Cardioprotective agents

This invention relates to certain hydroxy derivatives of 3,4-dihydro-2,5,7,8-tetraalkyl-2H-1-benzopyran-2-carboxylic acids and the lactones thereof, to the processes and intermediates useful for their preparation and to their use as free radical scavengers useful in the treatment of tissue damage implicated with free oxygen radicals.

This application is a 371 of PCT/U.S. Pat. No. 93/02102 filed Mar. 8, 1993. 
This invention relates to certain hydroxy derivatives of 
3,4-dihydro-2,5,7,8-tetraalkyl-2H-l-benzopyran-2carboxylic acids and the 
lactones thereof, to the processes and intermediates useful for their 
preparation and to their use as free radical scavengers useful in the 
treatment of tissue damage implicated with free oxygen radicals. 
More particularly, this invention relates to compounds of the formulae 
##STR1## 
their individual isomers and mixtures thereof, and the pharmaceutically 
acceptable salts thereof wherein 
R is H or C.sub.1-4 alkyl, 
R.sub.1 is C.sub.1-4 alkyl, 
R.sub.2 is H or C(O)R.sub.3, 
R.sub.3 is H or C.sub.1-9 alkyl, 
R.sub.4 is OR or N(R).sub.2, 
R.sub.5 is H, --C(O)R or C.sub.1-4 alkyl, and 
n is zero or one. 
As used herein the term alkyl includes the straight and branched-chain 
radicals having the designated number of carbon atoms with methyl and 
ethyl being preferred. The --C(O)R.sub.3 moiety embraces formyl and the 
straight and branched-chain alkylcarbonyl moieties with formyl, 
methylcarbonyl and ethylcarbonyl being preferred. In the instance wherein 
R.sub.4 forms an amide it is preferred that both alkyl groups be the same 
and that the alkyl radicals are methyl or ethyl in both mono- or 
di-alkylated amido situations. When variables such as R are used more than 
once to define a structure, it is to mean that in each instance the 
variable may represent a different moiety. 
The compounds of the present invention include stereoisomers; the term 
"stereoisomer" is a general term for all isomers of individual molecules 
that differ only in the orientation of their atoms in space. It includes 
mirror image isomers (enantiomers), geometric isomers (cis/trans), and 
isomers of compounds with more than one chiral center that are not mirror 
images of one another (diastereoisomers). 
In general the compounds of Formulae 1A and 1B (collectively referred to as 
compounds of Formula 1) may be prepared, isolated and converted to the 
desired salts by chemical processes, work-up and crystallization 
techniques analogously known in the art. Conveniently, the starting 
materials are either known or may be prepared by standard procedures. 
The preparation of the compounds of Formula I may be schematically depicted 
in the following reaction schemes A and B. 
##STR2## 
wherein R and R.sub.1 are as previously defined an Ac is the preferred 
acyl moiety. 
In this reaction sequence the acids (2) are sequentially esterified and 
acetylated to produce compounds (3) which are dehydrogenated, using a 
reagent such as DDQ (2,3-dichloro5,6-dicyano-1,4-benzoquinone) to the 
intermediate (4). Cis-dihydroxylation with a reagent such as osmium 
tetroxide gives the lactones (6) and the dihydroxyesters (5). Both can be 
hydrolyzed to the dihydroxy acids (9) (in which the hydroxy groups are 
cis- to each other) but only one can relactonize to (10). Starting with 
resolved (2), i.e., the R- or S-enantiomers of (2), two of the four 
possible enantiomers of (10), and four of the eight possible enantiomers 
of (9) can be obtained. Trans-dihydroxylation with a reagent such as 
dimethyldioxirane gives the lactones (7) and dihydroxyesters (8) which, 
analogously give the remaining enantiomers of (9) and (10). 
Similarly, as shown in Reaction Scheme B, starting from the homologous 
acids (11) the foregoing process technique of Reaction Scheme A gives the 
.delta.-lactones (12) and the dihydroxy acids (13). Cis- and 
trans-dihydroxylation of the amides (14) gives the dihydroxy amides (15); 
the amides being derived by hydrolysis and amidation of compounds (4) or 
amidation of compounds (11). 
##STR3##

The following examples illustrate the details and techniques for the 
preparation of the compounds of this invention. 
EXAMPLE 1 
METHYL (2-R,S)-ACETYLOXY-2,5,7,8-TETRAMETHYL-2-H-1-BENZOPYRAN-2-CARBOXYLATE 
A solution of 100 g of 
(2-R,S)-3,4-dihydro-6-hydroxy2,5,7,8-tetramethyl-2-H-1-benzopyran-2-carbox 
ylic acid and 1 g of p-toluene sulfonic acid in 700 ml of dry methanol is 
stirred at reflux temperature for 20 hours. About 400 ml of methanol is 
evaporated and residue is allowed to cool for crystallization. The ester 
is collected, washed with a little methanol, and dried. 
The ester is dissolved in 500 ml of pyridine, 250 ml of acetic anhydride is 
added and the resulting solution is stirred overnight at room temperature. 
Addition of water and ice results in precipitation of the acetate that is 
collected, washed with water, and dried at 80.degree. C. and 0.1 mm 
pressure in the presence of phosphorous pentoxide. The product can be 
recrystallized from a mixture of ethyl acetate and heptane. 
To this ester acetate is added 1.1 equivalent (99.93 g) of 
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in 600 ml of toluene and 
the mixture is stirred at reflux temperature for 24-48 hours. The mixture 
is allowed to cool, is filtered to remove solids, and is passed through a 
column filled with activated alumina to remove colored material. This 
process may have to be repeated to remove all color. The eluate is 
evaporated and the residue is recrystallized from a mixture of toluene and 
heptane, to give 57.32 of the title compound. The NMR spectrum in 
CDCl.sub.3 shows two doublets at .delta. (vs. TMS) 5.70 and 6.56 ppm with 
a coupling constant J=7 Hz, confirming the structure. 
EXAMPLE 2 
METHYL 
2S-(-)-6-ACETYLOXY-2,5,7,8-TETRAMETHYL-2-H-1-BENZOPYRAN-2-CARBOXYLATE 
To a hot solution of 78.07 g (311.9 mmol) of 
(2-R,S)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-carbox 
ylic acid in 400 ml of 2-propanol is added 37.80 g (311.9 mmol) of 
S-(-)-.alpha.-methylbenzylamine and the solution is allowed to cool slowly 
in a refrigerator over several days. The resulting crystals of 
diastereomeric salt are collected and recrystallized 3 times from 
2-propanol, again taking care slow crystallization occurs each time. The 
resulting product (45.13 g, 39%, m.p. 149.degree.-50.degree. C.) is 
suspended in 400 ml of water, 100 ml of 2N HCl is added, and the acid is 
extracted with ethyl acetate. The extract is dried over sodium sulfate, 
filtered, and evaporated to give 30.40 g (39%) of the S-(-)-enantiomer, 
m.p. 157.degree.-9.degree. C., .alpha.!.sub.D.sup.25 =-71.26 (c=1.03 in 
CH.sub.3 OH). 
This product is esterified, acetylated and dehydrogenated with DDQ as 
described in Example 1 to give the title compound, .alpha.!.sub.D.sup.25 
=-246.86 (c=1.05 in CH.sub.3 OH). 
EXAMPLE 3 
METHYL2R-(+)-6-ACETYLOXY-2,5,7,8-TETRAMETHYL-2-H-1-BENZOPYRAN-2-CARBOXYLATE 
The combined filtrates from crystallization and recrystallization of the 
diastereomeric salt from Example 2 are evaporated and converted to free 
acid, 46.68 g (60%). To this residue is added 22.60 g (186.5 mmol) of 
R-(+)-.alpha.-methylbenzylamine in 2-propanol and, after slow 
crystallization and 2 recrystallizations, 48.78 g of diastereomeric salt, 
m.p. 149.degree.-50.degree. C. (mixed melting point depressed to 
112.degree.-124.degree. C.), is obtained and converted to free acid, m.p. 
157.degree.-9.degree. C., .alpha.!.sub.D.sup.25 =+73.75 (c=1.04 in 
CH.sub.3 OH) 
This product is esterified, acetylated, and dehydrogenated with DDQ as 
described in Example 1 to give the title compound, .alpha.!.sub.D.sup.25 
=-217.31 (c=1.04 in CH.sub.3 OH). 
EXAMPLE 4 
10-ANTI-(.+-.)-7-ACETYLOXY-2,3,-DIHYDRO-10-HYDROXY-2,6,8,9 
-TETRAMETHYL-2,5-METHANO-5-H-1,4-BENZODIOXEPIN-3-ONE 
To 24.07 g (176.8 mmol) of N-methylmorpholine N-oxide monohydrate in 200 ml 
of water and 100 ml of acetone is added 5 ml of a 2.5% (w/v) solution of 
osmium tetroxide in t-butanol and the solution is stirred for 30 minutes. 
To this solution is added dropwise over 5-7 hours a solution of 51.24 g 
(168.4 mmol) of methyl 
(2-R,S)-6-acetoxy-2,5,7,8-tetramethyl-2-H-1-benzopyran-2-carboxylate, 
described in Example 1, in 350 ml of acetone. The mixture is stirred at 
room temperature overnight and at reflux temperature for 6 hours. After 
allowing the mixture to cool, a solution of 4 g of sodium bisulfite in 50 
ml of water is added, and the mixture is stirred for 30 minutes, filtered 
through supercel and evaporated. During all these manipulations, care 
should be taken to avoid contact with the very poisonous osmium salts that 
should also be properly disposed of. The residue is acidified with dilute 
sulfuric acid and is extracted twice with ethyl acetate. The extract is 
washed with dilute sulfuric acid, water and a saturated sodium bicarbonate 
solution, dried over sodium sulfate, filtered and evaporated to give 48.57 
g of an oil. Crystallization from ethyl acetate/heptane gives 38.81 g of 
material that was recrystallized to give 17.62 g of the title compound and 
15.71 g of a second crop, described in the next example. Recrystallization 
of the first crop gives a pure sample of the title compound, m.p. 
210.degree.-11.degree. C., UV (CH.sub.3 CN): .lambda..sub.max 289 
(.epsilon.=1925), 282 (sh), 224 (sh), 206 (47,266); IR (KBr) 1762 
cm.sup.-1 ; .sup.1 H-NMR (DMSO); .delta.(ppm vs TMS) 6.49 (1, s, OH), 5.54 
(1, s, 5-H), 4.43 (1, s, 10-H), 2.38 (3, s, COCH.sub.3), 2.18 (3, S, 
Ar--CH.sub.3), 2.14 (3, s, Ar--CH.sub.3), 2.09 (3, s, Ar--CH.sub.3), 1.69 
(3, s, 2--CH.sub.3). 
EXAMPLE 5 
METHYL TRANS, 
CIS-(.+-.)-6-ACETYLOXY-3,4-DIHYDRO-3,4-DIHYDROXY-2,5,7,8-TETRAMETHYL2H-1-B 
ENZOPYRAN-2-CARBOXYLATE 
The second crop of the material obtained in the preceding example consists 
of two compounds, as indicated by thin layer chromatography, that can be 
separated by chromatography on silica gel, using mixtures of heptane and 
ethyl acetate, 3:1 and 2:1, for elution. One is the compound described in 
Example 4, the other is the title compound. 
EXAMPLE 6 
10-ANTI-(.+-.)-2,3DIHYDRO-7,10DIHYDROXY-2,6,8,9-TETRAMETHYL-2,5-METHANO-5-H 
-1,4-BENZODIOXEPIN-3-ONE 
To a solution of 17.62 g of the 7-acetate of the title compound described 
in Example 4, in 200 ml of methanol under nitrogen is added 100 ml of 2N 
NaOH. The mixture is stirred at reflux temperature for 2 hours, cooled, 
acidified with 2N HCl and extracted three times with ethyl acetate. The 
extract is washed with water and twice with a sodium bicarbonate solution, 
dried over sodium sulfate, filtered and evaporated. The bicarbonate washes 
are acidified and reextracted with ethyl acetate to give, after drying and 
evaporation, acidic product. This is slurried in anhydrous ethyl ether to 
which gaseous HCl is added. After standing at room temperature overnight, 
solvent and gas are evaporated, the residue is taken up in ethyl acetate 
and is washed with a bicarbonate solution, dried, and evaporated. The two 
fractions of non-acidic product thus obtained may require purification by 
chromatography before recrystallization from ethyl acetate/heptane to 
obtain the title compound, m.p. 179.degree.-81.degree. C. UV (CH.sub.3 
CN).lambda..sub.max 298 nm (.epsilon.=3322), 229 (sh), 206 (39123); IR 
(KBr) 1766 cm.sup.-1 ; .sup.1 H-NMR (CD.sub.3 OD).delta. (ppm vs TMS) 5.37 
(1, s, 5-H),4.23 (1, s, 10H). 
EXAMPLE 7 
TRANS, 
CIS-(.+-.)-3,4-DIHYDRO-3,4,6-TRIHYDROXY-2,5,7,8-TETRAMETHYL-2-H1-BENZOPYRA 
N-2-CARBOXYLIC ACID 
The 6-acetate methyl ester of the title compound, described in Example 5, 
is stirred with 1N 50% methanolic NaOH under nitrogen for 5 hours at 
reflux temperature. After cooling, the solution is acidified with 2N HCl 
and extracted with ethyl acetate. The extract is washed with water and 
twice with a sodium bicarbonate solution. The bicarbonate washes are 
acidified, saturated with sodium chloride and extracted 4 times with ethyl 
acetate. After drying over sodium sulfate, filtration and evaporation of 
solvent, an oil is obtained that crystallizes from ethyl acetate/heptane 
to give the title compound. UV (CH.sub.3 CN).epsilon..sub.max 295 nm 
(.epsilon.=3802), 223 (sh), 201 (35620); IR (KBr) 1717 cm.sup.-1 ; .sup.1 
H-NMR (D.sub.2 O).delta. (ppm vs TMS) 4.78 (1, s, 4-H), 4.32 (1, s, 3-H), 
2.19-2.22 (9, 3s, Ar--CH.sub.3), 1.70 (3, s, 2--CH.sub.3). 
EXAMPLE 8 
10-ANTI-(+)-(2S, 5R, 
10R)-7-ACETYLOXY-2,3,-DIHYDRO-10HYDROXY-2,6,8,9-TETRAMETHYL-2,5-METHANO-5- 
H-1,4-BENZODIOXEPIN-3-ONE 
Starting with 12.18 g of the 2S-enantiomer described in Example 2 and 
utilizing the procedure described in Example 4, 11.98 g of crude product 
is obtained. Crystallization from 40 ml of ethyl acetate gives 2.49 g of 
product. Chromatography of the filtrate on silica gel (elution with ethyl 
acetate/heptane: 1/2) gives a fraction containing an additional 3.7 g of 
the same product and recrystallization of the combined product from ethyl 
acetate/heptane gives 5.01 g (41%) of the title compound, m.p. 
201.degree.-5.degree. C., .alpha.!.sub.D.sup.25 =+58.92 (c=1.02 in 
CH.sub.3 OH). UV, IR, and .sup.1 H-NMR correspond to those of the racemic 
compounds described in Example 4. 
EXAMPLE 9 
10-ANTI-(+)-(2S, 5R, 10R)-2,3-DIHYDRO-7,10 -DIHYDROXY 
2,6,8,9TETRAMETHYL-2,5-METHANO-5-H-1,4BENZODIOXEPIN-3ONE 
The 7-acetate of the title compound, described in the preceding example is 
hydrolyzed and relactonized by the procedure described in Example 6 to 
give the title compound, m.p. 172.degree.-3.degree. C., 
.alpha.!.sub.D.sup.25 =+63.24 (c=1.05 in CH.sub.3 OH). UV, IR, and .sup.1 
H-NMR correspond to those of the racemic compound, described in Example 6. 
EXAMPLE 10 
10-ANTI-(-)-(2R, 5S, 10S)-7-ACETYLOXY-2,3, 
-DIHYDRO-10-HYDROXY-2,6,8,9-TETRAMETHYL-2,5-METHANO-5-H-1,4-BENZODIOXEPIN- 
3-ONE 
The antipode of the compound described in Example 8 is obtained in 50% 
yield by the same procedure but starting from the R-enantiomer described 
in Example 3. m.p. 210.degree.-1.degree. C., .alpha.!.sub.D.sup.25 
=-63.32 (c=1.15 in CH.sub.3 OH). UV, IR, and .sup.1 H-NMR spectra 
correspond to those of the (+)-enantiomer and the racemate, described in 
Example 4. 
EXAMPLE 11 
CIS, CIS-(+)(2R, 3S, 
4S)-3,4-DIHYDRO-3,4,6-TRIHYDROXY-2,5,7,8TETRAMETHYL-2-H-1BENZOPYRAN-2-CARB 
OXYLIC ACID 
To 3.06 g (1 mmol) of the lactone acetate described in the preceding 
example, in 50 ml of methanol under nitrogen is added 50 ml of 2N sodium 
hydroxide and the mixture is heated to reflux temperature for 20 minutes 
The resulting solution is cooled, acidified with 60 ml of 2N hydrochloric 
acid, and concentrated to remove methanol. The remaining aqueous solution 
is extracted four times with ethyl ether and extract washed with a sodium 
bicarbonate solution. The aqueous phase is combined with the bicarbonate 
washes, carefully acidified with a minimum of 2N hydrochloric acid, 
saturated with sodium chloride, and extracted four times with ethyl 
acetate. The extract is dried over sodium sulfate, filtered and evaporated 
to give 2.87 g of the title compound, m.p. 115.degree. C. 
(dec.), .alpha.!.sub.D.sup.25 =+57.45.degree.(c=1.02 in MeOH). UV 
(CH.sub.3 CN).epsilon..sub.max 295 nm (.lambda.=3530), 225 (sh), 204 
(35820); IR (KBr) 1718 cm.sup.-1 ; .sup.1 H-NMR (DMSO) .delta. (ppm vs 
TMS) 4.67 (1, d, J =3.8, 4-H), 3.82 (1, d, J =3.8, 3-H), 2.1-2.2 (9, 3s, 
Ar--CH.sub.3), 1.62 (3, s, 2--CH.sub.3); Anal.: C, H. The NMR spectrum 
indicates that the compound contains about 10% of the lactone described in 
the next example. 
EXAMPLE 12 
10-ANTI-(-)-(2R,5S,10S)-2,3-DIHYDRO-7,10-DIHYDROXY-2,6,8,9-TETRAMETHYL-2,5- 
METHANO-5-H1,4-BENZODIOXEPIN-3-ONE 
The crystallization mother liquor, obtained in the preceding example, is 
evaporated, suspended in anhydrous ethyl ether, and gaseous hydrogen 
chloride is bubbled in. The mixture is allowed to stand at room 
temperature overnight and is evaporated. The residue is taken up in ethyl 
acetate, washed with a sodium bicarbonate solution, dried over sodium 
sulfate, filtered, and evaporated. Crystallization from ethyl 
acetate/heptane gives 530 mg of the title compound, m.p. 
171.degree.-2.degree. C., .alpha.!.sub.D.sup.25 =-68.63.degree. (c=1.02 
in CH.sub.3 OH). UV, IR and .sup.1 H-NMR spectra correspond to those of 
the enantiomer described in Example 9, and the racemic compound of Example 
6. 
EXAMPLE 13 
10-SYN-(+)-(2S,5S,10R)-7ACETYLOXY-2,3-DIHYDRO-10HYDROXY-2,6,8,9-TETRAMETHYL 
-2,5-METHANO-5-H-1,4-BENZODIOXEPIN-3ONE 
An approximately 0.1 M solution of dimethyldioxirane in acetone is obtained 
by adding 250 g of potassium peroxymonosulfate (oxone.sup.R) in portions 
to a stirred suspension of 120 g of sodium bicarbonate in 200 ml of water 
and 140 ml of acetone under a partial vacuum of about 150 mm and 
collecting the distillate in a dry ice-acetone-cooled trap. This solution 
(100-120 ml) is added to 3.04 g (1 mmol) of methyl 
2S-(-)-6-acetyloxy-2,5,7,8-tetramethyl-2-H1-benzopyran-2-carboxylate 
(described in Example 2) in 50 ml of acetone and the mixture is stirred at 
room temperature for 2 hours. The solution is dried over magnesium 
sulfate, filtered, and evaporated to dryness at room temperature under 
reduced pressure to give 3.74 g of the crude epoxide, that is quite 
unstable, and to which is added immediately 1.96 g of anhydrous potassium 
acetate and 20 ml of acetic acid. The mixture is heated to reflux 
temperature for 1 hour, evaporated to dryness, and taken up in ethyl 
ether. The resulting solution is washed with water, a saturated sodium 
bicarbonate solution, and a saturated sodium chloride solution, filtered 
and evaporated to give 2.96 g of an oil. Chromatography on silica gel in 
ethyl acetate/hexane:1/2, gives several fractions, one of which (2.36 g) 
is recrystallized from ethyl acetate/hexane to give the title compound, 
m.p. 200.degree.-201.degree. C. .alpha.!.sub.D.sup.25 =+78.04 (c=1.02 in 
CH.sub.3 OH). UV(CH.sub.3 CN).epsilon..sub.max 289 nm (.epsilon.=2037), 
283 (sh), 224 (sh), 206 (42685); IR (KBr) 1798, 1734 cm.sup.-1 ; .sup.1 
H-NMR (DMSO), .delta. (ppm vs TMS) 6.30 (1, m, OH), 5.67 (1, d, J =6 Hz, 
5-H), 4.44 (1, dd, J.sub.1 =4, J.sub.2 =6 Hz, 10-H), 2.43 (3, s, 
COCH.sub.3), 2.07-2.17 (9, 3s, Ar--CH.sub.3), 1.62 (3, s, 2--CH.sub.3). 
EXAMPLE 14 
TRANS, 
TRANS-(-)-(2S,3R,4R)-3,4-DIHYDRO-3,4,6-TRIHYDROXY-2,5,7,8-TETRAMETHYL-2-H- 
1-BENZOPYRAN-2-CARBOXYLIC-ACID 
To a solution of 460 mg (1.5 mm) of the lactone acetate described in the 
preceding example in 10 ml of methanol under nitrogen is added 10 ml of 2 
N NaOH and the mixture is heated to reflux temperature for 30 minutes. The 
solution is cooled, acidified with 15 ml of 2 N HCl, and concentrated to 
remove methanol. The residue is saturated with sodium chloride and 
extracted twice with ethyl acetate. The extract is dried over sodium 
sulfate, filtered and evaporated. Crystallization of the residue from 
ethyl acetate/hexane gives 270 mg of the title compound 
.alpha.!.sub.D.sup.25 =-41.88.degree. (c=1.01 in H.sub.2 O, pH=3.20). UV 
(H.sub.2 O).lambda..sub.max 292 nm (.epsilon.=3441), 221 (11197); IR (KBr) 
1741 cm.sup.-1 ; .sup.1 H-NMR(DMSO), .epsilon. (ppm vs TMS) 4.48 (1, d, 
J=2.5 Hz, 4-H), 4.09 (1, d, J=2.5 Hz, 3-H). 
EXAMPLE 15 
10-SYN-(+)-(2S,5R,10S)-2,3DIHYDRO-7,10-DIHYDROXY-2,6,8,9-TETRAMETHYL-2,5-ME 
THANO-5-H-1,4-BENZODIOXEPIN-3ONE 
Treatment of 1.18 g of the acid described in the preceding example with 
ethereal hydrogen chloride, as described in Example 12, gives the title 
compound, m.p. 185.degree. C., .alpha.!=+93.55.degree. (c=1.07 in 
CH.sub.3 OH). UV (CH.sub.3 CN) .lambda..sub.max 298 nm (.epsilon.=3567), 
224 (sh), 206 (39200); IR(KBr) 1763 cm.sup.-1 ; .sup.1 H-NMR(CD.sub.3 OD), 
.epsilon. (ppm vs TMS) 5.49 (1d, J=4.5, 5-H), 4.21 (1, d, J=4.5, 10-H); 
MS: MH.sup.+ =265. 
EXAMPLE 16 
10-SYN-(-)-(2R,5S,10R)-7-Acetyloxy-2,3DIHYDRO-10 
-HYDROXY-2,6,8,9-TETRAMETHYL-2,5-METHANO-5-H-1,4-BENZODIOXEPIN-3ONE 
Following the procedure described in Example 13, but starting from the 
2R-(+)-enantiomer described in Example 3, the title compound is obtained, 
m.p. 203.degree.-4.degree. C., .alpha.!.sub.D.sup.25 =-81.27 (c=0.95 in 
CH.sub.3 OH). UV, IR and .sup.1 H-NMR spectra correspond to those of the 
enantiomer described in Example 13. 
EXAMPLE 17 
METHYL CIS, TRANS-(2R,3R,4R) 
-4,6-DIACETYLOXY-3,4-DIHYDRO-3-DIHYDROXY-2,5,7,8-TETRAMETHYL2-H1-BENZOPYRA 
N-2-CARBOXYLATE 
In the reaction described in the preceding example, a second product is 
obtained, which is assigned the structure of the title compound on the 
basis of the NMR spectrum. .sup.1 H-NMR (CDCl.sub.3) .delta. (ppm vsTMS) 
5.83 (1, d, J=2.9 Hz, 4-H), 4.29 (1, m, 3-H), 2.67 (3, s, OCH.sub.3), 2.32 
(3, s, COCH.sub.3), 2.22 (3, s, COCH.sub.3) 1.92-2.08 (9, 3s, ArCH.sub.3), 
1.70 (3, s, 2--CH.sub.3); m.p. 180.degree. C. 
EXAMPLE 18 
METHYL CIS, 
TRANS-(2R,3R,4R)-6-ACETYLOXY-3,4-DIHYDRO-3,4-DIHYDROXY-2,5,7,8-TETRAMETHYL 
-2-H1-BENZOPYRAN-2-CARBOXYLATE 
An 0.1 M solution of dimethyldioxirane in acetone (60 ml), prepared as 
described in Example 13, is added to 1.37 g (4.5 mmol) of 2R-(+)-olefine 
(Example 3) in acetone. The mixture is stirred at room temperature for 1.5 
hours to form the epoxide. Five drops of water and about 0.2 g of silica 
gel are added to the solution and stirring is continued overnight. The 
main product, as indicated by thin layer chromatography, is isolated by 
chromatography, 0.83 g, and is recrystallized from ethyl acetate/hexane. 
MS: MNH.sub.4.sup.+ =356; .sup.1 H-NMR (CDCl.sub.3) .delta. (ppm vs TMS) 
4.70 (1, d, J=2.9, 4-H), 4.18 (1, m, 3-H), 3.67 (3, s, OCH.sub.3), 2.33 
(3, s, COCH.sub.3), 2.05-2.13 (9, 3s, Ar--CH.sub.3), 1.70 (3, s, 
2--CH.sub.3). 
EXAMPLE 19 
TRANS, TRANS-(+)-(2R,3S,4S)-3,4-DIHYDRO-3,4,6 
-TRIHYDROXY-2,5,7,8-TETRAMETHYL-2-H-1-BENZOPYRAN-2-CARBOXYLIC ACID 
The lactone acetate described in Example 16 is hydrolyzed with 1N 50% 
methanolic NaOH, as described in Example 14 to obtain the title compound, 
.alpha.!.sub.D.sup.25 =+34.6 (c =0.77 in CCl.sub.3 /CH.sub.3 OH: 2/1). 
UV, IR and .sup.1 H-NMR spectra correspond to those of the enantiomer 
described in Example 14. 
EXAMPLE 20 
10-SYN-(-)-(2R,5S,10R)-2,3DIHYDRO-7,10-DIHYDROXY-2,6,8,9-TETRAMETHYL-2,5-ME 
THANO-5-H-1,4-BENZODIOXEPIN-3-ONE 
A solution of 1.22 g of the acid described in the preceding example in 70 
ml of toluene containing 0.1 g of p-toluenesulfonic acid is refluxed for 1 
hour. After cooling and addition of some ethyl acetate, the solution is 
washed with a sodium bicarbonate solution, dried over sodium sulfate, 
filtered and evaporated to give 0.77 g of oil. Crystallization from ethyl 
acetate/hexane gives the title compound, m.p. 178.degree. C., 
.alpha.!.sub.D.sup.25 =-83.8.degree. (c=0.933 in CH.sub.3 OH). UV, IR and 
.sup.1 H-NMR spectra correspond to those of the enantiomer described in 
Example 15. 
EXAMPLE 21 
11-SYN-(.+-.)-8-ACETYLOXY-2,3,4,6-TETRAHYDRO-11-HYDROXY-2,7,9,10-TETRAMETHY 
L-2,6-METHANO-1,5-BENZODIOXOCIN-4-ONE 
Following the procedure described in Example 1, (2R, 
S)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid 
is esterified, acetylated, and dehydrogenated with DDQ to give methyl 
((2R, S)-6-acetyloxy-2,5,7,-tetra-methyl-2H-l-benzopyran-2-acetate, .sup.1 
H-NMR (CDCl.sub.3) .delta. (ppm vsTMS) 6.52 (1, d, J=10, 4-H), 5.72 (1, d, 
J=10, 3-H), 3.61 (3, s, OCH.sub.3), 2.68 (2, s, COCH.sub.2), 2.31 (3, s, 
COCH.sub.3), 2.02-2.10 (9, 3s, ArCH.sub.3), 1.56 (3, s, 2--CH.sub.3). 
Cis-hydroxylation with osmium tetroxide, as described in Example 4, gives 
two products that are separated by column chromatography on silica gel. 
One is the title compound, m.p. 179.degree.-81.degree. C. MS: 
MNH.sub.4.sup.30 =338; IR (KBr) 1762, 1714 cm.sup.-1 .sup.1 H-NMR 
(CDCl.sub.3) .delta. (ppm vsTMS) 5.38 (1, d, J=3, 6-H), 4.07 (1, d, J=3, 
11-H), 2.88 (1, d, J=20, COCH.sub.2), 2.68 (1, d, J=20, COCH.sub.2), 2.31 
(3, s, COCH.sub.3), 2.02-2.12 (9, 3s, Ar--CH.sub.3), 1.61 (3, s, 
2--CH.sub.3). 
EXAMPLE 22 
TRANS,CIS-(.+-.)-6-ACETYLOXY-3,4-DIHYDRO-3,4-DIHYDROXY-2,5,7,8-TETRAMETHYL- 
2-H-1-BENZOPYRAN-2-ACETIC ACID, METHYL ESTER 
The second product obtained in the reaction described in the preceding 
example is the title compound, m.p. 135.degree.-145.degree. C., identified 
by its MS (MNH.sub.4.sup.+ =370) and the hydrolysis product described in 
the next example. 
EXAMPLE 23 
TRANS,CIS-(.+-.)-3,4DIHYDRO-3,4,6-TRIHYDROXY-2,5,7,8-TETRA-METHYL-2-H-1 
BENZOPYRAN-2-ACETIC ACID, METHYL ESTER 
To a solution of 930 mg of the acetate, described in the preceding example, 
in 30 ml of methanol under nitrogen, is added a solution of 4.0 g of 
potassium carbonate in 20 ml of water and the mixture is stirred at room 
temperature overnight. After acidification with 2N HCl and evaporation of 
methanol, the product is extracted into ethyl acetate and the extract is 
washed with a sodium bicarbonate solution and dried over sodium sulfate, 
filtered, and evaporated. Recrystallization from ethyl acetate/heptane 
gives 440 mg of the title compound, m.p. 162.degree.-3.degree. C. IR (KBr) 
1716 cm.sup.-1 ; .sup.1 H-NMR (CDCl.sub.3) .delta. (ppm vs.times. TMS) 
7.26 (1, s, ArOH), 4.87 (1, d, J=5, 4-H), 4.08 (1, d, J=5, 3-H), 2.82 (2, 
s, CH.sub.2 CO), 2.31 (3, s, COCH.sub.3), 2.10-2.31 (9, 3s, ArCH.sub.3), 
1.45 (3, s, 2--CH.sub.3). 
EXAMPLE 24 
CIS, 
CIS-(.+-.)-6ACETYLOXY-3,4-DIHYDRO-3,4DIHYDROXY-2,5,7,8-TETRAMETHYL-2-H-1-B 
ENZOPYRAN-2-CARBOXAMIDE 
To a solution of 18.62 g of the olefin described in Example 1, in 200 ml of 
methanol under nitrogen is added 200 ml of 2N NaOH and the mixture is 
refluxed for 5 hours. After cooling, the mixture is acidified with 220 ml 
of 2 HCl and methanol is removed by evaporation. The product is extracted 
into ethyl acetate, and the extract is washed with a sodium bicarbonate 
solution. Acidification and reextraction with ethyl acetate gives 
(2R,S)-6-hydroxy2,5,7,8-tetramethyl-2-H-1-benzopyran-2-carboxylic acid. 
The acid is dissolved in 100 ml of acetic anhydride and heated to boiling, 
allowing the acetic acid that is formed to escape. Excess acetic anhydride 
is removed by evaporation under reduced pressure. The residue is dissolved 
in 300 ml of dry tetrahydrofuran and the solution is saturated with 
gaseous ammonia with cooling. After stirring at room temperature for 2 
hours, the mixture is evaporated to dryness, the residue is taken up in 
ethyl acetate, washed with 2N HCl, water, and a NaHCO.sub.3 solution, 
dried over Na.sub.2 SO.sub.4, filtered and evaporated. The residue is 
recrystallized from ethyl acetate/heptane to give 8.15 g of 
(2R,S)-6-acetoxy-2,5,7,8-tetramethyl-2-H-1-benzopyran-2-carboxamide. 
Cis-hydroxylation with osmium tetroxide, following the procedure described 
in Example 4, gives a crude product that is subjected to column 
chromatography on silica gel. One of the fractions is recrystallized from 
ethyl acetate/heptane to give 1.1 g of the title compound. IR (KBr) 1758, 
1702 cm.sup.-1 ; .sup.1 H-NMR (DMSO).delta. (ppm vs TMS) 4.68 (1, d, J=4, 
4-H), 3.82 (1, d, J=4, 3-H) which indicates a cis,cis rather than a 
trans,cis configuration; MS: MNH.sub.4.sup.+ =341. 
The compounds of this invention are free radical scavengers. Free radical 
reactions have been implicated in the pathology of more than 50 human 
diseases. Radicals and other reactive oxygen species are formed constantly 
in the human body both by deliberate synthesis (e.g. by activated 
phagocytes) and by chemical side-reactions. They are removed by enzymic 
and non-enzymic antioxidant defence systems. Oxidative stress, occurring 
when antioxidant defences are inadequate, can damage lipids, proteins, 
carbohydrates and DNA. A few clinical conditions are caused by oxidative 
stress, but more often the stress results from the disease and can make a 
significant contribution to the disease pathology. For a more detailed 
review see B. Halliwell in Drugs, 1991, 42, 569-605. 
There is a growing body of information that suggests a pathophysiologic 
role of oxygen free-radical-mediated lipid peroxidation following central 
nervous system trauma or stroke, either ischemic or hemorrhagic. A 
reduction in cerebral tissue concentration of endogenous antioxidants has 
been observed, as well as an increase in lipid peroxidation products. 
Inhibitors of brain lipid peroxidation counteract and reduce cerebral 
tissue damage, as well as to prolong life of traumatized animals. These 
findings have been reviewed by E. D. Hall and J. M. Braughler in Free 
Radical Biology and Medicine, 1989, 6, 303-313 and elsewhere. M. Miyamoto 
et al., (J. Pharmacol. Exp. Ther., 1989, 250, 1132) report that 
neurotoxicity due to excessive glutamine release is similarly reduced by 
antioxidants. They suggest the use of agents that inhibit brain lipid 
peroxidation for treatment of neurodegenerative diseases such as 
Huntington's and Alzheimer's disease in which excessive glutamic acid 
release has been observed. M. R. Hori et al., (Chem. Pharm. Bull. 1991, 
39, 367) report on anti-amnesic activity of brain lipid peroxidation 
inhibitors in rats. The role of oxygen free radicals in Parkinson's 
disease has been reviewed recently (Free Radical Biol. Med., 1991, 10, 
161-169) and a free radical scavenger has been tested clinically with some 
success (Fundam. Clin. Pharmacol., 1988, 2, 1-12). 
Ischemia followed by reperfusion causes formation of oxygen-derived free 
radicals and increased lipid peroxidation and results in tissue injury. 
Administration of free radical scavengers to animals subjected to 
ischemia/reperfusion reduces these effects in heart, lung, kidney, 
pancreas, brain and other tissues. 
Vitamin E, i.e., .alpha.-tocopherol, a well known compound of the formula 
##STR4## 
is a natural anti-oxidant that reacts with oxygen-derived free radicals as 
well as hydrogen peroxide. It has been shown that it is intercalated in 
lipid membranes and that its biological function is to protect 
biomembranes against oxidative attack. The antioxidant 
3,4-dihydro-2,5,7,8-tetramethyl-2-H-2-benzopyran-6-ol moiety of 
.alpha.-tocopherol is constantly regenerated by the ubiquitous redox 
systems. 
The compounds of the present invention are also useful in treating the 
process of inflammation which is known to involve the release of 
superoxide radicals from phagocytic cells which cause some of the symptoms 
of rheumatoid arthritis and other inflammatory diseases such as ulcerative 
colitis and inflammatory dermatological disorders such as psoriasis. Of 
particular use of this anti-inflammatory effect of the compounds of this 
invention is the treatment of inflammatory lower bowel disease. 
Inhalation injury of the lungs is typically caused by heat and chemical 
irritation, and chemical injury is the leading lethal cause of smoke 
inhalation injury. Smoke inhalation leads to lung injury due to an 
increase in pulmonary microvasculature and pulmonary edema. This process 
is accompanied by increased lipid peroxidation in lung tissue. An 
inhibitor of lipid peroxidation was shown to reduce these symptoms in 
animals subjected to hot sawdust smoke by Z. Min et al., (J. Med. Cell. 
PLA, 1990, 5, 176-180). They suggest the use of antioxidants in treatment 
of smoke inhalation-lung injury, adult respiratory distress syndrome and 
emphysema. 
Reactive oxygen species also play a role in the formation of foam cells in 
atherosclerotic plaques (reviewed by D. Steinberg et al., New Engl. J. 
Med., 1989, 320, 915-924) and the free radical scavenger probucol has a 
marked antiatherosclerotic effect in hyperlipidemic rabbits (Carew et al., 
Proc. Nat. Acad. Sci. USA, 1987, 84, 7725-7729. Degenerative retinal 
damage and diabetogenic retinopathy have also been listed as target for 
treatment with free radical scavengers (cf. J. W. Baynes, Diabetes, 1991, 
40, 405-412; S. P. Wolff et al., Free Rad. Biol. Med., 1991, 10, 339-352). 
The compounds may also be useful in the treatment of cancers, and 
degenerative diseases related to aging, stroke, and head trauma, since 
oxygen-derived free radicals have been identified among causative factors. 
For reviews, see B. Halliwell and C. Gutteridge, Biochem. J., 1984, 219, 
1-14; TINS 1985, 22-6. Antioxidants have also been shown to be useful in 
the treatment of cataracts, Free Rad. Biol. Med., 12:251-261 (1992). 
In vitro and in vivo activity for the compounds of this invention may be 
determined by the use of standard assays which demonstrate the free 
radical scavenging property, affinity for cardiac tissue and 
cardioprotective properties, as well as by comparison with agents known to 
be effective for these purposes. 
Exemplary of the assay useful for determining the free-radical scavenging 
property of the compounds of this invention is by the in vitro inhibition 
of lipid peroxidation in rat brain homogenates. 
The free radical scavenging properties of the compounds may readily be 
evaluated wherein superoxide radicals are generated by 4 mU of xanthine 
oxidase in the presence of 0.1 mM xanthine and detected by reduction of 40 
.mu.M nitro blue tetrazolium (NBT) to the diformazan dye in a 
spectrophotometric assay as described by C. Beauchamp and I. Fridovick, 
(Analyt. Biochem. 1971, 44, 276-287). 30 U of superoxide dismutase 
inhibited this reduction by 90% which is due to superoxide radicals. In 
the presence of a superoxide scavenger (test compound) there is a 
competition for the superoxide radical and thus a reduction in the color 
formation of NBT demonstrates the superoxide radical scavenging property 
of the test compound. 
Inhibiting the process of lipid peroxidation may be assayed using tissue 
homogenates for measuring the anti-oxidant activity of biological fluids 
by the methodology of J. Stocks et al., (Clin. Sci. Mol. Med., 1974, 47, 
215-222), wherein a brain tissue homogenate of treated adult Sprague 
Dawley rats is utilized. 
Samples of total volume 1 ml of diluted brain homogenate and with the 
scavenger at an appropriate dilution are incubated. Non-incubated samples 
are taken as background. Controls are run without scavenger and a sample 
containing only buffer is taken as blank. After incubation at 37.degree. 
C. for 30 minutes, 200 .mu.l of 35% perchloric acid is added, the samples 
centrifuged and 800 .mu.l of the supernatants mixed with 200 .mu.l of 1% 
thiobarbituric acid. The pink condensation product of thiobarbituric acid 
reactive material is developed at 100.degree. C. in a boiling water bath 
for 15 minutes, and absorbance read at 532 nm. 
For ex vivo inhibition of tissue including heart or brain tissue, lipid 
peroxidation in mice may be utilized to demonstrate the ability of the 
compounds to penetrate and act as free radical scavengers in these 
tissues. This assay involves pretreatment of male CD1 mice by subcutaneous 
administration of the test compound. One hour later the tissues are 
excised, homogenized 1+9 (w/v) in 20 mM potassium phosphate buffer at pH 
7.3 (0.14 M KCl) and incubated at 1/100 concentration in 1 ml of buffer at 
37.degree. C. for 30-120 minutes. At the end of the incubation 200 .mu.l 
of 35% perchloric acid is added and proteins removed by centrifugation. To 
800 ml of the supernatant are added 200 .mu.l of 1% TBA and the samples 
are treated to 100.degree. C. for 15 minutes. The TBA-adduct is extracted 
into 2 times 1 ml of n-butanol. The fluorescence is measured at an 
excitation wavelength of 515 nm and an emission wavelength of 553 nm 
against a standard prepared from malondialdehyde dimethylacetal. 
Stimulated human leukocytes release radicals and other oxygen metabolites, 
which, during inflammation, act as microbicidal agents. At the same time, 
they release proteolytic enzymes, such as elastase, which are also 
microbicidal but potentially threaten the connective tissue of the host. 
An endogenous .alpha..sub.1 -proteinase inhibitor (.alpha..sub.1 Pi) 
normally protects the host tissue from protelytic digestion. .alpha..sub.1 
Pi is however, inactivated by the leukocyte-derived oxidants. Antagonism 
of the inactivation of .alpha..sub.1 Pi is an indication of the disclosed 
radical scavengers. The concentration needed to protect 50% of the 
elastase inhibitory capacity of .alpha..sub.1 Pi (PC.sub.50) depends on 
the amount of stimulated leukocytes present. 
Method: The procedure described by Skosey and Chow was followed (see J. L. 
Skosey and D. C. Chow in Handbook of Methods for Oxygen Radical Research 
(Greenwald, R. A., ed.) 1985, pp.413-416, CRC Press, Boca Raton). In 
short, human .alpha..sub.1 Pi was incubated with zymosan-stimulated human 
peripheral-blood leukocytes in the absence or presence of the scavengers. 
The amount of a .alpha..sub.1 Pi protected from oxidative inactivation was 
determined by its residual elastase inhibitory capacity. 
Inhibition of 5lipoxygenase can be determined on purified enzyme obtained 
from rat basophilic leukemia (RBL-1) cells. The assay is described by 
J.-F. Nave et al., Prostaglandins, 1988, 36, 385-398 and in Biochem. J., 
1991, 278, 549-555. Eicosa-5(Z), 8(Z)-dienoic acid is used as substrate 
and the oxygenated products (5-hydroperoxy- and 
5-hydroxyeicosa-6,8-dienoic acids) are extracted and analyzed by HPLC. 
The relevance to inflammation matter has been reviewed by Weiss (see S. J. 
Weiss, N. England J. Med., 1989, 320, 365-376). Lung emphysema is 
associated with a genetic defect in .alpha..sub.1 Pi; the disease is 
further enhanced by oxidants inhaled during cigarette smoking, which leads 
to oxidative inactivation of .alpha..sub.1 Pi in the lung tissue (see J. 
Travis and G. S. Salvesen, Annu. Rev. Biochem., 1983, 52, 655-709). 
Oxidized .alpha..sub.1 Pi has also been isolated from rheumatoid synovial 
fluid (see P. S. Wong and J. Travis, Biochem. Biophys. Roc. Commun., 1980, 
06, 1440-1454). The degradation of hyaluronic acid, a macromolecule 
accounting for the viscosity of synovial fluid, is triggered by superoxyl 
radicals released from human leukocytes in vitro (see R. A. Greenwald and 
S. A. Moak, Inflammation, 1986, 10, 15-30). Furthermore, nonsteroidal 
anti-inflammatory drugs were shown to inhibit the release of superoxyl 
radicals from leukocytes (see H. Strom and I. Ahnfelt-Ronne, Agents and 
Actions, 1989, 26, 235-237 and M. Roch-Arveiller, V. Revelant, D. Pharm 
Huy, L. Maman, J. Fontagne, J. R. J. Sorenson and J. P. Giroud, Agents and 
Actions, 1990, 31, 65-71), and 5-aminosalicylic acid may exert its 
therapeutic activity in inflammatory bowel disease by a radical scavenger 
mechanism (see I. Ahnfelt-Ronne, O. H. Nielsen, A. Christensen, E. 
Langholz, V. Binder and P. Riis, Gastroenterology, 1990, 98, 1162-1169). 
Therefore, it is believed that the compounds of this invention may be 
useful in the mentioned pathologic situations and that inflammatory bowel 
disease may be a special target. An immune stimulatory effect of 
antioxidants has also been reported in that they enhanced lymphocyte 
activity (R. Anderson and P. T. Lukey, Ann. N.Y. Acad. Sci., 1987, 498, 
229-247) in vitro in the presence of triggered leukocytes, and ex vivo 
after pretreatment of human volunteers. 
Thus, using standard and well known methodology, as well as by comparison 
with known compounds found useful, it is to be found that the compounds 
are free radical scavengers useful in the prevention and treatment of such 
disease states related to neurotoxicity due to excessive glutamic acid 
release, to Huntington's disease, Alzheimer's disease and other cognitive 
dysfunctions, (e.g. memory, learning and attention deficits), amnesia, and 
Parkinson's disease, as well as the treatment and prevention of tissue 
damage in heart, lung, kidney, pancreas and brain tissues induced by 
ischemia/reperfusion, and to allay acute blood loss due to hemorrhagic 
shock. 
The compounds of this invention can be utilized both prophylactically and 
therapeutically. The amount of active ingredient for therapeutic 
administration can vary over a wide range and is dependent upon such 
factors as the species of patient to be treated, its age, health, sex, 
weight, nature and the severity of the condition being treated. The term 
"patient" refers to a warm-blooded animal such as, for example, rats, 
mice, dogs, cats, guinea pigs, primates and humans. Generally, a 
therapeutically effective amount of the active ingredient to be 
administered will range from about 0.1 mg/k g to 30 mg/kg of body weight 
per day. For prophylactic administration, corresponding lower doses can be 
utilized. Preferably, the compounds of the present invention will be 
administered to the patient in combination with a pharmaceutically 
acceptable carrier which is any substance which aids in the administration 
of the compound without substantially affecting its therapeutic 
properties. 
Most preferably, the compounds are administered intravenously particularly 
under crisis situations wherein it is essential that the therapeutic agent 
be gotten to its site of action as quickly as possible, such as in those 
emergency conditions caused by coronary infarction, stroke and surgical 
interventions, conditions which can cause severe reperfusion damage. 
The compounds of this invention also can be orally administered, preferably 
using more active ingredient per day than when parenterally administered, 
preferably taking divided doses 3 to 4 times per day. Preferably, enteral 
administration in post "crisis" situations, particularly after release 
from hospitalized conditions. The compounds can be used in standard dosage 
unit forms such as tablets, capsules, dragees, lozenges, elixirs, 
emulsions, suspensions, and in cases wherein topical application is 
preferred by suppository or sub-lingual administration. Tablets and 
capsules containing from 100 to 400 mg of active ingredient are preferred 
modes of enteral administration. Of course, in the treatment of 
inflammation the preferred method of administration is by depot injection 
directly to the situs of the inflammation area with follow-up enteral 
means of administration. 
In preparing solid dose forms such as tablets, the active ingredient is 
generally blended with conventional pharmaceutical carriers or excipients 
such as gelatin, various starches, lactose, calcium phosphate or powdered 
sugar. The term pharmaceutical carrier as used herein also includes 
lubricants employed to improve the flow of tablet granulations and which 
prevent adhesion of tablet material to the surfaces of tablet dies and 
punches. Suitable lubricants include, for example, talc stearic acid, 
calcium stearate, magnesium stearate and zinc stearate. Also included 
within the definition of a pharmaceutical carrier as used herein, are 
disintegrating agents added to assist the breakup and dissolution of 
tablets following administration, as well as coloring and/or flavoring 
agents to enhance the aesthetic qualities of the tablets and make them 
more acceptable to the patient. 
Suitable liquid excipients for the preparation of liquid dosage unit forms 
include water and alcohols such as ethanol, benzyl alcohol and the 
polyethylene glycols, either with or without the addition of a surfactant. 
In general, the preferred liquid excipients, particularly for injectable 
preparations, include water, physiological and saline solutions, dextrose 
and glycol solutions such as an aqueous propylene glycol or polyethylene 
glycol solutions. In order to minimize or eliminate irritation at the site 
of injection, such compositions may contain a non-ionic surfactant having 
a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The 
quantity of surfactant in such formulations ranges from about 5 to 15% by 
weight. The surfactant can be a single component having the 
above-identified HLB, or a mixture of two or more components having the 
desired HLB. Illustrative of surfactants useful in parenteral formulations 
are the class of polyoxyethylene sorbitan fatty acid esters as, for 
example, sorbitan monooleate and the high molecular weight adducts of 
ethylene oxide with a hydrophobic base, formed by the condensation of 
propylene oxide with propylene glycol. In certain topical and parenteral 
preparations, various oils can be utilized as carriers or excipients. 
Illustrative of such oils are mineral oils, glyceride oils such as lard 
oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil. For 
insoluble compounds, suspending agents may be added as well as agents to 
control the viscosity, as for example, magnesium aluminum silicate or 
carboxymethylcellulose. In addition to these excipients, buffers, 
preservatives and emulsifying agents may also be added. Typical enema 
preparation of the retention type enema utilize small volumes, generally 
much less than about 150 mL for an adult, typically volumes of only a few 
milliliters are preferred. Excipients and solvents for use in retention 
anemas should, of course, be selected so as to avoid colonic irritation 
and should also be selected so as to minimize absorption of the various 
agents. 
The compounds of this invention can also be administered topically. This 
can be accomplished by simply preparing a solution of the compound to be 
administered, preferably using a solvent known to promote transdermal 
absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without 
other excipients. Preferably topical administration will be accomplished 
using a patch either of the reservoir and porous membrane type or of a 
solid matrix variety. 
Some suitable transdermal devices are described in U.S. Pat. Nos. 
3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generally 
contain a backing member which defines one of its face surfaces, an active 
agent permeable adhesive layer defining the other face surface and at 
least one reservoir containing the active agent interposed between the 
face surfaces. Alternatively, the active agent may be contained in a 
plurality of microcapsules distributed throughout the permeable adhesive 
layer. In either case, the active agent is delivered continuously from the 
reservoir or microcapsules through a membrane into the active agent 
permeable adhesive, which is in contact with the skin or mucosa of the 
recipient. If the active agent is absorbed through the skin, a controlled 
and predetermined flow of the active agent is administered to the 
recipient. In the case of microcapsules, the encapsulating agent may also 
function as the membrane. 
In another device for transdermally administering the compounds in 
accordance with the present invention, the pharmaceutically active 
compound is contained in a matrix from which it is delivered in the 
desired gradual, constant and controlled rate. The matrix is permeable to 
the release of the compound through diffusion or microporous flow. The 
release is rate controlling. Such a system, which requires no membrane is 
described in U.S. Pat. No. 3,921,636. At least two types of release are 
possible in these systems. Release by diffusion occurs when the matrix is 
non-porous. The pharmaceutically effective compound dissolves in and 
diffuses through the matrix itself. Release by microporous flow occurs 
when the pharmaceutically effective compound is transported through a 
liquid phase in the pores of the matrix. 
The compounds of the present invention may be incorporated into an aerosol 
preparation by means commonly known to those skilled in the art. The 
aerosol preparation may be prepared for use as a topical aerosol or may be 
prepared for inhalation. The aerosol preparation may be in the form of a 
solution or suspension and may contain other ingredients such as solvents, 
propellants and/or dispersing agents. Typical examples of aerosol 
preparations are shown in Remington's Pharmaceutical Sciences, 18th ed., 
Mack Publishing Company, Easton, Pa. pp. 1694-1712 (990) incorporated 
herein by reference. 
Of course, as is true in most instances wherein certain classes of chemical 
compounds have been found to have beneficial therapeutic end-use 
applications, certain sub-generic groups and certain specific compounds 
are preferred. In this instance the preferred compounds of Formula IB and 
preferably wherein R is methyl, R.sub.1 is methyl, and/or n is zero. When 
R.sub.2 is C(O)R.sub.3, R.sub.3 is preferably C.sub.1-9 alkyl, more 
preferably C.sub.1-6 alkyl and most preferably methyl.