AU606036B2 - Novel polyoxygenated labdane derivatives, processes for their preparation and their use as medicaments - Google Patents
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Abstract
Polyoxygenated labdane derivatives which carry one or more aminoacyl groups as substituents are suitable, due to their pharmacological properties, for use in the treatment of cardiac and circulatory diseases, hypertension, glaucoma, allergies, broncho- constriction and as immunomodulators.
Description
lu 1e (si of Applicanlt TDA DA E D E T Seal f- Company and Sign atures of Its OfficerS as C) prescribed'l by Its Articleas of Associat(ion.
[OECHST AKTIENGESELLSCHAT..........
'James Murray -j
I
4~5 ~3 66 Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION OR IGINAL)I Class I t. Class Application Number: Lodged: 6S-470/ 6 Complete Specification Lodged: Accepted: Published: Priority: EThis d o u e t o ta n th amenwits inide wider Sectionl 49 and1( is correct for, Related Art
S
Namte of Applicant: rs fo Sevie HOECHST AKTIENGESELLSCHAFT Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany YATENDRA KHANDELWAL, RANANUJAM RAJGOPALAN, ALIHUSSEIN NOMANBHAI DOHADWALLA, RICHARD HELMUT RUPP, NOEL JOHN DE SOUZA EDWD. WATERS SONS, QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
~1 **Comrplete Specification for the invention entitled: es S.
S
S
NOVEL POLYOXYGENATED LABDANE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS The following statement is a full description of this invention, including the best method of performing it known to US Hoechst Aktiengeaelljchaft hb JAuthorized signa ppa. Reuter i.V. La ice PAT 510 l;:
(I
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i, -la- HOECHST AKTIENGESELLSCHAFT HOE 85/F 214
I
Dr.LA/mU if Novel polyoxygenated labdane derivatives, processes for their preparation and their use as .medicaments Polyoxygenated labdane derivatives are already known from the following patents or publications: German Offenlegungsschriften Nos. 2,557,784, 2,640,275 and 2,654,796; European Patent Applications having publication numbers 0,189,801, 0,191,166 and 0,193,132.
Tetrahedron Letters No. 19, pages 1669-1672 (1977), J.
Chem. Soc., Perkin Trans. 1, 767 (1982).
The pharmacological properties of the polyoxygenated labdanes described and their derivatives make them suitable for application in the treatment of heart and circulatory diseases, hypertonia, glaucoma, allergy, bronchoconstriction and as immunomodulators.
The polyoxygenated labdane derivatives of the invention S20 have not yet been described in the literature which has elm S been published. The compounds of the stated prior art, l which are structurally related to the compounds of the invention, are labdane derivatives in which one or more hydroxyl groups are acylated. In contrast thereto, the compounds of the invention have aminoacyl groups. As a result of this, the compounds of the invention become oe water-soluble, a property which is lacking in compounds of the prior art. Due to this water-solubility, the compounds of the invention can be used very beneficially in aqueous galenical formulations, for example in injectables.
A further advantage of the introduction of aminoacyl groups is that, depending on the structural nature of such a substituent and its position in the molecule, the pharmacological profile of the compounds is modified in a manner such that, in contrast to the compounds already known, it becomes possible to obtain substances which are more effective, for example, in one case for the treatment
-I
"r t 2 of diseases such as, for example, congestive cardiac myopathy, or in another case for hypertension, or finally for diseases such as glaucoma.
The present invention therefore relates to derivatives of polyoxygenated Labdanes and processes for their preparation. The novel polyoxygenated labdane derivatives and their pharmaceutically acceptable salts possess valuable properties such as, for example, broncho-spasmolytic, antiallergic, antihypertensive, anti-inflammatory and positively inotropic activity. They also effect the reduction of intraocular pressure in glaucoma.
The novel derivatives of the polyoxygenated labdanes have the formula I
OR
1 T I t*R
OR
2 3
OR
wherein: R denotes hydrogen or a hyroxyl group; either all three S S 25 or only two or one of the substituents R 1
R
2 and R 3 denote the radical 4 OR
R
1* U I (CH )-N S2 n and the other or 7 30 others denote hydrogen, R 4 and R 5 which may be identical or different, standing for hydrogen or an alkyl or aryl group; n stands for an integer from 0 to 10; R 6 denotes hydrogen if R 7 stands for hydrogen, alkyl, substituted alkyl, cycloalkyl, aralkyl, aryl, a heterocyclic hydro- S* 35 carbon, amino, substituted amino, hydroxyl, acyl, dialkylaminoalkyl, carbamyL, lkoxycarbonyl or alkoxycarbonylalkyl, or R 6 and R 7 are identical and stand for alkyl, substituted alkyL, aryl or aralkyl, or R 6 denotes an alkyl
I~
-1 3 group, and R 7 denotes substituted alkyl, cycloalkyl, aralkyl or dialkylaminoalkyl, or R 6 and R 7 together with the nitrogen atom to which they are attached represent a heterocyclic radical which may contain one or more heteroatoms and may be singly or multiply substituted by alkyl, aralkyl, aryl, hydroxyl or other heterocyclic groups, and also pharmacologically acceptable salts thereof.
The abovementioned definition of the derivatives of polyoxygenated labdanes includes all the possible stereoisomers and combinations thereof.
Preferred are compounds of the formula I wherein R represents the hydroxyl group and the substituents R 1
-R
3 each represent an aminoacyl group, n representing 0 or an integer from 1 to Also preferred are compounds of the formula I wherein R denotes the hydroxyl group, R I hydrogen and R 2 and/or R 3 20 the said aminoacyl group, n representing an integer from 1 to ao0 The abovementioned definitions of alkyl, alkoxy and al- Skanoyl for the substituents R 4 to R7 include radicals with up to 6 C atoms and the definition cycloalkyl includes radicals with 3 to 7 C atoms. The term "heterocyclic I hydrocarbon radicals" is understood to mean 5- to 6n. ember ring systems onto which a benzene ring or a further heterocyclic 6-member ring may be condensed and which 30 contains one or more, preferably 1 to 3, heteroatoms from the group comprising nitrogen, oxygen and sulfur.
Suitable examples of the alkyl groups for R 1
R
7 are straight-chain or branched alkyl groups containing up to 6 carbon atoms, preferably up to 4 carbon atoms, for example the methyl, ethyl, isopropyl, tert-butyl or n-butyl radical.
i-- Ii I Suitable examples of the substituted alkyl groups for R 6 and R 7 are hydroxyalkyl such as, for example, hydroxyethyl, carboxyalkyl such as for example carboxyethyl, carbalkoxyalkyl such as, for example, carbethoxyethyl or the ethylindole group.
A suitable example of the cycloalkyl group for R 6 and R 7 is provided by cycloalkyl groups containing 5-7 C atoms, preferably the cyclohexyl group.
A suitable example of the aralkyl group for R 6 and R 7 is the phenylalkyl group, for example the benzyl group, wherein the phenyl group may be substituted by one or more substituents such as halogen, alkyl, alkoxy, nitro or trifluoromethyl.
A suitable example of the aryl group for R 4 to R 7 is the phenyl group which may be substituted by one or more subs e. stituents such as halogen, alkyl, alkoxy, nitro or tri- 20 fluoromethyl.
Suitable examples of the heterocyclic radicals for R 7 are S quinoline and pyridine. As a suitable example of the acyl group mention may be made of alkanoyl, aroyl, aralkanoyl or a heteroaroyl group containing up to 10 carbon atoms and one or more heteroatoms from the group comprising oxygen, nitrogen and sulfur.
S.Examples of alkanoyl groups are formyl, acetyl, propionyl, 30 butyryl, isobutyryl, valeryl, palmityl and bromoisobutyryl.
The alkanoyl groups may contain one or more double bonds such as, for example, in the acrylyl, stearyl or oleyl 'eg groups. The alkanoyl groups may also contain one or more S triple bonds and additionally one or more double bonds.
An example of such an alkynyl group is the propiolyl group.
Aroyl groups are represented by the benzoyl group, in which the phenyl group may be substituted by one or more substituents such as alkyL, alkoxy, halogen, nitro or trifluoromethyl. An example of aralkanoyl or heteroaroyL groups is provided by phenylacetyl or pyridine-3-carbonyL groups.
Suitable as the diaLkyLaminoalkyl group for R 6 and R 7 are di(CC-C 4 )aLkyLamino(Cl-C 4 )aikyL groups, for example the diethyLaminoethyL group.
Suitable examples of the heterocyclic radicals formed by R6 and R 7 together with the nitrogen atom to which they are attached are piperdiw, pyrroLidline, morphoLine, ~i crz i:,thiomorphoLine, imidlazoLe and theophylline, which may be substituted singly or multiply by aLkyL, aLkoxy, aryL, araLkyL, hydroxyL, amino-substituted aLkyL, aryL or amino groups.
Suitable examples c( salts of the substances of the invention formed from inorganic and organic acids are hydrose chloridle, hydrobromidle, sulfate, phosphate, acetate, oxaLate, tartarate, citrate, maLeate or fumarate.
0* R R Suitable examples of the group 11 1 t 6 are the following radicals. 2cCC N N-ethyLaminoacetyL N,N-diethyLaminoacetyL see.. N-benzyL-N-methyL aminoacetyL j N-ethyl -N-methyLaminoacetyL j 4'-phenyLpiperidinoacetyL aniLinoacetyL N-methyLaniL iroacetyL N,N-diphenyLaminoacetyL e~g N-acetyLaminoacetyL 35 N-phenyL acyL am inoacetyL 4' -hydroxyp iper id inoacetyL th iomorphoL inoacetyL is op ropy Lam inoace tyl ci) 11 A l I I -6
I
0 0 tert-butyLaminoacetyL diethanotam inoacetyL N-(N',N'-diethyLaminoethyL)-N-methytaminoacetyL hydraz inoacetyL hydroxyam inoacetyt phenyLhydraz inoacetyt aminoacetyL benzyLaminoacetyL N-benzyL-N-8-ethanotaminoacetyL 4-benzoyLaminopiper idinoacetyt 4-hydroxy-4-phenyLp iper idi noacetyt ,S-ataninoacetyL tert-butyL-B-aLaninoacetyL tryptaminoacetyL aminoquinoLL inoacetyL imidazoLytacetyL th jophyl Iinoacetyl 8-(N-ethyLamino)propionyL B- CN, N-d jet hyLam inc)p rapionyL 20 N,N-benzyL-N-methyL amino) prop ionyL B-(4'-phenyLpiperidino)propionyL B-an iiinoprop ionyL B- CN-met hyL an ii o)p ropionyL N, N-d iphenyL amino) prop ionyL B-(B -phenyLethyLamino)propionyL B-C N-acetyL amino) prop ionyL 8-N-phenacy Iamino )prop ionyL B-(4'--hydoxypiperidino)propionyL 8-thiomorphoLinopropionyL 8-isopropyL am inoprop ionyL B-tert-butyLarninopropionyL B-diet hanaL am inoprop iony I B-N-(N',N'-diethyLamino)ethyL-N-methyLaminopropionyL B-hydrazimap rapionyL B-hydroxyLaminopropionyL B-phenythydrazinopropionyL B-amimop ropionyL B-benzyL aminoprop jonyL I I 0* S. S
S.
S
S
5*55 S. 55
S
S
-7 $-(N-benzyL-N-8-ethanoLamino)propiony1 8-(N-benzoytaminopiperidino)propionyL $-4-hydrox y-4-pheny .p iper idino )p rop jonyt 0-(s'-aLanino)propionyL tert-butyL-8 -aL anino)propionyL 6-tryptaminopropionyL B-aminoquinoLinopropionyL 8-ii~i dda zop rop ionriy 0-thiophyLLinopropionyL N-C thy lam ino) prop jonyL a-N,N-d ie thy Iamino )p rop jonyL a-(N-benzyL-N-methyLamino)propionyI a-(N-ethyL-N-methyLamino)propionyL c-(41-phenyLpiperidino)propionyt c-anitinopropionyL a-N-met hy Ianijuno )prop jonyL N-d iph eny Iamino) p rop jonyL a-($'-phenyLethy~amino)propionyL (I-(N-acety~amino)propionyL 20 a-phenacyLaminopropionyL a-(4'-hydroxypiper idino)propionyL a-thiomorphoL inopropionyL a-isopropyLaminopropionyL a-tert-butyLaminopropionyL a-diethanoL am inoprop ionyl a-(N,N'-diethyLamino)ethyL-N-methyLaminopropionyI (1-hydraz inopropionyL a-hydroxyL aminopropionyl a-pheny~hydraz inopropionyl a-aminopropionyL ot-benzyL am inoprop jonyL ot-(N-benzyL-N-8-ethanoLamino)propionyL a-(N-benzoyI amino-piper i dino)prop ionyL (%-(4-hydroxy-4-phenyLpiperidino)propionyL a-(B-aLanino)propionyL (X-(tert-butyLaLanino)propionyL (X-tryptaminoprop ioflyt o-aminoquinoLinopropionyL
I
I I -8a-imidazoLoprop jonyL c-theophyLL inopropionyL y-(N-ethyLamino)butyryL NN-d jet hyLamino )bu ty ryL y-(N-benzyL-N-methyLam ino)butyryL y-(N-ethyL-N-methytamino)butyryL y-(4'-phenyLpiperidino)butyryL -y-ani IinobutyryL N-me thy Ianii o )bu ty ryL X-(N,N--diphenyL amino)butyryt y-(B'-pheny~ethyLamino)butyryL y-(N-acetyLamino)butyryt y-(N-phenacyLamino)butyryL y-(41-hydroxypiperidino)butyryL y-thiomorphoL inobutyryL y-isopropyLaminobutyiyL -y-(tert-butyLamino)butyryL y-diethanoLaminobutyryL ,N'-diethytamino)-ethyL-N-methyLamino)butyryt y-hydrazinobutyryL y-hydroxyLaminobutyryL y-phenyLhydrazinobutyryL y-(N-benzyL-N-8-ethanoL amino )butyryL y-(4-benzytaminopiperidino)butyryL y-(4-hydroxy-4-phenyLp iper idino)butyryL -y-(B'-aLanino)butyryL :9:9y-(tert-butyL-8'-aLanino)butyryL y-tryptaminobutyryL ,y-aminoquinoL inobutyryL 999~** y-imidazoLinobutyryL 6-theophyLtinobutyryL 0 N-et hy Iamino )vat ery I 6-(N,N-diethyt amino)vaLeryL 6 -(N-benzyt-N-methyLamino)va~eryL 6-(N-ethyl-N-methyLamino)vaLeryL 6 -(4'-phenyLpiperidino)vaLery.
I
-9- 6-aniL inovaLeryL S-C N-met hy Ian ii o )valeryL 6- N ,N-d iphenyt amno) vale ryL 6-(B-phenyLethyLamino)vaLeryL 6-(N-acetyL amino)vaLeryL 6-(N-phenacyL amino)vaLeryL 6- -hydroxyp ipe ri di no) va Ieryt 6-thioinorphoLinovaLeryL 6- isop ropyt am inova Ieryt tert-butyLamino)vaLeryL 6-d jet hanoi am inova Ie ry I 6-CN N di e th y aminno -e th yI- N -me th y Iaminno )v a Ie r y 6-h yd ra z in ova Ie r y 6-am inova Ie ry I 6-benzy lam inovaIe ry L 6- p h en y hy d ra zi no va Ie r y 6- (N -be n zyI- N -e t ha no Iaminno )v a Ie r y 6- (4-be n zy a m ino p ipe r id in o) va e r yL '*00%6-C4-hydroxy-4-phenyLpiper idino)vaLeryL 00 20 6-CB-a~anino)va~eryL 6-C tert-butyL-B-aL anino)vaLeryL 0 0*6ty tmio aee 6-aiinoquinoLinovaLeryL 6-imidazoLinovaLeryL 6-theophyLLinovaLeryL 12-p iper id inoL auroy I 12-morphoL inoLauroyL 0*0*0 12-pyrroLidinoLauroyL 12-C4'-inethyLpiperazino)IauryL Without remaining exclusiveLy Limited to the cited compounds, the preferred compounds of the invention are the following: 8,13-epoxy-i-piper idinacetoxy-68,70,9a-tr ihydroxyL abd-14en-il-one.
8,13-epoxy-1-piperidinacetoxy-60,70,9ca-trihydroxy~abd- 14-en-i 1-one hydroxychLoridle heinihydrate.
10 8,13-epoxy-6$-piperidinacetoxy-ct,7R,9cz-trihydroxy18bd- 14-en-22-one.
8,13-epoxy-6Q-niorphoLinoacetoxy-1ct,70,9cx-trihydroxyLabd- 14-en-I 1-one.
8,13-epoxy-1-morphoL inoacetoxy-1cx,70,9ct-trihydroxyLabd- 14-en-il-one hydrochloride.
8,13-epoxy-6B-(N-methyLpiperazinoacetoxy)-~x,7,9z-trihydroxytabd-14-en-1 1-one dihydrochioride.
8,l3-epoxy-60-pyrroLidonoacetoxy-ct,76,9cz-trihydroxy~abd- 14-en-il-one.
8,13-epoxy-68-(N-methyL-N-cycLohexy~aminoacetoxy)-c1,7,9ttrihydroxyLabd-14-en-11-one.
8,13-epoxy-6B-(cx'(N-morphoLino)propionyLoxy)-l*,7,9xtr ihydroxyLabd-14-en-i 1-one hydrochLor ide.
8, 13-epoxy-6B-(ca'-C4N-methyLpiperaz ino)propionyLoxy 1c,7B,9c-trihydroxyLabd-14-en-11-one.
8, 13-epoxy-68-(i' (N-piper idino)propionyLoxy)-1o,78,9atrihydroxyLabd-14-en-1 1-one hydrochloride.
0000 8,13-epoxy-7$-piperidinoacetoxy-ci,6a,9cz-trihydroxyLabd- 14-en-li-one.
0: 8, i3-epoxy-78-p iper idinoacetoxy-ca,6 ,9t-tr ihydroxyl abd- 14-en-li-one hydrochloride.
8,13-epoxy-78-morphoL inoacetoxy-iQ,6$,9ct-trihydroxyLabd- 8,13-epoxy-78-morphoL inoacetoxy-1cz,68,9ca-trihydroxyLabd- 14-en-li-one hydrochloride.
8, 13-epoxy-70-(N-methyL-N-cycLohexyLaminoacetoxy)-,6,9ttrihydroxyLabd-14-en-i1-one.
8,13-epoxy-7$-methyLpiperazinodacetoxy-,6,9a-tr ihydroxy- Labd-14-en-ii-one hydrochloride 8,i3-epoxy-7f3-(pyrroLidinoacetoxy)-ct,68,9ct-trihydroxy- *e Labd-14-en-11-one hydrochloride.
8,13-epoxy-78-(diethyLaniinoacetoxy)-1ct,68,9a-trihydroxy- Labd-14-en-11-one hydrochloride.
8,13-epoxy-7-Eai'(N-piperidino)propionyLoxy)-1(,6,9ttrihydroxyLabd-14-en-11-one.
8 ,13-epoxy-7$-(alx(N-morphoLino(propionyLoxy)-1a,6,9atrihydroxyLabd-14-en-ll-one.
8,13-epoxy-7B-(cz(4N-rethyLpiperazino)propionyLoxy)- 1x,68,9oi-trihydroxyLabd-l4-en-1 1-one dihydrochioride.
8, 13-epoxy-78-(piperidinobutyryLoxy)-a,6S,9cx-tr ihydroxy- L.abd-14-en-1 1-one hydrochLoride hemihydrate.
lc,6-dihydroxy-8,13-epoxy-78-(piperidinoacetoxy)-Labd- 14-en-Il-one hydrochloride.
la,78-dihydroxy-8,13-epoxy-6B-(piperidinoacetoxy)-Labd- 14-en-i 1-one.
1czt7-di-(piperdinoacetoxy)-8,13-6B-hydroxyLabd-14-en- 11 -o ne 1c,6,7$-tri-(piperidinoacetoxy)-8,13-epoxyLabd-14-en- 11 -o ne 8,13-epoxy-68(4'-hydroxypiperidinoacetoxy)-lz,789z-trihydroxyLabd-14-en-1 1-one hydrochloride dihydrate.
8,13-epoxy-68(thiomorphoL inoacetoxy)-lcz,78,9ct-trihydroxy- Labd-14-en-1 1-one hydrochloride sesquihydrate.
8,13-epoxy-68(4'-methyLpiperidinoacetoxy)-ca,7,9x-trihydroxyLabd-14-en-1 1-one hydrochloride dihydrate.
8, 13-epoxy-6BC4 '-benzoyl aminopiper idinoacetoxy)-1ca,78,9atrihydroxyLabd-14-en-11-one hemihydrate.
8,13-epoxy-68(homopiper idinoacetoxy)-la,?6,9c-trihydroxy- Labd-14-en-1 1-one hydrochloride.
8,13-epoxy-6B(y' -piperidinobutyryLoxy)-a,7,9a-trihydroxylabd-14-en-1 1-one hydrochloride hernihydrate.
8, 13-epoxy-6$(diethyLaminoacetoxy)-a,.7,9t-trihydroxy- Lab-14en-1-one monohydrochioride dihydrate.
.5e.-0y-mrh~nouyyox)l,6.ati hydroxylabd-14-en-11-one hydrochloride dihydrate.
8,13-epoxy-6(alx-aniL inopropionyLoxy)-lt,78,9cz-trihydroxy- :o 30 Labd-14-en-11-one.
8fl 3 -epoxy-6B(4'-hydroxy-4'-phenyLpiperidinoacetoxy)- 1c*78,9a-tr ihydroxyLabd-14-en-1 1-one hydrate.
8,l3-epoxy-68CtheophyL Iinoacetoxy)-1ca,78,9ct-trihydroxy- Labd-14-en-11-one.
8, l 3 -epoxy-68(benzyLaminoacetoxy)-la,7,9i-tr ihydroxy- Labd-14-en-1 1-one hydrochloride monohydrate.
8
,I
3 -epoxy-68(3'-methyLpiperidinoacetoxy)-1o,78,9a-trihydroxyLabd-14-en-1 1-one hydrochLoride sesquihydrate.
-12- 8,13-epoxy-7$(theophy1Linoacetoxy)-ci,68,9c*-trihydroxy- Labd-14-en-11-one monohydrate.
8,13-epoxy-70(Cy'-morphoLinobutyryLoxy)-l1t,60,9a-trihydroxyLabd-14-en-1 1-one hydrochloride hem ihydrate.
8,13-epoxy-78(cj'-aniL inopropionyLoxy)-1a,65,9c*-trihydroxy- Labd-14-en-1 1-one.
8,13-epoxy-78C4'-hydroxy-4'-phenyLpiperidinoacetoxy)- 1a,6B,9cz-trihydroxy~abd-14-en-l 1-one hydrochloride.
8,13-epoxy-70(aniLinoacetoxy)-ca,68,9cx-trihydroxyLabd-14en-li-one.
7-bt~a b iaex)8,13oyl,6,a-rhdroy Labd-14-en-1 1-one hydrochloride monohydrate.
8,13-epoxy-78(4'-hydroxypiperidinoacetoxy)-cx,66,9a-trihydroxyLabd-14-en-1 1-one hydrochloride.
8,13-epoxy-7B(y'-N-methyLpiperaz inobutyryLoxy)-cx,6 ,9ttrihydroxyLabd-14-en-1 1-one dihydrochioride monohydrate.
8,13-epoxy-78(morphoLinoLauryLoxy)-cz,6B,9a-trihydroxy- Labd-14-en-1 1-one hydrochloride mono, ydrate.
8, 13-epoxy-78(4 '-methyLpiperidinoacetoxy)-cz,6B,9t-tr ihydroxyLabd-14-en-1i-one hydrochloride.
8,13'epoxy-7B(thiomorphoL inoacetoxy)-lcx,68,9ct-trihydroxy- Labd-14-en-11-one hydrochloride sesquihydrate.
hdroxyLabd-14-en-11-one hydrochloride.
8, 1-epoxry-?(8-phth a dopomooopinylny-1,6o9x-yhydr-oxy-Labd-14-en-11-one donhydrte. ie riyrae 8,13-epoxy-68(morphol iinoobutryLoxy)-cz,78,9ca-trihydroxyLabd-14-en-11-onie mhydrochLorid ooydae M.P. 148-150 0
C.
8,13-epoxy-78( 6-piperidinovaLeryLoxy)-1a,60,9oL-trihydroxyLabd-14-en-11-ore ,onohydrochtoride. M.P. 223-224 0
C.
8, 1 3 -epoxy-68-(hexarnethyLeneiminoacetoxy)-la,7,9z-tr ihydroxyLabd-14-en-11-one hydrochloride hydrate. M.P. 192 0
C.
theophylline radical, where the said radicals may be singly or multiply substituted by (C -C 4 )alkyl, (C -C 4 )-alkoxy, phenyl, phenyl(C-C 2 )alkyl, hydroxyl, amino, hydroxy-(C -C )alkyl or substituted phenyl or amino groups, and also pharmacologically acceptable salts thereof.
:i i~ilW;~*;n ~lr*;r _1 13 78Ea'-(1',2',3',6'-tetrahydro-1',3'-dimethyL-2',61-dioxopurin-7'-y)propionyloxy-8,13-epoxy-l,68,9a-trihydroxylabd-14-en-11-one. M.p. 264-265 0
C.
8 ,1 3 -epoxy-78Ea'-(benzotriazo-1-y)acetoxy]-la,60,9atrihydroxylabd-14-en-11-one. M.p. 183-185 0
C.
The subject of the the preparation of derivatives of the the preparation of represented by the invention is furthermore a process for the novel poLyoxygenated Labdane formula I. The starting materials for these derivatives are two compounds formula II
ZCH
2
CH
3 in which R stands for hydrogen or the hydroxyl group and
R
1 and R 2 are hydrogen. The compound of the formula II SS SO S in which R denotes OH and R 1 and R 2 denote hydrogen is a constituent of the plant Coleus forskohlii and is additionally obtained from 6-acetyl-7-deacetylforskolin
(II,
R OH, R 1 Ac, R 2 OH) by hydrolysis. A further constituent of the said plant called 9-desoxyforskolin
(II,
R H, R 1 Ac) yields on hydrolysis the other starting substance of the formula II wherein R and R1 stand for hydro- :30 gen. The preparation of these substances from the plant Coleus forskohlii is reported on in the publications which are listed as the prior art.
S*0* The process for the preparation of polyoxygenated labdane derivatives of the formula I in which R stands either for hydrogen or a hydroxyl group and RI, R 2
R
3 individually stand either for a hydroxyl group or the group i, -A _I 14 S-C- H -N and R 4 R5, R 6 and R 7 correspond R4 7 to the definition cited above, comprises the reaction of the compounds of formula II (R H or OH, R 1
R
2
H)
with a haloalkanoyl halide of the formula III S14III X-C-C-(CH -Y
R
in which R 4
R
5 and n have the same meaning as defined for R4, R 5 and n in formula I and X and Y stand for a halogen atom, in the presence of a base. The base used may be an organic nitrogen-containing compound such as, for example, pyridine or triethylamine. The reaction may be carried out at temperatures between 0° C and room temperature and in solvents such as aromatic hydrocarbons, for example benzene, toluene, or ethers such as tetrahydrofuran ooe* or dioxane, or halogenated hydrocarbons such as methylene 20 chloride o-i hloroform. The duration of the reaction is 0** one half to six hours. The product is isolated by concen- Strating the reaction mixture by evaporation, then extracting with an organic solvent and washing the extract consecutively with dilute hydrochloric acid, water, sodium bicarbonate solution and water, then drying over drying Sagents such as anhydrous sodium sulfate and finally by o* ~concentrating by evaporation in vacuo. The residue remaining is a mixture of compounds which is optionally used without purification for further reaction with amines of 30 the formula IV SR6 HN iv
IV
R
in which R 6 and R 7 have the same meanings as defined for
R
6 and R7 in the formula I. The reaction takes place at temperatures between room temperature and 150 0 C over a period of 1 to 6 hours, with or without solvent. Aromatic 1 15 hydrocarbons such as benzene, toluene or ethers such as tetrahydrofuran or dioxane serve as solvents. The product is isolated from the reaction mixture by means of concentration of the reaction mixture, subsequent extraction with an organic solvent such as ethyl acetate and by purification of the extract by means of chromatography over silica gel and elution with ethyl acetate/petroleum ether.
Compounds of the formula I wherein R denotes hydrogen or hydroxyl, R 1 denotes hydrogen or the radical 0 R R S4 "6 2)-N 5 n 7
R
2 likewise denotes said radical and R 3 denotes hydrogen, wherein R 4 to R 7 and n have the meanings cited for the formula I, can be obtained by reaction of a compound of the formula I in which R and R 1 have the cited meanings,
R
2 represents hydrogen and R 3 represents the radical a.
1 4 /V6 a**a -C-C-(CH -N R, R 6 S5 R5 with a base such as an alkoxide, for example methoxide, ethoxide or tert-butoxide in the presence of solvents, *30 for example aromatic hydrocarbons such as benzene, toluene or ethers such as, for example, tetrahydrofuran or dioxane, over a period of 2 to 12 hours. The reaction can be accelerated or terminated by heating the reaction mixture S* to the boiling point of the solvent used. The product is isolated from the reaction mixture by concentrating by evaporation in vacuo, then extracting the residue with a s.olvent such as methylene chloride or ethyl acetate, washing the extract with water, drying over drying agents a taLyL, or K6 denotes an alkyL by evaporation in vacuo. Purification is carried out by means of chromatography and/or crystallization.
The compounds of the present invention and their salts exhibit the pharmacological properties which are attributed to the polyoxygenated labdanes and their derivatives already known, but in particular, depending on the nature and position of the substituents, a positive inotropic activity, antihypertensive activity, and also the ability to reduce the intraocular pressure. This is evident from the result of the following pharmacological investigations which were conducted to assess the substances of the present invention and their salts.
Positively inotropic activity The following two methods were used.
20 1. Isolated guinea pig heart (Langendorff method) gl A guinea pig of male or female sex weighing between 300 and 400 g is killed and the heart is removed along with 0 a small part of the aorta. The heart is immediately transferred to a perfusion apparatus in which the aorta 1 is mounted on the glass cannula. The perfusion solution, which comprises oxygenated Ringer's solution, is supplied at constant pressure from the reservoir which is heated to 37°C by water circulating from the thermostat. The com- S 30 pounds of the invention to be investigated are dissolved directly in water in order to prepare a solution of known *I concentration using stoichiometric 0.1 N HCL or salt3 thereof. The solution obtained is injected directly *into the aorta through a polyethylene cannula and the effects on the contraction force, heart rate and coronary blood flow are recorded on a 3-channel Physioscribe re- i corder. The percentage increase or decrease of the inotropic activity is calculated from the initial basal value.
17 17 2. Electrically stimulated left atrium A guinea pig of male or female sex weighing 400 g is killed, the heart is removed and placed in Ringer's solution at room temperature. The left atrium is then isolated, attached to an organ holder and the preparation. '.aced in an organ bath containing Ringer's solution at room temperature. A vigorous stream, comprising a mixture of carbon dioxide and oxygen (95% 02 and 5% CO 2 is fed into the organ bath. The left atrium is then electrically stimulated. An aqueous solution of known concentration is then prepared from one of the compounds of the invention or their salts, optionally using stoichiometric aqueous 0.1 N HCI solution.
This solution is added to the bath and the contraction force of the atrium is recorded for 7 to 10 minutes on a 4-channel Kohden recorder. The activity is calculated as S EC 50 from the data obtained.
S I g 3. In vivo test, on an anesthetized dog Beagle dogs of both sexes weighing between 10 and 15 kg are anesthetized with sodium pentobarbitol (35 mg/kg, 25 After introducing an endotracheal tube, the ooo femoral artery and vein are provided with a cannula for measuring the blood pressure or for administering drugs.
The pressure of the left ventricle is measured by means of a Millar catheter and the dp/dt max is calculated using a Hugo Sachs differentiometer. The heart rate is determined from ECG signals by means of a cardiotachometer.
All the parameters measured continuously are recorded with a Hellige six-channel recorder.
The compounds of the invention to be investigated are dissolved in distilled water. In all the experiments 1% solutions are used. The solutions are injected into the femoral vein and the dose response calculated.
OQ aILKYLP aLKoxy, naLogen, nitro or I I
I
18 The results obtained for representative compounds of the invention are shown in TabLe I below: 0S 0*
S.
SS 00 @0 0.4 6 .0 Table I IlsoLated guinea pig heart to. to.666 Guinea pig n atrium
EC
5 Pg/mi Compound nesthet ized og dp/dt max ED 2 o H
N
3 H10 32 27 40 2.3 0.052 co-CH- N 0 H 10 45 20 11 4.7 3 COCH NO0 HC1 H 30 23 34 35 0.5 0.11
COCH
2 I ~~CH 3 H 2.6 0.39 I HCI
-COCH
2 N H 3 i.
/J N/ *s S 5 L 9* S S S S S e S S S S *t S S S S r S Sea S S
I
S. S *SS S S S S *5 5 5 5 5 S S 5 S C S -S C Table I (cont.) Isolated guinea pig heart Dose increase in Guinea nig at r i u m pg/Mi Anesthetized dog dp/dt max ED (mg/kg)i.v.
50 Inotropic activity Chronotropic activity Coronary' f tow 11 I .1 HC 1.tI5 0 920 Me I 520 COCH 211Q 1.25 HC1 2.5H 2 0 -co (cH 2 4 -N9 cli 1.9 a i ji- a-aminoquinotinopropionyl 1 il Measurement of the intraocular pressure in conscious rabbits A male or female rabbit weighing from 2 to 3 kg is selected for the investigation. The intraocular pressure (IOP) is measured with a Schioetz tonometer after previous corneal anesthesia with 2% novocaine solution. A 2% aqueous solution is prepared by dissolving a compound of formula I using stoichiometric aqueous 0.1 N HCI solution or a salt of such a compound directly in water. After determining the basal value, 100 yl of the 2% solution of the test substance is instilled into one eye and the vehicle into the other. The IOP is measured at intervals of 0.5, 1, 2, 3, 4 and 5 hours. The percentage reduction of the IOP is calculated from the basal value.
The results for the representative compounds of the invention tested in this model are listed in the table below:
S
S.
S
S
S S
S
55 S. S
I
i I~ 1 ii: j r l i-i i Pi i! 1 ;e a L__ .i 6-(4'-phenyLpiperidino)vaLeryL IOP Lowering activity RR 2R3Dose Drop in Duration
HCOC
2 -N-0 QH 2 27.5 6
CH
3 COCH 2 .G9 H H 2 15 2 H H COCH 2 0 HCO-CH 2 -NOJ H 2 0 0S* 0 H H CQCH 2 216 H3 0 20 H CO(CH No( H 1 236 se* 2 4 H COCH-N S H COCH-ND 1 196 .2HC1.3H 0 Lowering of__blood pressure in conscious hypertensive rats The blood-pressure Lowering activity is determined in conscious rats with spontaneous hypertension For this purpose male SH rats (250 300 g, 12 16 weeks old) of the Wistar/Okamoto strain bred in-house are used.
The r a ts are 'warmed fto r 10 minutes a t 370 in a heating chamber before the blood pressure measurement.
ii-one nyaroxychloride hemihydrate.
,in I i.
13 The systolic blood pressure is measured in the conscious rats by means of the tail-cuff method, using a piezoelectric crystal to indicate the pressure pulse, an aneroid manometer for measuring pressure and a cardiscope (BFL-India) for indicating the disappearance and/or appearance of the pressure pulse.
The compounds of the invention to be tested are dissolved directly in water using stoichiometric 0.1 N HCL solution or the salts and administered orally in said form to the SH rats once daily for 5 days in a dose of 25 mg/kg. One group serves as control and receives the vehicle. The systolic blood pressure is recorded before the first administration of the drug and 2 hours thereafter. A drop in the systolic blood pressure is the difference between the blood pressure after the treatment and the basal value.
The results for the representative compounds of the invention and their salts are listed in the table below: 0 Compound Dose Drop in systolic S0* (mg/kg) blood pressure H p.o.
OH
OR
3
R
3 OR 2 2
R
3 -COCH 2-N H 25 14 1 H COCH 2 N 25 CO-CH-N CO-CH-N 0 25 38 iI CH
CH
3 3
E
trihydroxylabd-14-en-11-one.
I
'i a Effective doses of the compounds of the invention can be administered, for example, orally together with pharmacologically acceptable auxiliary and carrier materials in the form of gelatin capsules, tablets, elixirs, suspensions, syrups etc. These preparations contain at least in general, however, between about 4 and 70%, of the active compound. The quantity of the active compound in such preparations is adjusted so that a suitable dose is obtained. Preferably, such a dosage unit for oral administration contains between 0.1 and 30 mg of an active compound.
For the purpose of parenteral or topical administration, preparations such as solutions, suspensions, tinctures, ointments or creams, are prepared which contain at least 0.01%, in general, however, between about 0.5 and 5% (by weight) of the active compound. Preferably, a dosage unit contains between 0.01 and 10 mg of an active compound for said purpose.
The solutions or suspensions for parenteral administration may contain the following components: a sterile diluent, for example water, sodium chloride solution, vegetable oils, polyethylene glycols, glycerine, propylene glycol I 25 or other synthetic solvents; antibacterial agents such S, as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA and buffers such as acetate's, citrates or phosphates.
The invention is illustrated by the following examples.
I EXAMPLE 1 8 ,1 3 -Epoxy-la-piperidinoacetoxy-6B-70-9atrihydroxylabd-14-en-11-one A solution of chloroacetyl chloride (0.24 ml) in dichloromethane (2 ml) was added to a mixture of 8,13-epoxy- I l I I-
-L
la,68,78,9x-tetrahydroxylabd-14-en-11-one (1.0 9) dissolved in dichloromethane (10 mL) and dry pyridine (0.42 mL) which was cooled in an ice-salt bath. The reaction mixture was stirred for 1 1/2 hours at OOC and concentrated in vacuo. The residue was extracted with dichloromethane.
The organic Layer was separated, washed consecutively with dilute hydrochloric acid saturated sodium bicarbonate solution, and water and finally dried over anhydrous sodium sulfate. The extract was concentrated to give a residue (1.1 The residue was treated with piperidine (10 ml) and the mixture refluxed for two hours. The reaction mixture was then concentrated in vacuo and the residue extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The residue from the concentration of the extract was a mixture of products as indicated by thin-Layer chromatography. Purification of the mixture I-s.s of products by chromatography over a silica gel column and elution with ethyl acetate/petroleum ether as :20 eluent yielded the desired 8,13-epoxy-la-piperidinoacetoxy-68,7,9ca-trihydroxylabd-14-en-11-one with a melting point of 89-91 0 C. The other products of the mixture were also isolated. The details are described in Examples 3 and 4.
EXAMPLE 2 8 ,13-Epoxy-l-piperidinoacetoxy-68,70,9atrihydroxylabd-14-en-11-one hydrochloride hemihydrate c Diethyl ether (10 mL, saturated with dry HCI gas at OOC) was added to a methanolic solution of 8,13-epoxy-la-piperidinoacetoxy-68,78,9c-trihydroxyabd-14-en-11-one (0.5 g in 5 mL methanol). The mixture was then diluted with an excess of dry diethyl ether and the precipitated solid separated by means of filtration. Recrystallization of the solid from methanoL/ether yielded 8,13-epoxy-lt-piperidinoacetoxy-6B,7B,9a-tridhydroxyabd-14-en-11-one hydrochloridle hemihydrate with a melting point of 144- 146 0C EXAMPLE 3 8,13-Epoxy-78-piperidinoacetoxy-lct,6,9ztrihydroxyLabd-14-en-11-one a The process described in Example 1 was repeated. The mixture of products obtained by purification by means of chromatography over a silica gel column using ethyl acetate/petroleum vther as eLuents yielded 8,13-epoxy- 1c-piperidinoacetoxy-60,78,9ca-trihydroxyLabd-14-en-1 1-one, after removal of which further eLution gave the desired 8, 13-epoxy-78-p iper idinoacetoxy-cz,60,9x-tr ihydroxyLab- 14-en-il-one with a melting point of 162-164 0
C.
11 0 #*so The following compounds were prepared in a similar manner, using appropriate amines in place of piperidline Chydrochloride salts of the compounds were prepared by the procedure described in ExanmpLe 2): 8,i3-epoxy-70-piperidinoacetoxy-ct,6,9-tr ihydroxyLabd- 2514-en-li-one hydrochloridle, melting point 194-197 0
C.
258,13-epoxy-7B-morphoLinoacetoxy-li,60,9cz-trihydroxyLabd- 14-en-li-one hydrochloridle, melting point 174-175 0
C.
8,13-epoxy-70-morphoL inoacetoxy-la,68,9(x-trihydroxyLabd- V 14-en-li-one hydrochloride, melting point 202-204 0
C.
8,i3-epoxy-70-(N-cycLohexyL-N-methyLaminoacetoxy)-,6,9t- 4' 30 trihydroxyLabd-14-en-li-one hydrochloride, melting point Fl 198'a200 4
'C.
8,13-epoxy-78-(N-methyLpiperazinoacetoxy)-lc,68,9t-tr ihydroxyLabd-14-en-l 1-or~e hydrochloridle, melting point 193-194 0
C.
8,13-epoxy-7B-pyrroL idinoacetoxy-la,6B,9ci-trihydroxyLabd- 14-ern-11-one hydlrocht,;icle, melting point 189-192 0 C.4 8,i3-epoxy-70-diethyLaminoacetoxy-l1t,68,9a-trihydroxy- Labd-14-en-11-one hydrochLoridle, melting point 169-172 0
C.
8,13-epoxy-78-piperidinobutyroxy-ct,6$,9c-trihydroxy- IN Labd-14-en-11-one hydrochloridle, melting point 178-181 0
C.
8,13-epoxy-7B-Cot'(N-piperidino)propionoxy-l,6,9z-trihydroxyLabd-14-en-11-one, meLting point 199-201 0
C.
8,13-epoxy-78-[al (N-morphoL ino)propionoxy)-1a,68,9cz-trihydroxyLabd-14-en-11-one, melting point 191-193 0
C.
8, 13-epoxy-78-Ea (4N-methyLpiperaz ino)propionoxyJ-la,6,9ztr ihydroxyLabd-14-en-11'-one dlihydrochLoridle, melt ing point 258-268 0
C.
8,13-epoxy-7$-(theophyLL inoacetoxy)-1ci,68,9cz-trihydroxy- Labd-14-en-11-one monohydrate, melting point 1980 C.
8,13-epoxy-78-(y'-morphoLinobutyryLoxy)-ct,6$,9-trihydroxyLabd-14-en-1 1-one hydrochloridle hemihydrate, melting I point 203-208 0
C.
15 8,i3-epoxy-78-(a'-aniL inopropionyLoxy)-1a,68,9t-trihydroxyLabd-14-en-11-one, melting point 168-169 0
C.
8, 13-epoxy-78-(4'-hydroxy-4 '-phenyLpiper idinoacetoxy)lc,6$,9-trihydroxyLabd-14-en-11-one hydrochloridle, meLting point 119-1210~C.
8,13-epoxy-76-(aniLinoacetoxy)-cz,6B,9ca-trihydroxyLabd- 14-en-li-one, meLting point 186-190 0
C.
7B-(tert-butyLaminoacetoxy)-8,13-epoxy-ct,6B,9a-trihy- 1' droxyLabd-14-en-11-one hydrochloridle monohydrate, metting point 195 0 C (decomposes).
8,13-epoxy-7B-(41-hydroxypiper idinoacetoxy)-t,.6$,9ca-trihydroxyLabd-14-en-11-one hydrochloridle, melting point 185-190 0 C (decomposes).
8,13-epoxy-78-(-y'-N-methyLpiperaz inobutyryLoxy)-ca,6B,9ttrihydroxyLabd-14-en-11-one dlihydrochLoridle monohydrate, melting point 203-207 0
C.
8,13-epoxy-7B-(morphoL inoLauryLoxy)-la,60,9a-trihydroxytoo* Labd-14-en-11-one hydrochloridle, melting point 134-140 0
C.
,l 3 -epoxy-7$-(thiomorphoL inoacetoxy)-1cx,68,9%trihydroxy- Labd-14-en-11-one hydrochloridle sesquihydrate, melting point 169-171 0
C.
8,l 3 -epoxy-7B-(3'-methyLpiperidinoacetoxy)-Io,6,9a-tr ihydroxyLabd-14-en-1 1-one hydrochloridle, melting point 247-249 0
C.
8,13-epoxy-78-(4'-methyLpiperidinoacetoxy)-l,6,9c--trihydroxyLabd-14-en-1 1-one hydrochloride, melt ing point 196-199 0
C.
8,13-epoxy-78-(B-phthaLimidopropiony~oxy)-l1x,68,9a-trihydroxyLabd-14-en-l1-one monohydrate, melting point 245-247 0
C.
8,13-epoxy-78-(morphoLinoisobutyryLoxy)-cz,68,9-trihydroxyLabd-14-en-11-one hydrochloridle, 274 0
C.
8,13-epoxy-78-(6'-piperidinovaLeryLoxy)-la,68,9(x-trihydroxyLabd-14-en-li-one monohydrochLoride, melting point 223-224 0
C.
EXAMPLE 4 8, 13-Epoxy-6$-piper idinoacetoxy-iQ,78,9a-tr ihydroxyLabd- 14-en-i 1-one METHOD 1 The process described in Example 1 was repeated. The mixture of products obtained was purified by fLash column :00020 chromatography over silica gel using ethyl acetate/petro- Leum ether as eLuents. First compound eLuted was 0 as 8, 13-epoxy-ict-piper idinoacetoxy-60,7,9t-tr ihydroxyLabd- 14-en-li-one followed by the second compound 8,13-epoxy- 78-piperidinoacetoxy-lct,68,9ct-trihydroxyLabd-14-en-1i-one and further eLution yieled the product 8,13-epoxy-6apiperidinoacetoxy-lct,70,9ct-trihydroxyLabd-14-en-l i-one with a melting point of 111-113 0
C.
METHOD 2 6090 9* Se S9 0
C
8,13-Epoxy-78-piperjdinoacetoxy-lt,6B,9c-trihydroxyLabd- 14-en-il-one (0.1 M) was stirred with sodium methoxide (0.1 M) in dry dioxane (25 ml) for 12 hours. The reaction mixture was then concentrated in vacuo at 0 0 C and the residue was extracted with dichLoromethane. The extract was washed with water and dried over anhydrous sodium sulfate.
Concentration yielded a residue which on purification by medium Pressure Liquid chromatography yielded 8,13-epoxy-
_J
I I 65-piperidineoacetoxy-1a,78,9(x-trihydroxyLabd-14-el-11one with a melting point of 111-113 0
C.
METHOD 3
II
N
t.jj ii
U
[I
0e
V
V.
V V
VS
V. V
V
V.
S
8,13-Epoxy-7$-piperidinoacetoxy-ct,68,9ct-trihydroxyLabd- 14-en-li-one (1.0 g) was refluxed in dry piperidline ml) for 12 hours. The reactiohn mixture was then concentrated by evaporation in vacuo and residue extracted with ethyl acetate. The extract was then washed with water and sodium chloridle sotutidn and dried over sodium sulfate. Concentration of the extract yielded a residue which on purification by flash column chromatography yielded 8, 13-epoxy-6B-piper idinoacetoxy-ct,78,9ct-tr ihydroxyLabd-14-en-11-one (melting point 111-113O C).
The compounds Listed below were prepared in the same manner using appropriate amines in place of piperidline 20 (the hydrochloridle salts were prepared by the procedure described in Example 2): 8,13-epoxy-6B-morphoLinoacetoxy-cx,7B,9c-trihydroxyLabd- 14-en-il-one, melting point 210-2120C.
25 8,13-epoxy-68-morphoL inoacetoxy-ict,78,9a-trihydroxy- Labd-14-en-1i-one, melting point 152-155 0
C.
8,13-epoxy-6B-pyrroLidinoacetoxy-ia,70,9a-trihydroxy- Labd-4-en-11-one, melting point 116-1180C.
8,i3-epoxy-6$-(N-methyLpiperazinoacetoxy)-cz,7B,9t-tri- 30 hydroxyLabd-14-en-ii-one dlihydrochLoridle, melting point 182-184 0
C.
8,i3-epoxy-6B-(N-methyLcycLohexyLaminoacetoxy)-l,7,9ztrihydroxyLabd-14-en-ii-one, melting point 137-1390C.
8 ,i 3 -epoxy-68-Em'(N-morphoLino)propionoxy)-1a,7B,9a-tri- .hydroxyLabd-14-en-11-one dlihydrochLoridle, meLting point 179-180 0
C.
8,3eoy6-~lNpprdn~rpooy-c,891ti hydroxyLabd-14-en-li-one dihydrochLoride, meLt ing point 260-261 0
C.
4 .1 8,13-epoxy-68-EQ' C4N-methyLpiperazino)propionoxy-ct,7,9ttrihydroxylabd-14-en-1 1-one dihydrochioride, melting point 208-209 0
C.
8, 13-epoxy-6B-(4'-hydroxypiper idinoacetoxy)-1ct,7B,9atrihydroxylabd-14-en-1 1-one hydrochloridle dlihydrate, melting point 187-190 0
C.
8,13-epoxy-68-(thiomorphoL inoacetoxy)-1ct,78,9(x-trihydroxyLabd-14-en-1 1-one hydrochloridle sesquihydrate, melting point 173-176 0
C.
8, 13-epoxy-6B-(4'-methyLpiper idinoacetoxy)-la,7B,9t-tr ihydroxyLabd-14-en-11-one hydrochloridle dlihydrate, melting point 125-128 0
C.
ii 8,13-epoxy-6B-(4'-benzoylaminopiper idinoacetoxy)-la,7,9c- [i trihydroxyLabd-14-en-1 1-one hemihydrate, 122-124 0
C.
8, 13-epoxy-6B-(homopiperidinoacetoxy-lz,70,9c-trihydroxylabd-14-en-11-one hydrochloridle, 192 0 C (decomposes).
8,13-epoxy-68-(y'-piperidinobutyryLoxy)-lx,78,9t-trihydroxyLabd-14-en-11-one hydrochloridle hemihydrate, melting point 178-1810C.
20 6 ,3eoy6-deh~mnactx)lB9-rhdoy Labd-14-en-11-one monohydrochioridle dlihydrate, melting ~j point 160-163 0
C.
:o 8,13-epoxy-6B-(y'-morphoL inobutyryLoxy)-1ci,76,9ct-trihydroxyLabd-14-en-1 1-one hydrochloridle dlihydrate, melt ing point 232-233 0
C.
8,13-epoxy-6$-(a'-aniL inopropionyLoxy)-cx,7B,9ca-trihydroxyLabd-14-en-11-one, melting point 218-219 0
C.
8, 13-epoxy-68-(4'-hydroxy-4' henyLpiper idinoacetoxy la,78,9c-trihydroxyLabd-14-en-11-one hydrate, melting point 123-125 0
C.
0**e 8 ,l 3 -epoxy-6$-(theophyLLinoacetoxy)-la,7B,9a-trihydroxy- Labd-14-en-11-one, melting point 149-153 0 C (decomposes).
8, l 3 -epoxy-6$-(benzy~aminoacetoxy)-la,7,9z-tr ihydroxy- Labd-14-en-11-one hydrochloridle monohydrate, meLting point 169-172 0
C.
8, l 3 -epoxy-68-(3'-methyLpiper idinoacetoxy)-1rA,78,9a- tr ihydroxyLabd-14-en-1 1-one hydrochloridle sesquihydrate, melting point 188-190 0
C.
8, 13-epoxy-6$-thexamethyLeneiminoacetoxy)-ct,78,9a-tr ihydroxyLabd-14-en-11-one hydrochloride hydrate. M.p. 192 0
C.
8,13-epoxy-68-(6'-piperidinovaLeryLoxy)-la,7B,9a-trihydroxyLabd-14-en-1 1-one monohydrochLor ide monohydrate.
M.p. 148-150 0
C.
EXAMPLE 1c-68-Dihydroxy-7a-(piperidin oacetoxy)- 8, 13-epa xyL abd-14-e n- 11-one The process described in Example 1 was employed using 8,13-epoxy-1ci,6$,78-tr ihydroxyLabd-14-en-1 1-one in place of 8,13-epoxy-lct,68,9cL-tetrahydroxyLabcl-14-en-1 1-one. The mixture of products as indicated by thin-layer chromatography was purified by means of chromatography using a silica gel column eLution with ethyl acetate/petroLeum ether and yielded the desired product ie,68-dihydroxy-78-(piperidinoacetoxy)-8,13-epoxyLabd-14-en-1 1-one with a melting point of 197-198 0 C, which was eLuted first.
The other products of the mixture were also isolated.
The dletails are described in Examples 6, 7 and 8.
EXAMPLE 6 1a-78-Dihydroxy-6B-(piperidinoacetoxy)-8, 13- 4 epoxyLabd-14-en-11-one H The process described in Example 5 was repeated. The mixture of products obtained as indicated by thin-Layer chromatography was purified by means of chromatography using a silica gel column and ethyl acetate/petroleum ete as e~et.The compound lc,8dhdoy7-iei dinoacetoxy-8,13-epoxyLabd-14-en-11-one was eLuted first and further eLution yielded the product 1a,78-hydroxy-6BpiperidinoacetoxyLabd-14-en-11-one with a melting point of 184-185 0
C.
EXAMPLE 7 la-7B-Di(piperidinoacetoxy)-8,13-epoxy-68-hydroxyLabd- 14-en-i 1-one The process described in Example 5 was repeated. The mixture of products obtained by purification by means of chromatography over a siLica gel column and eLution with ethyl acetate/petroleum ether yielded the compounds la,6Bdihydroxy-78-piperidinoacetoxy-8, 13-epoxyLabd-i4-en-llone and 1a,78-dihydroxy-6B-piper idinoacetoxy-8, 13-Labd- 14-en-li-one which were removed consecutively, while further eLution gave the compound 1a,7B-di(piperidinoacetoxy)-8, 13-epoxy-6B-hydroxyLabd-14-en-l--one with a meLting point of 78-80 0
C.
EXAMPLE 8 ica,68,76-Tri (piperidinoacetoxy)-8,13-epoxyLabd- *20 The process described in Example 5 was repeated. The mixture of products obtained by purification by means of chromatography over a silica gel column and eLut ion with 25 ethyl acetate/petroleum ether yielded the compounds 1c,6B-dihydroxy-7$-piperidinoacetoxy-8, 13-epoxyLabd-14en-li-one and 1(%,7B-dihydroxy-68-piperidinoacetoxyLabd- 14-en-il-one and la,78-di (piper idinoacetoxy)-8,13-epoxy- 6a-hydroxyLabd-14-en-11-one which were removed consecutiveLy and further eLution gave the product la6,$ tri Cpiperidinoacetoxy)-8,i3-epoxyLabd-14-en-i 1-one (as a thick oil), which was converted into its hydrochloridle salt, melting point 121-123 0
C.
4R C) l 0~ 33 EXAMPLE 9 8,13-Epoxy-78-theophyLLinoacetoxy-cx,66,9-trihydroxy- Labd-14-en-1 1-one monohydrate TheophyLline (0.198 g, 1.1 mmoL) in anhydrous dimethyLformamidle (8 ml) was added dropwise to a stirred mixture of potassium carbonate (0.152 g, 1.1 mmol) and anhydrous dlimethylformamide (7 ml). The reaction mixture was stirred for a further two hours. 7$-ChLoroacetoxy-8,13epoxy-la,68,9cz-trihydroxyLabd-14-en-1 1-one (0.445 g, mmol) in anhydrous dlimethylformamidle (4 mL) was then added and was stirred overnight at room temperature. The reaction mixture was then poured onto ice and extracted with ethyl acetate. The extract was washed with water and sodium chloride solution and dried over anhydrous sodium sulfate. Concentration yieled a residue which on purification by flash column chromatography using ethyl acetate/diisopropyL ether as eLuent gave 8,13-epoxy-78- 0.20 theophyLLinoacetoxy-1ca,6$,9ca-trihydroxyLabd-14-en-11-one monohydrate with a melting point of 1980 C in 65% yield.
Goo* The following compoundsz were prepared in a similar manner using appropriate amines in place of theophyLLine: 2578Ec'-(1 ',2',3',6'-tetrahydro-1 ',3'-dimethyL-2',6'-dioxo- 0 e~g purin-7'-yL )propionyLoxy)-8,13-epoxy-cx,6B,9cx-trihydroxyabd-14-en-11-one. M.p. 264-2650C.
8 ,13-epoxy-78-Ca'l-(benzotriazoL-1-yL )-acetoxy)-ca,6B,9ttrihydroxyLabd-14-en-11-one. M.p. 183-185 0
C.
EXAMPLE 0S 00 0 lc, 7 -DimorphoLinopropionyLoxy-60,9a-dihydroxy-8,13epoxyLabd-14-en-1 1-one dlihydrochLor ide monohydrate 2-BromopropionyL chloridle (1.0 Wl was added to an icecooled mixture of 7-acetyLforskoLin (1.0 g) and pyridine 0 LL) '4l a DU C Oj i
I
34 ml) in dichloromethane (30 mL). The reaction mixture was stirred for 3 hours at room temperature and then washed consecutively with dilute hydrochloric acid, water and sodium chloride solution. The dichoromethane layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the resulting residue reacted with morpholine as described in Example 1. The crude product obtained in this manner was purified by column chromatography using ethyl acetate/petroleum ether/triethylamine (50:50:0.05) as eluent, and the product obtained was treated with ethereal HCL to obtain la,7$-dimorpholinopropionyloxy-68,9a-dihydroxy-8,13-epoxylabd-14-en-11-one dihydrochloride monohydrate, melting point 195-198 0 C (80% yield).
EXAMPLE 11 la,78-Di-(a'-morpholinopropionyoxy)-68,9a-dihydroxy-8,13epoxylabd-14-en-11-one dihydrochloride monohydrate.
S.
20 2-Bromopropiony chloride (1.0 ml) was added to an ice- S. cooled mixture of 7-acetylforskoin (1.0 g) and pyridine (1.0 ml) in dichloromethane (30 ml). The reaction mixture was stirred for 3 hours at room temperature and then washed consecutively with dilute hydrochloric acid, water was dried over anhydrous sodium sulfate, concentrated in vacuo by evaporation and the residue reacted with mor- ~pholine as described in Example 1. The crude product S" was purified by column chromatography using ethyl acetate/ petroleum ether/triethyamine (50:50:0.05) as eluent.
After treatment with ethereal HCL the title compound having a melting point of 195-198 0 C was obtained in yield.
The following compound was obtained in a similar manner using thiomorpholine instead of morpholine: 6
B-
9 a-dihydroxy-1a,7-di(a'-thiomorpholinopropionyloxy)- -t 357 8, 13-epoxytabd-14-en-one dihydrochLor ide trihydrate.
M.p. 186-188 0
C.
4 [1 ii c 0 0. 5 0 0 0 005 0000* so 0.
C
Claims (4)
1. A compound of the formula I 00 R 3 OR 2 wherein onaR denotes hydroxyl; R.and R 3 denote hydrogen, R 2 denotes the radical 0 R (cnH )n 0*0.7 00~ R 4 and R 5 are identical or different and repr nt hydrogen or (CI -C 4 )alkyl, n stands for 0 or an integer from 1I R6 denotes hydrogen and *R repent hydr gen, Mr bSt (C 1 )alkyl,>\ cclo yl, phenyl or pheayl -C 2 )alkyl, where the phen -radical may be singly or Multiply substituted y halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, nitro nd/or trifluoromethyl; pyridine, quinoline, o, hydroxy, (C,-C,)alkanoyl, (C 2 C)-alke ,benzoyl or phenyl (C 1 -C 6 )alkanoyl wherein the phen radical may be singly or multiply substituted by halo (C 1 -C 4 )alkyl, (C 1 -c 4 )alkoxy, nitro or -T 37 wherein R 4 and R 5 represent hydrogen or R 4 represents hydrogen and R 5 represents (C -C 4 )alkyl, R 6 represents (C 1 -C 4 )alkyl and R 7 represents cyclohexyl, or R 6 and R 7 together with the N atom to which they are attached represent the pi- Ar+ morpholino, thiomorphoJino, riF er: r, imidazole, theophyllino or pyrrolidino radical and n represents an integer from 0 to 5, and also pharmacologically acceptable acid addition salts thereof. A drug which contains a compound of the formula I as claimed in claim 1 and/or pharmacologically acceptable S salt. The use of a compound of the formula I and/or a pharmacologically acceptable salt for the preparation of S drugs. A process for the preparation of a compoud of formula I as defined in claim 1 wherein R, R R 2 R 3 R 4 Rs, R 6 and R 7 have the meanings as defined in claim 1 So** wherein •o a compound of the formula II *w CH2 OH CH 3 CHS R 08 CH 3 'H3 oE wherein R represents hydrogen or hydroxyl, is reacted with a compound of the formula III alfoaceto- 6 O,7,9xtrdhydroxytabd..en11-~one 4 0 3R X -C-C (CE)- 2 n III wherein X and Y denotes halogen and R 4 R, and n have the abovementioned meanings, in the presence of a base, and a compound of the formula IV 0SS* 0e ege S. S S S 55 S. 55 0 5 S S S
5.5. 5500 S S *5 0 S .555 S 5
55.. S OSSS S
555... S wherein R 1 and R 3 denote hydrogen and R 2 denotes the radical 0 11 N -c c- (CE 1 2 n AR is reacted with a compound of the formula V 6N wherein R 6 and Rhave the abovementioned meanings, and the individual compounds of formula I are isolated in the usual manner, and I DBM/KJS/CH (1.8) T) 3 optionally a compound of formula I, wherein R denotes hydrogen or hydroxyl and R represents hydrogen and R 2 represents hydrogen and R 3 represents the radical 0 6 ii 4 7 wherein R 4 to R, and n have the abovementioned meanings is reacted with an alkali(C -C 4 )alkoxide to form a oy a compound of the formula I, wherein denotes hydrogen, R rdenotes the radical Ce 0 R R 6 S. 2 n he and R denotes hydrogen. meanin The process as claimed in claim 6, wherein the reaction of a c of a compound of the formula II with a compound of the formula III is carried out in the presence of an organic nitrogen base at a temperature from 0 0 C to room temperature :and in an arnmatic hydrocarbon, an ether or in a halogenated Shydrocarbon, and the reaction of a compound of the formula IV with a compound of the formula V is carried out for 1-6 hours at temperatures from room temperature up to 150 0 C with or without solvents. A 1 ;iil 1 /t ii 2 to 12 hours. TRADEThe process as claimed in claim 6, wherein a 'THE ATRIUM', 2ND FLOOR 290 BURWOOD ROAD compound of the formula I is treated with sodium methoxide, aromatic hydrocarbons or ethers as solvents over a period of 2 to 12 hours. DATED this 2nd day of July, 1990. HOECHST AKTIENGESELLSCHAFT HAWTHORN VIC. 3122 WATERMARK PATENT S« TRADE MARK ATTORNEYS 'THE ATRIUM', 2ND FLOOR 290 BURWOOD ROAD HAWTHORN VIC. 3122 AUSTRALIA. 4 C 9*4
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DE3535086 | 1985-10-02 | ||
DE19853535086 DE3535086A1 (en) | 1985-10-02 | 1985-10-02 | NEW POLYOXYGENATED LABDAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINES |
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EP (1) | EP0217372B1 (en) |
JP (1) | JPS6289677A (en) |
KR (1) | KR870004051A (en) |
AT (1) | ATE60054T1 (en) |
AU (1) | AU606036B2 (en) |
DE (2) | DE3535086A1 (en) |
DK (1) | DK468186A (en) |
ES (1) | ES2019863B3 (en) |
GR (1) | GR3001559T3 (en) |
HU (1) | HU203234B (en) |
IL (1) | IL80201A0 (en) |
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Cited By (1)
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AU609980B2 (en) * | 1988-05-09 | 1991-05-09 | Hoechst-Roussel Pharmaceuticals Incorporated | Hydrazinocarbonyloxylabdanes, a process for their preparation and their use as medicaments |
Families Citing this family (15)
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US4963537A (en) * | 1985-03-01 | 1990-10-16 | Hoechst-Roussel Pharmaceuticals Inc. | Labdane compounds, pharmaceutical compositions and use |
ATE62683T1 (en) * | 1985-03-01 | 1991-05-15 | Hoechst Roussel Pharma | LABDAN DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS. |
JPS6310783A (en) * | 1985-11-15 | 1988-01-18 | Nippon Kayaku Co Ltd | Novel forskolin derivative |
AU591196B2 (en) * | 1985-11-15 | 1989-11-30 | Nippon Kayaku Kabushiki Kaisha | Novel forskolin derivatives |
DE3623300A1 (en) * | 1986-07-11 | 1988-01-21 | Hoechst Ag | 7-ACYLOXY-6-AMINOACYLOXYPOLYOXYLABDANE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
US4920146A (en) * | 1986-12-29 | 1990-04-24 | Hoechst Roussel Pharmaceuticals Inc. | Carbamoyloxylabdane compounds useful in reducing intraocular pressure |
US5646175A (en) * | 1987-12-28 | 1997-07-08 | Hoechst Marion Roussel, Inc. | Carbamoyloxylabdane compounds |
IN166900B (en) * | 1987-06-03 | 1990-08-04 | Hoechst India | |
JP2504934B2 (en) * | 1987-06-29 | 1996-06-05 | 日本化薬株式会社 | 1,6,7-Triacylforskolin derivative |
JPH0684367B2 (en) * | 1987-06-29 | 1994-10-26 | 日本化薬株式会社 | New method for producing forskolin derivative |
US5846992A (en) * | 1987-10-08 | 1998-12-08 | Hoechst Marion Roussel, Inc. | Synergistic intraocular pressure lowering combinations |
US4902696A (en) * | 1987-10-08 | 1990-02-20 | Hoechst-Roussel Pharmaceuticals, Inc. | Synergistic intraocular pressure lowering combinations |
EP0447962A1 (en) * | 1990-03-17 | 1991-09-25 | Hoechst Aktiengesellschaft | Labdanes and process for their preparation |
IL98913A0 (en) * | 1990-07-24 | 1992-07-15 | Hoechst Ag | Process for the preparation of 6-(3-substituted aminopropionyl)7-deacetylforskolin derivatives |
JP3557095B2 (en) * | 1998-04-20 | 2004-08-25 | 高砂香料工業株式会社 | Melanin production inhibitor |
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AU577928B2 (en) * | 1985-03-01 | 1988-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Labd-14-en-11-one derivatives |
AU577912B2 (en) * | 1984-12-14 | 1988-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Aminoacyllabdane derivatives |
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DE2557784C2 (en) | 1975-12-22 | 1986-04-17 | Hoechst Ag, 6230 Frankfurt | Forskolin, process for obtaining it and pharmaceutical preparations containing this compound |
DE2640275A1 (en) | 1976-09-08 | 1978-03-09 | Hoechst Ag | PHARMACOLOGICALLY EFFECTIVE SUBSTANCE FROM LABIATS |
DE2654796A1 (en) * | 1976-12-03 | 1978-06-08 | Hoechst Ag | POLYOXYGENATED LABDAN DERIVATIVES |
FR2460397A1 (en) * | 1979-07-05 | 1981-01-23 | Ducellier & Cie | ELECTRIC STARTER FOR INTERNAL COMBUSTION ENGINES IN PARTICULAR MOTOR VEHICLES |
DE3502685A1 (en) | 1985-01-26 | 1986-09-04 | Hoechst Ag, 6230 Frankfurt | FORSKOLIN, ITS ANALOGS AND DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF BY MEANS OF MICROBIAL CONVERSIONS AND THE USE OF THESE COMPOUNDS AS MEDICINAL PRODUCTS |
US4639443A (en) * | 1985-03-01 | 1987-01-27 | Hoechst-Roussel Pharmaceuticals Inc. | Labdane compounds, pharmaceutical compositions and use |
AU591196B2 (en) * | 1985-11-15 | 1989-11-30 | Nippon Kayaku Kabushiki Kaisha | Novel forskolin derivatives |
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- 1986-10-01 DK DK468186A patent/DK468186A/en unknown
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- 1986-10-01 HU HU864152A patent/HU203234B/en not_active IP Right Cessation
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- 1986-10-01 DE DE8686113486T patent/DE3676922D1/en not_active Expired - Fee Related
- 1986-10-01 JP JP61231365A patent/JPS6289677A/en active Pending
- 1986-10-01 ES ES86113486T patent/ES2019863B3/en not_active Expired - Lifetime
- 1986-10-02 KR KR1019860008271A patent/KR870004051A/en not_active Application Discontinuation
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AU577912B2 (en) * | 1984-12-14 | 1988-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Aminoacyllabdane derivatives |
AU577928B2 (en) * | 1985-03-01 | 1988-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Labd-14-en-11-one derivatives |
Cited By (1)
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AU609980B2 (en) * | 1988-05-09 | 1991-05-09 | Hoechst-Roussel Pharmaceuticals Incorporated | Hydrazinocarbonyloxylabdanes, a process for their preparation and their use as medicaments |
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DK468186A (en) | 1987-04-03 |
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EP0217372A2 (en) | 1987-04-08 |
DK468186D0 (en) | 1986-10-01 |
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IL80201A0 (en) | 1986-12-31 |
IN163242B (en) | 1988-08-27 |
ZA867495B (en) | 1987-05-27 |
KR870004051A (en) | 1987-05-07 |
HU203234B (en) | 1991-06-28 |
PT83478A (en) | 1986-11-01 |
ES2019863B3 (en) | 1991-07-16 |
HUT46319A (en) | 1988-10-28 |
AU6327086A (en) | 1987-04-09 |
EP0217372A3 (en) | 1988-03-30 |
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