CA1235705A - Phenethanolamines and uses thereof - Google Patents

Abstract

PHENETHANOLAMINES AND USES THEREOF

ABSTRACT OF THE DISCLOSURE
New compositions using particular B2 agonists and vehicle materials have been prepared and are useful for producing a topical anti-inflammatory effect in mammals. The selected B2 agonists have previously not been known to exhibit topical anti-inflammatory activity. The compositions can be for example in the form of sprays, ointments, creams, gels, lotions, and suppositories, all of which are to be applied to the mammal topically, as opposed to systemically.

Also, N-(3-Indolyl-isopropyl)- and N-(3-indolyl-t-butyl)-2-(4-hydroxy-3-methanesulfonamidophenyl)-2-hydroxyethylamines and their pharmaceutically accept-.
able salts are antiasthmatic agents as demonstrated by bronchodilation action and inhibition of smooth muscle contraction caused by antigen-induced release of chemical mediators.

Description

s~os PHENETHANOL~INES AND USES THEREOF

This invention relates g2nerally to anti-inflam-matory, topically applied nonsteroidal compositions and to their uses and relates more specifically to such compositions having as active ingredient ~2-adrenergic agonist(s).

This invention also relates to heterocyclic car-bon compounds of the indole series having an amino substituent and relates to drug bio-affecting and body-treating processes employing these compounds.

Applicants emphasize that although there are at least hundreds (perhaps thousands) of ~2-agonists known in the art, only salbutamol has been disclosed as having any topical anti-inflammatory activity~ It is believed that no~structure-to~activity relationship for predicting topical anti-inflammatory activity i9 known in the art at this time. The art area is very unpredictable.

Inflammation is exhibited by most skin di~eases.
A variety of inflammatory skin diseases and condition~
(including chronic and acute types) has resulted in an ongoing search for anti-inflammatory drugs.

~L2~57~)5 The introduction of steroids provided the derma-tologist with a class of anti-inflammatory agents that are therapeutically active against a wide spectrum of inflammatory skin diseases. ~owever, the effect of steroids in many inflammatory conditions, particularly in those of a chronic nature, is only palliative and requires extended use. And such extended use of steroids also results in various adverse effects, including atrophy of skin, striae, telangiectasia, steroid acne, and adrenal Ruppression, especially in children. Additionally, in various chronic inflamma tory skin diseases, the termination of steroid therapy has led to the reappearance of inflammatory symptoms and sometimes with increased intensity. In response to the drawbacks of using steroids, over the last 20 years many new nonsteroidal anti-inflammatory agents (i.e., NSAIA) have been developed for use in various diseases, including rheumatic diseases. These com-pounds generally appear to be free of some of the adverse effects of steroids, especially tissue atro-phy, adrenal suppression, and other less severe re-bound effe~cts.

One class of compounds included within the group of NSAIA is a group of compounds that are prostagland-in synthetase inhibitors. These materials are gener-ally active in reducing UVB-induced erythema (i.e., erythema induced by ultraviolet light) in guinea pigs;
but the materials are only slightly active or are in-active in other tests relating to dermatitis, includ-ing the croton oil and the oxazolone ear edema assays further described in the examples below. Therefore, other classes of nonsteroidal compounds with topical anti-inflammatory activity are of interest.

~235705 B adrenergic agonists (including Bl and B2 agonists) are compounds which have been proposed to act through the stimulation of adenylate cyclase, resulting in the conversion of adenosine triphosphate (i.e., ATP) to cyclic 3',5',-adenosine monophosphate (i.e., C-AMP). See, for example, R. J. Brittain, et al, Adv. Drug Res. 5, 197, 1970. The walls of essen-tially all nucleated mammalian cells contain the enzyme adenylate cyclase, which is stimulated by vari-ous compounds including prostaglandin E and B-adrener-gic drugs.

Adenylate cyclase activity has been reported to be present in human and animal epidermis. Disorders in adenylate cyclase activity and in C-A~P levels have been reported in proliferative skin diseases such as ec~ema, psoriasis, epidermolytic hyperkeratosis and lamellar ichthyosis.

In short, B agonists are a class of compounds which stimulate the adrenergic system of the human body.

Xaterials which are clas~ified as Bl agonists are B agonists which selectively react with the B
receptors and elicit cardiac stimulation.

Materials which are classified as B2 agonists selectively react with the B2 receptors which are present in the smooth muscles of the blood vessels and bronchi; these materials elicit bronchodilation and vasodilation.

~L;2357(~5 In U. S. Patent 4,323,575 to G. Jones, April 6, 1982, disubstituted catecholamines (which may or may not be B2 agonists) having topical anti-inflammatory activity are disclosed.

In U.S. Patent 3,341,584 to Larsen et al sulfon-anilides having the general formula I are disclosed.

~ lk- ~ formul~ I
X . ` \'~

As disclosed in tbat patent, the sulfonanilides of formula I, wherein Z is CHO~, are pharmacologically active phenethanolamines having actions which either resemble the effects of the adrenal medullary hormones or adrenergic neurotransmitters or oppose the effects of the adrenal medullary hormones or adrenergic neuro-transmitters. Alkyl and aryl-sulfonamido nuclearly substitu~ed phenalkanolamines have useful pharmacolog-ic effect~, suiting them variously as vasopressors, vasodepressors, analgesics, bronchodilators, ~-recep-tor stimulants, B-receptor stimulants, ~-receptor blocking agents, B-receptor blocking agents, papa-verine-like smooth muscle depressants, or anti-inflam-matory agents useful in controlling or preventing ana-phylaxis.

Anaphylaxis is defined in the McGraw-Hill Dictionary of Scientific and Te_hnical Terms, Second Edition, 1978, as hypersensitivity following parenter-al injection of an antigen, wherein local or systemic 123~705 allergenic reaction occurs when the antigen is rein-troduced after a time lapse. Topical is defined to be "local or designed for local application" and that term is so used in this application. Therefore, because anaphylaxis and topical inflammations are dif-ferent conditions physiologically, a drug which is useful in treating one of these conditions is general-ly not useful in treating the other condition.

In U.S. Patent 3,801,631, to Comer et al., patented April 2, 1974, 2-hydroxy-5'-[1-hydroxy-2-(2-methyl-l-phenyl-2-propylamino)ethyl]methanesulfon-anilide, called zinterol (which is included within the broad genus of sulfonic acid amides disclosed in U.S.
Patent No. 3,341,584 cited above) is disclosed.
Zinterol was there described as a potent anorexigenic agent, as an orally active bronchodilator, and as having analgesic activity.

In the article ~Adrenergic Sulfonanilides. 4.
Centrally Active B-Adrenergic Agonists", D. L. Temple et al, Journal of Medicinal Chemistry, Vol. 19, No. 5, Pgs. 626-633 ~1976), zinterol (compound No. 43) is described as a potent anorexiant and as a narcotic antagonist.

Additionally, in U.S. Patent 3,919,424 and in U.S. Patent 3,993,776, further description of the uses of zinterol is given.

Salbutamol is a B2 agonist. This material was described in R. Seely et al, Proc. Soc. Exp. Biol.
Med. 159, 223 (1978) as being useful as a topical anti-inflammatory agent.

12357~;

The synthesis of salbutamol is described in Drugs of the Future IV, 629 (1979). There, salbutamol is indicated as being useful as an anti-inflammatory agent when applied locally. It is further stated that salbutamol given orally in the control of asthma com-pares favorably with related drugs. A mechanism for the action of salbutamol is proposed. (See page 631 of the reference.) 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 inhibition of swelling in the paws of mice by injections of combinations of sal-butamol and aminophylline.

Other materials showing some ~tructural similari-ty to zinterol and having topical anti-inflammatory activity are disclosed in U.S. Patent 4,323,575 to Jones. These materials may or may not be ~-agonists and only testing would determine whether they are.

In U.S. Patent 4,088,756 to Voorhees, other ~-agonists which may or may not have anti-inflammatory activity are disclosed.

However, as further described below, which B2-agonists will be effective topical anti-inflammatory agents cannot be predicted with any reasonable degree of certainty. After much experimentation, applicants found that nearly all B2 agonists they tested for such activity were either ineffectlve, highly toxic, or both.

.

Therefore, despite what has been known in the prior art, there is a continuing need for non-steroid-al anti-inflammatory drugs which exhibit consi~tently good anti-inflammatory activity and which are nontoxic.

A very large body of prior art exists for 3-adrenergic agonist compounds of the catechol-type phenethanolamine series.

Larsen, et al., V.S. Patent 3,341,584 cited above broadly disclosed catechol type phenethanol~mines wherein one of the phcnyl ring hydroxy grou-ps was replaced with sulfonic acid amido thereby giving compounds with B-adrenergic biological activity.

Robinson, U.S. Patent 2,908,691, patented October 13, 1959, disclo~ed a broad group of hydroxy-phenalkylaminoalkylindoles specifically described as having various effects on the central nervous system as well as acting as antisecretory agents, effective in reducing gastric acidity. The most relevant compound of this reference would seem to be 3-(2-[2-hydroxy-2-(3,4-dihydroxyphenyl)ethylamino]propyl)indole tartrate. This compound was prepared AS Example 7 in the reference.

1235~705 SUMMARY OF THE INVENTION
Thus the present invention provides a compound having the formula II

~ ~ CH-CH2-NH-A-C-B-CH2-M II, or a pharmaceutically acceptable solvate or salt thereof, wherein A is (-CH2-)n and n is the integer O and B
is (-CH2)m and m is the integer O and wherein Rl is -CH3, M is an indole group, R3 is -OH, R4 is -NH-SO2-CH3, and R is selected from the group consisting of H and -CH3 The invention also provides a method of preparing the compounds of formula II as set-out above, and compo-sitions containing them.
An object of thl~ lnvention is a material which when placed into a suitable vehicle provides a compo-sition which when topically applied reduce~ the amount of topical inflammation of ~ mammal.

Another ob~ect of this invention is a composit~on in the form of an ointment, cream, lotion or other formulation to be topically applied to a mammal 30 as - 7a -to reduce or hinder the development of skin inflammation.

A further object of this invention is a method of using a compound (or compounds, in a mixture) for the purpose of reducing topical inflammation of mammals.

The above-described objects are satisfied by the compositions of the present invention, which comprise:

(a) An amount effective to produce a topical - .
anti-inflammatory effect of at least one compound (or pharmaceutically acceptable salt(s) or solvate(s) thereof) selected from the group consisting of compounds having the general formula II R
I
~3 ~H -C~ A- C~ C~

f~ -wherein R~ and R .are independently H or a lower alkyl group, provided that R and R cannot both be H, M is either H, a phenyl group, or an indole group of formula (a) ~ (a), _ A is ~-CH2-)n in which n is the integer 0, 1, or 2, and B is (-CH2)m in which m is the integer 0, 1, or 2, R is either -OH or -OCO~CH3, and R is either -NH-502-CH3 or -OCO~CH3; and (b) A dermatologically acceptable carrier therefor.

In a preferred aspect of the invention, Rl and R are both methyl groups and m and n are both 0. A
preÇerred compound for use in the methods and composi-tions of the invention is the compound of formula II
wherein n is 0, m is 0, Rl is4 3, 3 M is phenyl, R is -OH, and R is -NH-SO2-CH3.
This compound is known as zinterol (referred to hereinafter as compound III).

Another preferred compound for use in the methods and compositions of the invention is the compound of formula II where n n is 0, m is 0, R is -CH3, R is H, ~ is an indole group, R is -OH, and R
is -NH-SO2-CH3, which compound is hereinafter referred to as Compound IV.

Yet another preferred compound for use in the methods and compositions of the invention is the com-pound of formula II wherein n is 0, m is 0, R and R are both -CH3, M is an indole group, R is -OH, and R is -NH-SO2-CH3, which compound is hereinafter referred to as Compound V or azazinterol.

123S~7OS

A still further preferred compound for use in the methods and compositions of the invention is the com-pound of formula II whe:ein n is 0, m is 0, R and R are both -CH3, M is hydrogen, and R and R
are both -OCO ~ C~3. That compound is hereinafter referred to as bitolterol and is commercially avail-able for use in treating allergies but has not been known previously to be useful for treating topical inflammations.

In another aspect of the invention, a method for reducing topical inflammation in mammals comprises:
applying a compound of formula II topically to the mammal so that localized (as opposed to systemic) activity against topical inflammation results.

Further, according to the invention, a composi-tion to be topically applied to reduce the amount of topical inflammation of mammals comprises at least one compound of formula II present in a nontoxic amount sufficient to reduce inflammation and present in a pharmaceutically acceptable carrier material or materials, wherein A, B, R , R , R , R and M
are as described above.

In another preferred aspect of the invention, a composition to be topically applied comprises at least one compound selected from the group consisting of zinterol, compound IV, compound V, and bitolterol, at least one compound of which is present in an amount sufficient to reduce inflammation but insufficient to be toxic and present in a pharmaceutically acceptable carrier.

1~35705 It is emphasized that the term ~topical~ as used throughout this document means local or designed for local application to produce a local effect with preferably no concomitant systemic effect. Thus, the compounds to be used in the methods and compositions of the invention can be applied in any of a variety of ways, provided that they are not injected or swallow-ed. They can be applied, for example, cutaneously, nasally, vaginally, rectally, otically, and buccally.
They will be used with a dermatogically acceptable vehicle preferably chosen such that systemic absorp-tion of the active ingredient is hindered or reduced.

This invention also concerns antiasthmatic agents which are bronchodilators and potent yet selective inhibitors of smooth muscle contraction. The poten-cies and selectivities of these agents in inhibiting smooth muscle contraction caused by antigen-induced release of chemical mediators has been demonstrated in pharmacological tests utilizing im~unized guinea pig tracheal rings. These agents include compound IV and compound V and their pharmaceutically acceptable solvates and salts thereof, and the invention includes their utilization as antiasthmatic agents.

The compound~s) which are to be placed into 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, recited above, (or pharmaceutically acceptable salts and sol-vates thereof), wherein M is either a phenyl group, or an indole group or hydrogen, wherein A is (-CH2-)n and wherein n equals 0, 1, or 2; wherein B is (-CH2)m and wherein m is 0, 1, or 2; wherein and R are independently H or a lower alkyl group, provided that R and R cannot both be H; wherein R is either -OH or -OCO ~CH3; and wherein R
is eith~r -NH-SO2-C~3 or -OCO-~ C~3.

Applicants wish to emphasize that they tested many B2 adrenergic agonists (all of which are analogs of zinterol). Of approximately 45 such com-pounds, only four had consistently high topical anti-inflammatory activity without apparent toxicity in tests which are described in the example~ below. The remainder of the compounds, on the other hand, exhi-bited either toxicity when applied topically to the test animals, ineffective and/or incon~istent anti-inflammatory activity, or both.

The compound~s) to be placed into a vehicle so as to provide a composition suitable for topical use as an anti-inflammatory preparation in mammals are prepared in the following manner.

The preparation of zinterol is described in detail in U.S. Patent No. 3,801,631 to William T.
Comer et al, ~2'-hydroxy-5'-[1-hydroxy-2-(2-methyl-1-phenyl-2-propylamino)ethyl~methanesulfonanilide and Its Saltsr; and that patent is hereby incorporated herein by reference.

As used herein, Me stands for a methyl group. A
detailed description of the preparation of compounds IV and V is the following. Compound IV and V can be prepared by selecting from two general methods. The first synthetic method shown hereinafter ~23570~i Method 1 OH cataly~t + I~2N~S02cH3 ,a .... ~. ....
tb) VIII

involves reductive amination of an indolylcarbonyl compound with an appropriate phenethanolamine. 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 compound and phenolic amine in a solvent such as a lower alkanol, e.g. methanol, in the presence of a hydrogenation catalyst, e.g. a noble metal catalyst such as platinum oxide, in a hydrogen ?tmosphere. As an alternative, the reaction could also be carried out stepwise by first forming the condensation product of the carbonyl compound and the phenolic amine and then conducting the hydrogenation as a separate operation.

A variation of synthetic method 1 entails nucleophilic displacement by the phenolic amine on an indolylalkyl halide or an equivalent. This is shown below as Method lA.

1~3~05 Method lA

Compound IV tif R-H) + (VIII) - or Compound v (if R=Me) (c) wherein X is a typical leaving group such as halide, tosylate, etc~ Again, choice of reaction conditions and reagents for nucleophilic displacement reactions are well known and would be familiar to one practiced in the chemical arts.

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

Method 2 0~

2 ~ 2OEt3 (X) (IX) reduc~io4 Co~pound Iv tif R-~ . ._ , O r Co~pound v (if R-Me) (IX) ii7g)S

This process comprises alkylation of the phenolic bromoketone by the appropriate indolylalkylamine followed by reduction df the carbonyl group to a secondary alcohol. In practice, the phenolic OH group is protected during the nucleophilic displacement reaction. This is done to prevent participation by the phenolic group in nucleophilic attack of its own thereby giving unwanted ether byproducts. Generally, the protection is done via a benzyl group which is subsequently removed by catalytic reduction.

These general synthetic methods have been incor-porated into the actual synthetic schemes used to produce compounds IV and V. These specific schemes are outlined below.

Scheme A: Preparation of Compoun~ IV
e Br 8r ~ + C6H12N4 ~ 3 ~ 6H12N4 ~ R~52CH3 IX
A 1 EtOH

HCl . O~ ~Cl H2 ~ ~tON ~ ~S2CH3 VIII XI

Pt2 1 ~n ~L23~70S

OH
~,NHS02C~I3 IV

H2 Pd/G
l~eOH

[ ~ '~}~ ~ S2cR3 1)acetonitr$1e N 2) ~aBH
XII, R=H ~eok - R O
N~2 Br ~OCS2 ~CH3 X, R=H IX ' Scheme Aloutlines the preparation of compound IV.
Two pathways are depicted, both beginning with one of the. bromoketones, IX and IX'. In the upper pathway IX
is reacted with hexamethylenetetramine (C6H12N4) to yield a quaternary salt which is converted to the aminoketone XI followed by catalytic hydrogenation to the phenethanolamine VIII. Recuctive alkylation of

3-indolylacetone with VIII affords the subject compound IV as shownO The lower and preferred pathway proceed~
via nucleophilic attack of the indolylamine X or IX
(the O-benzyl analog of IX) followed by borohydride reduction to give the benzyl-blocked phenolic group intermediate (XII: R7H) as shown which is in turn catalytically reduced to the desired end product.

57~)S

Scheme B: Preparation of Compound V

R O ES:3~7 ~,NH Br~0~2Ph1) d ~xa~e X 2 ) NIBH4 X: R=Me IX ' EtOH
~ ~. ....

R ~ OH

0~2Ph H (XII: R=Me ) PtO2 ¦ MeO~

OH

Compound V

~LZ3570~;
Scheme B depicts the preparation of compound V
utilizing essentially the same pathway as shown in the lower part of Scheme A above. In Scheme B the appropriate indolylamine is reacted with IX', and the resulting adduct is reduced with borohydride to give the protected phenolic compound (XII: R2Me) as shown which is then converted via catalytic hydrogenation to the desired subject compound compound V.

These two synthetic schemes, supra., will be exemplified in greater detail hereinbelow. Intermedi-ate compounds util-zed in these syntheses are either available commercially, e.g. 3-indolyl acetone; or as described in the chemical literature such as the references cited in the Background of the Invention section hereinabove.

The preparation of bitolterol is discussed in U.S. Patent 4,138,581.

For medicinal use, the pharmaceutically accept-able solvates and salts are those complexes in which the solvent, metal cation or acid anion does not contribute significantly to toxicity or pharmacologic-al activity of the organic drug ion. The sulfonamido group is the acidic function utilized in metal salt formation. Examples of metal salts include the sodium, potassium, calcium, magnesium, aluminum and zinc salts. Metal and acid addition salts are obtained, respectively, either by reaction of the selected compound witk a suitable metallic base to form a metal salt or with an organic or inorganic acid to form an acid addition salt, preferably by contact ~2~705 in solution, or by any of the standard methods detail-ed in the literature and available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acidr isethion-ic acid, succinic acid, pamoic acid, cyclamic acid, pavalic acid, and the like. Useful inorganic acids are hydrohalide acids (such as ~Cl, HBr, HI), sulfuric acid, phosphoric acid, and ~he like.

Solvates as used herein are complexes comprising an organic drug molecule and a solvent moiety of formula RO~, wherein R most commonly is hydrogen or a - -Cl or C4 alkyl group. The most common solvate is the hydrate.

It is also to be understood that the compounds of the present invention include all the optical isomer forms, that is, mixtures of enantiomers, e.g., racemic modifications as well as the individual enantiomers and diastereomers. The individual optical isomers of the pheneth~nolamine class of compounds of which the instant compounds are members, have most generally been obtained by one of four basic methods. These are: 1) the fractional recrystallization of chiral acid salt derivatives; 2) derivatization with a chiral organic reagent, resolution, and regeneration of the original compound in optical isomer form; 3) synthesis of the single optical isomer using chiral intermediates; and 4) column chromatography utilizing chiral stationary phases. The application of these various methods are well known to practitioners in the art.

123S~

The compounds recited above which are to be placed into a vehicle so as to provide compositions suitable for topical use as anti-inflammatory prepara-tions in mammals can be placed into the following vehicles. The resulting mixtures are pharmaceutical preparations of the invention. The vehicle can be any nontoxic material or mixture of materials which is suitable for use in preparing pharmaceutically accept-able ointments, salves, lo~ions, sprays, suppositories and other similar medicaments. The vehicle, addition-ally, will be chosen so that it preferably hinders or reduces systemic absorption of the active material(s?
and it should nDt react with the active ingredient(s) described above. Additionally, the active ingredi ent(s) should be both soluble in the vehicle and should be released by ~he vehicle topically. Fur-thermore, the mixtures so formed will preferably be stable over an extended period of time, for example on the order of months or years.

The active ingredient(s) will generally be dis-solved into a component of the vehicle. For example, zinterol hydrochloride is both water soluble and soluble at least to some extent in various organic materials. For topical applications to the skin, because there is both an aqueous ph~se and a non aqueous phase in the skin, both water soluble and oil soluble portions of the vehicle will permeate the skin. Bowever, for topical use, one would use so~e organic phase in the vehicle (for example, petrolatum or mineral oil).

Vehicles for carrying active ingredients into the skin, for example, creams, lotions, gels, ointments, ~235705 suppositories, and sprays, as well as methods of pre-paration thereof, are well known in the art. In the present invention, at least one active ingredient will be dissolved in a portion of the vehicle in which it is soluble, and the resulting mixture will then be mixed in any suitable way with the remaining ingredi-ents of the vehicle.

The relative amount of vehicle to be mixed with active ingredient(s) (i.e., with the compounds des-cribed above) in forming the mixtures of the invention will be selected depending upon the solubility of the active ingredient(s) in the vehicle. ~owever, it is believed that the optimal concentration is generally the saturation point. Por zinterol hydrochloride, however, the optimal concentration thereof in a cream vehicle was found to be 0.2 w/v percent, although up to 0.7 w/v percent thereof will dissolve in creams.

The mi~tures of the invention will be administer-ed in the following way. Based upon the tests des-cribed in the examples below, the mixtures of the invention prepared from active ingredient(s) in suit-able vehicle should be applied as soon as possible after the skin has come into contact with the material(s) that caused the inflammation being treated.

The mixtures of the invention will be applied directly to the area of inflammation to produce a localized effect. Although in salbutamol (discussed above) a systemic effect ~as noted, none was found in preliminary tests done on the materials used in this invention. It is an advantage to have no systemic ..... . .

effect and to have minimal absorption of these materials.

Additionally, biological testing of compounds IV
and V demonstrates that they possess intrinsic bron-chodilator action and they are able to reverse antigen-induced tracheal contraction. This contractile res-ponse to antigen has been characterized as consisting of an initial spasm caused by release of preformed histamine followed by a sustained contraction due to the release of newly synthesized SRS-A (-~low reacting substance of anaphylaxis) (cf: srocklehurst: The Release of ~istamine and Formation of a Slow-Reacting Substance (SRS-A) During Anaphylactic Shock, Journal of Physiology, 151:416-435, 1960). The ability of the subject compounds to inhibit the contractile response mediated by SRS-A with significantly greater inhi-bitory potency compared with the released histamine contractile response demonstrates an advantage in selectivity for the subject compounds which would make them particularly useful as antiasthmatic agents. The utility of compounds IV and V in this regard can be demonstrateb in various pharmacologial tests which include inhibition of methacholine-induced broncho-spasm in rats, and inhibition of smooth muscle con-traction caused by antigen-induced release of chemical mediators in tracheal rings isolated from immunized guinea pigs. This latter method has been adapted from Adams and Lichtenstein: _ Vitro Studies of Antigen-induced Bronchospasm: Effective Antihistamine and SRS-A Antagonist on Response of Sensitized Guinea Pig and ~uman Airways to Antigen. Journal of Immunol., 122:555-562, (1979).

.. . .. ..

For use as antiasthmatics, therapeutic processes of this invention comprise systemic administration, by both oral and parenteral routes as well as by inhala-tion of an effective, nontoxic amount of compound IV
or compound V or a pharmaceutically acceptable salt thereof. An effective amount is construed to mean a dose which exerts the desired pharmacological acti-vity, such as those stated hereinabove without undue toxic side effects when administered to a mammal in need of such treatment. Dosage will vary, according to the subject and route of administration selected, with an expected range of about 0.1 mcg to 100 mg~kg body weight of a compound of Formula IV or V or a pha~a-ceutical acceptable acid addition salt thereof generally p~oviding the desired therapeutic effect.

Compounds IV and V can be formulated according to conventional pharmaceutical practice to provide pharmaceutical compositions of unit dosage form comprising, for example, tablets, capsules, powders, granules, emulsions, suspensions, and the like. These preparations contain the active ingredient, usually in admixture with nontoxic pharmaceutical excipients, to give solid dosage forms or as a solution, suspension, or emulsion to give a liquid preparation. It is understood that other standard pharmaceutical prac-tices also apply such as the addition of sweetening and flavoring agents or use of binders, etc. Further, the compositions may also contain other absorbing agents, stabilizing agents, wetting agents and buffers.

Additionally, liquid preparations of compounds IV
and V may be used for administration by inhalation given, for example, by nebulization. The instant . . ...

~ ;
~23S7~S

compounds can also be administered as a powder for insufflation, consisting of a blend of inert powder ingredients admixed with an appropriate amount of the instant compound of appropriate particle size, admi-nistered by a powder insufflation device. Generally, one part micronized drug is blended with 50 parts USP
lactose having appropriate microbial properties. This blend is encapsulated for use in a suitable insuf-flation device. Prior to use, the capsule must be punctured or opened to allow release of the powder blend.

EXAMPLES

In examples 1-4, the following types of tests (i.e., models) on animals were used. These were (1) croton oil-induced 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 assay, (which is a standard test, which is fully described in Tonelli et al., Endocrinology, vol. 77, pp. 625-634, 1965), topical application of four % croton oil in ethanol (v/v) to the ears of mice causes intercellular edema, vasodila-tion, and polymorphonuclear leucocyte infiltration into the dermis, leading to an increase over normal ~ ~L23~705 ear weight of about 70 to 100%. The inflammatory res-ponse is nearly maximal by 6 hours. In the croton oil tests, four volume % croton oil in ethanol was ~pplied to the inner aspect of both ears of each test mouse, and various test materials in vehicle systems were applied to the outer aspect of the ears immediately following croton oil application. Control animals were exposed either to croton oil alone or to croton oil followed by the vehicle alone.

Six hours after exposure to croton oil and/or test material, animals were sacrificed; and punch biopsies of the ears were weighed and compared to ~he respective vehicle control.

Compounds were tested in simple solutions, including dimethylacetamide/acetone/ethanol (i.e., D~AC/A/E v/v 40/30/30) and N-methyl pyrrolidone/
ethanol (NMP/E v/v 50/50). Comparative controls were chosen based on their known activity in each of the three above-described animal assays and included in all three tests (in Examples 1, 2 and 3) hydrocorti-sone valerate (HCV) in the croton oil and oxazolone assays, indomethacin (which is a potent ASPI~IN-like nonsteroidal anti-inflammatory agent) in the UVB test, and salbutamol (a B2 agonist, discussed above in the-Background of the Invention).

The percent inhibition of induced mouse ear edema (or erythema) for each of the three models (in Examples 1, 2 and 3) is calculated:
Control Ear Weight - Test Ear Weight Control Ear Weight X100 * Trade mark for acetylsalicylic acid (ASA) 12~S~705 The croton oil assay appeared to be more sensi-tive to steroidal anti-inflammatory agents than to ASPIRIN-like nonsteroidal anti--inflammatory agents.
Unexpectedly, unlike the ~SPIRIN-like nonsteroidal anti-inflammatory agents, the B2-agonists used in this invention were effective in reducing the croton oil-induced inflammation.

The anti-inflammatory activities of approximately 45 ~2-adrenergic agonists were evaluated in the croton oil-induced mouse ear edema assay (which pro-duces acute dermatitis); and the more active compounds were subsequently tested in the oxazolone-induced mouse ear edema assay (which produce-~ contact allergic dermatitis) and in the UV~-induced erythema assay in guinea pigs.

Out of the group of approximately 45 compounds which included zinterol and analogs thereof, four com-pounds (one of which was zinterol) demonstrated high topical cutaneous anti-inflammatory activity in the croton oil assay at 1.6 w/v % ~weight/total volume ethanol+test material). These four compounds were subsequently tested topically at other concentrations in the croton oil assay and were also tested topically in the oxazolone assay and in the UVB test. In these subsequent tests, zinterol appeared to be the most consistently active compound.

Given below in Table I are the results of zin-terol and the controls salbutamol and HCV, at 1.6 w/v%
and 0.2 w/v% in the croton oil assay in each of two solvent systems. Also included in Table I is data for bitolterol, a commercially available B2 agonist * Trade mark for acetylsalicylic acid (ASA) ~3';7~5 which has previously been used as an anti-allergy com-pound but which has not previously been known for utility as topically active against cutaneous inflam-mations. A direct comparison of bitolterol and zin-terol was made. Both exhibited similar topical anti-inflammatory activity. ~

The results in Table I show that in the croton oil assay, zinterol at 1.6 w/v percent and at 0.2 w/v percent and bitolterol at 1.6 w/v percent all showed good to moderate reductions in ear edema and were equivalent to or slightly less effective than hydro-cortisone valerate (i.e., HCV) but were more effective than salbutamol.

Example 2 Oxazolone-induced contact sensitization in mice is characterized by edema and cellular infiltration, primarily of the monocyte type, with close to 100%
increase in the mouse ear weight. (This model is fully described in N. J. Lowe et al., British J. of Dermatology, vol. 9~, pp. 433-438, 1977, which is hereby incorporated herein by reference. In this model, test materials were applied topically to the outer aspect of the challenged ear of each test animal immediately following the challenge application of oxazolone to the inner aspect of the ear. The animals were sacrificed at 8 or 24 hours after treatment; and punch biopsie-~ of the ears were weighed and compared to controls which were challenged as described above and exposed to the vehicle alone.

, . .

~;~357Q5 Table I

% Inhibition of Croton Oil-Induced ~ouse Ear Edema in Two Vehiclesl In D~AC~Acetone/ETOH~- In NMP/EToH3 Compound 1.6 w/vX 0.2 w/v~ 1.6 w/vX ~ ~ 0.2 w/v%
Zinterol 69a, 50b 54h,34i 69m, 63n 92r~ 585 81C, 66d 29i~6k 700~ 48P 56t, 44u 63e, 48f 201 73q ~7v, 38x 459 34Y, 61f 8itolterol 61 42X, 25Y

Salbutamol4 26a, ob _34j*,_45k 54m, 49n 23, OP
37q HCV 78C, 59d 25i, 38k 70n, 71q 71r, 625 16e, 48f 341, 64t, 6~u 599 73~

1 Each value is the mean of 10 to lS animals. Approximately 10 to 35X variability is observed in this test.
2 Dimethylacetamide/Acetone/Ethano1 tv/v, 40/40i30).
3 N-methyl 2-pyrrolidone/Ethano~ tv/v, 50/SO~

- 4 Tested in Ethanol/H20 (50~50) due to so~ubility lim~tations. --- ... , .... . - . . . . . . - - : .......... . . - . ..
a to Z- ~alues with the same alphabetical superscript were -observed in the same experiment.
* The minus sign indicates no inhib~tion, but rather potentiation, of the inflammation.

The oxazolone assay appeared to be sensitive to steroidal anti-inflammatory drugs and relatively in-sensitive to nonsteroidal anti-inflammatory drugs.
Again, unexpectedly, unlike the ASA-like nonstero-idals (such as indomethacin), the B2-agonists showed topical anti-inflammatory activity.

In Table II, the results of te~ts on percent of inhibition of oxazolone-induced edema in mouse ears using various concentrations of zinterol, salbutamol, or HCV as active ingredient are given for oxazolone in three solvent systems of D~AC!acetone/ethanol (v/v 40:30:30).

From the results in Table II, in the oxazolone assay, one can observe that zinterol at 3 and 1.6 weight percent showed slight reduction in ear edema with no dose-related effect and was equal to salbutamol but slightly less active than HCV.

Compounds in Tables I and II can be compared directly.
-Examp.le 3 .
Another series of tests were run for the sake ofcompleteness, although it was not expected that B2-agonists (which are vasodilators) would show results comparable to the ASA-like nonsteroidal agents (which are not vasodilators). In the UV~ test, cutaneous erythema is induced in guinea pigs. This test is a standard test widely used for testing anti-inflammatory agents and is fully described in R. F.

123S7~
Table I I

~ Inhibition X Inhibition of Oxazolone-Induçed of Oxazolone-Induced - Edema in ~ouse Earl~2 Edema in ~ouse Ear2~3 Concentration Concentration Compound0.2 w/v% 1.6 w/v% 1.6 w/v% 3 w/v%

Zinterol22a, -17b 4~c, 17d 35h, 30i 391 4~e 14i~ 43k Salbutamolla, _gb, 2C, od, 21h, 28i 311 HCY 16a, 16b 36C, 27d 38J. 81k 391 1 Above agents tested in DMAC/acetone/ethanol (V/Y'40:30:30).
2 Each value is the mean of 10 to 15 animals. Approximately 20 to 35X variability is observed in this test.
3 Above agents tested in N-methylpyrrolidone:ethanol (v/v 1:1).

a to 1,_ , Yalues,with the same alph,abetical $up,er,scri,pt,were, '' - obserYed in the same experiment, - - -A

... . . _ ~23~VS

Swingle, ~Evaluation for Anti-Inflammatory Activity~, in Anti-Inflammatory Agents, vol. 2, ed. by Scherrer and Whitehouse, pp. 34-122, London: Academic Press, 1974, hereby incorporated herein by reference. In the UV~ model, the test material was applied topically to the irradiated sites immediately following exposure to UVB. Erythema was scored on a O to 4 scale, 3 and 6 hours after irradiation.

In Table III, the percent changes in UVB-induced erythema in guinea pigs at 3 and 6 hours after treat-ment with zinterol are given, along with results of treatment with salbutamol and indomethacin.

As shown by the results in Table III for the UVB
assay, zinterol at 3 and 1.6 weight percent showed ~light to moderate activity with no consistent dose effect and was highly variable. Similar effects were ceen with salbutamol. However, indomethacin at 1 weight percent showed good to very good activity on a consistent basis.

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

Based upon the summary in Table IV, one can validly conclude that, at the same concentrations, zinterol appears to be almost as effective as ~CV and more effective than salbutamol in the croton oil assay. Therefore, zinterol is a promising candidate for reducing anti-inflammatory activity in humans, based upon the data disclosed above. Zinterol is expected to be devoid of many side effects which are exhibited by the current steroid therapy.

~23~)5 Table III

% Change in WB - Induced Erythema in Guinea Pig at 3 and 6 Hours after Treatment Drug Concentr~ ~ o3 ~ x ) ~ Dru~ ~c~tr~tlon (X)3 t r r ~ r Compound a ~ J J D .~ 1 Zinterol 0 13 NT* 9 26 48 18 27 ~9 Salbutamol4 9 ~4 ~39 +39 42 32 Indomethacin 72 43 ~00 74 ( lX) 54 ~8 93 85 82 5~ 91 87 1 All test material applied immediately post-irradiation.
2 Test material prepared in Dimethyl acetamide/
acetone/ethanol (v~v, 40/30/30) and given as w/v%.
3 Test material prepared in N-methyl 2-pyrrolidone/
ethanol (v/v, 50/50) and given as w/v%.
4 Tested in Ethanol/H20 (50/50) or NMP/H20 (50/50) due to solubility limitations.
* Not tested due to solubility limits at 1.6%.

~235~0~;

Tabie IV

Topical Anti-Inflammatory Activity of Zinterol in 3 Animal Models (Salbutamol, HOV and Indomethacin Tested as Comparative Controls) Croton Oil Assay Oxazolone Assay UV-B Assay (Ed~a) ~
Z~nterol ++~ ~ +

Salbutamol + + +

HCY ++~ . + NT~

Indomethacin + ~ +t+

Anti-Inflammatory Activity and (range of % inhibition) ~ 8 Slight (30-44)~ ~+ = moderate (45-S9) and +++ = high ( 60%) lNT = Not tested.

. .

. _ . . . . . ... _ . .

~23~705i Example 4 In further testing, two analogs of zinterol, com-pounds IV and V, were tested and were found to show anti-inflammatory activity comparable to that of zinterol.

In these tests, the anti-inflammatory effect of these three B2 agonists when applied topically to the croton oil-induced ear edema in mice was inves-tigated. In these tests, 50 ~1 of 4 weight percent croton oil in ethanol was applied to the inner aspects of the right and the left ears of Swiss albino mice, followed immediately by 25 ~1 of suspensions of 0.02, 0.2, and 0.8 weight percent of compound IV and com-pound V in N-methylpyrrolidone/Ethyl alcohol (i.e., NMP/ETO~) applied to the outer aspect of each ear.
Croton oil treated and nontreated control groups were included. These control groups are included in the data as described hereinbefore.

Six hours later, the animals were sacrificed with C2 gas, and a 5/16 inch punch biopsy of each ear was taken and weighed immediately.

The anti-inflammatory effects for the test agents were assessed by a comparison of the biopsy weights of the test and control groups.

The results of three studies for various concen-trations of test material in N~P/ETOH are given below in Table V and show that both compound IV and compound V are comparable to zinterol in reducing the mouse ear edema.

_ 34 -... ... ..

i7~5 Table V

% Reduction of Ear Edema ~eight as Compared to _ontrol Ears + S.D.

Test ~ateria7 Concentration (%)* Compound IV Compound Y Zinterol 0.02 70.6 29.9 14.2 25.6 ~3.6 Mean + S.D. 18.1+10.6 18.9+6.6 0.2 32.9 53~S 39.5 48.7 66.2 49-4 46.6 ~ean + S.D. 43.7+9.3 50.8+13.8 0.8 61.6 69.9 68.2 53.4 56.6 ~ean + S.D. 57.5+5.8 62.4+8.2 * Weight/Yolume . . .
- ~ata ~Yen oin the same line in Ta~les III and V were obtafned in the same experiment, an~ therefore a dlrect comparison is shown.

i 123~;7~
It will be appreciated that the compounds of formula II can be formulated into a wide variety of formulations by standard means well known to those skilled in the art. Such formulations include for example nasal sprays (one spray of which may be pre-pared, for example, with trichloromonofluoromethane, dichlorodifluoromethane, and oleic acid), rectal sup-positories, vaginal suppositories, ointments, creams, gels, and lotions.

The methods of preparation of compounds I~ and V
and their biological actions will appear more fully from a consideration of the followinq examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius and melting points are uncorrected.
The nuclear magnetic resonance (NMR) spectral charac-teristics refer to chemical shifts (~) expressed as parts per million tppm) versus tetramethylsilane ~TMS) as reference standard. The relative area reported for the various shifts and the proton NMR spectral data corresponds to the number of hydrogen atoms of a - -particular functional type in the molecule. The nature of the shifts as to multiplicity i9 reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDC13 (deuterchloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm ) having functional group identifica-tion value. The IR determinations were employed using _ 36 -lZ3~70S

potassium bromide (KB~) as dilLIent. The elemental analyses are reported as percent by weight.

Exhmple 5

5'-(2-Amino-l-hydroxyethyl)-2'-hydroxy-methanesulfonaDilide ~y~chlorlde(VIII) To a stirred solution of hexamethylenetetramine (27.4 9, 0.19 mole) in 6~0 mL chloroform was added in portions 5'-bromoacetyl-2'-hydroxymethanesulfo~anilide (IX; 40.0 9, 0.13 mole). The Tesulting suspension was refluxed for 16-18 hrs, cooled to room temperature, and then filtered. The solid obtained was wasbed with cbl~soform and dried in ~ir t~ give 56.6 9 (97.3~) of quat~nary salt prod~ct, m.p. 165-167.

This solid was dissol~ed in 400 mL ethanol and treated with 65 mL conc. HCl. Refluxing the resulting solution for several minutes ~aused the initiation of precipitation in the hot solution. The mixture was c~illed to aid in completion of precipitation. The solid, isolated by filtration, was washed by being stirred in water and refiltered. Recrystallization of this material from methanol-isopropyl ether gave a solid product, 5'-glycyl-2'-hydroxymethanesulfon-anilide hydrochloride, m_p. 21g-221.

A portion (7.3 9. D.026 mole) of this aminoketone hydrochloride and 10~ palladium-on-carbon (2.0 9) were suspended in 200 mL of hot 90 ethanol. This warm su~pension was reduced by sha~ing under 60 psi hydro-gen on a Parr hydrogenation apparatus. Following ~LX3S7QS

12-14 hrs of shaking, the hydrogenation mixture was removed from the Parr apparatus and the catalyst removed by filtration. The filtrate was,concentrated in vacuo to a white solid residue which was suspended in an isopropyl alcohol-isopropyl ether medium and refiltered to give a quantitative yield of VIII as the hydrochloride salt, m.p. 179-180 (dec.).

Example 6 2'-Hydroxy-5'-(1-hydroxy-2-[~-(3-indolyl)-2-propylamino]ethyl)methanesulfonanilide (Compound IV) The hydrochloride salt of VIII 15.65 9., 0.02 mole), prepared above, was converted to the base by suspension in 150 mL of ethanol followed by treatment with 2.0 mL of 10.0 N NaOH added dropwise with stir-ring. The original solid dissolved with concommitant precipitation of NaCl. The NaCl was removed by fil-tration and the filtrate was concentrated in vacuo to a white solid residue which was dissolved in l00 mL of methanol. A reductive alkylation was carried out by adding glacial acetic acid (1.2 9., 0.02 mole) and 3-indolylacetone (3.5 g, 0.02 mole), diluting the resulting solution to 150 mL with additional ethanol and then adding 0.2 g PtO2. This suspension was hydrogenated under 60 psi hydrogen until hydrogen uptake ceased (approximately 4 hrs). The suspension was removed from the hydrogenation apparatus, filter-ed, and the filtrate concentrated in vacuo to an oily residue which was dissolved in warm methanol treated with several drops of glacial acetic acid. Dilution with ethyl ether and stirring while chilling allowed ~23S70S

collection by filtration of a solid which was washed with methanol to given 4.7 9 of the acetate salt of compound IV, m.p. 196.5-197 (dec.).

This material was dissolved in a minimal amount of hot dimethylformamide, filtered and diluted with an equal amount of water to yield a precipitate which was isolated by filtration giving the free base of compound IV, m.p. l9a-199 ~dec.).

Anal. Calcd. 20 25 3 4 ~, 6.24; N, 10.41; S, 7.94. Found: C, S9,96; H,

6.15; N, 10.65; S, 8.05.

NMR (D~SO-d6): 0.98 (3,m); 2.75 (5,m); 2.93 (3,s); 4.52 (l,m); 6.00 (4,bs); 7.15 (8,m).

IR (~Br): 750, 1125/ llS0, 1240, 1280, 1325, lS00, 1610 and 2940 cm Example 7 Alternate Preparation of Compound IV

A solution of 3-(2-aminopropyl)indole (11.0 g, 0.06 mole) in 730 mL acetonitrile was stirred under a nitrogen atmosphere as 5'-bromoacetyl-2'-benzyloxy-methanesulfonanilide (12.5 g, 0.03 mole) was added in a single por~ion. After stirring at room temperature for 0.5 hr, a cold solution of sodium borohydride (4.8 g, 0.126 mole) in 219 mL methanol was added at a fast dropwise rate. Progress of the reaction was followed by disappearance of the bromoketone spot on thin layer ~235~0~

chromatography. Additional sodium borohydride is sometimes necessary for complete extinction of the aminoketone starting material. When reaction was complete, the solvent was removed in vacuo and the residue suspended in 0.5 liter of H2O and treated with 4N NaOH to bring about complete solution. This solution was washed well with ether and then the pH
was adjusted with acetic acid to pH 8. The resulting mixture was extracted with methylene chloride, the extracts combined and dried (MgS04) and then concen-trated ln vacuo to give 14.5 9 of residual gum.

This gum may be purified by chromatographing-on a silica gel column eluting with chloroform-methanol-ammonium hydroxide ~90:10:1) to yield 11.6 g of the benzyloxy derivative of compound IV.

The O-benzyl protecting group was removed by hydrogenating a mixture of the O-benzyl derivative of compound IV (11.5 9, 0.02 mole) and 1.8 9 of 10%
palladium-on-carbon ~made wet with absolute ethanol) in 820 mL methanol in a Parr low pressure apparatus.
Upon compl~tion of hydrogen take-up, the reduction mixture was filtered and the solid washed with addi-tional methanol. All methanol port~ons were combined and concentrated to a small volume (approximately 100 mL) and upon standing a white solid gradually preci-pitated. The solid was isolated by filtration, washed with methanol and dried in air to give 5.6 9 material, m.p. 197-198 (61%). This material was dissolved in 40 mL of hot dimethylformamide, filtered and 45 mL
H2O added to the filtrate. Trituration of this solution induced crystallization. Another 10 mL H2O
was added and the mixture was chilled in an ice bath _ . .. .. . .. . .. .

following which the solid was isolated by filtration and washed well with H2O. Drying in air provided S
g of compound IV, m.p. 197-200 (dec.).

Example 8 N-(2-Hydroxy-5-[1-hydroxy-2-([2-(lH-indol-3-yl)-1,1-dimethylethyl~amino)ethyl]
phenyl)methanesulfonamide (Compound V) A solution of 2-(2-amino-2-methylpropyl)indole (X, R=Me; 37.7 9, -0.2-mole) and triethylamine (10.1 9.
0.1 mole) in 1.2 liter-of dioxane which had been dis-tilled over sodium metal, was stirred under a nitrogen atmosphere as 5'-bromoacetyl-2'-benzyloxymethane-sulfonanilide (39.8 9, 0.1 mole) was added. The resulting mixture was left stirring for 8-12 hr at approximately 25 under the nitrogen atmosphere. The reaction mixture was filtered, removing some solid precipitate, and the filtrate was treated with a cold solution of sodium borohydride (15 9, 0.4 mole) in 1 liter of absolute ethanol. The borohydride solution was added dropwise to the stirred reaction filtrate.
Progress of the reaction was followed by disappearance of the bromoketone spot on thin layer chromatography.
Additional sodium borohydride is sometimes necessary for complete extinction of the aminoketone starting material. When reaction was complete, the solvent was removed in vacuo and the residue was dissolved in 0.2N
Na~H and washed with ether. The p~ of this solution was then adjusted with acetic acid to p~ 8 and this resulting mixture was extracted with methylene chloride, the extracts combined and dried (MgSO4) an 123~70S
then concentrated ln vacuo to give the crude O-benzyl derivative of compound V as a residual gum.

The O-benzyl protecting group was removed by hydrogenating a mixture of the O-benzyl derivative of compound V (3.25 9, 0.006 molej and 1.0 9 of Pd(OH)2/C (Pearlman catalyst) in 100 mL methanol in a Parr low-pressure hydrogenation apparatus. Upon completion of hydrogen ta~e-up, the reduction mixture was filtered and the solid suspended in water and lN
HCl added with warming so that product dissolved. The insoluble catalyst was removed by filtration and the - -acidic filtrate was made basic (pH B) with ammonium hydroxide. The resulting precipitate was isolated by filtration, washed with water, and dried in air to give a nearly quantitative yield of product (compound V) as the monohydrate, m.p. 211-212.

57.92; H, 6.72; N, 9.65; H2O, 4.14. Found: C, 58.05; H, 6.68; N, 9.64; H2O, 3.63.

NMR (DMSO-d6): 1.01 (3,s); 1.05 (3,s); 2.75 (4,m); 2.92 (3,s); 4.49 (l,m); 5.30 (6,bs); 7.12 (8,m).

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

The monohydrate product, obtained above, was con-verted to the hydrochloride hydrate by dissolution in dilute HCl followed by concentration in vacuo to a solid fo3m, m.p. 105-125. Calcd. for C21H27N3O4S.~Cl-H2O
C, 53.44; H, 6.41; N, 8.91; H2O, 3.82. Found: C, 53.19; H, 6.37; N, 8.92; H2O, 3.64.

~2,3570S

NMR (DMSO-d6): 1.28 (6,s); 2.95 (3,s); 3.17 (4,m); 3.80 (l,bs); 4.90 (l,m); 7.02 (4,m); 7.25 (3,m); 7.60 (l,m); 8.50 (l,bs); 8.78 (l,bs~; 9.30 (l,bs); 10.00 (l,bs); 11.10 (l,bs).

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

Claims (13)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of preparing a compound of formula II, II, wherein A is (-CH2-)n and n is the integer 0 and B is (-CH2)m and m is the integer 0 and wherein R1 is -CH3, M is an indole group, R3 is -OH, R4 is -NH-SO2-CH3, and R2 is selected from the group consisting of H and -CH3, said method comprising either:
i) (a) alkylating an indolylamine of formula X

X, by a bromoketone of formula IX
IX;
(b) and then treating the product of step (a) under reaction conditions so as to reduce the carbonyl group to a secondary alcohol, thereby forming said compound of formula II; or (ii) reacting a compound of formula VIII

VIII, with a compound selected from the group consisting of compound (b) and compound (c) (b) (c) , wherein X in (c) is a typical leaving group and wherein when compound (b) is used, reaction conditions are chosen so that reductive amination of compound (b) and reduction take place, so as to form a compound of formula II in which R2 is H; and wherein when compound (c) is used, reaction conditions are chosen so that nucleophilic displace-ment by compound VIII on compound (c) occurs so as to form said compound of formula II; and, if desired, converting said compound of formula I
to a pharmaceutically acceptable solvate or salt thereof.

2. A method of preparing a compound of formula II, II, wherein A is (-CH2-)n and n is the integer O and B is (-CH2)m and m is the integer O and wherein R1 is -CH3, M is an indole group, R3 is -OH, R4 is -NH-SO2-CH3, and R2 is selected from the group consisting of H and -CH3, said method comprising:
(a) alkylating an indolylamine of formula X

X, by a bromoketone of formula IX

IX;
(b) and then treating the product of step (a) under reaction conditions so as to reduce the carbonyl group to a secondary alcohol, thereby forming said compound of formula II; and if desired, converting said compound of formula II
to a pharmaceutically acceptable solvate or salt thereof.

3. A method of preparing a compound of formula II, II, wherein A is (-CH2-)n in which n is the integer O, wherein B is (-CH2)m in which m is the integer O, and wherein R1 is -CH3, M is an indole group, R3 is -OH, R4 is -NH-SO2-CH3, and R2 is either H or -CH3, said method comprising: reacting a compound of formula VIII

VIII, with a compound selected from the group consisting of compound (b) and compound (c) (b) (c) , wherein X in (c) is a typical leaving group and wherein when compound (b) is used, reaction conditions are chosen so that reductive amination of compound (b) and reduction take place, so as to form a compound of formula II in which R2 is H; and wherein when compound (c) is used, reaction conditions are chosen so that nucleophilic displacement by compound VIII on compound (c) occurs so as to form said compound of formula II;
and, if desired, converting said compound of formula II
to a pharmaceutically acceptable solvate or salt thereof.

4. The method of claims 1 or 3 wherein the leaving group is halide or tosylate.

5. A method according to claim 2, wherein R2 is H.

6. A method according to claim 2 wherein R2 is -CH3.

7. The method of claim 1 wherein A is (-CH2-)n and n is the integer 0 and B is (-CH2-)m and m is the integer 0 and wherein R1 is -CH3, M is the indole group, 3-indolyl, R3 is -OH, R4 is -NH-SO2-CH3, and R22 is H.

8. The method of claim 1 wherein A is (-CH2-)n and n is the integer 0 and B is (-CH2-)m and m is the integer 0 and wherein R1 and R2 are each -CH3, M is the indole group 1H-indol-3-yl, R3 is -OH and R4 is -NH-SO2-CH3.

9. A compound having the formula II

II, or a pharmaceutically acceptable solvate or salt thereof, wherein A is (-CH2-)n and n is the integer 0 and B
is (-CH2)m and m is the integer 0 and wherein R1 is -CH3, M is an indole group, R3 is -OH, R4 is -NH-SO2-CH3, and R2 is selected from the group consisting of H and -CH3.

10. The compound of claim 9 which is 2'-hydroxy-5'-(1-hydroxy-2-[1-(3-indolyl)-2-propylamino]ethyl)-methane sulfonanilide or a pharmaceutically acceptable metal or acid addition salt or hydrate thereof.

11. The compound of claim 9 which is N-(2-hydroxy-5-(1-hydroxy-2-([2-(1H-indol-3-yl)-1,1-di-methylethyl)amino)ethyl]phenyl)methanesulfonamide or a pharmaceutically acceptable metal or acid addition salt or hydrate thereof.

12. A pharmaceutical composition comprising a compound of formula II as in claim 9, 10 or 11, together with a pharmaceutically acceptable carrier.

13. A topical anti-inflammatory pharmaceutical composition comprising an effective amount of a compound having the general formula II as in claim 9, 10 or 11, together with a dermatologically acceptable carrier.