CA1131228A - Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them - Google Patents
Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA1131228A CA1131228A CA342,085A CA342085A CA1131228A CA 1131228 A CA1131228 A CA 1131228A CA 342085 A CA342085 A CA 342085A CA 1131228 A CA1131228 A CA 1131228A
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- formula
- cycloalkyl
- amino
- alkenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Case 500-5494 BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PREPARA-TION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Abstract of the disclosure Compounds of formula I, I
wherein X is oxygen or sulphur, and R1-R6 are various substituents The compounds are useful for treating coronary insuffi-ciency, intermittent claudication, cerebrovascular insults, spasms in muscles and hypertension.
Abstract of the disclosure Compounds of formula I, I
wherein X is oxygen or sulphur, and R1-R6 are various substituents The compounds are useful for treating coronary insuffi-ciency, intermittent claudication, cerebrovascular insults, spasms in muscles and hypertension.
Description
~ 3~2;~3 Case 500-5494 BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PREPARA-4 TION AND PHA~CEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to benzoxadia-zoles and benzothiadiazoles having a 4-dihydropyridine moiety.
The present invention provides in particular compounds of formula I, .. ~ N
R ~ ~=N
Il 11 R5 ~ ¦ R2 R
wherein : .
R1 is hydrogen, alkyl(Cl ~), hydroxyalkyl(C2 ~), alkoxy-alkyl(C3 6)~ alkenyl(C3_6), a].kinyl(C3 6)~ cyclo-L.~
'~
' ~3~Z8 s00-5494 r alkyl(C3_7), cycloalkylalkyl(C4 8)~ phenylalkyl (C7 9 or phenylalkenyl(Cg 12)~ the phenyl ring heing un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy ( 1-4)' R2 and R5, independently, are hydrogen, alkyl(Cl 6)' PhenYlalkYl(c7_l0)~ cycloalkyl(C3 7) or cycloalkyl-yl(C4_3), R3 and R4, independently are CN, COR7, COOR7, SIO)nR7 or COO-A-N ~ 8, where-n n is 0, 1 or 2, R7 is alkyl(Cl_6), alkenyl(C3_6), alkinyl(c3 6)' cyclo-alkyl(C3 7), cycloalkylalkyl(C4 83~ hydroxyalkyl (C2 6)~ alkoxyalkyl(C3 6)~ hydroxyalkoxyalkyl(C4 g), y (C2_6), alkYl(Cl_4)aminoalkYl(C2 6~ di[al-kyl(C1 4)~aminoalkyl, phenyl, phenylalkyl~C7 10)~ a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or suIphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, or alkyl(C1_~) substituted by a 5- or 6-mem-bered heterocyclic ring containing one heteroatom selëcted from nit:rogen, oxygen or suIp~ur and may contain additionally 1, 2 or 3 ring nitrogen atoms, A is alkylene(~ 6)~
.
,,., ,. ,,,, ... ~ ~ :
~; _ 3 ~3~Z~
. 500-5494 ( -R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or alkinyl(C3 6)' cycloalkyl(C3 7), cycloallcylalkyl (C4 8)~ hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6)~ hy-droxyalkoxyalkyl(C4 8)' aminoalkyl(C2 6)' alkyl-(Cl_4)aminoalkyl(C2_6), di[alkyl(Cl_4)]aminoalkyl, phenyl, phenylalkyl(C7_10), or R8 and Rg together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heteromember selected from oxygen, sulphur and a group --N-Rlo, wherein Rlo is alkyl (Cl_4), and R6 is hydrogen, haloaen, alkyl(Cl 4), alkoxy(Cl_4), alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-amino, di[alkyl(Cl ~)~amino, alkanoyl(Cl_5)amino, carbalkoxy(C2 5), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(Cl 4)sulfamyl or di[alkyl (Cl_4)]sulfamyl, and X is oxy~en or sulphur, with the proviso that when Rl -is hydrogen, alkyl(Cl ~), alkenyl~C3 6)' alkinyl (C3 6)~ cycloalkyl(C3_7), cycloalkylalkyl(C4 8)~
phenylalkyl~C7 9) or phenylalkenyl(Cg 12)' the phe-nylring being unsubstituted or mono-, di- or tri-substituted independently by halogen, hydroxy, alkyl(Cl_4) or alkoxy(Cl_4), R2.and R5, independently, ~re hyd~ogen or alkyl(Cl ~), Z;i~8 _ ~ _ 500-5494 (~ .
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl ~), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one o~ the sub-.stituents R3 and R4 is other than COR7I, wherein R7I is alkyl(Cl 6)~ alkenyl(C3 6j, alkinyl(C3_6), cycloalkyl~C3 7), cycloalkylalkyl(C4 8)' and is other than COOR7II, wherein R7II is alkyl(Cl 6)~ alkenyl (C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-allcyl(C4 8)' hydroxyalkyl(C2 6)' alkoxyalkyl(C3 6) or hydroxyalkoxyalkyl(C~ 8) In any of the above radicals alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 to 2 carbon atoms. The hy-droxy, alkoxy, hydroxyalkoxy, amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in COOR7 is pre ferably not attached to the a-carbon atom and is pre-ferably attached to the distal terminal carbon atom.
Any hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably has an ethylene or propylene moiety substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino respectively.
The alkyl moiety of cycloalkylalkyl is conveniently '~
3~2~8 _ 5 _ 500-5494 ( methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine. Cycloalkyl or the cyclo-alkyl moiety oE cycloalkylalkyl is conveniently cyclo-propyl or cyclopen~yl or cyclohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in Rl or COOR7 is preferably not in the a,~ position. Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is conve-niently allyl or 2-methylallyl. Alkinyl is convenient]y propinyl. Phenylalkenyl preferably has the trans-confi-guration and is for example cinnamyl. When Rl is optio-nally substituted phenylalkyl, the phenyl group is pre-ferably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same.
When R7 is alkyl, this is preferably branched.
When R7 contains a heterocyclic ring this may be for example furyl, thienyl, pyrrolyl, thiazolyl, isothia-æolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, mor-pholinyl or triazinyl.
When R8 and Rg together with the nitrogen atom to which they are bound, form a heterocyclic ring, this is preferably saturated and may be for example pyrroli-dine, piperidine, piperazine, N-alkylpiperazine, morpho-line, -azepane, di~ze~ane or M-alkyl-diazepane.
. . , , ' - 6 - ~ ~3~Z~ 500-5494 Rl is conveniently hydrogen. R2 is convenien'ly identical to R5. R2 is conveniently alkyl. R3 and/or R4 is conveniently COOR7 or COO-A-N 8. R7 is con-venientl~ alkyl, preferably branched or alkoxyalkyl, where the alkoxy moiety is preferably branched. A is conveniently ethylene~ R8 and Rg are conveniently alkyl or phenylalkyl.
The present invention also provides a process .~ -for the production of a compound of formula I as de-fined above, comprising replacing the moiety -HC=Y in a compound of formula II, R6 _N\
~X II
~IC=Y
wherein R6 and ~ are as defined a~ove, and --~C-Y is i~ for~
ii) a radical of forJnula -~C-C-C(=Z)R2 - ~ Hc-c(=~)x2 lii) a xadical of formula -HC
`~HC-C(=Z')R5 R~
wherein ~ and Z' are independently oxy-~en or I~Rl, and Rl to ~5 are as define~ above, by a moiety of ~ormula III, ,, . .. . _ ... ..
::
,: : . , .:
~3~28 500_5494 -R4 ~ 3 ~ ~ III
5 ~ R2 ~1 ..
erein ~1 to R5 are as defined above.
The process may be efected in conventional manner for analogous dihydrop~ridine syntheses, e.s.
according to Hantzsch. ~hen the moiety ~I~C=Y is formyl and when it is desired to produce a compound of f,ormula ~, wherein R2 is identical to R5 and ~3 is identical to R~, it is convenient to react a compowld of rormula II
with a compound o~ fo~mula IV, ~herein R4 and R5 are as define~ above, in the presence of a compound of formala V, H2NRl V
~ ~herein Rl is as de~lne~ a)~ove.
Preferably at least 2 moles of a compound of formula IV per mole of a compound of fo~mula II are present. Alternatively a compound of formula II may be reacted with a compound o~ formula VI, R5-C(NH-Rl)=CH-~4 VI
~7herein Rl, P~ and ~5 are as defined above.
Preerabl~ at least 2 moles of a corp~und o~ for-mula VI per mole of a compound o~ for~ula II are present.
Pre~erably also ~1 is hydrG.~en.
;~ .
. _, .. _ ,.. .... .. .. ..
, .
~ _- 8 ~3~ZZ8 5~0-549~--l~hen he moiet~- -HC=Y is for~yl and ~refer2~1y when it is desired to produce a com~o~d of Lormula I
wherein ~2 is dif erent to R5 and/or R3 is difLeren~ to R~, it is also possible to xeact such a co~pound of formula II with a compound of ~orrula IV and a compound of fol~ula VII, R -C(NH-R 1=CH~R ~ VII
wherein R2, Rl and R3 are as de~ined above.
It will be appreciated that a compound of formula VI may be formed as an intermediate during the reaction of a compound of for~ula IV and a compound of formula V. A
compound of formula II, ~herein -HC-~ is a radical ii) or iii), may be formed as an inte~lediate in the above reactions. They may however ~e produced by dif erent pro-cesses.
Alternatively or particularly for the prcd~ctio~
of a compound o~ formula I, t7herein R2 is different to K5 and/or R3 is different to R4, it is convenient to react a compound o~ fonm~la II, wherein the moiety -HC=Y is a ra-dical ii) ~7ith a compound of formula IV or VI~
and t~here appropriate, wlth a compound of fGrmula V. A
co~.pound of ol-mula II, wherein ~he moiety -HC=Y is a radical iii) ma~ be an intermediate.
'~J: .
~: , :
~3~Z~3 _ _~ 9 _ 500-5~94 In tl~ abo~e reac'~ions it is possi~le in certa-n installCes ~I;en ~2~ R3~ R~ and R5 are not identical that more than one isomer of formula ~ may be formed. If so the3~ may be separated in conventional m2nner, e.g. by .. . , ~ ... ... .. . ... . . . .. .
column or thin layer chromatography~
~ en ti~e starting material is a ccmpound cf formu-la II, wherein -~C=Y is a radical iii), the reaction is a ring cyclisation. ~'hen Z and Z' are both oxygen~ then an amine of formula V should be present.
However, all the abo~!e reactions may be effected under the same conditions.
The reaction may be effected conveniently in solu-tion. ~ suitable sol~ent is water, ethanol, dioxane, di-methyl ormamide, dimethyl sulphoxide, pyridine or glacial acetic acid. Suitable reaction tempexa~ures may be from 20 to 160~ C, preferably from 60 to 120 C.
Insofar as the production of starting ~aterials is not particularly described these compounds are kno.in or may be ~roduced in analoqous manner to kno~m compounds, The basic compounds of formula I may be con-verted into acid addition salt forms in conventional manner and vlce versa. Suitable acids are e.g. maleic ' :
1 3~
- 10 - 500_54~4 acid, oxalic acid, methanesulphonic acid, hydrochloric acid and hydrobromic acid.
In the following Examples the temperatures given are in degrees Centigrade and are uncorrected.
- - :- ,-. : , ~j ~ ~ 500-549~
~' Example 1: ~-(2,1,3-Benzoxadiaz~1-4-Yl)-2,6-dimethyl-1,4-dihydro-3-methoxyearbonyl-pyridine-5-carboxylic acid benzyl ester 3,0 g of 2,1,3-benzoxadiazol-4-aldehyde, 3,9 g of aeetoacetic acid benzyl ester, 2,3 g of 3-amino cro-tonie aeid methyl ester and 10 ml of ethanol are re-fluxed for 6 hours. The mixture is subsequently evapo-rated and the residual oil is ehromatographed on silica gel with ehloroform/aeetie aeid ethyl ester (8:1) to yield the title compound. The product is reerystallised from cyeiohëxane/diisopropylether, m.p. 131-136.
By using the process described in Example 1, ard corresponding starting compounds, e.g. a eompound of formula II, wherein -HC-Y is a radieal i~ and eom-pounds of formula IV and V, and for Examplec 2-9 and 12-16 a eompound of formula II, wherein HC=Y is a radieal ii), wherein Z is oxygen and a eompound of formula VI, the following eompounds of formula I may ke obtained, wherein y indieates the position of the dihydropyridine moiety:
.... .
:, ,. ~, ~L~3~28 500-5494 U) ~ *
~ ,nr~ o ,~ ~ ~r In ~ ~ O~ ~ ~ a) ~
N O t~ O C~ 1` a~ 111 ~ (~) 1` tJI ~15 ~I N ~I -1 ~I N ~/ ~ 1 ~1 0 ~1 I I I I I I I I I ~ I h 1 N O ~) OD E~ ~D F
N O
X: O O OU~ U~ O O U~ O U~ O U~
:
n ~ C X X m :~ ~c x U
: :
N N
--~
. ~ O ~) ~ z æ
. ~ N N
m ntn o u~ Lr) ~ N IS ) . I ~ ~ ~ ~ ~ m m . ~1 ~ N N ~ X N N U U N N
. I U U~ ) U ~D U ~ U C ) O N o o o C_) o o o o o o ~r O O o o o O o o o o o o u u~ u ~ u u u u ~ u ~
.
u~
~ ~ $
. ~D ~O
N t`') N N N N N
\ / \ /
Z Z :Z æ Z Z
N N N ~`3 N t~l _ ^~ --~ ~ N
C X
U ~ U U U ~ U U
O O O O O O O O
Z o æ Z Z o o o o o o ~; u u u u u c~ ~ u u ~ ~) u :C x m ~ u C~ ~u m ~ u[ ~ a I ~
X N ~ ~ o~ o ~t ~ ~7 ~ . ~
'~ .
, .' .
.
c ~ ~ 3~2%~
~.
'n r~ o ~
a~ ID N~1 ,_~
. I ~ ~ I I
~ 4 ~I r l t~ I O OC~ O ~D
E; o o In In ~ ~r ~ ~r ' ~ ~r X U~ O O O O O O O
~D
~'~ ~ ~ <
n ~: X m x :~ / / ~:
~; ~ o \ \
In n n n m ~ m ~ ~ :~
m ~ x ~ U
o o o o o o o o ~ O O Q O O O O O
P;' C~ V U ~ C~ U
Ln n In ~ s :c ~) ~ ~) t~l ~ N
m m m ~ m x ~ U C) O ~ C~ In \ I \ / . \/ ~
Z Z Z
^ ^ ~ ~3 ~ ~ ~ U~ In ~
~ :~ m :~ ~ ~ m X ~ O
_ _ ~ U ~ ~ ~ ~
o o o o o o o o o o o o o o o o V V
~ a O ~
c~ m <1<1<1<1 ~ ~
o o :~ m 5: ~ m u ~
X ~r In ~ ~ O -I
W
: .
.
~ 4 _ ~ ~3~ 500-54~4 C
The compounds of formula I exhibit pharmacolo-: gical activity. In particular, they lead to a dilation of the coronary vessels as 2emonstrated by the results of tests measuring the blood flow to the myocardi~m of S an anaesthetised cat by means of the microsphere me~hod (Rudolph A.~l. and l~eymann M.S.: Circulation Research 21, 163, 1967) upon administration of from 30 to 50 ,ug/kg i.v. or of from 50 to 150 ~ug~k~ i.d. of the active sub-stance.
The compounds of formula I also possess a fa-vourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the ~ctive substance.
- The compounds of formula I are thereore indi-cated for use in the treatment of coronary insuffi-: ciency.
The compounds of formula I increase the blood flow to limbs, e~g. leg musculature, as can be shown b~ means of the microsphere method on the anaesthetise~
cat upon administration of from 30 to 50 ~gJkg i.v. or from 50 to 150 ~g/~g i.d. of the compounds.
The compounds of formula I are therefore indi-cated for use in the treatment of interm1ttent claudi-cation and other peripheral disturbances of blood - 25 flow to limb muscles.
,",~
. ~ , . . :
,. ~ , , , , , ~
.
~L~.3~%~
- lS - 500-5494 .
The compounds of formula I increase cerebral blood flo~ t as can be sllown by means of the microsphere method on the anaesthetised cat upon adminis~ration of from 30 ~o 50 ~g/kg i.v. or from S0 to 150 ~g/kg i.d.
of the compounds.
The compounds of formula I are therefore indi-.- cate~ ~or use in the treatment of cerebxovascular in-sults.
The compounds of formula I possess calcium-antagonistic activity as indicated in standard tests,for example by an inhibition of a calci~m induced con-traction of isolated dog coronary arteries suspended in a depolarizing solution at concentration o lO 10 to lO 8 ~ of the compounds according to the pri~ci-lS ples of Godfraind and Kaba, Brit, J. Pharm. 36, 54~-560, 1969.
The compounds of formula I are thereCore indi-cated for use as spasmolytic agents for the treatment of spasms of muscles. For the above indicatio~ an inai-cated daily dose is from about 5 to lO0 mg, conve-n~ently administered in divided doses 2 to 4 times a day in unit dosage form con~aining from abo~t 1.25 mg to about 50 mg, or in sustained release form.
Ad~itionally, the compounds of formula I ex-hibit antihypertensive activity, as indica~ed in s~an-dard tests, e.g. in the C.rollman rat test ~see ~. Groll-, ~
- 16 - ~ ~ ~ ~ ~ ~ 500-5494 man, Proc. Soc. Expt. Biol. and Med~ 57, 104 ~1944)] on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compounds.
The compounds of formula I are therefore fur-ther indicated for use as antihypertensive asents. For this use an indicated daily dose is from about 5 to about lO00 mg, conveniently given in divided doses 2 to 4 times a day in unit dosa~e form containing about 1.25 mg to about 500 mg, or in sustained release form.
, A compound of formula I may be administered in ree base form. ~lternatively any sufficiently basic compound of formula I, e.g. those compounds wherein R3 or R4 contain an amino moiety, may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms. The present inven-tion also provides a pharmaceutical composition com-prising a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniaues to be in conventional forms, for example capsules or tablets.
The compounds of Examples l, 8 and 16 are the preferred compounds. The coronary insufficiency, the intermittent claudication, the cerebrovascular in-sufficiency and the spasmolytic activities are thepreferred utilities for compounds of formula I.
., .
' ' - 17 - ~ ~3~ 500-54g4 ( In one group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6~' alkoxy-alkyl(C3 6)~ alkenyl(C3 6)~ alkinyl(C3 6)~ cyclo-alkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7 9) or phenylalkenyl(C9 12)~ the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy (Cl_4~, R2 and R5, independently, are hydrogen, alkyl(Cl 6) or phen~lalkyl(C7_10)t R3 and R4, independently are CN, COP~7, COOR7 or S(O)nR7, wherein n is 0, l or 2, R~ is alkyl(Cl 6)' alkenyl(C3 6)' alkinyl(C3_~), cyclo-alkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxyalkyl (C2 6)~ alkoxyalkyl(C3 6), hydroxyalkoxyalkyl(C4 8)~
aminoalkyl(C2_6), alkyl(Cl_4)aminoa1kyl(C2 6), phenyl, phenylalkyl(C7 10)~ a 5- or 6-membered heterocyc~ c ring containing one heteroatom se-lected from nitrogen, oxygen or sulphur, or alkyl (Cl 4) substi~uted by a 5- or 6-membered hetero-cyclic ring containing one heteroatom selected from nitrogen,oxygen or sulphur, R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl_4), trifluoro-methyl, nitro, hydro~y, azido,amino, alkyl(C1 4)-~a .
. .
, ~ 18 - ~3~%~ 500-5494 ami.no, alkanoyl(Cl 5)amino/ carbalkoxy(C2 4), amino-carbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl-tCl 4)sulfamyl or di[alkyl(Cl 4)]sulfamyl, and X is oxy~en or sulphur, with the proviso tllat when R
is hydrogen, alkyl(C1_6), alkenyl(C3_6), alkinyl (C3 ~), cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7 9) or phenylalkenyl(C9 12)~ the phe-nylrin~ being unsubstituted or mono-, di- or tri-substituted independently by halogenr hydroxy, alkyl(Cl_4) or alkoxy(C]_4)~
R2.and R5, indepenclently, are hydrogen or alkyl(Cl 4), R6 is hydrogen, halogen, alkyl(Cl_4), alkoxy(Cl_4) f alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one of the sub-stituents R3 and R4 is other than COR7I, wherein R I is alkyl(Cl_6), alkenYl(C3_6~ 3 6 cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~ and is other than COO~7II, wherein R7II is alkyl(Cl 6)~ alkenyl (C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-alkyl(C4_8), hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6) or hydroxyalkoxyalkyl(C4 8) In another group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)/ alkoxy-alkyl(C3 6) ~ alkenyl(C3 6) f alkinyl(C3 6)' cyclo-alkyl(C3 7)~ cycloalkylalkyl(C~ 8)~ phenylalkyl(C7 9) ,,, ., ~ .. ,, . .. . :
' - 19 - ~3~22~ ~00-5494 ( or phenylalkenyl(Cg 12)~ the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl ~) or alkoxy (Cl_4) ~
R2 and R5, independently, are hydrogen, alkyl(Cl 6) or phenylalkyl (C7_10), ~R8 R is COO-A-N , and ~R
R4 is CN, COR7, COOR7, S(O)nR7 or COO-A-N ~ 8, wherein n is 2, R is alkyl(Cl_6), alkenyl(C3_6), 3 6 cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxy-alkyl(C2 6)~ alkoxyalkyl(C3_6), hydroxyalkoxy-alkyl(C4 8)~ aminoalkyl(C2 6)~ alkyl(Cl 4)amino-alkyl(C2_6), phenyl or phenylalkyl(C7_10), A is alkylene(Cl_6), R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or alkinyl(C3 6)' cycloalkyl(C3 7), cycloalkylalkyl (C4 8)~ hydroxyal}cyl(C~ 6)~ alkoxyal~yl(C3 6~' hy-droxyalkoxyalkyl(C4 ~), aminoalkyl(C2 6)' alkyl-(Cl_4)aminoal.kyl(c2_6)~ phenyl, phenylalkyl(C7_1 n or R8 and Rg together with the ni~rogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heterome~er selected from oxygen, ~ulphur and a group -N-Rl~, wherein Rlo is alkyl (Cl_4~, and ...... .... .. . . . .
:
_ 20 ~ ~ ~ ~ ~ 500~5494 ( R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(C~
alkylthio(Cl 4), alkylsulLonyl(Cl 4), trifiuoro-methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-amino, alkanoyl(Cl 5)amino, carbalkoxy(C2 5), amino-carbonyl, trifluoromethoxy, cyano or sulfamyl, and X is oxygen or sulphur.
In another group o~ compounds Rl is hydrogen, alkyl(Cl_6), alkenyl(C3_6), alkinyl (C3 6)~ cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~
phenylalkyl(C7 9~ or ~henylalkenyl(Cg 12)' the phenyl ring being unsubstituted or mono-, di-or trisubstituted independently by halogen, hydroxy, alkyl(Cl_4) or alkoxy~Cl_4), R2 and R5, independently, are hydrogen, alkyl~Cl 6)~
phenylalkyl(c7_10), cycloalkyl(C3_7) or cycloalkyl-alkyl (C~_8), R3 and Ra~ independently, are COR7I or COOR7II, wherein R7I is alkyl(Cl_6), alkenyl(C3_6), alkinyl(~3_6), cycloalkyl(C3_7), cycloalkylalkyl(C4_8~, and ~7II
is alkyl(Cl 6)~ alkenyl(C3_6), alkinyl(C3_6)r cycloalkyl(C3 7~, cycloalkylalkyl(C4_8), hydroxy-alkyl(C2 6)~ alkoxyalkyl(C3 6j or hydroxyalkoxyalkyl (C4~
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro or hydroxy, and .
ZZ~
_ 21 _ 500-5494 X is oxygen or sulphur, with the proviso, that at least one of the substituents R2 and R5 is phenylalkyl (C7 10)~ cycloalkyl.(C3 7) or cycloalkylal~yl(C4 8) A group of compounds are compounds of formula I, wherein Rl is alkyl(Cl 6)' alkoxyalkyl(C3 6)' alkenyl(C3 6)' alkinyl(C3 6)~ cycloalkyl(C3 7), R2 and R5, independently, are hydrogen or alkyl~Cl 6)' R3 and R4, independently, are COOR7, wherein R7 is other than phenylalkyl.
These compounds show surprisingly benefic al pharmacological activity than is expected for co~-pounds of this type, e.g. long lasting coronary lS suffic-ency activity in the tests mentioned above and good tolerability.
- In another group Rl lS alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-alkyl(C3 6)' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-alkyl(C3 7?, cycloalk~rlalkyl(C4 8~' phenylalkyl (~7 9) or phenylalkenyl(Cg 12~ the phenyL ring beins un-substituted or mono~, di- or trisubstituted indepen~
dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy ( Cl_ 4 ~ , R2 and R5, independently, are hydrogen, alkyl(Cl 6)~
Y ( 7-10)~ cycloalkyl(C3~7) or cycloalkyl-alkyl(c4-8)~ ~
. ~ ~
.~i .
:: : : .
- 22 - ~ ~3~ 500-54g~
( R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or COO-A-N 8, wherein n, R7, ~, R8 and Rg and subject to the proviso as defined above, provided that R3 and R4 are not both COOR7, wherein R7 is alkyl(Cl 6) In another group of compounds Rl is alkyl(Cl_6), alkenyl(C3_6), alkinyl(C3 6)' cyclo~
alkyl(C3 7), R2 and R5, independently, are hydrogen or alkyl(Cl_6), R3 and R4, independently, are C~, COR7, COOR7, S(O)nR7 /R~
or COO-A-N , wherein n, R7, A, R8 and Rg and subject to the proviso as defined above and pro-vided that R3 and R4 are not both COOR7, wherein R7 is alkYl(C1-6) In a sub-group R6 is alkylsulfonyl~Cl 4), hydroxy, azido, amino, a~kyl(Cl 4)amino, ai ~alkyl~Cl ~)]
amino, alkanoyl(Cl 5)amino, aminocarbonyl, tri-fluoro-methoxy, sulfamyl, alkyl(Cl ~)sulfamyl or di[alkyl (cl-4)]sulfamyl.
In another group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-alkyl(C3 6~' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-, ~
-- 2 3 ~ 2~B 5 ~ 0 5 4 9 4 alkyl (C3 7?, ycloalkylall;yl (C4_~), phenylall;yl (C.~ _3) or phenylal~enyJ.(C9 12)~ the phenyl ring bci.n~ un-substi.~u~ed or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4~ or zlkoxy S (C
R2 and R5, independently, are hydrosen, alkyl(Cl 6)~
phen~l21kyl(c7_l0), cYcloalkyl(c3-7) or cycloalkyl-allcyl (C4_8 ) ~
R3 and R4, independently are C~, COR7, COOR7, S (O) nX7 lQ or COO-~-N ~ 8, wherei.n n, R7, A, R3 and Rg ~ sub-ject to the proviso as defined above, provi.ded thzt R3 and R4 are not independently COR7, wherein R7 is alkyl(Cl 6)~ alkenyl(C3 6)~ al]cinyl(C3 6) or CGOR7, wherein R7 is other than phenyl or phenylalkyl as defined above.
The present invention relates to benzoxadia-zoles and benzothiadiazoles having a 4-dihydropyridine moiety.
The present invention provides in particular compounds of formula I, .. ~ N
R ~ ~=N
Il 11 R5 ~ ¦ R2 R
wherein : .
R1 is hydrogen, alkyl(Cl ~), hydroxyalkyl(C2 ~), alkoxy-alkyl(C3 6)~ alkenyl(C3_6), a].kinyl(C3 6)~ cyclo-L.~
'~
' ~3~Z8 s00-5494 r alkyl(C3_7), cycloalkylalkyl(C4 8)~ phenylalkyl (C7 9 or phenylalkenyl(Cg 12)~ the phenyl ring heing un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy ( 1-4)' R2 and R5, independently, are hydrogen, alkyl(Cl 6)' PhenYlalkYl(c7_l0)~ cycloalkyl(C3 7) or cycloalkyl-yl(C4_3), R3 and R4, independently are CN, COR7, COOR7, SIO)nR7 or COO-A-N ~ 8, where-n n is 0, 1 or 2, R7 is alkyl(Cl_6), alkenyl(C3_6), alkinyl(c3 6)' cyclo-alkyl(C3 7), cycloalkylalkyl(C4 83~ hydroxyalkyl (C2 6)~ alkoxyalkyl(C3 6)~ hydroxyalkoxyalkyl(C4 g), y (C2_6), alkYl(Cl_4)aminoalkYl(C2 6~ di[al-kyl(C1 4)~aminoalkyl, phenyl, phenylalkyl~C7 10)~ a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or suIphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, or alkyl(C1_~) substituted by a 5- or 6-mem-bered heterocyclic ring containing one heteroatom selëcted from nit:rogen, oxygen or suIp~ur and may contain additionally 1, 2 or 3 ring nitrogen atoms, A is alkylene(~ 6)~
.
,,., ,. ,,,, ... ~ ~ :
~; _ 3 ~3~Z~
. 500-5494 ( -R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or alkinyl(C3 6)' cycloalkyl(C3 7), cycloallcylalkyl (C4 8)~ hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6)~ hy-droxyalkoxyalkyl(C4 8)' aminoalkyl(C2 6)' alkyl-(Cl_4)aminoalkyl(C2_6), di[alkyl(Cl_4)]aminoalkyl, phenyl, phenylalkyl(C7_10), or R8 and Rg together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heteromember selected from oxygen, sulphur and a group --N-Rlo, wherein Rlo is alkyl (Cl_4), and R6 is hydrogen, haloaen, alkyl(Cl 4), alkoxy(Cl_4), alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-amino, di[alkyl(Cl ~)~amino, alkanoyl(Cl_5)amino, carbalkoxy(C2 5), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(Cl 4)sulfamyl or di[alkyl (Cl_4)]sulfamyl, and X is oxy~en or sulphur, with the proviso that when Rl -is hydrogen, alkyl(Cl ~), alkenyl~C3 6)' alkinyl (C3 6)~ cycloalkyl(C3_7), cycloalkylalkyl(C4 8)~
phenylalkyl~C7 9) or phenylalkenyl(Cg 12)' the phe-nylring being unsubstituted or mono-, di- or tri-substituted independently by halogen, hydroxy, alkyl(Cl_4) or alkoxy(Cl_4), R2.and R5, independently, ~re hyd~ogen or alkyl(Cl ~), Z;i~8 _ ~ _ 500-5494 (~ .
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl ~), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one o~ the sub-.stituents R3 and R4 is other than COR7I, wherein R7I is alkyl(Cl 6)~ alkenyl(C3 6j, alkinyl(C3_6), cycloalkyl~C3 7), cycloalkylalkyl(C4 8)' and is other than COOR7II, wherein R7II is alkyl(Cl 6)~ alkenyl (C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-allcyl(C4 8)' hydroxyalkyl(C2 6)' alkoxyalkyl(C3 6) or hydroxyalkoxyalkyl(C~ 8) In any of the above radicals alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 to 2 carbon atoms. The hy-droxy, alkoxy, hydroxyalkoxy, amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in COOR7 is pre ferably not attached to the a-carbon atom and is pre-ferably attached to the distal terminal carbon atom.
Any hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably has an ethylene or propylene moiety substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino respectively.
The alkyl moiety of cycloalkylalkyl is conveniently '~
3~2~8 _ 5 _ 500-5494 ( methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine. Cycloalkyl or the cyclo-alkyl moiety oE cycloalkylalkyl is conveniently cyclo-propyl or cyclopen~yl or cyclohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in Rl or COOR7 is preferably not in the a,~ position. Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is conve-niently allyl or 2-methylallyl. Alkinyl is convenient]y propinyl. Phenylalkenyl preferably has the trans-confi-guration and is for example cinnamyl. When Rl is optio-nally substituted phenylalkyl, the phenyl group is pre-ferably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same.
When R7 is alkyl, this is preferably branched.
When R7 contains a heterocyclic ring this may be for example furyl, thienyl, pyrrolyl, thiazolyl, isothia-æolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, mor-pholinyl or triazinyl.
When R8 and Rg together with the nitrogen atom to which they are bound, form a heterocyclic ring, this is preferably saturated and may be for example pyrroli-dine, piperidine, piperazine, N-alkylpiperazine, morpho-line, -azepane, di~ze~ane or M-alkyl-diazepane.
. . , , ' - 6 - ~ ~3~Z~ 500-5494 Rl is conveniently hydrogen. R2 is convenien'ly identical to R5. R2 is conveniently alkyl. R3 and/or R4 is conveniently COOR7 or COO-A-N 8. R7 is con-venientl~ alkyl, preferably branched or alkoxyalkyl, where the alkoxy moiety is preferably branched. A is conveniently ethylene~ R8 and Rg are conveniently alkyl or phenylalkyl.
The present invention also provides a process .~ -for the production of a compound of formula I as de-fined above, comprising replacing the moiety -HC=Y in a compound of formula II, R6 _N\
~X II
~IC=Y
wherein R6 and ~ are as defined a~ove, and --~C-Y is i~ for~
ii) a radical of forJnula -~C-C-C(=Z)R2 - ~ Hc-c(=~)x2 lii) a xadical of formula -HC
`~HC-C(=Z')R5 R~
wherein ~ and Z' are independently oxy-~en or I~Rl, and Rl to ~5 are as define~ above, by a moiety of ~ormula III, ,, . .. . _ ... ..
::
,: : . , .:
~3~28 500_5494 -R4 ~ 3 ~ ~ III
5 ~ R2 ~1 ..
erein ~1 to R5 are as defined above.
The process may be efected in conventional manner for analogous dihydrop~ridine syntheses, e.s.
according to Hantzsch. ~hen the moiety ~I~C=Y is formyl and when it is desired to produce a compound of f,ormula ~, wherein R2 is identical to R5 and ~3 is identical to R~, it is convenient to react a compowld of rormula II
with a compound o~ fo~mula IV, ~herein R4 and R5 are as define~ above, in the presence of a compound of formala V, H2NRl V
~ ~herein Rl is as de~lne~ a)~ove.
Preferably at least 2 moles of a compound of formula IV per mole of a compound of fo~mula II are present. Alternatively a compound of formula II may be reacted with a compound o~ formula VI, R5-C(NH-Rl)=CH-~4 VI
~7herein Rl, P~ and ~5 are as defined above.
Preerabl~ at least 2 moles of a corp~und o~ for-mula VI per mole of a compound o~ for~ula II are present.
Pre~erably also ~1 is hydrG.~en.
;~ .
. _, .. _ ,.. .... .. .. ..
, .
~ _- 8 ~3~ZZ8 5~0-549~--l~hen he moiet~- -HC=Y is for~yl and ~refer2~1y when it is desired to produce a com~o~d of Lormula I
wherein ~2 is dif erent to R5 and/or R3 is difLeren~ to R~, it is also possible to xeact such a co~pound of formula II with a compound of ~orrula IV and a compound of fol~ula VII, R -C(NH-R 1=CH~R ~ VII
wherein R2, Rl and R3 are as de~ined above.
It will be appreciated that a compound of formula VI may be formed as an intermediate during the reaction of a compound of for~ula IV and a compound of formula V. A
compound of formula II, ~herein -HC-~ is a radical ii) or iii), may be formed as an inte~lediate in the above reactions. They may however ~e produced by dif erent pro-cesses.
Alternatively or particularly for the prcd~ctio~
of a compound o~ formula I, t7herein R2 is different to K5 and/or R3 is different to R4, it is convenient to react a compound o~ fonm~la II, wherein the moiety -HC=Y is a ra-dical ii) ~7ith a compound of formula IV or VI~
and t~here appropriate, wlth a compound of fGrmula V. A
co~.pound of ol-mula II, wherein ~he moiety -HC=Y is a radical iii) ma~ be an intermediate.
'~J: .
~: , :
~3~Z~3 _ _~ 9 _ 500-5~94 In tl~ abo~e reac'~ions it is possi~le in certa-n installCes ~I;en ~2~ R3~ R~ and R5 are not identical that more than one isomer of formula ~ may be formed. If so the3~ may be separated in conventional m2nner, e.g. by .. . , ~ ... ... .. . ... . . . .. .
column or thin layer chromatography~
~ en ti~e starting material is a ccmpound cf formu-la II, wherein -~C=Y is a radical iii), the reaction is a ring cyclisation. ~'hen Z and Z' are both oxygen~ then an amine of formula V should be present.
However, all the abo~!e reactions may be effected under the same conditions.
The reaction may be effected conveniently in solu-tion. ~ suitable sol~ent is water, ethanol, dioxane, di-methyl ormamide, dimethyl sulphoxide, pyridine or glacial acetic acid. Suitable reaction tempexa~ures may be from 20 to 160~ C, preferably from 60 to 120 C.
Insofar as the production of starting ~aterials is not particularly described these compounds are kno.in or may be ~roduced in analoqous manner to kno~m compounds, The basic compounds of formula I may be con-verted into acid addition salt forms in conventional manner and vlce versa. Suitable acids are e.g. maleic ' :
1 3~
- 10 - 500_54~4 acid, oxalic acid, methanesulphonic acid, hydrochloric acid and hydrobromic acid.
In the following Examples the temperatures given are in degrees Centigrade and are uncorrected.
- - :- ,-. : , ~j ~ ~ 500-549~
~' Example 1: ~-(2,1,3-Benzoxadiaz~1-4-Yl)-2,6-dimethyl-1,4-dihydro-3-methoxyearbonyl-pyridine-5-carboxylic acid benzyl ester 3,0 g of 2,1,3-benzoxadiazol-4-aldehyde, 3,9 g of aeetoacetic acid benzyl ester, 2,3 g of 3-amino cro-tonie aeid methyl ester and 10 ml of ethanol are re-fluxed for 6 hours. The mixture is subsequently evapo-rated and the residual oil is ehromatographed on silica gel with ehloroform/aeetie aeid ethyl ester (8:1) to yield the title compound. The product is reerystallised from cyeiohëxane/diisopropylether, m.p. 131-136.
By using the process described in Example 1, ard corresponding starting compounds, e.g. a eompound of formula II, wherein -HC-Y is a radieal i~ and eom-pounds of formula IV and V, and for Examplec 2-9 and 12-16 a eompound of formula II, wherein HC=Y is a radieal ii), wherein Z is oxygen and a eompound of formula VI, the following eompounds of formula I may ke obtained, wherein y indieates the position of the dihydropyridine moiety:
.... .
:, ,. ~, ~L~3~28 500-5494 U) ~ *
~ ,nr~ o ,~ ~ ~r In ~ ~ O~ ~ ~ a) ~
N O t~ O C~ 1` a~ 111 ~ (~) 1` tJI ~15 ~I N ~I -1 ~I N ~/ ~ 1 ~1 0 ~1 I I I I I I I I I ~ I h 1 N O ~) OD E~ ~D F
N O
X: O O OU~ U~ O O U~ O U~ O U~
:
n ~ C X X m :~ ~c x U
: :
N N
--~
. ~ O ~) ~ z æ
. ~ N N
m ntn o u~ Lr) ~ N IS ) . I ~ ~ ~ ~ ~ m m . ~1 ~ N N ~ X N N U U N N
. I U U~ ) U ~D U ~ U C ) O N o o o C_) o o o o o o ~r O O o o o O o o o o o o u u~ u ~ u u u u ~ u ~
.
u~
~ ~ $
. ~D ~O
N t`') N N N N N
\ / \ /
Z Z :Z æ Z Z
N N N ~`3 N t~l _ ^~ --~ ~ N
C X
U ~ U U U ~ U U
O O O O O O O O
Z o æ Z Z o o o o o o ~; u u u u u c~ ~ u u ~ ~) u :C x m ~ u C~ ~u m ~ u[ ~ a I ~
X N ~ ~ o~ o ~t ~ ~7 ~ . ~
'~ .
, .' .
.
c ~ ~ 3~2%~
~.
'n r~ o ~
a~ ID N~1 ,_~
. I ~ ~ I I
~ 4 ~I r l t~ I O OC~ O ~D
E; o o In In ~ ~r ~ ~r ' ~ ~r X U~ O O O O O O O
~D
~'~ ~ ~ <
n ~: X m x :~ / / ~:
~; ~ o \ \
In n n n m ~ m ~ ~ :~
m ~ x ~ U
o o o o o o o o ~ O O Q O O O O O
P;' C~ V U ~ C~ U
Ln n In ~ s :c ~) ~ ~) t~l ~ N
m m m ~ m x ~ U C) O ~ C~ In \ I \ / . \/ ~
Z Z Z
^ ^ ~ ~3 ~ ~ ~ U~ In ~
~ :~ m :~ ~ ~ m X ~ O
_ _ ~ U ~ ~ ~ ~
o o o o o o o o o o o o o o o o V V
~ a O ~
c~ m <1<1<1<1 ~ ~
o o :~ m 5: ~ m u ~
X ~r In ~ ~ O -I
W
: .
.
~ 4 _ ~ ~3~ 500-54~4 C
The compounds of formula I exhibit pharmacolo-: gical activity. In particular, they lead to a dilation of the coronary vessels as 2emonstrated by the results of tests measuring the blood flow to the myocardi~m of S an anaesthetised cat by means of the microsphere me~hod (Rudolph A.~l. and l~eymann M.S.: Circulation Research 21, 163, 1967) upon administration of from 30 to 50 ,ug/kg i.v. or of from 50 to 150 ~ug~k~ i.d. of the active sub-stance.
The compounds of formula I also possess a fa-vourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the ~ctive substance.
- The compounds of formula I are thereore indi-cated for use in the treatment of coronary insuffi-: ciency.
The compounds of formula I increase the blood flow to limbs, e~g. leg musculature, as can be shown b~ means of the microsphere method on the anaesthetise~
cat upon administration of from 30 to 50 ~gJkg i.v. or from 50 to 150 ~g/~g i.d. of the compounds.
The compounds of formula I are therefore indi-cated for use in the treatment of interm1ttent claudi-cation and other peripheral disturbances of blood - 25 flow to limb muscles.
,",~
. ~ , . . :
,. ~ , , , , , ~
.
~L~.3~%~
- lS - 500-5494 .
The compounds of formula I increase cerebral blood flo~ t as can be sllown by means of the microsphere method on the anaesthetised cat upon adminis~ration of from 30 ~o 50 ~g/kg i.v. or from S0 to 150 ~g/kg i.d.
of the compounds.
The compounds of formula I are therefore indi-.- cate~ ~or use in the treatment of cerebxovascular in-sults.
The compounds of formula I possess calcium-antagonistic activity as indicated in standard tests,for example by an inhibition of a calci~m induced con-traction of isolated dog coronary arteries suspended in a depolarizing solution at concentration o lO 10 to lO 8 ~ of the compounds according to the pri~ci-lS ples of Godfraind and Kaba, Brit, J. Pharm. 36, 54~-560, 1969.
The compounds of formula I are thereCore indi-cated for use as spasmolytic agents for the treatment of spasms of muscles. For the above indicatio~ an inai-cated daily dose is from about 5 to lO0 mg, conve-n~ently administered in divided doses 2 to 4 times a day in unit dosage form con~aining from abo~t 1.25 mg to about 50 mg, or in sustained release form.
Ad~itionally, the compounds of formula I ex-hibit antihypertensive activity, as indica~ed in s~an-dard tests, e.g. in the C.rollman rat test ~see ~. Groll-, ~
- 16 - ~ ~ ~ ~ ~ ~ 500-5494 man, Proc. Soc. Expt. Biol. and Med~ 57, 104 ~1944)] on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compounds.
The compounds of formula I are therefore fur-ther indicated for use as antihypertensive asents. For this use an indicated daily dose is from about 5 to about lO00 mg, conveniently given in divided doses 2 to 4 times a day in unit dosa~e form containing about 1.25 mg to about 500 mg, or in sustained release form.
, A compound of formula I may be administered in ree base form. ~lternatively any sufficiently basic compound of formula I, e.g. those compounds wherein R3 or R4 contain an amino moiety, may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms. The present inven-tion also provides a pharmaceutical composition com-prising a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniaues to be in conventional forms, for example capsules or tablets.
The compounds of Examples l, 8 and 16 are the preferred compounds. The coronary insufficiency, the intermittent claudication, the cerebrovascular in-sufficiency and the spasmolytic activities are thepreferred utilities for compounds of formula I.
., .
' ' - 17 - ~ ~3~ 500-54g4 ( In one group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6~' alkoxy-alkyl(C3 6)~ alkenyl(C3 6)~ alkinyl(C3 6)~ cyclo-alkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7 9) or phenylalkenyl(C9 12)~ the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy (Cl_4~, R2 and R5, independently, are hydrogen, alkyl(Cl 6) or phen~lalkyl(C7_10)t R3 and R4, independently are CN, COP~7, COOR7 or S(O)nR7, wherein n is 0, l or 2, R~ is alkyl(Cl 6)' alkenyl(C3 6)' alkinyl(C3_~), cyclo-alkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxyalkyl (C2 6)~ alkoxyalkyl(C3 6), hydroxyalkoxyalkyl(C4 8)~
aminoalkyl(C2_6), alkyl(Cl_4)aminoa1kyl(C2 6), phenyl, phenylalkyl(C7 10)~ a 5- or 6-membered heterocyc~ c ring containing one heteroatom se-lected from nitrogen, oxygen or sulphur, or alkyl (Cl 4) substi~uted by a 5- or 6-membered hetero-cyclic ring containing one heteroatom selected from nitrogen,oxygen or sulphur, R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl_4), trifluoro-methyl, nitro, hydro~y, azido,amino, alkyl(C1 4)-~a .
. .
, ~ 18 - ~3~%~ 500-5494 ami.no, alkanoyl(Cl 5)amino/ carbalkoxy(C2 4), amino-carbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl-tCl 4)sulfamyl or di[alkyl(Cl 4)]sulfamyl, and X is oxy~en or sulphur, with the proviso tllat when R
is hydrogen, alkyl(C1_6), alkenyl(C3_6), alkinyl (C3 ~), cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7 9) or phenylalkenyl(C9 12)~ the phe-nylrin~ being unsubstituted or mono-, di- or tri-substituted independently by halogenr hydroxy, alkyl(Cl_4) or alkoxy(C]_4)~
R2.and R5, indepenclently, are hydrogen or alkyl(Cl 4), R6 is hydrogen, halogen, alkyl(Cl_4), alkoxy(Cl_4) f alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one of the sub-stituents R3 and R4 is other than COR7I, wherein R I is alkyl(Cl_6), alkenYl(C3_6~ 3 6 cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~ and is other than COO~7II, wherein R7II is alkyl(Cl 6)~ alkenyl (C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-alkyl(C4_8), hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6) or hydroxyalkoxyalkyl(C4 8) In another group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)/ alkoxy-alkyl(C3 6) ~ alkenyl(C3 6) f alkinyl(C3 6)' cyclo-alkyl(C3 7)~ cycloalkylalkyl(C~ 8)~ phenylalkyl(C7 9) ,,, ., ~ .. ,, . .. . :
' - 19 - ~3~22~ ~00-5494 ( or phenylalkenyl(Cg 12)~ the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl ~) or alkoxy (Cl_4) ~
R2 and R5, independently, are hydrogen, alkyl(Cl 6) or phenylalkyl (C7_10), ~R8 R is COO-A-N , and ~R
R4 is CN, COR7, COOR7, S(O)nR7 or COO-A-N ~ 8, wherein n is 2, R is alkyl(Cl_6), alkenyl(C3_6), 3 6 cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxy-alkyl(C2 6)~ alkoxyalkyl(C3_6), hydroxyalkoxy-alkyl(C4 8)~ aminoalkyl(C2 6)~ alkyl(Cl 4)amino-alkyl(C2_6), phenyl or phenylalkyl(C7_10), A is alkylene(Cl_6), R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or alkinyl(C3 6)' cycloalkyl(C3 7), cycloalkylalkyl (C4 8)~ hydroxyal}cyl(C~ 6)~ alkoxyal~yl(C3 6~' hy-droxyalkoxyalkyl(C4 ~), aminoalkyl(C2 6)' alkyl-(Cl_4)aminoal.kyl(c2_6)~ phenyl, phenylalkyl(C7_1 n or R8 and Rg together with the ni~rogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heterome~er selected from oxygen, ~ulphur and a group -N-Rl~, wherein Rlo is alkyl (Cl_4~, and ...... .... .. . . . .
:
_ 20 ~ ~ ~ ~ ~ 500~5494 ( R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(C~
alkylthio(Cl 4), alkylsulLonyl(Cl 4), trifiuoro-methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-amino, alkanoyl(Cl 5)amino, carbalkoxy(C2 5), amino-carbonyl, trifluoromethoxy, cyano or sulfamyl, and X is oxygen or sulphur.
In another group o~ compounds Rl is hydrogen, alkyl(Cl_6), alkenyl(C3_6), alkinyl (C3 6)~ cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~
phenylalkyl(C7 9~ or ~henylalkenyl(Cg 12)' the phenyl ring being unsubstituted or mono-, di-or trisubstituted independently by halogen, hydroxy, alkyl(Cl_4) or alkoxy~Cl_4), R2 and R5, independently, are hydrogen, alkyl~Cl 6)~
phenylalkyl(c7_10), cycloalkyl(C3_7) or cycloalkyl-alkyl (C~_8), R3 and Ra~ independently, are COR7I or COOR7II, wherein R7I is alkyl(Cl_6), alkenyl(C3_6), alkinyl(~3_6), cycloalkyl(C3_7), cycloalkylalkyl(C4_8~, and ~7II
is alkyl(Cl 6)~ alkenyl(C3_6), alkinyl(C3_6)r cycloalkyl(C3 7~, cycloalkylalkyl(C4_8), hydroxy-alkyl(C2 6)~ alkoxyalkyl(C3 6j or hydroxyalkoxyalkyl (C4~
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4), alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-methyl, nitro or hydroxy, and .
ZZ~
_ 21 _ 500-5494 X is oxygen or sulphur, with the proviso, that at least one of the substituents R2 and R5 is phenylalkyl (C7 10)~ cycloalkyl.(C3 7) or cycloalkylal~yl(C4 8) A group of compounds are compounds of formula I, wherein Rl is alkyl(Cl 6)' alkoxyalkyl(C3 6)' alkenyl(C3 6)' alkinyl(C3 6)~ cycloalkyl(C3 7), R2 and R5, independently, are hydrogen or alkyl~Cl 6)' R3 and R4, independently, are COOR7, wherein R7 is other than phenylalkyl.
These compounds show surprisingly benefic al pharmacological activity than is expected for co~-pounds of this type, e.g. long lasting coronary lS suffic-ency activity in the tests mentioned above and good tolerability.
- In another group Rl lS alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-alkyl(C3 6)' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-alkyl(C3 7?, cycloalk~rlalkyl(C4 8~' phenylalkyl (~7 9) or phenylalkenyl(Cg 12~ the phenyL ring beins un-substituted or mono~, di- or trisubstituted indepen~
dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy ( Cl_ 4 ~ , R2 and R5, independently, are hydrogen, alkyl(Cl 6)~
Y ( 7-10)~ cycloalkyl(C3~7) or cycloalkyl-alkyl(c4-8)~ ~
. ~ ~
.~i .
:: : : .
- 22 - ~ ~3~ 500-54g~
( R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or COO-A-N 8, wherein n, R7, ~, R8 and Rg and subject to the proviso as defined above, provided that R3 and R4 are not both COOR7, wherein R7 is alkyl(Cl 6) In another group of compounds Rl is alkyl(Cl_6), alkenyl(C3_6), alkinyl(C3 6)' cyclo~
alkyl(C3 7), R2 and R5, independently, are hydrogen or alkyl(Cl_6), R3 and R4, independently, are C~, COR7, COOR7, S(O)nR7 /R~
or COO-A-N , wherein n, R7, A, R8 and Rg and subject to the proviso as defined above and pro-vided that R3 and R4 are not both COOR7, wherein R7 is alkYl(C1-6) In a sub-group R6 is alkylsulfonyl~Cl 4), hydroxy, azido, amino, a~kyl(Cl 4)amino, ai ~alkyl~Cl ~)]
amino, alkanoyl(Cl 5)amino, aminocarbonyl, tri-fluoro-methoxy, sulfamyl, alkyl(Cl ~)sulfamyl or di[alkyl (cl-4)]sulfamyl.
In another group of compounds Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-alkyl(C3 6~' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-, ~
-- 2 3 ~ 2~B 5 ~ 0 5 4 9 4 alkyl (C3 7?, ycloalkylall;yl (C4_~), phenylall;yl (C.~ _3) or phenylal~enyJ.(C9 12)~ the phenyl ring bci.n~ un-substi.~u~ed or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(Cl 4~ or zlkoxy S (C
R2 and R5, independently, are hydrosen, alkyl(Cl 6)~
phen~l21kyl(c7_l0), cYcloalkyl(c3-7) or cycloalkyl-allcyl (C4_8 ) ~
R3 and R4, independently are C~, COR7, COOR7, S (O) nX7 lQ or COO-~-N ~ 8, wherei.n n, R7, A, R3 and Rg ~ sub-ject to the proviso as defined above, provi.ded thzt R3 and R4 are not independently COR7, wherein R7 is alkyl(Cl 6)~ alkenyl(C3 6)~ al]cinyl(C3 6) or CGOR7, wherein R7 is other than phenyl or phenylalkyl as defined above.
Claims (8)
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, alkyl(C1-6), hydroxyalkyl(C2-6), alkoxy-alkyl(C3-6), alkenyl(C3-6), alkinyl(C3-6), cyclo-alkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl (C7-9) or phenylalkenyl(C9-12), the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(C1-4) or alkoxy (C1-4), R2 and R5, independently, are hydrogen, alkyl(C1-6), phenylalkyl(C7-10), cycloalkyl(C3-7) or cycloalkyl-alkyl(C4-8), R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or , wherein n is 0, 1 or 2, R7 is alkyl (C1-6), alkenyl (C3-6), alkinyl (C3-6), cyclo-alkyl(C3-7), cycloalkylalkyl(C4-), hydroxyalkyl (C2-6), alkoxyalkyl(C3-6), hydroxyalkoxyalkyl(C4-8), aminoalkyl (C2-6), alkyl(C1-4)aminoalkyl(C2-6), di[al-kyl(C1-4)] aminoalkyl, phenyl, phenylalkyl(C7-10), a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogenr oxygen or sulphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, or alkyl(C1-4) substituted by a 5- or 6-mem-bered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, A is alkylene(C1-6), R8 and R9, independently, are alkyl(C1-6), alkenyl or alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl (C4-8), hydroxyalkyl(C2-6), alkoxyalkyl(C3-6), hy-droxyalkoxyalkyl(C4-8), aminoalkyl(C2-6), alkyl-(C1-4)aminoalkyl(C2-6), di[alkyl(C1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), or R8 and R9 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heteromember selected from oxygen, sulphur and a group =N-R10, wherein R10 is alkyl (C1-4), and R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoro-methyl, nitro, hydroxy, azido, amino, alkyl(C1-4)-amino, di[alkyl(C1-4)]amino, alkanoyl(C1-5)amino, carbalkoxy(C2-5), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C1-4)sulfamyl or di[alkyl (C1-4)]sulfamyl, and X is oxygen or sulphur, with the proviso that when R1 is hydrogen, alkyl(C1-6), alkenyl(C3-6), alkinyl (C3-6), cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phe-nylring being unsubstituted or mono-, di- or tri-substituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4), R2 and R5, independently, are hydrogen or alkyl(C1-6), R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one of the sub-stituents R3 and R4 is other than COR7I, whersin R7I is alkyl(C1-6), alkenyl(C3-6), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than COOR7II, wherein R7II is alkyl(C1-6), alkenyl (C3-6), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkyl-alkyl(C4-8), hydroxyalkyl(C2-6), alkoxyalkyl(C3-6) or hydroxyalkoxyalkyl(C4-8), which comprises replacing the moiety -HC=Y in a compound of formula II, II
wherein R6 and X are as defined above, and -HC-Y is i) formyl, ii) a radical of formula or iii) a radical of formula wherein 2 and Z' are independently oxy-gen or NR1, and R1 to R5 are as defined above, by a moiety of formula III, III
wherein R1 to R5 are as defined above.
wherein R1 is hydrogen, alkyl(C1-6), hydroxyalkyl(C2-6), alkoxy-alkyl(C3-6), alkenyl(C3-6), alkinyl(C3-6), cyclo-alkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl (C7-9) or phenylalkenyl(C9-12), the phenyl ring being un-substituted or mono-, di- or trisubstituted indepen-dently by halogen, hydroxy, alkyl(C1-4) or alkoxy (C1-4), R2 and R5, independently, are hydrogen, alkyl(C1-6), phenylalkyl(C7-10), cycloalkyl(C3-7) or cycloalkyl-alkyl(C4-8), R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or , wherein n is 0, 1 or 2, R7 is alkyl (C1-6), alkenyl (C3-6), alkinyl (C3-6), cyclo-alkyl(C3-7), cycloalkylalkyl(C4-), hydroxyalkyl (C2-6), alkoxyalkyl(C3-6), hydroxyalkoxyalkyl(C4-8), aminoalkyl (C2-6), alkyl(C1-4)aminoalkyl(C2-6), di[al-kyl(C1-4)] aminoalkyl, phenyl, phenylalkyl(C7-10), a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogenr oxygen or sulphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, or alkyl(C1-4) substituted by a 5- or 6-mem-bered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally 1, 2 or 3 ring nitrogen atoms, A is alkylene(C1-6), R8 and R9, independently, are alkyl(C1-6), alkenyl or alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl (C4-8), hydroxyalkyl(C2-6), alkoxyalkyl(C3-6), hy-droxyalkoxyalkyl(C4-8), aminoalkyl(C2-6), alkyl-(C1-4)aminoalkyl(C2-6), di[alkyl(C1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), or R8 and R9 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may con-tain a further heteromember selected from oxygen, sulphur and a group =N-R10, wherein R10 is alkyl (C1-4), and R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoro-methyl, nitro, hydroxy, azido, amino, alkyl(C1-4)-amino, di[alkyl(C1-4)]amino, alkanoyl(C1-5)amino, carbalkoxy(C2-5), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C1-4)sulfamyl or di[alkyl (C1-4)]sulfamyl, and X is oxygen or sulphur, with the proviso that when R1 is hydrogen, alkyl(C1-6), alkenyl(C3-6), alkinyl (C3-6), cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phe-nylring being unsubstituted or mono-, di- or tri-substituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4), R2 and R5, independently, are hydrogen or alkyl(C1-6), R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoro-methyl, nitro or hydroxy, and X is oxygen or sulphur, then at least one of the sub-stituents R3 and R4 is other than COR7I, whersin R7I is alkyl(C1-6), alkenyl(C3-6), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than COOR7II, wherein R7II is alkyl(C1-6), alkenyl (C3-6), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkyl-alkyl(C4-8), hydroxyalkyl(C2-6), alkoxyalkyl(C3-6) or hydroxyalkoxyalkyl(C4-8), which comprises replacing the moiety -HC=Y in a compound of formula II, II
wherein R6 and X are as defined above, and -HC-Y is i) formyl, ii) a radical of formula or iii) a radical of formula wherein 2 and Z' are independently oxy-gen or NR1, and R1 to R5 are as defined above, by a moiety of formula III, III
wherein R1 to R5 are as defined above.
2. A compound of formula I, whenever produced by a process according to claim 1.
3. A process for the production of 4-(2,1,3-benz-oxadiazolyl-4-)-2,6-dimethyl-1,4-dihydro-3-methoxy-carbonyl-pyridine-5-carboxylic acid benzyl ester which comprises reacting 2,1,3-benzoxadiazol-4-aldehyde with acetoacetic acid benzyl ester in the presence of 3-amino crotonic acid methyl ester.
4. The compound 4-(2,1,3-benzoxadiazolyl-4)-2,6-dimethyl-1,4-dihydro-3-methoxy-carbonyl-pyridine-5-car-boxylic acid benzyl ester whenever produced by the process of claim 3.
5. A process according to claim 1 wherein R1 is H, R2 is CH3, R3 is , R4 is COOCH3, R5 is CH3, R6 is H, X is 0, and y is 4.
6. The compound 4-(2,1,3-benzoxadiazolyl-4)-2 , 6-dimethyl-1,4-dihydro-3-ethoxycarbonyl-pyridine-5-carboxylic acid)-N-benzyl-N-methyl-2 amino-ethyl ester whenever produced by the process of claim 3.
7. The process according to claim 1 wherein R1 is H, R2 is CH3, R3 is , R4 is COOCH3, R5 is CH3, R6 is H, X is 0 and y is 4.
8. The compound 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-methoxycarbonyl-pyridine-5-car-boxylic acid-N-benzyl-N-methyl-2-amino-ethyl ester, whenever produced by the process of claim 7.
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1288878A CH640852A5 (en) | 1978-12-18 | 1978-12-18 | 1,4-Dihydropyridine derivatives, their preparation and use |
| CH1289078A CH643841A5 (en) | 1978-12-18 | 1978-12-18 | Novel 1,4-dihydropyridine derivatives, their preparation and use |
| CH12888/78 | 1978-12-18 | ||
| CH12890/78 | 1978-12-18 | ||
| CH3472/79 | 1979-04-11 | ||
| CH3477/79 | 1979-04-11 | ||
| CH347279 | 1979-04-11 | ||
| CH347779 | 1979-04-11 | ||
| CH562779 | 1979-06-15 | ||
| CH5627/79 | 1979-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1131228A true CA1131228A (en) | 1982-09-07 |
Family
ID=27509137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA342,085A Expired CA1131228A (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
Country Status (7)
| Country | Link |
|---|---|
| CA (1) | CA1131228A (en) |
| DE (1) | DE2949464A1 (en) |
| GB (1) | GB2041358B (en) |
| IL (1) | IL58974A (en) |
| NZ (1) | NZ192421A (en) |
| PT (1) | PT70601A (en) |
| SE (1) | SE7910151L (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3022030A1 (en) * | 1980-06-12 | 1981-12-17 | Bayer Ag, 5090 Leverkusen | 4-THIAZOLE or 4-IMIDAZOLE-SUBSTITUTED, 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| CH655658B (en) * | 1980-09-18 | 1986-05-15 | ||
| EP0080220B1 (en) * | 1981-11-17 | 1986-02-19 | FISONS plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| ZA83959B (en) * | 1982-03-10 | 1984-09-26 | Sandoz Ltd | 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| EP0094159B1 (en) * | 1982-05-10 | 1990-03-14 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| FR2528431B1 (en) * | 1982-06-15 | 1986-01-10 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
| AU561213B2 (en) * | 1983-06-02 | 1987-04-30 | Teijin Limited | 1, 4-dihydropyridine derivative |
| CH663616A5 (en) * | 1983-06-21 | 1987-12-31 | Sandoz Ag | 1,4-DIHYDROPYRIDINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME. |
| FR2554109A1 (en) * | 1983-11-01 | 1985-05-03 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS AS MEDICAMENTS |
| US4994476A (en) * | 1984-10-31 | 1991-02-19 | Bristol-Myers Company | Dihydropyridin-3,5-dicarboxylates incorporating aryloxypropanolamine moieties |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| IT1201454B (en) * | 1985-08-19 | 1989-02-02 | Boehringer Biochemia Srl | 1,4-dihydropyridine-2-SUBSTITUTED |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670824C3 (en) * | 1967-03-20 | 1978-08-03 | Bayer Ag, 5090 Leverkusen | 1,4-Dihydropyridine-33-dicarboxylic acid alkyl ester |
| DE2117571C3 (en) * | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Asymmetrical 1,4-dihydropyridine-33-dicarboxylic acid esters, process for their preparation and their use as pharmaceuticals |
| DE2218644C3 (en) * | 1972-04-18 | 1982-08-19 | Bayer Ag, 5090 Leverkusen | Basic esters of 1,4-dihydropyridines, processes for their preparation and their use as pharmaceuticals |
| GB1455502A (en) * | 1973-02-20 | 1976-11-10 | Yamanouchi Pharma Co Ltd | 1,4-dihydropyridine derivatives |
| FR2320750A1 (en) * | 1975-08-12 | 1977-03-11 | Hexachimie | 1,4-DIHYDRO PYRIDINES AND THEIR THERAPEUTIC APPLICATION |
| DE2616991A1 (en) * | 1976-04-17 | 1977-10-27 | Bayer Ag | Thio-substd. dihydro-pyridine derivs. - coronary vasodilators and antihypertensives prepd. e.g. by reacting dicarbonyl cpds. with amines and thio-substd. ketones |
| DE2740080A1 (en) * | 1977-09-06 | 1979-03-15 | Bayer Ag | 2-Aminoalkyl-1,4-di:hydro-pyridine derivs. - with broad spectrum of effects on the heart and circulation, e.g. lowering blood pressure and spasmolytic effect |
-
1979
- 1979-12-08 DE DE19792949464 patent/DE2949464A1/en not_active Ceased
- 1979-12-10 SE SE7910151A patent/SE7910151L/en not_active Application Discontinuation
- 1979-12-14 GB GB7943112A patent/GB2041358B/en not_active Expired
- 1979-12-17 NZ NZ192421A patent/NZ192421A/en unknown
- 1979-12-17 PT PT70601A patent/PT70601A/en unknown
- 1979-12-17 IL IL58974A patent/IL58974A/en unknown
- 1979-12-17 CA CA342,085A patent/CA1131228A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NZ192421A (en) | 1982-09-07 |
| PT70601A (en) | 1980-01-01 |
| GB2041358A (en) | 1980-09-10 |
| IL58974A0 (en) | 1980-03-31 |
| SE7910151L (en) | 1980-06-19 |
| GB2041358B (en) | 1982-11-17 |
| DE2949464A1 (en) | 1980-06-26 |
| IL58974A (en) | 1983-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4466972A (en) | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them | |
| CA1131228A (en) | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them | |
| KR880005092A (en) | Novel derivatives of benzimidazoles effective as antiulcers | |
| KR20000070645A (en) | 1-phenyl-4-benzylpiperazines: dopamine receptor subtype specific ligands (d4) | |
| GB2103203A (en) | 1,4-dihydropyridines, their preparation and pharmaceutical compositions containing them | |
| EP0000150B1 (en) | Dihydropyridine derivatives, process for their production and pharmaceutical compositions containing them. | |
| US4656192A (en) | Tropolone derivatives, processes for the preparation thereof and the use thereof as anti-tumor agents | |
| US3823152A (en) | 3-substituted-2-piperidinethiones and homologues thereof | |
| KR880001988B1 (en) | Process for preparing heterocyclic compounds | |
| KR950703557A (en) | Heteroaryl Compounds Used as Pharmaceuticals | |
| US4378359A (en) | Theophyllinylmethyldioxolane derivatives, methods for their preparation and pharmaceutical compositions containing them | |
| JPH01294670A (en) | 2-(piperadinyl)-2-oxoethylene-substituted flavonoid derivative, its production and pharmaceutical composition containing said derivative | |
| SU1395143A3 (en) | Method of producing derivatives of 1,6-naphthyredene in the form of racemates or enantiomers or acid-additive salts thereof | |
| EP0170460B1 (en) | Derivatives of N-[2-(tetrahydro-3,5-dioxo-1H-pyrrolizin-7a(5H)-yl)ethyl]amine | |
| US3794725A (en) | Pharmaceutical compositions containing certain 3-nitro-furyl-4-azolidinylidene-azolones-5 and method of use | |
| US3888983A (en) | Derivatives of thiazolino-pyrimidin-6-ones, in inducing analgesia | |
| US4585589A (en) | Water-soluble alkanoyloxy and alkoxycarbonyloxy rifampicin derivatives, process for its preparation, intermediates, and its pharmaceutical composition as antibacterials | |
| ATE48994T1 (en) | BENZIMIDAZOLE DERIVATIVE, PROCESS FOR ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION. | |
| US4510150A (en) | Pharmaceutical compositions effective against coronary heart disease and hypertension | |
| EP0039919B1 (en) | Benzoxazole and benzothiazole derivatives with anti-allergic activity | |
| US3081302A (en) | Certain-p-acetaminophenoxyacetamido derivatives | |
| US4567271A (en) | Benzoxadiazoles and benzothiadiazoles | |
| US5124325A (en) | Therapeutic agents of metabolic bone disease | |
| US4500708A (en) | Benzothiazine derivatives | |
| US5580894A (en) | Isoxazolyl enaminones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |