporated by reference.

Pharmaceutically acceptable solvates and salts for medical use are such complexes in which the Solvent, metal cation, or acid anion did not significantly affect toxicity or pharmacological activity of the organic drug ion contributes. The sulfonamido group is the one used in metal salt formation, acidic function. Examples of suitable metal salts are sodium, potassium, calcium, magnesium, aluminum and zinc salts. The metal and acid addition salts are obtained either by reacting the selected Combination with a suitable metal base to form a metal salt or with an organic or inorganic one Acid with formation of the acid addition salt · Preferred catfish are brought into solution or according to one of the standard methods described in detail in the literature and known to the person skilled in the art in contact. Usable organic acids are, for example, carboxylic acids such as maleic acid, acetic acid, tartaric acid, Propionic acid, fumaric acid, isethionic acid, succinic acid, Pamoic acid, cyclamic acid and pavalic acid (pavalic acid) and the like.

Inorganic acids which can be used are hydrohalic acids (such as HCl, HBr, HJ), sulfuric acid, phosphoric acid and the like.

15th
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The solvates described here are complexes that contain a organic drug molecule and a solvent residue of the formula ROH, where R is usually hydrogen atom or a C ^ ^ alkyl group. The most common solvate is the hydrate.

The compounds used according to the invention also include all optically isomeric forms, i.e. mixtures of enantiomers, e.g. racemic modifications, as well as the individual enantiomers and diastereoisomers. The respective optical isomers of the compound class the Phönethano! amine, to which the invention Connections are generally obtained by one of four basic methods. These methods are: (1) fractional crystallization of chiral acid salt derivatives; (2) Derivatization with a chiral organic reagent, dissolution and recovery of the original compound as optical isomer; (3) synthesis of the respective optical isomer using chiral intermediates; and (4) column chromatography using chiral stationary phases. Implementation of this Process is known to the person skilled in the art.

The above, for the creation of what is called anti-inflammatory Preparations for topical administration to mammals are suitable to be included in a carrier Compounds can be incorporated into any of the following vehicles. The mixtures obtained represent pharmaceutical preparations according to the invention. Suitable carriers can include all non-toxic materials or mixtures of materials which are for use in the manufacture of pharmaceutical SaI-

₆ '·· "^ 407861

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ben, pastes, lotions, sprays, suppositories and others, similar formulations are useful. Furthermore, the carrier is selected so that it is preferably the systemic one Absorption of the active ingredient or ingredients prevented or reduced. In addition, the carrier should do not react with the active substance or substances described above. Furthermore should the active ingredient (s) may be soluble in the carrier and topically released from the carrier. The so produced Mixtures should preferably be stable over a longer period of time, e.g. months or years be.

The active ingredient or ingredients will generally be dissolved in a component of the carrier. Zinterol hydrochloride is, for example, both in water and, at least partially, in various organic materials soluble. When applied topically to the skin, both water-soluble and oil-soluble penetrate Parts of the wearer the skin because the skin contains an aqueous and a non-aqueous phase. To the topical application, one will use a small amount of an organic phase in the carrier (e.g. petrolatum or mineral oil).

Carrier for the transport of active ingredients into the skin, e.g. creams, lotions, gels, ointments, suppositories and Sprays and processes for producing these preparations are known. According to the invention, there is at least one active ingredient dissolved in the part of the carrier in which it is soluble, and the remaining mixture then becomes more suitable Way mixed with the remaining part of the carrier.

2 ο 4 U / b b I

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The relative amount of the carrier which is mixed with the active ingredient (s) (ie with the compounds described above) to form the mixtures according to the invention is selected depending on the solubility of the active ingredient (s) in the carrier. However, the optimal concentration is generally at the saturation point. For Zinterol hydrochloride, however, it has been found that its optimal concentration in a cream vehicle is 0.2 w / v. -% , although up to 0.7 w / v. - Dissolve% of it in creams.

The mixtures according to the invention can be used in the following manner administered. On the basis of the tests described in the examples, the inventive Mixtures made up of one or more active ingredients in a suitable carrier, as soon as as possible after the skin has come into contact with the material or materials that are causing the inflammation to be treated cause to be applied.

The mixtures according to the invention are applied directly to the applied to the inflamed area to cause a localized effect. Although at (the above) If a systemic effect was observed with salbutamol, no such effect was found in preliminary tests found the materials according to the invention. It is advantageous that there is no systemic effect and that these materials are minimally absorbed.

Furthermore, biological tests with the compounds IV and V show that they have a specific bronchodilator Have an effect and are able to reverse the "antigen-induced tracheal contraction. This con -

Co

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there is a tractile response to antigens, from an original spasm, which was caused by the release of pre-formed histamine and a subsequent, on the release of newly synthesized SRS-A (slow reacting substance of anaphylaxis) [See Brocklehurst, The Release of Histamine and Formation of a Slow-Reacting Substance (SRS-A) During Anaphylactic Shock, Journal Physiology, 151: 416-435, I960] caused by long-lasting contraction. the Ability of the title compounds to inhibit the SRS-A mediated contractile response significantly more effectively such as the contractile response caused by released histamine, demonstrates a selectivity advantage of the title compounds in making them suitable for use appear particularly useful as antiasthmatic agents. The utility of the compounds IV and V in this regard can be shown by various pharmacological tests which show the inhibition of methacholine-induced bronchospasm Rats and the inhibition of smooth muscle contraction by antigen-induced chemical release Mediators caused in tracheal rings isolated from immunized guinea pigs include. That the latter procedure was edited by Adams and Lichtenstein: In Vitro Studies of Antigen-Induced Bronchospasm: Effective Antihistamine and SRS-A Antagonist on Response of Sensitized Guinea Pig and Human Airways to Antigen; Journal of Immunol., 122: 555-562 (1979).

The use of the above compounds as antiasthmatics is by systemic administration both by oral route and parenterally as well as by inhalation of an effective, non-toxic amount of Compound IV

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or V or a pharmaceutically acceptable salt thereof. An effective amount means a dose that exerts the desired pharmacological effect when administered to mammals, including humans, without exhibiting undesirable toxic side effects. The dose varies depending on the host and the chosen route of administration, the dose to achieve the desired therapeutic effect usually in the range from about 0.1 meg to 100 rag / kg body weight of the compound of the formulas IV or V or a pharmaceutically acceptable salt thereof.

The compounds IV and V can be converted into pharmaceutical agents in accordance with customary pharmaceutical processes Unit dosage form such as tablets, capsules, powders, granules, emulsions, suspensions and the like will. These preparations contain the active ingredient, usually together with non-toxic, pharmaceutical ones Excipients, whereby solid dosage forms are obtained, or as a solution, suspension or emulsion, whereby a liquid preparation is obtained. According to pharmaceutical practice, the addition of sweeteners can also be used and flavorings or the use of binders, etc. take place. In addition, the agents according to the invention also absorbents, stabilizers, Contains wetting agents and buffers.

The liquid preparations of compounds IV and V can be administered by inhalation, e.g. Nebulization, can be used. The present compounds can also be administered as a powder for insufflation consisting of a mixture of inert

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Powder ingredients and an appropriate amount of the present compounds in appropriate particle size. B The administration is then carried out through a powder insufflation device. Usually 1 part of micronized drug is mixed with 50 parts of USP lactose, has the corresponding microbial properties, mixed. This mixture is used in a encapsulated in a suitable insufflation device. Before use, the capsule must be used to release the powder mixture punctured or opened.

Examples

In Examples 1 to 4, the following animal test models are used.

(1) croton oil-induced ear edema in mice;

(2) oxazolone-induced ear edema in mice;

(3) UVB-induced erythema in guinea pigs. example 1

The croton oil assay (which is a standard test which is fully described by Tonelli et al., Endocrinology, Volume 77, Pages 625-634, 1965 is; reference is hereby made to these parts of the literature) a 4% strength croton oil solution in ethanol (V / V) is applied topically to mouse ears. This leads to intercellular edema, vasodilation and polyraorphonuclear Leukocyte infiltration into the skin, causing the weight of the ears to an amount of about 70 to 10096 increases above normal weight. The inflammatory Response reached almost ^ s maximum after 6 h. During execution of the croton oil test were 4 vol # croton oil in ethanol applied to the inside of both ears of each test mouse. The materials to be tested were

• * * we *

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systems applied to the outside of the ears immediately after croton oil administration. The control animals were treated with either croton oil alone or with croton oil and the vehicle alone.

6 hours after the administration of the croton oil and / or the The animals were sacrificed with test material. Biopsy samples were taken from the ears (punch biopeies) and weighed and compared with the respective values of the control animals treated with a vehicle alone.

The compounds were tested in the form of simple solutions, e.g. in dimethylacetamide / acetone / ethanol (DMAC / A / E V / V 40/30/30) and N-methylpyrrolidone / ethanol (NMP / E V / V 50/50). Because of their known activity in the three animal assays mentioned above, all three tests (according to Examples 1, 2 and 3) comparative experiments carried out, namely with hydrocortisone valerate (HCV) in the croton oil and oxazoion assay, indomethacin (which is a powerful, aspirin-like, non-steroidal, anti-inflammatory agent) in the UVB test and Salbutamol (a β ^ agonist mentioned above in the discussion of the prior art).

The percent inhibition of induced mouse ear edema (or erythema) is used on all three models (according to Examples 1, 2 and 3) according to the following Calculated equation:

Ear weight of the control animals _{Ear weight of the test animal Y} -inn ear weight of the ^{control animal ιυυ}

The croton oil assay seemed more responsive to steroid, antiinf laminator is more like an aspirin-like, non-

M / 25 027 26

address steroid, anti-inflammatory agents. Surprisingly and in contrast to the non-steroidal anti-inflammatory agents similar to ABpirin, the β ₂ agonists according to the invention effectively reduced croton oil-induced inflammation.

The anti-inflammatory activities of about 45 ßoadrenergic Agonists were identified using the croton oil-induced mouse ear edema assay (that of acute dermatitis leads) rated. The compounds that were more potent in this test were then determined using the oxazolone-induced Mouse ear edema assays (leading to contact allergy dermatitis) and the UVB-induced erythema assay tested on guinea pigs.

From this group of about 45 compounds containing Zinterol and its analogs, 4 compounds (one of which was Zinterol) showed strong topical, cutaneous, anti-inflammatory activity in the croton oil assay when administered at 1.6 W / V % (weight / Total volume of ethanol + test material). These four compounds were then tested topically in the croton oil assay at other concentrations as well as in the oxazolone assay and in the UVB test. These tests showed that Zinterol was the most consistently effective compound.

Table I below shows the results obtained from the croton oil assay for Zinterol and for the comparison compounds salbutamol and HCV when 1.6 W / V % and 0.2 W / V % were administered in two solvent systems. Table I also includes the values for Bitolterol, a commercially available one

«A * A

M / 25 027 2R

ß ₂ agonist, which was previously used as an antiallergic compound, but whose topical effectiveness against cutaneous inflammation was not known. Bitolterol and Zinterol were compared directly, and it was found that both had similar topical anti-inflammatory activity.

The results in Table I show that Zinterol at 1.6 W / V % and at 0.2 W / V % and Bitolterol at 1.6 W / V% in the croton oil assay reduced ear edema well to moderately. The two compounds were the same or slightly less effective than hydrocortisone valerate (HCV), but they were more effective than salbutamol.

Example 2

The oxazolone-induced contact sensitization in mice is primarily due to edema and cellular infiltration of the monocyte type, with one nearly 100% increase in mouse ear weight occurs. (This Model is from N.J. Lowe et al., British J. of Dermatology, Volume 96, pages 433-438, 1977, fully described; reference is hereby made to this publication.) At The test materials are applied to this test model immediately after the challenge application of oxazolone the inner part of the ears - applied topically to the outer part of these ears of each test animal. The animals were killed 8 or 24 hours after * treatment. Biopsy samples (punch biopsies) were taken from the ears, weighed and compared to values from control animals challenged as described above was' and which were treated with the carrier alone.

ο "<

Μ / 25 027

Table I.

% Inhibition of croton oil-induced mouse ear edema in two different vehicles

Connect- In DMAC / Acetone / EtOH ^ In NMP / EtOH ³ 1, b \ i / Y% 0.2 W / V9

dung 1, ö ΤΛί / Vyo 0.2 W / V96 1, b W / V% 0.2 W / V? 6

Zinterol 69 ^a , 50 *> 54 ^, 34 ^ 69 ^, 63 "92 * \ 58S

81C, 66 ^d 29J, 6 ^k 70 °, 56 48P *. 44 "

636, 48 * 20 '73 <»57 *. 38 ^

459 34y,

Bitoiterol - .61 42 ^X ,

34Z

Salbutamol ⁴ 26 ^a , '0 ^b -34i *, - 45 ^k 54 ^m _t 49 "

23 °, OP

HCV 78C, 59a 253, 38 * 70 ", 7W 71» *, 62 *

16 ^e , 48 ^f 34 ¹ , "64 *, 67"

599. 73V

· ; '

1 Each value is the mean value obtained from 10 to 15 animals; one observes in this test a Fluctuation range of around 10 to 35%

2 dimethylacetamide / acetone / ethanol (V / V 40/40/30). 3 N-methyl-2-pyrrolidone / ethanol (V / V 50/50)

4 Tested due to limited solubility in ethanol / H ₂ 0 (50/50)

a to ζ The values with the same letter designation were obtained in the same experiment ^ The minus sign does not mean inhibition, but rather a potentiation of the inflammation.

The oxazolone assay appeared to be steroid, anti-inflammatory Addressing drugs, however, was relatively insensitive to non-sterile, anti-inflammatory Medicinal products. Surprisingly, and unlike aspirin-like, nonsteroidal compounds (like indomethacin) showed the ßg agonists topical, anti-inflammatory activity.

M / 25 027

In Table II are the test results expressed as the percent inhibition of the oxazolone-induced mice-5 ear edema, when using different concentrations of Zinterol, Salbutamol or HCV as active ingredients Administration of oxazolone in a solvent system composed of DMAC / acetone / ethanol (V / V 40/30/30).

From the results of Table II for the oxazolone assay it can be seen that Zinterol at 3 and 1.6 wt.% resulted in a slight reduction in ear edema without a dose-dependent effect. Zinterol is with Similar to salbutamol but slightly less effective than HCV.

The compounds in Tables I and II can be compared directly.

example ~?

Another set of experiments was carried out for completeness, although it could not be expected that β ₂ agonists (which are vasodilators) would produce results comparable to those for aspirin-like, nonsteroidal agents (which are not vasodilators). The UVB test induces cutaneous erythema in guinea pigs. This is a commonly used standard test for anti-inflammatory agents that is described by KF Swingle, "Evaluation for Anti-Inflaminatory Activity", in Antiinflammatory Agents, Volume 2, edited by Scherrer and Whitehouse, pp. 34-122, London: Academic Press, 1974 , is fully described; reference is hereby made to this publication. In this attempt, they become

Μ / 25 027 Κ>

materials to be tested immediately following the UVB irradiation applied topically to the irradiated areas. The erythema became 3 and 6 h after the irradiation assessed on a scale from 0 to 4.

In Table III, the 3 and 6 hours after treatment with Zinterol, Salbutamol and Indomethacin are obtained Values expressed as the percentage change in UVB-induced erythema in guinea pigs, compiled.

From the results of Table III for the UVB assay it can be seen that Zinterol at 3 and 1.6 wt. % Exhibited light to moderate activity with no uniform dose effect and was highly variable. Similar effects were obtained with salbutamol. In contrast, indomethacin showed consistently good to very good activity at 1% by weight. vitat.

M / 25 027

3?

Table II

Connection % inhibition d. dung oxazolone-induced _{1 2} edema in the mouse ear '

concentration __ 0.2 W / V% 1.6

% Inhibition of the oxazolone-induced Edema in the mouse ear2f3

concentration
1.6 W / V # 3 W / V%

Zinterol

22 ^a , -

48 ^C , 17 ^d

» ³⁰ y

Salbutamol

-la, -9b.

2C,

2l \ 28 ^ 311

HCV

16 ^a , 16 ^b 36C, 27 ^d

38h

The above agents were tested in DMAC / acetone / ethanol (V / V 40/30/30)

Each value is the mean value obtained from 10 to 15 animals; one observes in this test a Fluctuation range of around 20 to 35%

The above remedies were in N-methylpyrrolidone / Ethanol (V / V l / l) tested.

to 1 The values with the same letter designation were obtained in the same experiment.

M / 25 027

Table III

% Change in UVB-induced erytherae in guinea pigs 3 and 6 hours after treatment

Drug conc. (%) Drug conc.

1.5

1.6

Time (h)

Connection D. 3 6th 43 3 6th NT * 3 6th 3 6th Zinterol 0 13th 48 9 26th 48 18th 37 56 54 75 25th 9 19th 27 +9 +39 Saibutamol * 9 +4 +39 71 42 32 " 74 45 25th Indomethacin 72 100 74 (IX) 54 93 85 82 ■ 91 87

1 All materials to be tested were applied immediately after irradiation.

2 The test material was prepared in dimethylacetamide / acetone / ethanol (V / V, 40/30/30), the concentration is given as ¥ / V% .

3 The test material was dissolved in N-methyl-2-pyrrolidone /

. Ethanol (v / V, 50/50) produced, the concentration is given as W / V%.

4 Tested due to limited solubility in ethanol / Vfasser (50/50) or NMP / H ₂ 0 (50/50).

* Not tested due to the solubility limit at 1.6%.

M / 25 027> 3

The results in Tables I, II and III are in the following Table IV compiled.

Table IV

Topical anti-inflammatory activity of Zinterol in 3 animal models (salbutamol, HCV and indomethacin were tested as comparison compounds)

10 Zinterol
Salbutamol
HCV
Indomethacin Croton oil
Assav Oxazolone
As say UVB
As a ay (Edema) { Breath; ^ krythem; 15th ι NT ¹

Anti-inflammatory activity and percentage range of inhibition

+ = weak (30-44); ++ = moderate (45-59); +++ = strong (60%) ¹ NT = not tested

From Table IV it can be seen that Zinterol at the same concentration was almost as effective in the croton oil assay like HCV and is more effective than salbutamol. Based on these data, Zinterol is considered to be a very promising agent with anti-inflammatory activity for use in Looking at people. In addition, Zinterol shows many of those found in common steroid therapy Side effects not.

Example 4

In further experiments, two Zinterol analogues were found, viz compounds IV and V, tested. It has been shown that the anti-inflammatory activity of this

M / 25 027 34.

Compounds with that of Zinterol is comparable.
5

In these attempts the anti-inflammatory Effect of the three ß2 agonists when administered topically on croton oil-induced ear edema in mice. it's correct. 50 μl of a 4% strength by weight croton oil solution were used applied in ethanol to the inner parts of Swiss albino mice. Immediately afterwards were 25 / μl each of a suspension of 0.02, 0.2 and 0.8% by weight of compounds IV and V in N-methylpyrrolldone / ethyl alcohol (NMP / EtOH) applied to the outer parts of the ears. The trial included croton oil-treated and untreated control groups. The control groups were included in the results, such as described above.

6 hours later, the animals were sacrificed with COg gas. Of each A 7.9 mm (5/16 inch punch biopsy) sample was removed from the ear and weighed immediately.

The anti-inflammatory effects of the agents to be tested was rated based on a comparison with the weight of samples from animals from the test and control groups.

The results of three studies with different concentrations of materials to be tested in NMP / EtOH are compiled in Table V below. It can be seen that both the connection IV and compound V are comparable with Zinterol in terms of the reduction of mouse ear edema are.

HA

M / 25 027 59

l Table V

% Reduction in ear edema weight compared to the ear edema weight of the control animals + SD

TeBtmaterial

Concentration Compound IV Compound V Zinterol (W / V-96) __

0.02 10.6 29.9

25.6

Mean (MW) + standard deviation 10 (S.D.) 18.1 + 10.6

0.2 32.9 53.5

• 48.7

49.4

MW + SD 43.7 + 9.3
0.8 61.6 69.9

53.4 • MW + S.D. 57.5 + 5.8

The results reported in Tables III and V in the same cell were obtained from the same experiment obtain. A direct comparison is therefore given.

The compounds of the general formula II can be used in a large number of formulations known to the person skilled in the art are processed. Such formulations include, for example, nasal sprays (such a spray can e.g. using tricloromonofluoromethane, dichlorodifluoromethane and oleic acid), rectal suppositories, Vaginal suppositories, ointments, creams, gels and lotions.

The processes for making compounds IV and V and their biological effects can be better understood from the following examples. The examples

14.2 23.6 18th , 9 + 6.6 39.5 66.2 46.6 50 , 8 + 13.8 68.2 56.6 62 , 4 + 8.2

Μ / 25 027 36

serve to explain the invention, but they are not intended to "limit it."
5

In the examples, the temperature ^{data are expressed in °} C., the melting points are not corrected. In the case of nuclear magnetic resonance spectra (NMR), the chemical shift ( S ), expressed as parts per million (ppm) compared to tetramethylsilane (TMS) as the standard, is given. The relative area under the individual signals in the NMR spectra corresponds to the number of hydrogen atoms of a specific functional group in the molecule. The multiplicity of the signals is expressed as a broad singlet (bs), singlet (s), multiplet (m) or doublet (d). Abbreviations used are DMSO-dg (Deuterodlmethylsulfoxid), CDCl, (Deuterochloroform) j otherwise these are common abbreviations. In the case of the infrared (IR) spectra, only those wave numbers are given (cm ") which are important for the identification of a functional group. The IR spectra were recorded using potassium bromide (KBr) as the diluent. The elementary analyzes are in wt. % stated.

B e i s ρ 1 e. 1 5

5 '- (2-Amino-1-hydroxyethyl) -2'-hydroxymethanesulfon ariilid-hyd roQhlo r14

To eine.r stirred solution of 27.4 g (0.19 mol) of hexamethylenetetramine in 650 ml of chloroform are added in portions 5 'Broraacetyl-2 ¹ -hydroxymethansulfonanilid (IX; 40.0 g ,, 0, i3 mol). The suspension obtained is refluxed for 16 to 18 hours, cooled to room temperature and. then filtered. The solid obtained

M / 25 027 57

is washed with chloroform and air-dried, 56.6 g (97.3%) of the quaternary salt, melting point 165 to 167 ^° C., being obtained.

This solid is dissolved in 400 ml of ethanol and treated with 65 ml of concentrated HCl. The resulting solution is refluxed for a few minutes, after which a precipitate separates out in the hot solution. The mixture is cooled to completely precipitate the precipitate. The filtered solid is washed by stirring in water and then filtered again. Recrystallization of this material from methanol-isopropyl ether gives a solid, namely 5'-glycyl-2'-hydroxyraethansulfonanilid hydrochloride, mp. 219 to 221, ⁰ C.

A portion (7.3 g, 0.026 mole) of this aminoketone hydrochloride and 10% palladium on carbon (2.0 g) were added in 200 ml 90 ° hot ethanol suspended. The warm suspension was shaken at 4.2 bar (60 psi) hydrogen pressure reduced in a Parr hydrogenator. After shaking for 12 to 14 hours, the hydrogenation mixture became removed on the Parr device and the catalyst filtered off. The filtrate became a solid, concentrated white residue, which is dissolved in isopropyl alcohol isopropyl ether is suspended. Filtering off gives the compound VIII in quantitative yield as the hydrochloride, m.p. 179 to 180 ° (decomp.).

Example 6

2'-Hydroxy-5 '- (1-hydroxy-2- [3- (3-indolyl) -2-propyl amino ~ 1-ethvl) methanesulfonanilide (Compound IV) 35

Μ / 25 027 58;

-

The> hydrochloride of compound VIII prepared according to the process described above (5.65 g, 0.02 mol) ^: is converted into the base by mixing it in 150 ml
Suspended ethanol and then treated by the dropwise addition of 2.0 ml of a 10.0N NaOH with stirring. \ The original solid thereby while at the same below) precipitation of NaCl dissolves. The NaCl is filtered off \

and the filtrate in vacuo to a white, solid back?

stood concentrated, which is dissolved in 100 ml of methanol. >

A reductive alkylation is carried out by adding \.

Glacial acetic acid (1.2 g, 0.02 mol) and 3-indolylacetone (3.5 g, \

0.02 mol) is added, the resulting solution with ethanol to \

150 ml diluted and then 0.2 g PtO «is added. This suspension becomes at 4.2 bar (60 psi) hydrogen pressure

hydrogenated until the hydrogen uptake has ended (un- I

about 4 h). The suspension is from the hydrogenation!

direction removed, filtered and the filtrate in a vacuum \

concentrated to an oily residue, which in warm *

Of methanol and a few drops of glacial acetic acid behan- with \

is delt. Dilute with ethyl ether and stir under ,,

simultaneous cooling gives, after filtering off, a solid which is washed with methanol, with

4.7 g of the acetate of compound IV are obtained, m.p.
196.5 to 197 ° (dec.).

This material is dissolved in the minimum amount
hot dimethylformamide, filtered and diluted with
the same amount of water, giving a precipitate which, after filtering off, represents the free base of compound IV, melting point 198 ° to 199 ° (decomp.).

M / 25 027

Analysis: for

Calculated: C 59.53% H 6.24% N 10.41% S 7.94% found: 59.96 6.15 10.65 8.05

NMR (DMS0-d ₆ ): 0.98 (3, m), 2.75 (5, m), 2.93 (3, s),

4.52 (1, m), 6.00 (4, bs), 7.15 (8, m) IR (KBr): 750, 1125, 1150, 1240, 1280, 1325, 1500, 1610 and 2940 cm " ^1st

Example 7 Alternative preparation of compound IV

A solution of 11.0 g (0.06 mol) of 3- (2-aminopropyl) indole is stirred in 730 ml of acetonitrile under a nitrogen atmosphere and gives all at once 12.5 g (0.03 mol) 5'-bromoacetyl-2'-benzyloxymethanesulfonanilide to. To Stirring for 30 minutes at room temperature, a cold solution of sodium borohydride (4.8 g, 0.126 mol) is rapidly added dropwise. in 219 ml of methanol. The course of the reaction is shown on the basis of the spot for the bromine ketone in the thin-layer chromatogram tracked. Sometimes it is necessary to add more sodium borohydride in order for this to act as a Starting material serving aminoketone reacted. When the reaction is complete, the solvent becomes im Vacuum removed and the residue suspended in 0.5 1 water and treated with 4N NaOH to complete Achieve solution. This solution is washed thoroughly with ether and then the pH is adjusted with acetic acid on 8 a. The mixture obtained is extracted with methylene chloride, the extracts are combined and dried (MgSO ^) and then concentrate in vacuo to give 14.5 g of a gummy residue.

M / 25 027 40

This gum is chromatographed on a silica gel column purified, eluting with chloroform-methanol-B ammonium hydroxide (90/10/1). 11.6 g are obtained of the benzyloxy derivative of compound IV.

The O-benzyl protective group is removed by adding a mixture of the O-benzyl derivative of the compound IV (11.5 g, 0.02 mol) and 1.8 g of 1Obiges palladium-on-carbon (moistened with absolute ethanol) in 820 ml of methanol hydrogenated in a Parr low pressure apparatus. After the uptake of hydrogen has ceased, the reduced mixture is filtered and the solid is washed with methanol. All methanol fractions are combined and concentrated to a small volume (about 100 ml). A white solid gradually precipitates on standing. The solid is filtered off, washed with methanol and air dried to give 5.6 g of product is obtained, Fp.197 to 198 ⁰ C (dec.). This material is dissolved in 40 ml of hot dimethylformamide, filtered and 45 ml of H ₂ O are added to the filter. Crystallization occurs when this solution is rubbed. A further 10 ml of water are added, the mixture is cooled in an ice bath, the solid is filtered off and washed thoroughly with water. Drying in air gives 5 g of compound IV, melting point 197 ° to 200 ° (decomp.).

Example 8

N- (2-Hydroxy-5- [i-hydroxy-2 - ([2 ~ (1H-indol-3-yl) -1,1-dimethylethyl] amino) ethyl] phenyl] methanesulfonamide (Compound V )

A solution of 2- (2-amino-2-methylpropyl) indole (X, R = Me; 37.7 g, 0.2 mol) and triethylamine (10.1 g, 0.1 mol) in 1.2 l of dioxane, which is distilled off over sodium metal

M / 25 027 4T

is carried out with stirring under a nitrogen atmosphere with 5'-bromoacetyl-2-benzyloxymethanesulfonanilide (39.8 g, 0.1 mol) added. The mixture obtained is stirred for about 8 to 12 hours at about 25 ° under a nitrogen atmosphere. The reaction mixture is filtered, some of the solid precipitate is removed and the filtrate is treated with a cold solution of sodium borohydride (15 g, 0.4 mol) in 1 l of absolute ethanol. One drips the Borohydride solution to the filtrate with stirring. The course of the reaction is shown on the basis of the spot for the bromoketone tracked in thin-layer chromatogramra. The addition of more sodium borohydride is sometimes necessary in order to bring the aminoketone serving as starting material to full reaction. When the reaction is complete, the solvent is removed in vacuo and the residue is dissolved in 0.2N NaOH and washed with Washed ether. The pH of this solution is then adjusted to 8 with acetic acid. The mixture obtained extracted with methylene chloride, the extracts are combined, dried (MgSO ^) and then concentrated in a vacuum, the crude O-benzyl derivative of Compound V is obtained as a gummy residue.

The O-benzyl protecting group is removed by adding the mixture of the O-benzyl derivative of the compound V (3.25 g, 0.006 mol) and 1.0 g of Pd (OH) ₂ / C (Pearlman's catalyst) in 100 ml of methanol in hydrogenated a Parr low pressure hydrogenator. When the uptake of hydrogen has ceased, the reduction mixture is filtered and the solid is suspended in water. 1N HCl is added with heating so that the product dissolves. The insoluble catalyst is filtered off, the acidic filtrate is made basic (pH 8) with ammonium hydroxide. The he

te

M / 25 027 42

Any precipitate is filtered off, washed with water and air-dried, the product (compound V) being obtained as a monohydrate in an almost quantitative yield, melting point 211 to 212 ^° C.

Analysis: for C ^ H ^ N ^ O ^ S.HgO

Calculated: C 57.92% H 6.72% N 9.65% H ₂ O 4.14% found 58.05 6.68 9.64 3.63

NMR (DMSO-Cl ₆ ): 1.01 (3, s), 1.05 (3, s), 2.75 (4, m),

2.92 (3, s), 4.49 (1, m), 5.3O (6, bs), 7.12 (8, m)

IR (KBr): 740, 1010, 1115, 1125, 1235, 1280, 1460, 1500, 1600 and 1610 cm "" ¹ .

That obtained according to the method described above Monohydrate is converted into hydrochloride hydrate by dissolving it in dilute HCl and then in a vacuum constricts to a foam-like solid, m.p. 105 to .125 °. .

Analysis: For C ₂₁ H ₂₇ M ₃ O ₄ SJCLH ₂ O

Calculated: C 53.44% H 6.41% N 8.91% H ₂ O 3.82% found: 53.19 6.37 x 8.92 3.64

NMR (DMSO-U ₆ ): '1.28 (6, s), 2.95 (3, s), 3.17 (4, m),

... 3.80 (1, bs), 4.90 (1, m), 7.02 (4, m), 7.25 (3, m), 7.60 (I, m), 8, 50 (1, bs), 8.78 (i, bs), 9.30 (1, bs), 10.00 (1, bs), 11.10 (1, bs)

IR (KBr): 750, 960, 1150, 1295, 1320, 1400, 1460, 1515-1
and 1620 cm. .

Claims (1)

M / 25 027 1 Claims M.) Pharmaceutical agent containing: (a) at least one compound of the general formula II __ R ¹ R ³ _ /> - CH-CH _o -NH-ACB-CH _o -M (II) 'OH R ^ where ₁ ρ
R and R independently of one another a hydrogen atom or a lower alkyl group "mean, where R and R ² cannot mean a hydrogen atom at the same time; M is a phenyl or indole group or a hydrogen atom means; A is the group (-CH ₂ -) _n , where η is 0, 1 or 2; B is the group (-CH ₂ -) _m , where m is 0, 1 or 2;
R ^{3 represents} -OH or -OCO- (O) -CH ₃ ; and R ^{4 is} -NH-SO ₂ -CH ₅ or -OCO- ^ O) -CH ₃ , or a pharmaceutically acceptable salt or sol-vate of it, in combination with (b) a compatible, topically acceptable carrier. 2. Agent according to claim 1, wherein m and η are 0, R ^{3 is} -OH and R ^{4 is} -NH-SO ₂ -CH ₃ . '35 M / 25 027 2 3. Agent according to claim 2, wherein M is a phenyl 1 2
group, R and R represent a methyl group and m and η represent O. 4. Composition according to claim 2, wherein M is an indole group 1 2
and R and R represent a methyl group and η and m represent O « '. ■ 5. Agent according to claim 2, wherein η and m are O, R is a methyl group,
mean an indole group. 1 2 hen, R a methyl group, R a hydrogen atom and M 6. Agent according to claim 1, wherein η and m are O, R ^ and R for -OCO- ^ Ö ^ -CH, and M is hydrogen atom means. 7. Composition according to claim 1, wherein the carrier dermato · is logically compatible. 8. Composition according to claim 7 »wherein the carrier is so selected is that it prevents or reduces the systemic absorption of the compounds of general formula II. 9. Composition according to claim 2 in the form of a cream, lotion or gel. 10. Composition according to claim 2 in the form of a spray. 11. Composition according to claim 2 in the form of a suppository. (12.) Compounds of the general formula II M / 25 027 R ¹ /, - CH-CH ₀ -NH-ACB-CH ₉ -MOH R ² (ID where A is (-CH ₂ -J _n and η is O and B is (-CH ₂ -) _m and m is O, R ^{1 is} -CH ₃ , M is an indole group, R ^{3 is} -OH, R is -NH-SO ₂ -CH, and R ^{2 is} a hydrogen atom or a methyl group, and their pharmaceutically acceptable salts or solvates. 13. The compound of claim 12 which is 2'-hydroxy-5 '- (i-hydroxy-2- [1- (3-indolyl) -2-propylamino] ethyl) methanesulfonanilide or their pharmaceutically acceptable metal or acid addition salts or hydrates. 14. Compound according to claim 12, namely N- (2-hydroxy-5- [i-hydroxy-2 - ([2- (1H-indol-3-yl) -1,1-dlmethylethyl] amino) ethyl] -phenyl) -methanesulfonamide or their pharmaceutically acceptable metal or acid addition salts or hydrates. 15. Process for the preparation of the compounds of claims 12 to 14, characterized in that one (a) an indolylamine of the general formula X NH ₂ where R is a hydrogen atom or a methyl group,
with a phenolic bromoketone of the formula IX M / 25 027 OH NHSO ₂ CH ₃ (IX) alkylated, and (b) the reaction product subsequently. treated so that the carbonyl group becomes a secondary alcohol is reduced to form a compound of Formula II. 16. A process for the preparation of the compounds of claims 12 to 14, characterized in that one Compound of formula VIII H ₂ N OH NHSO ₂ CH ₅ (VIII) OH with the compound of the formula (b) or the general formula (c): (b) (C) wherein X is a common leaving group (e.g. halide or tosylate); where, when using the compound (b), the reaction conditions are chosen so that a reductive amination of the compound (b) and a reduction to form a compound of the general formula (II) in which R represents a hydrogen atom takes place; and where When using the compound (c), the reaction conditions are chosen so that with the compound of the formula (VIII) a nucleophilic substitution on the compound »Ο ♦ · "* 340786 Μ / 25 027 5 (c) takes place with the formation of a compound of the general formula (II). 17. A pharmaceutical agent containing at least one of the compounds according to any one of claims 12 to 14, optionally in combination with a pharmaceutically acceptable carrier and / or excipients. 18. A pharmaceutical agent in unit dose form for systemic administration to mammals, containing a pharmaceutical carrier and a non-toxic, anti-asthmatic amount of the compound Claim 13 or 14 from 0.1 μg to 100 mg / kg body weight. 19. A pharmaceutical agent in aerosol form containing a compound according to claim 12, which is in an antiasthmatic effective concentration is mixed with a suitable propellant sy s tera. 20. Pharmaceutical agent in powder form for insufflation, containing a mixture of inert, for Ingredients suitable for insufflation and a compound according to claim 12, wherein the inert ingredients and the compound of claim 12 suitable for transport into the bronchioles after insufflation Have particle size. 21. Use of the connections. Of the general Formula (II) according to claim 1 for the treatment of inflammatori severe diseases.