CA1275093A - Carbacyclins, processes for their manufacture and their use as pharmaceuticals - Google Patents
Carbacyclins, processes for their manufacture and their use as pharmaceuticalsInfo
- Publication number
- CA1275093A CA1275093A CA000487598A CA487598A CA1275093A CA 1275093 A CA1275093 A CA 1275093A CA 000487598 A CA000487598 A CA 000487598A CA 487598 A CA487598 A CA 487598A CA 1275093 A CA1275093 A CA 1275093A
- Authority
- CA
- Canada
- Prior art keywords
- group
- atoms
- hydrogen
- alkyl
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- -1 hydroxymethylene group Chemical group 0.000 claims abstract description 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 150000003839 salts Chemical group 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical class C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 238000006266 etherification reaction Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 235000013350 formula milk Nutrition 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000036772 blood pressure Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 210000001772 blood platelet Anatomy 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101100310593 Candida albicans (strain SC5314 / ATCC MYA-2876) SOD4 gene Proteins 0.000 description 3
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 description 3
- 101100190148 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PGA2 gene Proteins 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 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 3
- 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
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940076134 benzene Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- 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
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/62—Unsaturated compounds containing ether groups, groups, groups, or groups containing rings other than six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to carbacylin derivatives with the general formula I:
I, where n is 1 or ?d R1 represents the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a hydroxymethylene group or group where the OH group is in the .alpha. - or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms, or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C- group ?esents an alkyl group with 1 to 4 C-atoms, and R5 repre? a hydroxy group and, when R2 represents a hydrogen atom and its salts with physiologically tolerable bases.
For its preparation a compound of the general formula II, II
where R4, R5 R9, A, W, Y, D and E have the significance as quoted above, by reaction with a halogen alkane derivative with the general formula III
The invention relates to carbacylin derivatives with the general formula I:
I, where n is 1 or ?d R1 represents the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a hydroxymethylene group or group where the OH group is in the .alpha. - or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms, or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C- group ?esents an alkyl group with 1 to 4 C-atoms, and R5 repre? a hydroxy group and, when R2 represents a hydrogen atom and its salts with physiologically tolerable bases.
For its preparation a compound of the general formula II, II
where R4, R5 R9, A, W, Y, D and E have the significance as quoted above, by reaction with a halogen alkane derivative with the general formula III
Description
~ 7 ~
The invention relates to new carbacyclin derivatives, processes for their manufacture and their use as pharmaceuticals.
In U.S. patent 4,~20,632 9-alkylated carbacyclin derivatives are described which possess ant:ithrombosis, antisecretion and bronchiodilatory properties. In addition they have thrombocyte aggregation inhibiting effect. It was found that by replacement of the methylene group in the 3-position of these carbacyclins by oxygen or by extension of the chain in the 9-position hiologically active derivatives are produced which are effective for a longer period of time, have greater selectlvity and possess better efficacy. Derivatives with extended chains in the s-pOsitiOn can be linked to polymeric carriers with only slight loss of biological activity. The compounds in accordance with the invention act in a bronchiodilatry manner and are suitable for inhibiting thrombocyte aggregation, for lowering blood pressure by a process of vasodilation and for :Lnhibiting gastric acid secretion.
The present invention thus provides carbacyclin derivatives with the general formula I:
~fll2~n~Rl ~.
Ii~2 C-~' ~ ~
~""s ~ 1, R g ~ A-W-D-E-R~
wherein n is 1 or 3 and Rl repressnts the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, Rg represents an alkyl group with 1 to 10 C-atoms or the group -C_C(CH2)m-R6 where m is a numbsr from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans- -CH=CH- or .i ..
~ 3 -C_C-group, W is a hydroxymethylene group or ~H3 OH
group where the OH group is in the ~ - or ~ -position, D is a straight-chain saturated alkylene group with 1 to 5 C-a-toms or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C C group, R~ represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hydrogen atom, its salts with physiologically tolerable bases.
Compounds conforming to formula I repres~nt both (5E) and (5Z)-isomers.
Alkyl groups R2 are straight or branched chain alkyl groups with 1 to 4 C-atoms such as, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary butyl.
Alkylene groups D are straight-chain or branched chain, satura-ted alkylene radicals, with up to 5 C-atoms such as, 1,2-methylene, 1,1-tri-methylene, 1,1-tetramethylene or 1,1-pentamethylene. For example, mention may be made of methylene, ethylene, 1,2-propylene~ ethylethylene, trimethylene, tetramethylene, pentamethylene, l-methyltetramethylene, l-methyltetramethylene, l-methyltrimethylene.
The groups already given for R4 can be taken into conslderation as the alkyl groups R9 with 1 to 10 C-atoms.
For salt formation with the free acids ~R2=H), inorganic and organic bases are suitable such as are familiar to the expert for formation of physiological tolerable salts. For example, mention may be made of the following: alkali hydroxides such as calcium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, and tris-~hydroxymekhyl)-methylamine.
rq~
1~
75~
The Invent/on fwrther provldes a process for the manu-facture of carbacyc/Ins of the general formula I where X Is an oxygen atom, In whlch a compound of the general formula T~, ~
~ 7 , I T
where R4, R5, Rg, A, W, Y, D and E have the slgnlflcance as quoted above, posslbly after protectlon of any free hydroxy groups present by means of a halogen alkane ac/d derlvatlve wlth the general formula lll, fla l - (Crl2 ) -C
OT1~3 III
where n Is 1 or 3, Hal Is a chlorlne or bromlne atom and R~ Is an alkyl radlcal wlth 1 to 4 C-atoms or an alkall metal, Is etherl-fled In the presence of a base, and Isomers are, as requlred, subsequently separated In any requlred order and/or protected hydroxy yroups are freed and/or free hydroxy groups are esterl-- fled, e~herlfled and/or a free carboxyl group Is esterlfled and/or an esterlfled carboxyl group Is saponlfled or a carboxyl group Is converted Into an amlde or converted Into a salt wlth a phys/ologlcally tolerable base.
~' ~ Reactlon of the compound of general formula ~ wlth a halogen alkane acld derlvatlve of the general formula~ Is car-rled out at ternperatures between 0C and 100C, preferably between 10C and 80C In an aprotlc solvent or mlxtures of so/-vents, for example, dlmethyl sulfoxlde, dlemthylformamlde, and tetrahydrofuran. Posslble bases are those whlch are ~amlllar to the expert for etherlflcatlon~ for example, sodlum hydrlde, potasslum tert.-butylate and butyl llthlum.
Saponlflcatlon of the carbacyclln ester Is carrled out by methods well-known to the expert such as for examp/e wlth ~7~ 3 baslc catalysts.
The ester group COOR2 ~or R1, where R2 represents an alkyl group wlth 1 to 4 C-atoms, Is Introduced by methods we/l-known to the expert. The carboxy compounds are converted forexample wlth dlazo hydrocarbons In a conventlonal manner. Ester-Iflcatlon wlth dlazo hydrocarbons takes place for exampl0 by mlx-lng a solutlon of the dlazo hydrocarbon In an Inert solvent, prefarably In dlethyl ether, wlth the carboxy compound In the same or In a dlfferent Inert solvent such as, for example, methy-lene chlorlde After completlon of the reactlon after 1 to 30 . mlnutes the solvent Is removed and the ester /s purlfled by nor-mal methods. Dlazo alkanes are already known In the art or can be manufactured by well-known methods ~Org, Reactlons Vo/. 8, Pages 389-394 (1954)7-Carbacyclln derlvatlves of the general formula I wlth R1 belng a carboxyl group can be converted Into salts uslng sult-able quantltles of the correspondlng Inorganlc bases wlth accom-panylng neura/Isatlon, For example, on dlssolutlon of the corre-spondlng PG aclds In water contalnlng the stolchlometrlc quantlty of the base the solld Inorganlc salt Is obtalned after evapora-tlon of the water or after addltlon of a solvent mlsclble wlth water, for example, alcoho/ or acetone.
The amlne salts are prepared In a conventlonal manner.
For thls purpose the PG acld Is, for examPle, dlssolved In a sultable solvent such as ethanol, acetone, dlethyl ether or ben-zene and at least the stolchlometrlc quantlty of the am/ne Is added to thls solvent. I~n thls connectlon the salt Is normally produced In a solld form or Is Isolated In a conventlonal way after evaporatlon of the solvent.
Functlonal modlflcatlon of the free 0~ groups takes p/ace by conventlonal methods. For Introductlot7 of tl~e ether protectlon groups the react/on /s carr/ed out e.g. wlth dlhy-dropyran In methylene chlorlde or chloroform wlth use of a n acld condensatlon agent swch as, e.g. p-toluene-sulfon/c acld. The dlhydropyran Is used In excess preferably wlth 4 to 10 t/mes the theoretlcally requlred amount. At 0C to 30C the reactlon Is normally completed after 15 to 30 mlnutes.
The acy/ protectlon group are Introduced by causlng a compound of the general formula I to react In a conventlonal man-ner wlth carboxyllc acld derlvatlve such as, for example, theacId chlorIde or the acId anhydrIde.
Freelng of a functlonally modlfled OH group In the com-pounds of general formula I takes p/ace by conventlonal methods.
For example, the spllttlng off of ether protectlon groups Is car-rled out In an aqueous solutlon of an organ/c acld such as acet/c acld or proplonlc ac/d, or In an aqueous solutlon of an Inorganlc acld such as, e.g. hydrochlorlc ac/d. To /mprove the solublllty, It Is conventlone to add an Inert organ/c so/vent mlsclble wlth O water. Sultable organlc solvents Include for example alcohols, such as methanol and ethanol, and ethers such as dlmethoxy-ethane, dloxane and terahydrofuran. Tetrahydrofuran Is used by preference. Spllt-off Is preferably carr/ed out at temperatures between 2QC and 80C.
The sllyl ether protectlve groups are spllt off for examp/e wlth tetrabutylammonlum fluorlde. The followln~ are for example sultable for use as so/vents: tetrahydrofuran, dlethyl ether, d/oxane, methylene chlorlde etc. The spllt-off react/on Is carr/ed out preferably at temperatures between 0C and 80C.
Saponlflcatlon of the acy/ groups Is carrled out for example wlth alkall or alkallne earth carbonates or hydroxldes In an alcohol or an aqueous solutlon of an alcohol. Posslble alco-hols are allphatlc alcohols suc/7 as, e.g. methanol, ethanol orbutanol etc., preferably methanol. As aIkall carbonates and ~7513~3 hydroxldes mentlon should be made of potasslum and sodlum salts, potasslum salts, however, belng preferred. The followlng are for example sultable as alkallne earth carbonates and hydroxldes:
calclum carbonate, calclum hydroxlde and barlum carbonate. The reactlon takes place at -10C to ~70C, preferably at 25C.
If the startlng product contaJns OH groups In the prostan radlcal these OH groups are also made to react. If In concluslon end products are requ/red whlch contaln hydroxyl groups In the prostan radlcal It ~s best to begln wlth startlng products In whlch these are preferably protected Intermedlarlly wlth easlly spllt-off ether or acy/ radlcals.
All the other compounds of formula I can be produced by processes as descrlbed In Patent Appllcatlons DE-OS Nos.
28 45 770, 32 37 200, 33 22 893 and 34 05 181. If the radlcal ~9 represents an alklnyl group, sald radlcal Rg can be Introduced by the method publIshed by R.T. Hansen et al. JACS, 100, 2244 ~ 1g78) .
The compounds In accordance wlth the Inventlon are sultable In partlcular for the treatment of dlsorders of the car-dlovascular system, the stomach, the pancreas, the l/ver and the kldneys. They have blood-pressure lowerlng and bronchlodl/atory effects. Furthermore they are sultable for Inhlbltlng thrombo-cyte aggregat/on. Thus these new carbacyclln derlvatlves of for-mula I represent valuable pharmaceutlcal agents. In addltlon, whlle exert/ng a slmllar prostaglandlns and prostacycllns they show hlgher speflclty and above all exhlblts /onger effectlve-ness. In compar/son to PGI2 they are marked by greater stabll-lty. The hlgh t/ssue speclf/clty of the new carbacycllns /s evl-dent In Investlgatlons on nonstrlated musc/e organs such as, e.g.
gu/nea plg l/eum or on Isolated rabblt trachea where far /ess stlmulatlon /s to be observed than on appllcatlon of natural prostaglandlns of the E, A or F type.
~1 ,~..~
The new carbacyclln analogues possess propertles typl-cal for prostacycllns, e.g. Iowerlng of the reslstance of the perlpheral arterles and coronary vessels, Inhlbltlon of thrombo-cyte aggregatlon and dlssolutlon of platelet clots, myocardlalcytoprotectlon, lowerlng of systemlc blood pressure wlthout slmultaneous lowerlng of the card/ac output and coronary clrcula-tlon; treatment of apoplexy , prophylaxls and therapy In the event of coronary heart dlseases, coronary thrombosls, myocardlal Infarctlon, perlphero-vascular dlseases, arteosclerosls and thrombosls; prophylaxls and therapy In the event of Ischaemlc attacks of the central nervous system, therapy In the vent of shock, Inhlbltlon of bronchlo-constrlctlon, Inhlbltlon of gastrlc acld secretlon and cytoprotectlon of the gastrlc and Intestlnal mucous membrane; cytoprotectlon In the llver, pancreas and kld-neys, antlallerglc propertles, lowerlng of the pulmonary vascular reslstance and of the pulmonary blood pressure, promotlon of kld-ney clrculatlon, use Instead of herapln or as an adJunct In dlal-ysls or hemoflltratlon, preservatlon of blood plasma, In partlcu-lar of blood platele~ preserves, Inhlbltlon of labour palns,treatment of pregnancy toxlcosls, Increase of cerebral clrcula-tlon, treatment of asthma etc. In addltlon the new carbacyclln analogues possess antlprollferatlve propertles. The new carbacy-cllns can In addltlon be used In comblnatlon for example wlth ~ -bloc~ers or dluretlcs.
The new carbacycllns are In addltlon marked by suppres-slon of reJectlon reactlons and by thelr antlmetastatlc effects.
As a result of thelr use, the ductus botalll Is l<ept open (prlor to operatlons). ~urthermore, they are sultable for treatment of dlarrhoea and for Improvement of bowel movements.
Carbacycllns of formu/a I, In whlch Rg slgnlfles the radlca/ -C-C~ (CH2)m~R6, wlth R6 represent/ng OH or NH2 groups can readlly be llnked to polymerlc carrlers wlthout great loss of blologlcal actlvlty. The new carbacycllns prohlblt thrombocyte ~7~
aggregates be/ng formed on the upper surface of these potymerlc carr/ers such as artlflclal blood vessels or artlflclal cardlac valves.
The dosage of such compounds Is 1-1500 ug/~g/day when admlnlstered to human patlents. The unlt dosage for the pharma-ceutlcally acceptable carrler amounts to 0.01-100 mg.
On Intravenous InJectlon In awake, hypertonlc rats In doses of 5, 20 and 100 ug/kg body welght, the compounds In accor-dance w/th the Inventlon exhlblt a marked blood-pressure lowerlng and longer lastlng effect than PGE2 and PGA2 wlthout as Is the case wlth PGE2 produclng dlarrhoea or wlth PGA2 cardlal arrhythmla.
On Intravenous InJectlon In narcotlzed rabblts the com-pounds In accordance wlth the Inventlon In comparlson wlth PGE2 and PGA2 exhlblt more pronounced and longer-lastlng blood-pres-sure lowerlng wlthout other nonstrlated musc/e organs or organ functlons belng affected.
For parenteral admlnlstratlon sterlle InJectable, aque-ous or oll solutlons are used. For oral appllcatlon tablets, coated tablets or capsules are sultable.
The Inventlon thus also relates to pharmaceut/ca/s based on compounds of the general formula I and normal auxlllary and carr/er substances.
The substances In accordance wlth the Inventlon are Intended to serve In comblnatlon wlth the auxlllary substances famlllar and normally encountered In galenlcs, e.g. for the manu-facture of blood-pressure lowerlng agents.
3~ The standard dosage range for ampou/es Is 0.1 to 0.
mg, for the tablets 0.1 - 1 mg.
~7~ 3 The present Inventlon wlll be further Illustrated by way of the followlng Examples.
, ~ methyl-7 CX-(tetrahydropyran-2-yl-oxy-6 ~-[3 ~ -(tetrahydropyr-an-2-yl-oxy)-4-methyl-~,7-tetradehydro-trans-1-octenyl~-blcyclo-[3.3.0~octane-3-one.
10To a suspenslon of 4.28 g (22.5 mmo/~ cUII In 25 ml of absolute ether, 27 ml of a 1,6 N methylllthlum solutlon In ether Is added carefully In drops at -5C whlle stlrrlng wlthln 15 mln-utes and to thls solutlon 2.21 g ~5-mmo/) of 7 ~ -(tetrahydro-yran-2-yl-oxy)-6 ~-~3 ~ -(tetrahydropyran-2-yl-oxy)-4-methyl-156,7-tetradehydro-trans-1-octenyl]-bl-cyclo[3.3.-Joct-1-ene-3-one ¢cf. ~Æ OS 31 42 733) In 20 ml-of ether Is slowly added In drops at -25C to -30C, 100 ml of N~14Cl solutlon Is added carefu/ly and the m/xture /s extracted wlth ether. After washlng wlth sat-urated common salt solutlon, 2.37 g of the crude product Is obtalned after drylng and evaporatlon and thls Is chromatographed on a column of 120 g slllca ge/. Elutlon wlth hexane ether (7:3) ylelded 1.54 g ~67%) of the above-named product.
The invention relates to new carbacyclin derivatives, processes for their manufacture and their use as pharmaceuticals.
In U.S. patent 4,~20,632 9-alkylated carbacyclin derivatives are described which possess ant:ithrombosis, antisecretion and bronchiodilatory properties. In addition they have thrombocyte aggregation inhibiting effect. It was found that by replacement of the methylene group in the 3-position of these carbacyclins by oxygen or by extension of the chain in the 9-position hiologically active derivatives are produced which are effective for a longer period of time, have greater selectlvity and possess better efficacy. Derivatives with extended chains in the s-pOsitiOn can be linked to polymeric carriers with only slight loss of biological activity. The compounds in accordance with the invention act in a bronchiodilatry manner and are suitable for inhibiting thrombocyte aggregation, for lowering blood pressure by a process of vasodilation and for :Lnhibiting gastric acid secretion.
The present invention thus provides carbacyclin derivatives with the general formula I:
~fll2~n~Rl ~.
Ii~2 C-~' ~ ~
~""s ~ 1, R g ~ A-W-D-E-R~
wherein n is 1 or 3 and Rl repressnts the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, Rg represents an alkyl group with 1 to 10 C-atoms or the group -C_C(CH2)m-R6 where m is a numbsr from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans- -CH=CH- or .i ..
~ 3 -C_C-group, W is a hydroxymethylene group or ~H3 OH
group where the OH group is in the ~ - or ~ -position, D is a straight-chain saturated alkylene group with 1 to 5 C-a-toms or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C C group, R~ represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hydrogen atom, its salts with physiologically tolerable bases.
Compounds conforming to formula I repres~nt both (5E) and (5Z)-isomers.
Alkyl groups R2 are straight or branched chain alkyl groups with 1 to 4 C-atoms such as, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary butyl.
Alkylene groups D are straight-chain or branched chain, satura-ted alkylene radicals, with up to 5 C-atoms such as, 1,2-methylene, 1,1-tri-methylene, 1,1-tetramethylene or 1,1-pentamethylene. For example, mention may be made of methylene, ethylene, 1,2-propylene~ ethylethylene, trimethylene, tetramethylene, pentamethylene, l-methyltetramethylene, l-methyltetramethylene, l-methyltrimethylene.
The groups already given for R4 can be taken into conslderation as the alkyl groups R9 with 1 to 10 C-atoms.
For salt formation with the free acids ~R2=H), inorganic and organic bases are suitable such as are familiar to the expert for formation of physiological tolerable salts. For example, mention may be made of the following: alkali hydroxides such as calcium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, and tris-~hydroxymekhyl)-methylamine.
rq~
1~
75~
The Invent/on fwrther provldes a process for the manu-facture of carbacyc/Ins of the general formula I where X Is an oxygen atom, In whlch a compound of the general formula T~, ~
~ 7 , I T
where R4, R5, Rg, A, W, Y, D and E have the slgnlflcance as quoted above, posslbly after protectlon of any free hydroxy groups present by means of a halogen alkane ac/d derlvatlve wlth the general formula lll, fla l - (Crl2 ) -C
OT1~3 III
where n Is 1 or 3, Hal Is a chlorlne or bromlne atom and R~ Is an alkyl radlcal wlth 1 to 4 C-atoms or an alkall metal, Is etherl-fled In the presence of a base, and Isomers are, as requlred, subsequently separated In any requlred order and/or protected hydroxy yroups are freed and/or free hydroxy groups are esterl-- fled, e~herlfled and/or a free carboxyl group Is esterlfled and/or an esterlfled carboxyl group Is saponlfled or a carboxyl group Is converted Into an amlde or converted Into a salt wlth a phys/ologlcally tolerable base.
~' ~ Reactlon of the compound of general formula ~ wlth a halogen alkane acld derlvatlve of the general formula~ Is car-rled out at ternperatures between 0C and 100C, preferably between 10C and 80C In an aprotlc solvent or mlxtures of so/-vents, for example, dlmethyl sulfoxlde, dlemthylformamlde, and tetrahydrofuran. Posslble bases are those whlch are ~amlllar to the expert for etherlflcatlon~ for example, sodlum hydrlde, potasslum tert.-butylate and butyl llthlum.
Saponlflcatlon of the carbacyclln ester Is carrled out by methods well-known to the expert such as for examp/e wlth ~7~ 3 baslc catalysts.
The ester group COOR2 ~or R1, where R2 represents an alkyl group wlth 1 to 4 C-atoms, Is Introduced by methods we/l-known to the expert. The carboxy compounds are converted forexample wlth dlazo hydrocarbons In a conventlonal manner. Ester-Iflcatlon wlth dlazo hydrocarbons takes place for exampl0 by mlx-lng a solutlon of the dlazo hydrocarbon In an Inert solvent, prefarably In dlethyl ether, wlth the carboxy compound In the same or In a dlfferent Inert solvent such as, for example, methy-lene chlorlde After completlon of the reactlon after 1 to 30 . mlnutes the solvent Is removed and the ester /s purlfled by nor-mal methods. Dlazo alkanes are already known In the art or can be manufactured by well-known methods ~Org, Reactlons Vo/. 8, Pages 389-394 (1954)7-Carbacyclln derlvatlves of the general formula I wlth R1 belng a carboxyl group can be converted Into salts uslng sult-able quantltles of the correspondlng Inorganlc bases wlth accom-panylng neura/Isatlon, For example, on dlssolutlon of the corre-spondlng PG aclds In water contalnlng the stolchlometrlc quantlty of the base the solld Inorganlc salt Is obtalned after evapora-tlon of the water or after addltlon of a solvent mlsclble wlth water, for example, alcoho/ or acetone.
The amlne salts are prepared In a conventlonal manner.
For thls purpose the PG acld Is, for examPle, dlssolved In a sultable solvent such as ethanol, acetone, dlethyl ether or ben-zene and at least the stolchlometrlc quantlty of the am/ne Is added to thls solvent. I~n thls connectlon the salt Is normally produced In a solld form or Is Isolated In a conventlonal way after evaporatlon of the solvent.
Functlonal modlflcatlon of the free 0~ groups takes p/ace by conventlonal methods. For Introductlot7 of tl~e ether protectlon groups the react/on /s carr/ed out e.g. wlth dlhy-dropyran In methylene chlorlde or chloroform wlth use of a n acld condensatlon agent swch as, e.g. p-toluene-sulfon/c acld. The dlhydropyran Is used In excess preferably wlth 4 to 10 t/mes the theoretlcally requlred amount. At 0C to 30C the reactlon Is normally completed after 15 to 30 mlnutes.
The acy/ protectlon group are Introduced by causlng a compound of the general formula I to react In a conventlonal man-ner wlth carboxyllc acld derlvatlve such as, for example, theacId chlorIde or the acId anhydrIde.
Freelng of a functlonally modlfled OH group In the com-pounds of general formula I takes p/ace by conventlonal methods.
For example, the spllttlng off of ether protectlon groups Is car-rled out In an aqueous solutlon of an organ/c acld such as acet/c acld or proplonlc ac/d, or In an aqueous solutlon of an Inorganlc acld such as, e.g. hydrochlorlc ac/d. To /mprove the solublllty, It Is conventlone to add an Inert organ/c so/vent mlsclble wlth O water. Sultable organlc solvents Include for example alcohols, such as methanol and ethanol, and ethers such as dlmethoxy-ethane, dloxane and terahydrofuran. Tetrahydrofuran Is used by preference. Spllt-off Is preferably carr/ed out at temperatures between 2QC and 80C.
The sllyl ether protectlve groups are spllt off for examp/e wlth tetrabutylammonlum fluorlde. The followln~ are for example sultable for use as so/vents: tetrahydrofuran, dlethyl ether, d/oxane, methylene chlorlde etc. The spllt-off react/on Is carr/ed out preferably at temperatures between 0C and 80C.
Saponlflcatlon of the acy/ groups Is carrled out for example wlth alkall or alkallne earth carbonates or hydroxldes In an alcohol or an aqueous solutlon of an alcohol. Posslble alco-hols are allphatlc alcohols suc/7 as, e.g. methanol, ethanol orbutanol etc., preferably methanol. As aIkall carbonates and ~7513~3 hydroxldes mentlon should be made of potasslum and sodlum salts, potasslum salts, however, belng preferred. The followlng are for example sultable as alkallne earth carbonates and hydroxldes:
calclum carbonate, calclum hydroxlde and barlum carbonate. The reactlon takes place at -10C to ~70C, preferably at 25C.
If the startlng product contaJns OH groups In the prostan radlcal these OH groups are also made to react. If In concluslon end products are requ/red whlch contaln hydroxyl groups In the prostan radlcal It ~s best to begln wlth startlng products In whlch these are preferably protected Intermedlarlly wlth easlly spllt-off ether or acy/ radlcals.
All the other compounds of formula I can be produced by processes as descrlbed In Patent Appllcatlons DE-OS Nos.
28 45 770, 32 37 200, 33 22 893 and 34 05 181. If the radlcal ~9 represents an alklnyl group, sald radlcal Rg can be Introduced by the method publIshed by R.T. Hansen et al. JACS, 100, 2244 ~ 1g78) .
The compounds In accordance wlth the Inventlon are sultable In partlcular for the treatment of dlsorders of the car-dlovascular system, the stomach, the pancreas, the l/ver and the kldneys. They have blood-pressure lowerlng and bronchlodl/atory effects. Furthermore they are sultable for Inhlbltlng thrombo-cyte aggregat/on. Thus these new carbacyclln derlvatlves of for-mula I represent valuable pharmaceutlcal agents. In addltlon, whlle exert/ng a slmllar prostaglandlns and prostacycllns they show hlgher speflclty and above all exhlblts /onger effectlve-ness. In compar/son to PGI2 they are marked by greater stabll-lty. The hlgh t/ssue speclf/clty of the new carbacycllns /s evl-dent In Investlgatlons on nonstrlated musc/e organs such as, e.g.
gu/nea plg l/eum or on Isolated rabblt trachea where far /ess stlmulatlon /s to be observed than on appllcatlon of natural prostaglandlns of the E, A or F type.
~1 ,~..~
The new carbacyclln analogues possess propertles typl-cal for prostacycllns, e.g. Iowerlng of the reslstance of the perlpheral arterles and coronary vessels, Inhlbltlon of thrombo-cyte aggregatlon and dlssolutlon of platelet clots, myocardlalcytoprotectlon, lowerlng of systemlc blood pressure wlthout slmultaneous lowerlng of the card/ac output and coronary clrcula-tlon; treatment of apoplexy , prophylaxls and therapy In the event of coronary heart dlseases, coronary thrombosls, myocardlal Infarctlon, perlphero-vascular dlseases, arteosclerosls and thrombosls; prophylaxls and therapy In the event of Ischaemlc attacks of the central nervous system, therapy In the vent of shock, Inhlbltlon of bronchlo-constrlctlon, Inhlbltlon of gastrlc acld secretlon and cytoprotectlon of the gastrlc and Intestlnal mucous membrane; cytoprotectlon In the llver, pancreas and kld-neys, antlallerglc propertles, lowerlng of the pulmonary vascular reslstance and of the pulmonary blood pressure, promotlon of kld-ney clrculatlon, use Instead of herapln or as an adJunct In dlal-ysls or hemoflltratlon, preservatlon of blood plasma, In partlcu-lar of blood platele~ preserves, Inhlbltlon of labour palns,treatment of pregnancy toxlcosls, Increase of cerebral clrcula-tlon, treatment of asthma etc. In addltlon the new carbacyclln analogues possess antlprollferatlve propertles. The new carbacy-cllns can In addltlon be used In comblnatlon for example wlth ~ -bloc~ers or dluretlcs.
The new carbacycllns are In addltlon marked by suppres-slon of reJectlon reactlons and by thelr antlmetastatlc effects.
As a result of thelr use, the ductus botalll Is l<ept open (prlor to operatlons). ~urthermore, they are sultable for treatment of dlarrhoea and for Improvement of bowel movements.
Carbacycllns of formu/a I, In whlch Rg slgnlfles the radlca/ -C-C~ (CH2)m~R6, wlth R6 represent/ng OH or NH2 groups can readlly be llnked to polymerlc carrlers wlthout great loss of blologlcal actlvlty. The new carbacycllns prohlblt thrombocyte ~7~
aggregates be/ng formed on the upper surface of these potymerlc carr/ers such as artlflclal blood vessels or artlflclal cardlac valves.
The dosage of such compounds Is 1-1500 ug/~g/day when admlnlstered to human patlents. The unlt dosage for the pharma-ceutlcally acceptable carrler amounts to 0.01-100 mg.
On Intravenous InJectlon In awake, hypertonlc rats In doses of 5, 20 and 100 ug/kg body welght, the compounds In accor-dance w/th the Inventlon exhlblt a marked blood-pressure lowerlng and longer lastlng effect than PGE2 and PGA2 wlthout as Is the case wlth PGE2 produclng dlarrhoea or wlth PGA2 cardlal arrhythmla.
On Intravenous InJectlon In narcotlzed rabblts the com-pounds In accordance wlth the Inventlon In comparlson wlth PGE2 and PGA2 exhlblt more pronounced and longer-lastlng blood-pres-sure lowerlng wlthout other nonstrlated musc/e organs or organ functlons belng affected.
For parenteral admlnlstratlon sterlle InJectable, aque-ous or oll solutlons are used. For oral appllcatlon tablets, coated tablets or capsules are sultable.
The Inventlon thus also relates to pharmaceut/ca/s based on compounds of the general formula I and normal auxlllary and carr/er substances.
The substances In accordance wlth the Inventlon are Intended to serve In comblnatlon wlth the auxlllary substances famlllar and normally encountered In galenlcs, e.g. for the manu-facture of blood-pressure lowerlng agents.
3~ The standard dosage range for ampou/es Is 0.1 to 0.
mg, for the tablets 0.1 - 1 mg.
~7~ 3 The present Inventlon wlll be further Illustrated by way of the followlng Examples.
, ~ methyl-7 CX-(tetrahydropyran-2-yl-oxy-6 ~-[3 ~ -(tetrahydropyr-an-2-yl-oxy)-4-methyl-~,7-tetradehydro-trans-1-octenyl~-blcyclo-[3.3.0~octane-3-one.
10To a suspenslon of 4.28 g (22.5 mmo/~ cUII In 25 ml of absolute ether, 27 ml of a 1,6 N methylllthlum solutlon In ether Is added carefully In drops at -5C whlle stlrrlng wlthln 15 mln-utes and to thls solutlon 2.21 g ~5-mmo/) of 7 ~ -(tetrahydro-yran-2-yl-oxy)-6 ~-~3 ~ -(tetrahydropyran-2-yl-oxy)-4-methyl-156,7-tetradehydro-trans-1-octenyl]-bl-cyclo[3.3.-Joct-1-ene-3-one ¢cf. ~Æ OS 31 42 733) In 20 ml-of ether Is slowly added In drops at -25C to -30C, 100 ml of N~14Cl solutlon Is added carefu/ly and the m/xture /s extracted wlth ether. After washlng wlth sat-urated common salt solutlon, 2.37 g of the crude product Is obtalned after drylng and evaporatlon and thls Is chromatographed on a column of 120 g slllca ge/. Elutlon wlth hexane ether (7:3) ylelded 1.54 g ~67%) of the above-named product.
2~3-oxa-9 ~-methyl-16-methyl-18,19-tetradehydro-carbacy-clln.
The 5-rlng ketone descrlbed In Example 1 Is caused to react In accordance wlth EP 55208 wlth dlmethoxyphophono-methyl-acetate In the presence of potasslum tert.-butylate, then reduced wlth llthlum alumlnum hydrlde and the E-conflgurated alkyl a/co-hol Is flnally converted wlth ~ or esters of the 2-chloro or 2-bromo-acet/c acld In the presence of bases wlth subsequent spllt-off of the tetrahydropyranyl protect/ve groUp to form 3-oxa-9 ~-methyl-16-methyl-18,19-tetrahydro-carbacyclln.
~ 9 ~
The 5-rlng ketone descrlbed In Example 1 Is caused to react In accordance wlth EP 55208 wlth dlmethoxyphophono-methyl-acetate In the presence of potasslum tert.-butylate, then reduced wlth llthlum alumlnum hydrlde and the E-conflgurated alkyl a/co-hol Is flnally converted wlth ~ or esters of the 2-chloro or 2-bromo-acet/c acld In the presence of bases wlth subsequent spllt-off of the tetrahydropyranyl protect/ve groUp to form 3-oxa-9 ~-methyl-16-methyl-18,19-tetrahydro-carbacyclln.
~ 9 ~
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of carbacyclins of the general formula I
I, wherein n is 1 or 3 and R1 represents the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans -CH=CH- or -C?C- group, W is a hydroxymethylene group or group where the OH group is in the ? - or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms,or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hydrogen atom, its salts with physiologically tolerable bases, in which a compound of the general formula II, where R4, R5, R9 A, W, Y, D and E have the significance as quoted above, by reaction with a halogen alkane derivative with the general formula III
III
wherein n is 1 or 3, Hal is a chlorine or bromine atom and R8 is an alkyl radical with 1 to 4 C-atoms or an alkail metal is etherified in the presence of a base, and isomers are, when required, subsequently separated in any required order and/or protected hydroxy groups are freed and/or free hydroxy groups are esterified, etherified and/or a free carboxyl group is esterified and/or an esterified carboxy group is saponified or a carboxy group is converted into an amide or converted into a salt by means of a physiologically tolerable base.
I, wherein n is 1 or 3 and R1 represents the group COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y is hydrogen, A is a trans -CH=CH- or -C?C- group, W is a hydroxymethylene group or group where the OH group is in the ? - or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms,or a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hydrogen atom, its salts with physiologically tolerable bases, in which a compound of the general formula II, where R4, R5, R9 A, W, Y, D and E have the significance as quoted above, by reaction with a halogen alkane derivative with the general formula III
III
wherein n is 1 or 3, Hal is a chlorine or bromine atom and R8 is an alkyl radical with 1 to 4 C-atoms or an alkail metal is etherified in the presence of a base, and isomers are, when required, subsequently separated in any required order and/or protected hydroxy groups are freed and/or free hydroxy groups are esterified, etherified and/or a free carboxyl group is esterified and/or an esterified carboxy group is saponified or a carboxy group is converted into an amide or converted into a salt by means of a physiologically tolerable base.
2. A process according to claim 1, in which any free hydroxy groups present are protected and after the etherification the hydroxy groups are regenerated.
3. A process according to claim 1 or 2, in which D is selected from methylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene and 1-methyltrimethylene.
4. Carbacyclin derivatives with the general formula I:
I, wherein n is 1 or 3 and R1 represents the groups COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y
is hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a hydroxymethylene group or group where the OH group is in the .alpha.- or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms, is a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hdyrogen atom, its salts with physiologically tolerable base.
I, wherein n is 1 or 3 and R1 represents the groups COOR2 where R2 is hydrogen or an alkyl with 1 to 4 C-atoms, R9 represents an alkyl group with 1 to 10 C-atoms or the group -C?C(CH2)m-R6 where m is a number from 1 to 8 and R6 is hydrogen, hydroxy or amino, Y
is hydrogen, A is a trans- -CH=CH- or -C?C-group, W is a hydroxymethylene group or group where the OH group is in the .alpha.- or .beta. -position, D is a straight-chain saturated alkylene group with 1 to 5 C-atoms, is a branched chain saturated alkylene group with 2 to 5 C-atoms, E is a -C?C group, R4 represents an alkyl group with 1 to 4 C-atoms, and R5 represents a hydroxy group and, when R2 represents a hdyrogen atom, its salts with physiologically tolerable base.
5. A compound according to claim 4, in which D is selected from methylene, ethylene, 1,2-propylene, ethylethylene, , trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, and 1-methyltrimethylene.
6. 3-Oxa-9-methyl-16-methyl-18,19-tetradehydro-carbacyclin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3428266A DE3428266A1 (en) | 1984-07-27 | 1984-07-27 | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DEP3428266.1 | 1984-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1275093A true CA1275093A (en) | 1990-10-09 |
Family
ID=6242048
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000487598A Expired CA1275093A (en) | 1984-07-27 | 1985-07-26 | Carbacyclins, processes for their manufacture and their use as pharmaceuticals |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0190233B1 (en) |
| JP (1) | JPS61502823A (en) |
| AT (1) | ATE83232T1 (en) |
| AU (1) | AU588543B2 (en) |
| CA (1) | CA1275093A (en) |
| DE (2) | DE3428266A1 (en) |
| DK (1) | DK119886A (en) |
| ES (1) | ES8606841A1 (en) |
| GR (1) | GR851843B (en) |
| HU (1) | HU196175B (en) |
| WO (1) | WO1986000895A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3542745A1 (en) * | 1985-11-29 | 1987-08-06 | Schering Ag | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US4735966A (en) * | 1986-08-25 | 1988-04-05 | Syntex (U.S.A.) Inc. | Novel substituted (4.2.0)bicyclooctane derivatives with valuable therapeutic properties |
| US5374654A (en) * | 1987-07-24 | 1994-12-20 | Schering Aktiengesellschaft | 9-substituted carbacyclin derivatives, processes for their preparation, and their use as medicinal agents |
| DE3725031A1 (en) * | 1987-07-24 | 1989-02-02 | Schering Ag | NEW 9-SUBSTITUTED CARBACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE4134156A1 (en) * | 1991-10-11 | 1993-04-15 | Schering Ag | 9-SUBSTITUTED BICYCLO (3.3.0) OCTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2038333B (en) * | 1978-01-26 | 1982-10-06 | Erba Farmitalia | 12 -formyl- (20 12)octanor-9-deoxy-9 -methylene pgi derivatives |
| DE2845770A1 (en) * | 1978-10-19 | 1980-04-30 | Schering Ag | NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| CA1201712A (en) * | 1980-02-28 | 1986-03-11 | Paul A. Aristoff | Carbacyclin analogs |
| DE3048906A1 (en) * | 1980-12-19 | 1982-07-15 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US4533749A (en) * | 1982-02-16 | 1985-08-06 | The Upjohn Company | 9-Substituted carbacyclin analogs |
| US4487961A (en) * | 1982-02-16 | 1984-12-11 | The Upjohn Company | 9-Substituted carbacyclin analogs |
| HU190007B (en) * | 1982-05-06 | 1986-08-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | Process for producing new aromatic prostacylin analogues |
| JPS59141536A (en) * | 1983-02-01 | 1984-08-14 | Sumitomo Chem Co Ltd | Novel bicyclooctane derivative and preparation thereof |
| 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 |
-
1984
- 1984-07-27 DE DE3428266A patent/DE3428266A1/en not_active Ceased
-
1985
- 1985-07-18 WO PCT/DE1985/000246 patent/WO1986000895A1/en active IP Right Grant
- 1985-07-18 AT AT85903810T patent/ATE83232T1/en not_active IP Right Cessation
- 1985-07-18 HU HU853650A patent/HU196175B/en unknown
- 1985-07-18 AU AU46767/85A patent/AU588543B2/en not_active Ceased
- 1985-07-18 DE DE8585903810T patent/DE3586891D1/en not_active Expired - Fee Related
- 1985-07-18 JP JP60503488A patent/JPS61502823A/en active Pending
- 1985-07-18 EP EP85903810A patent/EP0190233B1/en not_active Expired - Lifetime
- 1985-07-25 GR GR851843A patent/GR851843B/el unknown
- 1985-07-26 ES ES545617A patent/ES8606841A1/en not_active Expired
- 1985-07-26 CA CA000487598A patent/CA1275093A/en not_active Expired
-
1986
- 1986-03-14 DK DK119886A patent/DK119886A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES545617A0 (en) | 1986-05-16 |
| ATE83232T1 (en) | 1992-12-15 |
| HU196175B (en) | 1988-10-28 |
| JPS61502823A (en) | 1986-12-04 |
| DE3428266A1 (en) | 1986-01-30 |
| ES8606841A1 (en) | 1986-05-16 |
| AU4676785A (en) | 1986-02-25 |
| EP0190233B1 (en) | 1992-12-09 |
| WO1986000895A1 (en) | 1986-02-13 |
| DK119886D0 (en) | 1986-03-14 |
| GR851843B (en) | 1985-11-26 |
| DK119886A (en) | 1986-03-14 |
| AU588543B2 (en) | 1989-09-21 |
| HUT39158A (en) | 1986-08-28 |
| EP0190233A1 (en) | 1986-08-13 |
| DE3586891D1 (en) | 1993-01-21 |
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Legal Events
| Date | Code | Title | Description |
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| MKLA | Lapsed |