CA1235662A - 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-inflammatary 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

~'~3~i662 PHENETHANOLAMINES AND USES THEREOF

.

This invention relates generally to anti-inflam-matory, topically applied nonsteroidal compositions and to their uses and relates more specifiaally to such compositions having as active ingredient B2-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-afecting and body-treating processes employing these compounds.

Applicants emphasize that although there are at least hundreds (perhaps thousands) of B2-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 is known in the art at this time. The art area is very unpredictable.

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

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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. However, 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 suppression, 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-pby, adrenal suppression, and other less severe re-bound effects.

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.

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B adrenergic agonists tincluding ~1 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-AMP levels have been reported in proliferative skin diseases ~uch as eczema, psoriasis, epidermolytic hyperkeratosis and lamellar ichthyosis.

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

Materials which are classified 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.

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In V. S. Patent 4,323,575 to G. ~ones, April 6, 1982, disubstituted catecholamines (which may or may not be ~2 agonists) having topical anti-in~lammatory activity are disclosed.

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

~ Ik- ~ ~ormula X

As disclosed in that patent, the ~ulfonanilides of fo:mula I, wherein Z i9 C~O~, are pharmacologically active phenethanolamines having actions which either resemble the effects of the adrenal medullary hormones or adrenergic naurotransmitters or oppose the effects of the adrenal medullary hormones or adrenergic neuro-transmitters. Alkyl and aryl-sulfonamido nuclearly substituted phenalkanolamines have useful pharmacolog-ic effects, suiting them variously as vasopressors, vasodepressors, analgesics, bronchodilators, -recep-tor stimulants, B-receptor stimulants, a -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 Technical Terms, Second Edition, 1978, as hypersensitivity following parenter-al injection of an antigen, whereln local or systemic -~3 ~Z3SÇ~Z

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 condi~ions 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 anotexigenic agent, as an orally active bronchodilator, and as having analgesic activity.

In the article "Adrenergic Sulfonanilides. 4.
Centrally Active ~-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) a~ being useful as a topical anti-inflammatory agent.

. .

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The synthesis of salbutamol is described in Drugs of the Future IV, 629 (1979). There, s~lbutamol 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 structural 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 ~2-agonists will be effective topical anti-inflammatory agents cannot be predicted with any reasonable degree of certainty. After mllch experimentation, applicants found that nearly all ~2 agonists they tested for such activity were either ineffective, highly toxic, or both.

~Z356~;2 Therefore, despite what has been known in the prior art, there is a continuing need for non-steroid-al anti-inflammatory drugs which exhibit consistently good anti-inflammatory activity and which are nontoxic.

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

Larsen, et al., U.S. Patent 3,341,584 cited above broadly disclosed catechol type phenethanolamines wherein one of the phenyl ring hydroxy groups 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, disclosed 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.

An object of this invention i9 a material which when placed into a suitable vehicle provides a compo-sition which when topically applied reduces the amount of topical inflammation of a mammal.

Another object of this invention i5 a composition in the form of an ointment, cream, lotion or other formulation to be topically applied to a mammal so as 1~356~

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

? ~H-C~ A- c-B~

, 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 ~, a phenyl group, or an indole group of formula (a) ~ (~), A is ~ CH2-)n in which n i9 the integer 0, 1, or 2, and B ls (-CH2)m ln which m i8 the $nte~er 0, 1, or 2, R is either -O~ or -OCO ~ C~3, and R i8 either -N~_~02-CH3 or -oCO ~ 3 excluding ~he compounds of formula II
wherein collectively R is -CH3 and R
is H or -CH3; M is an indole group; A is the group (-CH2-)n, in which n is 0; B
is the group (-CH2-)m, in which m is 0;
R is -OH and R ls -NH-SO2-CH3; and (b) A compatible, topically acceptable vehicle for combining said ite~ (a) given above therewith.
In a pr~ferred ~apect of th~ lnventlon, Rl and R ar~ both ~ethyl groups ~nd ~ and n nr~ both 0. A
preferred compound for use in the methods and composi-tion~ of the invention is the compound of formula II
wherein n is 0, m is 0, Rl is -CH3, R is -CH3, M is phenyl, R i5 -OH, ~nd R is -N~-SO2-CH3.
This compound is known as zinterol (referred to here~nafter as compound III).

Another preferred compound for use in the methods and composition-~ of the invention i8 the compound of forDula II wherein n is 0, m is 0, sl is -C~3, R is H, M i~ an indole group, R is -O~, and R
is -N~-SO2-C~3, ~hich compound i~ hereinafter referred to as Compound IV.

Yet another preferred compound for use in the methods and oompositions of the invention iq the com-pound of formula I~ wherein n i~ 0, m i8 O, Rl and R are both -CH3, M is an indole group, R i9 -OH, and R is -NH S02-CH3, which compound is hereinafter reerred to as Compound V or azazinterol.

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A still further preferred compound for use in the methods and compositions oP the invention is the com-pound of formula II wherein n is 0, m is 0, R and R are both -CH3, M is hydrogen, and R and R
are both -OCO ~ CH3. 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 in1ammations.

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 tbe 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, 8, 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.

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It is emphasized that the term "topical" as used throughout this document means local or designed for locai 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 ir.vention 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 immunized guinea pig tracheal rings. These agents include compound IV and compound V and their pharmaceutically acceptable solvates and salts thereoi, 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 (-C~2)m and wherein m is 0, 1, or 2; wherein R

. .

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and R are independently ~ or a lower alkyl group, provided that R and R cannot both be H; wherein R is either -OH or -OCO ~ C~3; and wherein R
is either -NH-SO2-CH3 or -OCO-~ C~3.

Applicants wish to emphasize that they tested many ~2 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 examples below. The remainder of the compounds, on the other hand, exhi-bited either toxicity when applied topically to the test animals, ineffective and/or inconsistent 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]methanesul~onanilide and Its Salts~.

As used herein, ~e 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. $he first synthetic method shown hereinafter/

.. .~ , .
.

`` ~2356~2 Method 1 H H2 ~ j Compound IV
H2N ~ catalyst - ~. :.. :
.. ,~ . .. .
~b) 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 atmosphere. 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 i9 shown below as ~ethod lA.

~ . .. . .. ...

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Meth~d lA

" ~ Compound IY (if R=H) (VIII) or N Compound V (if R=Me) tc) wherein X is a typical leavin~ 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 pteparation of compound V as shown.

Method 2 ~<R'd2 r~J~

tX) tIX) Compound IV (if R~H) or Compound V ~ if R=Me) ~Z3566~2 This process comprise~ 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. ~hese specific schemes are outlined below.

Scheme A: Preparation of Compound IV
! e 8r 3r ~ C6~1~R4 ~ > C ~ ~ N~52C~3 IX

Q 1 EtOH
~Cl OH HCl H2~o~s2c~3 ~eo~ J~,~SO2CH3 VIII XI

Pe2 1 ~ - 15 -~35~Z

X2 ~ Pd/C
~eOH

R ~ ~

o - N2 ' :,

2) NaB~
XII, R=H ~eO~

R O
NH2 Br ~ ~HcH22h~3 X, R=H IX' Scheme A outlines 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 tC6H12N4) to yield a quaternary salt which is converted to the aminoketone XI followed by catalytic hydrogenation to the phenethanolamine VIII. Reductive alkylation of

3-indolylacetone with VIII affoxds the subject compound IV as shown. ~he lower and preferred pathway proceeds 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: R~) as shown which iq in turn catalytically reduced to the desired end product.

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Scheme B: Preparation of Compound V

BrJ~S02C~31) ~ x 2) NaBH4 X: R=Me ~_ ' EtOH , R ~ O~
N~S02C~3 H tXII: R=Me ) Pt2 1 ~e OH

~lSOzCH3 Compound V

,, 6~Z

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 8 the appropriate indolylamine is reacted wlth IX', and the resulting adduct is reduced with borohydride to give the protected phenolic compound (XII: R=Me) 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 utilized in these syntheses are either available commercially, e.g. 3-indolyl acetone; or as described in the chemical li~erature such as the references cited in the Background of the ~nvention 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. ~etal and acid addition salts are obtained, respectively, either by reaction o~ the selected compound with a ~uitable metallic base to form a metal salt or with an organic or inorganic acid to form an acid addition salt, preferably by contact ~ ~.

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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 acid, isethion-ic acid, succinic acid, pamoic acid, cyclamic acid, pavalic acid, and the like. Useful inorganic acids are hydrohalide acids (such as HCl, HBr, HI), sulfuric acid, phosphoric acid, and the like.

Solvates as used herein are complexes comprising an organic drug molecule and a solvent moiety of formula ROH, 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, mi~tures of enantiomers, e.g., racemic modifications as well as the individual enantiomers and diastereomers. The individual optical isomers of the phenethanolamine 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 intermediate~; and 4) column chromatography utilizing chiral stationary phases. The application of these various methods are well known to practitioners in the art.

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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, lotions, 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 not 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 the 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 phase and a non-aqueous phase in the ~kin, both water soluble and oil soluble portions of the vehicle will permeate the skin. However, for topical use, one would use some 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, .. .

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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 ~7ill 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. However, it is believed that the optimal concentration is generally the saturation point. For 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 mixtures 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) tha~ caused the inflammation being treated.

The mixtures of the invention will b~ applied directly to the area of inflammation to produce a localized effect. Although in salbutamol (discussed above) a systemic effect was noted, none was found in preliminary tests done on the materials used in this invention. It is an advantage to have no ~ystemic `~ ~ 2 3 S 6 6 Z

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 (slow reacting substance of anaphylaxis) (c~: Brockl.ehurst: The Release of ~ist.amine and Formation of a Slow-Reacting Substance (SRS-A) Durlng Anaphylactic Shock, Journal of Physiologyl 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 electivity 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 demonstrated in various pharmacologial tests which include inhibi~ion 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: In Vitro Studies of Antigen induced Bronchospasm: Effective Antihistamine and SRS-A Antagonist on Response of Sen~itized Guinea Pig and ~uman Airways to Antigen. Journal of Immunol., 122:555-562, ~1979).

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For use as antiasthmatics, therapeutic processes of this invention comprise systemic administration, by both oral and parenteral routés 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 ~harma-ceutical acceptable acid addition salt thereof generally providing 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 . ~ . .

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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 in~ufflation 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 dejcribed in Tonelli et al., Endocrinolo~Y, 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 infiltcation into the dermis, leading to an increase over normal :
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ear wei~ht of about 70 to 100%. The inflammatory res-pon~e is nearly maximal by 6 hours. In the croton oil tests, four volume ~ croton oil in ethanol ~as applied to the inner aspect of both ears of each test mouse, and various test materials in vehicle systems ~ere 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 the 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 ASPIRIN-like nonsteroidal anti-inflammatory agent) in the UVB test, and salbutamol (a B2 agonist, discussed above in the aackground 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 Weigh~ X100 * Trade mark for acetylsalicylic acid (ASA) ~3566Z

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 ASPIRIN-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 produces contact allergic dermatitis) and in the UVB-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 ~ests, 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 ~CV, at 1.6 w/v%
and 0.2 w/v% in the croton oil assay in each oi two solvent systems. Also included in Table I is data for bitolterol, a commercially available B2 agonist * Trade mark for acetylsalicylic acid (ASA) ~356~;2 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, ~interol 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., ~CV) 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 Dermatoloqy, vol. 96, pp. ~33-438, 1977. In this model, ~est materials were applied topically to the outer aspect of the challenged ear of each test animal im,lediately 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 biopsies of the ears were weighed and compared to controls which were challenged as described above and exposed to the vehicle alone~

~`~``.;
.~, .

1;~35~

Table I

% Inhibition of Croton Oil-Induced ~ouse Ear Edema in Two Vehiclesl ~-7r 5~'TI~8;77EIOH~ In N~P/EToH3 Compound l.~ wT X ~ vX 1.6 w/vX 0.2 w/v%
Zinterol 69a, 50b 54h,34i 69m, 63n 92r, sgs 81C, 66d 29j~6k 700~ 48P 56t, 44u 63e, 48f 201 73q 57v, 3gx 45~ ~4Y~ 61~

Bitolterol 61 42X, 25Y

Salbutamo14 26a~ ob _34j*,_45k 54m, 4gn 23, OP
37q HCV 78C, 59d 25i, 38k 70n~ 71q 71r, 625 16e, 48f 341, 64t, 67U
599 73v i 1 Each value is the mean of 10 to 15 animals. Approximately 10 to 35X variability is observed in this test.
2 Dimethylacetamide/Acetone/Ethanol tV/Y3 40/40/30) 3 N-methyl 2-pyrrolidone/Ethano~ (v/v, 50/50).

4 Tested in Ethanol/H~O (50/50) due to so~ubility limitations~
a to Z Yalues witn the same alphabetical superscript were obserYed in the same experiment.
* The minus sign indicates no inhibition, but rather potentiation, of the inflammation.

lZ356fi;~

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 tsuch as indomethacin), the ~2-agonists showed topical anti-inflammatory activity.

In Table II, the results of tests on percent of inhibition of oxazolone-induced edema in mouse ears using various concentrations of zin~erol, salbutamol, or HCV as active ingredient are given for oxazolone in three solvent systems of DMAC/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 ~CV.

Compounds in Tables I and II can be compared directly.

Example 3 Another series of tests were run for the sake of completeness, although it was not expected that ~2-agonists ~which are vasodilators) would show resul~s comparable to the ASA-like nonsteroidal agents (which are not vasodilators). In the UVB tes~, cutaneous erythema is induced in guinea pigs. This test is a standard test widely u3ed for testing anti-inflammatory agents and i8 fully described in R. F.

! ,. J

1~356~2 Table II

% Inhibition X Inhibition of Oxazolone-Induçed of Oxazolone-Induced Edema in ~ouse Earl-2 Edema in Mouse Ear2~3 Concentration Concentration Compound _0.2 w/v% 1.6 w/v% ~ ~ 7~ 7V~-Zinterol 22a~ _17b 48C~ 17d 35h, 30i 391 4le 14i, ~3k Salbutamol _la, _gb 2c, od9 21h, 281 311 HCY 16a, 16b 36C, 27d 38h, 8i 391 31J, 42k 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 Values with the same alphabetical superscript were observed in the same experiment.

~3~6~2 Swingle, ~Evaluation for Anti-Inflammatory Activity", in Anti-Inflammatorv Agents, vol. 2, ed. by Scherrer and Whitehouse, pp. 34-122, London: Academic Press, 1974. In the UVB model, the test material was applied topically to the irradiated sites immedia~ely 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 resul~s in Table III for the UVB
assay, zinterol at 3 and 1.6 weight percent showed slight to moderate activity with no consistent dose effect and was highly variable. Similar effects were seen 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 a HCV and more effective than salbutamol in the croton oil assay. Therefore, zinterol is a promising candidate for reducing anti-inflammatory activity in hu~ans, based upon the data disclosed above. Zinterol is expected to be devoid of many side efiects which are exhibited by the current steroid therapy.

1235~6Z

Table III

% Change in UVB - Induced Erythema in Guinea Pig at 3 and 6 Hours after Treatmentl Drug Concentration tX)2 Drug Concentrat;on ~%)3 Time (Hr.~ _ Compound ~ 3 6 3 6 Zinterol 0 13 NT* 9 26 48 18 . 27 +9 Salbutamol4 9 +4 +39 ~39 42 32 Indomethacin 72 43 100 74 82 5~ 91 87 1 All test material applied immediately post-irradiation.
Test material prepared in Dimethyl acetamide/acetone/ethanol (v/v, 40/30~30) and given as w/v~.
Test material prepared in N-methyl 2-pyrrolidoneJethanol (v/v, 50/SO and given as w/v%.
4 Tested in Ethanol/H20 (50/50) or N~P/H20 (50/50) due to solubility limitations.
*Not tested due to solubility 1imits at 1.6%.

~Z3S662 Table IV

Topical Anti-Inflammatory Activity of Zinterol in 3 Animal Models (Salbutamol, HCV and Indomethacin Tested as Comparative Controls) Croton Oil Assay Oxazolone Assay UV-g Assay (Edema) (Edema) - _ (Erythema) Zinterol ++~ + +

Salbutamol + ~ +

HCV ++~ NT~

Indomethacin + + +~+

Anti-Inflammatory Activity and (range of % inhibition) + = Slight (30-44), +~ = moderate (45-59) and ~++ = high ( 60%) lNT = Not tested.

. .

~Z35662 ~xample g 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 ~2 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 o~ compound IV and com-pound V in N-methylpyrrolidone/Ethyl alcohol (i.e., NMP/ETOH) 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 NMP/ETOH are given below in Table V and show that both compound IV and compound V are comparable to ~interol in reducing the mouse ear edema.

_ 34 -~Z3S~62 Table V

X Reduction of Ear Edema ~eight as Compared to Control Ears + S.D.

Test ~aterial Concentration (%)* Compound IY Compound V Zinterol 0.02 10.6 29~9 14.2 25.6 23.6 Mean + S.D. 18.1+10.6 18.g+6.6 0.2 32.9 53.5 39.5 48.7 66.2 49.4 46.6 Mean ~ S.D. 43.7+9.3 50.8+13.8 0.8 61.6 69.9 68.2 53.4 56.6 Medn + S.D. 57.5+5.8 62.4+8.2 * Neight/Yolume .
. . ~ata i.`~en on the samë ~in~ in Tables III and Y were . ........... .... . . . .. . . . . .
`- obta~ned in the sam~ experiment, an~ therefore a direct comparison is shown.

.. ...... .. . . .

1~35~Z

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 IV and V
and their biological actions will appear more fully from a consideration of the following examples and appended claims which are given for the purpose of illustration only and are not to be con~trued as limiting the invention in sphere or scope. In the following examples, used to illustrate the forPgoing 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 (ppm) vereus 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 i reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDC13 (deuterchloroorm) and are otherwise conventional. The lnfrared tIR) spectral descriptions include only absorption wave numbers (cm ) having functional grouR identifica-tion value. The IR determinations were employed using r~

- ~3L235~16Z

potassium b~omide (~Br) as diluent. The elemental analyses are seported as percent by weight.

Example 5

5'-(2-Amino-l-hydroxyethyl)-2'-hydroxy-methanesulfonanilide Hydrochloride(VIII) ~ o a stirred solution of hexamethylenetetramine (27.4 9, 0.19 mole) in 650 mL chloroform was added in portions 5'-bromoacetyl-2'-hydroxymethanesulfonanilide (IX; 40.0 9, 0.13 mole). The resyl~ing suspension was refluxed for 16-18 hrs, cooled to room temperature, and then filtered. The solid obtained was washed with chloroform and dried in air to give 56.6 9 (97.3~) of quaternary salt product, m.p. 16~-167.

This solid was dissolved in 400 mL ethanol and treated with 65 mL conc. HCl. Refluxing the resulting solution for several minutes caused the initiation of precipitation in the hot solution. The mixture was chilled to aid in completion of precipitation. The solid, isolated by filtration, was washed by beiny 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. 219-221.

A portion (7.3 9. 0.026 mole) of this aminoketone hydrochloride and 10~ palladium-on-carbon (2.0 g) were suspended in 200 mL of hot 90 ethanol. Thi~ warm suspension was reduced by shaking under 60 psi hydro-gen on a Parr hydrogenation apparatus. Following ~35662 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 ~III as the hydrochloride salt, m.p. 179-180 (dec.).

Example 6 2'-Hydroxy-5'~ hydroxy-2-[3-t3-indolyl)-2-pro~xlamino~ethYl)methanesulfonanilide (Compound IV) The hydrochloride salt of VIII (5.65 g., 0.02 mole), prepared above, was converted to the base by suspension in 150 mL of ethanol followed by treatment wi~h 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 100 mL of methanol. A reductive alkylation was carried out by adding glacial acetic acid (1.2 g., 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 9 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 ln vacuo to an oily residue which was dissolved in warm methanol treated with several drops of glacial acetic acid. Dilution with ethyl ether and stireing while chilling allowed ~3S~6Z

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 tdec.).

This material was dissolved in a minimal amount of hot dimethylformamide, filtered and diluted ~7ith an equal amount of water to yield a precipitate which was isolated by filtration giving the free base of compound IV, m.pO 198-199 ~dec.).

nal. Calcd- for C20H25N3O4S: C, 59.53;
H, 6.24; N, 10.41; S, 7.94. Found: C, 59,96; ~,

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 t4,bs); 7.15 (8,m).

IR (KBr): 750, 1125, 1150, 1240, 1280, 1325, 1500, 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 9, 0.03 mole) was added in a single portion. After stirring at room temperature for 0.5 hr, a cold solution of sodium borohydride (4.8 g, 0.126 mole~ in 219 mL me~hanol was added at a fast dropwise rate. Progress of the reaction was followed by disappearance of the bromoketone spot on thin layer .
' ~ .

" :lZ3S66Z

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 in 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 g, 0.02 mole) and 1.8 g of 10%
palladium-on-carbon tmade wet with absolute ethanol) in 820 mL methanol in a Parr low pressure apparatus.
Upon completion of hydrogen take-up, the reduction mixture was filtered and the solid washed with addi-tional methanol. All methanol portions 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 :~35~6;2 following which the solid was isolated by filtration and washed well with H2O. Drying in air provided 5 g of compound IV, m.p. 197-200 (dec.).

Example 8 N-(2-Hydroxy-5-[1-hydroxy-2-([2-(lH-indol-3-yl)-l,l-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 g.
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 g, 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 l liter of absolute ethanol. The borohydride solution was added dropwise to the stirred reaction filtrate.
Progress of ~he 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 ln vacuo and the residue was dissolved in 0.2N
NaOH and washed with ether. The pH 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 "` ~Z35~

then concentrated in vacuo to give the crude O-ben~yl 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 g, 0.006 mole) and 1.0 g of Pd(OH)z/C (Pearlman catalyst) in 100 mL methanol in a Parr low-pressure hydrogenation apparatus. Upon completion of hydrogen take-up, the reduction mixture ~as 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 8) 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 foam, m.p. 105-125. Calcd. for C21H27N3O4S-HCl-H2O
C, 53.44; H, 6~41; N, 8.91; H2O, 3.82. Found: C, 53.19; H, 6.37; N, 8.92; ~2' 3.64.

lZ3566~

NMR ~DMSO-d6): 1.28 (6,s); 2.95 (3,s); 1.17 (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, llS0, 1295, 1320, 1400, 1460, 1515, and 1620 cm

Claims (11)

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

1. A composition comprising:

(a) an amount effective to produce n topical anti-inflammatory effect of at least one compound, or pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of compounds having the general formula II

I I, wherein R1 and R2 are independently H or a lower alkyl group, provided that R1 and R2 cannot both be hydrogen;

wherein M is a phenyl group, indole group or hydrogen;

wherein A is the group (-CH2-)n, in which n is 0, 1, or 2;

wherein B is the group (-CH2-)m, in which m is the integer 0, 1 or 2;

wherein R3 is either -OH or -OCO?CH3; and wherein R4 is either -NH-SO2-CH3 or -OCO?CH3;
excluding the compounds of formula II wherein collectively R1 is -CH3 and R2 is H or -CH3; M is an indole group; A is the group (-CH2-)n, in which n is 0; B is the group (-CH2-)m, in which m is 0; R3 is -OH and R4 is -NH-SO2-CH3;

(b) a compatible, topically acceptable vehicle for combining said item (a) given above therewith.

2. A composition according to claim 1, wherein and n are both 0, wherein R3 is -OH, and wherein R4 is -NH-SO2-CH3.

3. A composition according to claim 2, wherein M is a phenyl group, wherein R1 and R2 are both methyl groups, and wherein m and n are both the integer 0.

4. A composition according to claim 2, wherein M is an indole group, wherein R1 and R2 are both methyl groups, and wherein m and n are both the integer 0.

5. A composition according to claim 2, wherein n equals the integer 0, m equals the integer 0, R1 is a methyl group, R2 is hydrogen, and M is an indole group.

6. A composition according to claim 1, wherein n equals the integer 0, m equals the integer 0, R3 and R4 are both groups, and M is hydrogen.

7. A composition according to claim 1, wherein said vehicle is a dermatologically acceptable vehicle.

8. A composition according to claim 7. wherein said vehicle is chosen to hinder or reduce systemic absorption of said compound of formula II.

9. A composition according to claim 2, wherein said composition is in a cream, lotion or gel.

10. A composition according to claim 2, wherein said composition is in a spray formulation.

11. A composition according to claim 2, wherein said composition is in a suppository formulation.