Note: Descriptions are shown in the official language in which they were submitted.
~S~2~ : ~
Certain guanidine derlvatives oi tert~carbinamlrle~
posse~s antlhypertenQive (hypoten~lve ) activity. Specific
example~ are tert-alkyl cya~oguan~dine~ such ~8 1-tert~
3-cyanoguanidlne a~ d~scribed in S. M. Gadekar, S. N~bi,
and E~ Cohen, JO Med. Chem~, 11 811 (1968), and varioue
- derlv~tives of tert-butyl guanidine~, as de~cribed in J~ H.
~` .
Short ~ C. W. Ours, W. J~, Ranu Jr., J. Med. Chem., 11 1129
68). -~
Urea deriratives, however, are not repre3ented .:
; i -: - .
10 in compreh~nsive dlscugsiQn~ of antihypertensire aeent3.
qhese di~cusslons include W. T. C~mer and A. W. Gomoll,
Mediclnal Chemistry, ~hird ~dltion, A~ Burger, Wiley-Inter~
sc~lence, New York, 1970, ?P 1019-1064, a~d Medicinal
Chemi~try, Volume 7, "Antlhypertensl~e Agents~" E. Schlittler, ;~
Academic Pre~s, New ~ork, 1967. The urea-derivat~v~ compound~
of thi~ invention provide e~ective tr~atment oi hyperten~ion,
yet dif~er ~tructurallg and ch~mically over currently known
~11 antihyperten~lve agent3.
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According to thi~ invention there is provided
compound~ repre~,ented by the ~ormula
R - C - N - O - N -
R3 H
where
Rl~ R2 and P~3 are Cl ~ C3 9,~yl, C2 ~ G
alk~nyl5 with the provi~o~ that the total ` ~:
number o~ carbon atom~ of Rl, plu~ R2, plus
R3 doe~ not exceed 5, and that two of R
R2 ar~d R3 may be ,~oined to form a cyclo~
- 10 alkgl or ¢y~loalkengl group or suitable .:
, , ,
pharm,~eutical Balt8 o~ the~e compounds, ~uch ~ ;
a~ ~od~3m, pot~ælum, and calc~um~ ~ ~
'S 8 ln~renti~n al~o include~ pharmaceutlcal : ~ -
compos,itions cont,~ning the~e compounds and method3 o~
uslng them. .
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- 3 - ;
~05~0~9
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me antlhypertenslve compounds mo~t pre~erred
because of thelr high level of antlhypertenslve activity are ~
tert-butyl-3- (oxo-1 cyclohexen-l-yl) `,
urea
l-tert~amg1-3- (3 oxo-l-cyclohexen-1-yl) - ~ ~
urea -: .
miethy~cyclopentyl)-3 (3-oxo-1-cyclo- : ~
~ . ,.. ,~ .
: ~ 10 hexen-l-yl)llrea.
9YllT~lliSI8 :
` The compour~ds o~ this invention are read~l~r pre- .
,i pared a~ represerlted by the following equation:
i! O
" ~ To~OE
R2 - C - N - C - NH + i - '?
R3 2 ~,1~ Bsn~ene . ~; .
:, o ~' '' '
~ " `~ .
~: ~2 ~ ~ ~ J
R3
Reactant~ are heated at reflux ln benzene with ~;
catal~ of rtoluene~ulfQnic acid. me wat~r removal
::! ; .
through the reflu~ng procedure yield~ the compound product.
., ~.
~,, The salts o~ the compound~ of thi~ inventic~n can ;
j -20 be prepared by treating the compound with a~ alcoholic or
;' aqueoua ~olution o:e an e~u~molar a~ount o~ the reæpective :
alkali hydr~xide and ev~porating to dr~ness. In general,
because the salts oi the~e co~p~und~ hydrol~æe readilg, .
, such sal~s are les~ ~de~1rable ~or u~e in ~o~aula~ing pharmà~
ceutical con~positions o~ th~ i~ve~lon th~n the compounds
~, se.
~OSlO'h9
~XAMPLE 1
l-tert-butyl-3~ (3-oxo-1-cyclohexen-1-yl)urea ~ ~ ; ?
To a ~olution of 11.2 g of 1,3- cyclohexan~dione
in 250 ml o~ benzene is added 11.6 g tert-butylurea and 100
; mg of ~-toluene~ulfonic acid. me solutlon i8 heated at ~ -
re~lux under nltrogen with water removal ~or three hour~
At the end of this peri od the ~olut~ on 1~ cooled and the
prectpitated product removed ~ f$1tration. q~he preclpitate
i~ recry~talllzed ~rom acetonitr~le to ~ve 14 g o~ l~tert~
lû butyl-3-(3-oxo-1 cyclohexen--l-yl)urea, m-pO 223-225Co
~ he in~rared and n. m" r O ~pectra are c onslstent
wi !;h the a~signed structure.
EXAMP~S 2 - ~,
U~ing the procedure deYcribed ln Example 1~ the
reactants 3hown in column 1 produce the respectlve product~ i
as shown in column 2~ ;:
Reactant~O
CH3 " CH3 O
2 H3c~cH2-c~NHco~H2 ~ 0~0 H3C CH2 C ~IHC ~ ~)
CH3 CH3 H -
m.p. 225 227C.
~ 3 - CH3 O
3 H2C=~-~C-~cONH2 ~ ~ H2C-CH-C NHC N ~
I CH3 H ~ :
`, m.p. 220C (dec~)
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~1~5~
Example Be:Lctant~ 0 Product~
r~ CH3 0 ~ r~ C~ 1t` ¢~) `'
4 ~ N-C-N~2 ~ N ~ ~
O ' , ' .. ~,
CH3 ~ ~CH3
<~N-C-~2 + C~ ~-C-N~
H H
O
NH2 + 0~ C~ C-N-~
m.p. 230G ~dec. )
O :.
C~H5 " ,C2H5 ~ ;
7C2H5-C-l~C-NH2 ~ C~ C2H5-C-~HC~
CH3 0 0 CH3
m.p, 2Igo (dec. )
H H O . ~:
8 ~/C \ CH3 0 ~ C ~, , 3 ,~ )
H C ~H2-C-~HC-~H2 ~ 0~ H2CCH2 . C
CH3
'
~ CH3 0 ~ C~3 R
9 ~H2
~HC-NH2 ~ ~, NE~C-N~
O O
CH3 0 , 3 :~
10CH3CH2C~2-~-~c ~2 ~ 0~CH3CH2C~2-c ~3HC~H¢ :
~H3 3 ~ ~
m.p. 184-185 . -
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~s~
The compound~ v~ thi~ lnvent:Lon can be adrnlnl~tered
in the treatment o~ hyperten~ion by any mean~ that e~fectR
contact of the active lngredient compound with the ~lte of
actlon in the body of a warm-blooded animal. For example,
ad3ninistration can be parenteral, l.e., ~ubcutaneou~, lntra-
venou~, intramu~cular, or intraperitoneal, alternatively or
concurrently, admini~tration c~n be by the oral route.
For the purpose of thl~ dl~clo~ure~ a warm-blooded
animal is a member of the aninal kingdom po~e~8ed of a
0 homeo~tatlc ~echani~m and includes ma~mal~ and b~rd~
e dosage admlni3tered i8 dependent on the age,
health, and weight o~ the recipient, the extent o~ di~ease,
kind o~ concurrent trea~ment, frequency of treatment and the
ef~ect de~lred. U~uallys a dail~ dosate o~ active ingredient
;
compound can be from about 0.1 to 50 mllligram8 per kilogram
o~ body weight. Ordinarily, from 0.5 to 40, and pre~erably
1.0 to 20, milligrams per kilogram per day administered ~n
one or more dose~ daily ~s ef~ect~ve to obtain de~ired
re~ults. For the more potent compounds of the invention,
~ methylc~cl,~pentyl)-3-(3-o~o-1-cyclohexen-1-yl)urea,
l-tert-butyl-3-(3-oxo-l-cyclohexen-1-yl)~lrea and 1 tert-
.; amyl-3-(3-oxo-1-cyclohexen~ l)urea, the daily dosage range~
: are ~rom about 0.1 to 20 mg/kg, pre~erably 0.5 to 15 mg/kg,
and more prePerably 1.0 to 10 mg/kg. ~ .
The antlhypertensive activ~ty o~ the compounfl~ oi
this invention i~ evidenced by test~ conducted in hyperten~ive
ratæ and by ~urther tests whlch ~h~w a blood pre8su~R
lowering e~ect in normotensive dogs.
In these tests rats are made hypertensive by re~
peated in~ections o~ deæoxycortico~terone acetate (DOCA)
and by givlng the rat~ saline solution to drink e~sentiall~
accordlng to the method described by Stan~on and Wh~te
- 7 ~
.
~(~5~2~ ;
~rch. Intern. Pharmacodyn., ~;~) 351 (1965,~7. Graded
dose levels of each compound are administ~red orall~ to .
groups Or eight-hypertensi~e rat~. The compound is pre~
pared in an aqueous polyvin~l alcohol/acacia vehicle and
administer~d at a volume to body weight ratio of 5.0 ml/kg~
Sixteen hypertensive rats receiving the aqueous ~ehicle by
the ~ame route serve a3 control~ ~or each te~t. At various .
~nterval~ of time a~ter treatment~ u~ually 90 minute~, the
~ystolic arterial blood pressure o~ each rat i~ determined
by a mod~catlon of the m~crophon~-mano~eter technique ~; -
/~riedman, M. and ~reedJ S.C., Proc~ Soc~ ~gp. Biol. and
Med., 70, 670 (1959 ~ . That do~e o~ compound ~hich produces
a 30 mm mereury (mm Hg) reduction ln blood pres~ure when
compared to the mean sy~tolic arteria1 blood pressure o~ the
contr~l animals i~ then determlned (E~ective Dose 30).
For exampleg an ED30 o~ 15 mg/kg orally wa~ obtained with
l-tert-butyl-3-(3-oxo-1-cyclohexen-1-yl)urea; an ED30 value
of 8.5 mg/kg was obtalned orally with l~ methylcyclo-
pentyl)-3-(3-o~co-il-cyclohexen-1-yl)urea.
In a test involving dogs~ the~e compounds are
admini~tered i ntra~enously (1. v. ) to eight anestheti~ed
normotens~e dogs according to a cumulati~e do~e ~chedule.
Arterial blood pre~sure i~ recorded d~rectly through an
arterial cannula and a polygraph by which lt i~ determined
that the compound ~hows statistical~y signl~icant blood
pressure lowerinæ in comparison to the predo~ing control
value and to the e~ect of vehicle on control animals.
The compounds o~thiæ inventlon can be employed
in use~ul pharmaceutical compos~tions in such dosage forms
., .
, 3~ aæ tablet~, capsules, powder packets, liquid solutions,
suspenslons or el~xlrs ~or oral admir~istration; liquid ~or
parenteral u~e, and in certaln cases, au~pension~ ~or
parenteral useO In ~uch c~mposition~, the actlve ingredient
' ~,
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will ordinarily be pre~ent ln an amount of at least 0.5% by
wei~ht on the total wei~ht of the compositlon and not
more than 95~ by weight.
~esides the active ingredlent compound of thi~ ~ ~
inventionJ the antihypertensive compositlon can contain - :
a ~olld or liqu~d non-to~ic pharmaceutical carrier ~or th~ : -
actlve ingredient. :
The capsules, tablets, and pow~er~ will ~en~rally
ronstltute ~rom about 1~ to about 95~ and preferabl~ ~rom ;~
about 5~ to 90~ by we~ght of active ingredlent. These
do~age forms pre~erably contaln ~rom about 5 milllgram~ to
about 500 mllligrams of active in~redient, with about 7
mlll~gram~ to about 250 milligrams most pre~erred.
The pharmaceutical carrier can be a sterlle l~quid
such as water, or a suitable 4i~1, including those o~ petroleum,
animal, or ~ege~able oil o~ ~ynthetic origin, for example~
peanut oil, soybean oil, mdneral oil, ~esame oil, and the
l~ke. In general, water, saline; aqueous dextrose (gluco~e),
and related sugar solutions and g~ycol~ ~uch as propylene
glycol or polyethyle~e glycols are pre~erred liquid carrier~,
particularly for inJectlble solutions. Sterile in~ectible
solut~on~ w~ll ordlnaril~y contain from about 0.5% to about
25~ and preferably about 1% to about 10% by ~eight o~ the ~ :
. active ingredlent.
Oral adminl~tratlon can be in a ~uitable su~pen~ion `;
or syrup, in which the active ingredient ordinarily will
con~titute from about 0.7 to about 10~ and pre~erably about
1~ to about 5% by weight. me pharmaceutical carrier in the
composltion can be an aqueous vehicle such a~ an aromatic
wat0r, a ~yrup, or a pharmaceutlcal mucilage. : -~
uitable pharmaceut~cal carrier are described ln ~:
"Re~ington's Pharmaceutical Sciences" by ~ Martin, a
~ 9 ~ :
:~ :
'
59~ 9
well-kn~wn ~e~erence text ln thls ~ield.
The ~ollow~ng examples w~ urth~r illu~trate
the preparation of~ pharmeceutical compo~itionæ o~ the ln~ :
vention,
E ~ LE A
A large number of unlt cap~ules are prepared by
filling ~tandard two-piece hard gelatln c~p~ule~ each wlth
250 m~ gr~ms o~ powd~red 1-tert~butyl-3-~3~oxo-1 cyclo-
hexen-l-yl)urea~ 110 mi~3rams o~ lactose, 32 milligram~
o~ talc, and 8 mllllgram~ 8tearate.
EXAUP~E B
A mixture of l;~ methylcyclopentyl)-3-(3-o~o-1- .
eyclohexen-l-yl~urea in soybean o~l is prepared and inJected
by means of a positive displacement pump into gelatln to
~orm so~t gelatin capsulas cont~ining 35 milllgram~ of the : ~;
active lngredient. me capsules are wa~hed in petroleum
~ ether and dried.
'~ _XAMPIE C
A large number of tablet~ are prepared by conven-
tional procedure~ BO that the doæage unit i~ 100 milligram~of actlve ingxedient, 7 milllgram~ o~ ethyl cellulo~e, 0.2
~dlligram~ o~ colloidal silicon dio~ide, 7 milligr~m~ o*
ma~nesium steara~e, 11 milligram~ of microcrystalline cell-
ulo~e, 11 mllligrams o~ corn~arch and 98.8 mlll~gram~ of
lacto~e~ ~pproprlate coatings may be appl~ed to increa~e
pal~tabili~y or delay a~orption.
EXANELE D
A parenteral compo~ltion suitable for admini~tration
by inJection is prepared by ~tirrlng L55~ by wei~t o~ l-tert~
. 30 butyl-3-(3-o~o-1-cyclohexen l-yl)urea in 10~ by volume
-~ propylene glycol and water. me ~olution iæ eterilized by
f~ltra~ion~
..
, ~
- ~V5~2~ -
EX~MPLE E
An aqueou~ ~uspenslon is prepared ~or oral ad~
ministration ~o that each 5 milliliter~ contain 50 milligrams ~ -
of finely divided l-tert-butyl-3-(3-oxo-1-cyclohexen-1-yl)~
urea, 500 milligr~m~ of acacia, 5 mllligram o~ 80dium
benzoate, 1.0 grams of sorbltol solution, U~S~PD~ 5 milli~
grams o~ sodium saccharln, and OJO25 m~ terg OP vanilla ~ ;
tlncture.
~XAMPLE F
A parenteral compositlon sultable ~or administration
b~ in~ection i9 prepared by dis~olv~ng ~ by weight o~
tert-amyl-3-~3~oxo-1-c~clohexen~ l)urea in sodium ~hloride
; in~ect~on U.S.P. XV and ad~usting the pH o~ the solution to : :
.,
between 6 and 7. The solution ls sterilized by Piltration.
A wlde variety of compositions included within
thi~ invention can be prepared by ~ub~t~tuting other com-
j pounds embraced by this invention ~or the speci~ic co~pounds
named ln Example~ A-F above and substituting other ~ultable ~ ~
pharmaceutical carriers described in "Remington's Pharmaceutical ~: ;
Science~
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