CH659067A5 - PHENETANOLAMINE AND USE OF SUCH COMPOUNDS FOR PRODUCING PHARMACEUTICAL AGENTS. - Google Patents

Description

The invention relates to phenylethanolamine compounds with indolyl substituents and processes for the preparation of these compounds. The compounds according to the invention have a biological effect and can therefore be used as active ingredients in pharmaceutical compositions.

The invention also relates to the use of phenylethanolamine derivatives in the manufacture of anti-inflammatory, non-steroids, pharmaceutical agents for topical administration. In particular, these agents contain one or more β2-adrenergic agonists as active ingredient.

Although hundreds (if not thousands) of β2 agonists are known, a topical anti-inflammatory effect has only been described for salbutamol. At the present time, it is assumed that no structure-effect relationship is known for the prediction of a topical, anti-inflammatory effect, on the contrary, such an effect can hardly be predicted.

Most skin diseases are associated with inflammation. The multitude of inflammatory skin diseases and skin conditions (including those of a chronic and acute nature) results in a constant search for anti-inflammatory drugs.

The introduction of steroids provides the dermatologist with a class of anti-inflammatory agents that are therapeutically effective against a wide range of inflammatory skin diseases. In many inflammatory conditions, especially chronic conditions, the steroids only have a palliative effect and require extensive use. 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, stopping steroid therapy in various chronic, inflammatory skin diseases has led to the recurrence of inflammatory symptoms, sometimes even with increased intensity. In view of the disadvantages of using steroids, many non-steroidal anti-inflammatory agents (i.e.

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NSAIA) for use in various diseases, including rheumatic diseases. These compounds generally appear to be free from the adverse side effects of the steroids, particularly tissue atrophy, adrenal suppression, and other less severe side effects.

A class of compounds belonging to the NSAIA group is a group of compounds that are prostaglandin synthetase inhibitors. These materials generally effectively reduce UVB-induced erythema (i.e., ultraviolet-induced erythema) in guinea pigs. However, these materials are only weakly effective or even inactive in further dermatitis tests, including the croton oil and oxazolone ear edema assay described in the examples. The creation of additional, non-steroid classes of compounds with topical, anti-inflammatory activity is therefore of great interest.

ß-adrenergic agonists (including the ßr and ß2 agonists) are compounds which, as described for example by R.J. Brittain et al. in Adv. Drug Res. 5,197,1970, act by stimulating adenylate cyclase, which leads to a conversion of adenosine triphosphate (ATP) into cyclic 3 ', 5'-adenosine monophosphate (C-AMP). The walls of essentially fully nucleated mammalian cells contain the enzyme adenylate cyclase, which is stimulated by various compounds, including prostaglandin E and beta-adrenergic drugs.

Adenylate cyclase activity has been described to be present in the epidermis of humans and animals. Disorders of adenylate cyclase activity and C-AMP levels have been reported in proliferative skin disorders such as eczema, psoriasis, epidermolytic hyperkeratosis and lamellar ichthyosis.

In short, ß-agonists are a class of compounds that stimulate the adrenergic system of the human body.

Materials that are classified as ß agonists are ß agonists, which react selectively with the ß, receptors and cause cardiac stimulation.

Materials that are classified as ß2 agonists react selectively with the ß2 receptors that are present in the smooth muscles of the blood vessels and bronchi. These materials cause bronchodilation and vasodilation.

British Patent 4,323,575 describes disubstituted catechol amines (which can be β2-agonists) with topical, anti-inflammatory activity.

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

Those sulfonanilides of the formula I in which Z stands for CHOH are pharmacologically active phenethanolamines with an action which either resembles the effects of the adrenal cortex medinal hormones or the adrenergic neurotransmitters or counteracts these effects. Phenalkanolamines which are alkyl- and aryl-sulfonamido-substituted at the core have useful pharmacological effects, due to which they can be used in a variety of ways as vasopressors, vasodepressors, analgesics, bronchodilators, a-receptor stimulants, ß-receptor stimulants, a- Receptor blockers, ß-receptor blockers, papaverine-like depressants of smooth muscles or anti-inflammatory

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Agents useful for controlling or preventing anaphylaxis are suitable.

Anaphylaxis is defined in the McGraw-Hill Dictionary of Scientific and Technical Terms, 2nd Edition, 1978, as hypersensitivity following parenteral injection of an antigen, where a local or systemic allergenic response occurs when the antigen reappears after a certain period of time is administered. Topical application is defined as “local application or intended for local application” and is used in this sense in the context of the present invention. Because anaphylaxis and topical inflammation are different physiological conditions, a drug that is useful for treating one condition is generally not useful for treating the other condition.

US Pat. No. 3,801,631 describes the 2-hydroxy-5'- [1-hydroxy-2- (2-methyl-1-phenyl-2-propylamino) ethyl] methanesulfonanilide called zinterol (this compound also falls within the range of sulfonic acid amides described in U.S. Patent 3,341,584). Zinterol is described as a powerful, anorexigenic agent, an orally active bronchodilator, and an analgesic.

In the article «Adrenergic Sulfonanilides, 4th Centrally Active ß-Adrenergic Agonists», D.L. Tempie et al., Journal of Médicinal Chemistry, Volume 19, No. 5, pages 626-633 (1976), Zinterol (Compound No. 43) is described as a strong anorexic and as a narcotic antagonist.

U.S. Patents 3,919,424 and 3,993,776 disclose other uses of Zinterol.

Salbutamol is a ß2 angonist. This connection is described in R. Seely et al., Proc. Soc. Exp. Biol. Med. 159,223 (1978), as a useful topical, anti-inflammatory agent.

The synthesis of salbutamol is described in Drugs of the Future IV, 629 (1979). Salbutamol is mentioned there as a useful anti-inflammatory agent when administered locally. In addition, salbutamol when administered orally is said to be superior in the control of asthma-related drugs. A mechanism for the action of salbutamol is proposed (see page 631 of the above publication).

The publication by Saiichirou Seo et al., “Inhibition of Adjuvant Arthritis by Salbutamol and Aminophylline”, European J. of Pharmacology, 63.267-274.1980, describes the inhibition of swellings on mouse paws after injections of salbutamol and aminophylline combinations .

Other materials which have structural similarities to Zinterol and which are top-safe, anti-inflammatory are described in U.S. Patent 4,323,575. These materials can be beta-agonists; whether they are, however, could only be determined by experiment.

US Pat. No. 4,088,756 describes further (R) agonists which have anti-inflammatory activity.

As will be explained below, it is not possible to predict with sufficient certainty which β2-agonists are effective, topical, anti-inflammatory agents. After many attempts, it has now been found that almost all the β2 agonists tested for such an effect were either ineffective or highly toxic, or both.

Despite the known compounds, there is therefore a constant need for non-steroidal, anti-inflammatory drugs which have good anti-inflammatory activity and are not toxic.

The prior art for β-adrenergic agonists based on phenethanolamine compounds of the catechol type is extremely 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 gives compounds with β-adrenergic, biological activity.

In US Pat. No. 2,908,691, hydroxyphe-nalkylaminoalkylindoles are broadly disclosed which have different effects on the central nervous system and which act as anti-secretory agents for reducing gastric acidity. The most important compound appears to be 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, gives an agent 15 which, when administered topically, reduces topical inflammation in mammals.

It was also an object of the invention to provide a pharmaceutical composition in the form of an ointment, cream, lotion or other formulation which reduces or prevents skin inflammation when applied topically to 20 mammals.

These objects are achieved by the compounds of the formula II 'according to the invention and by the use according to the invention according to claim 11 of compounds of the formula II for the preparation of agents for the treatment of topical inflammations.

The compounds of the formula

30th

: 3 ^>

'a

R

ch-ch "nh-a-c-b-ch -m

I 2 12

R

(ii)

r '

35 wherein R1 and R2 independently represent a hydrogen atom or a lower alkyl group, wherein R1 and R2 cannot simultaneously represent a hydrogen atom; M is a phenyl group or an indole group of the formula

40

Oc

(a)

45 or a hydrogen atom;

A represents the group (-CH2-) n, where n is 0.1 or 2;

B represents the group (-CH2-) m, where m is 0.1 or 2, where n and m are integers;

50.

R3 is -OH or -OCO- / 0 y-CH3; and

R4 represents -NH-S02-CH3 or -OCO- ^ Ö ^ -CH3;

also include the new compounds of formula ch I 3

ho - (\ f) ch-ch -nh-c-ch -m

\ / I 2 12 2 (HO

oh r nh-so2-ch3

65

wherein M is indolyl and R2 is hydrogen or methyl, which together with their pharmaceutically acceptable salts form the subject of claim 1.

In formula II above, R1 and R2 are preferably methyl groups and m and n are 0. Preferred is the compound of formula II in which n and m are 0, R1 and R2 are -CH3, M is a phenyl group, R3 is -OH and R4 represent -NH-S02-CH3. This compound is known as Zinterol (hereinafter referred to as compound III).

Another preferred compound for use in pharmaceutical compositions for treating topical inflammations is the compound of the formula II in which n and m are 0, R1 is a methyl group and R2 is a hydrogen atom, M is an indole group, R3 is -OH and R4 is - NH-S02-CH3. This compound is referred to below as compound IV.

Another preferred compound for use in pharmaceutical compositions for the treatment of topical inflammations is the compound of the formula II in which n and m are 0, R1 and R2 are -CH3, M is an indole group, R3 is -OH and R4 is -NH -S02-CH3 stand.

This compound is referred to below as compound V or azazinterol.

Another preferred compound for use in pharmaceutical compositions for treating topical inflammations is the compound of the formula II in which n and m are 0, R1 and R2 are a methyl group, M is a hydrogen atom and R3 and R4

stand for-OC <K °> CH3. This compound is referred to below as Bitolterol and is commercially available. It is used to treat allergies, but it was not previously known that it can also be used to treat topical inflammations.

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

In addition, the invention relates to a topical pharmaceutical composition for reducing topical inflammation in mammals, which comprises at least one compound of the formula II 'according to claim 1 in a non-toxic but sufficient amount to reduce the inflammation in a pharmaceutically acceptable carrier material or carrier materials.

Another preferred embodiment relates to a pharmaceutical agent to be administered topically, which contains the compound IV or the compound V in a non-toxic amount which is sufficient to reduce inflammation and in a pharmaceutically acceptable carrier.

In a preferred use according to the invention, zinterol or bitolterol is used.

The term “topical” used in the present invention means local application or intended for local application in order to produce a local effect, preferably without an accompanying, systemic effect. The compounds used in the agents according to the invention can therefore be administered in a variety of ways, but they cannot be injected or swallowed. For example, they can be administered cutaneously, nasally, vaginally, rectally, otically or buccally. They are administered together with a dermatologically compatible carrier, which is preferably selected so that the systemic absorption of the active ingredient is prevented or reduced.

The pharmaceutical agents according to the invention also include anti-asthmatic agents which

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Bronchodilators and strong but selective inhibitors of smooth muscle contraction are. The efficacy and selectivity of these agents in inhibiting smooth muscle contraction caused by antigen-induced chemical mediator release have been demonstrated by pharmacological tests using immunized guinea pig trachearings. These agents contain active ingredients which are selected from the compounds IV and V and their pharmaceutically acceptable solvates and salts.

The compound (s) to be included in a carrier to provide agents suitable for topical use as an anti-inflammatory preparation (s) in mammals, including humans, 15 are the compounds of the above formula II (or their pharmaceutically acceptable salts and solvates). In this formula, M represents a phenyl or indole group or a hydrogen atom, A represents - (CH2-) n, where n represents 0.1 or 2; B represents (-CH2) m-, where m represents 0.1 or 2; R1 20 and R2 independently of one another represent a hydrogen atom or a lower alkyl group, where R1 and R2 cannot simultaneously be a hydrogen atom; R3 stands for

-OH or -OCO

NH-S02-CH3 or-OCO

<D- CH3;

; and R4 stands for

CH ,.

In the context of the present invention, a 30 lower alkyl group means a straight-chain or branched hydrocarbon radical having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms.

Many β2-adrenergic agonists (all of which are 35 Zinterol analogs) have been tested. Of approximately 45 such compounds, only 4 showed strong topical, anti-inflammatory activity without toxic effects in the tests described in the examples below. The remaining compounds, when administered topically to the test animals, were either toxic, ineffective and / or of inconsistent anti-inflammatory activity, or both.

The compound (s) to be included in a vehicle to provide a pharmaceutical agent useful as an anti-inflammatory preparation for topical use in mammals are prepared in the following manner.

The preparation of Zinterol is described in detail in US Pat. No. 3,801,631 "2'-hydroxy-5 '- [l-hydroxy-2- (2-methyl-l-phenyl-5o 2-propylamino) ethyl] methanesulfonanilide and whose 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 55 of compounds (IV) and (V) is given below. You can choose between two general methods. The compounds of the formula II according to claim 1 are prepared analogously.

+ h2n

DJ

OH

nhso2ch3

OH

(VIII)

H2

catalyst

Compound IV

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One synthetic method involves the reductive amination of an indolylcarbonyl compound with a suitable 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 dissolving 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, e.g. shakes a noble metal catalyst, such as platinum oxide, in a hydrogen atmosphere. Alternatively, the reaction can also be carried out in stages by first converting the carbonyl compound and the phenolic amine to the corresponding condensation product and then carrying out the hydrogenation as a separate process stage.

A variation of synthetic method 1 consists in a nucleophilic substitution on an indolylalkyl halide or an equivalent thereof by the phenolic amine. This process is reproduced below as process 1A io.

Procedure 1A

■ N

H

(c)

+ (VIII)

Compound IV (when R = H) or

Connection V (if R = Me)

In the general formula (c), X is a usual one. The second method useful for the preparation of the compounds (IV) and leaving group, such as a halide, tosylate or the like. (V) is generally below

Here too, the choice of reaction conditions and synthesis methods 2 is shown. This general method of reagents for the nucleophilic substitution reaction can also be used to prepare compound (V) known to those skilled in the art. To be 25.

Procedure 2

(x)

2Wi3

(ix)

Compound IV (when R = H) reduction ^ or

^ Connection V (if R = Me)

This process involves the alkylation of an indolylalkylamine with a corresponding phenolic bromoketone. The carbonyl group is then reduced to a secondary alcohol group. In practice, the phenolic OH group is protected during nucleophilic substitution. This is necessary in order to prevent the phenolic group from being attacked nucleophilically and thus undesired ether by-products from being formed. In general, a benzyl group serves as a protective group, which is then removed by catalytic reduction.

These general synthetic methods have been adopted in the synthetic schemes used to prepare compounds IV and V. These schemes are given below.

Scheme A: Preparation of Compound IV

0 NHSO5CH, CHCl, Br x Ifìì 3 + C6H12N4 f-

OH

(IX)

0 br

0 - NHS02CH3

OH

EtOH HCl

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HCl h2n-

HCl

NHSO0CII3 H5 n

OH ^ ^ (* H ~ N U

Ol Pd / C 2

(VIII)

Oh

EtOH

H

2 PtO,

DI ^ O '

H

NHSO-CH, / 2 3

(XI)

eçrWetT

IV

Mr

Pd / C MeOH

Î

OH

6qrf, aC

H

SO2CH2 IJAcetonitrll

XII, R = H

N-

OCH2Ph f

2) NaBH. MeOH

R

NHS02CH3

H

X, R = H

OCH Ph

IX '

Scheme A shows the preparation of compound IV. Two reaction routes are shown, both starting from one of the bromoketones IX and IX '. In the upper reaction pathway, compound IX is reacted with hexamethylenetetramine (QH12N4) to form a quaternary salt, which is converted into the aminoketone XI and then into the phenethanolamine VIII by catalytic hydrogenation. The reductive alkylation of 3-indolylacetone with VIII gives the

Title compound IV. The second and preferred reaction route leads via a nucleophilic reaction of indolylamine X and IX '(the O-benzyl analogue of IX) and subsequent 45 borohydride reduction to the intermediate with benzyl-blocked phenolic group (XII: R = H). This intermediate product is then catalytically reduced to the desired end product.

Scheme B: Preparation of compound V

CO

R «« ■ *

NHS02CH3 0CH2Ph

X: R = Me

IX '

1)

Et3M

Dtoxan

N *

2) NaBH. 4th

EtOH

8th

ions, as well as the individual enantiomers and diastereoisomers. The respective optical isomers of the class of phenethanolamines to which the compounds according to the invention belong are generally obtained by one of five 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 an optical isomer; (3) synthesis of the respective optical isomer using chiral intermediates; and (4) column chromatography using chiral stationary phases. The implementation of these processes is known to the person skilled in the art.

The above compounds to be included in a vehicle to provide agents useful as an antiin-15 flammable preparation for topical administration to mammals can be included in one of the following vehicles. The mixtures obtained represent pharmaceutical preparations according to the invention. Suitable carriers can all be non-toxic materials or mixtures of materials which are suitable for use in. Scheme B explains the preparation of the compound for the preparation of pharmaceutical ointments, pastes, Lotio-V, wherein essentially the same reaction path as in NEN, sprays, suppositories and other similar formulations-second part of scheme A is followed. Wrestling in the scheme are useful. Furthermore, the carrier is so-B, the corresponding indolylamine is reacted with IX 'and 25 is selected such that it preferably prevents or reduces the systemic absorption of the adduct obtained, then with borohydride to the active substance or substances, protect phenol compound (XII : R = Me) reduced. In addition, the carrier should not be converted to the desired active substance or the active substances compound V described above by catalytic hydrogenation. react. Furthermore, the active ingredient (s) in the carrier should

These two synthesis schemes will be soluble in more detail and will be released topically from the carrier. The interconnections used for this are ended. The mixtures thus prepared should preferably not be commercially available, e.g. 3-indolylacetone, or for a prolonged period, e.g. over months or years, are in the chemical literature, as in the discus-stable.

State of the art publications cited, The active ingredient or ingredients are generally written. 35 dissolved in a component of the carrier. Zinterol hydrochloride

The preparation of bitolterol is described in US Pat. No. 4,138,581, for example, both in water and, at least to which reference is hereby made. partially soluble in various organic materials.

Pharmaceutically acceptable solvates and salts for medical purposes. When applied topically to the skin, social applications are such complexes in which the water-soluble as well as the oil-soluble parts of the carrier do not signify the solvents, the metal cation or acid anion because the skin Skin contains an aqueous and a non-aqueous fikant for the toxicity of the pharmacological activity of the or phase. A total pharmaceutical ion will be used for topical application. The sulfonamido group using a small amount of an organic phase in the carrier is the acidic function used in the metal salt formation. (e.g. petrolatum or mineral oil).

Examples of suitable metal salts are sodium, potassium, Cal carriers for the transport of active substances into the skin, cium, magnesium, aluminum and zinc salts. The metal 45 e.g. Creams, lotions, gels, ointments, suppositories and and acid addition salts are obtained either by reak sprays, and processes for the preparation of these preparations of the selected compound with a suitable metal are known. According to the invention, at least one active base is dissolved with the formation of a metal salt or with an organic substance in the part of the carrier in which it is soluble and see or inorganic acid with formation of the acid addi- the remaining mixture is then suitably mixed with ion salt. The reactants are preferably mixed in this way in the remaining part of the carrier.

Solution or according to one of the details described in the literature. The relative amount of the carrier which is in contact with the standard process active ingredient (s) written and known to the person skilled in the art (ie in contact with the compounds described above. Useful organic acids are b) to form the mixtures according to the invention

for example carboxylic acids, such as maleic acid, acetic acid, is mixed depending on the solubility of the

Tartaric acid, propionic acid, fumaric acid, isethionic acid, Bern-55 or the active substances selected in the carrier. The optimal rock acid, pamic acid, cyclamic acid and pavalic acid (pa concentration, however, is generally the saturation valic acid) and the like. Point. For zinterol hydrochloride, however, it was found

Usable, inorganic acids are halogen water - that its optimal concentration in a cream carrier (such as HCl, HBr, HJ), sulfuric acid, phosphorus - is 0.2 w / v%, although up to 0.7 w / w. /

Acid and the like. Dissolve vol .-% of it in creams.

The solvates described here are complexes which form an or- The mixtures according to the invention can be administered in the following ganic drug molecule and a solvent residue manner. On the basis of the tests in the two formulas ROH, in which R usually describes a hydrogen play, the atom according to the invention or a Q ^ -alkyl group should contain. The mixture that consists of one or more active ingredients in the most common solvate is the hydrate. 65 suitable carrier were produced as soon as possible

The loan used in accordance with the invention after the skin has come into contact with the material or materials also includes all optically isomeric forms, that is to say contact which the inflammation to be treated contains mixtures of enantiomers, e.g. racemic modifica- cause to be applied.

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nrso2CH3

OCJ T

H (XIIï R = Me)

Pt02

OH

R

MeOH »2

Compound V

The mixtures according to the invention are applied directly to the inflamed surface in order to cause a localized effect. Although a systemic effect was observed with (the abovementioned) salbutamol, no such effect was found in preliminary tests with 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 activity and are able to reverse the antigen-induced tracheal contraction. This contractile response to antigens is believed to consist of an original spasm caused by the release of pre-formed histamine and a subsequent one based on the release of newly synthesized SRS-A (slow reacting substance of anaphylaxis) [cf. Brocklehurst, The Release of Histamine and Formation of a SIow-Reacting Substance (SRS-A) Düring Anaphylactic Shock, Journal Physiology, 151: 416-435, 1960]. The ability of the title compounds to inhibit the contractile response mediated by SRS-A significantly more strongly than the contractile response caused by released histamine demonstrates a selectivity advantage of the title compounds which makes them appear particularly useful for use as anti-asthmatic agents. The utility of compounds IV and V in this regard can be demonstrated by various pharmacological tests that inhibit methacholine-induced bronchospasm in rats and inhibit smooth muscle contraction isolated by antigen-induced chemical mediator release from immunized guinea pigs Tracheal rings caused include. The latter procedure was worked on by Adams and Lichtenstein: In Vitro Studies of Anti-gen-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 anti-asthma agents is by systemic administration both by the oral and parenteral route and by inhalation of an effective, non-toxic amount of the compound IV or V or a pharmaceutically acceptable salt thereof. An effective amount means a dose which, when administered to mammals, including humans, exerts the desired pharmacological effect without showing undesirable toxic side effects. The dose varies depending on the host and the chosen route of administration, the dose for achieving the desired therapeutic effect usually being in the range from about 0.1 mcg to 100 mg / kg body weight of a compound of the formulas IV or V or a pharmaceutically acceptable salt thereof .

The compounds IV and V can be formulated according to conventional pharmaceutical methods into pharmaceutical agents in unit dose form, such as tablets, capsules, powders, granules, emulsions, suspensions and the like. These preparations contain the active ingredient, usually together with non-toxic, pharmaceutical excipients, to obtain solid dosage forms, or as a solution, suspension or emulsion, to give a liquid preparation. According to pharmaceutical practice, the addition of sweeteners and flavors or the use of binders etc. can also be carried out. In addition, the agents according to the invention can also contain absorbents, stabilizers, wetting agents and buffers.

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The liquid preparations of compounds IV and V can be administered by inhalation, e.g. by fogging. The present compounds can also be administered as a powder for insufflation, 5 consisting of a mixture of inert powder ingredients and a suitable amount of the present compounds in a suitable particle size. Administration is then through a powder insufflation device. Usually 1 part of micronized drug is mixed with 50 parts of USP xo lactose, which has appropriate microbial properties. This mixture is encapsulated for use in a suitable insufflation device. Before use, the capsule must be punctured or opened to release the powder mixture.

15

Examples

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

(1) croton oil-induced ear edema in mice; 20 (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 fully described by Tonelli et al., Endocrinology, Volume 77, pages 625-634, 1965; reference is hereby incorporated by reference) becomes one 4% croton oil solution in ethanol (V / V) applied topically to mouse ears. This leads to intercellular edema, Va-30 sodilation and polymorphonuclear leukocyte infiltration into the skin, whereupon the weight of the ears increases by about 70 to 100% above normal weight. The inflammatory response almost reached the maximum after 6 hours. When the croton oil 35 test was carried out, 4% by volume croton oil in ethanol was applied to the inside of both ears of each test mouse. The materials to be tested were applied to the outside of the ears in carrier systems immediately after the croton oil administration. The control animals were treated either with Kro-40 tonöl alone or with croton oil and the vehicle alone.

The animals were sacrificed 6 hours after the administration of the croton oil and / or the test material. Biopsy samples were taken from the ears (punch biopsies), weighed 45 and compared with the respective values of the control animals, which were 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 as above (NMP / E V / V 50/50). Because of their known activity in the three animal assays mentioned above, comparative tests were carried out in all three tests (according to Examples 1, 2 and 3), namely with hydrocortisone valerate (HCV) in the croton oil and oxazolone assay, indomethacin (which is a 55 strong, Aspirin-like, non-steroidal, anti-inflammatory agent) in the UVB test and salbutamol (a β2 agonist, which was already mentioned above in the discussion of the prior art).

The percent inhibition of induced mouse ear 60 edema (or erythema) is calculated in all three models (according to Examples 1, 2 and 3) according to the following equation.

Ear weight d. Control animals-it ear weight d. Test animals ear weight d. Control animals x 100

The croton oil assay appeared to be more sensitive to steroid, anti-

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flammatory agents as aspirin-like, non-steroids, previously used as an anti-allergic compound

to address anti-inflammatory agents. Surprisingly found that its topical efficacy against cutaneous wise and, in contrast to aspirin-like, nothing-was not known. Bitolterol and raw, anti-inflammatory agents reduced the inventions. Zinterol were compared directly, it turned out

ß2 agonists according to the invention in an effective manner that both have a similar topical, anti-inflammatory activity.

induced inflammation. possess vity.

The anti-inflammatory activities of about 45 β2. The results in Table I show that Zinterol at 1.6

Andrenergic agonists were reduced to moderate to moderate ear edema using the croton oil indu W / V% and at 0.2 W / V% and bitolterol at 1.6 W / V% in the graceful mouse ear edema assay (which led to acute dermatitis croton oil assay) . Which leads) evaluated. The more effective two compounds in this test compared to hydrocortisone

Subsequently, the oxazolone inducer (HCV) had the same or slightly less effective bonds, they were adorned mouse ear edema assays (which for contact allergy-Der- but more effective than salbutamol).

matitis) and based on the UVB-induced erythema

says tested on guinea pigs. Example 2

From this group of approximately 45 compounds, which is the oxazolone-induced contact sensitization in mice.

Zinterol and its analogues were shown to show 4 veins is characterized by edema and cellular infiltration, mainly bindings (one of which was Zinterol) a strong topical, ku of the monocyte type, with an almost tan, anti-inflammatory activity in the croton oil Assay 100% increase in mouse ear weight is done. (This model when administered at 1.6 W / V% (weight / total volume is by N.J. Lowe et al., British J. of Dermatology,

Ethanol + test material). These four compounds have been fully described in Volume 96, pages 433-438, 1977; then in the croton oil assay also at other concentrations this publication is hereby incorporated by reference). Topically tested in this as well as in the oxazolone assay and in the UVB test. The test materials will be the test model - immediately. These tests showed that Zinterol was applied evenly after the challenge application of oxazolone on the internal

most effective connection. part of the ears - topically on the outer part of this ear

Table I below shows those from the croton oil are of each test animal. The animals were killed 8 or say results obtained for Zinterol and for the comparative 24 h after treatment. The ears became

Compounds Salbutamol and HCV taken during the administration of biopsy samples (punch biopsies), weighed and 1.6 W / V% and 0.2 W / V% in two solvent systems in each case compared with the values of control animals, which were compiled as men. Table I also includes the values described above, a challenge was administered and which

for Bitolterol, a commercially available β2 agonist, 30 che were treated with the vehicle alone.

Table I

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

connection

In DMAC / acetone / EtOH2 1.6 W / V% 0.2 W / V%

In NMP / EtOH3

1.6 W / V% 0.2 W / V%

Zinterol

69a, 50b 81c, 66d 63e, 48f 45S

54h, 34 '29J, 6k 201

69m, 63 "70 °, 48P 731

92r, 58s 56 ', 44 "57v, 38x 34", 61f

Bitolterol

61

42 \ 25y 34z

Salbutamol4

26a, 0b

-34) *, - 45k

54m, 491.

23 °, 0P 371

HCV

78c, 59d 16e, 48f 59®

25i, 38k 34 ',

70 ", 711

71r, 62s 64 ', 67 "73v

1 Each value is the mean obtained from 10 to 15 animals; a fluctuation range of about 10 to 35% is observed in this test

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 / H20 (50/50) a to z The values with the same letter designation were obtained in the same experiment

* The minus sign means no inhibition, but rather a potentiation of the inflammation.

11

659 067

The oxazolone assay appeared to respond to steroidal anti-inflammatory drugs, but was relatively insensitive to non-steroidal anti-inflammatory drugs. Surprisingly, and in contrast to aspirin-like, non-steroid compounds (such as indomethacin), the β2 agonists showed topical, anti-inflammatory activity.

Table II shows the test results, expressed as percent inhibition of oxazolone-induced mouse ear edema, when using different concentrations of zinterol, salbutamol or HCV as active substances when administering oxazolone in a solvent system composed of DMAC / acetone / ethanol (V / V 40/30 / 30) compiled.

It can be seen from the results of Table II for the oxazolone-as-say that at 3 and 1.6% by weight, Zinterol resulted in a slight reduction in ear edema without a dose-dependent effect. Zinterol is comparable to salbutamol, but is slightly less effective than HCV.

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

Example 3

For the sake of completeness, a further series of experiments was carried out, although it could not be expected that β2 agonists (which are vasodilators) would produce results comparable to those for aspirin-like, non-steroid agents (which are not vasodilators). The UVB test induces cutaneous erythema in guinea pigs. This is a commonly used 5 standard anti-inflammatory test, developed by K.F. Swingle, "Evaluation for Anti-Inflammatory Activity," in Anti-Inflammatory Agents, Volume 2, Editor Scherrer and Whitehouse, pages 34-122, London: Acade-mic Press, 1974; reference is hereby made to this publication. In this test, the materials to be tested are applied topically to the irradiated areas immediately after UVB radiation. The erythema was assessed 3 and 6 hours after irradiation on the basis of an i5 grading scale from 0 to 4.

Table III summarizes the values obtained 3 and 6 hours after treatment with zinterol, salbutamol and indomethacin, expressed as a percentage change in the UVB-induced erythema in guinea pigs. 20 From the results of Table III for the UVB assay it can be seen that at 3 and 1.6% by weight, Zinterol showed slight to moderate activity without a uniform dose effect and was highly variable. Similar effects were obtained with salbutamol. In contrast, indomethacin showed uniformly good to very good activity at 1% by weight.

Table II compound

Zinterol

Salbutamol HCV

% Inhibition d.

Oxazolone induction

Edema in the mouse ear 1-2

concentration

0.2 W / V% 1.6 W / V%

22a, - 17b

- la, - 9b 16a, 16b

48 °, 17d 41e

2C, 0d,

36 °, 27d

% Inhibition of oxazolone induction. Edema in the mouse ear2'3 concentration 1.6 W / V%

35h, 30 '14), 43k

21h, 28 '

38 \ 8 '3 P, 42k

3 W / V% 39 '

31 '

39 '

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

2 Each value is the mean obtained from 10 to 15 animals; a fluctuation range of about 20 to 35% is observed in this test

3 The above agents were tested in N-methylpyrrolidone / ethanol (v / v 1/1). a to 1 The values with the same letter designation were in the same

Received experiment.

Table III

% Change in UVB-induced erythema in guinea pigs 3 and 6 h after treatment 1

1.6

%) 2 3

Drug conc. 1.6

o / "\ 3

Time (h)

Connect

3rd

6 3 6

3rd

6

3rd

6

Zinterol

0

13 NT *

9

26

48

18th

37

56

75

25th

9

19th

27th

+ 9

Salbutamol4

9

+ 4 +39 +39

42

32

74

71

45

25th

659 067

Table III

12

Connect

Drug conc. (%) J 1.6 3

Drug conc. (%) 3 1.6 3

Time (h)

6 3 6 3

Indomethacin (1%)

72 54 82

43 48 54

100 93 91

74 85 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 W / V%.

3 The test material was prepared in N-methyl-2-pyrrolidone / ethanol (V / V, 50/50), the concentration is given as W / V%.

4 Tested for limited solubility in ethanol / water (50/50) or NMP / H20 (50/50).

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

The results in Tables I, II and III are summarized in Table IV below.

Table IV

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

Croton oil

Oxazolone

UVB

Assay

Assay

Assay

(Edema)

(Edema)

(Erythema)

Zinterol

+ + +

+

+

Salbutamol

+

+

+

HCV

+ + +

+

NT1

Indomethacin

+

+

+ + +

Anti-inflammatory activity and percentage inhibition range

+ = weak (30-44); + + = moderate (45-59); + + + = strong (60%) NT1 = not tested

Table IV shows that Zinterol is almost as effective as HCV and more effective than salbutamol at the same concentration in the croton oil assay. Based on this data, Zinterol is considered a promising agent with anti-inflammatory activity for use in humans. In addition, Zinterol does not show many of the side effects that occur with conventional steroid therapy.

The test included control groups treated and untreated with croton oil. The control groups were included in the results as described above.

6 hours later the animals were killed with CO 2 gas. A 7.9 mm (5/16 inch punch biopsy) sample was taken from each ear and immediately weighed.

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

The results of three tests with different concentrations of materials to be tested in NMP / 35 EtOH are summarized in Table V below. It can be seen that both compound IV and compound V are comparable to Zinterol in terms of reducing mouse ear edema.

40 Table V

% Reduction in ear edema weight compared to the ear edema weight of the control animals + S.D.

Example 4

In further experiments, two Zinterol analogues, namely the compounds IV and V, were tested. The antiinflammatory activity of these compounds has been shown to be comparable to that of Zinterol.

In these experiments, the anti-inflammatory effect of the three β2 agonists when administered topically on croton oil-induced ear edema in mice was determined. 50 ml of a 4% by weight croton oil solution in ethanol were applied to the inner parts of Swiss albino mice. Immediately afterwards, 25 μl of a suspension of 0.02, 0.2 and 0.8% by weight of the compounds IV and V in N-methylpyrrolidone / ethyl alcohol (NMP / EtOH) were applied to the outer parts of the ears. The

45 concentration (w / v%)

0.02

so mean (MW) ± standard deviation S.D.)

55 0.2

Test material connection IV connection V

MW ± S.D.

0.8

60

MW ± S.D.

10.6 25.6

18.1 ± 10.6 32.9 48.7 49.4

43.7 ± 9.3 61.6

53.4

57.5 ± 5.8

29.9

53.5

69.9

Zinterol

14.2 23.6

18.9 ± 6.5

39.5 66.2

46.6

50.8 ± 13.8

68.2

56.6

62.4 ± 8.2

The results given in Tables III and V in the same row were obtained in the same experiment. A direct comparison is therefore given for 65.

The compounds of general formula II can be processed into a large number of formulations known to the person skilled in the art. Such formulations include

13

659 067

for example, nasal sprays (such a spray can be produced, for example, using trichloromonofluoromethane, dichlorodifluoromethane and oleic acid), rectal suppositories, vaginal suppositories, ointments, creams, gels and lotions.

The processes for the preparation of the compounds IV and V and their biological action can be better understood from the examples below. The examples serve to illustrate the invention but are not intended to limit it.

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 of the NMR spectra corresponds to the number of hydrogen atoms of a certain 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-d6 (Deuterodimethylsulfoxid), CDC13 (Deuterochloroform); otherwise they are common abbreviations. In the infrared (IR) spectra, only those wavenumbers are given (cm-1) that are important for the identification of a functional group. The IR spectra were recorded using potassium bromide (KBr) as a diluent. The elementary analyzes are given in% by weight.

Example 5

5'- (2-amino-l-hydroxyethyl) - 2'-hydroxymethanesulfonanilide hydrochloride (IX)

5'-Bromoacetyl-2'-hydroxymethanesulfonanilide (IX; 40.0 g; 0.13 mol) is added in portions to a stirred solution of 27.4 g (0.19 mol) of hexamethylene tetramine in 650 ml of chloroform. The suspension obtained is heated under reflux for 16 to 18 h, cooled to room temperature and then filtered. The solid obtained is washed with chloroform and air-dried to give 56.6 g (97.3%) of the quaternary salt, mp. 165 to 167 ° C.

This solid is dissolved in 400 ml of ethanol and concentrated with 650 ml. HCl treated. The solution obtained is heated under reflux for a few minutes, whereupon a precipitate separates out in the hot solution. The mixture is cooled in order 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'-hydroxymethanesulfonanilide hydrochloride, mp. 219 to 221 ° C.

A portion (7.3 g, 0.026 mol) of this amino ketone hydrochloride and 10% palladium-on-carbon (2.0 g) were suspended in 200 ml of 90 ° hot ethanol. The warm suspension was reduced with shaking at 4.2 bar (60 psi) hydrogen pressure in a Parr hydrogenator. After shaking for 12 to 14 hours, the hydrogenation mixture on the Parr device was removed and the catalyst was filtered off. The filtrate was concentrated in vacuo to a solid, white residue which is suspended in isopropyl alcohol-isopropyl ether. Filtration yields the compound VIII as a hydrochloride in a quantitative yield, mp. 179 to 180 ° (dec.).

Example 6

2'-Hydroxy-5'- (l-hydroxy-2- [3- (3-indolyl) -2-propylamino] ethyl) methanesulfonanilide (Compound IV)

The hydrochloride of compound VIII (5.65 g, 0.02 mol) prepared according to the process described above is converted into the base by suspending it in 150 ml of ethanol and then by dropwise addition of 2.0 ml of a 10, ON Treated NaOH with stirring. The ur-5 original solid dissolves with the simultaneous precipitation of NaCl. The NaCl is filtered off and the filtrate is concentrated in vacuo to a white, solid residue which is dissolved in 100 ml of methanol. Reductive alkylation is carried out by adding glacial acetic acid (1.2 g, 0.02 mol) and 10-indolylacetone (3.5 g, 0.02 mol), diluting the resulting solution to 150 ml with ethanol and then Add 0.2 g Pt02. This suspension is hydrogenated at 4.2 bar (60 psi) hydrogen pressure until hydrogen uptake is complete (approximately 4 hours). The suspension is removed from the hydrogenation device, filtered and the filtrate is concentrated in vacuo to an oily residue which is dissolved in warm methanol and treated with a few drops of glacial acetic acid. Dilution with ethyl ether and stirring with simultaneous cooling gives, after filtering off, a solid which is washed with methanol 20 to give 4.7 g of the acetate of compound IV, mp. 196.5 to 197 ° (dec.).

This material is dissolved in the minimal amount of 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, mp. 198 to 199 ° (dec.) .

Analysis: calculated for C20H25N3O4S: C 59.53% H 6.24% N 10.41% S 7.94% found: 59.96% 6.15% 10.65% 8.05% 30 NMR (DMSO-d6 ): 0.98 (3, m), 2.75 (5, m), 2.93 (3, s), 4.52 (1, m), 6.00 (3, bs), 7.15 (8, m)

IR (KBr): 750.1125, 1150, 1240, 1280, 1325, 1500, 1610 and 2940 cm-1.

35 Example 7

Alternative preparation of compound IV

A solution of 11.0 g (0.06 mol) of 3- (2-aminopropyl) indole in 730 ml of acetonitrile is stirred under a nitrogen atmosphere and 12.5 g (0.03 mol) of 5 'are added all at once. -Brom-40 acetyl-2'-benzyloxymethanesulfonanilide too. After stirring for 30 minutes at room temperature, a cold solution of sodium borohydride (4.8 g, 0.126 mol) in 219 ml of methanol is quickly added dropwise. The course of the reaction is followed by the spot for the bromoketone in thin-layer chromatograms of 45 grams. Sometimes the addition of additional sodium borohydride is required for the aminoketone used as the starting material to react. When the reaction is complete, the solvent is removed in vacuo and the residue is suspended in 0.5 l of water and treated with 4N NaOH 50 to achieve a complete solution. This solution is washed thoroughly with ether and the pH is then adjusted to 8 with acetic acid. The mixture obtained is extracted with methylene chloride, the extracts are combined, dried (MgSO 4) and then concentrated in vacuo, where 14.5 g of a gummy residue is obtained.

This gum is purified by chromatography on a silica gel column, eluting with chloroform-methanol-ammonium hydroxide (90/10/1). 11.6 g of the benzyloxy derivative of the compound IV are obtained. 60 The O-benzyl protective group is removed by mixing the O-benzyl derivative of the compound IV (11.5 g, 0.02 mol) and 1.8 g of 10 % Palladium-on-carbon (moistened with absolute ethanol) in 820 ml of methanol in a Parr low pressure device. When the hydrogen uptake has ended, the reduced mixture is filtered and the solid is washed with methanol. All methanol fractions are pooled and concentrated to a small volume (approximately 100 ml). When standing up, it gradually comes to mind

659 067

white solid. The solid is filtered off, washed with methanol and air-dried to give 5.6 g of product, mp. 197 to 198 ° C. (dec.). This material is dissolved in 40 ml of hot dimethylformamide, filtered and 45 ml of H20 are added to the filtrate. When this solution is rubbed in, crystallization takes place. 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. Air drying gives 5 g of compound IV, mp. 197 to 200 ° (dec.).

Example 8

N- (2-Hydroxy-5- [l-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 1.21 Dioxane, which has been distilled off over sodium metal, is mixed with 5'-bromoacetyl-2'-benzyloxymethanesulfonanilide (39.8 g, 0.1 mol) with stirring under a nitrogen atmosphere. 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 11 absolute ethanol. The borohydride solution is added dropwise to the filtrate with stirring. The course of the reaction is followed by the spot for the bromoketone in the thin layer chromatogram. The addition of additional sodium borohydride is sometimes required to fully react the starting aminoketone. When the reaction is complete, the solvent is removed in vacuo and the residue is dissolved in 0.2N NaOH and washed with ether. The pH of this solution is then adjusted to 8 with acetic acid. The mixture obtained is extracted with methylene chloride, the extracts are combined, dried (MgS04) and then concentrated in

14

Vacuum, whereby the crude O-benzyl derivative of compound V is obtained as a rubbery residue.

The O-benzyl protecting group is removed by mixing the mixture of the O-benzyl derivative of Compound V (3.25 g, s 0.006 mol) and 1.0 g Pd (OH) 2 / C (Pearlman catalyst) in 100 ml Methanol hydrogenated in a Parr low pressure hydrogenator. When the uptake of hydrogen has ended, the reduction mixture is filtered and the solid is suspended in water. IN HCl is added while heating, so that the product dissolves. The insoluble catalyst is filtered off, the acidic filtrate is made basic with ammonium hydroxide (pH 8). The precipitate obtained is filtered off, washed with water and air-dried, the product being obtained in almost quantitative yield

15 Product (compound V) obtained as a monohydrate, mp. 211 to 212 ° C.

Analysis: calculated for C21H27N3O4SH2O: C 57.92% H 6.72% N9.65% H204.14% found: 58.05% 6.68% 9.64% 3.63%

20 NMR (DMSO-dg): 1.01 (3, s), 1.05 (3, s), 2.75 (4, m), 2.92 (3, s), 4.49 (1, m), 5.30 (6, bs), 7.12 (8, m)

IR (KBr): 740.1010.1115.1125.1235.1280.1460.1500, 1600 and 1610 cm-1.

. The 25 monohydrate obtained according to the process described above is converted into the hydrochloride hydrate by dissolving it in dilute HCl and then concentrating in vacuo to a foam-like solid, mp 105 to 125 C.

Analysis: Calculated for C2iH27N304S-HCl-H20: C 53.44% H 6.41% N8.91% H20 3.82% found as: 53.19% 6.37% 8.92% 3.64%

NMR (DMSO-d6): 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 (1, m), 8.50 (1, bs), 8.78 (1, bs), 9.30 (1, bs), 10.00 (1, bs), 11.10 (1, bs) IR (KBr): 750.960, 1150, 1295, 1320, 1400, 1460, 1515 35 and 1620 cm-1.

C.

Claims (18)

659 067 PATENT CLAIMS 1. Compound of the formula CH, i 3 H0-i y ~ f'-CH2-NH- <r: c "2-M | oh r2 (II ') nh-so2-ch3 wherein M represents an indolyl group and R2 represents a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt or solvate thereof. 2,2'-Hydroxy-5'- (l-hydroxy-2- [l- (3-indolyl) -2-propylamino] ethyl) methanesulfonanilide or its pharmaceutically acceptable metal or acid addition salts or hydrates, as compounds according to claim 1. 3. N- (2-Hydroxy-5- [l-hydroxy-2- ([2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] ethyl] phenyl) methanesulfone amide or its pharmaceutically acceptable metal or acid addition salts or hydrates as compounds according to claim 1. 4. A process for the preparation of a compound of formula II 'according to any one of claims 1-3 or a pharmaceutically acceptable salt or solvate thereof, characterized in that a) an indolylamine of the formula ch3 I. h2n-c-ch2- I. R2 ■ m in which R2 denotes a hydrogen atom or a methyl group and M denotes an indolyl group, with a phenolic bromoketone of the formula nhso2ch3 (ix) H2N ö oh nhso2CH3 (viii) oh reacted with the compound of formula b) m Y wherein M is indolyl, is reacted under the conditions of the reductive amination and the compounds obtained are converted, if appropriate, into a pharmaceutically acceptable salt or solvate. 5. A process for the preparation of a compound of formula II 'according to claim 1, wherein R2 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof, characterized in that a compound of the formula ch-ch -nh-a-c-b-ch -m À2 m so wherein R1 and R2 independently represent a hydrogen atom or a lower alkyl group, where R1 and R2 cannot simultaneously represent a hydrogen atom; M represents a phenyl or indole group or a hydrogen atom; ss A represents the group (-CH2-) “, where n stands for 0.1 or 2; B represents the group (-CH2-) m, where m is 0.1 or 2; / ~~ \ R3 is -OH or -OCO- ^ OV CH3; and R4 represents -NH-S02-CH3 or -OCO- ^ Ö ^ -CH3; 65 or a pharmaceutically acceptable salt or solvate (b) thereof in the manufacture of a topical application agent for treating topical inflammations Combination with a compatible, topically acceptable carrier. 5 6. A process for the preparation of a compound of formula II 'according to claim 1, wherein R2 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof, characterized in that a compound of formula 7. Pharmaceutical composition containing at least one compound of formula II ', in which M indolyl and R2 water 20 means substance or methyl, in combination with a pharmaceutically acceptable carrier. 8. Composition according to claim 7 in unit dosage form for systemic administration to warm-blooded animals, containing a pharmaceutical carrier and a non-toxic, anti-asthmatic amount of one of the compounds 2'-hydroxy-5 '- (l-hydroxy-2- [l- (3-indolyl ) - 2-propylamino] -ethyl) - methanesulfonanilide, N- (2-hydroxy-5- [l-hydroxy-2- ([2- (1H-indol-3-yl) - l, l-dimethylethyl] -amino ) - ethyl] phenyl) - methanesulfon amide or its pharmaceutically acceptable metal or acid addition salts or hydrates. 9. Composition according to claim 7 in aerosol form, containing a compound of formula II ', which is mixed in an anti-asthmatic concentration with a suitable propellant system. 10. Composition according to spoke 7 in powder form, for insufflation, containing a mixture of inert ingredients suitable for insufflation, the inert ingredients and the compound of the formula II 'being one for transport into the 40 bronchioles have a suitable particle size after insufflation. 10th m-ch2-ch-x I. ch, (c) (x) where X is a cleavable group with a connecting 11. Use of a compound of the formula R 35 alkylated, and b) the carbonyl group is subsequently reduced to a secondary -OH group in the reaction product, and the compound obtained is optionally converted into a pharmaceutically acceptable salt or solvate. 12. Use according to claim 11, wherein m and n are 0, R3 is -OH and R4 is -NH-S02-CH3. 13. Use according to claim 12, wherein M is a phenyl group, R1 and R2 are a methyl group and m and n are 0. 14. Use according to claim 12, wherein M is an indole group and R1 and R2 are a methyl group and n and m are 0. 15. Use according to claim 12, wherein n and m are 0, R1 is a methyl group, R2 is a hydrogen atom and M is an indole group. 15 tion of the formula VIII nucleophilically substituted and the compound obtained optionally converted into a pharmaceutically acceptable salt or solvate. 16. Use according to claim 11, wherein n and m for 0 stand, R3 and R4 stand for -OCQ - ^ "Ö ^ - CH3 and M means a hydrogen atom. 17. Use according to any one of claims 11-16, wherein the carrier is dermatologically compatible and preferably the carrier is selected so that it prevents or reduces the systemic absorption of the compounds of formula II. 18. Use according to any one of claims 11-16 for the manufacture of an agent in the form of a cream, lotion, gel, spray or suppository.