SE460761B - PHENETANOLAMINES WITH THE BETA 712 AGONIST EFFECT AND WITH TOPIC ANTI-INFLAMMATORY EFFECT, THEIR PROCEDURES FOR PREPARATION AND COMPOSITIONS INCLUDING THESE COMPOSITIONS - Google Patents

Description

10 15 20 25 30 460 761 in various chronic inflammatory skin diseases the breakdown of steroid teraoin led to the recurrence of inflammatory symptoms and sometimes with increased intensity tet. In view of the inconveniences of using ste- roider has for the last twenty years manyánva igkn energy; da anti-inflammatory drugs (ie NSAIA) developed for use in various diseases including rheumatic diseases. These associations generally appear to be free from some of the adverse effects associated with those with steroids, especially tissue atrophy, adrenal suppression and other less serious recurring effects gar.

A class of associations within the NSAIA group is that group of compounds that are prostaglandin synthetase inhibitors.

These materials are generally active when it comes to reduce UVB-induced erythema (ie erythema induced by ultraviolet light) in guinea pigs; the materials are, however time only slightly active or inactive in other test, dermatitis including croton oil and the oxazolone ear edema test, which are described in more detail below.

Therefore, other classes of non-steroidal compounds are included topical anti-inflammatory activity of interest. Û-adrenergic agonists (including ßl- and ß-2anonis- ter) are compounds which are believed to act by stimulating adenylate cyclase, resulting in the conversion of adeno centrifosphate (ie ATP) to cyclic 3 ', 5'-adenosine monophosphate barrels (ie C-AMP) see for example R.J. Brittain et al, Adv. Drug Res. 5, (1970), 197. The walls of essentially everyone mammalian cell nuclei contain the enzyme adenylate cyclase, which is stimulated by various compounds including prostaglandin E and β-adrenergic drugs.

Adenylate cyclase activity has been reported to be present in human and animal epidermis. Disorders of adenylate cyclase wzsg-x Fass-s. _, -. .. '. 10 15 20 30 35 460 761 ÄÉ activity and C-AHP levels have been reported at proliferative skin diseases such as eczema, psoriasis, à epidermolytic hyperkeratosis and lamellar ichthyosis.

In summary, Û agonists are a class of compounds, which stimulates the adrenergic system in the human body A pen.

Materials classified as fi ä agonists are β-agonists which selectively react with the β1 receptors and exercises cardiac pacing.

Materials classified as .02 agonists react selective with, the Ö2 receptors, which are present in it smooth the muscles of blood vessels and bronchi; these materials rial exercises bronchodilation and vasodilation.

British Patent 4,323,575 discloses disubstituted catecholamines (which may be β2 agonists) with whip anti-inflammatory activity.

U.S. Patent 3,341,584 discloses sulfonanilides with the general formula I X As disclosed in this patent, the sulfonanilides are included formula I, wherein Z is CHOH, pharmacologically active compounds ethanolamines with effects similar to either of adrenal medullary hormones or adrenal- 1 neurotransmitters or counteract the effects of adrenal medullary hormones or adrenergic neuro- transmitters. The nucleus substituted alkyl and aryl sul- 10 15 20 25 30 460 761 phonamidophenalkanolamines have useful pharmacological 3 effects, making them versatile. only as vasopressors, vasodepressors, analgesics, bronchodilators, (X-receptor stimulators, β-receptor stimulators, GC receptor blockers, / 9 receptor blockers, rare, poppy-like smooth muscle depressants or anti-inflammatory drugs to control or prevent anaphylaxis.

Anaphylaxis is defined in the McGraw-Hill Dictionary of Scien- tific and Technical Terms, 2nd ed., 1978, as of hypersensitivity following parenteral injection of an antigen, wherein local or systemic allergenic reactions occur when the antigen is reintroduced thereafter that a certain time has elapsed. The term "topical" defines as "local or intended for local administration" and said term is used in this sense in the present landscape context. Therefore, since anaphylaxis and inflammatory inflammations are physiologically different conditions, is generally a medicinal product which is useful for act of one of these conditions, not applicable to treatment of the second condition.

U.S. Patent 3,801,631 discloses the compound 2-hydroxy-5 '- [1-hydroxy- 2- (2-methyl-1-phenyl-2-propylamino) -' ethyl methanesulfonanilide, which is called zinterol and which generically covered by the sulfonic acid amides disclosed in the aforementioned U.S. Patents 3,34? 584. Zinterol har described as a potent anorexigenic agent, as an oral active bronchodilator and with analgesic activity.

In the article "Adrenergic Sulfonanilides. 4. Centrally Acti- velß-Adrenergic Agonists "by D. L. Temple et al in Journal of Medicinal Chemistry, Vol 19, no. 5, p. 626-633 (1976), zinterol (compound no. 43) is described as a potent analogue rexigent agent and as a drug antagonist. ~; f .._ = ». =. '»: - e'- N 10 15 20 (fl 30 35 460 761 Additional uses of zinterol are further disclosed in the U.S. Patents 3,919,424 and 3,993,776.

Salbutamol is a ßz agonist. This compound has besk-f rivits by R. Seely et al, Proc. Soc. Exp. Biol. With. 223 (1978) as a useful topical anti-inflammatory agent. toric agent. ' The synthesis of salbutamol is described in Drugs of the Future IV, 629 (1979). It states salbutamol to be useful as anti-inflammatory agent when administered topically. Far- It is stated that oral administration of saibutamoi during asthma can be well compared to related drugs. average. A mechanism for the action of salbutamol is proposed (see page 631 in the reference).

A 1980 publication by Saiichirou Seo et al, "lnhihi- tion of Adjuvant Arthritis by Salbutamoi and Aminophyl- line, Ü European J. of Pharmacology, 63, 267-274, 1980, describes inhibition of swelling in the paws of mice by injections of a combination of salbutamol and ami- nofyllmn.

Other compounds with some structural similarity to zinte- role and with topical anti-inflammatory activity are revealed in U.S. Patent 4,323,575. These compounds are possibly fl å agonists, which can only be determined ge- nom testing.

U.S. Patent 4,088,756 discloses others [Island agonists, with or without anti-inflammatory activity.

However, as stated above, one can not with anyone reasonable degree of certainty predict which ßz agonists are are effective topical anti-inflammatory agents. After extensive experiments, we have found that practically 460 761 10 15 20 25 30 35 liga / 52 agonists which have been tested with respect to said activity were either ineffective or highly toxic shall or both.

Despite what is known in the art, there is therefore a continuing need for non-steroidal anti-inflammatory drugs medicinal products which show good anti-inflammatory risk activity and which are non-toxic.

An extensive literature is available regarding β-adrenergic agonist compounds of the series comprising catechol-type phenethanolamines.

The aforementioned U.S. Patents 3,341,584 disclose catechol-type phenethanolamines, wherein one of the phenyl ring the hydroxy groups have been replaced by sulfonic acid amindo, when obtaining compounds with biological / β-adrenergic activity.

U.S. Patent 2,908,691 discloses a comprehensive group of hydroxyphenalkylaminoalkylindoles, which are fikt is described as having different effects on the central nervous system as well as they have the effect of antisecretory agents and are effective in reducing stomach acid. The most the relevant compound in this reference appears to be 3- (2- [2-hydroxy-2- (3,4-dihydroxyphenyl) ethylamine] propyl) indole- tartrate. This compound is prepared in Example 7 in Reference ningen.

An object of the present invention is to provide maintain an compound which, when incorporated into an appropriate rare gives a composition, as in topical administration reduces the amount of topical inflammation in a mammal.

Another object of the present invention is to provide a position in the form of an ointment, cream, lotion or other * Ym ..; d 10 15 20 25 30 35 460 761 rescue, which can be administered topically to a mammal ~ animals to reduce or prevent the development of skin inflammation.

The above objects are achieved by means of the compositions according to the present invention, which include (a) one for producing a topical anti-inflammatory effective amount of at least one compound (or pharmaceutical culturally acceptable salt or solvate thereof) with the men formula II 1 R 3 I R CH-CH -NH-A-C-B-CH -M II 0 | -2 '2 2 () OH R R4 wherein R 1 and R 2 are independently hydrogen or a ' lower alkyl group, with the proviso that R 1 and R 2 do not both may be hydrogen, M is either hydrogen, a phenyl group or an indole group of formula (a) (a) N A äñ (-CH2-) n where.n. is the integer 0.1 or 2, and B is (-CH2) m where m is the integer 0,1 or 2, Éšär -OH or 4 .. _ joco- (EZ) -CH3 and R are -Nu-so2-cu3 or -oco- {šL> -CH3, and (b) a dermatologically acceptable carrier therefor.

In a preferred embodiment of the invention, R 1 and R 2 both methyl groups and m and n are both 0. A preferred one a -., - «~ _¿ -., - f» .¿.fç¿ .-, _ ««, 10 15 20 25 30 35 compound for use in the present invention is a compound of formula II, wherein n is 0, m is 0, R 1 is methyl, R 2 is methyl, M is phenyl, R 3 is -OH and R 4 is -NHSO 2 -CH 3. This compound is known as zin-- terol (hereinafter referred to as compound III).

Another preferred compound for use according to the invention is the compound of formula II wherein n is 0, m is 0, R 1 is methyl, R 2 is hydrogen, M is an indole group, R 3 is -on and R4 is -Nu-soz-cu3, which compound 1 is designated as compound IV.

Another preferred compound for use in According to the present invention, the compound of the present invention is where II is 0, m is 0, R1 and R2 are both methyl, 3 is -OH and R 4 is -NH-SO 2 -CH 3, the compound hereinafter referred to as M is an indole group, R ler azazinterol.

A further preferred compound for use in According to the present invention, it is the compound of the formula II wherein n is 0, m is 0, R 1 and R 2 are both methyl, H is I 3 4 I nu n: a hydrogen and R and R both are -OCO - <:> - CH3. This association hereinafter referred to as bitolterol and is commercial available for use in the treatment of allergy but has not previously been known to be useful for the treatment of topical inflammations.

In a slightly different aspect of the invention, a method is intended to reduce topical inflammation in mammals, which involves administering a compound of the formula II topically to the mammal so that local (as opposed to systemic) activity against topical inflammation is achieved.

Furthermore, according to the invention, a composition comprises which is administered topically to reduce the amount of topical 10 15 20 25 30 460 761 inflammation in mammals, at least one compound with Formula II present in a non-toxic amount, which is sufficient to reduce inflammation, and present in a pharmaceutically acceptable carrier material, wherein in formula II A, B, R 1, R 2, R 3, R 4 and M have the above meanings.

According to another preferred aspect of the invention, takes a composition intended for topical administration at least one compound consisting of zinterol, compound IV, compound V and / or bitolterol, which is present in a amount, which is sufficient to reduce inflammation but which is insufficient to be toxic and is being in a pharmaceutically acceptable carrier.

It should be noted that the term "topical" in the present the contexts relate to local administration for providing a local effect with preferably not any concomitant systemic effect. Thus can the compounds used according to the invention are administered race in any way provided that they not injected or swallowed. They can, for example, administered cutaneously, nasally, vaginally, rectally, otically and buccal. They were used together with a dermatologist -gically acceptable carrier, which is preferably selected from one such a way that <fi H1 systemic absorption of the active the component is prevented or reduced.

The invention also relates to antiasmatic agents which are bronchodilators. dilators and potent yet selective inhibitors of smooth muscle contraction. The powers and selectivity of these agents in inhibiting smoothing muscle contraction caused by antigen-induced release production of chemical mediators has been demonstrated in pharmaco- logical tests using trachea rings from immunized guinea pig. These agents include compound IV 10 15 20 25 30 35 460 761 10 and compound V and their pharmaceutically acceptable solvates and salts and the invention includes theirs use as anti-asthmatic agents.

The compounds to be introduced into a carrier for held by a composition suitable for use as an anti-inflammatory drug for mammals animals, are the above compounds of formula II (or pharmaceutically acceptable salts and solvates thereof), wherein M is either a phenyl group or an indole group or hydrogen; wherein A is (-CH 2 -) n where n is 0.1 or 2; vari B is (-CH 2) m, where m is 0.1 or 2; wherein R 1 and R 2 dependent on each other is hydrogen or a lower alkyl group, with the proviso that R 1 and R 2 may not both be hydrogen; wherein 1: 3 is -on enef -oco @ cu3, - een var: m4 is -Nu-so2-cn3 or -oco - @ - cn3.

It should be noted that we have tried many / 32-address energetic agonists (all of which are analogous to zinterol). Of about 45 such compounds, dast 4 high topical anti-inflammatory activity without any apparent toxicity to tests described in examples below. Other associations exhibited either toxicity when administered topically to the experimental animals, were ineffective and / or exhibited contradictory anti- inflammatory activity.

The compounds which are intended to be introduced into a hürnre for providing a composition for topical use as an anti-inflammatory preparation for mammals read as follows.

The preparation of zinterol is described in detail therein U.S. Patent 3,801,631, so reference is made to this patent in respect of the manufacture of said compound. 10 15 20 25 30 35 460 761 11 A detailed description of the presentation is given below of compounds IV and V. Compounds IV and V can be prepared provided by two general methods. The first synthesis the method can be illustrated as follows: Method 1 OH hrs SOZCHJ catalyst (b) VIII this method.includes reductive amination of an indolyl carbonyl compound with a suitable phenethanolamine. The choice of reagents and conditions for reductive aminations are well known to those skilled in the art. In general, the reaction is carried out by shaking a solution of the appropriate carbonyl the compound and the phenolic amine in a solvent such as a lower alkanol, for example methanol, in the presence of a hydrogenation catalyst, for example a noble metal catalyst lysator such as platinum oxide, in a hydrogen atmosphere. Alternatively the reaction can also be carried out stepwise by first forms the condensation product of the carbonyl compound and the phenolic amine and then performs the hydrogenation as a separate process.

A variation of the synthesis method 1 involves nucleophilic penetration with the phenolic amine on an indolylalkyl- halide or an equivalent compound. This is shown below as method 1A.

Method lg _ compound IV if (R = Hl I + (VIII) _____, or X compound V if (R = Me) B12 (fi) 2 E compound IV f, §, e, ".'_ ¿~ '..;. ~. ~ .f' e-.«.-.'-. 1.. ._ 10 20 25 30 460 761 12 In the above reaction formula, X is a typical derivative group such as halide, tosylate, etc. Also in this case is the choice of reaction conditions and reagents for leophilic displacement reactions well known to those skilled in the art. in the chemical field.

The second process that can be used for production of compound IV or 2.

Method 2 R - OR compound IV (if R = H) _____ / <> x / flfl e R _ + B fl go Q; compound V (if R = He) u ___ N_- _ O 2 3 HRS . '. .

X IX In the above reaction formula, Me = methyl.

The process involves alkylation of the phenolic bromine ketone with a suitable indolylalkylamine, followed by reduction tion of the carbonyl group to a secondary alcohol. In practice The phenolic OH group is protected under the nucleotide file the constriction reaction. This is done in order to prevent the phenolic group from participating in the nucleophilic attack and thereby give rise to undesirable ethereal products. In general, said group is protected via a syl group, which is then removed by catalytic reduction tion.

These general synthesis methods have been used for the actuaries syntheses used to prepare IV and V. The specific synthetic methods for the position of these compounds is illustrated below. before- ., ä »J-wxà-vav-zå- - w w 460 761 13 Reaction Scheme A: Preparation of Compound IV è 6 Br: lWSO (¶ NHSO CH ~ cncla o 2 3 ißr 0 zsa-cnu ---> cnæu ' Q 6124 6124 Q OH ÄÄ 'QR 5 Ix ~ V A .non . ~ Hcl 10 Hcl rmso ca ncl 'm * 2 3 n - Nusozc fl: H2 l --- z-- 3 N o o ”Pd / c 2 Eco !! OH VIII. . XI _ ¿ 15 i - _ 9:02 r H V- 0 ”mxso cn 2 3 20 Û g Û N H _ou_ Iv 25; 'w-'H-'f fl i ”pd / c' f" "- '. Ä ._._'- -'..- __.

'- ~ ~ .. ~ V -.'. ^ _ "'° 1 ~ V' 'MeoH- fl'“ ffw- ._ q - - R I] OH šo ca I - 2 3 Uacetonitrile 30 I H2 N ocuzrh. n 2) NaBH xII, R = 1 ~ x - MeO “-« i -n. _ _ _ 35 '' rm 0 zmso cn.

'+ @ U ^ F 2 ßfvw @ i 2 at 00:12 Ph x, 2 = _u Ix ' 10 15 20 25 30 35 14 Reaction Scheme A illustrates the preparation of compound IV. Two paths are indicated, both of which are based on bromoketones IX and IX '. At the upper road turnover compound IX with hexamethylenetetramine (C H N 4) for 6 12 obtaining a quaternary salt, which is converted to the amino ketone XI, followed by catalytic hydrogenation to phenethanolamine VIII. Reductive alkylation of 3-indo- lylacetone with compound VIII gives compound IV as is shown. The lower and preferred pathway is via the nucleotide felt attack of the indolylamine X on the compound IX '(O- the benzyl analog of compound IX), followed by borohydride production to obtain the intermediate with a benzyl which to the desired blocked phenolic group (XII: R = H), as shown, compound in turn is catalytically reduced damage the end product.

Reaction Scheme B: Preparation of Compound V P ECB ” - NH 'dioxane 2 O NHSOZCHS 1) I + Br "z OCHZPÖ 2) NaBH¿ X: R = M8 IX 'EtÛH IR 11 ° I _ I V (gfm / * eïzïzizïß n 2 '* (xI1 = R = Me) Pt0 He0H 2 22 OH ___ / J !! a- _Q: §] \ L | I / \ / L \ ßš2l_ llllSOzClls OH 460 761 15 The reaction scheme illustrates the preparation of the n V during use_of essentially the same path as is shown in the lower part of Reaction Scheme A above. I reak- Scheme B is reacted with the appropriate indolylamine compound IX 'and the resulting adduct is reduced with borohydride to obtain the protected phenolic compound (XII: R = Me), as shown, which compound thereof via catalytic hydrogenation is converted to the desired one association V.

The above two synthesis methods will be illustrated in more detail below. The intermediates used in these syntheses are either commercially available, for example 3-indolylacetone, or are described in the chemical literature, for example the references given above.

The preparation of bitolterol is described in the American patent 4,138,581, so reference is made to said patent.

For medical use, they are pharmaceutically acceptable the solvates and salts such complexes, where the solvent, metal cation or acid anion do not significantly contribute to the toxicity or pharmacological activity in the organic drug ion. The sulfonamido group is the acid function used in metal salt formation.

Examples of metal salts include sodium, potassium, calcium the cium, magnesium, aluminum and zinc salts. Metal- and acid addition salts are obtained by reacting it selected compound with a suitable metal base for obtaining those of a metal salt respectively with an organic or Inorganic acid to form an acid addition salt, present by contact in solution, or by any of the standard methods described in the literature and are well known to those skilled in the art. Examples of useful organisms acids are carboxylic acids such as maleic acid, acetic acid, 10 15 20 25 30 35 460 761 16 tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid tartaric acid, pamoic acid, cyclamic acid, pavalic acid and similar nande. Useful inorganic acids are halide hydrochloric acids (such as HCl, Hßr, HI), sulfuric acid, phosphoric acid and the like. nande.

Useful solvates are complexes which include an organic one drug molecule and a solvent group of the formula ROH, where R is mostly hydrogen or a C1-C4 alkyl group.

The most common solvate is the hydrate.

It will be appreciated that the compounds of the present invention finning includes all optical isomeric forms, i.e. mixtures of enantiomers, for example racemic modifiers cations, as well as individual enantiomers and diastereomers more. The individual optical isomers of compounds belonging to the phenethanolamine class to which the present the compounds belong, are obtained most generally by someone of four basic methods listed below. These are: 1) frak- ionized recrystallization of chiral acid salt derivatives; 2) derivatization with a chiral organic reagent, cleavage and regeneration of the original the optical isomeric form; 3) appeared by the individual the optical isomer using chiral intermediates dukter; and 4) column chromatography using chiral stationary phases. The use of these methods is well known to those skilled in the art. The above compounds, which intended to be introduced into a carrier for delivery those of compositions suitable for topical use such as anti-inflammatory preparations for mammals, may be introduced in the following carriers. The mixtures obtained are pharmaceutical technical preparations according to the invention. The carrier can be a non-toxic material or a mixture of materials, suitable for use in the manufacture of pharmaceuticals culturally acceptable ointments, lotions, aerosols, suppositories and other similar drugs. Further distinction here 10 15 20 25 30 35 460 761 ' 17 is chosen in such a way that it preferably hinders or reduces systemic absorption of the active substance component and it should not react with the above active ingredients. stand. In addition, the active ingredient should be both be soluble in the carrier and are released topically by the carrier.

The mixtures thus prepared should preferably be be further stable for an extended period of time, for example of the order of months or years: The active ingredient is usually dissolved in a component by the wearer. For example, zinterol hydrochloride both soluble in water and at least to some extent in various organic materials. Because there is both one aqueous phase and an anhydrous phase in the skin occurs at the topical administration to the skin of both water-soluble and oil-soluble parts of the wearer to penetrate the skin. Too topical use, however, any organic phase should be used in pure (for example petroleum jelly or mineral oil).

Carrier for applicerino of the active ingredients reach the skin, for example creams, lotions, gels, ointments, suppositories sitoria and aerosols, _} as methods of preparation hence are well known to those skilled in the art. According to the present invention, at least one active ingredient is dissolved in one portion of the carrier in which it is soluble and the interfering mixture the mixture is then mixed in an appropriate manner with other constituents of the carrier.

The relative amount of carrier to be mixed with the the active ingredient (ie with a compound described above) for the preparation of mixtures according to the invention depending on the solubility of the active ingredient in the carrier. However, it is assumed that the optimal concentration the formation generally consists of the saturation point. For zinte- However, hydrochloride has the optimum concentration of of which in a cream carrier was found to be 0.22 (vint / vw- lymph) although up to 0.7% (w / v) can be dissolved in 10 15 20 25 30 35 460 761 18 creams.

The mixtures according to the invention are administered on the following way. Based on the 1 examples described below- the tests according to the invention, which have been prepared with the active ingredient in a suitable carrier, apply as soon as possible after that the skin has come into contact with the material or smiles the materials that cause it for treatment Inflammation.

The mixtures according to the invention are applied directly to the area of inflammation for the provision of a local fekt. Although using salbutamol (as shown above) a systemic effect has been found, it has not been possible demonstrate any such effect in the preliminary tests which have been made in accordance with the present invention. It is an advantage that no systemic effect arises and that these compounds are absorbed to a minimum.

Furthermore, biological testing of the compounds has 1? and V demonstrated that they exhibit inherent bronchodilatory and that they are capable of reversing anti-induction row tracheal contraction. This contraction response to anti- gene has been characterized as consisting of an initial spasm caused by the release of pre-formed hemispheres tamin, followed by a delayed contraction due to the release of newly synthesized SRS-A (slow-reacting) anaphylaxis substance; see Brocklehurst: The Release of Hist- amine and Formation of a Slow-Reacting Substance (SRS-A) During Anaphylactic Shock, Physiolouï Journal, 15I: 4l6- 435, 1960). The ability of the compounds of the invention to gene to inhibit the contraction response mediated by SRS-A with significantly greater inhibitory potency compared to brought with the contraction response to released histamine demonstrates an advantage of the present compounds in the selection 15 20 25 30 460 761 19 activity, which makes them particularly useful as antiasmatic agents. The usefulness of the compounds IV and V in this regard can be demonstrated by different pharmacological tests, which include inhibition of metacholin-induced bronchospasm in rats and inhibition of smooth muscle contraction, caused by antigen-induced release of chemical mediators in tra- which have been isolated from immunized mar- wine. The latter method has been adapted from Adams and Lichtenstein: In Vitro Studies of Antigen-Induced Source- -chospasm: Effective Antihistamine and SRS-A Antagonist on Response of Sensitized Guinea Pig and Human Airways to Antigen. Journal of Immunol., 122: 5S5-562, (1979).

For use as antiasmatic agents are administered according to the invention an effective, non-toxic amount of IV or compound V or a pharmaceutical removable salt thereof systemically orally or parenterally or by inhalation. An effective amount refers to a dose, which exerts the desired pharmacological action, such as that which have been stated above, without any unduly toxic bi- I effects when administered to a mammal, which is in need of such treatment. The dosage varies depending on the object and the mode of administration within one range from about 0.1 μg to 100 mg / kg body weight of a compound of formula IV or V or a pharmaceutical culturally acceptable acid addition salt thereof.

Compounds IV and V can be prepared according to conventional pharmaceutical practice for the provision of pharmaceutical units in unit dosage form, such as pelvis includes tablets, capsules, powders, granules, emulsions, suspensions and the like. These preparations contains the active ingredient, usually in mixtures with non-toxic pharmaceutical excipients, for addition administration of solid dosage forms or as a solution suspension or emulsion to provide 10 15 20 25 30 35 of a liquid preparation. It should be understood that also other standard pharmaceutical practices are included, such as the additive of sweeteners and flavorings or the use of demedel, etc. Furthermore, the compositions may also contain other absorbents, stabilizers, wetting agents and buffering agents.

Liquid preparations of compounds IV and V may be further be used for administration by inhalation, e.g. pelvis by nebulization. The present compounds can also administered as a powder for insufflation, which powder consists of a mixture of inert powder constituents parts mixed with an appropriate amount of a compound present invention with the appropriate particle size and the powder is administered by means of a powder suffocation device. In general, some microni- serate drug with 50 parts lactose USP with appropriate microbial properties. This mixture is encapsulated for turning in a suitable insufflation device. Before turning, the capsule must be punctured or opened to the mixture must be able to be released.

Example In Examples 1-4, the following types of tests were used (ie models) in animals, namely (1) croton oil induction rat ear edema in mice, (2) oxazolone-induced ear edema in mice and (3) UVB-induced erythema in guinea pigs.

Example 1 In the croton oil test (which is a standard test, which fully described by Tonelli et al., §nd2gri§3l22ï¿ vol. 77, p. 625-634, 1965, to which reference is made in the present context) causes topical application of four volume percent croton oil in ethanol in the ears of mice Intercellular edema, vasodilatlon and null morphonuclear 10 IS 20 25 30 35 '. 460 761 21 leukocyte infiltration into the dermis, leading to a increase in ear weight by 70-100% above normal the weight. The inflammatory response is close to maximal ground after 6 hours. In the croton oil test was applied four volume percent croton oil in ethanol in both inner ears in each experimental mouse and different test materials in the human system. tmw afpllmænaavæ 1 yn1esG: wnw, mnmdeâ1 # :! +! = «: L: u '» n- the oil application. Control animals were exposed either for croton oil separately or for croton oil followed by carrier separately.

Six hours after exposure to croton oil and / or test material the animals were killed: punched biopsies of The ears were weighed and compared with the respective carrier roll.

The compounds were tested in simple solutions including dimethylacetamide / acetone / ethanol (ie DHAC / A / E in volume holding 40/30/30) and N-methylpyrrolidone / ethanol (NHP / B in the volume ratio 50/50). Comparative control samples were selected based on their known activity at each one of the three animal experiments described above and included those in all three tests (in Examples 1, 2 and 3) hydrocortisone valerate (HCV) in croton oil and oxazo the experiments, indomethacin (which is a potent, aspirin similar, non-steroidal anti-inflammatory agent) in the UVB test and salbutamol (a [} 2 agonist as has discussed above in the description of the background of the invention. basic).

The percentage inhibition of induced ear edema (or erythema) in mice for each of the three models The compounds (in Examples 1, 2 and 3) are calculated according to the form: Controller weight - Tester weight K 100 Controller weight 10 15 20 25 30 35 460 761 22 The croton oil test seems to be more sensitive to steroids anti-inflammatory agents than for aspirin-like, non- In contrast to those asnirin-like, non-steroidal anti-inflammatory drugs unexpectedly, the 62 agonists of the present invention were steroidal anti-inflammatory drugs. finning effective for reduction of croton oil induced inflammation. The fl anti-inflammatory effects of cirrhosis 45I52 adrenergic agonists were evaluated in the test with croton oil-induced ear edema in mice (which to acute dermatitis); the more active associations origin tested then by the experiment with oxazolone-induced ear edema in mice (giving contact allergy dermatitis) and in the search with UVB-induced erythema in guinea pigs.

In the group of about 45 compounds including zinterol and analogues thereof exhibited four compounds (of which one was zinterol) high topical, cutaneous anti-inflammatory action activity in the crown tonne oil test at the level of 1.61 (weight / total volume of ethanol + test material). These four compounds are tested was then applied topically in other concentrations with tonal oil test and was also tested topically with oxazolone testct and with the UVB test. At these subsequent orovninqar zinterol proved to be the most active throughout Association.

Table I below shows the results for zinterol and the control substances salbutamol and HCV at levels 1.6% (weight / volume) and 0.2% in each of two solvent systems. In Table I (weight / volume) in the croton oil test also includes data for bitolterol, a commercially available available / 32 agonist, which has previously been used as an anti- allergic.compound but which has not previously been known to be topically active with respect to cutaneous inflammation tioner. A direct comparison between bitolterol and zinte- role has been performed. Both exhibited similar topical anti-inflammatory properties. inflammatory activity. 10 15 20 460 761 23 The results in Table I show that in the croton oil test zinterol at a concentration of 1.6% (w / v) and 0.2% (w / v) and bitolterol in a concentration of 1.6% (w / v) both showed good to moderate re- production of ear edema and were equivalent to or slightly less effective than hydrocortisone valerate (ie HCV) but more effective than salbutamol.

Example 2 Oxazolone-induced contact sensitization in mice is characterized by edema and cellular infiltration, primarily by monocyte type, with an almost 100% increase in ear folds. ten in mice. (This model is fully described by N. J. Lowe et al., British J. of Dermatolooy, vol. 96, sid. 433-438, 1977, to which reference is made in the present 5 context). In this model, the test materials É were applied topically in the outer ear of each experimental animal, immediately followed by an application of oxazolone in the inner ear. The animals killed 8-24 hours after treatment: punched biopsies says of the ears were weighed and compared with control samples, which had been exposed to oxazolone and vehicle only as above. 460 761 24 Table I % Inhibition of croton oil-induced ear edema in mice . . U 1 and two bars I DMAC / aCetOn / ETOHZ I IJMP / ETOH 3 1.6% 0.2% 1.6% 0.2% Compound (w / v) (w / v) (w / v) (w / v) zinterol 693, sob 54h, 34i 69m, 63 ”92”, 585 s1 °, 66d 295, sk 7o °, 489 56t, 44 ” 639, 4sf 201 73q 57 ”. 38 * 459 34Y, 61f ßitoiterol 61 42x, 25 Y '342 sa1butamo1426a, ob -34jf-45k 54m, 49 ” 23 °, op 37q Hcv 7s °, 59d 253, 38k 70 ", 71q 71f, 625 ' 168, 4sf 341 64t, 67 ” 599 73v Q Each value is the mean value for 10-15 animals. About 10-35% variability is observed in this test. 2 Dimethylacetamide / acetone / ethanol (volume ratio 40/40/30). 3 N-methyl-2-pyrrolidone / ethanol (50/50 by volume). 4 Tested in ethanol / H 2 O (50 / SO) due to solvent restrictions. a / Z Values with the same letter in the alphabet were observed in the same attempt.

* The minus sign indicates the absence of inhibition and snare potentiation of the inflammation. 10 15 20 25 30 35 460 761 25 The oxazolone test has been shown to be a sensitive steroid. anti-inflammatory drugs and relatively insensitive to non-steroidal anti-inflammatory drugs. Contrary, to aspirin-like non-steroids (such as indomethacin) the β2 agonists again unexpectedly showed topical anti-inflammatory toric activity.

Table II gives the results of experiments on percentages. possible inhibition of oxazolone-induced edema in mouse ears using different concentrations of zinterol, salbutamol or HCV as an active ingredient in oxazolone in a system of three solvents, namely DMAC / acetone / ethanol in the volume ratio 40:30:30.

From the results in Table II regarding the oxazolone test can it is found that zinterol in concentrations 3 and 1.6% by weight showed little reduction in ear edema without any dose-related effect and was equivalent to salbuta ~ mol but slightly less active than HCV.

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

Exemgel 3 , Another trial series was performed for completeness although it was not expected that / 32 aconists (as are vasodilators) would show results comparable to the aspirin-like non-steroidal agents (which are not vasodilators). The UVB test induces cutaneous erythema in guinea pigs. This test is a standard test, which has widely used for testing anti-inflammatory drugs theoretical means and which is fully described by K.F.

Swingle, "Evaluation for Anti-Inflammatory Activity", in Anti-Inflammatory Agents, vol. 2, edited. by Scherrer and Whitehouse, pp. 34-122, London: Academic Press, 1974, to which reference is made in the present context. At UVH- model, the test material was applied topically to the contaminants »W k * \ 'r .-, .- - ~. * 460 761 26 laid the sites immediately after exposure to UVB.

Erythema was evaluated on a scale of O-4 at 3 and 6 hours. but after irradiation. ..._ ~ .., ._.._......._. ~. ~.-... ~ ... W 27 460 761 gabell 11 % Inhibition of% Inhibition of oxazolone induct oxazolone inducârât edema of the mouse ear edema of the mouse ' Association Concentration Concentration 0.2% 1.6% 1.6% 3% (weight / vol) (weight / vol) (weight / vol) (weight / vol . zza, -17b 4a °, 17 35h, 3oí 391 Zlnterol _ _ e. Y _ 41 143.43 ' salbutamol -1a, -9b 2 °, o z1h, 2si '31' ncv 16a, 16b 3s ° 3sh, ai 39 ' 313.42 * The above agents were tested in DMAC the ratio 40:30:30 / acetone / ethanol in volume Each value refers to the mean value for 10-15 animals.

Approximately 20-35 variability is observed in this test.

The above agents were tested in N-methylpyrrolidoneethanol in volume ratio 1: 1.

Values with the same letter in the alphabet were observed in the same attempt. 10 15 20 25 Table III shows the percentage changes in UVB-induced erythema in guinea pigs 3 and 6 hours after treatment with zinterol together with the results of action with salbutamol and indomethacin.

As can be seen from the results in Table III for the UVB test zinterol at a concentration of 3 and 1.6 weight percent call moderate activity without any concomitant dose effect and the effect was extremely variable bel. Similar_effects could be observed with salbuta- mole. However, indomethacin indicated a concentration of 1% by weight of good to very good activity on unanimous basis.

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

Based on the summary in Table IV, one can draw ' the firm conclusion that in the same concentrations terol appears to be practically as effective as HCV and more effective is salbutamol in the croton oil test.

Therefore, zinterol is a promising candidate for reduction of anti-inflammatory activity in humans, based on the above data. Zinterol is believed to be absent of many side effects, which are exhibited by the current steroid therapy. 460 761 29 Table III Percentage change in UVB-induced erythema in mar: pigs 3 and 6 hours after treatment lineï Pharmaceutical Concentrates. (%) 2 Pharmaceutical Concentrates. (%) 3 1.6 3 _ 1.6 _ 3 ____ Time '__ Compound 3 6 3 6 3 6 3 6 Zinterol 0 13 NT * 9 26 48 18 37 56 75 25 9 19 27 +9 sa1bucamo14 9 +4 +39 +39 42 32 74 '71 45 25 Indo-ethacin 72%, 190 ”1 (1%) 54 48 93 85 82 54 7f 87 All test materials were applied immediately after irradiation. 2 Test material prepared in dimethylacetamate / acetone / ethyl acetate zero in the volume ratio 40/30/30; concentration stated in% (weight / volume). Test material prepared in N-methyl-2-pyrrolidone-ethane zero in the volume ratio 50/50; the concentration given in% (weight / volume). Tested in ethanol / H O (50 / SO) or NHP / H 2 O (50/50) due to solubility limitations.

Not tested due to solubility limitations at 1.6%. .w- 460 761 f 30 Table IV V Topical anti-inflammatory activity of zinterol at three animal models Salbutamol, HCV and indomethacin were tested for comparison Secondary control test) Croton oil test Oxazolone test UVB test edema edema erythema Zinterol +++ + '+ Zalbutamol + + + HVC +++ + ET! Indomethacin + + +++ Anti-inflammatory activity and (percentage inhibitory tion interval) T = Ring (30-44); ++ = moderate (45-59); + * + = high (60%) ET = Not tested.

UI 460 761 31 Example.4 For further tests, two more analogues were tested zinterol, compounds IV and V, and these compounds was found to have an anti-inflammatory activity, which is comparable to that of zinterol. in these tests, the anti-inflammatory therapeutic effect of dessatre / Q2 agonists in topical application cation on croton oil-induced ear edema in mice. At these tests were applied 50 μl of 4 wt ethanol in the right and left inner ears of Swiss albino mice, immediately followed by 25 μl of suspensions of 0.02 % by weight, 0.2% by weight and 0.8% by weight of the IV and compound V in N-methylpyrrolidone / ethyl alcohol (ie NMP / ETOH),% if applied to each outer ear. Kro- tone oil treated and non-treated control groups included. These control groups are comprised of the following and data. § Six hours later, the animals were killed with carbon dioxide and biopsy of each ear was taken with a 3 mm punch and weighed immediately.

The anti-inflammatory effects of the test agents are evaluated. by a comparison of the biopsy weights of the test and the control groups.

The results. of three survey numbers at different concentrations of the test material in NMP / ETOH are given in Table V and shows that both compound IV and compound V are comparable with zinterol to reduce mouse nodules.

-Yzw 460 761 32 Table V -Percentric reduction of ear edema volume compared with con- Ä troll ears + standard deviation Test material Concentration (%) * Compound lv Compound V Zinterol 0.02 10.6 29.9 14.2 25.6 23.2 Mean1stand.deviation.18,1i10,6 18,9: 6,6 0.2 32.9 53.5 39.5 48.7 66.2 49.4 46.6 Medehákdeistand.avvik. 43.7: 9.3 50.8113.8 0.8 61.6 69.9 68.2 53, Ã 56.6 Mean value: standard deviation.57,515.8 62,438,2 * weight / volume Data reproduced on the same line in tables [LI and IV was held in the same experiment and therefore a direct movement. 10 15 20 25 30 35 460 761 33 It will be appreciated that the compounds of formula II may prepared into a variety of preparations by standard toder, which are well known to those skilled in the art. Dylika prepa- rat includes, for example, nasal sprays (such a spray can be prepared, for example, with trichloromonofluoromethane, dichlorodifluoromethane and oleic acid), rectal suppositories, vaginal suppositories, ointments, creams, gels and lotions down.

The methods for the preparation of compounds IV and V. is further illustrated by the following working examples In these examples, the temperature indications refer to Celsius degrees and the melting point indications are uncorrected.

Nuclear Magnetic Resonance (NMR) spectral data refer to sia the chemical displacements (6), expressed as parts per million (ppm) relative to tetramethylsilane (TMS) as reference standard. The relative surface area specified for the different offsets and proton NHR spectral data corresponds to the number of hydrogen atoms in a special functional type in the molecule. The nature of the displacements in terms of multiplicity is given as broad singlet (bs), sinalette (s), multiplet (m) or doublet (d). Use abbreviated compounds are DMSO-d6 (deuterodimethylsulfoxide), CDCl3 (deuterodimethylsulfoxide). terochloroform) and otherwise has conventional meanings lser. Infrared (IR) spectral data includes only absorption tiOnSVå9tal (Cm_1) with identifier entry value for the fun- Ä tional group. The IR determinations were made using use of potassium bromide (Kßr) as a diluent. Ele- mentar analysis data are given as weight percent.

Example 5 5 '- (2-amino-1-hydroxyethyl) -2'-hydroxymethanesulfonanilide-Ü hydrochloride (VIII) To a stirred solution of 27.4 g (0.19 mol) of hexamethylcn- 10 15 20 25 30 35 1 460 761 34 tetramine in 650 ml of chloroform was added portionwise 40.0 g (0.13 mol) 5'-bromoacetyl-2'-hydroxymethanesulfonanilide (VIII). The resulting suspension was boiled 16-18 hours, cooled to room temperature and then filtered. after. The resulting solid was washed with chloroform and dried in air to give 56.6 g (97.3%) of a quaternary salt product with melting point 165-1s7 °.

This solid was dissolved in 400 ml of ethanol and was treated with 65 ml of concentrated hydrochloric acid. Ålloppskok- of the resulting solution several minutes precipitation in the hot solution. The mixture was cooled completion of the precipitation. The solid material, which was isolated by filtration, washed by stirring in water and filtered again. Recrystallization of this material from ethanol-isopropyl ether gave a solid product. namely 5'-glycyl-2'-hydroxymethanesulfonanilide-hydro- chloride with melting point 219-2210. 7.3 g (0.026 mol) of this umhichetone hydrochloride as well 2.0 g of 10% palladium-on-carbon was suspended in 200 nl of heat (900) ethanol. This hot suspension was reduced by shaking below 60 psi of hydrogen in a Parr hydrating apparatus.

After 12-14 hours of shaking, the hydrogen mixture was removed. 01 from the Parr apparatus and the catalyst were removed by filtration. The filtrate was concentrated in vacuo to a white solid residue, which was suspended in isopropyl alcohol hol isopropyl ether and filtered again to give compound VIII as the hydrochloride salt in quantitative terms replacement with melting point 179-1809 (decomposition).

Example 6 2'-hydroxy-5 '- (1-hydroxy-2- [3- (3-indolyl) -2-propylamine] - ethyl) methanesulfonanilide (Compound IV) __ "“ ¿- "^” -. ~ Ff'.š- \. A fl lwf; . _ in if ' 460 761 É 35 5.65 g (0.02 mol) of the above hydrochloride salt of compound VIII was converted to the base by suspension in 150 ml of ethanol, followed by treatment with 2.0 ml 10.0 N sodium hydroxide, which was added dropwise below stirring. The original solid was dissolved with simultaneous precipitation of sodium chloride. Sodium- chlorine was removed by filtration and the filtrate was concentrated. was concentrated in vacuo to give a white solid. stood, which was dissolved in 100 ml of methanol. Reductive alcohol was performed by the addition of 1.2 U (0.02 mol) of and 3.5 g (0.02 mol) of 3-indolylacetone, diluting the resulting solution to 150 ml with additional zero and then the addition of 0.2 g of PtO2. This suspension was hydrogenated under 60 psi of hydrogen until its hydrogen uptake ceased (after about 4 hours). The suspension was removed from the hydrogenator and filtered and the filtrate was concentrated in vacuo to an oil reflux stood, which was dissolved in hot ethanol, which was treated with several drops of glacial acetic acid. By dilution with ethyl ether and stirring under cooling was recovered by filtration a solid which was washed with methanol and which gave 4.7 g of the acetate salt of compound IV with melt point 196.5-1970 (decomposition).

This material was dissolved in as little heat as possible dimethylformamide, filtered and diluted with an equal large amount of water to obtain a precipitate, which was isolated by filtration to give the free base of compound IV, m.p. 198-1990 (Sun. division).

Analysis calculated for C 2 OH 25 N 3 O 4 S: k calculated c, 59.53; u, 6.24; n, 10.11; s, 1.04; ' Found: C, 59.96; H, 6.15; N, 10.65; S, 8.05. ' 0:98 (3rm); (5lm); (3171): 41.32 ,, _., r "" C-I '_. ¿.¿- «n ¿fi vïyæslgw; , - \ ¿, ~; '¿-; vzl; 1 - 10 15 20 25 30 460 761 36 (1, m1; 6.00 (4, bs); 7.15 (8, m).

IR (KBr): 750, 1125, 1150, 1240, 1280, 1325, 1500, 1610 and 2940 cm -1.

Example 7 Alternative preparation of compound IV A solution of 11.0 g (0.06 mol) of 3- (2-aminopropylindole) in 730 ml of aceonitrile was stirred under a nitrogen atmosphere that 12.5 g (0.03 mol) of 5'-bromoacetyl-2'-benzyloxy- methanesulfonanilide was added in a single portion. After stirring 0.5 hours at room temperature a cold was added solution of 4.89 g (0.126 mol) of sodium borohydride in 219 ml methanol by constant dropwise addition. Reaction course pet was followed by the disappearance of the bromoketone spot at thin layer chromatography. Additional sodium borohydride is required sometimes to completely consume aminoketone starting the material. When the reaction was complete, it was drained the solvent in vacuo and the residue was suspended in 0.5 l of water and treated with 4N sodium hydroxide for that one would obtain a complete solution. Solution was washed well with ether and then the pH was adjusted with acetic acid at pH 8; The resulting mixture was extracted with methylene chloride, the extracts were combined and dried over magnesium sulfate and then concentrated in vacuo to obtain 14.5 g of a residual rubber. This rubber can be purified by chromatography on a silica column eluting with chloroform-methanol-ammonium hydroxide (90: 10: 1) to give 11.6 g of the benzyloxy derivative of compound IV.

The O-benzyl protecting group was removed by hydrogenation of a mixture of the O-benzyl derivative of compound IV (11.3 Q; 0.02 mol) and 1.8 g of 10% palladium-on-carbon (moistened with ab- 15 20 25 30 35 460 761 37 solute ethanol) in 820 ml of methanol in a Parr apparatus. After hydrogen uptake was complete, it was filtered the reduction mixture and the solid material are washed with additional methanol. All methanol portions_ combined and concentrated to a small volume (about 100 ml) and when the mixture was allowed to stand, the show a white solid. The solid material was isolated by filtration, washed with methanol and dried in air to obtain 5.6 “Material between Snïlt- points 197-198 ° (61%). This material was dissolved in 40 ml hot dimethylformamide, filtered and 45 ml of water were added. to the filtrate. Trituration of this solution induced cerade crystallization. An additional 10 ml of water was added. was added and the mixture was cooled in an ice bath, after which it solidified the material was isolated by filtration and washed well with water. Drying in air gave 5 g of compound IV with melting point 197-2000 (decomposition).

Example 8 N- (z-hydroxy-s- [1-hydroxy-z - ([2- (111-111401-3-3-1) -1,1-4: - methylethylaminolethyl] phenyl) methanesulfonamide (compound 71) A solution of 37.7 g (0.2 mol) of 2- (2-amino-2-methylpropyl) indole (X, R = Me) and 10.1 q (0.1 mol) of triethylamine in 1.2 liters of dioxane, which had been distilled over sodium metal, was stirred under a nitrogen atmosphere while 39.3 P 10.1 HO 5'-Bromoacetyl-2'-benzyloxymethanesulfonanilide was added.

The resulting mixture was stirred for 8-12 hours at about 250 under nitrogen atom. The reaction mixture was filtered, whereby a certain amount of solid precipitate was removed, and The solution was treated with a cold solution of 15 ((0.4 mol) sodium borohydride in 1 liter of absolute ethanol. Borohydride soluble was added dropwise to the stirred reaction filter. tratet. The course of the reaction was followed by disappearance of bromkcton stain at thin layer krrmunf fl zrwfi. ¥ l'-w- ligare sodium borohydride krdves sometimes für ful! s'1wd! ~ ' 10 15 20 25 30 35 460 761 38 consume the aminoketone starting material. When the reaction was complete, the solvent was removed in vacuo and the residue was dissolved in 0.2 N sodium hydroxide and washed des with ether. The pH of this solution was adjusted with acetic acid. acid at pH 8 and the resulting mixture was extracted with methylene chloride, the extracts were combined and dried over magnesium sulfate and then concentrated in vacuo obtaining the crude O-benzyl derivative of the compound V like a rubber. The O-benzyl protecting group was removed by hydrogenation of a mixture of the O-benzyl derivative of the present V (3.25 g; 0.006 mol) and 1.0 g of Pd (OH) 2 / C (Pearl catalyst) in 100 ml of methanol in a Parr shaker. After complete hydrogen uptake, the filter the reduction mixture and the solid was suspended in water and 1N hydrochloric acid was added while heating, so that the product dissolved. The insoluble The catalyst was removed by filtration and the acidic filtrate was alkalized (pH 8) with ammonium oxide. The precipitate obtained was isolated by filtration. , washed with water and dried in air to dry. providing an almost quantitative exchange of the product (compound V) as the monohydrate with the melting point 211-212 °.

Analysis for C21H27N3O4SrH2O: Calculated: C, 57.92; H, 6.72; N, 9.65; H 2 O; 4.14: Found: C, 58.05; H, 6.68; N, 9.64; H 2 O; 3.63.

NMR (DMSO-d 6): 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, 1500 and 161o cm'1.

The monohydrate product obtained above was converted to the chloride hydrate by dissolving in dilute hydrochloric acid IN followed by concentration in vacuo to a solid foam with Qmšílf-nnnl-f-nn 102-17110 10 460 761 39 Analysis for C H N O S ° HCl'H O: 21 27 3 4 2 calculated C, 53.44; H, 6.41; N, 8.91; H 2 O, 3.82 Found: C, 53.19; H, 6.37; N, 8.92; H 2 O, 3.64.

NMR (DMSO-d 6): 1.28 (6, s); 2.95 (3, s): 3.17 (4, m): 3.80 (l, bs); 4.90 (1.1m); 7.02 (4, m); 7.25 (3, m); 7.60 (1.1m); 8.50 (1, bs); 8.78 (1.sb); 9.30 (1, bs); 10.00 (l, bs); 11.10 (l, bs). ' IR (KBr): 750, 1150, 1295, 1320, 1400, 1460, 1515, and 1620 cm_1.

Claims (19)

460 761 PATENUE CLAIM 1. that it comprises Composition, (a) an amount effective to provide a topical anti-inflammatory effect of at least one compound or even net thereof, a pharmaceutically acceptable salt or solvate thereof of the general formula II wherein R 1 and R 2 are independently hydrogen or a lower alkyl group, with the proviso that R 1 and R 2 are not R 2 | R 2 -NH-A-C-B-CH 2 -M B is the group (-CH 2 -) m, where m is the integer 0.1 or 2; (b) a compatible, topically acceptable carrier for uptake; and 1. 2, k ä n n f! from the fact that m and n are both 0, that 33 know 0 t | 0 RB (ISM-CH OH R 4 can both be hydrogen; M is a phenyl group, an indole group or hydrogen; A is the group (-CH ) n, where n is 0.1 or 2; R 3 is -ou or -oco 2 <4> cu R 4 is -Nu-soz-cH 3 or -oco <1: >> cu 3; and those of the compound (a ) there 30 A composition according to claim n a d that R 4 is -NU-SO -CH. 2 3 35 Composition cnlint claim H 1 J Jnrlv, u | _f4 is a phenyluruçu, 1 t is -Oll coh få C k II 460 761 41 are methyl groups and m and n are both the integer 0. 4. A composition according to claim 2, characterized in that M is an indole group, R1 and R2 are both methyl groups and m and n are both whole O. 5. A composition according to claim 2, characterized in that n is the integer 0, m is the integer O, R] is a methyl group »R2 is hydrogen and M is an indole group. The composition of claim 1, wherein n is the integer 0, m is the integer 0, R 3 and R 4 are both the group -OCO <::)% CH 1 and M is hydrogen. 7. A composition according to claim 1, characterized in that the carrier is a dermatologically acceptable carrier. 8. A composition according to claim 1, characterized in that the carrier is one which prevents or reduces systemic absorption of the compound of formula II 9. A composition according to claim 2, characterized in that it is in the form of a cream, lotion or gel. 10. A composition according to claim 2, characterized in that it is in the form of an aerosol preparation. 11. A composition according to claim 2, characterized in that it is in the form of a suppository preparation. Q 12. Compounds of formula II ue, »-, -.:;,. ~ ,, _. R 4 CH-CH 2 -NH-A-ç-B-CH 2 -H 'III I OH R 2 R 4 or a pharmaceutically acceptable solvate or salt thereof, wherein A is (-CH 2 -ln, where n is the integer 0, and B is (-CH 2) m, where m is the integer 0, R 1 is methyl, M is an indole group, R 3 is -o fl, 124 is -rHH-soz-cy and 9.2 is hydrogen or methyl. The compound 2'-hydroxy-E '- (1-hydroxy-2- [1- (3-indolyl) -2-propylamino] ethyl) methanesulfonanilide or a pharmaceutically acceptable metal or acid addition salt or hydrate thereof according to claim 12. The compound Q- (2-hydroxy-5- [1-hydroxy-2 - ([E-11H-yn4oI-3-yl) -1,1-dimethylethylaminolethyl] phenyl] methanesulfonamide or a pharmaceutically acceptable metal or acid addition salt or hydrate thereof according to claim 12. A pharmaceutical composition in unit dosage form suitable for systemic administration to a mammal and comprising a pharmaceutical carrier and the compound of claim 13 or 14 in an amount which is non-toxic but anti-asthmatic and is effective. 1 mcg to 100 mg / kg body weight of the mammal. A pharmaceutical composition comprising a compound according to claim 12 mixed in an effective anti-asthmatic concentration with a suitable propellant system and packaged for aerosol administration. A pharmaceutical composition L in the form of a powder for insufflation comprising a mixture of instant parts which are acceptable for insufflation and which are mixed with a compound according to claim 12, wherein they the inert constituents and said compounds have a suitable particle size for transport to the bronchioles after insufflation. A process for the preparation of compounds of formula II wherein B is (-CH 2 -) n, where n is the integer 0, and B is (-CH 2) m, where m 'is the whole number 0, R 1 is methyl, H is an indole group, R 3 is -OH, R 4 is NH-SO 2 -CH 3 and R 2 is hydrogen or methyl, characterized therefrom, (a) alkylating a phenolic bromoketone of formula X with an indolylamine of formula IX IX and (b) treating the product of step (a) under such reaction conditions that the carbonyl group is reduced to a secondary alcohol to give said precursor formula II. 19. A process for the preparation of compounds of formula II, wherein the substituents have the meanings given in claim 18, characterized in that a compound of formula VIII OH 10 lvIII, HN-WSO CH 3. oa. With a compound of formula (b) or (c) IN - B 20 (b) (C) wherein X in the compound (C) is a typical leaving group (for example halide or tocylate), wherein, if a compound of formula (b) is used, the reaction conditions are selected so that reductive amination of compound (b) and reduction take place to form a compound of formula II, wherein R 2 is hydrogen, and wherein, if using a compound of formula (c), the reaction conditions are selected so that nucleophilic repression of compound VIII (C) of formula II. at the association takes place during the formation of the said