CA1105463A - Dihydropyridine-derivatives and their production - Google Patents

Dihydropyridine-derivatives and their production

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Publication number
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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Prior art keywords
carbon atoms
alkyl
formula
compound
alkoxy
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CA305,727A
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French (fr)
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Peter Neumann
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Sandoz AG
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Sandoz AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/04Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic 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
    • C07D413/04Heterocyclic 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • 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)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (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.

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 ' ~
- 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
- 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~
. ~ .
- 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.

.
- 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
- 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~

.
- 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.

Claims (4)

WHAT WE CLAIM IS:
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.
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.
CA305,727A 1977-06-20 1978-06-19 Dihydropyridine-derivatives and their production Expired CA1105463A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH7520/77 1977-06-20
CH752077 1977-06-20
CH2865/78 1978-03-16
CH286578 1978-03-16

Publications (1)

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CA1105463A true CA1105463A (en) 1981-07-21

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ID=25691589

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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)

* Cited by examiner, † Cited by third party
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.
FI793848A (en) * 1978-12-18 1980-06-19 Sandoz Ag BENZOXADIAZOLER OCH BENZOTHIADIAZOLER DERAS FRAMSTAELLNING OCH PHARMACEUTICAL COMPOSITION INNEHAOLLANDE DESSA
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
ZA83959B (en) * 1982-03-10 1984-09-26 Sandoz Ltd 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them
DE3208628A1 (en) * 1982-03-10 1983-09-22 Bayer Ag, 5090 Leverkusen NEW COMPOUNDS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
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
HU198844B (en) * 1984-06-14 1989-12-28 Sandoz Ag Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient
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
KR20040088519A (en) 2002-02-22 2004-10-16 뉴 리버 파마슈티칼스, 인크. Active Agent Delivery Systems and Methods for Protecting and Administering Active Agents

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GB1552911A (en) * 1975-07-02 1979-09-19 Fujisawa Pharmaceutical Co 1,4 dihydropyridine derivatives and the preparation thereof

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AU3725278A (en) 1980-01-03
FI781867A (en) 1978-12-21
ATA443178A (en) 1984-03-15
LU88342I2 (en) 1994-05-04
IL54948A0 (en) 1978-08-31
EP0000150A1 (en) 1979-01-10
CY1239A (en) 1984-06-29
IE781231L (en) 1978-12-20
PT68191A (en) 1978-07-01
JPS54103876A (en) 1979-08-15
IT7849939A0 (en) 1978-06-19
FI64938B (en) 1983-10-31
AT376220B (en) 1984-10-25
FI64938C (en) 1984-02-10
HK65184A (en) 1984-08-31
MY8500041A (en) 1985-12-31
SG20584G (en) 1985-03-08
NL930126I1 (en) 1993-11-01
DE2860708D1 (en) 1981-08-27
DK149855B (en) 1986-10-13
DK262578A (en) 1978-12-21
NL930126I2 (en) 1995-02-16
IE47212B1 (en) 1984-01-25
NZ187617A (en) 1980-12-19
AU524000B2 (en) 1982-08-26
IT1105364B (en) 1985-10-28
EP0000150B1 (en) 1981-05-20
DK149855C (en) 1987-04-21
JPS6360755B2 (en) 1988-11-25
IL54948A (en) 1982-01-31
ES470917A1 (en) 1979-10-01

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