Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ .
037
~` ~
Detailed Description of the Inven~ion .~ --
This inve~tion relates to novel benzopyrans and more -
particularly relates to 5H- [l]benzopyrano[3,4-d] pyridines ~
represented by the formula : ~:
Rl ~ ~ 1 R2
- wherein each Rl is loweralkyl, R2 is alkyl, cycloalkyl or - `~
.~. ~. - .
Y ~ whereln Y lt a strtlght or ;~
~ branched chain alkylene group having from I to 10 carbon atoms `
i . and each R4, R5 and R6 are the same or different members of ~he .
group consisting of hydrogen, halo, trifluoromethyl or lower-
alkyl; and R3 is hydroxy, acyloxy, loweralkoxy~ loweralkenyloxy, .
loweralkynyloxy or
O - / ~7
OC X - N /
R8
..~, ~ .
- 3 ``
' ~
.,
, ~, c
::
db/ f~
10;~795~
X ls a stralght or branched chain alkylene group having fr~m
one to eight carbon atoms, and wherein R7 and R8 are the same `- .
or different members of the group consisting of hydrogen or
loweralkyl, or
0 ~ (CH2) ~ Rg
- C- X -N z ~
(CH2)b-" :
wherein X is a straight or branched chain alkylene group
having from one to eight carbon atoms, a is an integer from
1 to 4, b is an integer from 1 to 4, Z is CH2, 0, S or NRlo .`~
with Rlo being hydrogen or loweralkyl, with the limitation `~
that when Z is 0 or S, the sum of a and b is 3 or 4; and
when Z is NRlo , the sum of a and b is 3-5; Rg is hydrogen ~ .:
or loweralkyl, and the pharmaceutically acceptable salts . -: .
;. . ~
thereof. `
i As used herein, the term "loweralkyl" refers to
15 Cl-C6 straight or branched chain alkyl groups including .;~
methyl, ethyl, _-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, _-pentyl, iso-pentyl, neo-pentyl~ n-hexyl and
,.. ~ ~ . ,
~ the like.
, ~ ,
The term "alkyl" refers to straight and branched ~X
chain alkyl radicals having from one to twenty carbon atoms
such as methyl, n-amyl, 3-methyl-2-octyl, 2-nonyl, 2-eicosanyl
and the like.
,'
,,.. ,. . ..... .. , .. , ,. ............. . . ~
... . -- - .: .
~037955 ~:
,. ~
"Cycloulkyl", as used h~rein, reEers to cycLlc
saturated aliphatic radicals having three to eight carbon
atoms in a ring, such as cyclopr~pyl~ cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl.
The term "halo" includes chloro, fluoro, bromo ~ ;
and iodo.
-~ The term "acyloxy" refers to acetoxy, propionyloxy,
butyryloxy and the like. - ;~
The term "loweralkoxy" refers to a loweralkyl
group connected to an oxygen such as: methoxy, ethoxy, ;~
propyloxy, butoxy and the like.
The term "lower alkenyloxy" refers to 2-propenyloxy,
(3-methyl-2-propenyl)oxy and (1,3-dimethyl-2-propenyl)oxy. `
The term "lower alkynyloxy" includes 2-propynyloxy
(3-methyl-2-propynyl)oxy and (1-methyl-2-propynyl)oxy.
When R3 is an ester, the term "pharmaceutically
acceptable salts" refers to acid addition salts prepared by ~ ~`
reacting the basic esters of the benzopyrans with an organic
or inorganic acid, or by reacting the benzopyrans with the
,
salt of an appropriate acid. When R3 is hydroxy, the term
refers to alkali metal, alkaline earth metal, ammonium
and substituted ammonium salts such as hydrochloride, hydro-
bromide~ sulfatej bisulfate, acetate, valerate, oleate, ,
laurateJ borate, benzoate, lactate, phosphate~ tosylate,
citrate, maleate, succinate, tartrate, napsylate and the~like.
S
. ~ ,
''~
... , . , . . - - ~ ~.- ..
~03795~
When R3 is hydroxy, the compounds of this . ~:~
invention are prepared by dehydrogenation of the correspond-
ing 1~2~3~4-tetrahydro-5H~lJbenzopyrano~3~4-d~pyridine with~
for exampleJ palladium on carbon in a boiling inert solvent, ~ ~
or by debenzylation and dehydrogenation of the corresponding ` ~`
N-benzyl 1,2,3,4-tetrahydro compound. When R3 is hydroxy,
and R2 is alkyl or cycloalkyl, the tetrahydro compounds can
be prepared according to the method described in U.S. Patent
No. 3,576,798. When R3 is hydroxy, and R2 is
R4 `~
~ R5
the compounds are prepared according to the following
reaction scheme~
.
,,,,~ ~ ,
.,''.'~ ' ``
- :~
': '.
''"",;,
~C~379SS :~:
r- :~
~ T
~
3 ~ u~
-P~ ~ ~Oo
O _ C~
o~o~l5
Q
- 7- ~ ~
.. . .
~C~37
Compounds wherein R3 is acyloxy are prepared by
reacting the corresponding compound wherein R3 is hydroxy -~
with the appropriate acyl anhydride such as acetic anhydride. ~; :
The esters of this inventionJ R3 ~
-CC-X-N ~~~~~(cH2)a ~ Rg
- (CH2)
are prepared by reacting equimolar quantities of the
corresponding benzopyranopyridine, and the appropriate
acid or its saltJ in the presence of a carbodiimide such
as dicyclohexyl carbodiimide, in a suitable solvent such as
methylene chloride, chloroform and the like.
Some of the heterocyclic acids which can be used ``~
in the process are~
~-piperidinobutyric acid, -.
~-morpholinobutyric acid, -~
~-~2-methylpiperidino)-butyric acidJ 3
~-piperidinovaleric acid, .
~-pyrrolidinobutyric acidJ ~:
B-piperidinopropionic acid, - ~ :
~-thiomorpholinobutyric acid and
homopiperidinoacetic acid I ; -
Reaction between the benzopyranopyridine starting
material and the heterocyclic acidj or salt thereofJ is ~:
readiIy effected by combining about equimolar amounts of the
reactants and a slight excess of a carbodiimide such as
~Lo3795~
dicyclohexylcarbodiimide. The reaction proceeds readlly at
room temperature and i9 generally completed in about 4 ~o
20 hours. After the reaction is terminated, the reaction
mixture can be filtered to remove the by-product of
dicyclohexylurea, and the solvent can be distilled off
using a rotary evaporator. The residue can be directly
crystalli~ed from a suitable solvent such as benzene/ether
or the residue can be chromatographed and the desired
material isolated from the appropriate chromatographic -
fractions. If the basic esters are obtained, the acid `
addition salts such as those named above, if desired, can be
prepared by methods well known in the art.
The compounds of this invention, in the form of the ~
free bases, can be used as neutralizing agents since they ~ ~-
form salts with acids.
The pharmacological activity of the compounds of
this invention renders them useful as drugs although it should
be understood that every compound of the invention will not
necessarily have each activity possessed by the others.
The compounds of this invention are useful as -
. .
analgesic agents, and generally at dosages of from 1 to 10 ~ -~
mg./kg. of body weight daily. The analgesic activity was
established in the standard mouse-writhing t~st L~hittle, Brit.
J. Pharmacol., 22, 296 (1964)~ and confirmed in the hot
plate assay rWoolfe, G. and MacDonald, A.D., J. Pharmacol.
Ex~er. Therap., 80, 300, (1944)7 and the rat tail flick test ;-
_g~
; .
' ~
~03795~
~D'Amour and Smith, J. Pharmacol. Exper. Therap., 72: 74,
(1941)~7. The compounds are additionally useful as anti- ~:
anxiety agents and anti-depressant agents. - :
' :''`':: ~ . ,
'". -'~
.' ''.',' ~, ' '`~'~
, ~ ~
~: ? ~ .
' ~ ~
.:
, :'
~ ~ .
- 1 0 - ::
'`' :
. - - ''. ':
... .
~,03795~ -
The following examples further illustrate this
invention:
Example 1
5,5-Dimethyl-10-hydro~y-8-(3-methyl-2-octyl)-5H~17
benzopyrano~3,4-d~pyridine _ ~
:,
Ch ~ ~ -fHCh(CH2)4CH3
CH3
~ A mixture Of 4.20 g. Of 5,5-dimethyl-10-hydroxy-
8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5Ht~benzopyrano~
C3,4-dJpyridine, 0. 8 g. of 10% palladium on carbon and 80
ml. of xylene was stirred and refluxed for 25 hours. After
cooling, the catalyst was removed by filtration. The filtrate
was evaporated in vacuo and the product was recrystallized
from autonitrile; m.p. 155-157.
Calcd. for C23H31N02 CJ 78-14; H~ 8-84; N~ 3-97 ;
Found: C~ 77.93; H~ 9.00; N~ 3.85 -~
Example 2
5,5-Dimethyl-10-hydroxy-8-methyl-5~ benzopyrano
C3,4-d~pyridine i~ prepared by dehydrogenating 5~5-dimethyl-
10-hydroxy-8-methyl-1,2,3,4-tetrahydro-5~17benzopyrano~
20 L3,4-d~pyridine following the procedure of Example 1.
- 1 1 -
` ~ ` .
.. . .. .
~1)37955
Example 3 `.~ ~-
5,5-Dimethyl-lO-hydroxy-8-(l-pentyl)-SH-rl~ben~
pyrano~3,4-d~pyridine is prepared by dehydrogenating 5,5
dimethyl-10-hydroxy-8-(1-pentyl) -1J 2,~3/4-tetrahYdrO-5~-r1
benzopyrano~3,4-d~pyridine following the procedure of
Example 1.
Example 4 : .
5,5-Dimethyl-10-hydroxy-8-(2-heptyl)-5H~ benzo- ~ :
pyrano h,4-d~pyridine is prepared by dehydrogenating 5,5-
dimethyl-10-hydroxy-8-(2-heptyl)-1,2,3~4-tetrahydro-5Hfl~
benzopyrano[3,4-dJpyridine following the procedure of Example
1 . ,
Example 5 . ::
5,5-Dimethyl-10-hydroxy-8-(1-cyclohexylethyl)-5H
~1benzopyrano~3J4-d~pyridine is prepared by dehydrogenating
5,5-dimethyl-10-hydroxy-8-(1-cyclohexylethyl)-1,2,3,4-
tetrahydro-5H~ benzopyranof3,4-d~pyridine following the ~.
procedure of Example 1.
....
Example 6 1: ~ :
. : ~
5,5-Dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-
5~fl~ben7-opyrano~3,4-d7pyridine is prepared by dehydrogenating
5-,5-dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-1,2~3,4
tetrahydro-5H~l~benzopyrano~3,4-d~pyridine following the :~
procedure of Example 1.
-12~
,,, ~, .
"` , ''' ,
. . . -- . ,: . .
~, . .,, . , , " .. , . ~ , . . -
.03795S
Example 7
5,5-Dimethyl-10-hydroxy-8- (2-tetradecyl)-5H-~/benæo-
: pyrano~3,4-d7pyridine is prepared by dellydrogenating SJS-
dimethyl-lO-hydroxy-8-(2-tetradecyl) 1~2~3,4-tetrahydro-5H-
~7benzopyrano~3,4-dVpyridine followlng the procedure of
Example 1.
Example 8
5~5-Dimethyl-lo-hydroxy-8-(2-eicosyl)~5H~lJben
pyrano~3,4-d~pyridine is prepared by dehydrogenating 5,5-
dimethyl-10-hydroxy-8-(2-eicosyl)-1~2,3,4-tetrahydro-5H~
benzopyrano~3,4-d~pyridine following the procedure of
Example 1.
'"''' ':
Example 9
5,5-Dimethyl-10-hydroxy-8-ethyl-5Hf~7benzopyrano
~3,4-dJpyridine is prepared by dehydrogenating 5,5-dimethyl- ;
10-hydroxy-8-ethyl-1,2,3,4-tetrahydro-5H~l~benzopyranoL3,,4-d,7
pyridine following the procedure of Example 1.
Example 10
5,5-Dimethyl-10-hydroxy-8-iso-propyl-5H{1;7benzo-,
pyrano~3,4-dlpyridine is prepared by dehydrogenating 5~5-
: dimethyl-10-hydroxy-8-iso-propyl-1~2,3,4-tetrahydro-5H~lJ `~
benzopyranoC3,4-d~pyridine following the procedure of
Example 1.
-13-
;-
,
';, ,:
1037~3155 ` :~`
Example 11
5,5-Dimethyl-10-hydroxy-8-(2-hexyl)-5l~{1~benzo-
pyranoL3,4-d~pyridine is prepared by dehydrogenating 5,5
dimethyl-10-hydroxy-8-(2-hexyl)-1,2,3,4-tetrahydro-5HLl~
benzopyrano~3,4-dJpyridine following the procedure of ;
Example 1.
Example 12 ~-
10-Acetoxy-5,5-dimethyl-8~(3-methyl-2-octyl)-5H-~7
ben~opyranol~3,4-d~pyridine
~N ~ OCOCH
~ ~ CH3
CH3 ~ o ~ tHCH(CH2)4CH3
CH3 CH3 `;`
A mixture of 3.53 g. (0.01 mole) of 5,5-dimethyl- -
10-hydroxy-8-(3-methyl-2-octyl)-5Hfl,7benzopyranor3,4-d~
pyridine/ 1.22 g.(0.012 mole) of acetic anhydride, and 5 ml.
of pyridine was stirred at room temperature f-or 24 hours.
The reaction mixture was evaporated in vacuo, and the
residue was taken up in ether.- The ether solution was
washed with water, dried with anhydrous sodiuln sulfate, and
- -
evaporated in vacuo. The residue was purified by chroma~
tography on a Florosil~ activated aluminum magnesium silicate i ; ~ ~
22 mm x 30 inch column with chloroform to give the pure product. --
Calcd. for C2sH33NO3: C, 75.91; H~ 8-41; N~ 3-54
Found: C, 75.62; H, 8.52; N, 3.38 -~
". . - . .
-14~
,- "~
' . ~- ' ',~
'~ ,' ';
,: , .'
,. i ... .. .
~037~5~;i
Example 13
10-Acetoxy-5,5-dimethyl-8-ethyl-SHfl~benzopyrano-
~3,4-dJpyridine is prepared by reactiTlg 5,5-dimethyl-10-
hydroxy-8-ethyl-5Htl~benzopyranoL3,4-~¦pyridine and acetic
anhydride in the presence of pyridine according to the ~:~
. method of Example 12. : ;
Example 14
lO~Acetoxy-5,5-dimethyl-8-_-pentyl-5Ht~lbenzo- ~
pyrano ~,4-d~pyridine is prepared by reacting 5,5-dimethyl- -
-~ 10 lo-hydroxy-8-n-pentyl-5HtlJbenzopyranol3~4-d~pyridine and
acetic anhydride in the presence of pyridine according to ~`
the method of Example 12. ;
; Example 15 ;`~
: 10-Acetoxy-5,5-dimethyl-8-(2-heptyl)-5H~l]benzo- ;
pyrano/3,4-d.7pyridine is prepared by reacting 5,5-dimethyl-
10-hydroxy-8-(2-heptyl~-5HtiJbenzopyrano~3,4-d]pyridine and
acetic anhydride in the presence of pyridine according to
the method of Example 12. `
Example 16 .
10-Acetoxy-5,5-dimethyl-8-(1-cyclohexylethyl)-5Htl/ ;
benzopyranoL~,4-d~pyridine is prepared by reacting 5,5-dimethyl- :
10-hydroxy-8-(1-cyclohexylethyl)-SHtlJbenzopyrano~3~4-d~
pyridine and acetic anhydride in the presence of pyridine
' according to the method of Example 12.
" .
';`
'~
1(~379~5 ~ : ~
Exampl~ 17 ~ ` ~
.
10-Acetoxy-5,5-dimethyl-8-(3-cycl.opropyl-2-propyl)- ~ :
5~flJbenzopyrano[3,4-d~pyridine is preparcd by reacting 5,5-
dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-5H~Vbenzo- ~-
S pyrano~3,4-d¦pyridine and acetic anhydride in the presence . ;
of pyridine according to the method of Example 12. ;~
: Example 18 - ::
lo-Acetoxy-5~5-dimethyl-8-(2-tetradecyl)-5Hl~J- ~
- benzopyranol3,4-dJpyridine is prepared by reacting 5,5- ;- :
dimethyl-lO-hydroxy-8-(2-tetradecyl)-5HtlJbenzopyranol3,4-d~
pyridine and acetic anhydride in the presence of pyridine
according to the method of Example 12. : .
Example 19
lO-Acetoxy-5J5-dimethyl-8-(2-eicosyl~-5Htl~benzo~
,
pyranol3,4-d~pyridine is prepared by reacting 5,5-dimethyl-
10-hydroxy-8-(2-eicosyl)-5Hfl~benzopyranoL3,4-dJpyridine and
acetic anhydride in the presence of pyridine according to
the method of Example 12.
Example 20 .
; 20 lO-Acetoxy-5,5-dimethyl-8-n-butyl-5HtlJbenzopyrano~
L3,4-d~pyridine is prepared by reacting 5,5-dimethyl-10
hydroxy-8-n-butyl-5HtlJbenzopyrano~3~4-d~pyridine and
acetic anhydride in the presence of pyridine according to :
the method of Example 12. . ~ s
-16- ~ '
__...... .. _ .... __ ,: .
... , . . : .
~037955 :
Example_21
10-Acetoxy-5,5-dimethyl-8-iso-propyl-5Htl7ben~o-
pyrano~3,4-d~pyridine is prepared by reacting 5~5-dimethyl-
10-hydroxy-8-iso-propyl-5Hfl~benzopyrano/3J4-d~pyridine
and acetic anhydride in the presence of pyridine according
to the method of Example 12. -
Example 22 ~ :~
:,,
10-Acetoxy-5,5-dimethyl-8-(2-hexyl~-5HZ~benzo~
pyranol3,4-dlpyridine is prepared by reacting 5,5-dimethyl-
1~-hydroxy-8-(2-hexyl)-SH~lJbenzopyranol3,4-dJpyridine
and acetic anhydride in the presence of pyridine according ~`
to the method of Example 12. ;~ -
Example 23
Preparation of 2-(3,5-dimethoxyphenyl)-5-(4-fluorophenyl) ~-~
~entane
.
A solution of 77 g. of 3-(4-fluorophenyl)propyl-
bromide in 300 ml. of ether was added dropwise over a 2 hour '
period to a refluxing solution of 10 g. of magnesium in 100
ml. of ether. The reaction mixture was refluxed for an ~:
additional 30 minutes after the addition was completed. A
solution of 68 g. of 3~5-dimethoxyacetophenone in 100 ml.
of ether was th~n added dropwise to the reaction and the
reaction mixture was refluxed for 1-1/2 hours. To the
reaction was added 300 ml. of a saturated ammonium chloride `
solution dropwise with stirring. The layers were separated
and the aqueous layer extracted with ether. The ether
-17-
"'~
'',' : ~
,
ex~ract was dried ov~r magne~iulll sul~aL~ an~J ~ ? c~h~r
removed in vaclo to glve an oil. An acl~itional 111.7 ~. of
3(4-fluorophenyl)propylbromide was worked up in the above
manner. The products from both runs were hydrogenated in -`
ethanol-HCl using palladium as the catalyst. The solvents
and catalyst were removed and the crude material distilled
to yield 169.0 g. of 2-(3,5-dimethoxyphenyl)-5-(4-fluoro-
phenyl)pentane, b.p. 145-155/0.05 mmHg.
Analysis Calcd. for ClgH2302F: C, 75.60; H, 7.69
Found: C, 75.87; H, 7.98
Example 24
Preparation of 2-(3,5-dihydroxyphenyl)-5-(4-fluorophenyl)
nentane
`,
Fifty grams of the above prepared 2-(3,5-dimethoxy-
phenyl)-5-(4-fluorophenyl)pentane, 450 ml. of acetic acid
and 180 ml. of 48% HBr in water were mixed. While cooling,
the mixture was saturated with hydrogen bromide gas (approx- `
imately 1/2 hour). The reaction was placed in an 87 bath
and stirred for 17 hours. The reaction was then concentrated
in vacuo and the residue neutralized with K2C03 and NaHC03,
extracted with ether, treated with charcoal and MgS04 and -~
filtered to yield 45 g. of 2-(3~5-dihydroxyphenyI)-5-(4- ~ `
fluorophenyl)pentane as a brown oil which distills at 180/
O.01 mmHg.
Analysis Calcd. for C17H2sO2F: C, 74.20; H, 6.98 ~`
Found: C, 73.56; H, 7.04
-18- ~`
:,.. :. . , -. -, ~ , ,
:... . - ,.: - ~ , . .. ; . ,
~ ~379~5 :~
Example 25
Preparation of 2-Benzyl-8-~5-(4-fluorophenyl)-2-pentyl7-
10-hydroxy-5-oxo-1,2,3,4-tetrahydro-5~ 7benzopyrano~3,4-d7
pyridene hydrochloride
..._ . .. . . _
To 45 g. of 2-(3,5-dihydroxyphenyl)-5-(4-fluorophenyl)-
pentane dissolved in 100 ml. of methanesulfonic acid were
added in portions, 57 g. of 1-benzyl-3-keto-4-carbethoxy pip-
eridine hydrochloride. While stirring, 68 g. of POC13 ~`
were added and the solution was stirred for 5 days at room
temperature. Water (300 ml.) and 180 ml. of CHC13 were then
added and the reaction mixture stirred for 30 minutes. After
the addition of 100 ml. of 15% NaOH, the reaction was stirred ~
for an additional ten (10) minutes. The CHC13 layer was ~ -
separated and extracted with 10% HCl. The CHC13 layer was
concentrated and CH3CN added thereto to yield 55 g. of the
desired product as the hydrochloride salt, m.p. 254-256C. ;`;
Analysis Calcd. for: C, 70.80; H, 6.14; Cl, 6.97; N, 2.75
Found: C, 70.15; H, 6.17; Cl, 7.23; N, 2.74
Exam~le 26
:, .
Preparation of 2-Benzyl-5,5-dimethyl-8-~5-(4-fluorophenyl)-
2-pentyl~-10-hydroxy-1,2,3,4-tetrahydro-5H~l~benzopyrano
- _ _ r3,4-d~pyrldine
Sixty five grams of the above-prepared 2-Benzyl-8-
~5-(4-fluorophenyl)-2-pentylJ-10-hydroxy-5-oxo-1,2,3,4
25 tetrahydro-5H~l~benzopyrano~3,4-d7pyridine hydrochloride ~
were suspended in 300 ml. of CHC13. After adding a KHCO3 ~ ~ -
solution, the reaction was stirred for 30 minutes. The
chloroform layer was separated, dried over MgSO4, concentrated
-19- ~; .
~ 0~7955
taken up in benzene and concentrated again. The concentrate
was taken up in 185 ml. of hot aniso;Le and the resulting
solution was added dropwise to a solution of CH3MgBr in ;~
anisole (prepared by adding 180 g oi. CH3Br in 500 ml. of
ether to 40 g. of Mg in 150 ml. of ether, evaporating the
ether and adding 300 ml. of anisole)~ The reaction mixture
was stored overnight at 62C. Water (200 ml.) was added `~
slowly, followed by 400 ml. of 10% H2S04. The anisole was
removed by steam distillation and the resulting solid was
taken up in chloroform, neutralized with KHC03, dried over
MgS0~, concentrated and the product (36.5 g.), m.p. 188-190C.,
~ .
crystallized from CH3CN.
~ ~ ,
;.,: .... ~ . ,.
~ ~ .
`,"'. ~ " .
-20~
. :: -.':. : :: - ' : :- - .. . - .
~()37955
Examele 27
5,5-Dimethyl-8-~5-(4-fluorophenyl)-2-pentyl~-10-hydroxy- . ~`
_ 5H~ benzopyrano~3,4-dlpyridine
- '
OH
I I ":
CH3 ~ CH(CH2 3 ~ F ~ ;
A mixture of 4.75 g. of 5,5-dimethyl-8-l5-(4-fluoro~
phenyl)-2-pentyl~-10-hydroxy-l,Z,3~4-tetrahydro-5H~l~benzopyrano- ~ -
~3,4-d~pyridine, 1.0 g. of 10% palladium on carbon~ and 120 ~;
ml. of xylene was stirred and refluxed for 22 hours. After
removal of the catalyst, the filtrate was evaporated Ln vacuo
and the residue was purified by chromatography on a Florisil -
column (150 g.). The column was first eluted with chloroform,
followed by 5% methanol in chloroform to give the pure `
product; m.p. 72-74. -
Calcd. for C2sH26FNO2: C, 76-69; H, 6.70; N~ 3.58
Found: C, i7.12; H~ 7.15; N, 3.61
Example 28
5,5-Dimethyl-8-~5-phenyl-2-pentyl7-10-hydroxy-5H^~l~benzo~
pyrano~3,4-d7pyridine is prepared from 5,5-dimethyl-8-~5-phenyl~
2-pentylJ-10-hydroxy-lJ2,3,4-tetrahydro-5H-,J17benzopyrano~3,4-d,~
pyridine following the procedure of Example 27.
~ -21-
~L~37~SS ~` ~
Example ~ -
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-/Z-(piperidino~
butyryloxy)-5H-rlJbenzopyrano~3~4-d/pyridine hydro-
chloride_
N ~ C(c~2)3-
3 HCl
CH3 ~ ~ ~ CHCH~CH2)4CH3
CH3 CH3 ` ;` ~-~
A mixture of 3.53 g. (0,01 mole) of 5,5-dimethyl- ` ~ ,~
10-hydroxy-8-(3-methyl-2-octyl)-5H-ll~benzopyrano~3~4-d~
pyridine, 2.07 g. (0.01 mole) of ~-piperidinobutyric acid ;~
hydrochloride, 2.16 g. (0.0105 mole) oE N,N'-dicyclohexyl- ~ ` -
- 10 carbodiimide~ and 160 ml. of dried methylene chloride was
stirred overnight at room temperature. The reaction mixture
was cooled at approximately 5C. for several hours and was
filtered to remove dicyclohexylurea. The filtrate was
evaporated in vacuo and the residue was dissolved in 12.5
ml. of methylene chloride and 50 ml. of cyclohexane. After
standing overnight in the cold room (approximately 5C.), the `~
mixture was filtered again and the filtrate was evaporated
in vacuo. The residue was recrystallized from methylene
chloride/ether~ giving 4.1 g. of the productJ m.p, 134-137. -
Calcd- for C32H46N2O3-HCl: CJ 70.76; H~ 8-72; N~ 5-16
Found: CJ 70.71; H, 8.91; Nj~5.21
-22~
1037gS5
Exam~le 30
5,5-Dimethyl~ pentyl)-10-~4-(piperidino)-
butyryloxy~-SH-ll~benzopyrano~3,4-dlpyridine hydrochlorid~
is prepared according to the method of Example 29 by
reacting equimolar quantities of 5,5--dimethyl-10-hydroxy- `~;
8-(1-pentyl)-5H-~l~benzopyranoL~,4-d~pyridine and ~-piper-
idinobutyrlc acid hydrochloride in the presence of dicyclo- ``~
hexylcarbodiimide.
Example 31
.
- lO 5,5-Dimethyl-8-(2-heptyl)-10-l4-(piperidino)butyry-
loxy~-5H-~lJbenzopyranol3,4-d~pyridine hydrochloride is
prepared according to the method of Example 29 by reactin~
equimolar quantitie~ of 5,5-dimethyl-8-(2-heptyl)-10-hydroxy- ~;
5HflJbenzopyranoL~,4-d~pyridine and ~-piperidinobutyric acid ~
hydrochloride in the presence o dicyclohexyl carbodiimide. ~-
Example 32
5,5-Dimethyl-8-(1-cyclohexylethyl)-10-~4-(piper-
idino)butyryloxy~-5H-[lJbenzopyrano~,4-d~pyridine hydro~
chloride is prepared according to the method of Example 29
by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy~
8-~1-cyclohexylethyl)-5H~l~benzopyranol3,4-d¦pyridine and ~
- piperidinobutyric acid hydrochloride in the presence of dicy- -- `
clohexyl carbodiimide. ~ ;~
:- -23-
~,
, , , . , ;,; ~
~ 0379SS
`~
Exa~p le 33 ~ -
5~5-Dimethyl-8-(3-ryclopropyl-2~propyl)-lo-f4-
(piperidino)-butyryloxy~-5H-llJbenzopyranol3~4-dJpyridine
hydrochloride is prepared according to the method of ;~
Example 29 by reacting equimolar quantities of 5,5-dimethyl- -~
lo-hydroxy-8-(3-cyclopropyl-2-propyl)-5H-~lJbenzopyranoL3J4-d~ `
:.:. ...
pyridine and ~-piperidinobutyric acid hydrochloride in the
presence of dicyclohexyl-carbodiimide.
. ~ :
Example 34
-
; 10 5,5-Dimethyl-8-(2-tetradecyl)-10-~4-(piperidino)-
butyryloxy~-5H~ benzopyrano~,4-d~pyridine hydrochloride
is prepared according to the method of Example 29 by reacting
~. ~
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-tetradecyl)-
SH-~l~benzopyranol~,4-d~pyridine and ~-piperidinobutyric acid ~`
hydrochloride in the presence of dicyclohexyl carbodiimide.
Example 35 `~
i, .
5,5-Dimethyl-8-(~-eicosyl)-10-L~-(piperidino)~
butyryloxy~-5H-[lJbenzopyranoL3J4-d~pyridine hydrochloride ;~
is prepared according to the method of Example 29 by reacting ~;
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-~2-eicosyl)-
5H-Cl~benzopyranoL3,4-d~pyridine and ~-piperidinobutyric acid -
hydrochloride in the presence of dicyclohexyl carbodiimide.
.. .
-24~
1~)37~5~
Example 36 . .
5,5-Dimethyl-8-ethyl-10-~4--(piperidino)-butyryloxy~
5H-~11benzopyrano~3J4-d~pyridine hydr~chloride is prepared
according to the method of Example 29 by reacting equimolar `~ :
s quantities of 5,5-dimethyl-10-hydroxy-8-ethyl-5H-ll¦benzo- ;~.
pyranol~,4-d~pyridine and ~-piperidinobutyric acid hydrochloride
in the presence of dicyclohexyl carbodiimide. ~-
Example 37
5,5-Dimethyl-8-methyl-10-L~-(piperidino)-butyry- ~ -.
loxy~-5H-~lJbenzopyrano~3,4-d.~pyridine hydrochloride is ~`
prepared according to the method of Example 29 by reacting ;~
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-methyl-
- 5H ll~benzopyrano[3,4-d~pyridine and ~-piperidinobutyric acid
hydrochloride in the presence of dicyclohexyl carbodiimide. `.; . :
ExamRle 38
5,5-Dimethyl-8-iso-propyl-10-L4-(piperidino)~
butyryloxy~-5H-ll~benzopyranol3,4-d~pyridine hydrochloride
is prepared according to the method o~ Example 29 by reacting ..
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-iso-propyl~
SH-ll~benzopyrano/3,4-d~pyridine and ~-piperidinobutyric acid ``~
hydrochloride in the presence of dicyclohexyl carbodiimide. ;.
-25- .. ~
, "~' ' :~ . '
:
;: "~
'',' :':~
-; .. ..
`
lQ379S5
Example 39
,~. . .
535-Dimethyl-8-(2-hexyl)-10-~4-(piperidino)-
butyryloxy~-5H-/l~benzopyrano~3,4-d~pyridine hydrochloride `~
is prepared according to the method of Example 29 by reacting
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-hexyl)- :
5H-~lJbenzopyranor3~4-d~pyridine and ~-piperidinobutyric acid
; hydrochloride in the presence of dicyclohexyl carbodiimide.
- Example 40
5,5-Dimethyl-8-[5-phenyl-2-pentyl7-10-~4-(piperidino)- : ~
butyryloxy~-5H-l Vbenzopyrano~3,4-dlpyridine hydrochloride : ~ -
is prepared according to the method of Example 29 by reacting
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-~5-phenyl-2-
pentyl~-5H-~iJbenzopyrano~3J4-d~pyridine and ~-piperidino-
butyric acid hydrochloride in the presence of dicyclohexyl
carbodlimide.
Example 41 `.
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-~4-(morpholino)- ~ ....
butyryloxy~-5H~ ben2Opyrano~3,4-d~pyridine hydrochloride is
prepared according to the method of Example 29 by reacting .
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-
octyl~ -5H~ benzopyrano C3J4-d7pyridine and ~-morpholinobutyric `~
acid hydrochloride in the presence of dicyclohexyl
carbodiimide.
-26
-- -- ,
1037~55 ~ ~ ~
Example_42 i~
5J5-Dimethyl-8- (3-methyl-2-octyl) -10-~4- (pyrrolidino) ..
butyryloxy7-5H-[l~benzopyrano~,4-d~pyridine hydrochloride
is prepared according to the method o Example 29 by reacting
equimolar quantities of 5,5 dimethyl-10-hydroxy-8-(3-methyl- `
2-octyl)-5H-Ll~benzopyranol3,4-d~pyridine and ~-pyrrolidino-
butyric acid hydrochloride in the presence of dicyclohexyl
carbodiimide.
~.; ' .`: ' , :'
Example 43 .~;
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(2-methyl- ~ .
piperidino)butyryloxy~-5H-~lJbenzopyrano~3~4-d~pyridine
hydrochloride is prepared according to the method of Example .
29 by reacting equimolar quantities o~ 5,5-dimethyl-10-hydroxy- ~-~
8-(3-methyl-2-octyl)-5H-~lJbenzopyranoli,4-d7pyridine and
15 ~-(2-methylpiperidino)butyric acid hydrochloride in the
presence of dicyclohexyl carbodiimide.
' '" ~ ,
Example 44
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-~5-(piperidino) .
valeryloxy~-5H~ benzopyranol3g4-~pyridine hydrochloride
20 is prepared according to the method of Example 29 by .
reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-
8-(3-methyl-2-octyl)-5H-[l~benzopyrano~,4-d~pyridine and
~ -piperidinovaleric acid hydrochloride in the presence of . ~.
dicyclohexyl carbodiimide.
-27-
:.':-: ,
.... . . .. .. . _ . .. .. .. _
., , ., .. - .
... . . .... .. . . .
~,~37gSS ' ~,;,`` '`':
Example 45
5,5-Dimethyl-8-(3-m~thyl-2-octyl)-10-~4-(pyrrolidino~
butyryloxy~7-5H-~l~benzopyrano~3,4-d~pyridine hydrochloride .
is prepared according to the method of ~xample 29 by reacting
equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-
2-octyl)-5H-[l/benzopyranor3,4-d~pyridine and ~-pyrrolidino-
butyric acid hydrochloride in the presence of dicyclohexyl ~` :
carbodiimide. .~
Example 46 - ::
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-~3-(piperidino) .
! ~
propionyloxy~-5H-~l~benzopyranol3,4-d~pyridine hydrochloride
is prepared according to the method of Example 29 by reacting .equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl- .
2-octyl)-5H-LllbenzopyranoL3,4-d~pyridine and B-piperidino-
propionic acid in the presence of dicyclohexyl carbodiimide.
Example. 47
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-~4-(thio- .
morpholino)butyryloxy~-5H-~llbenzopyranol3,4-d~pyridine
hydrobromide is prepared according to the method of Example 29
by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-
(3-methyl-2-octyl)-5H-[l~benzopyranol3,4-dJpyridine and ~
thiomorpholinobutyric acid hydrobromide in the presence of
dicyclohexyl carbodiimide.
;,
-28-
lV37~55 ~ ~
The compounds of this invention can also be `~
prepared by the simultaneous dehydrogenation and debenzyl~
ation of the corresponding N-benzyl-1~2,3,4-tetrahydro-benzo-
pyranopyridine as illustrated in the following example.
The N-benzyl compound can be prepared according to the
method described in U,S, Patent No. 3,576,798. `
Example 48
5,5-Dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-rl7 ~`~
benzopyranoL3,4-d~pyridine ~-~
A mixture of 2.23 g. of 2-benzyl-5,5-dimethyl-10-
hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-ll~benzo-
pyrano~3,4-d~pyridine, 0.8 g. (10%) palladium on carbon,
and 100 ml. of xylene was stirred and refluxed for 24 hours.
After removal of the catalyst, the filtrate was evaporated
in vacuo and the residue was recrystallized from acetonitrile; ; ~ -
m.p. 154-156.
""` -::
. ~
-29-
, ". .~, ,
~'
.
: ' .
., ~, .
- . ... , . . . . ~ . .. :
. .: . . , - ~ ~ ., - .
. . . . . .
~037955 ~` :
Examp le 4 9
5,5-Dimethyl-10-Methoxy-8-(3-Methyl-2-Octyl)-5H-
-Benzopyrano~3~4~ pyridine ., ~ ~
N -
OCH
~ ~H3
CH3 ~ O CHCH(CH2)4CH3
- CH3 CH3
Methyl iodide (5.11 g., 0.036 mole) was added
dropwise to a stirred solution of 10.59 g. (0.03 mole) of
5,5-dLmethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-ll~benzopyrano
[3,4-d~pyridine in 300 ml. of N,N-dimethylformamide containing
1.78 g. (0.033 mole) of sodium methoxide. The mixture was
stirred at room temperature for 18 hours and 300 ml. o~ water
was added and extracted with petroleum ether (30-60). The
combined petroleum ether extracts were washed with water, dried
with anhydrous sodium sulfate and evaporated in vacuo. The
residue was puri~ied by chromatography on a Florisil~ column
with chloroform or by distillation under reduced pressure to
give the pure product.
Analysis Calcd. for C24H33NO2: C, 78.43; H, 9.05; N, 3.81
Found: C, 78.125 H, 9.19; N, 3.80
-30-
. . .
~ .
.: .
;. :
; . .. . .
- 1~37~SS
Example 50
5,5-Dimethyl-8-~5-(4-Fluorophenyl)-2-Pentyl~-10-
Methoxy-5H- ~lBenzopyrano~3~4-~pyridine '`~.
N~ OCH3
CH3- ~ o ~ CH(CH2)3
CH3 CH3 ,
By reacting 5,5-dimethyl-8-L~-(4-fluorophenyl)- .
2-pent~lJ-10-hydroxy-5H-~lJbenzopyranoL~,4-d~pyridine with
methyl iodide according to the procedure of Example 49,
5,5-dimethyl-8-C5-(4-fluorophenyl)-2-pentyl~-lO-methoxy-5H- ~'"''' '.~.:
l~Jbenzopyrano~3,4-d~pyridine is prepared. .
Analysis Calcd. for C26H28FNO2: C, 77.01; H, 6.96; N, 3~.46
Found: C, 77.23; H, 7.12; N~ 3.44
Example 51 : `. ; J; ' ;~
5,5-Dimethyl-8-(3-Methyl-2-Octyl)-10-(2-Propynyloxyj-
5H-~17BenzopyranoL3-,4-d7Pyridine ~ "'.
~ CH3
C~3 ~ o CHbH(cH2)4cH3
CH3 CH3
,', ~,
'''':
-31~
~ ~ :
~.`'' ~
iO37g5S .'; .' .
Freshly diYtilled 2-propynyL hromide (1.43 ~
0.012 mole) was added dropwise to a stirred solution of 3.53
g. (0.01 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-
octyl)-SH-ll7benzopyrano~3,4-d~pyridine in 80 ml. of
N,N-dimethylformamide containing 0.65 g. (0.012 mole) of
- sodium methoxide. After the addition, the mixture was stirred
at room temperature for 19 hours and 80 ml. of water was -
added and extracted with petroleum ether (30-60). The
combined petroleum ether extracts were washed with water,
dried by anhydrous sodium sulfate and evaporated in vacuo.
The residue was purified by chromatography on a FlorisilO
column with chloroform to yield the pure product.
.::~, . .. ;
Analysis Calcd. for C26H33NO2: C, 79.76; H~ 8.50; NJ 3 57
Found: C, 79 39; H~ 8.53; N, 3 41 `~ -
.
Example 52
`5,5-Dimethyl-8-~5-(4-Fluorophenyl)-2-PentyL~-lO- J
(2-Pru~ ~ 4-d~Pyridine
¦~ ~ 0cH2cH=cH2
CH3 ~L--CH(CH2)
5,5-Dimethyl-8-~5-(b,-:fluorophenyl)-2-pentylJ-10
~2-propenyloxy)-5H-[l~benzopyranoL3,4-d~pyridine was prepared
by reacting 5,5-dimethyl-8-~5-(4-fluorophenyl)-2-pentylJ-10-
hydroxy-5H-~l~benzopyrano~!3,4-dlpyridine with 2-propenyl
-32-
.... ... . ~ .................... -........... ... .
: . .
"~
~37 ~
bromide following the procedure of E,xample 51.
Analysis Calcd. for C2gH30FN02: C, 77.93; H, 7.01; N, 3.25
Found: C, 78.56; H, 7.18; N, 3.24
The present invention includes within its scope,
5 pharmaceutical compositions comprising, as an active .
ingredientJ at least one of the compounds of this invention
:: .
in association with a pharmaceutically acceptable carrier
or diluent. The compounds of this invention exhibit both
oral and parenteral activity and can be formulated in dosage
forms for oral, parenteral or rectal administration
Solid dosage forms for oral administration include
capsules, tablets, pLlls, powders and granules. In such
solid dosage forms, the active compound is admixed with at ` ~ ~
least one inert diluent such as sucrose, lactose or starch. `` ~`
15 Such dosage forms can also comprise, as is normal practice, `~
additional substances other than inert diluents, e.g.,
lubricating agents such as magnesium stearate, and sweetening
and flavoring agents. Tablets and pills can additionally
be prepared with en;teric coatings.
Liquid dosage forms for oral administration include ~-
pharmaceutically acceptable emulsions, solutions~J suspensions,
syrups and elixirs containing inert diluents commonly used
.in the art, such as water. Besides inert diluents, such
compositions can also include adjuvants, such as wetting
agents, emulsifying and suspending agents and sweetening,
flavoring and perfuming agents. `
.
-33-
,
"
1~37~5~; ~
Preparations according to this invention for
parenteral administration include sterile aqueous or non-
aqueous solutions, suspensions or emulsions. Examples of
no~-aqueous solvents or vehicles are propylene glycol,
5 polyethylene glycolJ vegetable oils, such as olive oil, ~-
and injectable organic esters such as ethyl oleate. Such
dosage forms may also contain adjuvants such as preserving, ~
wetting, emulsifying and dispersing agents. They may be ~ ~;
sterilized by, for example, filtration through a bacteria-
retaining filter, by incorporating sterilizing agents into
the composltions, by irradiating the compositions, or by
; heating the compositions. They can also be manufactured in
the form of sterile solid compositions which can be dissolved
in sterile water, or some other sterile injectable medium -
immediately before use.
Compositions for rectal administration are
suppositories which may contain in addition to the active -~
substanceJ excipients such as cocoa butter or a suppository
wax. - -
The dosage of active ingredient in the c~mpositions
of this invention may be varied; however, it is necessary ;~
that the amount of the active ingredient shall be such that ;~
a suitable dosage form is obtained. The selected dosage
depends upon the desired therapeutic effect, on the route
of administration and on the duration of the treatment.
-34~
~Q379S~
The following example further illustrates the `~ ;
pharmaceutical compositions whic~ are a feature of this
invention~
.,~.
Example 53
Tablets weighing 200 mg. and having the following ~.
composition are prepared by standard tableting procedures~
In~redient
5,5-Dimeth~l-10-hydroxy-8-(3-methyl-2-
octyl)-5H~ ~benzopyrano~3,4-d~pyridine--------- 100
; 10 Starch -------------~-------------~~~~~~~~~~~~~ 94 .,`
Colloidal silica - ----------~ ------------- 5 ~ :~
Magnesium stearate ----------------------------
It will be understood by those skilled in the art .~``.::
that the above composition can contain any of the compounds
of this invention.
',''', ` ~ ' ,
-35-
;',:
, ., . - , . : ;.
