Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
  • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
  • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to new prostaglandin derivatives of the formula I. wherein R 1 is hydrogen or lower alkyl; R 2 hydroxy; R 3 is hydrogen; or R 2 and R 3 together oxo; R 4 is hydrogen or lower alkyl; R 5 is fluorine, lower alkyl or trifluoromethyl; R 6 is hydrogen, fluorine or lower alkyl; R 7 Hydrogen; R 8 hydroxy; or R 7 and R 8 together oxo; A and B, and X and Y, on their own denote hydrogen or together a carbon-carbon bond; with the condition that R 2 and R 3 together are oxo when R 7 and R 8 are together oxo; and with the further condition that A and B represent hydrogen when R 7 is hydrogen; and with the third condition that X and Y represent a carbon-carbon bond when R 1 and R 7 are simultaneously hydrogen; their enantiomers and racemates.
• the invention further relates to a process for the preparation of prostaglandin derivatives of the formula. I and new intermediates that occur in this process.
• the invention further relates to new pharmaceutical preparations which contain prostaglandin derivatives of the formula I.
• lower alkyl used here refers to straight-chain or branched alkyl groups having 1 to 7 carbon atoms, such as methyl and ethyl.
• lower alkane carboxylic acid refers to alkane carboxylic acid with 1-7 C atoms such as formic acid and acetic acid.
• halogen or halo refers to fluorine, chlorine, bromine and iodine.
• all compounds with one or more asymmetric carbon atoms can be produced as Race. Mate. These racemates can be cleaved at a suitable point in the preparation by methods known per se, the corresponding optically pure enantiomers then being obtained as secondary products.
• the optically active enantiomers of the formula I can be prepared from optically active compounds of the formula II.
• a wedge-shaped line ( ⁇ ) means a substituent that is in the beta position (above the molecular level), a broken line (/////) denotes a substituent in the alpha position (below the molecular level).
• aryl denotes mononuclear aromatic hydrocarbon groups such as phenyl or tolyl which are unsubstituted or can be substituted in one or more positions with alkylenedioxy, halogen, nitro or lower alkoxy, as well as multinuclear aryl groups such as naphthyl, anthryl, phenanthryl and.Azulyl, which can be substituted with one or more of the aforementioned groups.
• Preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl.
• aryl, lower alkyl denotes groups in which aryl and lower alkyl are as defined above, in particular benzyl.
• hydrolyzable ester or ether group refers to any ester or ether group that is obtained by hydrolysis. can be converted into the hydroxy group of such .
• Ester phenomenon are those in which the acyl radical is' siner of a lower alkanoic acid Carbonic acid or aryl-lower alkanoic acid, phosphoric acid, carbonic acid or lower alkanedioic acid.
• ester groups can be formed from acid anhydrides and acid halides, in particular chlorides or bromides, the lower alkanecarboxylic anhydrides, for example acetic anhydride and caproic anhydride;
• Aryl-lower alkanoic anhydrides for example benzoic anhydride, lower alkanedioic anhydrides, for example succinic anhydride, and chloroformic acid star, for example trichloroethyl chloroformic acid esters, are preferred.
• a particularly suitable ether protecting group is, for example, tetrahydropyranylaether or 4-methoxy-5,6-dihydro-2H-pyranylaether.
• ethers are aryl methyl ethers, such as benzyl, benzhydryl or trityl ether, or a-lower alkoxy lower alkyl ethers, for example methoxymethyl or allyl ether or trialkylsilyl ether such as trimethylsilyl ether or dimethyl tert-silyl ether.
• a group of compounds of the formula I can be represented by the formula IA wherein R 1 to R 6 , X and Y have the above meaning, with the proviso that X and Y represents a carbon-carbon bond when R 1 is hydrogen, being represented.
• the hydrolysis of the protected hydroxyl group R9 is characterized by conventional ether and ester hydrolysis. be performed.
• Acidic aqueous hydrolysis can be used if the hydroxyl group is protected by an ether bond.
• the preferred methods of ether hydrolysis include treating a compound of formula II with a kissable inorganic acid.
• the hydroxy group can be regenerated by treatment with a base in an aqueous medium. Any conventional method of ester hydrolysis can be used in this conversion.
• Aqueous sodium hydroxide is to be mentioned among the preferred bases.
• Ether protecting group R 9 such as tetrahydropyranyloxy.
• Hydrogenation of a CC bond represented by X and Y following hydrolysis of R 9 in a compound of Formula II can be accomplished by any conventional hydrogenation method, such as catalytic hydrogenation.
• the preferred hydrogenation methods include hydrogenation in the presence of a catalyst such as platinum or platinum oxides. Any conventional hydrogenation catalyst can be used here.
• the reaction conditions are also those for ordinary hydrogenation reactions.
• the oxidation of hydroxyl groups following the hydrolysis of R 9 in a compound of the formula II and the oxidation of hydroxyl groups in a compound of the formula III can be carried out by conventional oxidizing agents which oxidize a hydroxyl group to the keto group: preferred oxidizing agents are chromate Oxidizing agents such as chromium trioxide.
• oxidizing agents such as chromium trioxide.
• a compound II or III is used as the starting material, which is either a racemate or is in optically active form.
• R 5 and R 6 have the meaning given above, and R 6 represents aryl or di (lower alkylamino) and V represents halogen, or a phosphonate of the formula XIV wherein R 5 and R 6 have the above meaning; wherein R 5 and the above meaning and R 1 represent aryl, aryloxy or lower alkoxy,
• a compound of formula V can be obtained with a reducing agent.
• All conventional reducing agents which selectively reduce a keto group to the hydroxyl group can be used to carry out these reactions:
• Preferred reducing agents are hydrides, in particular aluminum hydrides such as alkali metal aluminum hydrides and borohydrides such as alkali metal borohydrides, zinc borohydride being particularly preferred.
• Temperature and pressure are not critical in carrying out this reaction; the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. In general, it is preferable to carry out the reaction at a temperature from -30 ° C to the reflux temperature of the reaction mixture.
• the reduction can be carried out in the presence of an inert organic solvent.
• an inert organic solvent Any conventional inert organic solvent or water can be used here, for example the above-mentioned inert organic solvents.
• Preferred solvents are methanol, dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.
• the conversion of a compound of formula VI in 'VII is a compound of formula carried out by hydrogenation.
• the hydrogenation can be carried out under the conditions described above for the hydrogenation of a C 1 -C 4 bond following the hydrolysis of R 9 in a compound of the formula II.
• the compound of formula VII is converted into a compound of formula VIII by esterification or etherification of the free hydroxy group with a hydrolyzable ether or ester protecting group.
• This esterification or etherification can be carried out according to the usual esterification and etherification processes.
• Preferred ester groups are lower alkanoyloxy, especially acetoxy, a preferred ether group is tetrahydropyranyloxy.
• the compound of formula VIII is converted into a compound of formula IX by treatment with a reducing agent from sodium to as a base. If solvents other than hexametnylphosphoramide and bases other than sodium bis-trimethylsilylamide are used, the compound of formula II-B is obtained in poorer yield. However, conventional inert organic solvents can also be used alone or in a mixture with hexamethylphosphoramide. On the other hand, the solvent system can consist solely of hexamethylphosphoramide. In carrying out this reaction are Tem p ERA-ture and pressure are carried out is not critical, the reaction can be at room temperature and atmospheric pressure or at higher or lower temperatures. In general, it is expedient to work at temperatures of 0-50 ° C.
• the conversion of compound of formula VI into compound of formula X can be carried out analogously to the conversion of compound of formula VIII into compound of formula IX.
• the X ⁇ XI conversion can be carried out analogously to IX ⁇ II-A and the hydrogenation of the double bond in the conversion of XI or XII to III can be carried out as described for the reaction II-A ⁇ II-B .
• the esterification of the carboxy group in connection with the compound XI and XII can be carried out analogously to the esterification of a carboxy group in the compound II-A.
• the compounds of formula I; their optical antipodes and racemates are valuable as pharmaceuticals. In particular, they are valuable as bronchodilators, anti- made.
• the compounds to be administered are administered orally in a mixture of tris (hydroxymethyl) aminomethane in 95% ethanol (5% w / v). A mixture of tris (hydroxymethyl) aminomethane in ethanol was used as placebo.
• the compounds were tested on non-anesthetized rats with acute gastric fistula.
• fasted female rats (medium weight 250 g) were surgically catheterized in the inferior vena cava (for the purpose of constant infusion of saline and administration of the test compounds); on the bile duct (to drain bile and pancreatic secretion, which can contaminate the stomach contents through reflux); at the stomach entrance (for the purpose of infusing a small volume of water during the experiment); and at the stomach exit (for collecting the contents of the stomach and for continuous monitoring of the pH by a microelectrode).
• the stomach was flushed with water for 60 minutes before administration of the compounds.
• the pH (measured at 10 minute intervals) of the secretion flow in each animal was approximately 1.5.
• the compound to be administered dissolved in saline, was intravenously administered at a dose of 16 ⁇ g / kg, and samples were continuously collected for 60 minutes.
• the pH, the volume, the total acidity ( ⁇ Aeq / ml) and the total acid release during 10 minutes were measured ( ⁇ Aeq / 10 minutes). The results are summarized in the table below.
• the starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-fluoro-3S-hydroxy-l (E) -octenyl] -5R-methyl-
• nat-11R-Metyhl-16,16-difluoro-15-R-hydroxy-9-osoprosta-5 (z) -13 the nat-11R-methyl-16, 16-difluoro-9, 15-dioxoprosta-5 13 (E) -dienoic acid obtained.
• nat-16 16-methyl-9S-hydroxy-15R- [2- nyloxy] -prost-5 (Z) -eklare the nat-16, 16- obtained hydroxy-9-oxoprosta-5 (Z) -enoic acid.
• the starting compound was obtained from 3, 3aR, 4, 5, 6, 6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R-hydroxy-1 (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3.3aR, 4.5, -6.6aS-hexahydro-4R- (4R-methyl-4R-trifluoromethyl-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5, -6,6aS-hexahydro-4R- [4R-methyl-4R-trifluoromethyl-3R- [2-tetra-hydro- (2H) -pyranyloxy] -octanyl] -5R-methyl-2H-cyclopenta [b] -furan-2-ol.
• the starting compound was prepared from 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R-hydroxy-l (E) -octenyl] -5R-methyl-2H-cyclopenta [b ] furan-2-one via 3,3aR, -4, 5, 6, 6aS-hexahydro-4R- (4R-trifluoromethyl-4R-fluoro-3R-hydroxy-octanyl) -5R-methyl-2H-cyclopenta [b] furan-2-one and 3,3aR, 4,5,6,6aS-hexahydro-4R- [4R-trifluoromethyl-4R-fluoro-3R- (2-tetrahydro- (2H) -pyranyloxy) -octanyl] -5R- methyl-2H-cyclopenta [b] furan-2-ol.
• nat-16,16-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid became nat-16,16-dimethyl-9,15-dioxoprost-5 (Z) -enoic acid receive.
• nat-16R-trifluoromethyl-16R, 11R-dimethyl-15R-hydroxy-9-oxoprost-5 (Z) -enoic acid was converted into nat-16R-trifluoromethyl-16R, 11R-dimethyl-9, 15- obtained dioxoprost-5 (Z) -enoic acid.
• the active ingredient and the corn starch were mixed and sieved. This premix was then mixed with the calcium phosphate and half of the magnesium stearate, sieved and compacted. The granules thus obtained were sieved, the remaining magnesium stearate added, and pressed.

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• 1977
  • 1977-07-05 US US05/813,068 patent/US4163016A/en not_active Expired - Lifetime
• 1978
  • 1978-06-28 AU AU37518/78A patent/AU3751878A/en active Pending
  • 1978-07-03 FR FR7819765A patent/FR2396748A1/fr not_active Withdrawn
  • 1978-07-04 GB GB787828749A patent/GB2001311B/en not_active Expired
  • 1978-07-04 EP EP78100303A patent/EP0000207A1/fr not_active Ceased
  • 1978-07-04 DE DE19782829331 patent/DE2829331A1/de not_active Withdrawn
  • 1978-07-04 SE SE7807544A patent/SE7807544L/xx unknown
  • 1978-07-04 AT AT0484978A patent/AT363623B/de not_active IP Right Cessation
  • 1978-07-05 JP JP8103978A patent/JPS5414945A/ja active Pending
  • 1978-07-05 NL NL7807292A patent/NL7807292A/xx not_active Application Discontinuation
• 1979
  • 1979-04-06 US US06/027,589 patent/US4212993A/en not_active Expired - Lifetime

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