GB1577647A - Prostaglandins - Google Patents

Prostaglandins Download PDF

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GB1577647A
GB1577647A GB7981/77A GB798177A GB1577647A GB 1577647 A GB1577647 A GB 1577647A GB 7981/77 A GB7981/77 A GB 7981/77A GB 798177 A GB798177 A GB 798177A GB 1577647 A GB1577647 A GB 1577647A
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oxo
trans
cis
lysergyl
ester
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

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Description

(54) PROSTAGLANDINS (71) We, SANDOZ LTD., of 35 Lichtstrasse. 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement.
This invention relates to prostaglandins and in particular prostanoic ergolin-8-ylalkyl esters, thioesters and amides.
It is to be appreciated that the term prostanoic acid covers any natural or synthetic prostaglandin acid, and the term ergoline covers any natural or synthetic ergoline derivative.
The present invention provides especially compounds of formula l.
wherein D is a group of formula
wherein A is a radical of formula a),
wherein 1 to 3 of the four methine groups marked α, ss, γ and # are replaced by nitrogen, or a radical of formula b),
wherein either one of the ring members L and M is nitrogen and the other of the ring members L and M is methine, or each of L and M is nitrogen, 1 to 3 of the methine groups marked a. (3. y and 6 may be replaced by nitrogen. and the six-membered ring is unsubstituted or mono-substituted by chlorine, bromine, alkylamino, dialkylamino. alkoxy or alkvlthio. each alkyl moiety of the last four radicals being independently of l to 5 carbon atoms.
W is oxygen. sulphur or imino.
X is -CH2-CH2- or -CH=CH-(trasls).
Y is -CH2-CH2- or -CH=CH-(cis or trans), Z is -CH2-CH2- or
(cis or trans).
R, is alkyl of l to l() carbon atoms or cvcloalkyl of 3 to 9 carbon atoms, R2 is hydrogen or alkyl of 1 to 7 carbon atoms.
R3 and R4 are. independently. hydrogen. alkanovl of l to 2() carbon atoms or benzoyl, and R is an ergolinylalkvl radical of formula 11.
wherein n is 1 or 2, R5 is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl, R6 and R,(, are, independently, hydrogen, chlorine or bromine, R7 is alkyl of 1 to 4 carbon atoms other than tert.-butyl, and (i) each of R8 and R9 is hydrogen, or (ii) R8 and Rg together form a bond, or (iii) R8 is hydrogen, and R9 is alkoxy of 1 to 4 carbon atoms, with the proviso that when Z is
(cis or trans), then X is -CH2-CH2. and R, is 1-methylpentyl.
In formula I the 15-ORx group has the a- or ss- configuration, and the side chain in the 8 position of the ergolinylalkyl radical has the a- or (3-configuration.
When A is a radical of formula a). this is. for example, pyrazol-1.yl, imidazol-1-yl, triazolyl, e.g. 1 ,2,4-triazol-1-yl. or 1,2,3 ,4-tetrazol-1-yl.
When A is a radical of formula b), preferably 0, 1 or 2 methine groups. as defined above, of the six-membered ring are replaced by nitrogen. Preferably M is nitrogen. Preferred examples of such radicals are benzimidazolyl or purinyl. The radical of formula b) is preferably unsubstituted. When it is mono-substituted the ring has preferably a substituent attached to a carbon atom in the ring position marked a or 6. The alkyl of the ring substituents defined above preferably have 1 or 2 carbon atoms, especially one carbon atom. The preferred ring substituent is the dialkylamino group.
When R1 is alkyl, this preferably has 5 to 8 carbon atoms. It is conveniently branched in the a-position. Suitable examples are pentyl; 1,1-dimethylpentyl; 1-methylpentyl: heptyl, or 1-methylheptyl.
When R, is cycloalkyl. this preferably is cyclopentyl or cyclohexyl.
When R3 is alkanoyl, this preferably has 2 to 5 carbon atoms, and is conveniently acetyl.
When R4 is alkanoyl, this preferably has 8 to 20 carbon atoms, and is conveniently n-octanoyl or lauroyl.
When Rs is alkyl, this is conveniently methyl.
When R7 is alkyl. this has conveniently 1 to 3 carbon atoms, and is conveniently methyl or isopropyl.
When R., is alkoxy, this is conveniently methoxy.
Preferred significances in the prostanoic moiety are as follows: D is D4 or D6.
A is imidazol-l-yl, W is oxygen or imino.
Xis-CH=CH-(trans).
Y is -CH=CH-(cis) or -CH2-CH2-.
Z is -CH2-CH2- R, is alkyl, R2, R3 and R4 are hydrogen.
the -ORr group is in the a-configuration.
Preferred significances in the ergolinylalkyl moiety are as follows:n is 1: Rs is hydrogen or methyl: R7 is methyl: (i) R, R9, R6 and Rio are each hydrogen, or (ii) RS and R are together a bond and each of R6 and Rl" is hydrogen, or (iii) R8, R9 and Rl,) are each hydrogen and R6 is bromine, (iv) R8 and R9 are each hydrogen, and R6 and Rio are each bromine; (v) R8 and R9 are together a bond, R6 is bromine and Rl,) is hydrogen.
In one group of compounds, R and W together are dihydrolysergylamino, Z is 1,2-cyclopropyl and/or D is Dl: D2: D5 or D6.
An ester, thioester or amide as defined above, may be produced by condensing an appropriate prostanoic acid or a reactive functional acid derivative thereof with an appropriate 8-hydroxyalkylergoline. 8-thioalkylergoline or 8-amino-alkylergoline.
In particular the invention provides a process for the production of a compound of formula I, as defined above, which comprises a) for the production of a compound of formula I, condensing a compound of formula III,
wherein D, Rl, R,, R. X, Y and Z are as defined above, or a reactive functional acid derivative thereof, with a compound of formula IV, H-WR IV wherein R and W are as defined above. or b) for the production of a compound of formula Ia.
wherein R. R,. R. R. W. X. Y and Z are as defined above.
splitting off HA by deamination from a compound of formula Ib.
wherein A. R. R. R2. R,. W. X. Y and Z are as defined above.
in methanol.
Process a) may be effected in conventional manner for the production of esters, thioesters and amides of prostanoic acids. bearing in mind the nature of the reactants.
Conveniently a reactive functional acid derivative is produced iii situ using N.N'carbonyldiimidazole and a prostanoic acid. In order to activate an hydroxylalkyl-ergoline or thioalkyleroline conveniently a catalytic amount of a solution of sodium imidazole in tetrahvdrofuran is present.
When a compound of formula Ill is used. wherein D is D2. the imidazole formed in situ may lead to an end product of formula I. wherein D is D6 and A is imidazol- 1-yl.
For the production of a compound of formula l. wherein D is D2. and for an alternative preparation of amides. other reactive functional acid derivatives. e.g. the 2-thiopyridyl derivative. are preferably used.
Process b) is preferably effected in methanol at from O"C to 50"C. for example room temperature. The reaction time is in general from 2 to 30 hours for a satisfactorv yield. The process may be effected in an inert organic solvent. e.g. tetrahvdrofuran or methylene chloride. The process may be effected in water as solvent. At a pH of more than 7, e.g. up to 9, the reaction may proceed quicker than at below 7. Sodium bicarbonate, potassium bicarbonate, sodium acetate or a tertiary amine, e.g. pyridine or triethylamine may be present to afford a suitable pH.
Process b) is the preferred process for the production of a compound of formula Ia, especially when W is oxygen or sulphur.
A process [process c)j is also provided for the production of a compound of formula lila,
wherein' A, R1, R2, R3, X, Y and Z are as defined above, which comprises aminating a compound of formula IIIb,
wherein Rl, R2, RX, X, Y and Z are as defined above.
Process c) may be effected in conventional manner for analogous aminations. The reaction is conveniently effected at a temperature of from ü to 40"C, preferably room 'temperature, in an inert organic solvent.
In certain instances, e.g. when A is purinyl, an isomerization of the amine may take place, so that 2 final products of formula III are produced, [see, for example, Example 4].
There is also provided a process for the production of a compound of formula III, wherein D is D8. which comprises d) for the production of a compound of formula III, wherein D is D8 and one of the substituents R3 and R4 is hydrogen. and the other is alkanoyl of 1 to 20 carbon atoms or benzoyl. splitting off a protecting group from a compound of formula V.
wherein A, R,. R,. X. Y and Z are as defined above. and one of the substituents R" and R12 is an alkanoyl group of l to 20 carbon atoms or benzoyl. and the other is a protecting group.
e) for the production of a compound of formula Ill, wherein D is D8 and at least one of the substituents R, and R4 is alkanoyl of l to 20 carbon atoms or benzoyl, acylating a compound of formula III. wherein D is D8 and at least one of the substituents is hydrogen, or f) for the production of a compound of formula IIIc,
wherein A, Rl, R2, R3, X, Y and Z are as defined above, reducing selectively the carbonyl group of a compound of formula lila as defined above.
Process d) may be effected in conventional manner for the splitting off of suitable protecting groups, e.g.tetrahydro-2H-pyran-2-yl, in the prostaglandin art, as described in Example 6e.
Process e) may be effected in conventional manner for acylation of analogous compounds, as described in Example 6d.
Process f) may be effected in conventional manner for reduction of analogous compounds, e.g. using sodium borohydride, as described in Example 6c. The resulting 9a and 9ss isomers may be separated in conventional manner.
Preferably all the above-mentioned reactions are effected using pure starting materials and reagents, e.g. in anhydrous form. Preferably a nitrogen atmosphere is used.
The prostaglandins may be purified in conventional manner.
Free base forms of the compounds of formula I and compounds of formula III, wherein D is D6 or D8, may be converted into acid addition salt forms and vice versa. Suitable acids for salt formation include tartaric acid and methanesulphonic acid.
The prostaglandins may exist in racemic or optically active form. The optically active forms may be produced in conventional manner, e.g. from optically active starting materials.
Insofar as the production of any starting material is not particularly described this may be prepared in known manner, or analogous to know processes or to processes described herein.
A group of compounds of formula I is characterized in that in formula l(a) D is D3 wherein the side chain OR4 has the a configuration when R4 is other than hydrogen or has the (3-configuration; (b) W is S; (c) R is dihydrolysergyl; (d) n is 2; (e) R5 is alkyl of 1 to 4 carbon atoms. or benzyl; (f) at least one of R5 and R6 is chlorine or bromine (g) R7 is alkyl of 2 to 4 carbon atoms other than tert-butyl; (h) Rs is hydrogen and R9 is alkoxy of 1 to 4 carbon atoms (i) the 8-ergoline side chain has the a-configuration (j) R1 is alkyl of 1 to 10 carbon atoms, and/or Rl is alkanovi of 1 to 20 carbon atoms.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
I.R. refers to characteristic bands of a sample in methylene chloride solution, unless stated otherwise. N.M.R. spectrum may be used to confirm the structures of the compounds obtained.
The usual vacuum used is 10 mm Hg.. and the usual high vacuum 0.1 mm Hg. "Iysergyl" refers to (6-methyl-9. 10-didehydro-8ss-ergolinyl)methyl.
Unless otherwise stated, the exemplified compounds are optically active and have absolute configurations at C-8 and C-12 identical to the respective configurations at C-8 and C-12 in prostanoic acid.
cis or trnsls -(+) or (-) methylene as used hereinafter to the respective (+) or (-) optical isomer of cis or trn/ls 2-(2'-bromoethyl)cyclopropane-1-carboxylic acid, which may be used in the synthesis of the corresponding opticallv active compound of formula Ill, wherein Z is
using conventional stereospecific procedures.
EXAMPLE l N-Dih r oisol\sergyl-11α, 15(S)-dihydroxy-9-oxo-13-trans-prosten-amide [process a)] A solution of li(l mg pure prostaglandin E. in 4 ml absolute dimethvlformamide is treated with 76 mg N.N'-carbonvldiimidazole and is stirred for 31/2 hours at room temperature. 13() mg finely powdered dihydroisolysergylamine is added. After stirring for 7 days. the solvent is removed under high vacuum at room temperature and the oily residue is chromatographed on 250 g Sephadex LH20 (Registered Trade Mark) with methylene chloride + 1% methanol as eluant to yield the title compound in free base form.
I.R.: 1740, 1660, 1520 cm-l The free base is converted by treatment with methane-sulphonic acid into the methanesulphonate salt form.
Production of esters In analogous manner to that described in Example 1 using the appropriate prostaglandin of formula III and compound of formula IV, wherein W is oxygen, together with a catalytic amount of sodium imidazole in tetrahydrofuran, there are obtained the following esters of formula I: a) 9α, 11α, 15(S)-trihydroxy-5-cis,13-trans-prostadienoic acid lysergyl ester; M.Pt. of hydrogen tartrate 117 - 1200; b) 1 1a, 15(S)-dihydroxy-9-oxo- 13-trnns-prostenoic acid lysergyl ester; M.Pt. of hydrogen tartrate 158 - 1600; c) 11a,15(S)-dihydroxy-9-oxo-13-trans-prostenoic acid 2,13-dibromodihydrolysergyl ester, I.R.: 1740 (broad) cm-' d) 11 a, 15 (S)-dihydroxy-9-oxo-5-cis, 13-trnns-prostadienoic acid lysergyl ester; I.R.: 1740 (broad) cm e) lla,l5(S)-dihydroxy-9-oxo-13-trans-prostenoic acid 1-methyllysergyl ester; I.R.: 1740, 1735 (shoulder) cm-' f) 1 lea 15 (S)-dihydroxy-9-oxo- 1 3-trans-prostenoic acid 10a-methoxydihydrolysergyl ester; I.R.: 1740 (broad) cm- g) lla,l5(S)-dihydroxy-9-oxo-13-trans-prostenoic acid 2-(2-chloro-6-methylergolin-8 ss- yl)ethyl ester; I.R.: 1740, 1735 cm-' h) 11α, 15(S)-dihydroxy-9-oxo-15-methyl-5-cis, 13-trans-prostadienoic acid lysergyl ester; I.R.: 1745, 1735 (shoulder) cm-' i) 11a,15(S)-dihydroxy-9-oxo prostanoic acid lysergyl ester; I.R.: 1740 (broad) cm-' j) lla,15(R)-dihydroxy-9-oxo-16(R)-methyl-5-cis-prostenoic acid lysergyl ester; I.R.: 1740, 1735 (shoulder) cm k) 1 1a.15(R)-dihydroxy-9-oxo-16(R)-methyl-2, 3-trans-(+)-methylene-5-cis-prostenoic acid lysergyl ester; -I I.R.: 1740, 1735 (shoulder) em 1) 15-cyclohexyl- 11 a, 15(R)-dihydroxy-9-oxo- 16,17,18, 19,20-pentanor-5-eis-prostenoic acid lysergyl ester; I.R.: 1740 (broad) cm-' m) 11α, 15(R)-dihydroxy-9-oxo- 16(R)-methyl-2.3-trans-( - )-methylene-5-cis-prostenoic acid lysergyl ester; -I I.R.: 1740, 1735 (shoulder) cm-'.
In analogous manner to that described in Example 1 and using, when A is imidazole, the appropriate prostaglandin of formula III, wherein D is D2 in the presence of imidazole, or the appropriate prostaglandin of formula Ill, wherein D is D6 and appropriate compound of formula IV. wherein W is oxygen together with a catalytic amount of sodium imidazole in tetrahydrofuran. the following esters of formula I, wherein D is D6, are produced: aa) 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis, 13-trans-prostadienoic acid lysergyl ester; I.R.: 3450, 1740. 1730 cm-' ab) 15(R)-hydroxy-llu-imidazol-l'-yl-9-oxo-5 13-trans-prostadienoic acid lysergyl ester; I.R.. 3550. 3450, 1745-1740 cm-' ac) 15(S)-hydroxv-l Icr-imidazol-l '-yl-9-oxo-13-trans-prostenoic acid lysergvl ester, M.Pt. of hydrogen tartrate 104" - 1060: ad) 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid dihyd roisolysergyl ester; I.R.: 3450. 1740. 1720. 1500 cm-' ae) 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid 2,13 dibromodihydrolysergyl ester: I.R.: 3450. 1740, 1715. 1500 cm-' af) 15(S)-hydroxy-9-oxo-1',2',4'-triazol-1'-yl-5-cis, 13-trans-prostadienoic acid lysergyl ester; I.R.: 1740, 1720 cm-' ag) 15(R)-hydroxy-11α-imidazol-1'-yl-9-oxo-16(R)-methyl-5-cis-prostenoic acid lysergyl ester; I.R.: 1740, 1720, 1500 cm-l ah) 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis, 13-trans-prostadienoic acid 1methyllysergyl ester I.R.: 1740, 1725 cm ai) 15-cyclohexyl-15(R)-hydroxy-1 1a-imidazol-1 '-yl-9-oxo-16, 17,18, 19.20-pentanor-5 cis, I 3-trans-prostadienoic acid lysergyl ester; I.R.: 1740, 1720 cm-' aj) 15(R)-hydroxy-11α-imidazol-1'-yl-9-oxo-16(R)-methyl-2,3-trans-(-)-methylene-5- cis-prostenoic acid lysergyl ester; I.R.: 1740, 1720 cm ak) 15(S)-hydroxy-1 1a-imidazol-1 '-yl-9-oxo-13-trans-prostenoic acid 2,13dibromodihydrolysergyl ester; I.R.: 1740, 1715, 1500 cm-'.
al) 15(R)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid dihydroisolysergyl ester; I.R.: 3450, 1740, 1720, 1500 cm-'.
Production of thioesters In analogous manner to that described in Example 1 using the appropriate prostaglandin of formula III and thiol of formula IV together with a catalytic amount of sodium imidazole in tetrahydrofuran, the following compounds of formula I are produced: ba) S-lysergyl-11α, 15(S)-dihydroxy-9-oxo-13-trans-thioprostenoate; I.R.: 1740, 1695 cm bb) S-lysergyl- l SS-hydroxy- l la-imidazol- 1 '-yl-9-oxo-5-cis, 13-trans-thio-prostadienoate (starting from prostaglandin A,); I.R.: 1740, 1700 cm-' Production of amides In analogous manner to that described in Example 1 using the appropriate prostaglandin of formula III and the appropriate amine of formula IV the following amides of formula I are produced: ca) N-lysergyl-11a,15(S)-dihydroxy-9-oxo-13-trans-prostenamide; I.R.: (CH2CI2 + CH,OH) : 3400 (broad), 1740, 1660. 1520 cm-l cb) N-dihydrolysergyl 1 la. l5(S)-dihydroxy-9-oxo-13-trans-prostenamide; I.R.: 1740. 1665, 1520 cm-' cc) N-[2-(6-methyl-ergolin-8(3-yl)ethyl-11α,15(S)-dihydroxy-9-oxo-13-trans- prostenamide; I.R.: 3400. 1740, 1660. 1520 cm-' cd) N-lysergyl-1 la, 15(R)-dihydroxy-9-oxo-16(R)-methyl-2,3[trans-(-)-methylene-5- cis-prostenamide; I.R.: 1740, 1665. 1520 cm-' ce) N-lysergyl 9a,11a,15(S)-trihvdroxv-5-cis.13-trans-prostadienamide I.R.: 166(). 1520 cm-' cf) N-lysergyl 11α, 15(S)-dihydroxy-9-oxo-prostanamide; I.R.: (CH;CI. + CH,OH) : 3400 (broad). 1740, 1660, 1520 cm-' cg) N-lysergyl-l5(S)-hydroxy -9-oxo-5-cis, 13-trans-prostadienamide; I.R.: 1740. 166(). 1520 cm ch) N-(l -methyllysergyl) 15(S)-hydroxy-I la-imidazol-1 '-yl-9-oxo-5-cis,13-trans- prostadienamide: I.R.: 1725. 1660. 152() cm-' ci) N-[2-(6-methylergolin-8ss-yl)ethyl]-15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5- cis, 13-trans-prostadienamide I.R.: 1725. 1665, 1525 cm-' cj) N-lysergyl-15(S-acetoxy-11α-imidazol-1'-yl-9-oxo-5-cis, 13-trans-prostadienamide; I.R.: 1730 (broad). 1660. 1520 cm-' ck) N-lysergyl- 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienamide; I.R.: 3450, 1740. 1665, i520 cm-i cl) N-lysergyl-15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-13-trans-prostenamide; I.R.: 1725, 1665. 1525 cm-'. Using the process described above esters. thioesters and amides of formula I. wherein R is lysergyl. dihydrolysergyl. isolysergyl. dihydroisolysergyl, 2-bromolysergyl. 13 bromodihydrolysergyl, 2,13-dibromodihydrolysergyl, 10a-methoxylysergyl. 10amethoxydihydroisolysergyl, 2, 13-dibromo- 10a-methoxydihydrolysergyl, or 2- or 13-bromo10a-methoxydihydrolysergyl and the prostanoic moiety is derived from 16, 16-dimethyl-PGE2; 16,16-dimethyl-PGF2α; 15-methyl-PGE2 15-methyl-POF2a; 16(R)- and 16(S)-methyl-13,14-dihydro-PGE2; 11-desoxy-PGE2, the 15 epi isomer thereof, as well as the 5,6-dihydro and the 5,6,13,14-tetrahydro derivative thereof; PGE2, the 15-epi isomer, and the 5,6-dihydro or 5,6,13,14-tetrahydro derivative thereof; PGFla, the 15-epi isomer, and the 13,14-dihydro derivative thereof may be obtained.
EXAMPLE 2 N-Lysergyl-15(S)-Hydroxy-9-oxo-5-cis, 10,13-trans-prostatrienamide a) 159 mg prostaglandin A2 is stirred with 167 mg of 2,2-dithiopyridine and 199 mg triphenylphosphine in 5 ml xylene for 24 hours at 200. The reaction mixture is concentrated to give an oil which is chromatographed on 100 g of Sephadex LH20 (Registered Trade Mark) (eluant CH2Cl2 + 2% CH3OH) to yield the S-(2-pyridyl)-15(S)-hydroxy-9-oxo-Scis, 10,13-trans-thioprostatrienoate.
b) 131 mg of the product from a) is stirred in 5 ml of tetrahydrofuran with 93 mg of lysergyl amine for 24 hours at 20 . The reaction mixture is chromatographed directly on Sephadex LH20 (eluant CH2CI2 + 0.5% CH30H) to give the pure title compound.
I.R.: 3450, 1730, 1710 em In analogous manner the following compounds are produced: a) N-dehydrolysergyl-15(S)-hydroxy-9-oxo-10,13-trans-prostadienamide; I.R.: 3450, 1705, 1665. 1520 cm-' b) N-lysergyl-15(R)-hydroxy-9-oxo-16(R)-methyl-2,3-trans-(-)-methylene-5-cis, 10- prostadienamide: I.R.: 3450. 1700, 1665. 1520 cm-'.
as well as the compounds of Examples 1 and I ca) to cg).
EXAMPLE 3 15(5)-hydroxv-9-oxo-5-cis,10,13-trans-prostatrienoic acid lyseigyl ester process b)] 248 mg of 15S-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis-13-trans-prostadienoic acid lysergyl ester are maintaind at room temperature in 9 ml of methanol for 30 hours. The methanol is removed under vacuum at room temperature. The oilv residue is immediately worked up by chromatography on Sephadex LH20 (Registered Trade Mark) (eluant: CH2CI2 + 0.25% CHROH) to yield the title compound.
I.R.: 3450, 1730, 1710 em Analogous to Example 3. the following compounds are also obtained from the corresponding compound of formula lIla. wherein A is imidazol-1-yl: a) 15(R)-hydroxy-9-oxo-5-cis.10,13-trans-prostatrienoic acid lysergyl ester; I.R.: 3560, 3350. 1720. 1695. 1600 cm-' b) 15(S)-hydroxy-9-oxo-5-cis, 10,13-trans-prostatrienoic acid dihydrolysergyl ester; I.R.: 3555, 3350. 1730. 1705 cm-i.
as well as the compounds of Examples 2 and 2a)-b).
EXAMPLE 4 15S-Jiydroxy-9-oxo-1 1 a-pu nil - 7' -yl-5-cis. 13-fl-ans-prostadien oic acid and 15S-hvdroxy-9- oxo-punn-9' -yl-5-cis. 13-trans-prostadieizoic acid process c) 356 mg of prostaglandin A2 and 127 mg of purine are dissolved in 4 ml of absolute dimethylformamide. and maintained at room temperature for 6 weeks. The progress of the reaction is followed by thin layer chromatography (eluant: CHCIR / 20% CH3OH + 1% CH3COOH). After concentration of the reaction mixture at room temperature under a high vacuum. the resulting oil is chromatographed on Sephadex LH20 (eluant: CH,C12 + 1% CHXOH). From this chromatography it is possible to obtain a mixture of the lla-purin-7'-yl derivative and the lla-purin-9'-vl derivative [mixture a)l and a mixture of the lla-purin-9'-yl derivative and prostaglandin A2 mixture b)l.
Mixture a) is chromatographed twice more on Sephadex yielding pure 15(S)-hydroxy-9oxo-lla-purin-7'-yl-5-cis.13-tmns-prostadienoic acid as the more polar product. I.R.: 1745, 1705. 1600. 1560 cm-'.
148 mg of mixture b) is treated with 23 mg imidazole and maintained at room temperature for 11/2 hours. The reaction mixture is dissolved in 100 ml of methylene chloride and washed with 0.01 N hydrochloric acid. The organic phase is separated off, dried, filtered and concentrated to yield 15(S)-hydroxy-9-oxo-11a-purin-9'-yl-5-cis,13- trans-prostadienoic acid. I.R.: 1745, 1705, 1600, 1580, 1500 cm EXAMPLE 5 15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis, 13-trans-prostadienoic acid [process c)] 315 mg of prostaglandin A2 and 96 mg imidazole are treated with 3 ml methylene chloride and maintained until a clear solution results. After evaporation of the solvent at room temperature the resultant oil is maintained at room temperature for 3 days and then chromatographed on Sephadex LH20 (eluant: CH2CI2 + 1% CH3OH) to afford the title compound.
I.R.: 3350, 3300, 174
The action of the compounds in inhibiting arterial blood pressure is indicated in standard tests, e.g. in the anaesthetized spontaneous hypertonic rat test or in the normotonic dog on i.v. administration of from 0.1 to 3 mg/kg animal body weight per day.
An indicated daily dose for the blood pressure lowering activity is from 10 to 50 conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 211g to 251lug or in sustained release form.
The action of the compounds in inhibiting blood platelet aggregation is indicated by in vitro tests, wherein an inhibition of rabbit plasma aggregation induced by adenosine phosphate or collagen is observed at a concentration of from 1 to 10 Fg/ml.
The compounds also exhibit a uterotonic effect for stimulating smooth muscle, as indicated in standard in vitro tests on an isolated uterus muscle at a dose of from 1 to 10 Fg.
The compounds also exhibit an inhibition of gastric secretion as indicated in standard tests, e.g. by an inhibition of pentagastrin induced secretion in rats at a dose of from 1 to 100 Fg/kg.
An indicated daily dose is from 1 to 20 mg conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.25 mg to 10 mg, or in sustained release form.
The above defined ergolinylalkyl-esters, -thiesters and -amides and compounds of formula III, wherein D is D6 or D8, may be administered in pharmaceutically acceptable acid addition salt form. The present invention accordingly provides a pharmaceutical composition comprising a prostenoic acid ergolinylalkylester, -thioester or -amide or a compound of formula III, wherein D is D6 or D8, in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Such compositions may be made in conventional maner so as to be, for example, a solution or tablet.
WHAT WE CLAIM IS: 1. A process for the production of a compound of formula I,
wherein D is a group of formula
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (57)

**WARNING** start of CLMS field may overlap end of DESC **. The action of the compounds in inhibiting arterial blood pressure is indicated in standard tests, e.g. in the anaesthetized spontaneous hypertonic rat test or in the normotonic dog on i.v. administration of from 0.1 to 3 mg/kg animal body weight per day. An indicated daily dose for the blood pressure lowering activity is from 10 to 50 conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 211g to 251lug or in sustained release form. The action of the compounds in inhibiting blood platelet aggregation is indicated by in vitro tests, wherein an inhibition of rabbit plasma aggregation induced by adenosine phosphate or collagen is observed at a concentration of from 1 to 10 Fg/ml. The compounds also exhibit a uterotonic effect for stimulating smooth muscle, as indicated in standard in vitro tests on an isolated uterus muscle at a dose of from 1 to 10 Fg. The compounds also exhibit an inhibition of gastric secretion as indicated in standard tests, e.g. by an inhibition of pentagastrin induced secretion in rats at a dose of from 1 to 100 Fg/kg. An indicated daily dose is from 1 to 20 mg conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.25 mg to 10 mg, or in sustained release form. The above defined ergolinylalkyl-esters, -thiesters and -amides and compounds of formula III, wherein D is D6 or D8, may be administered in pharmaceutically acceptable acid addition salt form. The present invention accordingly provides a pharmaceutical composition comprising a prostenoic acid ergolinylalkylester, -thioester or -amide or a compound of formula III, wherein D is D6 or D8, in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Such compositions may be made in conventional maner so as to be, for example, a solution or tablet. WHAT WE CLAIM IS:
1. A process for the production of a compound of formula I,
wherein D is a group of formula
wherein A is a radical of formula a),
wherein 1 to 3 of the four methine groups marked a, , y and 5 are replaced by nitrogen, or a radical of formula b),
wherein either one of the ring members L and M is nitrogen and the other of the ring members L and M is methine, or each of L and M is nitrogen, 1 to 3 of the methine groups marked a, ss, y and 5 may be replaced by nitrogen, and the six-membered ring is unsubstituted or mono-substituted by chlorine, bromine, alkylamino, dialkyl-amino. alkoxy or alkylthio, each alkyl moiety of the last four radicals being independently of 1 to 5 carbon atoms, W is oxygen, sulphur or imino, X is -CH,-CH,- or -CH=CH-(nans).
Y is -CH,-CH,- or -CH=CH-(cis or trans).
Z is -CH2-CH2- or
(cis or trans), R1 is alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 9 carbon atoms, R2 is hydrogen or alkyl of 1 to 7 carbon atoms, R3 and R4 are, independently, hydrogen. alkanoyl of 1 to 20 carbon atoms, or benzoyl, and R is an ergolinylalkyl radical of formula 11,
wherein n is 1 or 2.
R5 is hydrogen. alkyl of 1 to 4 carbon atoms. or benzyl.
R6 and R,(, are. independently. hydrogen or halogen.
R7 is alkyl of 1 to 4 carbon atoms other than tert.- butyl. and (i) each of Rs and R is hydrogen. or (ii) R8 and R., together form a bond. or (iii) R8 is hydrogen. and R., is alkoxy of l to 4 carbon atoms, with the proviso that when Z is
(cis or trans) then X is -CH2-CH2- and R, is 1-methylpentyl which comprises a) for the production of a compound of formula I, condensing a compound of formula III,
wherein D, R1, R2, RX, X, Y and Z are as defined above, or a reactive functional acid derivative thereof, with a compound of formula IV, H-WR IV wherein R and W are as defined above, or b) for the production of a compound of formula Ia,
wherein R, Rl R2, RX, W, X, Y and Z are as defined above, splitting off HA by deamination from a compound of formula Ib,
wherein A, R, R,, R2, R3, W, X. Y and Z are as defined above in methanol,
2. A process for the production of a compound of formula I defined in claim 1 substantially as hereinbefore described with reference to any one of the Examples 1 to 3.
3. A prostanoic ergolin-8-ylalkyl ester, thioester or amide whenever produced by a process according to claim 1 or 2.
4. A compound of formula I. as defined in claim 1.
5. A compound of claim 4 wherein Z is -CH-CH-
6. N-Dihydroisolysergyl- 11 a, 15 (S)-dihydroxy-9-oxo- 1 3-trans-prostenoic amide.
7. 9α, 11α, 15(S)-Trihydroxy-5-cis, 13-trans-prostadienoic acid lysergyl ester.
8. lla, 15(S)-Dihydroxy-9-oxo- 13-rrans-prostenoic acid lysergyl ester.
9. 1 ta, 15(S)-Dihydroxy-9-oxo- 13-trans-prostenoic acid 2,13 ,-dibromodihydrolysergyl ester.
10. 1 la, 15(S)-Dihydroxy-9-oxo-5-cis, 13-nans-prostadienoic acid lysergyl ester.
11. 11a,15(S)-Dihydroxy-9-oxo-13-trans-prostenoic acid 1-methyllysergyl ester.
12. 11a.15S-Dihydroxy-9-oxo-13-trans-prostenoic acid lOa-methoxydihydrolysergyl ester.
13. lla,15S-Dihydroxy-9-oxo-13-trans-prostenoic acid 1-(2-chloro-6-methyl-ergolin-8 ss-yl)ethyl ester.
14. 1 la, 15(S)-Dihydroxy-9-oxo- 15-methyl-5-cis, 13-trans-prostadienoic acid lysergyl ester.
15. 11a,15(S)-Dihydroxy-9-oxo-prostanoic acid lysergyl ester.
16. 11a,15R-Dihydroxy-9-oxo-16(R)-methyl-5-cis-prostenoic acid lysergyl ester.
17. 11a,15(R)-Dihydroxy-9-oxo-16(R)-methyl-2,3-trans-(+)-methylene-5-cis- prostenoic acid lysergyl ester.
18. 15-Cyclohexyl-1 1a,15(R)-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis- prostenoic acid lysergyl ester.
19. 11a,15(R)-Dihydroxy-9-oxo-16(R)-methyl-2,3-trans-(-)-methylene-5-cis- prostenoic acid lysergyl ester.
20. 15(S)-hydroxy-lla-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid lysergyl ester.
21. 15(R)-Hydroxy-1 la-imidazol-1 '-yl-9-oxo-5-cis,13-trans-prostadienoic acid lysergyl ester.
22. 15(S)-Hydroxy-1 1 a-imidazol- 1 '-yl-9-oxo- 13-trans-prostenoic acid lysergyl ester.
23. 15(S)-Hydroxy-lla-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid dihydroisolysergyl ester.
24. 15(S)-Hydroxy-1 la-imidazol- 1 '-yl-9-oxo-5-cis,13-trans-prostadienoic acid 2,13dibromodihydrolysergyl ester.
25. 15(S)-Hydroxy-9-oxo-1 ' ,2' ,4'-triazol-1 '-yl5-cis, 13-trans-prostadienoic acid lysergyl ester.
26. 15(R)-Hydroxy-11α-imidazol-1'-yl-9-oxo-16(R)-methyl-5-cis-prostenoic acid lysergyl ester.
27. 15(S)-Hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid 1methyllysergyl ester.
28. 15-Cyclohexyl-15(R)-hydroxy-1 la-imidazol-1 '-yl-9-oxo-16,17, 18,19,20-pentanor-5 cis , 13-trans-prostadienoic acid lysergyl ester.
29. 15(R)-Hydroxy- 1 la-imidazol-1 '-yl-9-oxo-16(R)-methyl-2,3-trans-(- )-methylene-5- cis-prostenoic acid lysergyl ester.
30. 15(S)-Hydroxy-lla-imidazol-1'-yl-9-oxo-13-trans-prostenoic acid 2',13'dibromodihydrolysergyl ester.
31. S-Lysergyl-11α, 15(S)-dihydroxy-9-oxo-13-trans-thioprostenoate.
32. S-Lysergyl-15(S)-hydroxy-1 la-imidazol-1 '-yl-9-oxo-5-cis,13-transthioprostadienoate.
33. N-Lysergyl-lla 15(S)-dihydroxy-9-oxo- 1 3-trans-prostenamide .
34. N-Dihydrolysergyl 1 la. 15(S)-dihydroxy-9-oxo-13-trans-prostenamide.
35. N-[2-(6-Methyl-ergolinyl-8ss-yl)ethyl-11α, 15S-dihydroxy-9-oxo-13-trans- prostenamide.
36. N-Lysergyl- 11 a. 15(R)-dihydroxy-9-oxo- 16(R)-methyl-2,3-flans-( - )-methylene-5cis-prostenamide.
37. N-Lysergyl-9α, 11α, 15(S)-trihydroxy-5-cis, 13-trans-prostadienamide.
38. N-Lysergyl- I la, 15(S)-dihydroxy-9-oxo-prostanamide.
39. N-Lysergyl-15(S)-hydroxy-9-oxo-5-cis,13-trans-prostadienamide.
40. N-(1-methyllysergyl-)15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis, 13-trans- prostadienamide.
41. N-[2-(6-Methylergol-in-8ss-yl)ethyl]-15(S)-hydroxy-11α-imidazol-1'-yl-9-oxo-5- cis,13-trans-prostadienamide .
42. N-Lysergyl- 15(S)-acetoxy-1 11 a-imidazol- 1 '-yl-9-oxo-5-cis, 13-transprostadienamide.
43. N-Lysergyl-15(S)-hydroxy-l ta-imidazol-1 '-yl-9-oxo-5-cis,13-trans- prostadienamide.
44. N-Lysergyl-15(S)-hydroxy- 11 a-imidazol-l '-yl-9-oxo-13tuarzs-prostenamide.
45. N-Lysergyl- 15(S)-hydroxy-9-oxo-5-ds. 10. 3-nans-prostatrienamide.
46. N-Dihydrolysergyl-15(S)-hydroxy-9-oxo-10, 13-trans-prostadienamide.
47. N-Lysergyl-15(R)-hydroxy-9-oxo-16(R)-methyl-2,3-trans-(-)-methylene-5-cis,10- prostadienamide.
48. 15(S)-Hydroxy-9-oxo-5-cis, 10. 13-trans-prostatrienoic acid lysergyl ester.
49. 15(R)-Hydroxy-9-oxo-5-cis. 10. 13-tmns-prostatrienoic acid lysergyl ester.
50. 15(S)-Hydroxy-9-oxo-5-cis. 10. 13-trans-prostatrienoic acid dihydrolysergyl ester.
51. 15(R)-Hydroxy-11α-imidazol-1'-yl-9-oxo-5-cis,13-trans-prostadienoic acid dihydroisolysergyl ester.
52. A compound of claim 4. wherein R is lysergyl, dihydrolysergyl, isolysergyl, dihydroisolvsergyl. 2-bromo-lysergyl. 13-bromodihydrolysergyl. 2.13 dibromodihyd'rolysergyl. I 0a-methoxylysergyl, 1 0a-methoxydihydroisolysergyl, 2,13 dibromo- 1 0a-methoxydihydrolysergyl. or 2- or 13-bromo-10a-methoxydihydrolysergyl, and the prostanoic moiety is chosen from 16.16-dimethyl-PGE,; 16,16-dimethyl-PGF3α: 15-methyl-POE2; 15-methyl-PGF2a; 16R- and 16S-methyl-13,14-dihydro-PGE2 11-desoxy-PGE2, the 15 epi isomer thereof, as well as the 5,6-dihydro and the 5,6,13,14-tetrahydro derivative thereof; PGE2, the 15-epi isomer, and the 5,6-dihydro or 5,6,13,14-tetrahydro derivative thereof; PGF"" the 15-epi isomer, and the 13,14-dihydro derivative thereof.
53. A compound of claim 4, wherein D is D4 or D6, A is imidazol-1-yl, X is -CH=CH-(trans)-, Y is -CH=CH-(cis) or -CH2-CH2-, Z is -CH2-CH2 Rl is alkyl, R2,R3,R4 are hydrogen, -ORl has the a-configuration, and W is O or -NH-.
54. A compound of claim 4 characterized in that in formula I, (a) D is D3, wherein the side chain OR4 has the a-configuration is other than when R4 is other than hydrogen or has the (3-configuration, D7 or D8; (b) W is S; (c) R is dihydrolysergyl; (d) n is 2; (e) R5 is alkyl of 1 to 4 carbon atoms, or benzyl; (f) at least one of R6 and Rlo is chlorine or bromine; (g) R7 is alkyl of 2 to 4 carbon atoms other than tert butyl; (h) R8 is hydrogen and R9 is alkoxy of 1 to 4 carbon atoms; (i) the 8-ergoline side chain has the a-configuration; (j) Rl is alkyl of 1 to 10 carbon atoms; and/or (k) R3 is alkanoyl of 1 to 20 carbon atoms.
55. A compound of claim 6 characterized in that in formula I, R and W together are dihydrolysergylamino; Z is 1,2-cyclopropyl; and/or D is D1; D2; D5; or D6;
56. A compound of any one of claims 3 to 55 in acid addition salt form.
57. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 3 to 56, in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
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SU741794A3 (en) 1980-06-15
ZA771215B (en) 1978-10-25
FI770572A (en) 1977-10-28
PT66269B (en) 1978-11-07
FR2353549A1 (en) 1977-12-30
FR2355837A1 (en) 1978-01-20
JPS52131600A (en) 1977-11-04

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