GB1565604A - 6-oxoprostaglandins - Google Patents

6-oxoprostaglandins Download PDF

Info

Publication number
GB1565604A
GB1565604A GB51701/77A GB5170177A GB1565604A GB 1565604 A GB1565604 A GB 1565604A GB 51701/77 A GB51701/77 A GB 51701/77A GB 5170177 A GB5170177 A GB 5170177A GB 1565604 A GB1565604 A GB 1565604A
Authority
GB
United Kingdom
Prior art keywords
oxo
pge1
compound
methyl
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
Application number
GB51701/77A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US05/829,678 external-priority patent/US4124601A/en
Priority claimed from US05/829,679 external-priority patent/US4205178A/en
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of GB1565604A publication Critical patent/GB1565604A/en
Expired legal-status Critical Current

Links

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
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

(54) 6-OXOPROST GLANDINS (71) We, THE UPJOHN COMPANY, a corporation organized and existing under the laws of the State of Delaware, United States of America, of 301 Henrietta Street, Kalamazoo, State of Michigan, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel prostaglandin derivatives. The novel compounds of this invention have the formula
wherein either A is hydroxy, hydroxy, hydrogen, methylene or ahydroxymethyl and the second 10, 11 bond is absent or A is hydrogen and the second 10, 11 bond is present; wherein D is (1)-(CH2)2-CH2R2'-wherein D is zero or an integer of from one to 5 and R2 and R2' are the same or different and are each hydrogen, methyl or fluorine, provided that -CR2R2' is not -CFMe-; (2) -CH2-O-(CH2)xwherein x is one, 2 or 3; or (3) -CH2-CH=CH-; wherein Q is
wherein R8 is hydrogen, or methyl or ethyl; wherein R1 is (1) -COOR3, (2) -CH2OH, (3) CH2NRsR28, (4) -CO NR,R2s or (5) tetrazol-5-yl, wherein R3 is (a) hydrogen, (b) C,~,2 alkyl, (c) C3~10 cycloalkyl, (d) C7~,2 aralkyl, (e) phenyl, (f) phenyl substituted with one, 2 or 3 chlorine atoms or C1-4 alkyl radicals, (g) -D-NH-CO-D-NF-COCH3, -D-NH-CO-C6H5, -D-NH-CO-CH3, -D-NH-CONH2 or -D-CH=N-NH-CONH2 wherein D is 1,4-phenylene, (h) 2-naphthyl, (i) -CHR11-COR10 wherein R10 is phenyl, p-bromophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl or 2naphthyl and R11 is hydrogen or benzoyl, or (j) a pharmacologically acceptable cation, R9 is hydrogen, methyl or ethyl, and R28 is hydrogen, C1-4 alkyl, C7-12 aralkyl, phenyl or (C14 alkyl) phenyl; wherein R4 is (1) -CR5R6-C9H20-CH2 (2) an optically substituted phenoxyalkyl or phenylalkyl radical of the formula
or (3) cis-CH2-CH=CH2-CH2CH3 wherein C9H29 is C1-9 alkylene, with one to 5 carbon atoms in the chain between-CR5R6 and the terminal methyl, R5 and R6 are the same or different and are each hydrogen, C14 alkyl or fluorine, provided that -CR5R6 is not-CFAlkyl- Z is --OO-, a valence bond or C1-9 alkylene optionally substituted by one or two fluorine atoms and with one to 6 carbon atoms in the chain between -CR5R6 and the benzene ring, provided that neither R5 nor R6 is fluorine when Z is -O-, T is C1-4 alkyl, C14 alkoxy, fluorine, chlorine or trifluoromethyl and s is zero, one, 2 or 3, provided that not more than two T's are other than alkyl and that, when s is 2 or 3, the T's may be the same or different; and X is trans-CH=CH-, cis-CH=CH-, -C#C- or -CH2CH2-. The compounds of this invention include mixtures of enantiomers of formula I and the C28 alkanoates thereof.
Particularly preferred compounds of the invention are the PGE derivatives, i.e. when A is hydroxy. The compounds of the invention are I lA-PGE derivatives, 11 - deoxy - PGE derivatives, 11 - deoxy - 11 - methylene - PGE derivatives and 11 - deoxy - 11 - hydroxymethyl - PGE derivatives when A is j3- hydroxy, hydrogen, methylene and a-hydroxymethyl, respectively, and the second 10, 11 bond is absent.
The compounds of the invention are PGE-type acids, esters and salts when R1 is -COOR3, 2 - decarboxy - 2 - hydroxymethyl - PGE - type compounds when R1 is hydroxymethyl, 2 - decarboxy - 2 - amino - PGE - type compounds when R1 is -CH2NR9R28, PGE-type amides when R1 is -CO-NR9R28 and 2decarboxy - 2 - tetrazol - 5' - yl - PGE - type compounds when R1 is tetrazol 5 - yl.
In the formulae given in this specification, broken line attachments to the cyclopentane ring or to side chains indicate substituents in a configuration, i.e. below the plane of the ring or side chain. Heavy (solid) line attachments indicate substituents in fi configuration, i.e. above that plane.
For those compounds of formula I wherein Q is
i.e. wherein the C-15 hydroxyl group is attached to the side chain in alpha configuration, the configuration at C-15 is identical with that of the naturally occurring prostaglandins such as PGE1 obtained from mammalian tissues. The 15epimer compounds are represented by formula I when Q is
and are identified variously as "15-epi" or "15ss" or "15R" by the appropriate prefix in the name. As is known in the art, "R" and "S" designations depend on the neighboring substituents. See R. S. Cahn, J. Chem. Ed. 41, 116 (1964).
A typical example of the compounds of formula 1 is represented by the formula
and named 6-oxo-PGE1, methyl ester. The formula II compounds is a species of the formula I compounds wherein D is -(CH2)3-, Q is
R1 is COOCH3, R4 is n-pentyl A is a-hydroxy and X is trans-CH=CH-.
Regardless of the number of carbon atoms in the chain between the oxo group and the terminal R1 group, these compounds are regarded as "6-oxo" compounds, from the designation of C-6 in the basic PGE1 formula referring back to the prostanoic acid skeleton. Compounds having longer or shorter chains are named following the accepted conventions using "homo" or "nor". For example the side chain -CH2-CO-(CH2)5-COOH is named "2a-homo-6-oxo...", whereas -CH2-COCH2)3-COOH is named "2-nor-6-oxo...".
The compounds of formula I are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. Examples of those biological responses, and means for administering such compounds, are summarised in our Application No. 25672/76 (Serial No. 1,554,022).
A pharmaceutical composition according to this invention comprises a compound of formula I in association with a pharmaceutically acceptable carrier.
Where used in the specification, "C1~4 alkyl" means methyl, ethyl, propyl, butyl or an isomeric form thereof. "C1~7 alkyl" means, in addition, pentyl, hexyl, heptyl and isomeric forms thereof. "C112 alkyl" means, in addition, octyl, nonyl, decyl, undecyl, dodecyl and isomeric forms thereof, "C118 alkyl" means, in addition, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and isomeric forms thereof. Examples of "C3~10 cycloalkyl", which includes alkylsubstituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4,-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
Examples of C7~10 phenylalkyl are benzyl, 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, and 3-phenylbutyl.
Examples of C7~12 aralkyl are, in addition 2-( 1 -naphthyl)ethyl, and (2-naphthyl)methyl.
Examples of phenyl substituted by one to 3 times by chlorine atoms or C1-4 alkyl radicals are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.
Examples of C19 alkylene with one to 5 carbon atoms, in the chain, within the scope of C9H29 as defined herein, are methylene, ethylene, trimethylene, tetramethylene, and pentamethylene, and those alkylene with one or more alkyl substituents on more or more carbon atoms thereof e.g. -CH(CH3)-, -C(CH3)2-, -CH(CH2-ch3)-, -CH2-CH(CH3), -CH(CH3)-CH(CH3)-, -CH2 C(CH3)2-, -CH2CH(CH3)-CH3-, -CH2-CH2-CH(CH2CH2CH3)-, -CH(CH3)-CH(CH3)-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-CH2, and -CH2-CH2-CH2-CH2-CH(CH3)-. Examples of C1-9 alkylene optionally substituted with one or 2 fluorine atoms, with one to 6 carbon in the chain, within the scope of C,H2j as defined herein, are those given above for C9H2g and hexamethylene, including hexamethylene with one or more alkyl substituents on one or more carbon atoms thereof, and including those alkylene groups with one or 2 fluorine substituents on one or 2 carbon atoms thereof, e.g. -CHF-CH2-, -CHF-CHF-, -CH2-CH2-CF2-, -CH2-CHF-CH2-, -CH2-CH2 CF(CH3)-, -CH2-CH2-CF2-CH2-, -CH(CH3)-CH2-CH2-CHF -CH2-CH2-CH2-CH2-CF2-, -CHF-CH2-CH2-CH2-CH2-CHF-, -CF2-CH2-CH2-CH-CH2-CH2, -CH2-CH2-CH2-CF2-CH2-CH2, and -CH2-CH2-CH2-CH2-CH2-CF2.
Examples of
as defined herein are phenyl, (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, (o-, m-, or p-)propylphenyl, (o-, m-, or p-)butylphenyl, (o-, m-, or p-)isobutylphenyl, (o-, m-, or p-(tert-butylphenyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl, 2,6-diethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, 2-propyl-(m- or p-)tolyl, 4-butyl-m-tolyl, 6-tert-butyl-m-tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-)trimethylphenyl, (o-, m- or p-)fluorophenyl, 2-fluoro-(m- or p)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-(difluorophenyl, (o-, m- or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5- or 6)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, a,a,a-trifluoro-(o-, m- or p-)tolyl, (o-, m- or p-)methoxyphenyl, (o-, m or p-)ethoxyphenyl, and (4- or 5-)chloro-2-methoxyphenyl.
Included in the compounds of formula 1 are the pharmacologically acceptable salts when R3 is a cation. Such pharmacologically acceptable salts useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc, and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, Nmethylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, - phenylethylamine, A-phenylethylamine, ethylene diamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine,, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2methylpyrrolidine, 1, 4-dimethylpiperazine, and 2-methylpiperidine, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N- butylethanolamine, 2 - amino - I - butanol, 2 - amino - 2 - ethyl - 1,3 - propanediol, 2 - amino - 2 - methyl - 1 - propanol, tris(hydroxymethyl)aminomethane, N - phenylethanolamine, N - (p tert - amylphenyl)diethanolamine, galactiamine, N - methylglycamine, Nmethylglucosamine, ephedrine, phenylephrine, epinephrine, and procaine.
Examples of suitable pharmacologically acceptable quatenary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and phenyltriethylammonium.
Processes for preparing the compounds of the invention will now be described.
According to a first sequence (Sequence A), the starting material is a compound of formula III
wherein A, D, Q, R4 and X are as defined above and R19 is the same as R, as defined above but is not -COOR3 when R3 is a pharmacologically acceptable cation. The compounds of formula III exist in equilibrium with the corresponding hemiacetals formed by intra-molecular reaction between the 6-oxo group and the 9-hydroxy group.
In Sequence A, (a) the compound of formula III is transformed to a compound of the formula
(b) the product of step (a) is oxidised to form a compound of the formula
and (c) the product of step (b) is transformed to a compound of formula I. In formulae IV and V, D, R5 and X are as defined above.
Q1 is
wherein R8 is hydrogen, methyl, or ethyl and R21 is 2-tetrahydropyranyl, 2tetrahydrofuranyl or a group of the formula
wherein R14 is C1-18 alkyl, C3-10 cycloalkyl, C7-12 aralkyl, phenyl substituted with one, 2, or 3 C1-4 alkyl radicals, either R15 and R16 are the same or different and are each hydrogen, C14 alkyl, phenyl or phenyl substituted with one, 2, or 3 C14 alkyl radicals or R15 and R16 are taken together and are (CH2)a or (CH2)b-O-(CH2)c-wherein a is 3, 4 or 5, b is one, 2 or 3, and c is one, 2 or 3 with the proviso that b plus c is 2, 3, or 4, and R17 is hydrogen or phenyl.
wherein R2, is as defined above.
R23 is the same as R,g but isCH2OR2, rather than -CH2OH.
In step (a) of Sequence A, the formula-III compound is transformed to a corresponding formula-IV compound.
When the blocking group R2, in Q1,
and R23 is 2 - tetrahydropyranyl or 2 - tetrahydrofuranyl, the appropriate reagent, e.g. 2,3 - dihydropyran or 2,3 - dihydrofuran, is used in an inert solvent such as dichloromethane in the presence of an acid condensing agent such as p toluenesulfonic acid or pyridine hydrochloride. The reagent is used in slight excess, preferably 1.0 to 1.2 times theory, and the reaction is carried out at 20--500C.
When R21 is of the formula R14-O-C(R15CHR16R17, as defined herein, including 1 - ethoxyethyl, the appropriate reagent is a vinyl ether, e.g. ethyl vinyl ether, isopropenyl methyl ether, isobutyl vinyl ether, or any vinyl ether of the formula R14-O-C(R15)=CR16R17 wherein R14, R15, R16, and R17 are as defined above; or an unsaturated cyclic or heterocyclic compound, e.g. 1 cyclohexen- 1 -yl-methyl ether or 5,6-dihydro-4-methoxy-2H-pyran.
See C. B Rees et al., J. Am. Chem. Soc., 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above.
The 6-oxo formula-IV compound, now with blocking groups at C-l 1 and C-15, is also accompanied by hemi-ketal compounds derived from formula XX but not blocked at C-ll and C-15. It is possible that the C-6 hydroxyl is also reactive to the blocking agent. Whether or not the C-6 hydroxyl is blocked is immaterial to the success of the following step (b). Any ether groups at C-6 are readily removed in the presence of the reagents used in step (b). Any hemi-ketal therefore equilibrates readily and rapidly to the 6-oxo compound IV and is transformed to the formula-V compound in step (b).
In step "b" of Chart A, the hydroxyl on the cyclopentane ring at the C-9 position of the formula-IV compound is oxidized to the oxo group of the formula-V compound.
Oxidation reagents useful for this transformation are known in the art. A useful reagent for this purpose is the Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39(1946). A slight excess beyond the amount necessary to oxidize the C-9 secondary hydroxy groups of the formula-IV reactant is used. Acetone is a suitable diluent for this purpose. Reaction temperature at least as low as about 0 C. should be used. Preferred reaction temperatures are in the range 0 to --500C.
Another useful reagent for this purpose is the Collins reagent, i.e. chromium trioxide in pyridine. See J. C. Collins, et al., Tetrahedron Lett., 3363 (1968).
Dicilloromethane is a suitable diluent for this purpose. Reaction temperatures of below 30"C. should be used. Preferred reaction temperatures are in the range 0 to +30"C. The oxidation proceeds rapidly and is usually complete in 5 to 20 minutes.
Examples of other oxidation reagents useful for this tranformation are silver carbonate on Celite (registered Trade Mark)-See Chem. Commun. 1102(1969)-, mixtures of chromium trioxide and pyridine (J. Am. Chem. Soc. 75, 422 (1953)) and Tetrahedron, 18, 1351 (1962)), t-butyl chromate in pyridine (Biochem. J. 84, 195 (1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (J. Am.
Chem. Soc. 89, 5505 (1967)), and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87, 5661(1965)).
In step "c" of Sequence A, the blocking groups R21 are replaced with hydrogen by said hydrolysis, thereby forming a compound of formula I. General procedures are known in the art. For the tetrahydropyranyl groups, for example, the formula-V compound is contacted with methanol-HCl or with acetic acidwater-tetrahydrofuran at 40--550C.
Salts containing pharmacologically acceptable cations are prepared from the formula-I compounds in free acid form, i.e. wherein R, is -COOH, by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which corresponding to the cations and amines listed above.
These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the formula-I acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a watermiscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired. Amine and quaternary ammonium salts are prepared by similar methods using appropriate solvents.
As discussed above, the compounds of formula I are administered in various ways for various purposes; e.g., intranveously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action.
For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is advantageous because of increased water solubility that R3 in the formula I compound is hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.
Various esters of formula I within the scope of R3 are optionally prepared from the corresponding acids of formula I, the corresponding acids of formula I, i.e. wherein R1 is -COOH, by methods known in the art. For example, the alkyl, cycloalkyl, and aralkyl esters are prepared by interaction of said acids with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, 1 - diazo 2 - ethylhexane, diazocyclohexane, and phenyldiazomethane, for example, gives the ethyl, butyl, 2-ethylhexyl, cyclohexyl, and benzyl esters, respectively. Of these esters, the methyl or ethyl is preferred.
Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography.
It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).
An alternative method for esterification of the carboxyl group of the novel compounds of formula I comprises transformations of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl, cycloalkyl or aralkyl iodide. Examples of suitable iodides are methyl, iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide and phenethyl iodide. The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.
The phenyl and substituted phenyl esters of the formula I compounds prepared by silylating the acid to protect the hydroxy groups, for example, replacing each -OH with -O-SiCH3)3. Doing that may also changeCOOH to -COO-Si < CH3)3. A brief treatment of the silylated compound with water will change -COO-SiCH3)3 back to -COOH. Procedures for this silylation are known in the art and are available. Then, treatment of the silylated compound with oxalyl chloride gives the acid chloride which is reacted with phenol or the appropriate substituted phenol to give a silylated phenyl or substituted phenyl ester. Then the silyl groups, e.g., -O-SiCH2)3 are changed back to -OH by treatment with dilute acetic acid. Procedures for these transformations are known in the art.
A preferred method for substituted phenyl esters is that disclosed in U.S.
Patent Specification No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed from the acid with isobutyl chloroformate in the presence of a tertiary amine.
Phenacyl-type esters are prepared from the acid using a phenacyl bromide, for example p-phenylphenacyl bromide, in the presence of a tertiary amine. See for example U.S. Patent Specification No. 3,984,454, German Offenlegungsschrift No.
2,535,693, and Derwent Farmdoc No. 16828X Compounds in which R1 is -CH2NR9R28 or -CO-NR9R28 are conveniently prepared from the formula-I acids, i.e. R1 is -COOH. The sequence of reactions is described in British Patent Application No. 53739/76. For example, the acid compound is converted to a mixed anhydride and thence to an amide. Carboxyl reduction of the amide yields the amine. Alternatively, the mixed anhydride is converted to an azide, thence to a urethane from which the substituted amines, primary or secondary, are readily available by methods known in the art.
Also included in the compounds of this invention are the C18 alkanoates.
Formic, acetic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, and octanoic acids, and isomeric forms thereof, may be used to form the alkanoates.
The formula-I compounds prepared by the process described above are transformed to C1~8 alkanoates by interaction with a carboxylating agent, preferably the anhydride of a ClB alkanoic acid. For example, use of acetic anhydride gives the corresponding diacetate. Similar use of propionic anhydride, isobutyric anhydride, and hexanoic acid anhydride gives the corresponding carboxyacylates.
The carboxyacylation is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or trimethylamine. A substantial excess of the anhydride is used, preferably 10 to 1,000 moles of anhydride per mole of the hydroxy compound reactant. The excess anhydride serves as a reaction diluent and solvent. An inert organic diluent, for example, dioxane, can also be added. It is preferred to use enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction, as well as any free carboxyl groups present in the hydroxy compound reactant.
The carboxylacylation reaction is preferably carried out at 0 to 1000C. The necessary reaction time will depend on such factors as the reaction temperature, and the nature of the anhydride. For acetic anhydride, pyridine, and a 25"C. reaction temperature, a 12-to-24-hour reaction time is used.
The carboxylated product is isolated from the reaction mixture by conventional methods. For example, the excess anhydride is decomposed with water, and the resulting mixture acidified and then extracted with a solvent such as diethyl ether. The desired carboxylate is recovered from the diethyl ether extract by evaporation. The carboxylate is then purified by conventional methods, advantageously by chromatography. Another process for the formula-I 6-oxo compounds-Sequence Bcomprises the steps of starting with a halo ether of the formula
(d) transforming that starting material to a compound of the formula
and (e) dehydrohalogenating and hydrolysis the product of step (d) to form a compound of formula IV, from which steps (b) and (c) of Sequence A may be used.
In Sequence B, A, B, D, Q, Q1, R4, R19
R23 and X are as defined above, and R3, is iodine, bromine or chlorine.
In the first step "d" of Chart B, the starting material VII is transformed to a corresponding formula-VIII compound. The blocking group R2, in Q1,
and R23 may be the same as or different than the blocking group R21 in Chart A, but the details as to reagents and procedures have already been described above for Chart A, step "a".
In step "e" of Charge B, the formula-VIII halo compound is subjected to dehydrohalogenation and hydrolysis to form the formula IV 6-oxo-PGF-type compound. In one method a halo compound VIII is contacted with silver carbonate and perchloric acid in an organic medium such as tetrahydrofuran. The reaction is followed with TLC (thin layer chromatography) to determine completion, normally 15-24 hr. at about 250C. The reaction is preferably done in absence of light.
In another method the ha rapidly to the formula-IV compounds during the oxidation and are thus readily transformed in the preparation of the formula-V compounds.
In Sequence C, as illustrated in the following chart, a process for preparing 6 oxo - 13,14 - didehydro - PGE - type compounds of formula Xis disclosed. The previously undefined groups in Sequence C are as follows:
R26 is the same as R4 as defined above but is not cis - pent - 2 - enyl.
R29 is bromine or chlorine.
wherein R2, is as defined above.
SEQUENCE C
SEQUENCE C - (cont'd)
SEQUENCE C - (cont'd)
The starting materials of formula XI are 15-oxo-PGF type compounds known in the art or available by methods described herein or known in the art. For example see U.S. Patent Specification No. 3,728,382. It is immaterial whether 5,6cis or 5,6-trans compounds are used as either one will ultimately yield the desired formula-X compound.
In the first step "h" of Sequence C the formula-XII trihalo compound is prepared, for example by reaction of the formula-XI compound with pyridinium hydrobromide perbromide in pyridine. Other halogenating agents are useful, e.g.
N-bromo- or N-chloro-succinimide. Other tertiary amines are useful for the selective monodehydrohalogenation.
In step "i", the formula -XIII compound is obtained as a mixture of alpha and beta hydroxy isomers by reduction of XII. For this reduction, use is made of any of the known ketonic carbonyl reducing agents which do not reduce ester or acid groups or carbon-carbon double bonds. Examples of those are the metal borohydrides, especially sodium, potassium, and zinc borohydrides, lithium (tritert-butoxy) aluminium hydride, metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride, lithium borohydride, or diisobutylaluminium hydride. For production of the preferred natural-configuration prostaglandin derivatives, the alpha form of the formula-XIII compound is separated from the beta isomer by silica gel chromatography using methods known in the art.
In step "j" the C-S and C-6 halogen atom/s are removed by selective dehalogenation for example by contact with zinc in methanolic ammonium chloride, to yield the formula-XIV monohalo compound. Other monohalo compounds within the scope of XIV are known in the art. See for example, U.S.
Patent Specification No. 4,029,681.
In step "k" the formula-XIV compound is halogenated and cyclized to form the formula-XV halo ether. For this purpose there are various methods available.
For the iodo compounds there may be used an aqueous system containing iodine, potassium iodide, and an alkali metal carbonate or bicarbonate, or an organic solvent system such as dichloromethane, containing iodine in the presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25"C., preferably 0--50C. for 1020 hours. Thereafter the reaction is quenched with sodium sulfite and sodium carbonate and the formula-XV compound separated from the reaction mixture.
For the bromo compounds, N-bromosuccinimide or n-bromoacetamide are useful. See Fieser et al., Reagents for Organic Synthesis, Vol. 1, pup. 74 and 78, Vol.
IV, p. 51, John Wiley and Sons, Inc., N.Y. For the chloro compound various methods are available, for example exchange of bromine with chlorine using the silver salt of chlorodifluoroacetic acid. See I. T. Harrison et al., Compendium of Organic Synthetic Methods, p. 346, 1971, Wiley Interscience, N.Y.
The formula-XV halo compounds are obtained as two isomers, one in minor and the other in major quantity, differing in their chromatography mobility. These C-S and C-6 isomers are separable by silica gel chromatography, but are normally not separated, as either one yields the desired formula XVII, XVIII, and X compounds.
In step "1" the formula-XVI compounds is formed as known in the art or described herein, replacing hydrogen atoms in free hydroxyls in Q2, R,9, and
with blocking groups R2,.
In step "m" the formula-XVI compound is treated with a dehydrohalogenation reagent preferably potassium t-butoxide, to form the formula-XVII 6-oxo-PGFtype compound.
The remaining steps in the process, "n" and "o", are analogous to those in Sequence A. For step "n", the formulation XVII compound is subjected to oxidation as in step "b" of Sequence A. In step "o" the formula-XVIII compound is hydrolyzed to remove blocking groups as in step "c" of Sequence A.
The formula-VII halo ether starting materials for Sequence B may be prepared from compounds of formula XIX:
The formula III 6-oxo-PGE, cr-type starting materials for Sequence A may be prepared from the formula-VII compounds. The starting materials of formula XIX are known in the art or are readily available by processes known in the art. In the following references, "USP" means U.S. Patent Specification No.; "DF" means Derwent Farmdoc No.: and "DOS" means German Offenlegungsschrift No.; As to PGF2&alpha; see USP 3,706,789; as to 15-methyl- and 15-ethyl-PGF2&alpha;, see USP 3,728,382; as to 16,16-dimethyl-PGF2&alpha; USP 3,903,131; as to 16,16-difluoro-PGF2&alpha; compounds, see USP 3,962,293 and 3,969,380; as to 16-phenoxy-17,18,19,20-tetranor-PGF2&alpha;, see DF 73279U; as to 17-phenyl-18,19,20-trinor-PGF2&alpha;, see DF 31279T; as to 11 deoxy-PGF2&alpha;, see DF 10695V; as to 2a,2b-dihomo-PGF2&alpha;, see DF 61412S and USP 3,852,316 and 3,974,159; as to 3-oxo-PGF2&alpha;, see USP 3,923,861; as to 3-oxa-17 phenyl-18,19,20-trinor-PGF2a, see USP 3,931,289; as to substituted phenacyl esters see DF 16828X; as to substituted phenyl esters, see USP 3,890,372; as to C-I alcohols, i.e. 2-decarboxy-2-hydroxymethyl compounds, see USP 3,636,120; as to C-2 tetrazolyl derivatives, see USP 3,932,389; as to A2PGF2,z, see DF 46497W and DOS 2,460,285; as to 5,6-trans-PGF2&alpha;, see USP 3,759,978; as to 2,2-dimethyl-PGF2&alpha; analogues, see DF 59033T and DOS 2,209,039; as to 11ss-PGF2&alpha; compounds, see USP 3,890,371; as to 11-deoxy-PGF2&alpha;, see DF 10695V; as to 11-deoxy-11 hydroxymethyl-PGF2&alpha;, see USP 3,931,282 and USP 3,950,363; as to 16-methylene PGF2&alpha;, see DF 19594W and DOS 2,440,919; as to 17,18-didehydro-PGF2&alpha; compounds, see USP 3,920,726; as to 3-(or 4-)oxa-17,18-didehydro-PGF2 compounds, see USP 3,920,723; as to lS-oxo-PGF2a, see USP 3,728,382; as to 15 deoxy-PGF2&alpha;, see 9239W; as to 13,14-cis compounds, see USP 3,932,479; as 11 deoxy-15-deoxy-PFG2&alpha; see DF 5694U; as to #-homo-PGF2&alpha; compounds, see DF 4728W; and as to 2,2-difluoro-PGF2&alpha; compounds, see DF 67438R.
As to 3-decarboxy-2-amino-PGF2et compounds, see British Patent Application No. 53739/76 Serial No. 1,554,041.
In the halogenation and cyclization of compound XIX to yield the formula-VII halo compounds, any of the halogenating methods described above for step "k" of Sequence C may be used. Here also it is immaterial whether 5,6-cis or 5,6-traits compounds of formula-XIX are used or which isomers of the formula-VII halo compounds are used.
The halo compound is converted to a mixture of compounds III and its hemiacetal by dehydrohalogenation and hydrolysis. See for example the methods of Sequence B, step "e" above.
Sequence D illustrates a method for preparing 2-decarboxy-2-hydroxymethyl compounds of formula XXV, wherein f is zero or an integer of from one to 4.
The formula-XXII starting materials for Sequence D are lactone intermediates known in the art or readily available by methods known in the art. For example when
SEQUENCE D
SEQUENCE D - (continued)
THP=tetrahydropyran-2-yl) and when R4 is n-pentyl, see Corey et al., J. Am. Chem. Soc. 92, 397 (1970). When R4 is -CR5R6-C9H29-CH3 wherein R5 and R6 are methyl or ethyl, see USP 3,954,833. When R5 and R6 re fluorine, see USP 3,962,293. When Q1 is
see USP 3,864,387 and USP 3,931,279.
When is
these 11ss lactones are obtained by isomerizing a corresponding lactone having the 11&alpha; configuration, with suitable blocking at the C-15 position if desired, by methods known in the art, such as by way of the 11-mesylate or 11-tosylate.
When
and R4 is alkyl, see USP 3,931,279 and DF 10695V; when R4 is phenyl-substituted, also see USP 3,931,279.
When
see DOS 2,437,622 and DF 12714W. For example a compound of the formula
is reduced at the -COOH position to the corresponding -CH2OH compound using diborane, and thereafter reacted with a suitable blocking agent.
In step "r" of Sequence D the starting material XII is condensed with an alkynyllithium compound of the formula LI-C#C-(CH2)f-C(R2)2-CH2-O-Si(CH3)3 XXVII See C. H. Lin et al. Synthetic Comm. 6, 503, (1976) and Lin, J. Org. Chem. 41, 4045 (1976). The lithium compound is conveniently prepared in situ from the silylated alkyne by reaction with methyl- or butyllithium in an ether such as diethylether or tetrahydrofuran. In working up the product the silyl groups are readily removed to yield XXIII.
In step "s" the formula-XXIII compound is oxidized at the C-9 position, preferably with Jones reagent. In this step some of the C-I alcohol groups are also oxidized to carboxylic acid groups. These are next esterified with diazomethane to facilitate removal of the by-product by chromatography. Blocking groups R2, are replaced with hydrogen in the conventional way, as by mild acid hydrolysis for THP, to yield the formula -XXIV compound.
In step "t" compound XXIV is reduced to the XXV compound without reducing C13-C14 or C17-C18 ethylenic bonds that are present. For this purpose catalytic hydrogenation is useful, for example, over palladium on barium sulfate.
Sequence E shows the steps of a method for preparing 6,15-dioxo compounds of formula XXXV.
The starting material is an equilibrium mixture of the formula-XXVIII 6-oxo PGF1,-type- and formula-XXIX hemiketal compounds. See for example Johnson et al. J. Am.
SEQUENCE E
Chem. Soc. 99, 4182 (1977).
In step "u", the blocking groups R21 are added, using methods described herein or known in the art. With dihydropyran, for example, the main product is the bis(THP ether).
In step "v" the free acid is formed by saponification of the carboxylic ester groups and acidification.
In step "w" the blocked 6-oxo-PGF, ,-type compound of formula XXXII is oxidized, for example with Jones reagent, to the formula-XXXIV 6,15-dioxo-PGE1- type compound.
Finally, in step "x" the blocking groups are removed in the conventional way to obtain the formula-XXXV product.
Sequence F shows the steps in a preferred method for preparing amides of formula XL.
The starting materials of formula XXXVI are 5-halo acids within the scope of formula VII herein.
In step "y" the formula-XXXVI halo acid is converted to amide XXXVII, e.g. by way of a mixed anhydride. For this purpose, compound XXXVI is treated with isobutyl chloroformate in the presence of a tertiary amine such as triethylamine and thereafter with an amine of the formula HN(R9)(R28).
In step "z" the halo amide XXVI I is then subjected to dehydrohalogenation and hydrolysis to obtain the SEQUENCE F
formula-XXXVIII compound. Silver carbonate and perchloric acid are used for this purpose.
In step "aa" the formula-XXXVIII 6-oxo-PGF1-type compound, having suitable blocking groups at C-ll and C-I5, is oxidized to a PGE,-type compound by methods known in the art, for example using Jones reagent at -15 to -200C.
Finally, in step "bb" the blocking groups are removed, to produce compound XL.
It should be understood that although the Charts have formulas drawn with a specific configuration for the reactants and products, the procedural steps are intended to apply not only to the other optically active isomers, but also to mixtures, including racemic mixtures or mixtures of enantiomeric forms.
If optically active products are desired, optically active starting materials or intermediates are employed or, if racemic starting materials or intermediates are used, the products are resolved by methods known in the art for prostaglandins.
The products formed from each step of the reaction are often mixtures and, as known to one skilled in the art, may be used as such for a succeeding step or, optionally, separated by conventional methods of fractionation, column chromatography, liquid-liquid extraction, and the like, before proceeding.
Compounds within the scope of formula I are transformed from one to another by methods known in the art. Accordingly, a formula-I compound wherein A is a- hydroxy may, for example, be transformed to one wherein A is methylene. A compound of formula I in which A is a-hydroxy may be transformed to one in which A is hydrogen and the second 10,11 bond is present, by acid dehydration. A compound wherein the C13-C14 group "X" is trans-CH=CH- may be transformed by known methods to another compound wherein the C,3C,4 group is cis-CH=CH-, -C-C-, or -CH2CH2-. For example, -C-=C- is obtained by selective bromination and dehydrobromination. A compound wherein the C2 substituent is -COOR3, e.g. a methyl ester, may be transformed by known methods to another compound having another C2 substituent within the scope of R1, as defined herein, for example -CH2OH CO-NR9R2s.
To obtain the optimum combination of biological response specificity, potency, and duration of activity, certain compounds within the scope of formula I are preferred. For example, it is preferred that Q is
wherein it is especially preferred that R8 is hydrogen, or methyl.
When Q is
it is preferred that R8 is methyl.
Another preference for the compounds of formula I, as to R1, is that R3 in -COOR3 is either hydrogen, C1-12 alkyl or a pharmacologically acceptable cation.
Further, when R3 is allkyl, it is more preferred that it is C1-4 alkyl, and especially methyl or ethyl.
For purposes of stability on long storage it is preferred for the compounds of formula I that R3 in -COOR3 is amido-substituted phenyl or phenacyl as illustrated herein.
For oral administration of formula-I compounds it is preferred that R, is -CO-NR9R28. It is especially preferred that at least one of R9 and R28 is hydrogen.
In D, it is preferred that d is 2, 3 or 4, most preferably 2. When R2 and R2, are both fluorine, it is preferred that R8 in Q is methyl, or that R4 is 1,1-dimethylpentyl, phenoxymethyl phenethyl.
A is preferably hydroxy, methylene or hydrogen, the second, 10, 11 bond being absent.
When R4 is -CH5R6-C H2gCH3, CgH2g is preferably C24 alkylene and most preferably trimethylene. Further, it is preferred that R5 and R6 are the same or different and are each hydrogen, methyl, ethyl or fluorine. When R5 and R8 are not hydrogen, it is also preferred that R5 and R6 are both methyl or fluorine. R4 is most preferably n-pentyl, l,l-dimethylpentyl or I,l-difluoropentyl.
When R4 is optionally substituted phenoxyalkyl or phenylalkyl as defined above, s is preferably zero or one. When s is other than zero, T is preferably methyl, chlorine, fluorine, trifluoromethy or methoxy with meta or para attachment to the benzene ring. When Z is --OO-, it is preferred that Rs and R6 are the same or different and each hydrogen, methyl or ethyl. It is further preferred, when R5 and R6 are not hydrogen, that R5 and R6 are both methyl. When Z is other than -0-, it is preferred that it is a valence bond, methylene or ethylene. Most preferably, R4 is phenoxymethyl or phenethyl.
The following Preparations and Examples illustrate how the compounds of this invention may be prepared.
All temperatures are in degrees centrigrade.
Infrared absorption spectra are recorded on a Perkin-Elmer model 421 infrared spectrophotometer. Except when specified otherwise, undiluted (neat) samples are used.
The NMR spectra are recorded on a Varian A-60, A-60D, T-60 or XL-100 Spectrophotometer in deutrochloroform solutions with tetramethylsilane as an internal standard. "Varian" is a registered Trade Mark.
Mass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer, a CEC Model 110B Double Focusing High Resolution Mass Spectrometer, or a LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 22 or 70 ev.), and samples are usually run as TMS (trimethylsilyl) derivatives.
"Brine" refers to an aqueous saturated sodium chloride solution.
"DBN" refers to 1,5-diazabicyclo[4.3.0]nonene-5.
"DABCO" refers to 1,4-diazabicyclo[2.2.2]octane.
"DBU" refers to 1,5-diazabicyclo[5.4.0]undecene-5.
"DIBAI" refers to diisobutylaluminium hydride.
"E" and "Z" follow Blackwood et al., cited above.
"Florisil" (registered Trade Mark) is a chromatographic magnesium silicate produced by the Floridin Co. See Fieser et al. "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, N.Y. (1967), p 393.
"HPLC" refers to high pressure liquid chromatography.
"Skellysolve B", refers to mixed isomeric hexanes.
"THP" refers to tetrahydropyran-2-yl.
"TLC" refers to thin layer chromatography.
"Concentrating", as used herein, refers to concentration under reduced pressure, preferably at less than 50 mm. and at temperatures below 35"C.
"Drying", as used herein, refers to contacting a compound, in solution, with an anhydrous agent such as sodium sulfate or magnesium sulfate to remove water and filtering to remove solids.
Silica gel chromatography, as used herein, is understood to include elution, collection of fractions, and combinations of those fractions shown by TLC to contain the desired product free of starting material and impurities.
All solvent proportions are by volume unless otherwise specified.
The A-IX solvent system used in thin layer chromatography is made up from ethyl acetate-acetic acid-2,2,4-trimethylpentane-water (90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 247 (1966).
Preparation 1 55-Iodo-9-deoxy-6,9-epoxy-PGF,,, Methyl Ester (Formula VII) A suspension of PGF,,, methyl ester as its 11,1 5-bis(tetrahydropyranyl)ether (2.0 g.) in 23 ml. of water is treated with sodium bicarbonate (0.7 g.) and cooled in an ice bath. To the resulting solution is added potassium iodide (1.93 g.) and iodine (2.82 g.) and stirring continued for 16 hr. at about 0 C. Thereafter a solution of sodium sulfite (1.66 g.) and sodium carbonate (0.76 g.) in 10 ml. of water is added.
After a few minutes the mixture is extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to yield mainly the bis(tetrahydropyranyl) ether of the title compound, 2.2 g., an oil. Hydrolysis of this ether in acetic acid-water-tetrahydrofuran (20:10:3) yields mainly the title compound, which is further purified by silica gel chromatography. Rf 0.20 (TLC on silica gel in acetone-dichloromethane (30:70)). The mass spectral peaks for the formula-VII compound (TMS derivative) are at 638, 623, 607, 567, 548, 511, and 477.
Following the procedures of Preparation 1, but replacing the formula-XIX starting material with the following formula-XIX compounds or C-I I derivatives within the scope of formula XIX: 1 5-Methyl-PGF2 (15R)-15-Methyl-PGF2&alpha; I S-Ethyl-PGF2a 16,1 6-Dimethyl-PGF2a 16,16-Difluoro-PGF2&alpha; 1 6-Phenoxy- 17,18,1 9,20-tetranor-POF2,, 17-Phenyl-18,19,20-trinor-PGF2&alpha; 1 1-Deoxy-PGF2 2a,2b-Dihomo-PGF2 3-oxa-PGF2 3-Oxa-17-phenyl-18,19,20-trinor-PGF2&alpha; there are obtained the corresponding formula-VII iodo compounds.
Preparation 2 6-Oxo-PGF, < =, Methyl Ester (Formula III) A solution of the formula-VII iodo compound, methyl ester (Preparation 1, 0.45 g.) in 20 ml. of tetrahydrofuran is treated with silver carbonate (0.250 g.) and perchloric acid (700, 0.10 ml.), and stirred at about 25 C. for 24 hr. The mixture is diluted with 25 ml. of ethyl acetate and the organic phase is washed with saturated sodium carbonate solution and brine, dried, and concentrated to an oil, 0.41 g.
Separation by silica gel chromatography eluting with ethyl acetate-Skellysolve B (3:1) yields the formula-Ill title compounds as a more polar material than the formula-VII starting material. The product is an oil, 0.32 g., having Rf 0.38 (TLC on silica gel in acetone-dichloromethane (1:1)); infrared spectral peak at 1740 cm-t for carbonyl; NMR peaks at 5.5, 3.2-4.8, 3.7, 2.1-2.7 # Preparation 3 5#-Iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, Mixed Isomers (Formula VII) and 9-Deoxy 6#,9&alpha;-epoxy-6#-hydroxy-PGF1 and 6-oxo-PGF1&alpha; (Formula III).
A solution of formula -VII iodo compound methyl ester (Preparation of 1, 1.0 g.) in 30 ml. of methanol is treated with 20 ml. of 3N aqueous potassium hydroxide at about 0 C. for about 5 min., then at about 25 C. for 2 hr. The mixture is acidified with 45 ml. of 2N potassium acid sulfate and 50 ml. of water to pH 1.0, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated to an oil, 1.3 g. The oil is subjected to silica gel chromatography, eluting with acetone-dichloromethane (30:70 to 50:50) to yield, first the formula-VII free acid compound and later, the formula-III compound mixed with its hemi-acetal, as a more polar fraction.
The formula-VII compound is an oil, 0.33 g., having Rf 0.33 (TLC on silica gel in acetone-dichloromethane (1:1) plus 2% acetic acid), [&alpha;]D=+20 (C=0.992 in chloroform), infrared spectral peaks at 3360, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, 1015, 970, and 730 cm-1, and mass specral peaks (TMS derivative) at 696.2554, 681, 625, 606, 559, 535, 479, and 173.
The mixture of 9-deoxy-65,9u-epoxy-65-hydroxy-PGF, and 6-oxo-PGF1Xt is a solid, 0.113 g., melting at 93-98 C., containing no iodine, having Rf 0.13 (TLC on silica gel in acetone-dichloromethane (1:1) plus 2% acetic acid) and having mass spectral peaks (TMS derivative) at 587, 568, 553, 497, 485, 478, 407, 395, 388, and 173.
Following the procedures of Preparations 2 and 3, but replacing the formula VII iodo compound therein with those formula-VII iodo compounds described subsequent to Preparation 1, there are obtained the corresponding formula-III compounds.
Following the procedures of Preparations 1, 2, and 3, as described above, but employing corresponding starting materials, there are prepared the formula-VII 9-deoxy-6,9-epoxy-5-halo-PGF,,-type compounds, including iodo, bromo, and chloro compounds, formula-III 6-oxo-PGF" -type compounds, and 9-deoxy-6,9-epoxy-6-hydroxy PGF1f-type compounds having the following structural features: 16-Methyl-; 16,16-Dimethyl-; 16-Fluoro-; 16,16-Difluoro-; 17-Phenyl-18,19,20-trinor-; 17-(m-trifluoromethylphenyl)-18,19,20-trinor-; 17-(m-chlorophenyl)-18,19,20-trinor-; 17-(p-fluorophenyl)-18,19,20-trinor-; 16-Methyl-17-phenyl-18,19,20-trinor-; 16,16-Dimethyl-17-phenyl-18,19,20-trinor-; 16-Fluoro-17-phenyl-18,19,20-trinor-; 16,16-Difluoro-17-phenyl-18,19,20-trinor-; 16-Phenoxy-17,18,19,20-tetranor-; 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-; 16-(m-chlorophenoxy)-17,18,19,20-tetranor-; 16-(p-fluorophenoxy)-17,18,19,20-tetranor-; 16-Phenoxy-18,19,20-trinor-; 16-Methyl-16-phenoxy-18,19,20-trinor-; 16-Methyl-13,14-didehydro-; 16,16-Dimethyl-13,14-didehydro-; 16-Fluoro-13,14-didehydro-; 16,16-Difluoro-13,14-didehydro-; 17-Phenyl-18,19,20-trinor-13,14-didehydro-; 17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-; 17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-; 17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-; 16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16-Fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16,16-Difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 16-Phenoxy-17,18,19,20-tetranor-13,14-didehydro-; 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-; 16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-; 16-Phenoxy-18,19,20-trinor-13,14-didehydro-; 16-Methyl-16-phenoxy-18,19,20-trinor-13,13-didehydro-; 13,14-Dihydro-; 16-Methyl-13,14-dihydro-; 16,16-Dimethyl-13,14-dihydro-; 16-Fluoro-13,14-dihydro-; 16,16-Difluoro-13,14-dihydro-; 17-Phenyl-18,19,20-trinor-13,14-dihydro-; 17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-; 17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-; 17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-; 16-Methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 16-Fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 16,16-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-; 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-; 16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-; 16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-; 16-Phenoxy-18,19,20-trinor-13,14-dihydro-; 16-Methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-; 2,2-Difluoro-; 2,2-Difluoro-16-methyl-; 2,2-Difluoro-16,16-dimethyl-; 2,2-Difluoro-16-fluoro-; 2,2-Difluoro-16,16-difluoro-; 2,2-Difluoro-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-; 2,2-Difluoro-17-(m-chlorphenyl)-18,19,20-trinor-; 2,2-Dilfuoro-17-(p-fluorophenyl)-18,19,20-trinor-; 2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16,16-dilfuoro-17-phenyl-18,19,20-trinor-; 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-; 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-; 2,2-Difluoro- 1 6-(m-chlorophenoxy)- 17,18,1 9,20-tetranor-; 2,2-Difluoro-16-phenoxy-18,19,20-trinor-; 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-; 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-; 2,2-Difluoro-16-methyl-l 3, 14-didehydro-; 2,2-Difluoro-16,16-dimethyl-13,14-didehydro-; 2,2-Difluoro- 1 6-fluoro- 13,1 4-didehydro-; 2,2-Difluoro-16,16-difluoro-13,14-didehydro-; 2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 2,2-Difluoro-17-(m-trifluoromethyphenyl)-18,19,20-trinor-13,14 didehydro-; 2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-; 2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-; 2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14 didehydro-; 2,2-Difluoro-16, 16-dimethyl-17-pheny1-1 8,19,20-trinor-13, 14- didehydro-; 2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-; 2,2,16, 16-Tetrafluoro-17-phenyl-l 8,19,20-trinor-1 3,1Cdidehydro-; 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-; 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor 13,1 4-didehydro-; 2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14 didehydro-; 2,2-Difluoro- 1 6-phenoxy- 18,1 9,204rinor- 13,1 4-didehydro-; 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14 didehydro-; 2,2-Difluoro- 13,1 4-dihydrn-; 2,2-Difluoro-16-methyl-13,14-dihydro-; 2,2-Difluoro-16,16-dimethyl-13,14-dihydro-; 2,2,1 6-Trifluoro- 13,1 4-dihydro-; 2,2,16,16-Tetrafluoro-13,14-dihydro-; 2,2-Difluoro- 1 7-phenyl- 18,1 9,20-trinor- 13,1 4-dihydro-; 2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor 13,14-dihydro-; 2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-; 2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-; 2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor 13,1 4-dihydro-; 2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 2,2,16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-; 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20 tetranor-13,14-dihydro-; 2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor 13,14-dihydro-; 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor 13,14-dihydro-; 2,2-Difluoro- 1 6-phenoxy- 18,1 9,20-trinor- 13,1 4-dihydro-; 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-; 1 6-Methyl-cis- 13; 16,16-Dimethyl-cis-13-; 1 6-Fluoro-cis- 13-; 16,16-Difluoro-cis-13-; 17-Phenyl-18,19,20-trinor-cis-13-; 17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-; 1 7-(m-chlorophenyl)- 18,1 9,20-trinor-cis- 13-; 1 7-(p-fluorophenyl)- 18, 9,20-trinor-cis- 13-; 16-Methyl- 1 7-phenyl- 18,1 9,20-trinor-cis- 13-; 16,16-Dimethyl-17-phenyl-18,19,20-trinor-cis-13-; 16-Fluoro- 17-phenyl- 18,1 9,20-trinor-cis- 13-; 16,16-Difluoro-17-phenyl-18,19,20-trinor-cis-13-; 1 6-Phenoxy- 17,18, 19,20-tetranor-cis- 13-; 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-; 16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-; 16-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-; 16-Phenoxy-18,19,20-trinor-cis-13-; 16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-; 2,2-Difluoro-cis-13-; 2,2-Difluoro-16-methyl-cis-13-; 2,2-Difluoro-16,16-dimethyl-cis-13-; 2,2-Difluoro-16-fluoro-cis-13-; 2,2-Difluoro-16,16-difluoro-cis-13-; 2,2-Difluoro-17-phenyl-18,19,20-trinor-cis-13-; 2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor cis-13-; 2,2-Difluoro- I 7-(m-chlorophenyl)- 18,1 9,20-trinor-cis- 13-: 2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-cis-13-; 2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-cis-13-; 2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor cis-13-; 2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-; 2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-; 2,2-Difluoro-16-fluoro-18-phenyl-19,20-dinor-cis-13-; 2,2-Difluoro-16,16-difluoro-18-phenyl-19,20-dinor-cis-13-; 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-; 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-; 2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor cis-13-; 2,2-Difluoro- 16-(p-fluorophenoxy)-17,18,19,20-tetranor- cis-13-; 2,2-Difluoro-16-phenoxy-18,19,20-trinor-cis-13-; 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-; 3-Oxa-; 3-Oxa- 16-methyl-; 3-Oxa-16,16-dimethyl-; 3-Oxa-16-fluoro-; 3-Oxa- 16,1 6-difluoro-; 3-Oxa-17-phenyl-l 8,19,20-trinor-; 3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinoe-; 3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-; 3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-; 3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-; 3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-; 3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-; 3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-; 3-Oxa-16-phenoxy-17,18,19,20-tetranor-; 3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-; 3-Oxa-16(m-chlorophenoxy)-17,18,19,20-tetranor-; 3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-; 3-Oxa-16-phenoxy-18,19,20-trinor-; 3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-; 3-Oxa-13,14-didehydro-; 3-Oxa-16-methyl-13,14-didehydro-; 3-Oxa-16,16-dimethyl-13,14-didehyxro-; 3-Oxa-16-fluoro-13,14-didehydro-; 3-Oxa-16,16-difluoro-13,14-didehydro-; 3-Oxa-17-phenyl-18,19,20-trinor-13,14-didehydro-; 3-Oxa- 1 7-(m-trifluoromethylphenyl)- 18,1 9,20-trinor- 13,14 didehydro-; 3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-; 3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-; 3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-; 3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14 didehydro-; 3-Oxa- 16-fluoro- 17-phenyl- 18,19,20-trinor-13,14-didehydro-; 3-Oxa- 16,16-difluoro- 17-phenyl- 18,1 9,20-trinor- 13,14 didehydro-; 3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-; 3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14 didehydro-; 3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-; 3-Oxa-16-phenoxy-18,19,20-trinor-13,14-didehydro-; 3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-; 3-Oxa-13,14-dihydro-; 3-Oxa-16-methyl-13,14-dihydro-; 3-Oxa-16,16-dimethyl-13,14-dihydro-; 3-Oxa-16-fluoro-13,14-dihydro-; 3-Oxa-16,16-difluoro-13,14-dihydro-; 3-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-; 3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro; 3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-; 3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-; 3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor 13,14-dihydro-; 3-Oxa- 1 6-(m-chlorophenoxy)- 17,18,1 9,20-tetranor- 13,1 4-dihydro-; 3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-; 3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-; 3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-; 3-Oxa-cis- 13-; 3-Oxa- 1 6-methyl-cis- 13-; 3-Oxa-16,16-dimethyl-cis-13-; 3-Oxa-16-fluoro-cis-13-; 3-Oxa-16,16-difluoro-cis-13-; 3-Oxa-17-phenyl-18,19,20-trinor-cis-13-; 3-Oxa- 1 7-(m-trifluoromethylphenyl)- 18,1 9,20-trinor-cis- 13-; 3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-cis-13-; 3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-cis-13-; 3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-cis-13-; 3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-; 3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-; 3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-; 3-Oxa-16-phenoxy-17,18,19,20-tetranor-cis-13-; 3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor cis-13-; 3-Oxa-16-(m-chlorophenoxy)-17,1 8, 19,20-tetranor-cis-l3-; 3-Oxa-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-; 3-Oxa-16-phenoxy-18,19,20,trinor-cis-13-; 3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-; Likewise following the procedures of Preparations 1, 2, and 3 as described above, but employing the corresponding starting materials, there are prepared the formula-VII 9-d eoxy-6,9-ep oxy- 5-iodo-PGF,,-type compounds, formula-III 6-oxo-PGF1&alpha;-type compounds, and 9-deoxy-6,9-epoxy-6-hydroxy PGF1&alpha;-type compounds having the following structural features: 2,3-Didehydro-; 2,2-Dimethyl-; 2a,2b-Dihomo-; 4-Oxa-4a-homo-; 7a-Homo-; 1Th-; 1 1-Deoxy-; 1 l-Deoxy-l l-methylene-; 1 l-Deoxy-l 1-hydroxymethyl-; 15 -; 15-deoxy-15-oxo-; 1 5-Deoxy-; I S-Methyl- 15(S)-; 15-Methyl-l 5(R)-; and cis- 17,1 8-Didehydro-.
Preparation 4 5#-Iodo-9-deoxy-6,9-epoxy-PGF1&alpha;, p-Phenylphenacyl ester (Formula VII).
A mixture of the formula-VII iodo acid compound (Preparation 3, Formula VII, 0.20 g.) p-phenylphenacyl bromide (0.50 g.), 0.4 ml. of diisopropylethylamine, and 10 ml of acetonitrile is stirred at about 25"C. for 40 min. It is mixed with dilute aqueous citric acid and brine and extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (25-100%)-Skellysolve B to yield the title 5-iodo compound as a colorless oil 0.20 g.
Preparation 5 5#-Iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, amide, less and more polar isomers (Formula VII) A solution of the formula-VII iodo-ether acid, mixed isomers (Preparation 3, 5.0 g.) in 50 ml. of acetone is cooled to about -10 C. and treated with 3.0 ml. of triethylamine and 3.0 ml. of isobutyl chloroformate. After 5 min. There is added 100 ml. of acetonitrile saturated with ammonia, and the reaction mixture allowed to warm to about 25 C. The mixture is filtered, and the filtrate concentrated. The residue is taken up in ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is subjected to silica gel chromatography, eluting with acetone (25-100?/,)-methylene chloride.
There are obtained the formula-VII iodo-ether, amide, less polar isomer, 0.02 g., having Rf 0.40 (TLC on silica gel in acetone); a fraction of mixed less and more polar isomers, 2.2 g.; and the more polar isomer, 1.5 g., having Rf 0.37 (TLC on silica gel in acetone), infrared absorption at 3250, 3150, 1160, 1610, 1085, 1065, 1050, and 965 cm-1, and NMR peaks at 6.4, 5.5, 3.5-4.7 and 0.9 .
Preparation 6 5#-Iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, Methylamide, mixed isomers (Formula VII) A solution of the formula-VII 5#-iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, mixed isomers (Preparation 3, 4.66 g.) in 50 ml. of acetone is treated with 1.42 ml. of triethylamine and cooled to -5 C. Thereupon 1.3 ml. of isobutyl chloroformate is added, with stirring at OOC. for 5 min, followed by 25 ml. of 3M methylamine in acetonitrile. The solution is stirred for 20 min. more as it warmed to about 25 C.
The mixture is filtered and concentrated. The oily residue is triturated with methylene chloride, and filtered to remove a precipitate. The filtrate is subjected to silica gel chromatography, eluting with acetone (5090%)-methylene chloride, to yield the 5#-iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, methylamide mixed isomers, 3.45 g., having NR peaks at 6.3, 5.45.7, 3.2-4.7, 2.78, and 0.7-2.65 8.
Preparation 7 5#-Iodo-9-deoxy-6#-,9&alpha;-epoxy-PGF1, n-Butylamide, Mixed Isomers (Formula VII) A solution of the formula-VII iodo-ether acid, mixed isomers (Preparation 3, 5.0 g.) in 50 ml. of acetone is cooled to about -10 C. and treated with 2.0 ml. of triethylamine and 1.9 ml. of isobutyl chloroformate. After 6 min. there is added a solution of 15 ml. of n-butylamine in 20 ml. of acetone. After about 15 min. the reaction mixture is allowed to warm to about 25 C. and stirred for 3 hr. The mixture is concentrated and the residue is taken up in ethyl acetate. The solution is washed with water and brine, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel, eluting with acetone (5-100%). methylene chloride to yield the title compounds, 5.3 g. The product is rechromatographed to remove color using silica gel and eluting with acetonemethylene chloride (1:3). From 0.48 g. there is obtained the title compounds as a pale yellow oil, 0.35 g., having Rf 0.63 (TLC on silica gel in acetone), and infrared absorption peaks at 3300, 3100, 1735, 1715, 1645, 1555, 1070, 1055, 1020, and 965 cm-'.
Preparation 8 6-Oxo-POF10, n-Butylamide I. There is first prepared (5Z)-9-deoxy-6,9&alpha;-epoxy-#5-PGF1, n-butylamide. A solution of 5g-iodo-6{,9a-epoxy-PFG1 n-butylamide (Preparation 7, 3.5 g.) in 100 ml. of benzene is treated with 8 ml. of DBN at 40-450C. for about 16 hr. The mixture is cooled, diluted with ice water, and extracted with chloroform, keeping a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and concentrated to an oil, 3.64 g. Of this 3.1 g. is taken up in warm diethyl ether, and the ether solution when cooled yields 1.5 g., mainly solid. The product is recrystallised from diethyl ether, 0.85., m.p. 102 104 C.
II. A solution of the above (5Z)-9-deoxy-6,9&alpha;-epoxy-#5-PGF1, n-butylamide (3.0 g.) in 25 ml. of tetrahydrofuran is treated with sufficient 10% aqueous potassium hydrogen sulfate solution to bring the pH to 5.0. The mixture is concentrated to remove tetrahydrofuran and the residue is taken up in water and ethyl acetate. Sodium chloride is added to saturation and the organic phase is separated. The aqueous phase is extracted with acetone-ethyl acetate (1:4) and the organic phases are combined. The organic phases are washed with brine, dried, and concentrated. The residue, 2.10 g., is chromatographed on silica gel, eluting with acetone (33-100%)-methylene chloride to yield a 1:1 mixture of the title compound together with the corresponding 9-deoxy-6,9a.epoxy.6-hydroxy compound, having Rf 0.57 (TLC on silica gel in acetone). The mixture is dissolved in 10 ml. of tetrahydrofuran and acidified with aqueous potassium hydrogen sulfate, thereby converting the mixture to substantially all 6-oxo-PGF1ft-, n- butylamide, having Rf 0.58 (TLC on silica gel in acetone). The product is recovered by concentrating the solution, portioning between ethyl acetate and water, washing the organic phase with brine, and concentration to an oil, 1.90 g., having a high resolution mass spectral peak (TMS derivative) at 641.4258.
Preparation 9 5{-Iodo-9-deoxy-6D-9a-epoxy-PGF" Benzylamide, mixed isomers (Formula VII) Following the procedures of Preparation 6, there are used 4.66 g. of the formula-VII 5#-iodo-9-deoxy-6#-9&alpha;-epoxy-PGF1, mixed isomers, and 1.08 g. of benzylamine instead of methylamine. The crude product is chromatographed on silica gel, eluting with acetone (50-70%)-methylene chloride, to yield the 5#-iodo- 9-deoxy-6#,9&alpha;-epoxy-PGF1, benzylamide mixed isomers, 4.1 g., having NMR peaks at 7.3 6.6, 5.3-5.7, and 3.5-4.6 #.
Preparation 10 5#-Iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, Anilide, mixed isomers (Formual VII) Following the procedures of Preparation 6, there are used 4.66 g. of the formula-VII 5#-iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, mixed isomers, and 0.94 g. of aniline. The crude product is chromatographed on silica gel, eluting with acetone (10-50%)-methylene chloride, to yield the 5#-iodo-9-deoxy-6#,9&alpha;-epoxy-PGF1, anilide mixed isomers, 4.0 g., having NMR peaks at 8.4 6.9-7.7, 5.3-5.7, and 3.4.7 8.
Example 1 6-Oxo-PGE1, Methyl Ester A. Refer to Sequence A. A solution of formula-III 6-oxo-PGF1&alpha;, methyl ester (0.50 g.) in 25 ml. of methylene chloride is treated with 3 ml. of dihydropyran and 3 ml. of a saturated solution of pyridine hydrochloride in methylene chloride and left standing about 5 hr. at about 25 C. or until TLC shows that the starting material has disappeared and that the bis(tetrahydropyranyl) ether has been formed, having Rf 0.22 (TLC) on silica gel in acetone-methylene chloride (1:9)) or Rf 0.47 (TLC on silica gel in acetone-methylene chloride (1:3)). The reaction mixture is concentrated, washed with aqueous sodium bicarbonate and brine, dried, and concentrated. The residue is subjected to silica gel chromatography, eluting with acetone (1025%) in methylene chloride to yield the formula-IV 11,15bis(tetrahydropyranyl)ether, methyl ester, having infrared peaks at 3500, 1745, 1730, 1200, 1160, 1130, 1110, 1075, 1035, 1020,980,915, 870, 815, and 735 cm mass spectral lines (TMS) at 552, 522, 366, 348, 331, 330, 304, and 85; and NMR spectral peaks at 5.5, 4.67, 3.65, 3.2-3.7, and 0.9 8.
B. The reaction product from part A, containing 6-oxo-PGF", 11,15bis(tetrahydropyranyl)ether, methyl ester corresponding to formula IV, is oxidized to compound V. A composite from several lots, weighing 0.93 g., in 20 ml. of acetone is treated at -100C. with 2.0 ml. of Jones reagent. After stirring for 1.5 hr. the reaction mixture is quenched with isopropanol and extracted with diethyl ether.
The extract is washed with brine, dried, and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (20-50%)-Skellysolve B to yield the formula-V 6-keto-PGE1, bis(tetrahydropyranyl)ether, methyl ester, 0.52 g., having Rf0.52 (TLC on silica gel in ethyl aetate-Skellysolve B (1:1)); and infrared peaks at 1745 and 1725 cm-1 (free of OH at 3000-3500).
C. The product of part B is hydrolyzed in 3 ml. of acetic acid and 1.5 ml. of water at 400 C. for 3 hr., then mixed with brine and extracted with chloroform. The organic phase is washed with brine, dried, and concentrated. The residue is subjected to silica gel chromatography eluting with ethyl acetate (25100 ,n)- Skellysolve B to yield 0.15 g. of the title compound, having infrared peaks at 3380, 1750, 1710, 1250, 1200, 1180, 1105, 1070, and 975 cm-', and mass spectral lines (TMS) at 526.3123, 511, 508, 495, 455, 436, 382, 313.2004, and 199. An analytical sample, recrystallized as needles from diethyl ether-hexane, m. 39--40"C., has Rf 0.33 (TLC on silica gel in ethyl acetate).
Example 2 6-Oxo-PGE1 A. Refer to Sequence B. There is first prepared the formula-VIII bis(tetrahydropyranyl)ether of 9-deoxy-6,9-epoxy-5-iodo-PGF1,z, methyl ester. The formula-VII product of Preparation 1(2.0 g.) in 20 ml. of methylene chloride, together with 4 ml. of dihydropyran and 1 ml. of a saturated solution of pyridine hydrochloride in methylene chloride, is left standing 16 hr. at about 25"C. The mixture is washed with aqueous sodium bicarbonate and brine, dried and concentrated to a colorless oil. The residue is subjected to silica gel chromatography, eluting with acetone (10%)-methylene dichloride, to yield about 3.0 g. having Rf 0.73 (TLC on silica gel in ethyl acetate); and infrared peaks at 1765, 1215, 1140, 1085, 1045, 1036, 985, 875, 820, and 740 cm-' (free of OH at 3000 3500).
B. The formula-IV 6-oxo-PGF-type compound is prepared in several steps as follows. The product of part A above (about 3.0 g.) is mixed with 100 ml. of benzene and 4 ml. of 1,5-diayabicycp[4.3.0]nonene-5 (DBN) and held at 40 C. for 4 hr., then at about 25 C. for 64 hr. The mixture is washed with ice-water, dried over magnesium sulfate, and concentrated to the enol ether, 9-deoxy-6,9-epoxy-#5- PGF1&alpha;, bis(tetrahydropyranyl)ether, methyl ester, 2.5g. having NMR peaks at 5.55, 4.5-5.1, 3.2-4.5, and 0.9 #; and infrared peaks at 1740, 1695, 1200, 1165, 1130, 1075, 1035, 1020, 975, and 870 cm-'.
The enol ether (2.25 g.) is dissolved in 25 ml. of diethyl ether, mixed with 10 ml. of a dilute aqueous solution of potassium hydrogen sulfate and stirred at about 25"C. The reaction is monitored by TLC (silica gel plates in acetone (10 /O)- methylene chloride) as a more polar material is slowly formed. After several hours 50 ml. of tetrahydrofuran is added and stirring continued. The mixture is concentrated and the residue is extracted with ethyl acetate. The extract is washed with brine, dried, and concentrated to an oil. The residue is subjected to silica gel chromatography eluting with acetone (1025 X ,)-methylene chloride to yield the formula-IV 6-oxo-PGF1a- bis(tetrahydropyranyl)ether, methyl ester, 1.91 g., having Rf 0.22 (TLC on silica gel in acetone (l0%)-methylene chloride), having the same infrared spectrum as the corresponding formula-IV intermediate of Example 1.
C. The acid form of the product of part B is prepared by saponifying that product. The methyl ester of part B (0.75 g.) in 25 ml. methanol and 7 ml. of 3 N. sodium hydroxide is stirred at about 25 C. for 3 hr. The mixture is chilled, saturated with sodium chloride, acidified with potassium hydrogen sulfate, and extracted with ethyl acetate. The extact is washed with brine, dried, and concentrated to an oil, 0.68 g., having Rf 0.61 (TLC on silica gel in A-IX solvent).
D. The formula-V 6-oxo-PGE-type compound is obtained as follows. The product of part C (0.68 g.) in 50 ml. of acetone is cooled to -lS0C. and treated with 2 ml. of Jones reagent added slowly with stirring. Stirring is continued at about the same temperature for one hr., then at -5"C. for 0.5 hr. The reaction is quenched with isopropanol and the mixture concentrated to about half volume. Brine is added and the mixture extracted with diethyl ether. The extract is washed with brine, dried, and concentrated to a yellow oil, 0.61 g., having Rf 0.64 (TLC) on silica gel in A-IX). After silica gel chromatography a fraction is obtained, 0.31 g.
E. The title compound is finally obtained on hydrolysis of the blocking groups.
The product of part D (0.31 g.) is treated in 7ml. of acetic acid and 3 ml. of water at 40 C. for one hr. and a further 16 hr. at about 25 C. Brine is added and the mixture is extracted with chloroform. The extract is washed with water, dried, and concentrated to an oil, 0.25 g. This product is subjected to silica gel chromatography, eluting with ethyl acetate (25-l00%)-hexane to obtain the title compound, 0.065 g. having NMR peaks at 5.72, 5.57, 3.84.3, 2.1-2.8, and 0.9 b: and infrared absorption peaks at 3420, 3000, 2800, 1755, 1740, 1710, 1315, 1255, 1190, 1160, 1110, 11065, and 970. An analytical sample is obtainedas needles on recrystallizing from diethyl ether-hexane, m. 67-69 C.
Following the procedures of Example 2, but replacing the preparation of the formula-IV 6-oxo-PGF-type compound in part B with a preparation using silver carbonate and perchloric acid, the same end product is obtained. Thus, instead of part B, the product of part A (2.5 g.) is mixed witth 80 ml. of tetrahydrofuran, silver carbonate (one gram) and 7 drops of 70% perchloric acid. The mixture is stirred vigorously at about 25"C. for 22 hr. Additional perchloric acid (3 drops) is added and stirring continued for 4 hr. The mixture is filtered, the filtrate treated with brine and sodium carbonate, and extracted with ethyl acetate. The extract is washed with brine, dried, and concentrated to an oil, 2.6 g. Silica gel chromatography, eluting with acetone (10-40%)-methylene chloride, yields the formula-IV 6-oxo-PGF"=, bis(tetrahydropyranyl)ether, methyl ester, an oil, 0.52 g., having Rf 0.35 (TLC on silica gel in ethyl acetate-cyclohexane (1:1)). Thereafter the 6-oxo-PGE, product is obtained following parts C, D, and E above. 6-Oxo-PGF, can be converted to its sodium salt.
Following the procedures of Examples 1 and 2 and Sequence B but replacing the formula-VII starting material with the appropriate formula-VII compounds obtained following Preparations 1, 2 and 3, there are obtained formula-VI compounds as follows: 2,2-Difluoro-6-oxo-PGE1, methyl ester (ISS)-l 15-Methyl-6-oxo-PGE, (1 SR)-l S-Methyl-6-oxo-POE1 16,1 6-Dimethyl-6-oxo-PGE, 2,2-Difluoro-16,16-dimethyl-6-oxo-PGE1, methyl ester 2,2-Difluoro-(15S)-15-methyl-6-oxo-PGE1, methyl ester 16-Phenoxy- 17,18,19,20-tetranor-6-oxo-PGE, 16-Phenyl-17,18,1 9,20-tetranor-6-oxo-PGE, 17-Phenyl- 18,19,20-trinor-6-oxo-PGE, 2,2-Difluoro-16-phenoxy- 17,18,19,20-tetranor-6-oxo-PGE" methyl ester 13,14-Dihydro-6-oxo-PGE1 2,2-Difluoro-13,14-dihydro-6-oxo-PGE1, methyl ester 2,2-Difluoro-13,14-didehydro-6-oxo-PGE1, methyl ester.
Preparation 11 6-Oxo-13,14-didehydro-PGF1&alpha;, 11,15-bis(tetrahydropyranyl)ether(Formula XVIII) A. Refer to Chart C. The 5#,6#,14-tribomo-15-oxo-PGF1&alpha;, methyl ester (XII) is first prepared. A solution of 15-deoxy-15-oxo-PGF2&alpha;, methyl ester (U.S. Patent Specification No. 3,728,382, 3.38 g. in about 25 ml. of pyridine is treated dropwise with a solution of pyridinium hydrobromide perbromide (7.08 g.) in 35 ml. of pyridine over 2.25 hr. Thereafter the mixture is stirred for 27 hr., diluted with ether and filtered. The filtrate is washed with water, cold hydrobromic acid (5%) aqueous sodium bicarbonate (5%), then dried and concentrated to yield 3.72 g. product.
Similarly an additional 1.06 g. is prepared and combined. The product is subjected to silica gel chromotography eluting with hexane-ethyl acetate (65:35) to yield XII, 2.83g., having NMR peaks at 0.90, 1.1-2.58, 2.58-3.4, 3.4-3.88, 3.67, 3.88-4.61, 6.96, and 7.03#; infrared peaks at 3400, 1730, 1585, 1610, 1245, 1200, 1170, 1085, and 1050 cm-1; and mass spectral peaks (TMS) at 746.0562, 636, 634, 632, 630, 555, 553, and 551.
There is also obtained, as a separate fraction from the chromatography of the reaction product, 5#-bromo-9-deoxy-6#,9-epoxy-14-bromo-15-deoxy-15-oxo- PGF1&alpha;, methyl ester, 0.93 g., having NMR peaks at 0.90, 1.10-3.03, 3.03-3,46, 3.65, 3.78-5.0, 6.91 and 7.00 #; infrared peaks at 3480, 2880, 2810, 1735, 1690, 1615, 1245, 1200, 1175, 1150, and 1080 cm-'; and mass spectral peaks (TMS concentrated to a mixture of C-15 epimers (XIII). Separation is achieved by silica gel chromatography eluting with hexane-ethyl acetate (3:2 followed by 1: 1), to yield first, the 15R epimer (XIII-15ss), 1.57 g. having NMR peaks at 0.9, 1.1-3.35, 3.35- 4.65, 3.66, and 5.75-6.21 #; infrared peaks at 3380, 1735, 1725, 1250, 1200, 1175 1075, and 1050 cm-1; high resolution mass spectral peak (TMS derivative) at 749.0362, and [&alpha;]D-11 in ethanol; and second, the 15S epimer (XIII-15&alpha;) 0.605 g. having NMR peaks at 0.9, 1.10-3.35, 3.35-4,6, 3.66, and 5.65-6.15 #; infrared peaks at 3380, 1740, 1650, 1435, 1250, 1175, 1120, 1080, and 1045 cm-1; high resolution mass spectral peak (TMS derivative) at 749.0384; and [&alpha;]D-4 in ethanol.
C. 14-Bromo-PGF2,t, methyl ester (XIV). A solution of XIII-lSa (0.60 g.) in 20 ml. of methanol is treated with ammonium chloride (0.11 g.) and zinc dust (0.28 g.).
The mixture is stirred for 1.5 hr., diluted with benzene and filtered. The filtrate is washed with 0.2 M. potassium acid sulfate, dried, and concentrated to yield 0.37 g., having Rf 0.26 (TLC on silver nitrate-treated silica gel in ethyl acetate); NMR peaks at 0.88, 1.1-2.71-3.55, 3.66, 3.80-4.35, 5.23-5.56 and 5.84 #; and infrared peaks at 3320, 2900, 2820, 1940, 1650, 1430, 1310, 1240, 1215, 1170, 1115, and 1030 cm-'.
D. 55-Iodo-9-deoxy-65,9-epoxy- 14-bromo-PGF,,, methyl ester (XV). A solution Of XIV (1.9 g.) in 30 ml. of methylene chloride is added to a suspension of iodine (2.85 g.), potassium iodide (1.88 g.) sodium acetate (0.92 g.) and water (6 ml.). The mixture is stirred for 2 hr., treated with 20 ml. of 2N. sodium thiosulfate, washed with aqueous 5% saline solution, dried and concentrated to yield XV, 2.95 g. an analytical sample obtained by subjecting a portion to silica gel chromatography had NMR peaks at 0.89, 1.1-3.18, 3.66, 3.6-4.8, and 5.88 #; mass spectral peaks (TMS) at 701.1183, 645, 637, 589, 547, 529, 510, and 173; and infrared spectral peaks at 3380; 1740, 1655, 1230, 1170, 1080, and 1050 cm-'.
E. 55-Iodo-9-deoxy-65,9-epoxy- [4-bromo-PGF1&alpha;, 11,1 5-bis(tetrahydropyranyl) ether, methyl ester (XVI). A solution of XV (1.0 g.) in 10 ml. of methylene chloride is treated with dihydropyran (3 ml.) and 3 ml. of a saturated solution of pyridine hydrochloride in methylene chloride. After 20 hr. the mixture is diluted with diethyl ether, washed with aqueous sodium bicarbonate (5%) and saline solution (5%), dried and concentrated. The residue is 1.12 g., having NMR peaks at 0.9, 1.05-2.20, 2.2-3.2, 3.2-4.35, 3.66, 4.35-4.15, and 5.7-6.1 #; and infrared peaks at 2900, 2820, 1760, 1440, 1350, 1210, 1125, 1090, 1035, 970, and 910 cm-1.
F. 6-Oxo-13,14-didehydro-PGF1&alpha;-PGF1&alpha;, 11,15-bis(tetrahydropyranyl)esther (XVII). A solution of XVI (1.1 g.) in 15 ml. of dimethyl sulfoxide and 1.5 ml. of methanol is treated with potassium t-butoxide (0.504 g.) for 20 hr. The mixture is diluted with 60 ml. of water, cooled, acidified, with 5% phosphoric acid, and extracted with diethyl ether. The organic phase is washed with brine, dried, and concentrated to an oil, 0.81 g., which is subjected to silica gel chromatography, eluting with hexane-ethyl acetate (7.5:2.5) to yield the title compound, 0.313 g., having NMR peaks at 0.9, 1.1-3.0, 3.05-5.1, and 6.5-7.5 #; and infrared peaks at 3300, 3900, 2810, 25002700, 2225, 17409, 1710, 1430-1460, 1190, 1120, 1075, 1035, 1015, 975 and 905 cm-1.
Example 3 6-Oxo-13,14-didehydro-PGE1.
Refer to Chart A. A solution of the formule-IV 6-keto-13,14-didehydro-PGF1&alpha;, 11,15-bis(tetrahydropyranyl)ether (Preparation 11, 1.1 g.) in 12 ml. of acetone is treated at -10 C. with 2.67 M. Jones reagent added dropwise in three 1 ml. aliquots at 15 min. intervals. The mixture is quenched with isopropanol added dropwise, diluted with diethyl ether, and partitioned with 5% aqueous sodium chloride, dried, and concentrated. The residue consists of the formula-V bis(tetrahydropyranyl)ether of the title compound, 0.26 g., having Rf 0.29 (TLC on silica gel in A-IX-cyclohexane (1:1)).
The product above is hydrolyzed in a mixture of acetic acid (15 ml.), water (7.5 ml.) and tetrahydrofuran (1.0 ml.) for 4.5 hr. at about 40 C., then diluted with 30 ml. of water and lyophilized to a yellow oil, 0.14 g. the oil is subjected to silica gel chromatography, eluting with hexane-ethyl acetate (3:2), to yield the title compound, 0.048 g., having NMR peaks at 0.90, 1.1-2.05, 2.05-3.33, 4.03-4.70, and 5.5-6.3 # mass; spectral peaks (TLC) at 582.3210, 567, 511, 492, 477, 436, 421, 410, 402, 387, 291.1768, 173, and 111; and infrared peaks at 3350, 2870, 2500-2600, 2810, 2240, 1740, 1710, 1450, 1400, 1155, and 1080 cm-l Preparation 12 6-Oxo-13,14-didehydro-PGF1&alpha; (Formula III) A solution of the 5#-iodo-9-deoxy-6#,9-epoxy-14-bromo-PGF1&alpha;, methyl ester (Preparation IID, 1.67 g.)in 30 ml. of dimethyl sulfoxide is treated with potassium tert-butoxide (1.63 g.) in 3 ml. of methanol at about 25 C. for 23 hr., then diluted with water (6 ml.) and reacted for a further 3 hr. The mixture is diluted with ether and partitioned with cold 3.5% phosphoric acid. The organic phase is washed with 5% sodium chloride solution, dried, and concentrated. The residue (0.87 g.) is subjected to silica gel chromatography eluting with hexane-ethyl acetate (1:1) to yield the formula-III title compound, 0.59 g., having NMR peaks at 0.90, 1.1-3.5, 3.7-5.2, and 5.28-6.51 S; mass spectral peak (TMS derivative) at 670.3836; and infrared absorption peaks at 3360, 2670, 2230, 1710, 1320, 1245, 1205, 1145, 1115, 1090, 1055, and 995 cm-'.
* Preparation 13 6-Oxo-13,14-didehydro-PGF1&alpha; and 6-Oxo-13,14-didehydro-(15R)-PGF1&alpha;.
A. There are first prepared the 5#-bromo-9-deoxy-6#,9-epoxy-14-bromo (15R and 15S)-PGF1&alpha; methyl ester compounds. A solution of the 5#-bromo-9-deoxy- 6#,9-epoxy-14-bromo-15-deoxy-15-oxo-PGF1&alpha;, methyl ester (Preparation 11A, 0.93 g.) in 15 ml. of methanol is added to a solution of sodium borohydride (0.46 g.) in 50 ml. of methanol at -50 C. The reaction is continued at about -30 C. for 1.5 hr. the mixture is carefully acidified with 5 ml. of acetic acid in 250 ml. of diethyl ether.
The solution is washed with 0.2 M. potassium hydrogen sulfate, 5% sodium chloride, and 5% sodium bicarbonate, then dried and concentrated to yield the mixed C-15 epimers. The product is combined with 0.39 g. from another run and subjected to silica gel chromatography, eluting with hexane-ethyl acetate (7:3). The respective fractions containing the 15R and 15S products yield 0.34 g. of the 15R and 0.34 g. of the 15S intermediate. The 15R compound has NMR peaks at 0.90, 1.1-2.75, 2.75-3.30, 3.66, 3.78-4.8, 5.80 and 5.90 #; and infrared peaks at 3350, 1710, 1650, 1430, 1365, 1240, 1190, 1070, and 1050 cm-1. The 15S compound has NMR peaks at 0.89, 1.1-3.2, 3.2-4.8, 3.66, 5.78, and 5.83 #; and infrared peaks at 3350, 1740, 1650, 1430, 1365, 1240, 1190, 1070, and 1050 cm-1.
B. A solution of the 15-S product from part A above (0.29 g.) in 5 ml. of dimethyl sulfoxide and 0.5 ml. of methanol is treated with potassium tert-butoxide (0.3 g.) for 20 hr. On hydrolysis of the methyl ester with 2 N. NaOH for 3 hr. followed by dilution with 5% sodium chloride, acidifying with 10% phosphoric acid, extraction with diethyl ether, washing with 5% sodium chloride, drying, and concentrating there is obtained 0.20 g. residue. The residue is subjected to silica gel chromatography, eluting with hexane-ethyl acetate (1:1 to 3:2), to yield the 15S title compound, 0.065 g., having the same properties as the product of Preparation 12.
Likewise, using the 1SR intermediate of part A there is obtained the corresponding 15R title compound having Rf 0.20 (TLC on silica gel plates in A-IX solvent).
Following the procedures of Example 4 Part B but substituting sodium methoxide for potassium tert-butoxide there as also obtained the title compounds.
Example 4 6-Oxo-13,14-didehydro-(15R)-PGE1 A. Refer to Sequence C. There is first prepared the formula XIV 14-bromo (15R)-PGF2&alpha;, methyl ester. Following the procedure of Preparation 11C above, the formula-XIII-15ss compound, (15R)-5#,6#,14-tribromo-PGF1&alpha;, methyl ester (1.52 g.) is treated with zinc dust and ammonium chloride in methanol to yield the formula XIV 15R compound, 1.13 g., having Rf (0.40 (TLC on silver nitrate-treated silica gel in ethyl acetate), NMR and infrared spectra very similar to those of the 15S epimer of Preparation 11 C.
B. 5N-Iodo-9-deoxy-6g,9-epoxy-14-bromo-(15R)-PGF,&num;=, methyl ester (XV).
Following the procedure of Preparation 1 lD, the formula-XIV 14-bromo-(15R) PGF2x" methyl ester (0.98 g.) is iodinated to the formula-XV iodo compound. The product is chromatographed on silica gel, eluting with ethyl acetate (30%)-hexane to yield the desired compound, 0.88 g., having NMR and infrared spectra very similar to those of the 15S epimer of Preparation 11D.
C. 5# - Iodo - 9 - deoxy - 6#,9- epoxy - 14 - bromo - (15R) - PGF1&alpha;, 11,15 bis(tetrahydropyran - 2 - yl ether), methyl ester (XVI). Following the procedure of Preparation 1 lE, the formula-XV 5 - iodo - 9 - deoxy - 6g,9 - epoxy - 14 bromo - (15R) - POF1a, methyl ester (2.16 g.) is reacted with dihydropyran to form the formula-XVI bis (THP ether). .24 g., having Rf 0.57 and 0.62 (TLC) on silica gel in ethyl acetate-cyclohexane (1:2) and having NMR and infrared spectra very similar to those of 15S epimer of Preparation 1 lE.
D. 6 - Oxo - 13,14 - didehydro - (15R) - Podia, 11,15 bis(tetrahydropyran - 2 - yl ether) (XVI I). Following the procedure of Preparation I IF, the formula-XVI 56 - iodo - 9 - deoxy - 6#,9-epoxy - 14 - bromo - (15R) PGF", 11,15 - bis(tetrahydropyran - 2 - yl ether), methyl ester (3.27 g.) is reacted with potassium t-butoxide in dimethyl sulfoxide-methanol removing a less polar byproduct by silica gel chromatography, to yield the product, 0.74 g., having Rf 0.51 (TLC on silica gel in a solvent prepared by diluting the organic phase from ethyl acetate-acetic acid-cyclohexane-water (9:2:5:10) with half its volume of cyclohexane), and having NMR and infrared spectra very similar to those of the 15S epimer of Preparation 11 F.
E. 6-0xo-13,14-didehydro-(ISR)-PGE,, 11,15-bis(tetrahydropyran-2-yl ether) (V). Refer to Sequence A. Following the procedure of Example 3, the formula XVII (or IV) 6-oxo-13,14-didehydro-(15E)-PGF1&alpha;, 11,15-bis(tetrahydropyran-2-yl ether) (0.46 g.) is oxidized with Jones reagent to the formula-V compound, 0.23 g., having Rf 0.55 (TLC on silica gel in the solvent of section D above, having NMR peaks at 0.90, 1.1-3.2, 3.2-4.65, 4.65-5.2 and 8.91 S, and infrared absorption bands at 2600-3200, 2220, 1740, 1710, 1195, 1120, 1070, 1035, 995, 980, 965, and 910 cm-l.
F. 6-Oxo-13,14-didehydro-(15R)-PGE,. Following the procedure of Example 3, the above bis(THP ether) (0.23 g.) is hydrolyzed and chromatographed to yield the title compounds, 0.10 g., m.p. 720C. when crystallized from diethyl ethermethylene chloridehexane, having Rf 0.36 (TLC on silica gel in the organic phase from ethyl acetate-acetic acid-cyclohexane-water (9:2:5: 10)), having NMR peaks at 0.90, 1.1-2.0, 2.03.2, 3.9-4.7, and 6.06.7 S, and mass spectral peaks (TMS derivative) at 567.299, 564, 549, 511, 492, 477, 421, 402, 387, 367, 201, and 111.
Example 5 2-Decarboxy-2-hydroxymethyl-6-oxo-PGE, (Formula XXV) I. Refer to Sequence D. There is first prepared the formula-XXIII 4,5acetylenic PGF1f, type compound. The formula-XXII bis(THP ether) lactone (Corey et al., J. Am. Chem. Soc. 92, 397 (1970)) (6.5 g.) in 30 ml. of tetrahydrofuran is reacted with 4-trimethylsilyloxy-1-pentynyl-lithium (C. H. Lin, J. Org. Chem. 41, 4045 (1976) (3.6 g.) at -70 to -600C. for about 0.5 hr. The adduct is isolated and dissolved in 30 ml. of isopropyl alcohol-water (4:1) and treated with about 0.5 ml. of 10% aqueous sodium hydrogen sulfate. The mixture is stirred at about 25 C. for 0.5 hr., treated with about 10 ml. of aqueous sodium bicarbonate, and concentrated to remove isopropyl alcohol. The residue is extracted with diethyl ether and the organic phase is washed with water, aqueous sodium hydrogen sulfate, aqueous sodium bicarbonate, and brine, dried, and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate-hexane (1:5), to yield the formula-XXIII 2decarboxy-2-hydroxymethyl-4,4,5,5-tetrahydro-6-oxo-PGF1&alpha;, 1 l,l5bis(tetrahydropyran-2-yl ether), 5.6 g. having NMR peaks at 5.68-5,36, 4.8- 4.5, and 4.5-3.18 #, infrared absorption peaks at 3440, 2210, 1675 and 975 cm-1, and mass spectral lines (TMS derivative) at 649.3986, 563, 557, 509, 479, 478, 463, and 85.
II. There is next prepared the formula-XXIV 2-decarboxy-2-hydroxymethyl4,4,5,5-tetrahydro-6-oxo-PGE1. The product of I above (2.6 g.) is treated in 50 ml. of acetone with Jones reagent (5.6 ml. of 2.67 M) in 30 ml. acetone added dropwise over 5 min. at -30 C. The reaction is quenched with aqueous sodium bisulfite and the mixture concentrated to remove acetone. The residue is extracted with ethyl acetate and the organic phase is washed with brine, dried, and concentrated. The resulting mixture is then methylated with diazomethane to form the methyl ester of any carboxylic acid present.
The above mixture containing 2-decarboxy-2-hydroxymethyl-4,4,5,5- tetradehydro-6-oxo-PGE1, 11,1 5-bis(tetrahydropyran-2-yl ether) and methyl ester by-products is hydrolyzed in 20 ml. of acetic acid-tetrahydrofuran-water (3:1:1) at 40-45 C. for 3 hr. The mixture is concentrated and the residue extracted with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate and brine, dried, and concentrated. The residue is chromatographed on silica gel (HPLC), eluting with acetone (25-50%)-hexane to obtain the more polar formula XXIV compound, 0.278 g., having NMR peaks at 5.705.42, 4.32-3.80, and 3.23 , infrared absorption bands at 3480, 2210, 1755, 1670, and 970 cm-1, and a high resolution mass spectral peak (TMS derivative) at 566.3299.
III. Finally, the title compound is obtained by catalytic hydrogenation of the above compound. The formula-XXIV compound of II above (0.35 g.), together with 35 mg. of palladium on barium sulfate and 5 ml. of pyridine is stirred under hydrogen at one atmosphere at about 25"C. for 0.5 hr. The solids are removed by filtration and the filtrate is concentrated. The residue is chromatographed on 30- 50 silica gel (HPLC), eluting with acetone-hexane (1:1) to yield the formula-XXV title compound, 0.178 g., having NMR peaks at 5.72-5.42, 4.34-3.78, and 3.60 #, infrared absorption bands at 3360, 1745, 1701, 1590, 1160, 1070, 1015, and 970 cm-1, and mass spectral lines (TMS derivative) at 570.3563, 555, 552, 499, 480, 465, 426, 409, 383, 375, 355, and 313.
Following the procedures of Example 6 and Sequence D, but replacing the formula-XXII starting material with the appropriate lactone known in the art, there are obtained the following formula-XXV compounds.
2-Decarboxy-2-hydroxymethyl-6-oxo- 1 6-phenyl- 17,18,19,20- tetranor-POE1, 2-Decarboxy-2-hydroxymethyl-6-oxo-( l SS)- 15-methyl-PGE 2-Decarboxy-2-hydroxymethyl-6-oxo- 13,14-dihydro-PGE 2-Decarboxy-2-hydroxymethyl-6-oxo-13,14-didehydro-PGE1, Alternatively, the 13,14-dihydro- and 13,14-didehydro- compounds are obtained by transformations of the above product of Example 5 or the formula XXIV intermediate of Example 5 using methods known in the art.
Example 6 6,l5-Dioxo-l5-deoxy-PGE1 (Formula XXXV) I. Refer to Sequence E. The formula-XXX 11,15-bis(tetrahydropyran-2-yl ether) of 6-oxo-PGF1,, methyl ester is first prepared. A solution of 6-oxo-PGF1,t, methyl ester (Johnson et al., J. Am. Chem. Soc. 99, 4182 (1977)) (0.3 g.) in 10 ml. of methylene chloride is treated with 2 ml. of dihydropyran and one ml. of a saturated solution of pyridine hydrochloride in methylene chloride and left standing at about 25"C. for several days. The mixture is washed with aqueous sodium bicarbonate, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone (0-20%)-methylene chloride, to yield the bis(THP ether), 0.23 g., having R, 0.20 (TLC on silica gel in acetone (10%)-methylene chloride).
II. There is next prepared the formula-XXXII acid. The product above, combined with another lot of similar material (total 1.30 g.) is stirred with 40 ml. of methanol and 10 ml. of 3 N sodium hydroxide at about 25"C. for 3 hr. The mixture is cooled in an ice bath, saturated with sodium chloride, acidified with potassium hydrogen sulfate and immediately extracted with ethyl acetate. The organic phase is washed with brine, dried, and concentrated. The acid has Rf 0.52 (TLC on silica gel in A-IX system).
III. There is next prepared the formula-XXXIV 15-oxo compound. The above product is immediately dissolved in 75 ml. of acetone, cooled to -150C., and treated with 3 ml. of Jones reagent added slowly within 30 min. Stirring is continued for one hr., allowing the temperature to rise to -30C.; then 0.5 ml. more Jones reagent is added, again at -100C. and stirring continued for 45 min. The reaction is quenched with isopropyl alcohol, dried, and concentrated to an oil, about 1.5 g.
IV. Finally, the title compound is obtained by hydrolysis. The above formula XXXIV 6,15-dioxo-PGE1, 1 l-tetrahydropyran-2-yl ether is treated with 12 ml. of acetic acid and 5 ml. of water at 400C. for 3 hrs. Then the mixture is cooled, diluted with brine, and extracted with chloroform. The organic phase is washed with brine, dried, and concentrated. The residue is chromatographed on 100 g. of silica gel, eluting with ethyl acetate (60--1000/,)-hexane, taking 50 ml. fractions and combining fractions 13-20, to yield the formula-XXXV title compound, 0.31 g., having Rf 0.36 (TLC on silica gel in A-IX system), NMR peaks at 7.37, 6.82, 6.18, 4.2, 2.1-2.9, and 0.9 '3, and infrared absorption bands at 3400-3200, 2600, 1745, 1715, 1675, 1630, 1290, 1245, 1160, 1095, 1075, 975, 850, and 735 cm-1.
Example 7 6-Oxo-PGE1, Amide (Formula I).
A solution of 6-oxo-PGE1 (Example 2, 0.17 g.) in 7 ml. of acetone is treated at -10"C. with 0.2 ml. of triethylamine and 0.2 ml. of isobutyl chloroformate. After 10 min. stirring the mixture is treated with 4 ml. of a saturated solution of ammonia in acetonitrile. After 15 min. at -100C. the cooling bath is removed and stirring continued for 5 min. The mixture is then concentrated to one-half volume and diluted with water and ethyl acetate. The organic phase is separated, washed with brine, dried, and concentrated. The oily residue is chromatographed on silica gel, eluting with acetone (40-100P,)-methylene chloride to yield the title compound.
0.075 g. An analytical sample is obtained by crystallizing from ethyl acetate-diethyl ether, a powder m.p. 84--6"C., having Rf 0.23 (TLC on silica gel in methanolacetic acid-chloroform (10:10:80)) and infrared absorption bands at 3540, 3420, 3200, 1745, 1710, 1655, 1620, 1295, 1245, 1160, 1110, 1075, 1025, and 975 cm-1.
Following the procedures of Example 8, but replacing the starting material with (15S)-15-methyl-6-oxo-PGE1 there is obtained the formula-I compound: (15S)-1 5-Methyl-6-keto-PGE, , amide.
Example 8 6-Oxo-PGE,, Methylamide (Formula XL).
I. Refer to Sequence F. There is first prepared the formula-XXXVII 11,15bis(tetrahydropyran-2-yl ether). A mixture of the formula-VII 55-iodo-9-deoxy- 6,9a-epoxy-PGF1, methylamide (Preparation 6, 1.2 g.) in 25 ml. methylene chloride, with 2 ml. of dihydropyran and 25 mg. of p-toluenesulfonic acid monohydrate is stirred at about 25"C. for one hr. The mixture is then diluted with 75 ml. of methylene chloride, washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated. The residue, an oil, is chromatographed on silica gel, eluting with acetone (590%)-methylene chloride to yield the bis(THP ether) of the 5-iodo compound, mixed isomers, an oil, 1.6 g., having Rf 0.10 and 0.03 (TLC on silica gel in acetone (10 /n)-methylene chloride).
II. There is next prepared the formula-XXXVIII 6-oxo-PGF1Q, methylamide, 11,1 5,-bis(tetrahydropyran-2-yl ether). A solution of the above formula-XXXVII compound in 60 ml. of tetrahydrofuran is treated with silver carbonate (0.75 g.) and about 0.3 ml. of perchloric acid, with stirring at about 25"C. for 20 hr. The mixture is filtered, diluted with ethyl acetate, washed with brine, dried, and concentrated to an oil, 1.4 g. The residue is chromatographed on silica gel, eluting with acetone (10--60%)-methylene chloride, to yield the formula-XXXVIII compounds, 0.48 g., having Rf 0.26 (TLC on silica gel in acetonemethylene chloride (1:1)).
III. Next is prepared the formula-XXXIX 6-oxo-PGE1, methylamide, 11,15bis(tetrahydropyran-2-yl ether). A solution of the above formula-XXXVIII compound (0.48 g.) in 15 ml. of acetone is treated at -15 to -20"C. with one ml. of Jones reagent added dropwise and stirred for 45 min. Thereafter one ml. of isopropyl alcohol is added, with stirring for about 30 min. Brine and ethyl acetate are added and the organic phase is washed with brine, dried, and concentrated to an oil, 0.42 g., consisting of the title compound as its bis(THP ether).
IV. Finally, the above formula-XXXIX bis(THP ether) (0.42 g.) is treated in 9 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at 400C. for 3.5 hr. The solution is diluted with 15 ml. of water and freeze-dried. The residue is taken up in 10 ml. of methylene chloride and chromatographed over silica gel, eluting with acetone (380%)-methylene chloride to yield the title compound, 0.11 g., having Rf 0.42 (TLC on silica gel in acetone), mass spectral lines (TMS derivative) at 597.3738, 582, 579, 507, 489, and 417, and infrared absorption bands at 3340, 1745, 1705, 1640, 1545, 1270, 1160, 1110, 1075, 1015, and 975 cm-1.
Example 9 6-Oxo-PGE1, n-Butylamide (Formula XL).
I. Refer to Sequence F. There is first prepared the formula-XXXVIIl6-oxo- PGF1Q, n-butylamide, 11,1 5-bis(tetrahydropyran-2-yl ether). A solution of 6-oxo PGF,a, n-butylamide (Preparation 8, 1.47 g.) in 50 ml. of chloroform is treated at about 25"C. with 8 ml. of dihydropyran and 5 ml. of methylene chloride saturated with pyridine hydrochloride. Additional amounts of reagents are added until the reaction is shown completed by TLC. The mixture is then washed with cold aqueous saturated sodium bicarbonate and brine, dried, and concentrated. The residue is chromatographed on silica gel, eluting with acetone-methylene chloride (1:2) to yield the formula-XXXVIII compound, 0.7 g., having Rf 0.41 (TLC on silica gel in ethyl acetate).
II. Next is prepared the formula-XXXIX 6-oxo-PGE1, n-butylamide, 11,15bis(tetrahydropyran-2-yl ether), using 0.7 g. of the above formula-XXXVIII compound and following the procedure of Example 8, Part III, there is obtained 0.39 g. of product, having Rf 0.55 (TLC on silica gel in ethyl acetate) and a strong infrared absorption band at 1740 cm-'.
III. Finally, the title compound is obtained by hydrolyzing the product of II above (0.39 g.) in 2 ml. of glacial acetic acid and one ml. of water at400C. for 3 hr.
The mixture is azeotroped with toluene, concentrating to a solid. The residue is chromatographed on silica gel, eluting with acetone-ethyl acetate (1:1) to yield the title compound, 0.2 g. An analytical sample is obtained on recrystallization from acetone-Skellysolve B, 0.15 g., having Rf 0.20 (TLC on silica gel in ethyl acetate), and m.p. 78--81"C.
Example 10 6-Oxo-PGE1, Benzylamide (Formula XL).
I. Refer to Sequence F. There is first prepared the formula-XXXVII 11,15 bis(tetrahydropyran-2-yl ether). Following the procedure of Example 6-I, the 55- iodo-9-deoxy-6g,9a-epoxy-PGF, benzylamide (Preparation 11, 2.0 g.) is reacted with dihydropyran. The product, an oil is chromatographed over silica gel, eluting with acetone (S-25%)-methylene chloride, to yield the bis(THP ether), 2.4 g., having Rf 0.73 (TLC on silica gel in acetone-methylene chloride (1:1)).
II. There is next prepared the formula-XXXVIII 6-oxo-PGF1, benzylamide, 11,15-bis(tetrahydropyran-2-yl ether) using the above formula-XXXVII compound.
There is first prepared (5Z)-9-deoxy-6,9cr-epoxy-A5-PGF" benzylamide, 11,15- bis(tetrahydropyran-2-yl)ether by treating the formula-XXXVII compound (2.4 g.) in 100 ml. of benzene with 4 ml. of DBN at 40450C. for 22 hr. The mixture is cooled, diluted with 25 ml. of benzene, and washed with 25 ml. of ice water. The benzene solution is dried and concentrated. The residue, an oil, is essentially the enol ether, (SZ)-9-deoxy-6,9a-epoxy-A5-PGF1, benzylamide, 11,15 bis(tetrahydropyran-2-yl ether).
The above product is converted to the formula-XXXVIII 6-oxo compound by treating with 50 ml. of tetrahydrofuran-S% hydrochloric acid (9:1) at about 25"C. for 15 min. The mixture is diluted with 50 ml. of brine and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated to yield the formula-XXXVIII bis(THP ether),
IV. Finally, the title compound is obtained by hydrolyzing the product of III above following the procedure of Example 8-IV. The product is chromatographed on silica gel, eluting with acetone (l(&num;60%)-methylene chloride to obtain the title compound, 0.18 g., having Rf 0.33 (TLC on silica gel in acetone-methylene chloride (1:1)), high resolution mass spectral peak (TMS derivative) at 659.3837, and infrared absorption peaks at 3460, 3400, 3300, 1750, 1725, 1705, 1660, 1600, 1500, 1310, 1290, 1260, 1155, 1100, 1065, 1030, 970, 755, and 690 cm-1.
Example 12 6-Oxo-PGE1, p-Phenylphenacyl Ester Refer to Sequence B. Following the procedures of Example 8, the formula-VII product of Preparation 4, 5#-iodo-9-deoxy-6,9-epoxy-PGF1&alpha;, p-phenylphenacyl ester, is converted, first to its bis(THP ether), ethen to the formula-IV 6-oxo-PGF1#- type compound which is oxidized at the C9 position to the formula-V compound which is finally hydrolyzed to the title compound.
Following the procedures of Example 12 and Sequence B but replacing the starting material with the corresponding p-phenylphenacyl ester made by methods described herein or known in the art, there are obtained the following compounds: (15S)-15-Methyl-6-oxo-PGE1, p-phenylphenacyl ester 16,16-Dimethyl-6-oxo-PGE1, p-phenylphenacyl ester.
Example 13 6-Oxo-PGE1, p-(p-Acetamidobenzamido)phenyl Ester Refer to Sequence B. A solution of the formula-VII 5#-iodo-9-deoxy-6,9- epoxy-PGF1&alpha; (Preparation 3) is converted to the mixed anhydride with isobutyl chloroformate in the presence of triehylamine in acetone solution at about -10 C.
Thereafter the substituted phenyl ester is obtained using p-(pacetamidobenzamido)phenolin pyridine at about 25 C.
Thereafter following the procedures of Example 8, the bis(THP ether) is formed and converted to the formula-IV 6-oxo-PGF" -type compound, which is oxidized at the C-9 position and finally deblocked by mild acid hydrolysis to form the title compound.
Following the procedures of Example 13 and Sequence B, but replacing that starting material of formula VII with the appropriate 5-halo compound and that phenol with the appropriate substituted phenol, there are prepared the following substituted phenyl esters: 6-Oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester (15S)-1 5-Methyl-6-oxo-PGE, , p-(p-acetamidobenzamido)phenyl ester 16,16-Dimethyl-6-oxo-PGE1, p-(p-acetamidobenzamide)phenyl ester (15S)-15-Methyl-6-oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester 16,16-Dimethyl-6-oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester.

Claims (57)

WHAT WE CLAIM IS:
1. A compound of the formula:
or a mixture of the enantiomers thereof; wherein either A is a-hydroxy, p-hydroxy, hydrogen, methylene or ahydroxymethyl and the second 10, 11 bond is absent or A is hydrogen and the second 10, 11 bond is present; wherein D is (1) (CH2)-CR2R'2wherein d is zero or an integer of from one to 5 and R2 and R'2 are the same or different and are each hydrogen, methyl or fluorine, provided that -CR2R2,- is not CFMe-; (2) -CH2O(CH2)x wherein x is one, 2 or 3; or (3) -CH2-CH=CH-; wherein Q is
wherein R8 is hydrogen, methyl or ethyl; wherein R1 is (1)-COOR3 (2)-CH2OH, (3) -CH2NR9R28, (4)-CO NR9R28 or (5) tetrazol-5-yl, wherein R3 is (a) hydrogen, (b) C1-12 alkyl, (c) C3-10 cycloalkyl, (d) C7-12 aralkyl, (e) phenyl, (f) phenyl substitued with one, 2 or 3 chlorine atoms or C1-4 alkyl radicals, (g) -D-NH-CO-D-NH-COCH3, -D-NH-CO-C6H5, -D-NH-CO-CH3, -D-NH-CONH2 or -D-CH=N-NH-COHN2 wherein D is 1,4-phenylene, (h) 2-naphthyl,(i)-CHR11-COR10 wherein R10 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl or2naphthyl and R11 is hydrogen, or benzoyl, or (j) a pharmacologically acceptable cation, R9 is hydrogen, methyl or ethyl, and R28 is hydrogen, C1-4 alkyl, C7-12 aralkyl, phenyl or (C-4 alkyl)phenyl; wherein R4 is (1)-CR5R6-C9H2g-CH3 (2) an optically substituted phenoxyalkyl or phenylalkyl radical of the formula
or (3) cis-CH2-CH=CH-CH2CH3 wherein CgH2g is C1-9 alkylene, with one to 5 carbon atoms in the chain between -CR5R6 and the terminal methyl, R5 and R6 are the same or different and are each hydrogen, C1-4 alkyl of fluorine, provided that -CR5R6- is not -CFalkyl-, Z is --OO-, a valence bond or C1-9 alkylene optionally substitued by one or two fluorine atoms and with one to 6 carbon atoms in the chain between -CR5R6 and the benzene ring, provided the neither R5 nor R6 is fluorine when Z is -O-, T is C1-4 alkyl, C1-4 alkoxy, fluorine, chlorine or trifluoromethyl ans s is zero, one, 2 or 3, provided that not more than two T's are other than alkyl and that, when s is 2 or 3, the T's may be the same or different; and X is trans-CH=CH-, cis-CH=CH-, -C#C- or -CH2CH2; or a C2-8 alkanoate thereof.
2. A compound as claimed in claim 1 wherein A is hydroxy.
3. A compound as claimed in claim 1 or claim 2 wherein D is -(CH2)d- CR2R21- wherein d, R2 and R2, are as defined in claim 1.
4. A compound as claimed in claim 3 wherein D is CH2)3-.
5. A compound as claimed in claim 3 wherein D is -(CH2)2-CF2-.
6. A compound as claimed in any preceding claim wherein X is trans CH=CH-.
7. A compound as claimed in any of claims 1 to 5 wherein X is -C-C-.
8. A compound as claimed in any of claims I to 5 wherein X is -CH2CH2-.
9. A compound as claimed in any preceding claim wherein Q is oxo.
10. A compound as claimed in any of claims 1 to 8 wherein Q is
wherein R8 is as defined in claim 1.
11. A compound as claimed in claim 10 wherein R8 is hydrogen.
12. A compound as claimed in claim 10 wherein R8 is methyl.
13. A compound as claimed in any of claims I to 8 wherein Q is
wherein Ra is as defined in claim 1.
14. A compound as claimed in any preceding claim wherein R, is -COOR3 where R3 is as defined in claim 1.
15. A compound as claimed in any of claims I to 13 wherein R1 is hydroxymethyl.
16. A compound as claimed in any of claims 1 to 13 wherein R1 is -CO NR9R28 wherein R9 and R28 are as defined in claim 1.
17. 6,15-Dioxo-15-deoxy-PGE1.
18. 6-Oxo-PGE, methyl ester.
19. 6-Oxo-PGE,.
20. 6-Oxo-PGE1, sodium salt.
21. 6-Oxo-PGE1, p-phenylphenacyl ester.
22. 6-Oxo-PGE1, p-(p-acetamidobenzamido)phenyl ester.
23. 6-Oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester.
24. 16,16-Dimethyl-6-oxo-PGE1.
25. 16,16-Dimethyl-6-oxo-PGE1, p-phenylphenacyl ester.
26. 16,16-Dimethyl-6-oxo-PGE1, p-(p-acetamidobenzamido)phenyl ester.
27. 16,16-Dimethyl-6-oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester.
28. 16-Phenoxy-17,18,19,20-tetranor-6-oxo-PGE1.
29. 16-Phenyl-17,18,19,20-tetranor-6-oxo-PGE1.
30. 17-Phenyl-18,19,20-trinor-6-oxo-PGE1.
31. 2-Decarboxy-2-hydroxymethyl-6-oxo-keto-PGE1.
32. 2-Decarboxy-2-hydroxymethyl-6-oxo-keto-16-phenyl-17,18,19,20-tetranor PGE1.
33. 6-Oxo-PGE1, amide.
34. 6-Oxo-PGE1, methylamide.
35. 6-Oxo-PGE1, n-butylamide.
36. 6-Oxo-PGE1, benzylamide.
37. 6-Oxo-PGE1, anilide.
38. 15(S)-15-Methyl-6-oxo-PGE1.
39. 15(S)-15-Methyl-6-oxo-PGE1, p-phenylphenacyl ester.
40. 15(S)-15-Methyl-6-oxo-PGE1, p-(p-acetamidobenzamido)phenyl ester.
41. 15(S)-15-Methyl-6-oxo-PGE1, &alpha;-semicarbazono-p-tolyl ester.
42. 2-Decarboxy-2-hydroxymethyl-6-oxo-15(S)-15-methyl-PGE1.
43. (15S)-i 5-Methyl-6-oxo-PGE,, amide.
44. (15R)-15-Methyl-6-oxo-PGE1.
45. 6-Oxo-13,14-didehydro-PGE1.
46. 2-Decarboxy-2-2-hydroxymethyl-6-oxo-13,14-didehydro-PGE1.
47. 13,14-Didehydro-6-oxo-(15R)-PGE1.
48. 13,14-Didehydro-6-oxo-PGE1.
49. 2-Decarboxy-2-hydroxymethyl-13,14-dihydro-6-oxo-PGE1.
50. 2,2-Difluoro-6-oxo-PGE1, methyl ester.
51. 2,2-Difluoro-16,16-dimethyl-6-oxo-PGE,, methyl ester.
52. 2,2-Difluoro-l 6-phenoxy-17,8,1 9,20-tetranor-6-oxo-PGE, , methyl ester.
53. 2,2-Difluoro-(15S)-15-methyl-6-oxo-PGE1, methyl ester.
54. 2,2-Difluoro-13,14-didehydro-6-oxo-PGE1, methyl ester.
55. 2,2-Difluoro-13,14-dihydro-6-oxo-PGE1, methyl ester.
56. A compound as claimed in claim I substantially as described in any of the Examples.
57. A pharmaceutical composition comprising a compound as claimed in any preceding claims in association with a pharmaceutically acceptable carrier.
GB51701/77A 1976-12-30 1977-12-12 6-oxoprostaglandins Expired GB1565604A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US75567476A 1976-12-30 1976-12-30
US75567576A 1976-12-30 1976-12-30
US05/829,678 US4124601A (en) 1976-12-30 1977-09-02 Certain 5-halo-6,9α-epoxy-14-bromo(or chloro)-PGF1 compounds
US05/829,679 US4205178A (en) 1976-12-30 1977-09-02 6-Keto prostaglandin E-type compounds

Publications (1)

Publication Number Publication Date
GB1565604A true GB1565604A (en) 1980-04-23

Family

ID=27505671

Family Applications (1)

Application Number Title Priority Date Filing Date
GB51701/77A Expired GB1565604A (en) 1976-12-30 1977-12-12 6-oxoprostaglandins

Country Status (7)

Country Link
JP (1) JPS5811438B2 (en)
AU (1) AU511711B2 (en)
BE (1) BE862547A (en)
DE (1) DE2753986C2 (en)
FR (1) FR2376134A1 (en)
GB (1) GB1565604A (en)
NL (1) NL190600C (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL51189A (en) * 1976-02-04 1985-08-30 Upjohn Co Prostaglandin analogs
FI71138C (en) * 1976-12-31 1986-11-24 Erba Farmitalia FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ACTIVE BISYCLISKA PROSTAGLANDINER
IT1098350B (en) * 1977-07-28 1985-09-07 Upjohn Co PROSTAGLANDINIC DERIVATIVES
JPS6022710B2 (en) * 1977-09-16 1985-06-03 小野薬品工業株式会社 Prostaglandin-like compounds
IT1089247B (en) * 1977-12-30 1985-06-18 Erba Carlo Spa 5-6-DI HYDRO-PROSTACYCLINE DERIVATIVES
DE2834248A1 (en) * 1978-08-04 1980-02-28 Hoechst Ag NEW PROSTAGLAND DERIVATIVES IN THE DELTA 2-PGF TIEF 2 AND DELTA 2-PGE TIEF 2 SERIES
DE2834249A1 (en) * 1978-08-04 1980-02-28 Hoechst Ag NEW PROSTAGLAND DERIVATIVES IN THE DELTA 2-11-DESOXY-PGF TIEF 2 BZW. PGE DEEP 2 SERIES
DE2913856A1 (en) * 1979-04-06 1980-10-23 Hoechst Ag NEW PROSTAGLAND DERIVATIVES IN THE 6-KETO-PGE TIEF 1 SERIES
DE2946116A1 (en) * 1979-11-15 1981-05-27 Hoechst Ag, 6000 Frankfurt NEW PROSTAGLAND DERIVATIVES IN THE 6-KETO-PGA (DOWN ARROW) SERIES 1 (DOWN ARROW)
DE3315356A1 (en) * 1982-04-30 1983-11-17 Ono Pharmaceutical Co. Ltd., Osaka USE OF PROSTAGLANDINE ANALOGS
JPS5920267A (en) * 1982-07-22 1984-02-01 Ono Pharmaceut Co Ltd Prostaglandin e1-mimic compound, its preparation and treating agent containing said compound
JPS62277352A (en) * 1986-01-30 1987-12-02 Ono Pharmaceut Co Ltd Novel 6-keto-prostaglandin e1 derivative, production thereof and remedy for cytopathy containing said derivative as active component
US4981872A (en) * 1987-01-19 1991-01-01 Sankyo Company Limited Prostaglandin derivatives, their preparation and their therapeutic use
US5219885A (en) * 1987-02-16 1993-06-15 Froelich Juergen Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration
DE3704825A1 (en) * 1987-02-16 1988-08-25 Froelich Juergen PROSTAGLANDIN E1 DERIVATIVES AS PHARMACEUTICAL ACTIVE SUBSTANCES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, IN PARTICULAR FOR TRANSCUTANEAL USE
DE3708537A1 (en) * 1987-03-13 1988-09-22 Schering Ag 6-OXOPROSTAGLANDIN-E DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE
JPH053100Y2 (en) * 1988-04-28 1993-01-26
ATE306256T1 (en) 1999-08-05 2005-10-15 Teijin Ltd AGENTS FOR IMPROVING NEUROPATHY WHICH CONTAIN NITROGEN-CONTAINING COMPOUNDS AS THE ACTIVE INGREDIENTS

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL51189A (en) * 1976-02-04 1985-08-30 Upjohn Co Prostaglandin analogs

Also Published As

Publication number Publication date
BE862547A (en) 1978-06-30
FR2376134A1 (en) 1978-07-28
FR2376134B1 (en) 1985-04-12
DE2753986C2 (en) 1986-05-07
AU3106777A (en) 1979-06-07
NL7714172A (en) 1978-07-04
AU511711B2 (en) 1980-09-04
NL190600B (en) 1993-12-16
JPS5384942A (en) 1978-07-26
NL190600C (en) 1994-05-16
DE2753986A1 (en) 1978-07-06
JPS5811438B2 (en) 1983-03-02

Similar Documents

Publication Publication Date Title
US4123441A (en) Enlarged-hetero-ring prostacyclin analogs
GB1565604A (en) 6-oxoprostaglandins
US4131738A (en) 6-Hydroxy-PGE1 compounds
US4303796A (en) 16-Phenoxy prostaglandin F2α analogs
US4225508A (en) 19-Hydroxy-PGI2 compounds
US4338457A (en) Composition and process
US4205178A (en) 6-Keto prostaglandin E-type compounds
US4112224A (en) Biheterocyclic-9,11-trideoxy-PGF compounds
US4225507A (en) 19-Hydroxy-19-methyl-PGI2 compounds
US4013695A (en) 4,4,5,5-Tetradehydro-PGE1 analogs
US4060534A (en) 9-Deoxy-9-methylene-PGF compounds
US4028350A (en) 9α,11αOR 11α,9αEpoxymethano-prostaglandans and process for their preparation
US4490537A (en) Enlarged-hetero-ring prostacyclin analogs
US4124601A (en) Certain 5-halo-6,9α-epoxy-14-bromo(or chloro)-PGF1 compounds
US3879438A (en) 4,5,13-Prostatrienoic acid derivatives
US4070384A (en) Process for preparing thromboxane B compounds from prostaglandin fα co
US4403100A (en) (11R)-11-Deoxy-11-alkyl-6-oxo-prostaglandins
US4100192A (en) Inter-phenylene-PG amides
US4107427A (en) Process and intermediates for preparing Thromboxane B1
US4490549A (en) Enlarged-hetero-ring prostacyclin analogs
US4490548A (en) Enlarged-hetero-ring prostacyclin analogs
US4243592A (en) 9,11-Dideoxy-10-oxa-TXB compounds
US4181798A (en) Methylenecyclopentane derivatives
US4171447A (en) Tri-halo prostaglandin intermediates
US4052552A (en) Thromboxane b analogs

Legal Events

Date Code Title Description
PS Patent sealed
704A Declaration that licence is not available as of right for an excepted use (par. 4a/1977)
PE20 Patent expired after termination of 20 years

Effective date: 19971211