Claims
- 1. A process for the preparation of a compound of Formula (I) ##STR35## wherein (1) is a single or double bond;
- (2) R, R.sub.1, and R.sub.2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR.sub.3 wherein R.sub.3 is lower alkyl, C(O)OR.sub.4 wherein R.sub.4 is hydrogen or lower alkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, NR.sub.6 R.sub.7, wherein R.sub.6 and R.sub.7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R.sub.3 wherein R.sub.3 is independently as defined above, NHCHO, NHSO.sub.2 R.sub.3 wherein R.sub.3 is independently as defined above, NHCONHR.sub.4 wherein R.sub.4 is as defined above, hydroxymethyl, halogen, trifluoromethyl, SR.sub.4 wherein R.sub.4 is independently as defined above, or nitro;
- (3) Q is CH.dbd.CH
- (4) X and y are (i) N, (ii) NR.sub.5 wherein R.sub.5 is hydrogen, lower alkyl, ##STR36## wherein R.sub.1 ' and R.sub.2 ' may be the same or different and are hydrogen or lower alkyl, C(O)R.sub.4 wherein R.sub.4 is independently as defined above, cyclolakyl or from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, (iv) S; with the proviso that X and Y cannot both be N, NR.sub.5 O, or S at once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR.sub.5 and that one of X and Y cannot be S at the same time the other of X and Y is NR.sub.5 ;
- (5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)OR.sub.4 wherein R.sub.4 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is, independently, as defined above, CH(R.sub.1 ')CO.sub.2 R.sub.2 ' wherein R.sub.1 ' and R.sub.2 ' are independently as defined above, halogen, trifluoromethyl, ##STR37## wherein R, R.sub.1 and R.sub.2 are independently as defined above, heteroaryl, or heteroaralkyl; which comprises contacting a compound of the formula ##STR38## wherein R, R.sub.1 and R.sub.2 are as defined above and a compound of the formula ##STR39## wherein Z, X and Y are as defined above; and which is in situ dehydrated and decarboxylated to yield a compound of the formula ##STR40## wherein X and y are as defined above and R, R.sub.1, R.sub.2 and Z are also as defined above.
BACKGROUND OF THE INVENTION
This is a divisional of U.S. patent application Ser. No. 032,730 filed Aug. 6, 1987, which is a continuation-in-part of U.S. patent application Ser. No. 910,692, filed Sept. 22, 1986 now abandoned which is a continuation-in-part of U.S. patent application Ser. No. 861,179, filed May 9, 1986 now abandoned.
The present invention is novel styryl pyrazoles and analogs thereof as well as pharmaceutical compositions and methods of use therefor.
Styryl isoxazole derivatives having cardiovascular activity are known. For example, European Patent Application Nos. 34754 and 5192 and German Application No. 2943-405 having Derwent Abstract Nos. 66318 D/37, 84501 B/47 and 34567 D/20, respectively, disclose a compound of the general formula ##STR1## However, the present compounds differ from such references by a completely different side chain from that shown above linked to the phenyl at the 2-position through an ether group in each reference. Further, European Patent Application No. 5186 reviewed by Derwent Abstract No. 844908/47 discloses an intermediate isoxazole of the formula ##STR2## for which no pharmaceutical utility is disclosed.
Pyrazole derivatives having biological, specifically antiinflammatory, activity are found in Belgian Pat. Nos. 819,890 and 844,972 abstracted in Derwent Abstract Nos. 20948W/13 and 09405Y/06, respectively. A similar derivative is disclosed in German Pat. No. 2920941 of Derwent Abstract No. 86535C/49. However, each of these disclosed pyrazole derivatives requires substituents on adjacent carbons of the pyrazole ring.
Specifically excluded from the compounds of the present invention are the compounds of French Pat. No. 2104932 of Derwent Abstract No. 46150T-B useful as hypocholesterolemics, antiinflammatories, analgesics, sedatives, antipyretics, and in some instances diuretics. The compounds of the French Patent generally have the formula ##STR3##
Finally, of lesser interest numerous imidazoles are known having various pharmaceutical activity. For example, U.S. Pat. No. 3812111 and British No. 1,046,248 disclose compounds of general formula ##STR4## respectively wherein the -- represents various substituents. However, the imidazoles are compounds differing from the present invention in that the compounds have a different ring system from the pyrazoles.
Thus, the novel compounds that are the present invention provide activity for use in the treatment of diseases in which 5-lipoxygenase enzyme activity contributes to the pathological condition. For example, the use for the present novel compounds, compositions and methods of use is for allergy, asthma, arthritis, skin disorders, such as psoriasis or acne, inflammation, for example, inflammatory bowel disease or pain, and further, also cardiovascular disorders including infarction, angina, arrhythmias, stroke, migraine, atherosclerosis, ulcers and other conditions particularly benefited by cytoprotective activity. An additional property of the present novel compounds now found to provide usefulness, for example, as sun screens, is absorption of ultraviolet light.
The present invention is a novel compound of the formula (I) ##STR5## and pharmaceutically acceptable salts thereof; wherein (1) is a single or double bond;
(2) R, R.sub.1, and R.sub.2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR.sub.3 wherein R.sub.3 is lower alkyl, C(O)OR.sub.4 wherein R.sub.4 is hydrogen or lower alkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, NR.sub.6 R.sub.7, wherein R.sub.6 and R.sub.7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R.sub.3 wherein R.sub.3 is independently as defined above, NHCHO, NHSO.sub.2 R.sub.3 wherein R.sub.3 is independently as defined above, NHCONHR.sub.4 where R.sub.4 is independently as defined above, hydroxymethyl, halogen, trifluoromethyl, SR.sub.4 wherein R.sub.4 is independently as defined above, or nitro;
(3) Q is (CH.sub.2).sub.n wherein n is an integer of zero to four, ##STR6## wherein R.sub.4 is independently as defined above;
(4) X and Y are (i) N, (ii) NR.sub.5 wherein R.sub.5 is hydrogen, lower alkyl, ##STR7## wherein R.sub.1 ' and R.sub.2 ' may be the same or different and are hydrogen or lower alkyl, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, or (iv) S; with the proviso that X and Y cannot both be N, NR.sub.5, O or S at once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR.sub.5 and that one of X and Y cannot be S at the same time the other of X and Y is NR.sub.5 ;
(5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)OR.sub.4 wherein R.sub.4 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, CH(R.sub.1 ')CO.sub.2 R.sub.2 ' wherein R.sub.1 ' and R.sub.2 ' are independently as defined above, halogen, trifluoromethyl, ##STR8## wherein R, R.sub.1 and R.sub.2 are independently as defined above, heteroaryl, or heteroaralkyl; with the overall proviso that when one of R, R.sub.1, and R.sub.2 is 2-hydroxy, X is O, Y is N and Q is CH.dbd.CH, then Z cannot be H or alkyl; and also with the overall proviso that when R, R.sub.1, and R.sub.2 are hydroxy or lower alkyl, Y and X are N or NH, and n is zero then Z cannot be furyl or phenyl unsubstituted or substituted with halogen, trifluoromethyl, alkyl, alkoxy or NO.sub.2.
The present invention is also a pharmaceutical composition for treating a disease such as allergy, asthma, arthritis, psoriasis, acne, inflammation, pain, or cardiovascular disorders comprising an antiallergic, antiinflammatory, analgesic, or beneficial cardiovascular effective amount of the compound of formula (I) ##STR9## and pharmaceutically acceptable salts thereof; wherein (1) is a single or double bond;
(2) R, R.sub.1, and R.sub.2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR.sub.3 wherein R.sub.3 is lower alkyl, C(O)OR.sub.4 wherein R.sub.4 is hydrogen or lower alkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is independently as defined above wherein R.sub.6 and R.sub.7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R.sub.3 wherein R.sub.3 is independently as defined above, NHCHO, NHSO.sub.2 R.sub.3 wherein R is independently as defined above, NHCONHR.sub.4 wherein R.sub.4 is independently as defined above, hydroxymethyl, halogen, trifluoromethyl, SR.sub.4 wherein R.sub.4 is independently as defined above, or nitro;
(3) Q is (CH.sub.2).sub.n wherein n is an integer of zero to four, ##STR10## wherein R.sub.4 is independently as defined above;
(4) X and Y are (i) N, (ii) NR.sub.5 wherein R.sub.5 is hydrogen, lower alkyl, ##STR11## wherein R.sub.1 ' and R.sub.2 ' may be the same or different and are hydrogen or lower alkyl, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, (iv) S; with the proviso that X and Y cannot both be N, NR.sub.5, O or S at once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR.sub.5 and that one of X and Y cannot be S at the same time the other of X and Y is NR.sub.5 ;
(5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R.sub.3 wherein R.sub.3 is independently as defined above, C(O)OR.sub.4 wherein R.sub.4 is independently as defined above, C(O)R.sub.3 wherein R.sub.3 is independently as defined above, CH(R.sub.1 ')CO.sub.2 R.sub.2 ' wherein R.sub.1 ' and R.sub.2 ' are independently as defined above, halogen, trifluoromethyl, ##STR12## wherein R, R.sub.1, and R.sub.2 are independently as defined above, heteroaryl, or heteroaralkyl; with the overall proviso that when R, R.sub.1, and R.sub.2 are hydroxy or lower alkyl, n is zero, Y and X are N or NH, then Z cannot be furyl or phenyl unsubstituted or substituted with halogen, trifluoromethyl, alkyl, alkoxy or NO.sub.2 and a pharmaceutically acceptable carrier.
The present invention is also a composition of the compound of formula I not including the overall provisos and a carrier from among the carriers known to be for use in combination with a sunscreen.
Further, the invention is a method for treating mammals having at least one of the diseases noted above by administering an amount effective to treat one of the diseases to such mammals a unit dosage form of the pharmaceutical composition as defined above.
Also, the invention is a method of using a compound of formula I; again as defined above but not including the overall provisos, as a sunscreen, for example, in a coating on humans, in paint and the like.
Finally, the present invention is a process of preparing a compound of formula I as defined above.
In the compounds of formula I the term lower alkyl is of one to four carbons, inclusive, and includes methyl, ethyl, propyl, or butyl and isomers thereof.
Halogen includes particularly fluorine, chlorine bromine or iodine.
Aryl is phenyl unsubstituted or substituted by one, two or three substituents of one or more of each of alkyl of one to four carbons, inclusive, OR.sub.4 wherein R.sub.4 is independently as defined above, ##STR13## wherein R.sub.4 is independently as defined above, wherein R.sub.4 is independently as defined above, C(O)OR.sub.4 wherein R.sub.4 is independently as defined above, hydroxymethyl NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are each independently as defined above, or nitro, or halogen.
Aralkyl is an aryl as defined above and attached through an alkylenyl such as methylenyl, ethylenyl, propylenyl, butylenyl and isomers thereof.
Heteroaryl means 2-, or 3-pyrrolyl; 2- or 3-furyl; 2- or 3-thiophenyl; 2-, 4-, or 5-oxazolyl; 2-, 4-, or 5-thiazolyl; 1-, 2-, or 4-imidazolyl, 2-, 3-, or 4-isothiazolyl, 2-, 3-, or 4-isoxazolyl, 1-, 2-, or 3-pyrazolyl, and 2-, 3-, 4-pyridyl.
The compounds of the present invention contemplate compounds having the following ring systems ##STR14## wherein R.sub.5 and Z are as defined above.
When R.sub.5 is hydrogen it is understood the ring system may be represented by the following equilibrium: ##STR15##
The compounds of formula I are useful both in the free base form, in the form of base salts where possible, and in the form of acid addition salts. The three forms are within the scope of the invention. In practice, use of the salt form amounts to use of the base form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, respectively or those derived from bases such as suitable organic and inorganic bases. Examples of suitable inorganic bases for the formation of salts of compounds of this invention include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like.
Salts may also be formed with suitable organic bases. Bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form such salts. These organic bases form a class whose limits are readily understood by those skilled in the art. Merely for purposes of illustration, the class may be said to include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di- and triethanolamine; amino acids such as arginine, and lysine; quanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like. (See for example, "Pharmaceutical Salts," J. Pharm. Sci. 66(1):1-19 (1977).)
The acid addition salts of said basic compounds are prepared either by dissolving the free base of compound I, I' or II in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid or base and isolating the salt by evaporating the solution, or by reacting the free base of compound I, I' or II with an acid as well as reacting compound I, I' or II having an acid group thereon with a base such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of the invention may contain an asymmetric carbon atom. Thus, the invention includes the individual stereoisomers, and the mixtures thereof. The individual isomers may be prepared or isolated by methods known in the art.
Compounds of the present invention that are preferred are of formula I wherein Y is N and X is NH or Y is N and X is O.
The most preferred compounds of the present invention are 5-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole, 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole, and 5-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole.
A physician or veterinarian of ordinary skill readily determines a subject who is exhibiting symptoms of any one or more of the diseases described above. Regardless of the route of administration selected, the compounds of the present invention of the formula I as described in pharmaceutical compositions above are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
The compounds can be administered in such oral unit dosage forms as tablets, capsules, pills, powders, or granules. They also may be administered rectally or vaginally in such forms as suppositories or bougies; they may also be introduced parenterally (e.g. subcutaneously, intravenously, or intramuscularly), using forms known to the pharmaceutical art. They are also introduced directly to an affected area (e.g., in the form of eye drops or by inhalation). For the treatment of asthma or allergies, particularly dermatological disorders; such as erythema, psoriasis and acne, the compounds may also be administered topically in the form of ointments, gels, or the like. However, in general, the preferred route of administration is orally.
An effective but nontoxic quantity of the compound is employed in treatment. The ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount of the compound to prevent or arrest the progress of the condition for which treatment is administered. In so proceeding, the physician or veterinarian could employ relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained.
Initial dosages of the compounds of formula I of the invention in pharmaceutical compositions are ordinarily in the area of 10 mg up to 2 grams per day orally, preferably 10 mg to 500 mg per dose orally given one to four times daily or as needed. When other forms of administration are employed equivalent doses are administered.
Additionally, the present invention is compositions comprising the compounds of formula I, for use as sunscreens, having a suitable carrier therefor.
The ultraviolet absorbing properties of the compounds of the present invention is generally shown by a comparison with p-aminobenzoic acid which is the active ingredient in most commercial sunscreens. Such properties are within the ultraviolet absorbing ranges of 260 to 300 nM range critical to effectiveness. A representative compound of the invention is compared to p-aminobenzoic acid in the following Table.
The methods of preparation for the compounds of the present invention may, generally, be accomplished in a manner according to the definition of X and Y.
For example, generally compounds of formula I wherein X and Y are each N or NR are prepared in a manner shown by Scheme I as follows: ##STR16## wherein R, R.sub.1, R.sub.2, R.sub.5 and Z are as defined above.
In Step 1 of Scheme I equimolar parts of hydrazine hydrate and a compound of the formula III wherein R, R.sub.1, R.sub.2 and Z are as defined above are combined in a solvent such as 1 part ethanol and 1 part butanol, or 2-propanol, and the like. A small amount of about 0.1 ml to 10 ml preferably 0.5 ml of acetic acid is added with the hydrazine hydrate. Optionally, the step 1 product of formula I.sub.1 is further reacted as shown in step II with a compound MR.sub.5 wherein M is an electrofuge such as halogen, sulfonate, or the like and R.sub.5 is as defined above but other than hydrogen to obtain a mixture of the compound of formual I.sub.1 ' and I.sub.1 " wherein R, R.sub.1, R.sub.2, R.sub.5 when not hydrogen and Z are as defined above. The compounds I.sub.1 ' and I.sub.1 " may be separated by conventional means.
Similarly compounds of formula I wherein X and Y are each N or NR.sub.5 wherein Q is CH.sub.2 and n is 1 can be prepared according to the following Scheme Ia using analogous conditions as provided above for Scheme I. ##STR17##
Further, the compounds of formula I.sub.2 ' are prepared as shown in the following Scheme II and IIa. ##STR18## wherein X and Y are O or N and S or N. ##STR19##
Triphenylphosphonium halide; preferably chloride, of the formula II.sub.2 or II.sub.2a are contacted by an excess of a compound of the formula III.sub.2 or III.sub.2a in a solvent such as dimethylsulfoxide, toluene, or the like to which an equivalent amount of potassium t-butoxide is added. The mixture is stirred at about room temperature for from 10 minutes to 2 hours or more under an inert atmosphere. A compound of formula I.sub.2 ' or I.sub.2a ' is obtained wherein R, R.sub.1, R.sub.2 and Z are as defined above and Y and X are each either N or O and N or S, respectively.
Mild hydrogenation by conventional methods by an ordinarily skilled artisan may be carried out to provide a compound of formula I.sub.2 " wherein R, R.sub.1, R.sub.2 and Z are as defined and Y and X are O or N and S or N, respectively.
Additionally, for compounds wherein Z is defined such that the two substituents on the heterocyclic ring of formula ##STR20## are the same, the compounds may be prepared according to the following Scheme III. ##STR21## wherein Z is ##STR22## and wherein R, R.sub.1, R.sub.2, and Q are as defined above and Y and X are either O and N or N and O.
The conditions of the reaction in Scheme III are, generally, carried out with equimolar parts of the compound of formula III.sub.3 and hydroxylamine hydrochloride in a solvent such as methanol, ethanol and the like in the presence of a buffer such as sodium acetate at reflux temperature until completion as determined by TLC. ##STR23## wherein R, R.sub.1, R.sub.2, and Z are as defined above.
The conditions of the synthesis in Scheme IV step 1 are, generally, carried out in a manner analogous to those described by C. Kashima et al, Bull. Chem. Soc. Japan, 46, 310 (1973) and C. Kashima et al, Heterocycles, 6, 805 (1977). Unexpectedly the step 2 dehydration when R.sub.4 is H or alkyl and also further decarboxylation when R.sub.4 is H are carried out in a one pot reaction together with step 1. Conditions for step 2 are analogous to those known in the art and, thus, within the ordinary artisan's skill. ##STR24##
The conditions of the above Scheme V are analogous to those described by M. Nitta, J. Chem. Soc. Chem. Commun., 877, 1982.
Finally, conditions analogous to those described in copending application PD-3493 U.S. Ser. No. 851,003, filed Apr. 11, 1986 are useful in step 1 of Scheme VI below. Step 2 of Scheme VI is carried out using anhydrous conditions in an inert solvent at about the temperature of 0.degree. to 50.degree. C. for from 90 min to 18 hours. ##STR25##
The compounds in Scheme VII are compounds wherein R, R.sub.1, R.sub.2 and Z are as defined above for compounds of formula III.sub.3 ' and III.sub.3 " but III.sub.1 ' and III.sub.1 " are symmetrical.
An alternate preparation for the compounds of formula III.sub.3 is as found in Scheme VIII as follows: ##STR26##
Finally, the compound of formula II.sub.2 as shown in Scheme II above can be prepared by the following method. ##STR27##
Under certain circumstance it is necessary to protect either the N or O of intermediates in the above noted process with suitable protecting groups which are known. Introduction and removal of such suitable oxygen and nitrogen protecting groups are well-known in the art of organic chemistry; see for example "Protective Groups in Organic Chemistry," J. F. W. McOmie, ed. (New York, 1973), pages 43ff, 95ff, J. F. W. McOmie, Advances in Organic Chemistry, Vol. 3, 191-281 (1963); R. A. Borssonas, Advances in Organic Chemistry, Vol. 3, 159-190 (1963); and J. F. W. McOmie, Chem & Ind., 603 (1979).
Examples of suitable oxygen protecting groups are benzyl, t-butyldimethylsily, ethoxyethyl, and the like. Protection of an N-H containing moiety is necessary for some of the processes described herein for the preparation of compounds of this invention. Suitable nitrogen protecting groups are benzyl, triphenylmethyl, trialkylsilyl, trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, and the like.
Under certain circumstances it is necessary to protect two different oxygens with dissimilar protecting groups such that one can be selectively removed while leaving the other in place. The benzyl and t-butyldimethylsilyl groups are used in this way; either is removable in the presence of the other, benzyl being removed by catalytic hydrogenolysis, and t-butyldimethylsilyl being removed by reaction with, for example, tetra-n-butylammonium fluoride.
In the process described herein for the preparation of compounds of this invention the requirements for protective groups are generally well recognized by one skilled in the art of organic chemistry, and accordingly the use of appropriate protecting groups is necessarily implied by the processes of the charts herein, although not expressly illustrated.
The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like.
Starting materials not described herein are available commercially, are known, or can be prepared by methods known in the art.
The salts of the compounds of formula I described above are prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compounds of formula I, respectively, to obtain pharmaceutically acceptable salts thereof.
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Date |
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Divisions (1)
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Number |
Date |
Country |
| Parent |
32730 |
Apr 1987 |
|
Continuation in Parts (2)
|
Number |
Date |
Country |
| Parent |
910692 |
Sep 1986 |
|
| Parent |
861179 |
May 1986 |
|
Patent Grant
4877881
