AU628026B2 - New acyllabdane derivatives, a process for their preparation,and their use as medicaments - Google Patents

New acyllabdane derivatives, a process for their preparation,and their use as medicaments Download PDF

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AU628026B2
AU628026B2 AU24649/88A AU2464988A AU628026B2 AU 628026 B2 AU628026 B2 AU 628026B2 AU 24649/88 A AU24649/88 A AU 24649/88A AU 2464988 A AU2464988 A AU 2464988A AU 628026 B2 AU628026 B2 AU 628026B2
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formula
group
alkyl
compound
hereinbefore defined
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Alihussein Nomanbhai Dohadwalla
Rajeshwari Kannan
Yatendra Khandelwal
Bansi Lal
Ramanujam Rajgopalan
Richard Helmut Rupp
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Hoechst AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78Ring systems having three or more relevant rings
    • C07D311/92Naphthopyrans; Hydrogenated naphthopyrans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02Silicon compounds
    • C07F7/08Compounds having one or more C—Si linkages
    • C07F7/18Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804Compounds having Si-O-C linkages

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyrane Compounds (AREA)

Description

Pro PAT 51,0 kurist Authorized Signat ry enbruck i.V. Lapice
I~
Cr-
B
*ppa. Is i 628026 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Form Class Int. Class Application Number: Lodged: 0 Co plete Specification Lodged: Accepted: .Published: *e Related Art: Name of Applicant: Address of Applicant: i Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main 80, Federal Republic of Germany YATENDRA KHANDELWAL, RAJESHWARI KANNAN, BANSI LAL, ALIHUSSEIN NOMANBHAI DOHADWALLA, RAMANUJAM RAJGOPALAN and RICHARD HELMUT RUPP EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: NEW ACYLLABDANE DERIVATIVES, A PROCESS 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: I. 1.
1 New acyllabdane derivatives, a process for their preparation, and their use as medicaments.
The present invention relates to labdanes of the formula i HO
OH
OR
7 OR6 in which R denotes vinyl, ethyl, cyclopropyl or CHOHCH 2 0H, 0
II
R
7 denotes ydre a group of the formula -C-A, A denoting OR 2 in which R 2 represents an alkyl group, or denoting N X and Y representing, if they are identical, hydrogen or alkyl, or,
Y
1 0 identical, hydrogen or alkyl, or, if X represents hydrogen or lower alkyl, Y representing an alkyl, substituted alkyl, cycloalkyl, aralkyl, aryl, amino or hydroxyl group, or X and Y, together with the nitrogen atom to which they are bonded, forming a heterocyclic ring which can contain a further hetero atom and can be substituted by an alkyl or aryl group, 1 5 R 6 denotes a group of the formula S 10
N
R
9
R
11 Y1 in which m is an integer from 0 to 10 and n is an integer from 1 to 10, and R 8 and R9 are identical or different and represent hydrogen or a lower alkyl group, or one of the substituents represents hydrogen and the other represents a hydroxyl, thio or aryl group, Rio denotes hydrogen and R 11 denotes hydrogen or a hydroxyl or alkyl group, and
X
1 represents hydrogen if Y represents hydrogen, alkyl, substituted alkyl, alkanoyl, aryl, cycloalkyl, aralkyl, a heterocycle, amino, substituted amino, hydroxyl, acyl, dialkylaminoalkyl, carbamoyl, carboxyalkyl or carbalkoxyalkyl, or X 1 and Y 1 represent, Sif they are identical, alkyl, substituted alkyl, aryl or aralkyl, or, if X represents 2 alkyl, Y 1 represents substituted alkyl, cycloalkyl, aralkyl or a dialkylaminoalkyl group, or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocycle which can contain one or more hetero atoms and be optionally substituted once or several times by alkyl, aryl, aralkyl, hydroxyalkyl, hydroxyl or other hetericyclic groups, and to their optical and geometric isomers and their pharmaceutically acceptable acid addition salts.
Preferred compounds of the formula i are those in which R has the abovementioned meaning, and either a) R 6 represents a group of the formula a R 1 io X -CO-(C)m-(C)n-N I I
R
9 R 11 o oo. •y o s v k e i 3 in which R 8
R
10 R11 X 1 and Y 1 have the abovementioned 0 meaning, and R 7 represents a group of the formula -C-A,
X
A denoting a radical of the formula OR 2 or -N in
Y
which R 2 X and Y have the abovementioned meanings, or 0 b) R. m: d R 7 represent a group of the formula -1-A, x A denoting a radical of the formula -OR 2 or -N in
Y
which R 2 X and Y have the abovementioned meanings, and R represents a group of the formula a R 8
R
1 0 -xi SCO-
(C)-N
R9 R 11 Y1 in which R 8
R
9
R
10 R11, X 1 and Y 1 have the abovementioned meanings.
C The term alky relates to straight-chain or branched saturated hydrocarbon radicals having 1 to 8 carbon atoms such as, for example, methyl, ethyl, propyl, 2- 15 methylpropyl, 1-pentyl, 3-hexyl or 2-octyl and the like.
Preferred alkyl groups have 1 to 6, in particular 1 to 4, carbon atoms.
Suitable examples of substituted alkyl groups are hydroxyalkyl such as hydroxyethyl, carboxyalkyl such as carboxyethyl, and carbalkoxyalkyl such as carbethoxyethyl, or halogenated alkyl.
Suitable cycloalkyl groups are C 3 -C7-cycloalkyl groups, in particular cyclopentyl or cyclohexyL.
An aralkyL group is to be understood to be a phenylalkyl group, preferably phenyl-C.-C 3 -alkyl, for example a 4 benzyl group in which the pheny group can be substituted once or several times by halogen, C 1 -C3-akyL, C 1
-C
3 alkoxy, nitro or trifluoromethyl.
An aryl group is to be understood to be a phenyl group which can be substituted once or several times by substituents such as halogen, C 1
-C
3 -aLky, C 1
-C
3 -alkoxy, nitro or trifluoromethyl.
An acyl group is to be understood to be C 1
-C
6 -akanoy,
C
2
-C
6 -akenoy, C 3
-C
6 -akynoy, aroyl, aralkanoy or a heteroaroyl group having up to 10 carbon atoms, it being possible for one or more carbon atoms to be replaced by oxygen, nitrogen and/or sulfur.
SExampl.es of alkanoyl groups are formyl, acetyl, propionyL, butyryL, isobutyryl, valeryl, palmityl and bromoisobutyr- 15 yl. The alkanoyl groups can contain one or more double bonds, for example an acryloyl, stearyl or oleoyl group.
The alkanoyl groups can also contain one or more triple bonds as well as one or more double bonds. An example of an alkynoy group of this type is the propiolyl group.
A representative of aroyl groups is the benzoyl group in which the phenyL group can be substituted once or several times by substituents such as C 1
-C
3 -akyL, C 1
-C
3 alkoxy, haLogen, nitro and trifluoromethyl. Examples of aralkanoyl and heteroaroyl groups are phenylacety and pyridine-3-carbony groups.
The dialkyLaminoalky groups are to be understood to be those in which each of the alkyl groups contains 1 to 6 carbon atoms, for example diethylaminoethyL.
If X and V or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocyclic ring, those which are preferred are piperidine, pyrrotidine, morpho- Line, piperazine, thiomorphotine, imidazole and theophyLLine, each of which can optionally be substituted in one or more positions by C 1
-C
4 -akyL, C 1
-C
4 -aLkoxy, aryl, aryl-CI-C 4 -alkyl, hydroxyl, amino or substituted
C
1
-C
4 -alkyl.
Suitable examples of the salts of the compounds according to the invention with inorganic or organic acids are the hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleate or fumarate.
In the formulae depicted here, the various substituents are shown as connected to the labdane nucleus in one of two modes of representation: a full line which indicates a substituent in the B-orientation above the plane of the molecule), and a broken line which indicates a substituent in the a-orientation below o* o the plane of the molecule). All the formulae are drawn in such a way that they depict the compounds in their 15 absolute stereochemical configuration. Where the starting materials having a labdane nucleus are naturally occurring or are derived from natural products they have, as do the final products, a labdane nucleus in the single absolute configuration depicted here. However, the pro- 20 cess according to the invention is also meant for the synthesis of labdanes of the racemic series.
In addition to the optical centers of the labdane nucleus, S the substituents thereon may also have chiral centers which contribute to the optical properties of the com- 25 pounds according to the invention and allow their separation by conventional methods, for example by the use of optically active acids. A wavy line connecting a group to a chiral center indicates that the stereochemistry of the center is unknown, i.e. the group may be present in either of the possible orientations. This invention embraces all the optical isomers and racemic forms of the compounds according to the invention where such compounds have chiral centers in addition to those of the labdane nucleus.
Some of the new, multiply oxidized labdane derivatives -6 according to the invention are Listed in Table 1 which fol Lows.
TabLe 1
OR
7 0%6 If I W a g- t
''IC
41 C C C
CC
49 0* a 4* 400449 44 4
COCH
2 NcI C0OC,' 2 4 7
COCH
2 -N 0
CO(H
2
)N(C
3
CO(CH
2 2
N(CH
3 2
CO(CH
2 2 NQCH3) Co (CH 2 )2-O
CO(CH
2 2 -Nc0 CO
(CM
2 2-
CO(CH
2 CM-d-\
COCH
2 CHNm C12 3
COCH
2 ?1,
COOC
2
HS
CON(C
2
H
5 2
COOC
2
H
5
COOC
2
HS
CON(C
2
HS)
2
COOC
2
H
5
CON(C
2
H
5 2
COOC
2
H
5
CON(C
2
H
5 2
COOC
2
H
5 CON (C 2
H
5 2
CONHC
6
H
5 x HC1 Netting point 268 0
C
HC1 253 0
C
HC1 -H 2 0 MCi HCi HCi HCi 225- 29 0
C
213- 15 0
C
239- 40 0
C
227- 28C 246- 47 0
C
218- 20 0
C
160- 64 0
C
175- 78 0
C
173-7750C 201- HC1*O,5 H120 HC1 HC1 -H20 HC1 5 H120 -7- The invention also relates to a process for the preparation of the new acyllabdanes of the formula I, which comprises reaction of compounds of the formula II
R
Ri'0 0
OH
OH R R10 X oco- t(CM
-N/
R9 Ry in which R 1 denotes a protective group for a hydroxyL group, such as, for example, t-butyLdimethylsiLy, and R, Rg-R 11 and X 1 and Y 1 have the abovementioned meanings, with a mixture of an alkyl haLoformate, for example ethyl chioroformate, and 4-dimethylaminopyridine in organic solvents, such as dichoromethane or ethyl acetate, at temperatures in the range 20 0 C to 70 0 C, to give compounds of the formula III *tI tt\ R S R0 Rt
III
OH
OR7 0 C0-(C)m-(bC) -N g 4 in which R' 1 represents a protective group, R 7 represents
-C-OR
2 in which R 2 denotes Cl-C 8 -alkyL, and R, R 8 -Rll,
X
1
Y
1 m and n have the abovementioned meanings.
Suitable protective groups for R 1 are: the methyl ether, t-butyl ether, allyl ether, benzyl ether, triarylmethyL ether, triakylsily ether or tetrahydropyrany ether or esters. It is particularly advantageous to use the t-butyLdimethylsiyL group as protective group. In order to obtain compounds of the formula III in which 0 X
R
7 represents -C-N the compb)unds of the formula y -8 II are treated with the appropriate carbamoyl chloride
X
0/ of the formula Cl--N in the presence of 4-dimethylaminopyridine and hydroquinone monomethyl ether in an organic solvent, such as pyridine, at a temperature in the range 20°C to 30 0 C. The reaction product of the formula III is obtained from the mixture by extraction with an organic solvent, and washing the organic layer with water, drying it over anhydrous sodium sulfate and concentrating in vacuo. A chromatographic method is used for purification.
Compounds of the formula III in which R 1 represents a protective group such as, for example, t-butyldimethylt, silyL are treated with reagents such as tetrabutylammonium fluoride at temperatures in the range 0 to 300C in S15 order to obtain corresponding compounds of the formula I 41 C with R 1
=H.
Compounds of the formula II are prepared by the process 4 4 which is described in EP-A 0,217,372 (HOE 85/F 214), from compounds of the formula IV 31 OR 20 .6 IV x OH
OH
OH
in which R 1 represents a protective group such as tbutyldimethylsilyl, and R represents a vinyl group.
Compounds of the formula IV are prepared from forskolin by the reaction sequence indicated below.
HO R 0 OHI I OH S H
OH
V
VI
9 The 1-OH group in forskolin is prctected with a group RI', as defined above, by methods known to the expert (cf. Reagents for Org. Synth., L.F. Fieser and M. Fieser, John Wiley Sons, Volumes 1 to 11).
The acetyl group in the 7-position in compounds of the formula VI is eliminated by alkaline hydrolysis by methods described in the literature (cf. J.C.S. Perkin I, 769 (1982)), which provides compounds of the formula IV.
Compounds of the formula I can also be obtained starting from compounds of the formula IV. Compounds of the formula IV in which R 1 has the above meaning are treated with carboxylic acids of the formula R 12
R
13
C=CH-
COOH, in which R 12 and R 13 represent hydrogen or an alkyl or aryl group, in the presence of 4-dimethylamino- 15 pyridine and DCC in organic solvents such as dry dimethylformamide, dry ethyl acetate etc., at temperatures in the range 20 to 300C for four hours, and the products of the formula VII R 0 OH
VII
H OCOCH-CR 12
R
13
SOH
in which R 1 and R 12 have the above meanings, is iso- Lated from the reaction mixture by dilution with water, subsequent extraction with organic solvents such as ethyl acetate, washing of the extract with water, drying over anhydrous sodium sulfate, and concentration in vacuo.
Chromatographic methods are used for purification.
In ordfir to obtain compounds of the formula VIII
R
1
I
OH
OH
OCOCH-CR
1 i 2
R
1 3 10 in which R 1 and R 12 have the above meanings, compounds of the formula VII are subsequently treated with alkali such as sodium hydroxide in water-soluble organic solvents such as acetonitrile.
Compounds of the formula VIII are subsequently treated with alkyl haloformate in the presence of pyridine and 4-dimethylaminopyridine in organic solvents such as dichloromethane or ethyl acetate, resulting in compounds of the formula IX in which A represents OR 2 and R 2 and
R
1
R
12 and R 13 have the above meanings, or with the appropriate carbamoyl chloride in the presence of 4dimethylaminopyridine and hydroquinone monomethyl ether in an organic solvent such as pyridine, which yields 'c compounds of the formula IX
IX
OCOA T -ocofl
OCOCH-CR
12
R
13
X
in which A represents N X and Y, and R 1
R
1 2 and 4
R
13 having the above meanings.
Compounds of the formula IX are treated with the appropriate amine of the formula HNX 1
Y
I
in which X 1 and Y1 20 have the abovementioned meanings, in an organic solvent such as dichloromethane, at 20 to 30°C for 16 to 24 hours.
The product is obtained from the reaction mixture by extraction with an organic solvent, washing of the extract with water, drying over anhydrous sodium sulfate and concentration in vacuo. The compounds of the formula I are purified by column chromatography.
The compounds according to the invention, and their salts, have the pharmacological properties attributed to the class of multiply oxidized labdanes and their derivatives. However, they exhibit, in particular, a selective i 11 positive inotropic effect, an effect lowering blood pressure, and a lowering of the intraocular pressure.
This is illustrated by the pharmacological investigations which follow and which were carried out to evaluate the compounds according to the invention, and their salts, and by the results obtained thereby.
Positive inotropic activity The following method was used for this: Guineapigs of both sexes and weighing 400 g are sacrificed, and the heart is removed and placed in Ringer's solution at room temperature. Both the left and the I right atria are then isolated, fixed in an organ holder and placed in a bath containing Ringer's solution and i t maintained at a temperature of 32°C. A mixture of 15 02 and 5% C02 is bubbled through the organ bath.
SElectrical stimulation of the atrium is then carried out.
SThe compound according to the invention is dissolved in water to give a solution of known concentration and is added to the bath. The contractility of the atrium is a 20 recorded for 7 to 10 minutes via an isometric strain 4 gage on a Nihon Kohden 4-channel pen recorder. The activity is expressed on the basis of the resulting data 4 r as the EC 50 t V The results obtained in this model for representative compounds according to the invention are listed in the table which follows.
(as hereinbefore defined), cycloalPwl, aralkyl (as hereinbefore defined), ary 1 11 11 y 1 I 1, 1i:
I
I
^v 1 1 12 i Compound Guineapig atrium
EC
5 0 g/mL
*HCI
OR
6 .44.s
I
o Ir Ir I
(C
C 41 -4 4 I $4 4 0 4 4r 4
CO(CH
2 2
NO
7 CO
(CH
2 2g
COCH
2 NcO
COCH
2 N"7 COOC2H
CON(C
2
H
5 2
COOC
2
H
5
CON(C
2
HS)
2 0,79 1,6 0,44 Measurement of intraocular pressure Measurement of the intraocular pressure rabbits in conscious For this experiment rabbits of both sexes and weighing 2 to 3 kg are used. The intraocular pressure (IOP) is measured with a Schiostz tonometer after corneal anesthesia with 2% strength novocaine solution. A 2% strength solution of a compound according to the invention is prepared, using the stoichiometric amount of 0.1 N HCl, by dissolving it or its salt directly in water. After the initial value has been determined, 100 pl of the solution of the test compound are inetilled into one of the eyes, and the vehicle is instilled into the other eye. The 1OP is measured at defined time intervals, i.e. 0.5, 1, 2, 3, 4 and 5 hours. The percentage decrease in the IOP is calculated using the initial value.
II I rr L-:i 13 The results obtained in this model for representative compounds according to the invention are Listed in the table which follows: Compound lOP-lowering effect
*HCI
OR
6 Dose X decrease percentage in IOP Duration (mins) 4$ 4 4 r$ C 4i 44 C C1 C: 4 lr 1444 4 144 4
CO(CH
2 2
NO
CO
(CH
2 2
O
COCH
2
NO
COCH
2
NO
COOC2
H
5
CON(C
2
H
5 2
COOC
2
H
CON(C
2
H
5 2 300 360 420 Determination of the Lowering of blood pressure BLood pressure in cats: Cats of both sexes and weighing 3 to 4 kg are anesthetized with ether and maintained under chloralose anesthesia (70 mg/kg Cannulas are placed in the femoral artery and in the femoral vein to record the blood pressure and to administer the medicament, respectively. The blood pressure in the femoral artery is recorded via a Statham P 23 Db pressure transducer on a Nihon-Kohden pen recorder for physiological purposes.
The compound to be tested is dissolved in distilled water and administered intravenously. The fall in blood pressure and the duration of the effect lowering blood pressure are noted.
1.
14 The results obtained in this model for representative compounds according to the invention are Listed in the ,table which follows: ,Coamp oun d
HCI
OR
7
OR
6 Dose FaLL in Duration (mg/kg) D.P. (ms) .4,4 .6 44 4* 4 a tsr alit a tt t I trtt a C 4 54 IS 4 4 6.4 4 1
I
I it a CI. C a a 4 I I I CO (OW 2 2 NOj
CO(CH
2 2 NcO
COCH
2
O
COCH
2
NO
COOC
2
H
5 CON (C 2 HS) 2
OOC
2
H
5
CON(C
2
H
5 2 The invention is illustrated by the examples which follow: ExampLe 1 Ils-t-ButydimethytsiLyLoxy-78-crotomyLoxy-68,9GL-dihydroxy-8, 13-epoxyLabd-14-en-1--one DicycLohexyLcarbodiimide (2.5 g, 12.14 umoL) is added to a stirred mixture of 4-dimethyLaminopyridine (0.45 g, 3.68 mmoL), crotonic acid (1.0 9, 11.62 mmoL) and la-tbutyLdimethyLsiLyLoxy-8,13-epoxy-6S,70,9(x-trihydroxyLabd- 14-en-lI-one (4.0 g, 8.30 mmoL) in dry DMF (10 mL). The reaction mixture is stirred for four hours and then poured onto ice, and the mixture is extracted with ethyl 115 acetate. The organic Layer is washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash coLumn chromatography using ethyl acetate :petroLeum ether (1 9) as eLuant; melting point 114-160, yield 64 The compound 7B-acryLoyLoxy-1cz-t-butyLdimethyLs iLyLoxy- 6B,9ca-dihydro-8,13-epoxy-Labd-14-en-1 1-one is prepared in a corresponding way.
Example 2 1Q-t-ButyLdiuethys i LyLoxy-6S-crotonyLoxy-7B ,9a-dihydroxy-8,13-epoxyLabd-14-enl1-ofle f C Sodium hydroxide solution (9.6 ml, 1 N) is added, with stirring, to lc-t-butyLdimethyLsi LyLoxy-7B-crotonyLoxy- 66,9c-dihydroxy-8,13-epoxyLabd-14-en-11-one (2.8 g, 5.09 mmol) in acetonitriLe: water (1 320 ml), the mixture is stirred for a further 45 minutes and then concentrated in vacuo, and the residue is extracted with ethyl acetate.
The organic Layer is washed with water and then with 20 brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash column chromatography using ethyl acetote :petroLe.um ether (15 o as eLuant. MeLting point 85-87 0 C, yield 71,2 The compound 60-acryLoyLoxy-1ci-t-butyLdimethyLs iLyloxyj 7$,9(%-dihydroxy-8,13-epoxyLabd-14-en-11-one (melt ing point 164-166 0 C) is prepared in a similar manner.
Exampte 3 1aL-t-ButyLdimethyLsiLyl.oxy-6B-crotoflyLoxy-7B-ethoxycarbonyLoxy-8, 13-epoxy-9et-hydroxytabd-14-en-11-one Ethyl chLoroformate (2.5 ml, 26.14 mmol) is added to a stirred mixture of 4-dimethyLaminopyridine (0.1 g, 0.81 mmoL), pyridline (2.5 ml) and 1(x-t-butyLdilmethyLsiLyLoxy- -16- 68-crotony~oxy-7$,9ct-dihydroxy-8,13-epoxyLabd-14-en-11one (0.8 g, 1.45 mmoL) in dichloromethane (15 WL. The mixture -is stirred overnight and then treated with a further quantity of ethyl chLoroformate (2.0 mL, 20.91 mmoL) and pyridline (2 ml). The mixture is stirred for a further 12 hours, then heated at 60 to 70 0 C for 4 hours and then poured onto ice, and the mixture is extracted with ethyl acetate. The organic Layer is washed with dliLute HCI, water and then brine, dried over anhydrous sodium sulfate and concentrated. Melting point 116-18 0C The following compounds are synthesized in a simiLar manner: Ittf1. 65-AcryLoyLoxy-1ct-t-butyLdimethyLs iLyLoxy-76-ethoxycarbonyLoxy-8,13-epoxy-9ct-hydroxyLabd-14-en-11-one CC 15 2. lc-t-ButyLdimethyLsiLyLoxy-78-ethoxycarbonyLoxy-8,13epoxy-9c-hydroxy-66-piperidinoacetoxyLabd-14-en-11-one C Example 4 6B-AcryLoyLoxy-1cz,9G-dihydroxy--70-ethoxycarbonyLoxy-8, 13epoxytabd-14-en-11-one
C
TetrabutyLammonium fluoride trihydrate (0.89g, 2.54 mmol) C is added to a solution of 6B-acryLoyLl-t-butyLdimethyLsiLyLoxy-?B-ethoxycarbonyLoxy-8,13-epoxy-9a-hydroxyLabd- 14-en-lI-one (1.4 g, 2.3 mmoL) in THF (60 ml), and the mixture is stirred at room temperature for 10 minutes and i- 25 then concentrated in vacuo. The residue is extracted with ethyl acetate,- and the organic Layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash column chromatography using acetonitriLe :chloroform diisopropyL ether :petroleum ether (7 :25 25 18), yield 92.3%, o i L The following compounds are synthesized in a similar group, preferably phenyL-Cl-C 3 -aLkyL, for exampLe a
I
p 4 17 manner: 1. 6 8-CrotonyLoxy-1o,9a-dihydroxy-7B-ethoxycarbonyL ox),- 8, 13 -epoxyLabd-14-en-11-one, melt ing point 88-90 0
C.
2. 6 8-Crotonytoxcy-7B-N,N-diethyLaminocarbonyLoxy..19a-.
dihydroxy-8, l 3 -epoxyLabd-14-en-11-one, melting point 76-79 0 C 3. 68-Ac ryloyL oxy-?0-N,N-d jethyL am inocarbonyLoxy- 1a,9czdihydroxy-8, 13-epoxyLabd-14-en-11-one, melting point 168-70 0
C.
4. 1a,9cz-D ihydroxy-78-ethoxycarbonyL-8, 13-epoxy-6Bpiper idinoacetoxyLabd-14-en-11-one.
78-N,N-D iethyt aminocarbonyLoxy-cx,9-dihydroxy-8, 13- It. epoxy- 6 B-piperidinoacetoxyLabd-.en-11-one.
6. 7B-AniJ.inocarbonyloxy-lt,9cC-dihydroxy-8, 13-epoxy- 6B-morpholinoacetoxy-labd-1 4-en-il-one.
Vt 4, Example 60-AcrytoyLoxy-lcs-t-butyLdisethyts C ft aminocarbonyLoxy-8,13,-epoxy-9ci-hydroxyLabd-14-en-11-one VC t C C added to a stirred mixture of 4-dimethyLaminopyridine (0.1 g, 0.81 mmoL), hydroquinone monomethyL ether (0.05 g, 0.4 mmoL) and 60-acryLoyLoxy-l1t-t-butyLdimethyLsiLyLoxy- 7B,9a-dihydroxy-8,l3-epoxyLabd-14-en-1l-one (1.5 g, 2.79 mmoL) in pyridine (10 ml, the mixture is heated to refLux for 16 hours, a further quantity of N,N-diethyLcarbamoyL chloride (2 ml, 5.75 smoL) is added, and the mixture is heated to reftux for a further three hours and then concentrated in vacuo. The residue is extracted with ethyl acetate, and the organic Layer is washed with dliLute HCL, water and then brine, dried over anhydrous sodium sulfate and concentrated'. The residue is purified by flash column chromatography using chloroform.: diisopropyl ether :petroleum ether (I 1 yield one or more positions by Cl-C 4 -aLkyL, Cl-C 4 -aLkoxy, 18 The following compounds are synthesized in a similar manner: 1. la-t-ButyLdimethyLsi lyloxy-78-N,N-diethyLaminocarbonytoxy-8,13-epoxy-9a-hydroxy-68-piperidinoacetoxyLabd- 14-en-li-one.
2. 1Q-t-ButyLdimethyLs iLyLoxy-6$-crotonyLoy~y-7B-N,NdiethyLaminocarbonoxy-8,13-epoxy-9a-hydroxyLabd-14en-i1 1-one Example 6 70-N,N-DiethyLauinocarbonytoxy-c,9cs-dihydroxy-8,13epoxy-60-(3'-morphoL inopropionyLoxy)Labd-14-ea-11-one gift MorphoLine (1.5 mL, 17.2 mmol) is added to a stirred so!ution of 68-acryLoyLoxy-78-N,N-diethyLaminocarbonyLoxy-1a,9a-dihydroxy-8, 13-epoxyLabd-14-en-1 1-one (0.42 g, 0.80 mmoL) in dichLoromethane (15 ml), and the mixture is stirred at room temperature for a further 16 hours and then concentrated. The residue is extracted with ethyl acetate, and the organic phase is washed with water and brine, dried over anhydrous sodium sulfate and concen- :20 trated in vacuo. The residue is purified by flash column chromatography using ethyl acetate :petroleum ether triethyLamine (65 35 1) as eLuant. Melting point 180-82 0 C, recrystallized from chloroform/petroleum ether.
The following compounds are prepared in a simiLar manner: 1. 70-N,N-DiethyLaminocarbonytoxy-lc ,9c-dihydroxy-8,13epoxy-60-(3-piperidinobutyryLoxy)Labd-14-en-11-one.
2. 1c,9-Dihydroxy-7B-ethoxycarbonyLoxy-8,13-epoxy-60- (3'-piperidinobutyryLoxy)Labd-14-en-11-one.
3. 1oi,9cL-Dihydroxy-7B-ethoxycarbonyLoxy-8,13-epoxy-60- Some of the new, multiply oxidizedLabdane derivatives 19 (3'-morphoLinopropionytLoxy)Labd-14-en-11-one.
4. 1(1,90i-,Dihydroxy-68-(3 -N,N-dimethyLaminopropionyLoxy)- 78-ethoxycarbonyLoxy-8, 13-epoxyLabd-14-en-1 1-one.
78-N,N-D iethylamino-1ci,9c-dihydroxy-6-31-dimethyLaminopropionyLoxy)-8, 13-epoxyt abd-14-en-1 1-one.
Example 7 iethytaminocarbonyLoxy-1ct,9cL-dihydroxy-8, 13epoxy-6B-(3'-.orphot inopropionytoxy) Labd 14-en-i 1-one hydrochLoride hemihydrate I I10 Diethyl ether (10 mL, saturated with dry HCI gas at 2 0 0 0) is added to a methanolic soLution of 78-N,N-di- (,forethyLaminocarbonyLoxy-lea,9ox-dihydroxy-8, 13-epoxy-66-C3 morphoLinopropionyLoxy)Labd-14-en-11-one (0.3 g in 3 ml of methanol), the mixture is diluted with excess dry dliethyL ether, and the precipitate which has separated out is removed by filtration. Recrystallization of the oT solid from methanol/ether provides 7B-N,N-diethyLaminocarbonyLoxy-l1%,9ct-dihydroxy-8,13-epoxy-6B-(3'-morphoLino- C CC C41 propionyLoxy) Labd-14-en-1 1-one hydrochloridle hemihydrate, yield 95%, melting point 160-64 0
C.
The following compounds are synthesized in a similar manner: 1. 7B-N,N-D iethyLaminocarbonyLoxy-la,9a-dihydroxy-68-(3 N,N-dimethyLaminopropionyLoxy)-8, 13-epoxyLabd-14-en- 11-one hydrochloridle, melting point 239-240 0
C.
2. 78-N,N-D iethyLaminocarbonyLoxy-1et,9a-dihydroxy-8, 13epoxy-68-(3'-piperidinoipropionyL)Labd-14-en-11-one hydrochloride, metting point 246-247 0
C.,
3. 7B-N,N-DiethyLaminocarbonyLoxy-1a,9ct-dihydroxy-8, 13epoxy-6B-(3'-piperidinobutyryLoxy)Labd-14-en-1 1-one hydrochloride, melting point 173-175 OC.
4. 78-N,N-DiethyLaminocarbonyLoxy-lz,9c'-dihydroxy-8, 13epoxy-65-piperidinoacetoxyLabd-14-en-l 1-one hydrochloride, melting point 253 0
C.
5. 6B-(3'-N,N-D imethyLaminopropionyLoxy)-1a,9a-dihydroxy- 78-ethoxycarbonyLoxy-8,13-epoxyLabd-14-en-11-one hydrochLoride hemihydrate, melting point 213-215 0
C.
6. la,9a-Dihydroxy-76-ethoxycarbonyLoxy-8, 13-epoxy-68-- (3'-piper idinopropionyLoxy) Labd-14-en-1 1-one hydrochloride, melting point 227-228 0
C.
C r 7. 1c,9c-Dihydroxy-7B-ethoxycarbonyLoxy-8, 13-epoxy-66- (3'-morphoL inopropionyLoxy)Labd-14-en-11-one hydrochloride, melting point 218-220 0
C.
C 4.C 8. lci,9c-D ihydroxy-78-ethoxycarbonyLoxy-8, 13-epoxy-68- (3'-piperidinobutyryLoxy) Labd-14-en-11-one hydrachloride, melting point 175-178 0
C.
~e 9. 1a,9a-Dihydroxy-78-ethoxycarbonyLoxy-8, 13-epoxy-6Bpiper idinoacetoxyLabd-14-en-1 1-one hydrochloride, meLting point 2680C.
a a 4 10. 7B-Anilinocarbonyloxy-loc,%-dihydroxy-8,13-epoxy-63morpholinoacetoxy-labd-1 4-en-i 1-one hydrochloride sequihydrate, melting point 201-205 0
C.
Example 8 7B-Anilino-carbonyloxy-1c-t-butyldimethylsilyloxy-8, 13-epoxy- 9of-hydroxy-6B-morpholino acetoxy-labd-1 4-en-i 1-one Phenylisocyanate (0.075 ml, 0.69 mmol) was added to a stirred mixture of 1o(-t-butyldimethylsilyloxy-7B,9d-dihydroxy- 8,1 3-epoxy-6B-morpholinoacetoxy-labd-1 4-en-il-one (0.385 g, L I i i'l S 20a 0.632 mmol), triethylamine (0.096 ml, 0.688 mmol) in toluene ml). The reaction mixture was refluxed for 17 hrs. Another i aliquot of phenyl isocyanate (0.3 ml, 2.76 mmol) was added to the reaction mixture and refluxed for additional 3 hrs. The reaction mixture was concentrated under vacuo and extracted with chloroform. The organic layer was washed with water, saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue on purification by flash chromatography using ethyl acetate:pet. ether:acetonitrile (6:13:1) as eluent gave the pure product as a thick oil. Yield 90 I 4 C 4 I t 4 4 t t.
I
f t t t

Claims (7)

1. A compound of the formula I HO OH 's OR 7 OR 6 in which R denotes vinyl, ethyl, cyclopropyl or CHOHCH 2 OH, 0 II R 7 denotes hydegen, a group of the formula -C-A, A denoting OR 2 in which R 2 represents an alkyl group, X or denoting N X and Y representing, if they are identical, hydrogen or alkyl, Y or, if X represents hydrogen or lower alkyl, Y representing an alkyl, substituted alkyl (as hereinbefore defined), cycloalkyl, aralkyl (as hereinbefore defined), aryl (as i t hereinbefore defined), amino or hydroxyl group, or X and Y, together with the nitrogen atom to which they are bonded, forming a heterocyclic ring which can contain a further hetero atom and can be substituted by an alkyl or aryl (as hereinbefore defined) group, R 6 denotes a group of the formula lie Rio X R 8 R 10 x -CO-(C)m-(C)n-N R 9 R 1 1 in which m is an integer from 0 to 10 and n is an integer from 1 to 10, and Re and R 9 are identical or different and represent hydrogen or a lower alkyl group, or one of the substituents represents hydrogen and the other represents a hydroxyl, thio or aryl (as hereinbefore defined) group, Rio denotes hydrogen and R 11 denotes hydrogen or a A/-d hydroxyl or alkyl group, and X1 represents hydrogen if Y1 represents hydrogen, alkyi, w substituted alkyl, alkanoyl, aryl (as hereinbefore defined), cycloalkyl, aralkyl (as <i v /i 'li tives. However, they exhibit, in particular, a selective 3 -1 I 33 1 3 ;33" 1 ;333 3~ 22 hereinbefore defined), a heterocycle, amino, substituted amino, hydroxyl, acyl (as hereinbefore defined), dialkylaminoalkyl, carbamoyl, carboxyalkyl or carbalkoxyalkyl, or X1 and Y1 represent, if they are identical, alkyl, substituted alkyl (as hereinbefore defined), aryl (as hereinbefore defined) or aralkyl (as hereinbefore defined), or, if X 1 represents alkyl, Y 1 represents substituted alkyl (as hereinbefore defined), cycloalkyl, aralkyl (as hereinbefore defined) or a dialkylaminoalkyl group, or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocycle which can contain one or more hetero atoms and be optionally substituted once or several times by alkyl, aryl (as hereinbefore defined), aralkyl (as hereinbefore defined), hydroxyalkyl, hydroxyl or other heterocyclic groups and its optical and geometric isomers and its pharmaceutically acceptable acid addition salts.
2. A compound of the formula i as claimed in claim 1, in which R denotes the vinyl group, and R6 and R 7 have the indicated meanings, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
3. A compound of the formula i as claimed in claim 2, in which R 6 denotes a group of the formula *4* 0 Rg Rio X, II I I R R11 Y' 1\ I4 in which Rs, Rg, and Rio and R 11 are identical or different and each denote hydrogen or methyl, the total of m and n is an integer from 1 to 5, either Xi andY 1 are identical and 4 denote hydrogen or Cl--C 4 -alkyl, or one of the substitutents denotes hydrogen and the other denotes a C-C 4 -alkyl group, or X 1 and Y 1 represents, together with the nitrogen atom to which they are bonded, piperidino, pyrrolidine, morpholino, piperazino or thiomorpholino, *adaical-substituted in one or more positions by C 1 -C 4 -alkyl, C 1 C 4 -alkoxy, aryl (as herein before defined), aryl-C-C 4 -alkyl, hydroxyl, amino 0 II or substituted C 1 -C 4 -alkyl, and R 7 denotes the radical in which A represents ~~I 14:: V aC1-C 4 -alkoxy group or a group of the formula X, in which X and Y have the said -N Y meanings, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
4. A compound the formula I as claimed in claims 3, in which Re represents a group of the formula 0 -C -(CH2)m--NQ O 0 II in which m denotes the number 1 or 2, and R 7 represents the radical in which A denotes the ethoxy or diethylamino group, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
5. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises reaction of a compound orthe formula II CIi C C c C C I CI C (CO C SC C C i;i:B i a i caLcutatea using tne iflit IL vaLue. -24- ~R OHI 6 OH6 RB 1 0 X OCO M-C n-N/ I In R 9 R 1 1 in which R 1 is a protective group for an alcoholic hydroxyl group, and R 8 to R 11 and X 1 and Y 2 have the said meanings, either a) with a mixture of an alkyL haloformate and 4- dlimethyLaminopyridline to give a compound of the formula III R 1 C OH OR 7 C)M1C) -N/ R 9 R 1 1 4 in which R 7 represents a radlical of the formula 4* 0 two&". 1 -C-0-R 2 with R 2 representing Cl-C 8 -aLkyL, 4: or a t b) with a mixture of a compound of the formula X CL-C-N and 4-dimethylaminopyridine and hydro- quinone monomethyL ether to give a compound of the formuLa III in which R 7 represents a radlical of C0 X the formula -C-N in which X and Y have the same meanings, c) elimination, by customary methods, of the protec- tive group Ri' from a compound of the formula III, resulting in a compound of the formula I in Sur OrC IFIULCU. which R 1 denotes hydrogen, or d) reaction of a compound of the formula ix 0 R'O ".O OH OCOA OCOCH=CR 12 R 13 in which R 1 represents a protective group, A has the abovementioned meaning, and R 12 and R 13 each represent hydrogen or a lower alkyl or aryl group, with an Xl amine of the formula HN in which X, and Y, have the said meanings, and Y subsequent elimination, by customary methods, of the protective group Ri', resulting in a compound of the formula I in which R, is hydrogen.
6. A medicament containing a compound as claimed in claim 1 and customary S ~auxiliaries and vehicles.
7. A method of preparation of a medicament having a positive inotropic effect or an effect lowering the intraocular pressure or lowering the blood pressure comprising admixing in a pharmacologically effective ratio, an effective amount of a compound as claimed in claim 1, with pharmaceutically effective carriers and excipients. n DATED this 18th day of May, 1992. S' HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAW, HORN VICTORIA 3i22 AUSTRALIA
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AU5423686A (en) * 1985-03-01 1986-09-04 Hoechst-Roussel Pharmaceuticals Incorporated Labd-14-en-11-one derivatives
AU1741288A (en) * 1987-06-06 1988-12-08 Hoechst Aktiengesellschaft New polyoxygenated labdane derivatives, a process for their preparation, and their use as medicaments
AU3452189A (en) * 1988-05-09 1989-11-09 Hoechst-Roussel Pharmaceuticals Incorporated Hydrazinocarbonyloxylabdanes, a process for their preparation and their use as medicaments

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