NZ203115A - Carbaprostaglandin derivatives and medicinal compositions - Google Patents
Carbaprostaglandin derivatives and medicinal compositionsInfo
- Publication number
- NZ203115A NZ203115A NZ203115A NZ20311583A NZ203115A NZ 203115 A NZ203115 A NZ 203115A NZ 203115 A NZ203115 A NZ 203115A NZ 20311583 A NZ20311583 A NZ 20311583A NZ 203115 A NZ203115 A NZ 203115A
- Authority
- NZ
- New Zealand
- Prior art keywords
- carbaprostaglandin
- tetradehydro
- didehydro
- methyl
- general formula
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
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- 150000001875 compounds Chemical class 0.000 claims description 43
- 230000000903 blocking effect Effects 0.000 claims description 9
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- 238000000034 method Methods 0.000 claims description 7
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- 230000008569 process Effects 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
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- 210000000078 claw Anatomy 0.000 claims 1
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- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 28
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
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- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
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- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- BTDWSZJDLLLTMI-UHFFFAOYSA-N hex-2-yn-1-ol Chemical compound CCCC#CCO BTDWSZJDLLLTMI-UHFFFAOYSA-N 0.000 description 1
- MELUCTCJOARQQG-UHFFFAOYSA-N hex-2-yne Chemical compound CCCC#CC MELUCTCJOARQQG-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- MYHXHCUNDDAEOZ-FOSBLDSVSA-N prostaglandin A2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1C\C=C/CCCC(O)=O MYHXHCUNDDAEOZ-FOSBLDSVSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000002633 shock therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
-
- 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
- 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
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
1. Carbacyclin derivatives of the general formula I see diagramm : EP0086404,P12,F1 wherein R1 , R2 , R3 and R4 are hydrogen or alkyl of 1-2 C-atoms. R5 is alkyl of 1-2 C-atoms, as well as their salts with pharmaceutically acceptable bases.
Description
New Zealand Paient Spedficaiion for Paient Number £03115
203115
Priority Date(s):
Complete Specification Filed: j-.<^5> Class: CSvMW.,CQX5!>. f*6J IS3.I )K >
pu: ::-,r:-.cn D-r: .. M .^.R. .W?
F.O. j;.:rn-|, No: .. (95^
NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION
"NOVEL CARBACYCLINS, PROCESS FOR THE PREPARATION THEREOF, AND USE THEREOF AS MEDICINAL AGENTS"
We, SCHERING AKTIENGESELLSCHAFT, a body corporate organized according to the laws of Germany, of 170-178 Mullerstrasse, D-IOOO Berlin 65, Germany and Waldstrasse 14, 4619 Bergkamen, Germany, 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:-
rV \
*2*^^ 1
C J
203115
1
The present invention relates to (5E)-13>14,18*18,-19>19-hexadehydro-6a-carbaprostaglandin I2 derivatives/ their physiologically compatible salts# a process for the preparation thereof? and pharmaceutical compositions containing same. 5 New Zealand iPatent^No 193.S27 claims f.. n t 1
• carbacyclin derivatives of the general formula coor
I 1
(ch_)_
I 3
r ch
K-
wherein
R^ is hydrogen/ alkyl* cycloalkyl* aryl> or a 10 heterocyclic residuet
A is a -CH2-CH2-/ trans-CH=CH-, or -C^C-group, W is a free or functionally modified hydroxy-methylene group or a free or functionally modified
CH-5
i
-C—group, wherein the OH-group is in the a-position, *
OH
I 22 JAN 1986„
W /
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D and E together mean a direct bond or D is a straight-chain or branched, saturated or unsaturated alkylene group of 1-10 carbon atoms optionally substituted by fluorine atoms,
E is an oxygen atom or a -C=C-bond or a direct bond/ R2 is an alkyl/ cycloalkyl/ optionally substituted aryl> or heterocyclic group,
R3 is a free or functionally modified hydroxy groupt and/ if means a hydrogen atom/ the salts thereof with physiologically compatible bases.
The compounds possess the properties typical for prostacyclins/ such as> for example/ lowering of peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation/ and dissolution of platelet thrombi/ myocardial cytoprotection and thus lowering of systemic blood pressure, without simultaneously lowering stroke volume and coronary blood flow* treatment for stroke, prophylaxis and therapy of coronary heart disease> coronary thrombosis/ cardiac infarction, peripheral arterial diseases/ arteriosclerosis/ and thrombosis/ shock therapy/ inhibition of bronchoconstriction/ inhibition of gastric acid secretion and cytoprotection for gastric and intestinal mucosa; antiallergic properties/ lowering of pulmonary vascular resistance and pulmonary blood pressure, promotion of kidney blood flow, utilization in place of heparin or as adjuvant in dialysis of hemofiltration/ preservation of blood plasma
203115
stores/ especially blood platelet preserves, inhibition of labor» treatment of gestational toxicosis/ enhancement of cerebral blood flow# etc. Furthermore/ the novel prostaglandin analogs exhibit antiproliferative properties.
Among the compounds claimed in NZ Patent 19182 7 the (5E)-13/14>18jl8,19/19-hexadehydro-6a-carbaprostaglandin I2 compounds show such outstanding properties as blood-pressure-lowering agents and agents inhibiting thrombocyte aggregation that the dose can be further reduced whereby undesirable side effects are likewise even more strongly suppressed. The (5E)-13/14/18/18/19/19-hexar]ehydro-6a-carbaprostaglandin I2 compounds have not been disclosed by name in NZ 191827. Compounds wherein A means a -C^C-group have not been emphasized over the other compounds wherein A is a -CHj-C^- or trans-CH=CH-group.
The nomenclature of the compounds is based on a proposal by Morton and Brokaw (J. Org. Chem. 4_4_ :2280 [1979]). (5E)-6a-Carbaprostaglandin 12 accordingly has the following structural formula:
COOU
011
OH
*z-MN!936$
/
v. ./
2 031 1 5
Accordingly, the invention concerns (5E)-13,14,-18,18,19,19-hexadehydro-6a-carbaprostaglandin I^ derivatives of general Formula I
CO OH
11
OH
(I),
chc-ch oh
C =C - H,
wherein
R^, R2, R3, R4 represent a hydrogen atom or an alkyl group of 1-5 carbon atoms,
R5 is an alkyl group of 1-5 carbon atoms,
as well as the salts thereof with physiologically compatible
bases.
Suitable alkyl groups R^, R2, R3t R4, R5 are straight-chain and branched-chain alkyl residues of 1-5
carbon atoms, such as* for example, methyl, ethyl, propyl,
butyl/ isopropyl, isobutyl, pentyl. Preferred residues are
methyl, ethyl, propyl, and isopropyl, especially methyl and ethyl.
_ 6 _
203115
W
Suitable for the salt formation are inorganic and organic bases as known to those skilled in the art for the preparation of physiologically compatible salts. Examples are alkali hydroxides* such as sodium and potassium hydroxide# 5 alkaline earth hydroxides* such as calcium hydroxide* ammonia* amines, such as ethanolamine* diethanolamine, triethanolamine* N-methylglucamine» morpholine, tris(hydroxymethyl)methylamine* etc.
The invention furthermore relates to a process for 10 the preparation of the prostacyclin derivatives of this invention according to general Formula I* characterized by reacting a compound of general Formula II 0
(II) ,
Jii 111
/ 2 \3 / ;J
h =cdr-ch c > c c=c-j<_
: 5
othf omp wherein
Rp Rj, R^( R^j R5 have the meanings given above and
THP means the tetrahydropyranyl residue*
with a Wittig reagent of Formula III
Ph,P=Cll-(CH0) -C^ <=> (III),
^ 0
2031 1 5
wherein Ph is a phenyl group#
and subsequently separating isomers/ splitting off blocking groups# and optionally converting the carboxy group into a salt with a physiologically compatible base.
The reaction of the compound of general Formula II
with the Wittig reagent of Formula III# which is produced from the corresponding phosphonium salt with methanesulfinyl-methyl sodium or methanesulfinylmethyl potassium or potassium tert-butylate in dimethyl sulfoxide or dimethyl sulfoxide-10 tetrahydrofuran mixtures, is conducted at temperatures of 0-100° C, preferably 20-60° C, in an aprotic solvent or solvent mixture, preferably dimethyl sulfoxide# dimethyl forma-mide> or tetrahydrofuran. The thus-obtained olefins of a Z-and E-configuration are separated in the usual way# for ex-15 ample by column or layer chromatography. During the afore-described Wittig olefin-forming reaction* the formation of the 13 *14-acetylene bond also takes place* with hydrogen bromide being split off* at the same time.
The splitting off of the blocking groups is 20 effected in an aqueous solution of an organic acid# such as# for example, acetic acid# propionic acid# or others# or in an aqueous solution of an inorganic acid* e.g. hydrochloric acid. To enhance solubility* a water-miscible, inert organic solvent is suitably added. Organic solvents which can be 25 used for this purpose are, for example* alcohols# such as methanol and ethanol# and ethers* such as dimethoxyethane* dioxane* and tetrahydrofuran. Tetrahydrofuran is preferably
_ 8 _
203115
employed. The splittinq-off step is preferably conducted at temperatures of between 20° and 80° C.
The carboxylic acids of general Formula I can be converted into salts with suitable amounts of the correspond-5 ing inorganic bases* with neutralization. For example# the solid inorganic salt is obtained when dissolving the corresponding acids in water containing the stoichiometric quantity of the base* after evaporation of the water or after the addition of a water-miscible solvent* e.g. alcohol or 10 acetone. For the production of an amine salt* the PG acid is dissolved in a suitable solvent* e.g. ethanol* acetone* diethyl ether, or benzene* and at least the stoichiometric amount of the amine is added to this solution. During this process* the salt is ordinarily obtained in the solid form* 15 or is isolated in the usual way after evaporation of the solvent.
The compounds of general Formula II serving as the starting materials can be prepared* for example* by conventionally reacting an aldehyde of Formula IV (NZ 191827)
(IV)
/«* X,
JjN ^
JN -ft
I 22MmmSli
W1 —
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with a phosphonate of general Formula V
o ou 11 n K- }\
en o ii ii \ / \ /
3 \p_CH2-C C c C=C-R5
Cll O7
wherein R^> R^/ R / R^, and have the meanings given above,
in the presence of a deprotonating agent; such as, for example, sodium hydride or potassium tert-butylate, and a brominating agent, such as, for example, N-bromosuccinimide, to obtain a ketone of general Formula VI:
1 1
o 0
(vi)
/
'k /2 \3 /
ch - c l3 j c c c c =c-k,
OCO"
*V
o
After reduction of the keto group with sodium boro-
hydride and optionally separation of epimers, saponification L. of the ester group, for example with potassium carbonate in methanol, and ketal cleavage with aqueous acetic acid, as well as optionally epimer separation# the ketone of general 15 Formula VII is obtained:
_ 10 _
203115
(VII)
Ri n? S R/,
CH -CI3r-CH-C C C=C-R5
6ll OH
Etherification of the hydroxy groups with dihydro-pyran in the presence of catalytic amounts of p-toluene-sulfonic acid yields the compounds of general Formula II.
The phosphonates of general Formula V are produced conventionally by reacting an alkyl halogenide (producible from the corresponding alcohol by halogenation) of general Formula VIII
R, II, '
^ /
Hol-C CSC-Jt (VJII)
with the dianion formed from the phosphonate of general Formula IX:
ch3°\1I \\ \ y2
"P-CH C C — H (IX)
CHn0X
J
wherein R-^/ R2 / R3/ R4/ and R^ have the meanings given above.
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Another method for obtaining the phosphonates of general Formula V resides in reacting the anion of the dimethyl ester of methylphosphonic acid with an ester of general Formula X:
0 .ii H K K.
II ^ / V / , ,
r,0-c c c c=c-rr (x)
b J
wherein
R^> R^i R^> and R<_ have the above-indicated meanings and
Rg is an alkyl group of 1-5 carbon atoms,
obtainable from the corresponding malonic acid ester by alkylating with the halogenide of general Formula VIII and subsequent decarbalkoxylation. The ester of general Formula X is also obtainable from the carboxylic acid of general Formula XI:
0 R
H < / „ (XI)
ho-c c h wherein R^ and R2 have the meanings given above, by alkylation with the halogenide of general Formula VIII and subsequent esterification.
0*
12
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The compounds of this invention have blood-
pressure-lower ing and bronchodilatory effects. They are furthermore suitable for inhibition of thrombocyte aggregation. Consequently/ the novel prostacyclin derivatives of 5 Formula I represent valuable pharmaceutically active agents. Moreover> they exhibit, with a similar spectrum of activity as compared with corresponding prostaglandins, a higher specificity and, above all, a considerably longer duration of efficacy. As compared with VGI^, they are distinguished 10 by greater stability. The high tissue specificity of the novel prostaglandins is demonstrated on studies on smooth-muscle organs/ such as, for example, on the guinea pig ileum or on the isolated rabbit trachea, where a substantially lesser stimulation can be observed than that caused by the 15 administration of natural prostaglandins of the E, A, or F type.
erties typical for prostacyclins, such as, for example, lowering of peripheral arterial and coronary vascular resistance, 2 0 inhibition of thrombocyte aggregation, and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering the stroke volume and coronary blood flow; treatment for stroke, prophylaxis and therapy of coronary heart disease, coronary 25 thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, therapy of shock,
The novel carbacyclin derivatives possess the prop-
2031 1 5
inhibition of bronchoconstriction, inhibition of gastric acid secretion* cytoprotection for gastric and intestinal mucosa) cytoprotection in liver and pancreas; antiallergic properties, lowering of pulmonary vascular resistance and pulmonary blood pressure# promotion of kidney blood flow# utilization in place of heparin or as adjuvant in dialysis of hemofiltra-tion# preservation of blood plasma stores# especially blood platelet preservest inhibition of labor# treatment of gestational toxicosis# enhancement of cerebral blood flow, etc. Furthermore# the novel carbacyclin derivatives possess antiproliferative properties. The carbacyclins of this invention can also be employed in combination with 0-blockers or diuretics# for example.
The dosage of the compounds is 1-1#500 pg/kg/day if administered to human patients. The unit dosage for the pharmaceutically acceptable vehicle is 0.01 - 100 mg.
When injected intravenously into nonanesthetized, hypertonic rats in doses of 5# 20, and 100 pg/kg body weight# the compounds of this invention show a istronger blood-pressure-lowering effect of a longer duration as compared with PGE2 and PGA2t without triggering diarrhea* as does PGE2 or cardiac arrhythmias, as does PGA2-
When injected intravenously into anesthetized rabbits, the compounds of this invention# as compared with PGE2 and PGA2/ exhibit a stronger blood-pressure-lowering effect of a considerably longer duration/ without affecting other smooth-muscle organs or organ functions.
_ 14 _
2 0 31 1 5
Sterile, injectable, aqueous or oily solutions are used for paxenteral administration. Suitable for oral administration are, for example, tablets, dragees, or capsules.
The invention consequently also relates to medicinal agents based on the compounds of general Formula I and customary auxiliary agents and excipients.
The active agents of this invention are to serve, in conjunction with the auxiliary agents known and usual in 10 galenic pharmacy, for the preparation of blood-pressure-lowering agents, for example.
- is - 20^ ^ ^
Example 1
(5E) - (16RS) -13,14-Didehyd,;o-16-niethyl-
18,18,19/19-tetradehydro-6a-carbaprostaglandin I2
At 5° C, 4.75 g of potassium tert-butylate is added 5 within 45 minutes to a solution of 9.4 g of 4-carboxybutyl-triphenylphosphonium bromide in 2 0 ml of dimethyl sulfoxide and 7.8 ml of tetrahydrofuran; the reaction mixture is stirred for 45 minutes at 5° C. The red ylene solution is combined with a solution of 1.83 g of (1R,5S,6R/7R)-7-10 (tetrahydropyran-2-yloxy)-6-[(3S/4RS)-2-bromo-4-methyl-3-
(tetrahydropyran-2-yloxy)oct-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one in 3 ml of tetrahydrofuran and agitated for 4 hours at 40° C. The reaction mixture is poured on ice water, acidified with 35% citric acid solution to pH 4-5/ and extracted three 15 times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate/ and evaporated under vacuum. The residue is purified by chromatography on silica gel.- With hexane/ethyl acetate (3+2)/ 180 mg of the 5Z-configured olefin is initially obtained/ and as the more 20 polar component, 680 mg of (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR (CHC13): 3500 (broad), 2940, 2860, 2225, 1710, 1440 cm"1.
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To split off blocking groups, 680 mg of the above-obtained olefin-forming product is stirred for 20 hours at 25° C with 25 ml of a mixture of acetic acid/water/tetra-hydrofuran (65/35/10). The mixture is then evaporated under 5 vacuum and the residue chromatographed on silica gel. With ethyl acetate/acetic acid (99.9 + 0.1), 345 mg of the title compound is produced as a colorless oil.
IR: 3600, 3400 (broad), 2930, 2225, 1710, 1603,
1020 cm~^-.
The starting material for the above title compound is prepared as follows:
(a) (1R,5S,6R,7R)-3/3-Ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3-oxooct-l-en-6-ynyl]bicyclo[3,3,0]octane
At 0° C, a solution of 10.5 g of 3-methyl-2-
oxohept-5-ynephosphonic acid dimethyl ester in 70 ml of di-methoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 18 0 ml of dimethoxyethane; the mixture is stirred for one hour at 0° C and then 7.4 g of finely
2 0 pulverized N-bromosuccinimide is added thereto. Agitation is continued for 30 minutes at 0° C; the reaction mixture is combined with a solution of 11.4 g of (1R,5S,6R,7R)-3, 3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane in 90 ml of dimethoxyethane/ and stirred for 2 hours at 0° C.
The reaction mixture is poured on saturated ammonium chloride solution and extracted with ether. The organic extract is
203115
washed with water to render it neutral, dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (3+2) 8.2 g of the unsaturated ketone as a colorless oil.
IR: 2930, 2880, 1712, 1688, 1602, 1595, 1450, 1275, 945 cm-1.
(b) (1R,5S> 6R,7R)-7-Hydroxy-6-[(3S,4RS)-2-bromo-3-hydroxy-4-methyloct-l-en-6-ynyl]bicyclo-[3.3.0]octan-3-one
At -40° C, 2.5 g of sodium borohydride is added in incremental portions to a solution of 5.9 g of the ketone produced according to Example 1(a) in 140 ml of methanol, and the mixture is stirred for 30 minutes at -40° C. Subsequently the mixture is diluted with ether, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum.
The crude product (mixture of 15-epimers} is dissolved in 200 ml of methanol, 2.5 g of potassium carbonate is added and the mixture is stirred for 17 hours at 23° C under argon. Thereafter the mixture is concentrated under vacuum, diluted with ether, and washed neutral with brine. The mixture is dried over magnesium sulfate and evaporated under vacuum.
The evaporation residue is stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid/ water/tetrahydrofuran (65/35/10) and then evaporated under
203115
\
vacuum. Column chromatography on silica gel with ether/ methylene chloride yields first of all 1.6 g of the 158-configured alcohol, as well as 2.1 g of the title compound (PG nomenclature 15a-hydroxy) as the more polar component/ in the form of colorless oils.
IR: 3600, 3430 (broad), 2960, 2920, 2870, 1738, 1600, 1400 cm-1.
(c) (1R,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-
[(3Si4RS)-2-bromo-4-methyl-3~(tetrahydropyran-
2-yloxy)oct-l-en-6-ynyl]bicyclo[3.3.0]octan-
3-one
A solution of 1.6 g of the a-alcohol prepared according to Example 1(b), 16 mg of p-toluenesulfonic acid, and 1.5 g of dihydropyran in 50 ml of methylene chloride is agitated at 0° C for 35 minutes. The mixture is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate> and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (7+3) 2.17 g of the title compound as a colorless oil.
IR: 2940, 2870, 1735, 1450, 1120, 1018, 965 cm"1.
203115
Example 2
(5E)-(16RS)-13,14-Didehydro-16,20-dimethyl-
18,18,19,19-tetradehydro-6a-carbaprostaglandin I2
In analogy to Example 1> 1.6 g of (1R?5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[ (3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)non-l-en-6-ynyl]bicyclo13.3.0]octan-3-one yields 640 mg of (5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2942, 2860, 2224, 1710 cm"1.
After splitting off the blocking groups as described in Example 1, 0.3 g of the title compound is obtained as a colorless oil.
IR: 3600, 3350 (broad), 2932, 2224, 1710, 1602 cm-1.
The starting material for the above title compound is prepared as follows:
(a) (1R,5S,6R,7R)-3>3-Ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3-oxonon-l-en-6-ynyl]bicyclo[3.3.0]octane
Analogously to Example 1(a)> 6 g of 3-methyl-2-oxooct-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide, and 5.6 g of (IR,5S>6R,7R)-3,3-ethylene-dioxy-7-i>enzoyloxy-6-formylbicyclo [ 3 . 3 .0 ] octane yield 4.0 g of the unsaturated ketone as a colorless oil.
IR: 2935, 2883, 1713, 1687, 1602, 1596, 1275,
94 7 cm~^.
203115
(b) (1R,5S,GR,7R)-7-Hydroxy-6-((3S,4RS)-2-bromo-
3-hydroxv-4-methylnon-l-en-6-ynyl]bicyclo-
[3.3.0]octan-3-one
Analogously to Example 1(b), 3 g of the ketone prepared according to Example 2(a) yields, after reduction with 1.3 g of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent ketal splitting with 150 ml of a mixture of acetic acid/water/tetrahydrofuran, 1.2 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3610, 3400 (broad), 2960/ 2870, 1739, 1600 cm"1*
(c) (1R> 5S> GR> 7R)-7-(Tetrahydropyran-2-yloxy)-6-
[ (3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran-
2-yloxy)non-l-en-6-ynyl]bicyclo[3.3.0]octan-
3-one
In analogy to Example 1(c)> 0.78 g of the diol produced according to Example 2(b) and 0.7 g of dihydropyran yield 1.1 g of the title compound as a colorless oil.
IR: 2940, 2872, 1736, 1450, 1120, 965 cm"1.
Example 3
(5E)-(16RS)-20-Ethyl-13,14-didehydro-16-methyl-
18,18,19,19-tetradehydro-6a-carbaprostaglandin I2
Analogously to Example 1, 2 g of (IR,5S,6R,7R)-7-tetrahydropyran-2-yloxy)-6-[(3S> 4RS)-2-bromo-4-methyl-3-tetrahydropyran-2-yloxy)dec-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one yields, in the form of a colorless oil, 900 mg of
203115
(5E)-(16RS)-2 0-ethyl-l3>14-didehydro-16-methyl-18>18,19/19-tetradehydro-6a-carbaprostaglandin I2 11/15-bis(tetrahydro-pyranyl ether).
IR: 3500 (broad), 2948, 2862, 2220, 1708 cm"1. After the blocking groups have been split off according to Example 1/ 420 mg of the title compound is obtained as a colorless oil.
IR: 3600/ 3360 (broad)/ 2930, 2858/ 2220, 1708,
1601 cm"1.
The starting material for the above title compound is prepared as follows:
(a) (IR/5S,6R/7R)-3,3-Ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3-oxodec-l-en-6-ynyl]bicyclo[3.3.0]octane
In analogy to Example 1(a)/ 6.25 g of 3-methyl-2-oxonon-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide, and 5.6 g of (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.OJoctane result in 4.5 g of the unsaturated ketone as a colorless oil.
IR: 2940> 2880, 1712/ 1688/ 1601/ 1592, 1275,
948 cm-1.
V W.-V' .■
203115
(b) lIR,5S/6R,7R)-7-Hydroxy—6-[ (3S,4RS)-2-bromo-3-hydroxy-4-methyldec-l-en-6-ynyl]bicyclo-[3.3.0]octan-3-one
Analogously to Example 1(b), 4 g of the ketone 5 prepared according to Example 3(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal cleavage with acetic acid/ water/tetrahydrofuran (65/35/10), 1.5 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3610/ 3400 (broad)/ 2955, 2868/ 1738,
1601 cm-1.
(c) (IR,5S/6R,7R)-7-(Tetrahydropyran-2-yloxy) -6-
[(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)dec-l-en-6-ynyl]bicyclo[3.3.0]octan-
3-one
In analogy to Example 1(c)> 1.2 g of the diol prepared according to Example 3(b) yields 1.81 g of the title compound as a colorless oil.
IR: 2942, 2868, 1738, 1450, 1125, 960 cm-1.
(d) 3-Methyl-2-oxonon—5-ynylphosphonic Acid
Dimethyl Ester
At 20° C, 120 g of methylmalonic acid diethyl ester is added dropwise to a solution of 15.8 g of sodium in 34 0 ml of ethyl alcohol. After 30 minutes, 135 g of 1-bromo-25 2-hexyne (prepared from hex-2-yn-l-ol with phosphorus tri-bromide in pyridine) is added dropwise thereto and the
X oT> it t>
mixture heated for 16 hours under reflux. The mixture is thereafter filtered, the residue washed with methylene chloride and concentrated under vacuum. The residue is dissolved in 500 ml of methylene chloride; shaken twice with 5 respectively 50 ml of water, dried over magnesium sulfate, and concentrated under vacuum. The residue is distilled under vacuum at 14 torr and 148-152° C, thus obtaining as the distillate 155g of the alkylated methylmalonic acid ester which latter is heated under reflux for 4.5 hours in 10 1200 ml of dimethyl sulfoxide and 12 ml of water with 52 g of lithium chloride. The mixture is then poured on 5 1 of ice water, extracted with ether, the extract shaken with water, dried over magnesium sulfate, and concentrated under vacuum. Distillation of the residue yields, at 94-96° C and 15 14 torr, 95 g of the ethyl ester of 2-methyloct-4-ynoic acid as a colorless liquid.
At -70° C, 640 ml of a 1.5-molar butyllithium solution in hexane is added dropwise to a solution of 176 g of the dimethyl ester of methanephosphonic acid in 2 1 of 20 tetrahydrofuran. After 15 minutes, a solution of 90 g of the ethyl ester of 2-methyloct-4-ynoic acid in 300 ml of tetrahydrofuran is gradually added thereto. The mixture is stirred for 4 hours at -70° C, neutralized with acetic acid, and evaporated under vacuum. The residue is combined with 25 200 ml of water, extracted three times with respectively 500 ml of methylene chloride, the extract is shaken with 100 ml of water, dried over magnesium sulfate, and
"EZ.PA7-
j -9FEB 193
I RECEIVED k ——
24
203115
concentrated under vacuum. Distillation of the residue yields, at 0.35 torr and 126-128° C, 80 g of the title compound as a colorless liquid.
Example 4
(5E)-13,14-Didehydro-16,16-dimethy1-18 ,18,19,19-
tetradehydro-6a-carbaprostaglandin 12
Analogously to Example 1, 1.5 g of (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)oct-l-en-6-ynylJ bicyclo f 3.3.0]octan-10 3-one yields 610 mg of (5E)-13,14-didehydro-16,16-dimethyl-18,18/19,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis (tetrahydropyrari-2-yl ether) as a colorless oil.
IR: 3500 (broad), 2944/ 2862, 2222, 1708 cm"1.
After the blocking groups have been split off ac-15 cording to Example 1/ 2 90 mg of the title compound is obtained as a colorless oil.
IR: 3600/ 3400 (broad), 2930, 2862, 1708, 1600 cm"
w rf'
_ 25 _
2 031 1 5
(a) (IR,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy-6-(2-bromo-4,A-dimethyl-3-oxooct-l-en-6-ynyl)-bicyclo[3.3.0]octane
In analogy to Example 1(a), 6.25 g of 3,3-5 dimethyl-2-oxohept-5-ynephosphonic acid dimethyl ester/
3.7 g of N-bromosuccinimide> and 5.6 g of (1R>5Sf6R>7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo f 3.3.0]octane yield 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2940, 2878, 1710, 1688/ 1602, 1594, 1448, 10 1270, 944 cm"1.
(b) (IR,5S,6R,7R) -7-Hydroxy-6-[(3S)-2-bromo-4 » 4-dimethyl-3-hydroxyoct-l-en-6-ynyl]bicyclo-[3.3.0J octan-3-one
In analogy to Example 1(b), 4 g of the ketone 15 prepared according to Example 4(a) yields* after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal splitting, 1.4 0 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3600, 3410 (broad), 2958; 2865, 1738,
2 0 1600 cm-1.
203115
(c) (lR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-
l(3 S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-
2-yloxy)oct-l-en-6-ynyl]bicyclo[3.3.0]octan-
3-one
In analogy to Example 1(c), 1.2 g of the diol produced according to Example 4(b) yields/ with dihydropyran/ 1.6 g of the title compound as an oil.
IR: 2942/ 2870, 1738/ 1450, 1132, 960 cm-1.
Example 5
(5E)-13/14-Didehydro-18»18,19/19-tetradehydro-16,16/20-trimethyl-6a-carbaprostaglandin 12
Analogously to Example 1/ 1 g of (IR,5S,6R/7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)non-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one yields 400 mg of (5E)-13>14-didehydro-18/18,19/19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin I2 11/15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3510 (broad)., 2940/ 2858/ 2220/ 1708 cm"1.
After splitting off the blocking groups according to Example 1/ 410 mg of the title compound is obtained as a colorless oil.
IR: 3600/ 3340 (broad), 2940/ 2832/ 2220, 1708/
1600 cm-1.
_ 27 _
203115
The starting material for the above title compound is prepared as follows:
(a) (1R# 5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy-6-(2-bromo-4,4-dimethyl-3-oxonon-l-en-6-ynyl)-
bicyclo13.3.0]octane
In analogy to Example 1(a), 12.6 g of 3,3-dimethyl-2-oxooct-5-ynylphosphonic acid dimethyl ester, 7.4 g of N-bromosuccinimide, and 11.2 g of (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane /• 10 yield 8.7 g of the unsaturated ketone as a colorless oil.
IR: 2946, 2880, 1712, 1687, 1601, 1594, 1272,
948 cm
(b) (lR,5S,6R,7R)-7-Hydroxy-6-[(3S)-2-bromo-4,4-dimethyl-3-hydroxynon-l-en-6-ynyl]bicyclo-
[3.3.0]octan-3-one
Analogously to Example 1(b), 5 g of the ketone produced according to Example 5(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal splitting, 1.80 g of the ^ 20 title compound (15a-hydroxy) as a colorless oil.
IR: 3600, 3404 (broad), 2958, 2864, 1738,
1601 cm"1.
w
_ 28 -
203115
(c) (IR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-
| (3S) -2-bromo-4,4-dimethyl-3- (tetrahydropvran-
2-yloxy)non-1-en-6-ynyl]bicyclo[3.3.0]octan-
3-one
In analogy to Example 1(c), 1.5 g of the diol prepared according to Example 5(b) produces 2.20 g of the title compound as a colorless oil.
IR: 2942, 2878, 1738, 1125, 968 cm"1.
Example 6
(5E)-13114-Didehydro-18 >18,19,19-tetradehydro-6a-
carbaprostaglandin I2
Analogously to Example 1, 400 mg of (IR,5S#6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydro-pyran-2-yloxy)oct-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one yields 130 mg of (5E)-13,14-didehydro-18,18,19,19-tetra-dehydro-6a-carbaprostaglandin 11>15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2948, 2862, 2226, 1708 cm-1. After splitting off the blocking groups as described in Example 1, 62 mg of the title compound is obtained as a colorless oil.
IR: 3610, 3350 (broad), 2930, 2862, 2226, 1709,
1600 cm-1.
203115
The starting material for the above title compound is produced as follows:
(a) (IR,5S, 6R, 7R)-3, 3-Ethylenedioxy-7-benzoyloxy-6-(2-bromo-3-oxooct-l-en-6-ynyl)bicyclo[3.3.0]-octane
Analogously to Example 1(a), 5.8 g of 2-oxo-hept-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromo-succinimide, and 5.6 g of (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane yield 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2932, 2880, 1712, 1688, 1600, 1592, 1272,
948 cm 1.
(b) (IR,5S> 6R,7R)-7-Hydroxy-6-[(3S)-2-bromo-3-hydroxyoct-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one
Analogously to Example 1(b), 4 g of the ketone prepared according to Example 6(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal cleavage, 1.35 g of the title compound as a colorless oil.
IR: 3600, 3410 (broad), 2962, 2866, 1740, 1601 cm"1.
2 03 1 1
(c) (IR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-
6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl]bicyclo[3.3.0]octan-3-one
In analogy to Example 1(c), 1.20 g of the diol prepared according to Example 6(b) yields, with dihydro-pyran, 1.61 g of the title compound as a colorless oil. IR: 2945, 2882, 1739, 1125, 968 cm"1.
Example 7
(5E)-(16RS)-13,14-Didehydro-16-methyl-18 ,18,19,19-tetradehydro-6a-carbaprostaglandin I^ Tris(hydroxymethyl)aminomethane Salt
At 65° C, a solution of 121 mg of tris(hydroxymethyl ) aminomethane in 0.4 ml of water is addod to a solution of 358 mg of (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 in 60 ml of acetonitrile. The mixture is allowed to cool under agitation, decanted from the solvent after 16 hours, and the residue is dried at 25° C and 0.1 torr, thus obtaining 310 mg of the title compound as a waxy mass.
2031.15
. 31+.
Claims (10)
1. Carbacyclin derivatives of general Formula I wherein R1# R2j R3> R4 represent a hydrogen atom or an alkyl group of 1-5 carbon atomst R5 is an alkyl group of 1-5 carbon atoms, as well as the salts thereof with physiologically compatible bases.
2. (5E)-(16RS)-13/14-Didehydro-16-methyl-18,18/19,19-tetradehydro-6a-carbaprostaglandin I2. iV % (22 JfiNmg - 32- 203115
3. (5E)-(16RS)-13/14-Didehydro-l§ t20-dimethyl-18/18,19,19-tetradehydro-6a-carbaprostaglandin I2.
4. (5E)-(16RS)-20-Ethyl-13,14-didehydro-16-methyl-18,18*19,19-tetradehydro-6a-carbaprostaglandin I2•
5. (5E)-13/14-Didehydro-16 116-dimethyl-18,18/19/19-tetradehydro-6a-carbaprostaglandin I2.
6. (5E)-13/14-Didehydro-18,18/19/19-tetradehydro-16/16,20-trimethyl-6a-carbaprostaglandin I2•
7. (5E)-13 >14-Didehydro-18/18/19 >19-tetradehydro-6a-carbaprostaglandin I2-
8. (5E)-(16RS) -13 >14-Didehydro-16-methyl-18,18/19/19-tetradehydro-6a-carbaprostaglandin I2 tris(hydroxymethyl)aminomethane salt.
9. Process for the preparation of the carbacyclin derivatives of general Formula I> characterized by reacting a compound of general Formula II 0 (II) H=CBr-CH— 5 OTHP OTHP - 33 - 203125 wherein c in claw I Rl# R2# R3' R4' R5 have the meanings given^abovot and THP means the tetrahydropyranyl residue* with a Wittig reagent of Formula III PV»P=CH-(CH_) ,-C^ <=> (III), 3 ^ > ^-0 wherein Ph is a phenyl group* and subsequently separating isomers* splitting off blocking groups* and optionally converting the carboxy group into a salt with a physiologically compatible base.
10. Medicinal agents* consisting of one or more compounds of claim 1 and conventional auxiliary agents and excipients. SCHERING AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED BY!
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823204443 DE3204443A1 (en) | 1982-02-08 | 1982-02-08 | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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| EP (1) | EP0086404B1 (en) |
| JP (1) | JPH0611728B2 (en) |
| AT (1) | ATE24487T1 (en) |
| AU (1) | AU567867B2 (en) |
| CA (1) | CA1215362A (en) |
| CS (1) | CS235307B2 (en) |
| DD (1) | DD207901A5 (en) |
| DE (2) | DE3204443A1 (en) |
| DK (1) | DK156563C (en) |
| ES (1) | ES8400384A1 (en) |
| FI (1) | FI78064C (en) |
| GR (1) | GR77967B (en) |
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| IL (1) | IL67839A0 (en) |
| NO (1) | NO155729C (en) |
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| DE3408699A1 (en) * | 1984-03-08 | 1985-09-12 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US4927963A (en) * | 1989-04-28 | 1990-05-22 | Syntex (U.S.A.) Inc. | Novel processes for the synthesis of certain bicyclo(4.2.0)octane derivatives with valuable therapeutic properties |
| DE4135193C1 (en) * | 1991-10-22 | 1993-03-11 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De |
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| CA1201712A (en) * | 1980-02-28 | 1986-03-11 | Paul A. Aristoff | Carbacyclin analogs |
| DE3104044A1 (en) * | 1981-02-02 | 1982-08-26 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW PROSTACYCLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
-
1982
- 1982-02-08 DE DE19823204443 patent/DE3204443A1/en not_active Withdrawn
-
1983
- 1983-01-17 SU SU833534779A patent/SU1145926A3/en active
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| Publication number | Publication date |
|---|---|
| ES519627A0 (en) | 1983-11-16 |
| FI78064B (en) | 1989-02-28 |
| EP0086404B1 (en) | 1986-12-30 |
| CS235307B2 (en) | 1985-05-15 |
| NO830399L (en) | 1983-08-09 |
| IE830246L (en) | 1983-08-08 |
| DE3368609D1 (en) | 1987-02-05 |
| ES8400384A1 (en) | 1983-11-16 |
| GR77967B (en) | 1984-09-25 |
| EP0086404A1 (en) | 1983-08-24 |
| FI830414A0 (en) | 1983-02-07 |
| JPS58146531A (en) | 1983-09-01 |
| ATE24487T1 (en) | 1987-01-15 |
| CA1215362A (en) | 1986-12-16 |
| FI830414L (en) | 1983-08-09 |
| DK156563C (en) | 1990-01-29 |
| JPH0611728B2 (en) | 1994-02-16 |
| AU1118083A (en) | 1983-08-18 |
| ZA83851B (en) | 1983-10-26 |
| FI78064C (en) | 1989-06-12 |
| DK52383D0 (en) | 1983-02-08 |
| SU1145926A3 (en) | 1985-03-15 |
| DK156563B (en) | 1989-09-11 |
| DD207901A5 (en) | 1984-03-21 |
| NO155729B (en) | 1987-02-09 |
| IL67839A0 (en) | 1983-06-15 |
| DE3204443A1 (en) | 1983-08-18 |
| DK52383A (en) | 1983-08-09 |
| AU567867B2 (en) | 1987-12-10 |
| NO155729C (en) | 1987-05-20 |
| IE54554B1 (en) | 1989-11-22 |
| HU191197B (en) | 1987-01-28 |
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