FR2541999A1 - PHENETHANOLAMINES AND USES THEREOF - Google Patents

Abstract

NEW COMPOSITIONS ARE PREPARED USING SPECIFIC B AGONISTS AND VEHICULAR MATERIALS AND THEY ARE USEFUL FOR THE PRODUCTION OF A TOPICAL ANTI-INFLAMMATORY EFFECT IN MAMMALS. THE SELECTED B AGONISTS WERE NOT PREVIOUSLY KNOWN TO SHOW TOPICAL ANTI-INFLAMMATORY ACTIVITY. THE COMPOSITIONS MAY BE, FOR EXAMPLE, IN THE FORM OF SPRAYS, BALMS, CREAMS, GELS, LOTIONS, AND SUPPOSITORIES, ALL TO BE APPLIED TO MAMMALS TOPICALLY IN OPPOSITION TO SYSTEMIC. N- (3-INDOLYL-ISOPROPYL) - AND N- (3-INDOLYL-T-BUTYL) -2- (4-HYDROXY-3-METHANESULFONAMIDOPHENYL) -2-HYDROXYETHYLAMINES AND THEIR PHARMACEUTICAL SALTS ARE ACCEPTABLY ACCEPTABLE ASTHMATICS AS WELL AS DEMONSTRATE THEIR BRONCHODILATOR ACTION AND INHIBITION OF SMOOTH MUSCLE CONTRACTION CAUSED BY THE RELEASE INDUCED BY ANTIGEN OF CHEMICAL MEDIATORS.

Description

PHENETHANOLAMINES AND USES THEREOF

  The present invention generally relates to anti

  non-steroidal inflammatory agents for topical applications, and their use

  and more specifically relates to compositions which provide as active ingredients one or more agonist (s) 2: adrenergic. The present invention also relates to compounds

  hbetrocyclic carbon of the indole series possessing a

  killing amino and it relates to a drug having a biologically effective

  and methods of treating the body employing these compounds.

  The Applicant points out that although at least hundreds (perhaps thousands) of agonists are known to occur alone, salbutamol has been described as having topical anti-inflammatory activity. structure with the activity to predict a topical anti-inflammatory activity is not known in the state of the art currently The technique of

  location is very unpredictable.

  Inflammation is present in most diseases of the

  a variety of skin diseases and inflammatory conditions

  including the acute type and the chronic type, led to

  follow the research of anti-inflammatory drugs.

  The introduction of steroids has provided dermatologists with

  class of anti-inflammatory agents with a therapeutic activity

  However, the effect of steroids in many inflammatory conditions, especially those of a chronic nature, is only palliative and requires prolonged use. extended

  steroids also causes a variety of harmful effects, including

  skin, striae 9 of telangiectasia, steroid acne and adrenal suppression 9 especially in children 9 M 9

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  in various chronic inflammatory skin diseases, the end of steroid therapy has led to the reappearance of inflammatory symptoms and this sometimes with increased intensity In response to the disadvantages of the use of steroids, in the last 20 years many non-steroidal anti-infaiamatory agents

  (ie: NSAIA) have been developed for use in a variety of

  diseases, including rheumatoid diseases Fiales These compounds appear

  generally appear to be free of some of the harmful effects of steroids, especially atrophy of the tissue, suppression

  adrenal, or other less severe rebound effects.

  A class of compounds included in the NSAIA group consists of

  ren a group of compounds that are inhibitors of the synthetic synthetase

  taglandin These products are generally active in the reduction of UV'B-induced erythema (ie, erythema induced by light).

  ultraviolet) in guinea pigs; but these matters are only leg-

  actively active or are inactive in other tests concerning the

  matte, including tests of croton oil and oxazolone for ear edema described; More in detail in the examples below Other classes of neon steroid compounds having topical inflamation activity are therefore of interest. Adrenergic agonists (including agonists 81 and 2) are compounds which have been proposed to act on the intermediate stimulation of cyclase adenylate, leading to the conversion of triphosphae adenosine (ie ATP) to 3 ', 5'-adenosine cyclic mono phosphate (ie CA 7 t P) (Yoir, for example, Ro Jo

  Brittain and Cotlo, Adv Drug Res 5, 197, 1970) The walls of sensitive-

  all mammalian cells possessing a nucleus contain the enzyme cyclase adenylate which is stimulated by various compounds, including

  taken protaglandin E and 5-adrenergic drugs.

  Adenylate cyclase activity has been reported to be present in the epidermis of humans and animals Disorders of cyclase adenylate activity and levels of C-AMP have been reported.

  in proliferative diseases of the skin such as eczema, psoriasis

  In short, agonists represent a class of compounds which

  stimulates the adrenergic system of the human body.

  Substances classified as S agonists are S agonists that selectively react with receptors 81 and trigger a

2541999.

heart stimulation.

  Subjects classified as agonists e 2 selectively react with receptors 2 present in the smooth muscles of blood vessels and bronchi; these products trigger dilation of the bronchi and dilatation of the vessels. In U.S. Patent No. 4,323,475 to G Jones, April 6, 1982, disubstituted catecholamines (which may or may not be present) are described.

  agonists 2) having topical anti-inflammatory activity.

  In U.S. Patent No. 3,341,584 to Larsen et al, there are disclosed sulfonanilides having the general formula I: Z Alk-N 4 R 4

X

  As described in this patent, sulfonanilides of formula T in

  Z represents CHOH, are pharmacological phenethanomalins

  actively present actions that are similar to the ef-

  fetuses of adrenal medullary hormones or neurotransmitters

  adrenergic agents, or oppose the effects of adrenal medullary hormones

  nalic or adrenergic neurotransmitters Phenalkanolamines, whose nucleus is substituted by an alkyl or aryl-sulphonamido radical, have useful pharmacological effects making them suitable for various

  uses, such as: vasopressors, vapo-depressants, analgesics, broncho-

  dilators, a-receptor stimulants, P-receptor stimulants, a-receptor blocking agents, e-receptor blocking agents, papaverine-type smooth muscle depressants, or useful anti-inflammatory agents

  in the control or prevention of anaphylaxis.

  Anaphylaxis is defined in the McGraw-Hill Dictionary of Scientific and Technical Terms, second edition, 1978, as a hyper: sensitivity following a parenteral injection of an antigen, in which a local or systemic allergic reaction occurs when the antigen is reintroduced after a while The topical term is defined as "local or designed for local application" and this term is used here for this application.

  given that anaphylaxis and topical inflammations are conditions

  physiologically different, a drug useful for the treatment of

  one of these conditions is generally not useful in the treatment of

the other condition.

  In US Patent 3,801,631 to Comer et al, issued April 2

  1974, is described 2-hydroxy-5 '- 11-hydroxy-2- (2-methyl-1-phenyl) -2-

  propylamino) ethyl} methanesulfone-anilide, called Zinterol (which is included in the broad class of sulfonic acid amides described in US Pat. No. 3,441,584 cited above). Zinterol is described therein as a powerful anorectic agent, as an active bronchodilator by

  oral and as having analgesic activity.

  In the article "Adrenergic Sulfonanilides 4 Centrally Active E-adrenergic Agonists", by D L Temple et al, Journal of Medicinal

  Chemistry, Vol 19, No. 5, pp. 626-633 (1976), Zinterol (Compound

  se n 43) is described as a potent anorexiae and as a narcotic antagonist. In addition, in US Patent No. 3,919,424 and in US Pat.

  No. 3,993,776, there is another description of the uses of the

  Zinterol. Salbutamol is an agonist. This product is described in Seely et al., Proc Soc. Exp. Biol Med 159, 223 (1978) as

  being useful as a topical anti-inflammatory agent.

  The synthesis of salbutamol is described in "Drugs of the Future" IV, 629 (1979). Salbutamol is indicated therein as being useful as an anti-inflammatory agent when applied locally.

  besides indicated that salbutamol administered orally for the control 6-

  Asthma compares favorably with similar drugs A mechanism of action of salbutamol is proposed (see page 631 of the

reference indicated).

  A 1980 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 swelling of

  mouse paws by injection of combinations of salbutamol and ami-

  nophylline. Other products having some structural similarities with zinterol and having topical anti-inflammatory activity

  are described in Jones US Pat. No. 4,323,575. These products can be

  whether or not to be agonists B and only one test could

to undermine if they are.

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  In U.S. Patent No. 4,088,756 to Voorhees, there are described other

  agonists - who may or may not have anti-inflammatory activity

  matory. However, as described in more detail below, the B 2 agonists which will be effective topical anti-inflammatory agents can not

  can not be expected with a reasonable degree of certainty

  experiment, the Applicant found that almost all the B 2 agonists they tested to determine this activity were

  either ineffective, highly toxic, or both.

  Therefore, despite what is known in the prior art, it exists

  a continuing need for non-steroidal anti-inflammatory drugs

  having a sufficiently good anti-inflammatory activity and without being toxic. A very large amount of prior art exists for the β-adrenergic agonist compounds of the phenethanolamine series of

catechol type.

  Larsen et al., U.S. Patent No. 3,341,584, cited above, discloses catechol-type phenethanolamines in which one of the hydroxy groups of the phenyl ring is replaced by a sulfonic acid amide to give compounds having an activity. 3-adrenergic biological. Robinson, U.S. Patent No. 2,908,691 of October 13, 1959, mentions a broad group of hydroxy phenalkylaminoalkylindoles specifically disclosed for its various effects on the central nervous system as well as as an effective anti-secretory agent in the reduction of gastric acidity The most relevant compound of this reference

  appears to be 3- (2- {2-hydroxy-2- (3,4-dihydroxyphenyl) ethyl) tartrate.

  amino} propyl) indole This compound is prepared in Example 7 of this reference. An object of the present invention is a product which, when placed in a suitable vehicle, provides a composition which,

  when applied topically, reduces the amount of inflam-

topical treatment of a mammal.

  Another object of the present invention is a composition having

  the form of a balm, cream, lotion or other formu-

  to be applied topically to a mammal so as to reduce or

  prevent the development of inflammation of the skin.

  Another object of the present invention is a method of using

  The objects described above are obtained by the compositions of the present invention, which comprise: (a) an effective amount of a compound (or compounds in a mixture) for reducing mammalian inflammation; producing a topical anti-inflammatory effect of at least one compound of one or more pharmaceutically acceptable salt (s) or solvate (s) thereof) among the group consisting of compounds having the formula general II: RR c A _A CH -N 'A' c B CH)

R 4

  Wherein R 1 and R 2 are independently of each other H or lower alkyl, provided that R 1 and R 2 can not together represent hydrogen; M represents either H, a phenyl group or an indole group of formula (a) (a) A represents (-CH 2-) n wherein N is an integer of 0, 1 or 2; and B is (-CH 2) m wherein m is 0, 1 or 2; R 3 represents either -OH, or -OC OO, CH 3 I and R 4 represents either -NH-502-cH 3 or -oco-@ -CH 3, and

  (b) a dermatologically acceptable vehicle therefor.

  In a preferred aspect of the present invention, R 1 and R 2 represent

  both have methyl groups and m and N are both 0. A preferred compound for use in the methods and composition of the present invention is the compound of formula II wherein: n is 0; m is equal to O; R 1 represents -CH 3; R 2 is -CH 3; M represents a phenyl; R 3 is -OH; and R 4 is -NH-SO 2 -CH 3 o This compound is known as zinterol (hereinafter referred to as

compound III).

  Another preferred compound for use in the methods and compositions of the present invention is the compound of formula II wherein: n is 0; m is 0; R 1 represents -CH 3; R 2 represents H; M is an indole group; R 3 is -OH; and R 4 is -NH-SO 2 -CH 3, which compound is hereinafter referred to as compound I Another preferred compound for use in the methods and compositions of the present invention is the compound of formula II in which : n is equal to O; m is 0; R 1 and R 2 both represent -CH 3; M is an indole group; R 3 is -OH; and R 4 represents -NH-502-CH 3,

  this compound being hereinafter referred to as compound V or azazoline

  terol. Another preferred compound for use in the methods and compositions of the present invention is the compound of formula II wherein: n is 0; m is 0; Ri and R 2 both represent -CH 3; M represents a hydrogen; and

  R 3 and R 4 both represent -OC 0 - & - CH 3.

  This compound is hereinafter referred to as bitolterol and is commercially available for use in the treatment of allergies but has not been described to date as being

  useful for the treatment of topical inflammations.

  In another aspect of the present invention, a method of reducing mammalian topical inflammation comprises: applying a compound of formula II topically to mammals so that localized (as opposed to systemic) activity results; )

against topical inflammation.

  In addition, according to the present invention, a composition for application

  topically reducing the mammalian topical inflammation volume comprises at least one compound of formula II present in a non-toxic amount sufficient to reduce inflammation and present in a pharmaceutically acceptable material or materials in which A is present. , B, R 1, R 2, R 3, R 4 and M are such that

described above.

  According to another preferred aspect of the invention, a composition to be applied topically comprises at least one compound selected from the group consisting of zinterol, compound IV, compound V and

  bitolterol, at least one of these compounds being present in

  sufficient to reduce inflammation but insufficient to

  toxic and associated with a pharmaceutically acceptable vehicle.

  It is pointed out that the term "topical" as used throughout this document means "local" or "designed" for local application so

  to produce a "local" effect, preferably without any systematic effect.

  Therefore, the compounds to be used in the methods and compositions according to the invention may be applied in any of many ways provided they are neither injected nor swallowed. example dermal, nasal, vaginal, rectal, optic and oral They are used with a dermatologically acceptable vehicle, preferably

254,999.

  chosen, so that the systemic absorption of the active ingredient

be prevented or reduced.

  The present invention also relates to anti-asthmatic agents which are bronchodilators and potent inhibitors while being selective for contraction of smooth muscle. The potencies and selectivities of these agents in inhibiting smooth muscle contraction caused by release. Chemical-mediator-mediated antigen induced has been demonstrated in pharmacological tests using tracheal rings of immunized guinea pigs. These agents include compound IV and compound V and their solvate and pharmaceutically acceptable salts and the invention comprises their use.

as anti-asthmatic agents.

  The compound (s) that are to be placed in a vehicle so as to provide a composition (s) suitable for topical use as an anti-inflammatory preparation (s) in mammals are

  the compounds of formula II mentioned above (or their salts and their

  pharmaceutically acceptable solvates) in which:

  M is either a phenyl group, an indole group or a hydro-

  gene, A is (-CH 2) n and n is 0, i or 2, B is (CH 2) m m is 0, 1 or 2; R 1 and R 2 independently represent H or an alkyl group

  lower, provided that R 1 and R 2 can not represent

seems a hydrogen-

  R 3 represents either -OH or -OCO- @ CH 3; and R represents either -NH-SO 2CH 3 or -OCO-i <Ct 13, The applicant wishes to emphasize the fact that they have tested

  numerous adrenergic agonists (all being analogous to the zircon

  King). Of approximately 45 of these compounds, only four show reasonably high topical anti-inflammatory activity without apparent toxicity in the tests described in the examples below. The rest of these compounds, on the other hand, exhibit either toxicity when they are applied topically to the animals of the

  an ineffective anti-inflammatory activity and / or incon-

both.

  The compound (s) to be placed in a vehicle so as to provide

  a composition suitable for topical use as a preparation for

  anti-inflammatory drugs for mammals are prepared as follows. The preparation of zinterol is described in detail in US Pat. No. 3,801,631 to William To Comer et al., 2'-hydroxy-5-hydroxy-2- (2-methyl-1-phenyl) -2-propylamino ) ethyl} methanesulfonanilide and its salts "; and the contents of this patent are incorporated herein by reference.

  As used herein, Me represents a methyl group.

  Detailed description of the preparation of compounds IV and V is given below.

  Compounds IV and V can be prepared by a choice between two general methods. The first method of synthesis is indicated below, Method 1 OH (embedded image) COMPOUND IV +, H 2 NHSO Cu H + catalyst II / O + H 2 y OHCH

H

(b) v III

  This method comprises the reductive amination of an indolylcarboxylic compound.

  The choice of reagents and the conditions of the reductive aminations are well known to the human

  In general, the reaction is carried out by shaking a solution.

  of the appropriate carbonyl compound and the phenolic amine in a

  such as a lower alkanol, for example methanol in the presence of a hydrogenation catalyst, for example a noble metal catalyst such as platinum oxide in a hydrogen atmosphere or the reaction can also be implemented step by step forming

  first, the condensation product of the carbonyl compound and the amine

  phenolic and then conducting the hydrogenation as a

separate decision.

  A variant of synthetic method 1 involves nucleophilic displacement by the phenolic amine on an indolylalkyl halide or equivalent. This is indicated below under the method name A.

2541,999

  1 l Method 1 A COMPOUND IV (if R = H) 1 (-51ll | + VIII D e; VIII COMPOUND V (if R = Me) -, H (c) in which: X represents a typical leaving group such as a halide, a tosylate, etc. Again, the choice of reaction conditions and reagents for nucleophilic displacement reactions are well known and

  are familiar to those who possess the practice of the chemical arts.

  The second method which can be used for the preparation of compound IV or compound V is shown below as the general synthetic method. This general method can also be used for the preparation of compound V as shown o Method 2

NH OH

2, dt COMPOSE IV (if R-

  JE JE Br; 8 HO CH 0 2 3 COMPOUND V (if R = I

H

(X) (IX)

  This process involves the alkylation of phenolic bromoketone by

  an appropriate indolylalkylamine-followed by a reduction in the carbon group

  In practice, the phenolic OH group is protected during the nucleophilic displacement reaction. This is done to prevent the participation of the phenolic group in a nucleophilic attack by itself, thus giving rise to undesired ethereal byproducts. this protection is via a group

  benzyl which is then removed by catalytic reduction.

  These general methods of synthesis have been incorporated into the actual synthesis schemes used to produce the compounds IV and

  These specific schemes are described below.

25419 9 9

  Scheme A: Preparation of compound IV C) 13 r NH 902 CH 3

0 O

C 012 '4

OH

NHSO 2 CH 3

Br CHCII

CO 1 2 "4

AT

NHSO 2 CH 3

  H 2 Pd / G and OH ON viii H 2 Pto 9 'al O xi CH

H R 2 CH 3

H IV 1) acetronitiile R

0 NR 502 CH 3

  ## STR2 ## Scheme A describes the preparation of compound IV. Two lanes are

  both described starting with one of bromoketones IX and IX '.

  In the upper path, IX is reacted with hexamethylenetetra-

  (C 6 H 12 N 4) to give a quaternary salt which is converted to aminocetone XI which is followed by a catalytic hydrogenation to phenethanolamine VII Io alkylation by reduction of 3-indolylacetone with VIII gives The title compound IV as shown The lower and preferred route is via a nucleophilic attack of indolylamine X or IX '(the 0-benzylated analogue of IX) which is followed by reduction with a borohydride to give the benzyl blocked phenolic intermediate group (XII: R = H) as shown which is in turn catalytically reduced to

give the desired end product.

  Scheme B: preparation of the compound V And h '-> Br H X: R = Me H (XII: R = M 4 e) Pt O 2 Me OH HJ' 2 OH H Compound V

  Scheme B describes the preparation of compound V using

  If the same route as that shown in the lower portion of Scheme A above is followed in Scheme B, the appropriate indolylamine is reacted with IX 'and the resulting adduct is reduced with a borohydride to give the compound. protected phenol (XII: R = Me) as shown which is then converted by catalytic hydrogenation to give the desired title compound, VO. The above two synthetic schemes will be illustrated by examples in more detail below. The intermediate compounds used in these syntheses are either commercially available, for example indolyl acetone, or are described in the chemical literature, such as the references cited in the section above

  forming the background of the invention.

  The preparation of bitolterol is described in US Pat.

  No. 4,138,581, and this description is incorporated herein by reference.

ence.

  For medical use, salts and solvates

  The complexes in which the solvent, the metal cation or the acid anion do not contribute significantly to the toxicity or the pharmacological activity of the organic ion of the drug. The sulphonamido group is the acid function used in the invention. the formation of the metal salt Examples of salts

  metallic salts include sodium, potassium, calcium, magnesium

  Sium, aluminum and zinc The metal and acid addition salts are respectively obtained by either reacting the selected compound with a suitable metal base to form a metal salt, or with an organic or inorganic acid to form a salt. addition of acid, preferably by contact in solution or by any of the methods

  classics detailed in the literature and available to all

  Experienced organic acids are, for example,

  carboxylic acids such as maleic acid, acetic acid,

  tartaric acid, propionic acid, fumaric acid, iso-

  Examples of useful mineral acids are hydrohalic acids (such as, HCl, HBr, HI), sulfuric acid, propionic acid, pamoic acid, cyclamic acid and the like.

phosphoric acid and the like.

  The solvates as used herein are

  plexes comprising the molecule of an organic drug and a solvent moiety of the formula ROH, wherein R is most commonly hydrogen or a C 1 or C 4 alkyl group The solvate

the most common is hydrate.

  It should also be understood that the compounds of the present invention include all optical isomeric forms, i.e. mixtures of enantiomers, e.g. racemic modifications as well as individual enantiomers and diastereomers. The individual optical isomers of the class of phenethanolamine whose compounds according to the present invention are members have most generally been obtained by one of four basic methods. These methods are: 1) fractional recrystallization of chiral acid salt derivatives; 2) derivatization with a chiral organic reagent, resolution and regeneration of the original compound in its optical isomeric form; 3) synthesis of the simple optical isomer using chiral intermediates; and 4) column chromatography using chiral stationary phases. The application of these various methods are well known to experienced practitioners. The above-mentioned compounds which are to be placed in a vehicle so as to provide compositions suitable for topical use as an anti-inflammatory preparation in mammals can be placed in the following vehicles. The resulting mixtures are the pharmaceutical preparations according to the invention. The invention may be any non-toxic material or a mixture of materials

  suitable for use in the preparation of balms, ointments,

  suppositions and other similar pharmaceutically acceptable drugs In addition, the vehicle will preferably be

  chosen to prevent or reduce the systemic absorption of

  res active and it should not react with the active ingredient (s)

  described above In addition, the active ingredient (s) must

  wind) must be both soluble in the vehicle and it must be released by the vehicle topically In addition, the mixtures thus formed will preferably be stable over a prolonged period of time, for example

  example of the order of a few months or a few years.

  The active ingredient (s) is (are) generally dissolved in a vehicle component. For example, zinterol hydrochloride is both soluble in water and soluble to some extent in various organic materials For topical applications to the skin, since there is both an aqueous phase and a non-aqueous phase in the skin, both the water-soluble and the oil-soluble parts of the vehicle permeate through the skin However, for topical use, the vehicle must

  organic phase (eg oil or mineral oil)

  rale). Vehicles intended to carry the active ingredients in the

  eg creams, lotions, gels, balms, suppositories and pulverulent

  In the present invention, at least one active ingredient will be dissolved in a part of the vehicle in which it is soluble and the resulting mixture will then be mixed together. in a manner

  any suitable with the remaining ingredients of the vehicle.

  The relative amount of vehicle to be mixed with the ingredient (s)

  The active compound (s) (i.e. with the compounds described above) to form the mixtures according to the invention will be selected according to

  the solubility of the active ingredient (s) in the vehicle.

  However, it is believed that the optimum concentration is generally the saturation point. However, for zinterol hydrochloride, it was found that the optimum concentration thereof in a cream-based vehicle was 0.2 w / v. hundred, although up to 0.7 weight / volume

  percent of it dissolves in creams.

  The mixtures according to the invention will be administered in the following manner. On the basis of the tests described in the examples below, the mixtures according to the invention prepared from active ingredient (s) in a suitable vehicle must be applied as soon as possible after the skin comes into contact with the material (s) that caused the

the inflammation to be treated.

  The mixtures according to the invention should be applied directly to the area of inflammation to produce a localized effect. Although for salbutamol (discussed above), a systemic effect has been reported.

  noted, no such effects were found in the preliminary tests.

  materials used in accordance with the present invention.

  It is an advantage not to have a systemic effect and to have a

  minimum absorption of these materials.

  In addition, the biological test of compounds IV and V demonstrates that they

  possess an intrinsic bronchodilator action and are sus-

  able to suppress tracheal contraction induced by an antigen.

  This contractile response to an antigen has been characterized as consisting of an initial spasm caused by the release of a preformed histamine followed by sustained contaction due to the release of an

  SRS-A (slow-reacting anaphylaxis substance) newly synthesized

  (The ability of the subject compounds to inhibit the contractile response caused by SRS-A with significantly greater inhibitory potency compared to

  contractile response to released histamine has the advantage of selective

tivity for the benefit of the above compounds which make them particu-

  useful as anti-asthmatic agents.

  IV and V in this respect can be demonstrated by different pharmacological tests.

  which include inhibition of methacholine-induced bronchial spasm in rats and inhibition of smooth muscle contraction caused by antigen-mediated release of mediators

  isolated tracheal rings from guinea pigs

  This last method has been adapted from Adams and Lichtenstein: In Vitro Sudies of Antigen-induced Bronchospasm: Effective Antihistamine and SRS-A Antagonist on Response to Sensitized Guinea Pig and Human

  Airways to Antigen Journal of Immunol, 122: 555-562, (1979).

  For use as anti-asthmatics, the therapeutic methods

  in accordance with the present invention include system administration

  both oral and parenteral as well as by inhalation of an effective non-toxic amount of compound IV or compound V or a pharmaceutically acceptable salt thereof. "Effective amount" means a dose of who carries on the activity

  desired pharmacological system, as described below, without provoking

  toxic side effects when administered to a mammal

  The dosage should vary according to the subject and the route of administration chosen, the expected interval being

  from about 0.1 mcg to 100 mg / kg body weight of a compound of formula

  IV or V or a pharmaceutically acceptable acid addition salt

  of it generally providing the desired therapeutic effect.

  Compounds IV and V can enter formulas according to

  conventional pharmaceutical practice to provide pharmaceutical compositions

  in the form of a unit dosage comprising, for example,

  seals, powders, granules, emulsions, suspensions and the like.

  These preparations contain the active ingredient, usually in

  mixed with non-toxic phanraceutical excipients to give

  solid dosage forms or exist in the form of solutions, suspended

  or emulsions to give a liquid preparation It is necessary to understand

  other conventional pharmaceutical practices also apply.

  such as the addition of sweetening or flavoring agents or the use of binders, etc. In addition, the compositions may also contain other absorption agents, stabilizing agents,

wetting agents and tampons.

  In addition, liquid preparations of compounds IV and V may be used for administration by inhalation and given for example by nebulization. The present compounds may also be administered in the form of powder by insufflation consisting of a mixture of ingredients. Inert powder mixed with an appropriate amount of the present compound having a suitable particle size which is administered by a powder insufflation device. Generally, a micronized drug portion is mixed with 50 by: of lactose USP with appropriate microbial properties

  The mixture is encapsulated for use in an insufflation device.

  Before use, the capsule should be punctured or

  poured to allow the release of the powder mixture.

EXAMPLES

  In Examples I to 4, the following types of tests (ie, models) were used on the following animals: (1) Ear edema induced by croton oil in mice, (2) oxazolone-induced ear edema in mice and

  (3) Uf Bi-induced erythema in guinea pigs.

EXAMPLE 1

  In the croton oil assay (which is a standard test described in detail in Tonelli et al., Endocrinology, Vol. 77, pp. 625-634, 1965, and which incorporated herein by reference) a topical application of 4 % of croton oil in ethanol (v / Yv) on mouse ears

  interstitial edema, vasodilation, and

  Polymorphonuclear leukocyte filtration in the dermis, leading to

  an increase over the normal weight of the ear of about

  70% to 100% The inflammatory response is close to the maximum in 6 hours.

  In croton oil tests, 4% (by volume) of

  croton in ethanol are applied to the inner aspect of both

  each of the mice to be tested and various test materials in the vehicle systems are applied to the external appearance of the ears immediately following the application of croton oil. The control animals are exposed either to the croton oil alone, either at

  croton oil and then to the vehicle alone.

  Six hours after exposure to croton oil and / or

  test, the animals are sacrificed; and biopsies of a defined part of ears are weighed and compared to those obtained from

the sample vehicle used.

  The compounds are tested in simple solutions including dimethylacetamide / acetone / ethanol (i.e. DMAC / A / E v / v 40/30/30)

  and N-methyl pyrrolidone / ethanol (NMP / E v / v 50/50) Comparative controls

  These are chosen on the basis of their known activity in each of the three animal tests described above and included in each of the three tests (in Examples 1, 2 and 3): hydrocortisone valerate (HCV) in the oil of croton and oxazolone test, indomethacin (which

  is a powerful non-steroidal anti-inflammatory agent of the

  ne) in the UVB test, and salbutamol (agonist a 2, discussed above in

  the description of the background of the invention).

  The inhibition (in percent) of the induced edema of the mouse ear (or erythema) of each of the three models (in Examples 1, 2 and 3) is calculated by the formula: Weight of the ear of control weight of the ear tested x 100 weight of the control ear The croton oil test appears to be more sensitive to steroidal anti-inflammatory agents than to nonsteroidal anti-inflammatory drugs Ydiens genre aspirin Unexpectedly, unlike aspirin-like non-steroidal anti-inflammatory agents, the agonists used in the present invention are effective in reducing

  of inflammation induced by croton oil.

  The anti-inflammatory activities of approximately 45 agonists

  e 2 are evaluated by croton oil-induced mouse oedem (which produces acute dermatitis); and the most active compounds are then studied using the oxazolone-induced mouse ear edema test (which produces allergic contact dermatitis) and in the induced erythema test.

by UVB in guinea pigs.

  On the group of approximately 45 compounds including zin-

  terol and analogues thereof, four compounds (one of which is

  being them zinterol) demonstrate high topical anti-inflammatory skin activity using the croton oil test for 1.6% weight / volume (total weight / volume of ethanol + test material).

  four compounds are then topically tested at other concentrations.

  by using the croton oil test and also topically using the oxazolone test and the UVB test In these tests, zinterol appears to be the compound with the most sustained activity .

  Below in Table I are the results of the zinte-

  * (* rol and salbutamol and HCV (HCV = hydrocortisone valeriate) control for 1.6 w / v% and 0.2 w / v% in the croton oil test for each of the two Solvent systems Also included in Table I are the data of bitolterol, a commercially available agonist 62 that has previously been used as an antiallergic compound but whose utility was not previously known as a topically active agent against cutaneous inflammations A direct comparison of bitolterol and zinterol is carried out All

  both have similar topical anti-inflammatory activity.

  The results in Table I show that in the croton oil test, zinterol for 1.6 w / v% and for 0.2 w / v% and bitolterol for 1.6 w / v% all lead to good to moderate reductions in ear edema and that they are equivalent to or slightly less effective than hydrocortisone valerate (ie HCV) but are

more effective than salbutamol.

EXAMPLE 2

  Oxazolone-induced contact sensitization in mice is characterized by cell-mediated oedemas and infiltration, mainly of the monocyte type, for nearly 100% increase in the weight of the mouse ear. This model is described in detail in NJ Lowe

  et al, British j; of Dermatology, vol 96, pp 433-438, 1977, incor-

  As a reference in this model, the test products are applied topically to the outside of the endangered ear of each animal undergoing testing and this is immediately followed by the application of oxazolone indoors. The animals are sacrificed 8 or 24 hours after treatment; and the biopsy of a part of the ears is weighed and compared to the controls that are treated as

  described above and exposed to the vehicle alone.

TABLE I

  % inhibition of mouse ear oedem induced by croton oil for two vehicles 1 In DMAC / acetone / ETOH In NMP / ETOH 3 Compound 196 w / v% 0.2 w / v% 1.6 p / v% 092 p / v% Zinterol 69 a, 50 54 h 34 i 699 63 92 9 58 81 c 66 29 d, 6 k 70 48 P 56 t 9 44 u 6 e 8 f 70 o 48 e 63 f 8 201 73 q 47 v 38) g 34 Y, 61 f Bitolterol 61 42 x 25 y 34 Z Salbutamol 4 26 a O b 34 J 945 54 m 49 23 09 Op 27 q HCV 78 c 9 59 25 D, 381 (70 9 71 q 71 r 62 s -16 e, 48 f 3419 64 t 9 67 y 499 73 v 1 each value is the average of 10 to 15 animals In this test,

  10 to 35% variability is observed.

  2 dimethylacetamide / acetone / ethanol (v / v, 40/40/30).

  3 N-methyl 2-pyrrolidone / ethanol (v / v Y, 50/50).

  4 tested in ethanol / H 20 (50/50) because of limitations of

solubility 6.

  a z values with the same alphabetic exponent are oberved

in the same experience.

  the minus sign indicates that there is no inhibition but rather

a stimulation of inflammation.

  The oxazolone test shows a sensitivity to drugs

  steroidal anti-inflammatory drugs and relatively insensitive to

  Non-steroidal anti-inflammatory drugs again, unexpectedly

  due to non-steroidal aspirin-like (such as indomethacin), agonists 62 exhibit

topical anti-inflammatory.

  In Lablane 19, the results of tests on the percentage inhibition of oxazolone-induced secretion on the ears of seuris are given using various concentrations of zinterol salbutamol or HCV as an active ingredient for the treatment. oxazolone in

  D PAC / aceton / ethanol three-solvent systems (v / v 40/30/30).

  From the results of Table II in the oxazolone test, it can be seen that zinterol for 3 and 196% by weight exhibits a slight reduction in ear edema with no dose-related effect.

  it is equal to salbutamol but slightly less active than HCV.

  The compositions in Tables I and II can be compared directly

r Eent.

  Table II% inhibition for edema% inhibition of oxazolone-induced edema in oxazolone induced in mouse ear 1, 2 mouse auricle 2, 3 Concentration Concentration Compound 02 w / v 1.6 w / v 196 w / v 3 w / v% Zinterol 22 a, 17 b 48 c 17 35 h, 30 391 41 e 14 d, 43 k Salbutamol -la 9 b 2 c Od 21 h 28 i 311 HCV 6 to 16 to 36 27 38 h 8 391 31 J, 42 k 1 1 the above agents are tested in DMAC / acetone / ethanol (v / v

/ 30/30)

  2 each value is the average of 10 to 15 animals.

  approximately 20 to 35% is observed in this test.

  The above agents are tested in N-methylpyrrolidone / ethanol (v / v 1/1) where values having the same alpha exponent are observed

in the same experience.

EXAMPLE 3

  Another series of tests is being undertaken for reasons of

  despite the fact that agonists e 2 (which are vasodilators) are not expected to show comparable results to aspirin-like non-steroidal agents (which are not vasodilators). In the UVB test, cutaneous erythema is induced in guinea pigs This test is a standard test widely used to test anti-inflammatory agents and is described-completely in Ko F.

  Swingle, "Evaluation for Anti-Inflammatory Activity", in Anti-

  Inflammatory Agents, vol. 2, Scherrer and Whitehouse edition, pp. 34-122, London: Academic Press, 1974, incorporated herein by reference. In the UVB model, the test material is topically applied to the irradiated sites immediately afterwards. UV exposure Bo Erythema is

  note on a scale of 0 to 4, 3 and 6 hours after irradiation.

  In Table II, percent changes in UVB-induced erythema in guinea pigs at 3 and 6 hours after treatment with zinterol are indicated together with the results of treatment.

  with salbutamol and indomethacin.

  As indicated by the results of Table III for the UVB tests, the Zinterol at 3 and 1.6% by weight leads to mild to moderate activity with no apparent dose effect and which is highly variable.

  Similar effects are observed with salbutamol.

  domethacin at 1% by weight shows a good to very good activity on

a consistent base.

  The results indicated above in Tables I, II and III are summarized below in Table I. On the basis of the summary of Table IV, it can be validly concluded that for the same concentrations, the zinterol appears to be almost as effective as HCV and more effective than salbutamol in the croton oil test Zinterol is therefore a promising candidate for reducing anti-inflammatory activity in humans based on the data described above, Zinterol is expected to be

  free of many side effects of active therapy.

with steroids.

TABLE III

Compound Zinterol Salbutamol 4

Indometha-

  cine (1%)% change in UVB-induced erythema in guinea pig at 3 and 6 hours after treatment 1 Concentration of: Drug concentration (%) 2 drug (%)

1.6 3 1.6 3

Time in hours -

3 6 3

+ 9

9 ± 4 + 39 + 39

74 71

72 43

54 48

82 54

3 6 3 6

9 26 48 18

25

42 32

25

  1 any test material applied immediately after irradiation 2 test material prepared in dimethylacetamide /

  acetone / ethanol (v / v, 40/30/30) and indicated in% w / v.

  3 test material prepared in N-methyl-2-pyrrolidone / ethanol

(v / v, 50/50) and given in p / v%.

  4 tested in ethanol / H 2 O (50/50) or NMP / H (50/50) due to solublity limitations * not tested due to solubility limits set at 1.6% o NT *

TABLE IV

  Topical anti-inflammatory activity of Zinterol in 3 animal models (salbutamol, HCV and indomethacin tested as comparison control) Oil test Oxazo test IUVB trial of croton lone (edema) (edema) (erythema) Zinterol +++ + + Salbutamol + +

HCV +++ + NT

Indome-

  thacine + +++ Anti-inflammatory activity and% inhibition interval + = slight (30-44); ++ = moderate (45-49); and +++ = high (60%)

1 NT = not tested.

EXAMPLE 4

  In a further test, two zinterol analogs, compounds IV and V, were tested and found to have

  anti-inflammatory activity comparable to that of zinterol.

  In these tests, the anti-inflammatory effect of these three D agonists is studied when applied topically to the oedem of the ear induced by croton oil in mice. of croton oil at 4% by weight in ethanol is applied to the inside of the right and left ears of Swiss albino mice,

  what is immediately followed by an application of 25

  of 0.02, 0.2 and 0.8% by weight of compound IV and compound V

  in a mixture of N-methylpyrrolidone / ethyl alcohol (NMP / ETOH) with the exception of

  inside each ear Control groups treated with croton oil and untreated are included These control groups are included

  in the data as described above.

  Six hours later, the animals are sacrificed with C 02 gas and a biopsy of one 8 mm portion of each ear is taken and

weighed immediately.

  The anti-inflammatory effects of the agents tested are evaluated by comparing the biopsy weights of the test groups and the groups

control.

  The results of these three tests for various concentrations of the test material in NMP / ETOH are shown below in Table V and show that both compound IV and compound V are comparable to zinterol in the reduction of the edema of the ear

mouse.

% reduction

TABLE V

  oedem weight of the ear compared to control ears + S D. Test material 1 Concentration (%) Compound IV Compound V Zinterol

0.02 10.6 29.9 14.2

, 6, 23.6

average + So D 18.1 10.6 18.9 + 6.6

0.02 32.9 53.5 39.5

48.7 66.2

49.4 46.6

average S D 43.7 + 9.3 50.8 + 13.8

0.8 61.6 69.9 68.2

53.4 56.6

  average + S 57.7 + 5.8 62.4 + 8.2 weight / volume. The data shown on the same line in Tables III and V are obtained in the same experiment and therefore a comparison

direct is possible.

  It will be appreciated that the compounds of formula II may be included in a wide variety of formulations by standard means well known to those skilled in the art. Such formulations include, for example, nasal sprays (a spray may be prepared for example with trichloromonofluoromethane, dichlorodifluoromethane, and oleic acid), rectal suppositories, suppositories

  vaginal, balms, creams 9 gels and lotions.

  The methods of preparation of compounds IV and V and their biological effects will appear in more detail from the study of the examples

  and the attached claims which are given as illustrative

  Only in the following examples, used to illustrate the foregoing synthesis processes, the temperatures are

  expressed in degrees Celsius and the melting points are not corrected -

  The spectral characteristics of nucelar magnetic resonance (NMR)

  refer to the chemical variations (6) expressed in parts per million

  lion (ppm) relative to tetramethylsilane (TMS) as a reference standard. The relative areas indicated for the various variations and

  the proton NMR spectral data correspond to the number of

  Hydrogen tomes of a particular functional type in the molecule The nature of the variation as to its multiplicity is indicated as a large singlet (bs), singlet (s), multiplet (m) or doublet (d) Abbreviations used are DMSO-d 6 (dutodimethylsulfoxide), CDC 13

  (deuterochloroform) and are otherwise conventional

  Infrared (IR) spectra only include wavelengths

  absorbance (cm-) having an identification value of a functional group

  The IR determinations are used by using potassium bromide (K Br) as the diluent Elemental analyzes are indicated

in percent by weight.

EXAMPLE 5

  5 '- (2-amino-1-hydroxyethyl) -2'-hydroxymethane hydrochloride

  sulfoneanilide (IX) To a stirred solution of hexamethylenetetramine (2794 g, 0.19 mole) in 650 ml of chloroform was added per serving of

  5'-Bromoacetyl-2'-hydroxymethanesulfonanilide (IX, 4090 g, 0.13 mol).

  The resulting suspension is refluxed for 16-18 hours, cooled to room temperature and then filtered. The solid obtained is washed with chloroform and dried in air to give 56.6 g (97.3%) of product. This solid is dissolved in 400 ml of ethanol and treated with 65 ml of concentrated HCl. A reflux treatment of the solution which results for several minutes causes the initiation of the reaction. Precipitation in the hot solution The mixture is quenched to aid in the completion of the precipitation The solid, isolated by filtration, is washed by stirring in water and it is refiltered. The recrystallization of this material in a mixture of methanol / isopropyl ether give a

  solid product consisting of 5'-glycyl-2'-hydroxy-hydrochloride

  methanesulfonanilide, mp 219-221. A portion (7.3 g, 0.026 mol) of this aminoketone hydrochloride and 10% palladium on carbon (2.0 g) are suspended in ml of ethanol at 90 ° C. This hot suspension is reduced by stirring at 4.2 bar of hydrogen on a Parr hydrogenation apparatus After 12 to 14 hours of shaking, the hydrogenation mixture is

  removed from the Parr apparatus and the catalyst is removed by filtration.

  The filtrate is concentrated under vacuum to a white solid residue which

  it is suspended in an isopropyl alcohol / isopropyl ether medium.

  and refilter, which gives a quantitative yield of VIII

  as the hydrochloride, mp 179-180 (dec).

EXAMPLE 6

  2'-Hydroxy-4 '- (1-hydroxy-2- (3-indolyl) -2-propylamine) methyl)

  methanesulfonanilide (compound IV) The VIII hydrochloride (5.65 g, 0.02 mole), prepared above, was converted to base by suspending in 150 ml ethanol and then treating with 2.0 ml of NaOH 10.0 added dropwise with stirring The original solid dissolves with simultaneous precipitation of NaCl NaCl is removed by filtration 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

  addition of glacial acetic acid (1.2 g, 0.02 mol) and 3-indolyl-

  acetone (3.5 g, 0.02 mole), dilution of the resulting solution to ml with additional ethanol and then addition of 0.2 g of Pt O 2 This suspension is hydrogenated at 4.2 bar d until hydrogen uptake ceases (approximately 4 hours) The suspension is removed from the hydrogenation apparatus, filtered, and the filtrate is concentrated in vacuo to an oily residue which is dissolved in the hot methanol treated with several drops of glacial acetic acid Dilution with ethyl ether and stirring while cooling suddenly allows to collect by filtration a solid

  that is washed with methanol, which gives 4.7 g of the acetate of the

  pos IV, melting point 196.5-197 (dec).

254 1999

  This product is dissolved in a minimum amount of dimethyl

  hot mamide, filtered and diluted with an equal amount of water, which gives a precipitate which is isolated by filtration and the base is obtained

  free of compound IV, mp 198-199 (dec).

  On analysis, it can be seen that the product obtained has the formula:

C 20 H 25 N 3045

  and the following values are obtained:

C H N S

  calculated oo 59.53 6.24 10.41 7.94 found 59.96 6.15 10.65 8.05 NMR (DMSO-d 6): 0.98 (3, m); 2.75 (5, m); 2.93 (3, s); 4.52 (1, m); 6.00 (4, bs); 7.15 (8, m) o

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

EXAMPLE 7

  Preparation variant of compound IV A solution of 3- (2-aminopropyl) indole (11.0 g, 0.06 mol) in 730 ml of acetonitrile is stirred under a nitrogen atmosphere while 2-bromoacetyl-2 ' Benzyloxymethanesulfonanilide (12.5 g, 0.03 mol) is added in one portion. After stirring at room temperature,

  for 0.5 hours, a cold solution of sodium borohydride is added.

  dium (4.8 g, 0.126 mol) in 219 ml of methanol dropwise at a fast flow rate The progress of the reaction

  followed by the disappearance of the bromoketone task obtained by chroma-

  thin layer film An additional quantity of borohydride

  sodium is sometimes necessary for the complete extinction of the amino-

  ketone starting material When the reaction is complete, the solvent is removed under vacuum and the residue is suspended in 0.5 l of

  H 20 and it is treated with 4N NaOH to arrive at the complete solution.

  This solution is thoroughly washed with ether and then the pH is adjusted with acetic acid to 8%. The resulting mixture is extracted with methylene chloride, the extracts are combined and dried (Mg 504). and then concentrated under vacuum, which gives 14.5 g

of residual gum.

  This gum can be purified by chromatography on a colon

  silica gel, elution with chloroform / methanol / hydride

  ammonium oxide (90/10/1) to give 11.6 g of the benzyloxy derivative of

compound IV.

  The O-benzyl protecting group is removed by hydrogenation of a mixture of the O-benzyl derivative of compound IV (11.5 g, 0.02 mol) and 1.8 g of 10% palladium on carbon (made wet with absolute ethanol) in 820 ml of methanol in a low pressure Parr apparatus Upon completion of the absorption of hydrogen the reduced mixture is filtered and the solid is washed with additional methanol. of methanol are collected and concentrated to a small volume (approximately 100 ml) and after a certain residence time, a white solid progressively precipitates. The solid is isolated by filtration, washed with methanol and dried in air, which gives 6 g of product, melting point 197-198 (61%). This product is dissolved in 40 ml of hot dimethylformamide, filtered and 45 ml of H 2 O are added.

  The trituration of this solution induces crystallization.

  Another 10 ml of water is added and the mixture is quenched in an ice bath, after which the solid is isolated by filtration and washed thoroughly with water. mp 197: 200 (dec).

EXAMPLE 8

  N- (2-Hydroxy-5 {1-nhydroxy-2 - ({2 {(H-indol) 3-yl) -1,1-dimethyl-ethyl} amino) ethyl} phenyl) methanesulfonamide (Compound IV) A solution of 2 - (2-amino) 2-ethylpropyl) indole (X, R = Me, 37.7 g, 0.2 mole) and triethylamine (1091 g D 0.1 mole) in 1.2 liters of dioxane which was distilled over sodium The metal mixture is stirred under a nitrogen atmosphere while 5'-bromoacetyl-2'-benzyloxy: methanesulfonanilide (39.8 g, 0.1 mol) is added.

  the result is 8 to 12 hours at about 25% under the azo-

  The reaction mixture is filtered, a little solid precipitate is removed and the filtrate is treated with a cold solution of sodium borohydride (0.94 mole) in 1 liter of absolute ethanol.

  borohydride is added dropwise to the filtrate of the agri-

  The progress of the reaction is followed by the disappearance of the task

  bromoketone by thin-layer chromatography An additional amount of

  sodium borohydride is sometimes necessary for the ex-

  complete definition of aminoketone, the starting material

The solution is complete, the solvent is removed under vacuum and the residue is dissolved in 2N NaOH and washed with ether.

254199 9

  then adjusted with acetic acid to pH 8 and the mixture which

  The mixture is extracted with methylene chloride, the extracts are combined and dried (Mg 504) and concentrated in vacuo to give the crude 0-benzyl 6 derivative of the compound V in the form of a residual gum. The O-benzyl protecting group is removed by hydrogenation of a mixture of the 0-benzylated derivative of compound V (3.25 g, 0.006 mole) and 1.0 g of Pd (OH) 2 / C (Pearlman's catalyst) in 100 ml of methanol in an apparatus Parr hydrogenation at low pressure Upon completion of hydrogen uptake, the reduced mixture is filtered and the solid

  is suspended in water and HCl 1 N is added while heating.

  The insoluble catalyst is removed by filtration and the acidic filtrate is made basic (pH 8) with ammonium hydroxide. The precipitate which results is isolated by filtration, washed water and dried in the air to give an approximately quantitative yield of the product (compound V) in the form of

  monohydrate, mp 211-212 o.

  On analysis, it can be seen that the product obtained has the

  mule: C 21 H 27 N 3045 H 20 and the following values are obtained:

C H N H 20

  calculated 57.92 6.72 9.65 4.14 Found 58.05 6.68 9.64 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 (K Br): 740, 1010, 1115, 1125, 1235, 1280, 1460, 1500, 1600 and 1610 cm -1

  The monohydrate product obtained above is converted into chlorhydrin

  hydrated drate by dissolving in diluted HCl and then concentrating

  evacuation to a solid foam (melting point 105-125) o

  On analysis, it can be seen that the product obtained has the

  mule: C 21 H 27 N 304 S H H Cl H 20 and the following values are obtained:

C H N H 20

  calculated 53.44 6.41 8.91 3.82 found 53.19 6.37 8.92 3.64 NMR (DMSO-d 6): 1.28 (6, s); 2.95 (3, s); 3.17 (4, min); 3.80 (1, bs); 4.90 (1, 11); 7.02 (4, ru); 7.25 (3, ru); 7.60 (1, in); 8.50 (1, bs); 8.78 (1, bs); 9.30 (1, bs); 10.00 (1, bs);

11.10 (1, bs).

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

2541 9 9

Claims (8)

  Composition comprising: (a) an amount effective to produce an anti-inflammatory effect   at least one compound or a pharmaceutically acceptable salt or   tically acceptable thereof selected from the group consisting of compounds having the general formula II: Ri R CH M OH R 2   wherein: R 1 and R 2 are independently of each other H or lower alkyl, provided that R 1 and R 2 can not simultaneously represent hydrogen; M represents a phenyl group, an indole group or a hydrogen; A represents the group (-CH 2) n in which N is 0, 1 or 2; B represents the group (-CH 2) m in which m is 0, 1 or 2; R 3 represents either -OH or OCO- <CH 3; and R 4 represents either -NH-502-CH 3 or -O CO-4 z-CH 3; and (b) a compatible vehicle, acceptable to be combined topically   with said product (a) indicated above.   The composition of claim 1, wherein m and n are both O, wherein R 3 is OH and wherein R 4 is MNH-SO 2 -CH 3. 3. The composition of claim 2 wherein M is a phenyl group, R 1 and R 2 are both methyl groups and m and N are both equal to OO   Composition according to claim 2, wherein M represents   indole group, R 1 and R 2 are both methyl groups   and m and N are both equal to O o.   A composition according to claim 2 wherein N is 0, m is 0, R 1 is methyl, R 2 is hydrogen and M is an indole group, 6. A composition according to claim 1, wherein N is is   0, mn is 0, R 3 and R 4 are both groups of   pes -OCO-CH 3, and M represents hydrogen.   The composition of claim 1, wherein is a dermatologically acceptable carrier. 8. Composition according to claim 7, wherein cule is selected to prevent or reduce absorption compound of formula Iol.   9. Composition according to claim 2, in   composition is a cream, lotion or gel.   10. Composition according to claim 2, wherein the composition is in the form of a formulation II. Composition according to Claim 2, in which this vehicle   which this systemic vehicle of which which this this to spray. which this   composition is a formulation in the form of suppository.   O Compound having the formula XI i R 1 R 2 K or a solvate or a pharmaceutically acceptable salt thereof, wherein: A represents (-CH 2 _) n and N is O; and B is (-CH 2) m and m is 0; and R 1 is -CH 3; M represents an indole group; R 3 is -OH; R 4 is -NH-SO 2 -CH 3; and   R 2 is selected from the group consisting of H and -CH 3.   13. A compound according to claim 12, which is 2'-hydroxy-5β (1-hydroxy-2- {1- (33 indolyl) 2-propylamino} -ethyl) -methyl-sulfonanilide or a metal salt or a salt of addition acid or a hydrate pharmaceuti acceptable by drifting. 2541,999   The compound of claim 12, which is N- (2-hydroxy)   - {1-hydroxy-2 - ({2- (1H-indol-3-yl) -1- (1-dimethylethyl) amino) ethyl} phenyl) methanesulfonamide or a metal salt or an addition salt   acid or a pharmaceutically acceptable hydrate deriving therefrom.   A pharmaceutical composition in unit dosage form suitable for systemic administration to a mammal comprising a pharmaceutically acceptable carrier and an amount of the compound of claim 13 or claim 14 to form a   non-toxic dose but effective as anti-asthmatic.   Pharmaceutical composition comprising a composition according to   claim 12 blended in an effective concentration as   with a suitable propulsion system and a packaging for aerosol administration.   17. Pharmaceutical composition in the form of an insufflation powder comprising a mixture of acceptable inert ingredients for insufflation, in admixture with a compound according to claim   12, these ingredients and this compound having a particle size   appropriate to be transported in the bronchioles as a result of   sufflation. Process for preparing a compound of formula II: R 1 R 3 II 2 RCH-CH 2 -NH A-C-B-CH 2-M JH   R 4 wherein: A represents (-CH 2) n and N is O; and B is (-CH 2) m and m is 0; R is -CH 3; M represents an indole group; R 3 is -OH; R 4 is -NH-SO 2 -CH 3; and R is selected from the group consisting of H and -CH 3, this method consisting of: (a) an alkylation of a phenolic hromioketone of formula X: () II _R Ni 12 N by an indolylamine of formula IX: OH Br NHSO 2 CH 3 Br (b) and then in a treatment of the product of step (a) under reaction conditions such that the carbonyl group is reduced   to a secondary alcohol, thereby forming the compound of formula II.   19. The method of claim 18, wherein R 2 represents feel H.   20. The method of claim 18, wherein R 2 represents feel -CH 3.   A process for preparing a compound of formula II wherein: A represents (-CH 2) n wherein N is O; B is (-CH 2) m wherein m is 0; and R is -CH 3; M represents an indole group; R 3 is -OH; R 4 represents -NH-502-CH 3; and R 2 represents either H or -CH 3, 9 this method consisting of: -2541999   reacting a compound of formula VIII: OH o / XNN 2 NHSO 2 CH VIII H 2 N OH   with a compound selected from the group consisting of compound (b) and compound (c): H N   H (b) (c) wherein X in (c) is a typical starting group (for example: halide or tosylate); and wherein, when the put coma (b) is used, the reaction conditions are selected so that reductive amination of the compound (b) and a reduction take place and result in a compound of formula II in which R 2 represents H; and wherein, when using the compound (c), the reaction conditions are selected such that the ophthalmic displacement of the compound VIII on the compound (c) occurs so as to form the compound of formula I Io