CA1105463A - Dihydropyridine-derivatives and their production - Google Patents
Dihydropyridine-derivatives and their productionInfo
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- CA1105463A CA1105463A CA305,727A CA305727A CA1105463A CA 1105463 A CA1105463 A CA 1105463A CA 305727 A CA305727 A CA 305727A CA 1105463 A CA1105463 A CA 1105463A
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- 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
- A61K31/435—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract of the disclosure Compounds of formula I, I
wherein R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkyl-alkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsub-stituted or mono-, di- or trisubstituted in-dependently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, R2 and R5, independently, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl of 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkyalkoxy of 4 to 8 carbon atoms, R6 is hydrogen, halogen, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur are useful for treating coronary insufficiency and hyper-tension.
wherein R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkyl-alkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsub-stituted or mono-, di- or trisubstituted in-dependently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, R2 and R5, independently, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl of 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkyalkoxy of 4 to 8 carbon atoms, R6 is hydrogen, halogen, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur are useful for treating coronary insufficiency and hyper-tension.
Description
I~IPRO~E~IF.I~TS Ii~ OR }~ELATING TO OP~G~NIC COI`r1POl1iJDS
The present invention relates to dihyc~ro-pyridine derivati~es.
The pxesent invention provides co~pounds of formula I, . .
.~, .` ~$~`x R40C~C01~3 . I
R5 ' R2 Rl , wherein Rl is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkyl~
alkyl of 4 to 8 carbon atomS, phenylalkyl of 107 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring bei.ng unsub-stituted or mono-, di- or trisubstltuted in-dependently by haloqen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, lSR2 and R5, independent].y, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl vf 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon ' ~
The present invention relates to dihyc~ro-pyridine derivati~es.
The pxesent invention provides co~pounds of formula I, . .
.~, .` ~$~`x R40C~C01~3 . I
R5 ' R2 Rl , wherein Rl is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkyl~
alkyl of 4 to 8 carbon atomS, phenylalkyl of 107 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring bei.ng unsub-stituted or mono-, di- or trisubstltuted in-dependently by haloqen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, lSR2 and R5, independent].y, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl vf 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon ' ~
- 2 - 500~~5S
.
atoms, cycloalkyl of 3 to 7 carhon atoms, eyeloal]cylalkyl of 4 to 8 carbor. atoms, alkoxy of 1 to 6 earboll atoms, hydroxyalkoxy of 2 to 6 earbon atoms, alkoxyal]coxy of 3 to ~ earbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, eyeloalkyloxy of 3 to ? earbon atoms or eyeloalkylalkoxy of 4 to 8 earbon atoms, R6 is hydro~en, halo~en, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, eaeh of 1 to 4 earbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur.
In any of the above radicals alkyl of 1 to 6 earbon atoms is preferably of 1 to 4 carbon atoms, especi-ally of 1 or 2 earbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl rad1eal of 1 to 4 earbon atoms is prefe-rably of 1 or 2 earbon atoms. The alkyl moiety of cyclo~
alkylalkyl or cyeloalkylalkoxy is eonveniently methyl.
}7alo~en means fluorine, ehlorine or bromine and is espeeially ehlorine. Cyeloalkyl or the eyeloalkyl moiety of eyeloalkylalkyl or eyeloalkylal~oxy is convenientiy eyelopropyl or eyelopentyl or cyclohexyl The multiple bond of alkenyl, alkinyl, alkenYloxy, alkinyloxy or phenylalkenyl is preferably not in the ~ position. Alkenyl, alkenyloxy, a]kinyl or alkinyloxy
.
atoms, cycloalkyl of 3 to 7 carhon atoms, eyeloal]cylalkyl of 4 to 8 carbor. atoms, alkoxy of 1 to 6 earboll atoms, hydroxyalkoxy of 2 to 6 earbon atoms, alkoxyal]coxy of 3 to ~ earbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, eyeloalkyloxy of 3 to ? earbon atoms or eyeloalkylalkoxy of 4 to 8 earbon atoms, R6 is hydro~en, halo~en, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, eaeh of 1 to 4 earbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur.
In any of the above radicals alkyl of 1 to 6 earbon atoms is preferably of 1 to 4 carbon atoms, especi-ally of 1 or 2 earbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl rad1eal of 1 to 4 earbon atoms is prefe-rably of 1 or 2 earbon atoms. The alkyl moiety of cyclo~
alkylalkyl or cyeloalkylalkoxy is eonveniently methyl.
}7alo~en means fluorine, ehlorine or bromine and is espeeially ehlorine. Cyeloalkyl or the eyeloalkyl moiety of eyeloalkylalkyl or eyeloalkylal~oxy is convenientiy eyelopropyl or eyelopentyl or cyclohexyl The multiple bond of alkenyl, alkinyl, alkenYloxy, alkinyloxy or phenylalkenyl is preferably not in the ~ position. Alkenyl, alkenyloxy, a]kinyl or alkinyloxy
- 3 - 500-5~i55 pxeferably has 3 to 5 carbon atoms. Alkenyl or the al-~enyl moiety of alken~loxy is conveniently allyl or 2-methylallyl. Alkinyl or the alkinyl moiety of alkinylo~y is conveniently propinyl. Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl. ~hen Rl is optionally substituted phenylalkyl, the phenyl - group is preferably unsubstituted. I~hen the phenyl group is di- or tri-substituted, preferably the substituents are the same. When R3 and/or R4 is alkoxy, this is preferably `~ ethoxy or methoxy. When R3 and/or R4 is alkoxy-alkoxy or hydroxyalkoxyalkoxy, preferably the carbon chain between the two ether oxy~en atoms is of 2 carbon atoms.
The hydroxy group of hydroxyalkoxy or of hydroxyalkoxy-alkoxy is preferably not attached to the carbon atom lS attached to an ether oxygen atom. Rl is preferably hydro-gen. R2 .is conveniently identical to ~5. R~ and/or R5 is preferahly methyl. R3 and/or R~ Ls preferably alkoxy or alkoxyalkoxy, especially n-butyloxyethoxy. R6 is con-veniently halogen, alkyl or al~oxy, or especially hydro~
gen. R6 is conveniently adjacent to the dihydropyridine moiety which in turn is conveniently in the 4-position.
The present invention also provides a process for the production of a compound of formula I as defined 5~
. ~ .
The hydroxy group of hydroxyalkoxy or of hydroxyalkoxy-alkoxy is preferably not attached to the carbon atom lS attached to an ether oxygen atom. Rl is preferably hydro-gen. R2 .is conveniently identical to ~5. R~ and/or R5 is preferahly methyl. R3 and/or R~ Ls preferably alkoxy or alkoxyalkoxy, especially n-butyloxyethoxy. R6 is con-veniently halogen, alkyl or al~oxy, or especially hydro~
gen. R6 is conveniently adjacent to the dihydropyridine moiety which in turn is conveniently in the 4-position.
The present invention also provides a process for the production of a compound of formula I as defined 5~
. ~ .
- 4 - 500-5455 ' .
above, c~mprising replacing the moiety -HC-Y in a compound of foxmula II, r~.N~
~ /X XI
HC=Y
wherein R6 and x are as defined above, and -HC=Y is i) formyl, ii) a radical of formula -HC=C-C(=Z)R2 or ~ HC-C(-Z)R2 lii) a radical of formula -HC
~HC-C~-æ'~R5 ... COR4 wherein ~ and Z' are independently o~y-gen ol^ NRl, and Rl to ~5 are as defined above, by a moiety of fol^mula III, R~OC ~ COR3 III
wherein Rl to R5 are as defined above.
.
above, c~mprising replacing the moiety -HC-Y in a compound of foxmula II, r~.N~
~ /X XI
HC=Y
wherein R6 and x are as defined above, and -HC=Y is i) formyl, ii) a radical of formula -HC=C-C(=Z)R2 or ~ HC-C(-Z)R2 lii) a radical of formula -HC
~HC-C~-æ'~R5 ... COR4 wherein ~ and Z' are independently o~y-gen ol^ NRl, and Rl to ~5 are as defined above, by a moiety of fol^mula III, R~OC ~ COR3 III
wherein Rl to R5 are as defined above.
.
- 5 - 500-S~SS
' , .
Tlle process may be effected in conventional manner for analogous dihydropyridine syn~heses, e.~.
according to Hantzsch, When the moiety -iIC=Y is fol~yl and when it is desired to produce a compound of :~ormula I, wherein R2 is identical to R5 and R3 is identical to R4, it is convenient to react a compound of formula II
with a compound of formula IV, ~5co-c~l2-co-R~ IV
wherein R~ and R5 are as defined above, in the presence of a compound of formula V, H2N Rl V
wherein Rl is as deflned above.
Preferably at least 2 moles of a compound of formula IV per mole of a compound of formula II are present. Alternatively a compound of formula II may be reacted with a compound of formula VI, 1) R4 VI
wherein Rl~ R~ and R5 are as defined aklove.
Prefera~ly at least 2 moles of a compound of for-mula VI peX mola Df a compound of formula II are presentO
Preferably also Rl is hydrogen.
..
i3
' , .
Tlle process may be effected in conventional manner for analogous dihydropyridine syn~heses, e.~.
according to Hantzsch, When the moiety -iIC=Y is fol~yl and when it is desired to produce a compound of :~ormula I, wherein R2 is identical to R5 and R3 is identical to R4, it is convenient to react a compound of formula II
with a compound of formula IV, ~5co-c~l2-co-R~ IV
wherein R~ and R5 are as defined above, in the presence of a compound of formula V, H2N Rl V
wherein Rl is as deflned above.
Preferably at least 2 moles of a compound of formula IV per mole of a compound of formula II are present. Alternatively a compound of formula II may be reacted with a compound of formula VI, 1) R4 VI
wherein Rl~ R~ and R5 are as defined aklove.
Prefera~ly at least 2 moles of a compound of for-mula VI peX mola Df a compound of formula II are presentO
Preferably also Rl is hydrogen.
..
i3
- 6 ~ 500-5~55 When the moiety -~C~-Y is fo~lyl and pre~erably when it is desired to produce a compound of ~ormula I
wherein R2 i~ different to R5 and/or R3 is different to R4~ it is also possible to react sucll a compound o~ formula II with a compound o~ formula IV and a compound of ormula VII, 2 ( 1) H CO R3 VII
wherein R2, Rl and R3 are as defined above-It will be appreciated that a compound of formula VI may be formed as an in~ermediate during the reaction of a compound of formula IV and a compound of formula V, A
compound of formula II, wherein -HC-Y is a radical ii) or iii), may be formed as an intermediate in the above reactions. They may however be produced by different pro-ce~ses.
lS Alternatively or particularly for the production of a compound of formula I, wherein R2 is different to R5 - and/or R3 is different to R4, it is convenient to react a compound of formula II, wherein the moiety -HC-Y is a ra-dical ii) with a compound of ormula IV or VII
and where appropriate, with a compound of formula V. A
compound of formula II, wherein the moiety -HC=Y is a radical iii) may be an intermediate.
6~
.
wherein R2 i~ different to R5 and/or R3 is different to R4~ it is also possible to react sucll a compound o~ formula II with a compound o~ formula IV and a compound of ormula VII, 2 ( 1) H CO R3 VII
wherein R2, Rl and R3 are as defined above-It will be appreciated that a compound of formula VI may be formed as an in~ermediate during the reaction of a compound of formula IV and a compound of formula V, A
compound of formula II, wherein -HC-Y is a radical ii) or iii), may be formed as an intermediate in the above reactions. They may however be produced by different pro-ce~ses.
lS Alternatively or particularly for the production of a compound of formula I, wherein R2 is different to R5 - and/or R3 is different to R4, it is convenient to react a compound of formula II, wherein the moiety -HC-Y is a ra-dical ii) with a compound of ormula IV or VII
and where appropriate, with a compound of formula V. A
compound of formula II, wherein the moiety -HC=Y is a radical iii) may be an intermediate.
6~
.
- 7 - 500~5~55 In the above reactions it is possi~le in certa-n instances when R2, R3, R4 and R5 are not identical that more than one isomer of formula I may be fo~led. If so these may be sepaxated in conven~ional manner, e,~0 by thin layel~ chromatography.
~ en the sta^ting material is a compound of fol-mu-la II, wherein -HC=Y is a radical iii), the reaction is a ring cyclisation. When Z and Z' are both oxygen, then an am.ine of formula V snould be prcsent.
However, all the above reactions may be efected under t.he same conditions.
The reaction may be effectea conveniently in solu-tion. A suitable solvent is water, ethanol, dioxane, di-methyl formamide, dimethyl sulphoxide, pyridine or ~lacial acetic acid. Suitable reaction temperatures may be from 20 to 160 C, preferabl~ from 60 to 120~ C.
Insofar as ~le producti.on of starting materials ls not particularly described these compounds are known or may be produced in analoqous manner to know compounds.
In the following Exa~ples the temperatures ~iven are in degrees Centigrade and are uncorrected.
.
; ~ 8 - 5~-5~55 Exan~le 1: 4-52,1,3-Rehzox~dia70 )-2,6-d1me~ ~ b~'~ v~ ~5 dica~.box ~ e_ y~ er 3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acid ethyl ester, 2.5 ml of concentrated a~nonia and 10 ml of ethanol are refluxed for 6 hours.
The mixture is subsequently evaporated and the residual oil is chromatographed on silica gel with chloroform/
acet.ic acid ethyl ester (9:1) to yield the title compound.
The product is recrystalIised from toluene, m.p. 153-155.
By using the process described in Example 1, and corresponding stàrti.ng compounds, e.g. a compound of formula II, wherein -~iC=Y is a radical i) and com-pounds of formula IV and V, and for Examples 1~ and 19 a compound o ~ormula II,wherein -HC=Y is a radical ii)~
wherein Z is oxygen and a compound of formula VI, the following compounds of formula I may be obtained, wherein y ~ndicàtes the position of the dihydropyridine moiety:
5~
_ 9 _ 500-5455 Example Rl R2 R3 R4 ~5 R~ X ~ m.p.
; 2 H CH3 OC2H5 C2~l5 3 S 4146-14 3 ~ CH3 OC(CH3)3 OC(CE~) CH3 II S ~ 193 199 3 ~I3 O~H3CE~3 7-Cl 0 4207-211 6 }ICH3 OC2H5 C2HS 3 3 401 203 ~2 5 OC2H5C~I3 7-Cl S 4135-155 3 2 S C2HSCH3 ~-Cl S 51~8-200 3 C(CH3)3 C(CH3)3 CH3 H S
12 3 3 CH3 CH3 }I S
14 3 2 5 C2H5 CH 7-Cl S
16 3 2 5 C2H5CII 4~Cl S S
17 3 ~3 CH3 CH3 H 0 4 18 3 3 C2~l5 3 19 3C~I3 C2~5 3 H S
~he compounds of formula I exhibit pharma-2~ cological activity. In particular~ they lead to a dilation of the coronary vessels as de.monstrated by the results of te~ts r.easuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere .
.
~ - lo ~ 5~3 500-5455 method upon administration of the active substance i.v. or i.d. The compounds of formula I also possess a favourable ef~ect a~ainst an~ina pectoris, as shown by the increase of the coronary flo~ of an anesthetised cat UpOII administra-tion of th~ active substance.
The compounds of formula I are therefore indicated for use in the treatment of co~onary insufficiency. For this use an indicated daily dose is from about 5 to 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1O25 to about 50 mg, or in sustained release form.
Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollman rat test [see A. Grollman , Proc.
Soc. Expt. Biol. and kled. 57, 104 (1944)] on s.c. admini-stration of from 0.1 to 10 mg/kg animal body ~eight of the compounds.
The compounds are therefore further indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from about 5 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing about 1.25 mg to about 500 mg, or in sustained release form.
~ S~3 S00-5~55 The compounds of formula I may be administered in the form of a pharmaceutical composition. ~he prese~nt invention accordingly provides a pharmaceutical compo-SitiOll comprising a compound of foxmula I in association with a pharmaceutical carrier or diluent. Such composi-tions may be prepared by conventional techni~ues to be in conventional forms, for example capsules or tablets.
The compounds of Examples 1 and 2 are the pre-ferred compounds. The coronary insuffiency utility is the preferred utility In a group of compounds Rl is hydrogen, alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, phenylalkyl, or phenylalkyl; the phenyl ring being unsubstituted or substituted by one~two or three substituents chosen from one or t~lo halogen radicals, one or two alkyl groups of 1 to 4 carbon atoms, one to three alkoxy groups of 1 to 4 carbon atoms; R3 and R4, independently, are allyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, alkoxy, hydroxyalko~y of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydxoxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy,or cycloalkoxy of 3 to 6 carbon atoms, and R6 is other than alkylsulfonyl.
Conveniently Rl is hydrogen, R2 and R~ are each alkyl, especially methyl, R3 and ~ are each alkoxy, ~ .
especi.ally ethoxy, R6 is hyclrogen or halogerl, especially chlorine, especially in the 4 position, the dihydro-pyridine moiety is in the 4 or 5 position, and x is S.
Alternati.vely conveniently Rl is hydrogen, R2 and R5 are each al~yl, especially methyl, R3 and R4 are eacll alkyl or alkoxy, especially methyl, ethyl, tert.
butyl, methoxy, ethoxy or tert. bu~yloxy, R5 is hydrogen or halogen, especially chlorine,or alkoxy, especially methoxy, the dihydropyridine moiety is in the 4 o~ 5 position and R5 is in the 4, 5 or 7 position.
~ en the sta^ting material is a compound of fol-mu-la II, wherein -HC=Y is a radical iii), the reaction is a ring cyclisation. When Z and Z' are both oxygen, then an am.ine of formula V snould be prcsent.
However, all the above reactions may be efected under t.he same conditions.
The reaction may be effectea conveniently in solu-tion. A suitable solvent is water, ethanol, dioxane, di-methyl formamide, dimethyl sulphoxide, pyridine or ~lacial acetic acid. Suitable reaction temperatures may be from 20 to 160 C, preferabl~ from 60 to 120~ C.
Insofar as ~le producti.on of starting materials ls not particularly described these compounds are known or may be produced in analoqous manner to know compounds.
In the following Exa~ples the temperatures ~iven are in degrees Centigrade and are uncorrected.
.
; ~ 8 - 5~-5~55 Exan~le 1: 4-52,1,3-Rehzox~dia70 )-2,6-d1me~ ~ b~'~ v~ ~5 dica~.box ~ e_ y~ er 3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acid ethyl ester, 2.5 ml of concentrated a~nonia and 10 ml of ethanol are refluxed for 6 hours.
The mixture is subsequently evaporated and the residual oil is chromatographed on silica gel with chloroform/
acet.ic acid ethyl ester (9:1) to yield the title compound.
The product is recrystalIised from toluene, m.p. 153-155.
By using the process described in Example 1, and corresponding stàrti.ng compounds, e.g. a compound of formula II, wherein -~iC=Y is a radical i) and com-pounds of formula IV and V, and for Examples 1~ and 19 a compound o ~ormula II,wherein -HC=Y is a radical ii)~
wherein Z is oxygen and a compound of formula VI, the following compounds of formula I may be obtained, wherein y ~ndicàtes the position of the dihydropyridine moiety:
5~
_ 9 _ 500-5455 Example Rl R2 R3 R4 ~5 R~ X ~ m.p.
; 2 H CH3 OC2H5 C2~l5 3 S 4146-14 3 ~ CH3 OC(CH3)3 OC(CE~) CH3 II S ~ 193 199 3 ~I3 O~H3CE~3 7-Cl 0 4207-211 6 }ICH3 OC2H5 C2HS 3 3 401 203 ~2 5 OC2H5C~I3 7-Cl S 4135-155 3 2 S C2HSCH3 ~-Cl S 51~8-200 3 C(CH3)3 C(CH3)3 CH3 H S
12 3 3 CH3 CH3 }I S
14 3 2 5 C2H5 CH 7-Cl S
16 3 2 5 C2H5CII 4~Cl S S
17 3 ~3 CH3 CH3 H 0 4 18 3 3 C2~l5 3 19 3C~I3 C2~5 3 H S
~he compounds of formula I exhibit pharma-2~ cological activity. In particular~ they lead to a dilation of the coronary vessels as de.monstrated by the results of te~ts r.easuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere .
.
~ - lo ~ 5~3 500-5455 method upon administration of the active substance i.v. or i.d. The compounds of formula I also possess a favourable ef~ect a~ainst an~ina pectoris, as shown by the increase of the coronary flo~ of an anesthetised cat UpOII administra-tion of th~ active substance.
The compounds of formula I are therefore indicated for use in the treatment of co~onary insufficiency. For this use an indicated daily dose is from about 5 to 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1O25 to about 50 mg, or in sustained release form.
Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollman rat test [see A. Grollman , Proc.
Soc. Expt. Biol. and kled. 57, 104 (1944)] on s.c. admini-stration of from 0.1 to 10 mg/kg animal body ~eight of the compounds.
The compounds are therefore further indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from about 5 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing about 1.25 mg to about 500 mg, or in sustained release form.
~ S~3 S00-5~55 The compounds of formula I may be administered in the form of a pharmaceutical composition. ~he prese~nt invention accordingly provides a pharmaceutical compo-SitiOll comprising a compound of foxmula I in association with a pharmaceutical carrier or diluent. Such composi-tions may be prepared by conventional techni~ues to be in conventional forms, for example capsules or tablets.
The compounds of Examples 1 and 2 are the pre-ferred compounds. The coronary insuffiency utility is the preferred utility In a group of compounds Rl is hydrogen, alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, phenylalkyl, or phenylalkyl; the phenyl ring being unsubstituted or substituted by one~two or three substituents chosen from one or t~lo halogen radicals, one or two alkyl groups of 1 to 4 carbon atoms, one to three alkoxy groups of 1 to 4 carbon atoms; R3 and R4, independently, are allyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, alkoxy, hydroxyalko~y of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydxoxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy,or cycloalkoxy of 3 to 6 carbon atoms, and R6 is other than alkylsulfonyl.
Conveniently Rl is hydrogen, R2 and R~ are each alkyl, especially methyl, R3 and ~ are each alkoxy, ~ .
especi.ally ethoxy, R6 is hyclrogen or halogerl, especially chlorine, especially in the 4 position, the dihydro-pyridine moiety is in the 4 or 5 position, and x is S.
Alternati.vely conveniently Rl is hydrogen, R2 and R5 are each al~yl, especially methyl, R3 and R4 are eacll alkyl or alkoxy, especially methyl, ethyl, tert.
butyl, methoxy, ethoxy or tert. bu~yloxy, R5 is hydrogen or halogen, especially chlorine,or alkoxy, especially methoxy, the dihydropyridine moiety is in the 4 o~ 5 position and R5 is in the 4, 5 or 7 position.
Claims (4)
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl-alkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsub-stituted or mono-, di- or trisubstituted in-dependently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, R2 and R5, independently, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl of 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylalkoxy of 4 to 8 carbon atoms, R6 is hydrogen, halogen, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur, 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 Z and Z' are independently oxygen 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 of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl-alkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsub-stituted or mono-, di- or trisubstituted in-dependently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, R2 and R5, independently, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl of 1 to 6 car-bon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 car-bon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylalkoxy of 4 to 8 carbon atoms, R6 is hydrogen, halogen, alkyl or alkoxy or alkyl-thio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur, 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 Z and Z' are independently oxygen 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, as defined in claim 1, whenever produced by the process of Claim 1 or an obvious chemical equivalent.
3. A process according to claim 1 wherein 2,1,3-benzoxadiazole-4-aldehyde and acetoacetic acid ethyl ester are reacted in the presence of ammonia to form 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester.
4. 4-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester, whenever produced by the process of claim 3 or an obvious chemical equivalent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7520/77 | 1977-06-20 | ||
| CH752077 | 1977-06-20 | ||
| CH286578 | 1978-03-16 | ||
| CH2865/78 | 1978-03-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105463A true CA1105463A (en) | 1981-07-21 |
Family
ID=25691589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA305,727A Expired CA1105463A (en) | 1977-06-20 | 1978-06-19 | Dihydropyridine-derivatives and their production |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0000150B1 (en) |
| JP (1) | JPS54103876A (en) |
| AT (1) | AT376220B (en) |
| AU (1) | AU524000B2 (en) |
| CA (1) | CA1105463A (en) |
| CY (1) | CY1239A (en) |
| DE (1) | DE2860708D1 (en) |
| DK (1) | DK149855C (en) |
| ES (1) | ES470917A1 (en) |
| FI (1) | FI64938C (en) |
| HK (1) | HK65184A (en) |
| IE (1) | IE47212B1 (en) |
| IL (1) | IL54948A (en) |
| IT (1) | IT1105364B (en) |
| LU (1) | LU88342I2 (en) |
| MY (1) | MY8500041A (en) |
| NL (1) | NL930126I2 (en) |
| NZ (1) | NZ187617A (en) |
| PT (1) | PT68191A (en) |
| SG (1) | SG20584G (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH639659A5 (en) * | 1978-12-18 | 1983-11-30 | Sandoz Ag | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| DK525179A (en) * | 1978-12-18 | 1980-06-19 | Sandoz Ag | PROCEDURE FOR PREPARING BENZOXADIAZOLES AND BENZOTHIAZOLES |
| BE886259A (en) * | 1979-11-23 | 1981-05-20 | Sandoz Sa | NOVEL DRUGS BASED ON 1,4-DIHYDROPYRIDINE DERIVATIVES FOR THE TREATMENT OF CEREBROVASCULAR DEFICIENCY OR WITH SPAMOLYTIC ACTION |
| CH655658B (en) * | 1980-09-18 | 1986-05-15 | ||
| FI813460L (en) * | 1980-11-10 | 1982-05-11 | Sandoz Ag | NYA 4- (2,1,3-BENZOXADIAZOL-4-YL) -1,4-DIHYDRO-PYRIDIN DERIVATIVES DERAS FRAMSTAELLNINGSFOERFARANDE OCH DESSA INNEHAOLLANDE PHARMACEUTICAL COMPOSITION |
| DE3269219D1 (en) * | 1981-11-17 | 1986-03-27 | Fisons Plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| DE3207982A1 (en) * | 1982-03-05 | 1983-09-08 | Bayer Ag, 5090 Leverkusen | NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS |
| DE3208628A1 (en) * | 1982-03-10 | 1983-09-22 | Bayer Ag, 5090 Leverkusen | NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
| ZA83959B (en) * | 1982-03-10 | 1984-09-26 | Sandoz Ltd | 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| FR2528431B1 (en) * | 1982-06-15 | 1986-01-10 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
| FR2554109A1 (en) * | 1983-11-01 | 1985-05-03 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS AS MEDICAMENTS |
| IE57810B1 (en) * | 1984-03-27 | 1993-04-21 | Delagrange Lab | 1,4-dihydropyridine derivatives,their preparation and their use |
| NL194389C (en) * | 1984-06-14 | 2002-03-04 | Novartis Ag | Process for preparing a solid dispersion of a pharmaceutically active agent that has low water solubility in a solid matrix of a water-soluble polyalkylene glycol as a carrier. |
| GB8428552D0 (en) * | 1984-11-12 | 1984-12-19 | Sandoz Ltd | Organic compounds |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| GB8616047D0 (en) * | 1986-07-01 | 1986-08-06 | Sandoz Ltd | A 1 4-dihydropyridine derivatives |
| JP4625637B2 (en) | 2002-02-22 | 2011-02-02 | シャイア エルエルシー | Active substance delivery system and method for protecting and administering an active substance |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
-
1978
- 1978-06-12 DK DK262578A patent/DK149855C/en not_active IP Right Cessation
- 1978-06-12 FI FI781867A patent/FI64938C/en not_active IP Right Cessation
- 1978-06-15 DE DE7878100165T patent/DE2860708D1/en not_active Expired
- 1978-06-15 EP EP78100165A patent/EP0000150B1/en not_active Expired
- 1978-06-15 CY CY1239A patent/CY1239A/en unknown
- 1978-06-19 NZ NZ187617A patent/NZ187617A/en unknown
- 1978-06-19 AT AT0443178A patent/AT376220B/en not_active IP Right Cessation
- 1978-06-19 PT PT68191A patent/PT68191A/en unknown
- 1978-06-19 IL IL54948A patent/IL54948A/en unknown
- 1978-06-19 ES ES470917A patent/ES470917A1/en not_active Expired
- 1978-06-19 JP JP7332778A patent/JPS54103876A/en active Granted
- 1978-06-19 AU AU37252/78A patent/AU524000B2/en not_active Expired
- 1978-06-19 IE IE1231/78A patent/IE47212B1/en not_active IP Right Cessation
- 1978-06-19 IT IT49939/78A patent/IT1105364B/en active Protection Beyond IP Right Term
- 1978-06-19 CA CA305,727A patent/CA1105463A/en not_active Expired
-
1984
- 1984-03-05 SG SG205/84A patent/SG20584G/en unknown
- 1984-08-23 HK HK651/84A patent/HK65184A/en not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY41/85A patent/MY8500041A/en unknown
-
1993
- 1993-06-30 LU LU88342C patent/LU88342I2/en unknown
- 1993-07-01 NL NL930126C patent/NL930126I2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL930126I1 (en) | 1993-11-01 |
| EP0000150B1 (en) | 1981-05-20 |
| JPS54103876A (en) | 1979-08-15 |
| IE47212B1 (en) | 1984-01-25 |
| NL930126I2 (en) | 1995-02-16 |
| IT7849939A0 (en) | 1978-06-19 |
| NZ187617A (en) | 1980-12-19 |
| AT376220B (en) | 1984-10-25 |
| DK149855C (en) | 1987-04-21 |
| AU3725278A (en) | 1980-01-03 |
| PT68191A (en) | 1978-07-01 |
| IL54948A (en) | 1982-01-31 |
| JPS6360755B2 (en) | 1988-11-25 |
| ES470917A1 (en) | 1979-10-01 |
| CY1239A (en) | 1984-06-29 |
| DK149855B (en) | 1986-10-13 |
| DE2860708D1 (en) | 1981-08-27 |
| ATA443178A (en) | 1984-03-15 |
| FI781867A (en) | 1978-12-21 |
| IL54948A0 (en) | 1978-08-31 |
| AU524000B2 (en) | 1982-08-26 |
| SG20584G (en) | 1985-03-08 |
| MY8500041A (en) | 1985-12-31 |
| HK65184A (en) | 1984-08-31 |
| FI64938B (en) | 1983-10-31 |
| IE781231L (en) | 1978-12-20 |
| LU88342I2 (en) | 1994-05-04 |
| EP0000150A1 (en) | 1979-01-10 |
| FI64938C (en) | 1984-02-10 |
| DK262578A (en) | 1978-12-21 |
| IT1105364B (en) | 1985-10-28 |
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