CH624679A5 - Process for the preparation of prostaglandin-like 1,15-lactones - Google Patents

Abstract

Prostaglandin-like 1,15-lactones of the formula <IMAGE> in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by lactonisation of corresponding prostaglandin-like compounds of the formula <IMAGE> in which M1 is defined in Claim 1. Reduction of lactones with a 9-keto group in the cyclopentane ring results in corresponding 9 alpha - or 9 beta -hydroxyl compounds. The resulting lactones have prostaglandin-like properties and can be used for the same purposes as prostaglandins.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

  Is hydrogen or fluorine, R7 - (CH2) m-CH3, where m is a number from 1 to 5, cis-CH = CH-CH2-CH3 or a radical
EMI3.1
 means in which T denotes chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms, where the different radicals T can be the same or different, s is the number 0, 1, 2 or 3 and Z3 represents the oxa or methylene group, with the proviso that no more than 2 radicals T are different from alkyl and with the further proviso that Z3 means the oxa group only if R3 and R4, which may be the same or different,

   Are hydrogen or methyl, Y1 is trans-CH = CH-, -CH2CH2-, cis-CH = CH- or C = C- and Zl 1) cis-CH = CH-CH24CH2) g-CH2-, 2) cis-CH = CH-CH2- (CH2) g-CF2-, 3) cis-CH2-CH = CH4CH2) g-CH2-, 4) - (CH2) 3- (CH2) g-CH25) QCH2) 3tCH2) g-CF2 -, 6) -CH2-O-CH2- (CH2) g-CH2-.
EMI3.2




  wherein g is an integer from 1 to 3, characterized in that a compound of the formula I A with cyclopentane ring structures of the formula is obtained by the process according to claim 1
EMI3.3
 and then reduced the 9-keto group in the cyclopentane ring structures to the corresponding 9a and 9P hydroxy groups.



   The present invention relates to methods for producing new lactones of some known prostaglandins or prostaglandin analogs.



   The new compounds which can be prepared according to the invention have the following formula:
EMI3.4

EMI3.5
 or
EMI3.6
  



  is
R5 represents hydrogen or methyl, Rg represents hydrogen or the hydroxyl group, L1
EMI4.1
 or a mixture of
EMI4.2
 and
EMI4.3
 , where R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, R7 - (CH2) m -CH3, where my number is from 1 to 5, cis-CH = CH-CH2-CH3 or a residue
EMI4.4
 means in which T is chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms, where the different radicals T can be the same or different, s is 0, 1, 2 or 3 and Z3 is the Oxa or methylene group means, provided that

   that no more than 2 radicals T are different from alkyl and with the further proviso that Z3 means the oxa group only when R3 and R4, which may be the same or different, are hydrogen or methyl, Y1 trans-CH = CH-, -CH2CH2-, cis-CH = CH- or -CC and Z1 1) cis-CH = CH-CH2- (CH2) g-CH2-, 2) cis-CH = CH-CH2- (CH2) g-CF2-, 3) cis-CH2-CH = CH- (CH2) g-cH2- 4) - (CH2) 3- (CH2) g-CF2-, 5) - (CH2) 3- (CH2) g-CF2-, 6 ) CWffO-CH2- (CH2) 0-CH2-,
EMI4.5
 where g represents an integer from 1 to 3.



   The process for the preparation of these compounds of the formula (I A) is characterized in that a prostaglandin-like compound of the formula or
EMI4.6
 wherein Zl, Y1, L1 and R7 have the meaning given above, and M1 or
EMI4.7
  is lactonized.



   Further new compounds which can be prepared according to the invention have the following formula:
EMI5.1

EMI5.2
 and the further substituents are defined above.



   These new compounds of the formula (I B) are obtained according to the invention by first using the process described above for compounds of the formula (I A) with cyclopentane ring structures of the formula
EMI5.3
 and then reduced the 9-keto group in the cyclopentane ring structures to the corresponding 9a and 9ss hydroxy groups.



   The compounds which can be prepared according to the invention have a side-chain hydroxyl group on the C-15 in the above formulas. For a discussion of the stereochemistry of prostaglandins, see Nature 212, 38 (1966). Terms such as C-9, C-11, C-15 and the like refer to the carbon atom of the prostaglandin analog which has the same relative position as the carbon atom of the same number in prostanoic acid.



   Prostaglandin-like lactones are taken to mean 1,9, 1,11 or 1,1 5-lactones of a prostaglandin or prostaglandin analogue, provided that the C-9, C-1 l or CI 5 position is hydroxylated and thus to the lactone Education with the PG carboxyl group is capable. In the case of a PGE-like compound (for example PGE2), the term prostaglandin-like lactone therefore only refers to a 1,11- or 1,1 5-lactone.

  When a formula is used to represent a prostaglandin-like lactone or a prostaglandin analogue from which the prostaglandin-like lactone is made, the term prostaglandin-like lactone refers to the compound of this formula (or lactone made therefrom) or a mixture of these compounds ( or the lactone produced therefrom) and their enantiomers.



   The various prostaglandins, their esters, acylates and pharmacologically acceptable salts are extremely effective in causing various biological reactions. For this reason, these compounds are suitable for pharmacological purposes, see for example Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and literature references there.



   In the case of the PGE compounds, these biological reactions include: a) stimulation of the smooth muscles (demonstrated, for example, in tests with guinea pig ileum, rabbit duodenum or colon of voles), b) influencing the lipolytic activity (demonstrated by antagonism against the epinephrine-induced release of glycerol from isolated rat fat pads), c) inhibition of gastric secretion and reduction of undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors, d) combating cramps and facilitating breathing in asthmatic conditions, e) swelling of the nasal area ,

   f) the reduction in platelet adhesion (demonstrated by the adhesion of the platelets to glass) and the inhibition of platelet aggregation caused by various physical effects (for example arterial injury) or chemical effects (for example ATP, ADP, serotinin, thrombin and collagen) and Thrombus formation, g) action on mammalian reproductive organs as a means of inducing labor, abortion, as cervical dilators, regulators of oestrus and the menstrual cycle, and h) accelerating the growth of epidermal cells and keratin in animals.



   In the PGFa compounds, these biological reactions include: a) stimulation of the smooth muscles (demonstrated, for example, in tests with guinea pig ileum, rabbit duodenum or colon of voles), b) inhibition of gastric secretion and reduction of undesirable gastrointestinal effects with systemic Administration of prostaglandin synthetase inhibitors, c) the swelling of the nasal passages, d) the reduction in platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition by various physical effects (for example arterial injury) or chemical effects (for example ADP, ATP, serotinin, thrombin and collagen) caused platelet aggregation and thrombus formation,

   and e) exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical dilators, regulators of oestrus and the menstrual cycle.



   In the PGF1 compounds, these biological reactions include: a) stimulation of the smooth muscles (proven in tests with guinea pig ileum, rabbit duodenum or colon of voles), b) inhibition of gastric secretion and reduction of undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors, c) the fight against cramps and breathing relief in asthmatic conditions, d) the swelling of the nasal passages, e) the reduction of the platelet adhesion (demonstrated by the adhesion of the platelets to the glass) and the induction of the various physical effects (e.g. arterial injury) or chemical effects (e.g. ADP, ATP, serotinin, thrombin and colla;

  ; en) caused platelet aggregation and thrombus grooming, and f) exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical dilators, regulators of oestrus and the menstrual cycle.



   In addition to the known prostaglandins, numerous prostaglandin analogues have also been found. In particular, prostaglandin analogues of the formula are known
EMI6.1
 wherein
EMI6.2

EMI6.3

EMI6.4
 or
EMI6.5
 where R8 is hydrogen or the hydroxyl group, Li
EMI6.6
 or a mixture of and
EMI6.7
  wherein R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 and R4 only means fluorine when the other is hydrogen or fluorine, M1 or
EMI7.1
 where R5 is hydrogen or methyl,
R7 - (CH2) m-CH3, where m is a number from 1 to 5, cis CH = CH-CH2-CH3 or
EMI7.2
 where T is chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms,

   where different radicals T can be identical or different, s the number 0, 1, 2 or 3 and Z3 denote the oxo or methylene group, provided that no more than 2 radicals T can be different from alkyl and the further requirement, that Z3 is the oxo group only if R3 and R4, which may be the same or different, are hydrogen or methyl, Y, trans-CH = CH-, -CH2CH2-, cis CH = CH-or-CC-; and Z1 1) cis-CH = CH-CH2- (CH2) g-CH22) cisCH = CH-CH2- (cH2) g-cF2- 3) cis-CH2XH = CH- (CH2) g-CH2-, 4) - (CH2) 3- (CH2) g-CH25) - (CH2) 3- (CH2) g-CF2 -, 6) -CH2-O-CH2- (CH2) g-CH2-,
EMI7.3
 where g is the number 1, 2 or 3.



   The prostaglandin analogs of the formula I are known to correspond to the generally described prostaglandins in that they have a prostaglandin-like effect.



   In particular, the PGE, 8ss, 12a-PGE, 8 (3,12a-11-deoxy-PGE and 11-deoxy-PGE-like compounds correspond to the above PGE compounds by using the former for the same purposes as the PGE compounds are usable and can also be used in the same way as these.



   The PGFa, 8ss, 12a-PGFu, 8ss, 12α-11-deoxy-PGFα and 11-deoxy-PGF, -like compounds correspond to the above PGF <Connections insofar as the former can be used for the same purposes as the PGF connections and are also used in the same way as these.



   The PGD, 9ss-PGD, 8ss, 12α-PGD, 8ss, 9ss, 12α-PGD, 9-deoxy-PGD, 8ss, 12α-9-deoxy-PGD, 8ss, 12α - 9, 10-Didehydro-9-deoxy-PGD and 9.1 0-didehydro-9-deoxy-PGD-like compounds according to formula I correspond to the PGE or PGF compounds in that the former for the same purposes as that PGE or PGF compounds are useful and used in the same way as these.



   The PGA or 8ss, 12α-PGA-like compounds of formula I correspond to PGA compounds in such a way that the former are useful for and used in the same way as the PGA compounds. The PGB-like compounds of formula I correspond to the PGB compounds in that they can be used for the same purposes and are used in the same way as these.



   The prostaglandins described above are known to all cause multiple biological reactions, even at low doses. In numerous applications, the known prostaglandins also show a very short duration of the biological effect. In contrast, the prostaglandin analogs of the formula I are known to be much more selective in causing prostaglandin-like biological reactions, and they have a somewhat longer duration of action. All of these prostaglandin analogs are therefore, for at least one of the pharmacological purposes described, equally useful or even better than the corresponding prostaglandins.



   Another property of the prostaglandin analogs of the formula I, in comparison to the corresponding prostaglandins, is that the analogs can be effectively administered orally, sublingually, intravaginally, buccally or rectally, in numerous cases in which the corresponding prostaglandin is known to be only is effective with intravenous, intramuscular or subcutaneous injection or infusion. However, other routes of administration are known to facilitate the maintenance of uniform levels of these compounds in the body with fewer or smaller doses and allow self-administration by the patient.



   Methods for producing large ring lactones are known, see for example E. J. Corey et al., Journal of the American Chemical Society 96: 5614 (1974). Furthermore, certain 1,9-lactones of cyclopentyl-containing carboxylic acids are known, compare ZA-PA 737 357, Derwent Farsdoc CPI No. 28414V, which discloses 1,9-lactones of o) heterocyclic prostaglandin analogs, JA-PA 0037-793, Derwent Farmdoc CPI No. 61147W, which discloses the 15-deoxy-t5-methyl-PGF2a-1,9-lactone, and EJ Corey, et al., Journal of the American Chemical Society 97: 653 (1975), according to which the PGF2 -1,9- lactone and the PGF2 -1,15 lactone is known.

 

   Finally, JA-PA 50013-385, Derwent Farmdoc CPI No. 56267W, 1,9-lactones from PGF2 and (1SRS) -15-methyl-PGFza.



   The present invention relates to processes for the preparation of new lactones containing the cyclopentane ring and processes for their preparation.



   Preferred new compounds are the following:
1) a 1,9-, 1,11 - or 1,15-lactone of a prostaglandin analogue of the formula or
EMI7.4
  
EMI8.1
 wherein L1, M1, R7, Y1 and Z1 have the meaning given above.



  possess,
2) a 1,9- or 1,15-lactone of a prostaglandin analog of the formula or
EMI8.2

EMI8.3
 wherein L1, Ml, R7, Y1 and Z1 have the above meaning and W2 or
EMI8.4
 designated,
3) a 1,11- or 1,15-lactone of a prostaglandin analog of the formula
EMI8.5
 or
EMI8.6
 where L1, M1, R7, Y1 and Z1 have the above meaning,
4) a 1,15-lactone of a prostaglandin analog of the formula or
EMI8.7
 wherein L1, Ml, R7, Y1 and Z1 have the meaning given above.



   The following schemes illustrate methods by which the prostaglandins or prostaglandin analogs described above are converted into their 1,9-, 1,11 - or 1,15-lactones. Since all of these prostaglandins or prostaglandin analogues have a hydroxyl group at C-15, each is capable of forming a 1,15-lactone. Furthermore, 1,9- or 1,11-lactones of the above prostaglandins or prostaglandin analogues can be formed if the cyclopentane ring has a 9-hydroxyl or an 11-hydroxyl group. Correspondingly, the PGA-, PGB- and 1 1-deoxy-PGE-like compounds and their 8ss, 12-isomers can only form 1,15-lactones.



  The 11-deoxy-PGFα and 11-deoxy-PGFss-like compounds or their 8ss, 12α-isomers can only give 1,9- or 1,15-lactones, and the PGE-like compounds or their 8 (3rd , 12a isomers can only give 1.11 or 1.15 lactones, and finally the PGF and PGFss compounds and their 813.12a isomers can be 1.9, 1.11 and 1.15
Form lactones.



   The present description deals with all of the various lactones of all of the above-described prostaglandins or prostaglandin analogs; the following schemes deal with the methods according to which the desired one
Lactone product is obtained with high selectivity. In each
Lactonization is carried out according to known methods.



   For example, ZA-PS 737 357 (Derwent Farm doc CPI No. 28414V) teaches the production of 1,9-lactones of certain PG compounds by applying heat to undiluted samples of the PG-like product. However, this method is unsuitable for the purposes of the present invention since it only produces complex product mixtures.



   Another method for lactonizing PG-like
Compounds is known from JA-PA 5-0037-793 (Derwent Farm doc CPI No. 61147W) and JA-PA 5-0013-385 (Derwent Farm doc CPI No. 56267W), after which trifluoroacetic acid and trifluoroacetic anhydride are used as lactonizing agents . Lactonization of prostaglandin-like products is also carried out according to the lactonization process of S. Masau me, Journal of the American Chemical Society 97, 3515 (1975).



   In this process, one works with a ring closure catalyzed by mercury trifluoroacetate <o-hydroxy-t-butylthiolester.



   However, the preferred method for lactonizing prostaglandin analogues according to the present description consists in converting the carboxyl group of the prostaglandin-like compound into the corresponding 2-pyridine thiol ester and subsequent ring closure. The general method of this preferred lactonization was developed by E. J.



  Corey, Journal of the American Chemical Society 96, 5614 (1974), and their application to PGF2a is described by E.J. Corey, et al., Journal of the American Chemical Society 97, 653 (1975). According to this preferred method, the formation of the 2-pyridine thiol ester can be carried out by reacting the prostaglandin-like free acid with 1.5 equivalents of 2,2'-dipyridyl disulfide and 1.5 equivalents of triphenylphosphine in dry (anhydrous) oxygen-free xylene or benzene as a diluent. The 2-pyridine thiol esterification preferably takes place at room temperature within about 2 to 24 hours. The ring closure usually takes place by first diluting the thiolester thus obtained with dry, oxygen-free xylene or benzene and then heating to reflux temperature for 1 to 24 hours.



   A modification of the preferred method for lactonization is described by H. Gerlach, et al., Helv. Chim. Acta. 57 (8) 2661 (1974). It consists e.g. in a ring closure of an o) -hydroxy-2-pyridine thiol ester under catalysis with silver ions (perchlorate or fluoroborate) in benzene at room temperature.
EMI9.1
  



  Scheme B
EMI10.1

In the schemes, the substituents have the meaning given above.



   Scheme A shows a process according to which a PGE or 1 1-deoxy-PGE starting material of the formula LXXXI in PGE- or 1 1-deoxy-PGE-1,15-lactone LXXXII or PGFA, 11-deoxy-PGF ,, - , PGF- or 11-deoxy-PGF-1,15-lactone LXXXV is transferred.

  Scheme A further describes the use of an 8, ss, 12a-PGE or II-deoxy-8 (3,12a-PGE compound of the formula LXXXIII for the preparation of 8, ss, 12a-PGE or 11-deoxy-8, 13,12a-PGE-1,15-lactones LXXXIV or 8ss, 12a-PGFa-, 11-deoxy-8 (3, 1 2a-PGFa-, 85,12a-PGF- or 11-deoxy-8,13,12a -PGF -1.15-lactones LXXXVI.



   The lactonization methods described above are used to convert the compounds LXXXI or LXXXIII into the compounds LXXXII or LXXXIV. The compound LXXXIV or LXXXVI is then prepared from the compound OXXXIII by reducing the ring-shaped carbonyl group and then separating the C-15 epimers. Reduction and separation processes are usually carried out according to the methods described above.



   Scheme B shows a process for converting a PGA compound CI, a PGB compound CII or an 11-deoxy-PGE compound CV or their 8ss, 12a isomers into the corresponding PG-1,15-lactone CVI, where the cyclopentane ring structure of the starting material is retained. Since all compounds of the formulas CI to CV are monohydroxyl compounds, the lactonization is carried out according to the above processes without the use of selective blocking agents.



   All prostaglandin-like 1,1 5-lactones that can be produced according to the invention can be used for the same purposes as the corresponding free acid. In particular, these prosta glandin-1, 15-lactones can be administered in the same way as the corresponding free acids and for the same purposes in doses of about 5 to 1000 times the amount in which the corresponding free acid is administered in the same way .



   Surprisingly, when the prostaglandin-like 1,15-lactones obtained according to the invention are administered, the treated organism shows an increased tolerance and fewer undesirable side effects which are associated with each type of administration. If, for example, the new prostaglandin1, 15-lactones are administered intravenously, higher infusion rates can be used successfully, with undesirable local effects which occur when the corresponding acid is administered are reduced or eliminated.



   Furthermore, the PG-1,15 lactones obtainable according to the invention result in more uniform delivery rates from the injection site when administered intramuscularly and, in particular, a longer-lasting delivery than the corresponding free acid. With this route of administration, the prostaglandin-1,15-lactones mentioned therefore have a surprising and unexpectedly prolonged action.



   The PGA- or 8ss, 12a-PGA-like 1,15-lactones are therefore particularly useful agents for lowering blood pressure, since they show a longer-lasting effect and reduced gastrointestinal side effects compared to the free acids.



   The PGB- and 8ss-12a-PGB-like 1,15-lactones are surprisingly more effective than the free acids when used as vasoconstrictors and therefore more useful for the treatment of inflammatory and proliferative dermatoses (such as psoriasis), which usually have vasodilation.



  Furthermore, these PGB-1,15-lactones and 8B, 12a-PGB-1,15-lactones are surprisingly more suitable when applied topically to the nasal mucosa in the form of nasal drops or aerosols with regard to the effect of vascular constriction and the swelling of the nose. The unexpected improved properties derive from the surprisingly prolonged duration of action, the improved absorption and improved local and systemic compatibility of the lactones compared to the corresponding free acids.



   The PGD-1,15-lactones are therefore surprisingly better agents for lowering blood pressure, better antisecretory agents and agents for inhibiting platelet aggregation than the corresponding free acids. In addition, the lactones show a surprisingly improved stability, both as bulk chemicals and in the finished pharmaceutical formulations. When administered in therapeutic doses, these lactones surprisingly develop a longer duration of action than the corresponding free acids, an improved therapeutic index and a lower frequency of prostaglandin-dependent gastrointestinal and bronchiopulmonary side effects such as the free acids.

 

  These compounds are therefore surprisingly more useful than the free acids for the treatment of high pressure, gastrointestinal hyperacidity, gastrointestinal ulcers and coagulative disorders of the cardiovascular system.



   The PGE-1,15-lactones, 8ss, 12α-PGE-1,15-lactones, 11-deoxy-PGE-1,15-lactones and 11-deoxy-8ss, 12a-PGE-1,15-lactones are thus surprisingly more useful than the free acids for regulating the menstrual cycle, since they have fewer side effects, longer duration of action and reduced toxicity. In particular, these lactones cause pregnancy to be terminated at doses at which the gastrointestinal and cardiovascular side effects caused by prostaglandin are lower than with free acid.

  Furthermore, the PGE- and 8ss, 12a- PGE-like acids require special care in observing handling and storage conditions and in the formulation, so that the corresponding stability is ensured, while the PGE-1,15-lactones or 88 obtained according to the invention 12a-PGE-1,1 5-lactones are surprisingly more stable and therefore less attention needs to be paid to their stability. Surprisingly, these compounds are also more effective constrictors of the mucosal vessels in the nose, so that they swell the nose more effectively than the free acids. A particular advantage is that the lactones reduce the local irritation in the nose caused by the free acids (e.g. from nose drops or aerosols).



  The lactones are, surprisingly, also more useful than the free acids when used as bronchodilators, and they are particularly advantageous in preventing asthma attacks. Here they develop a prolonged duration of action and, surprisingly, there is no irritation of the larynx as with therapeutic doses of the corresponding acids. The cough that occurs at therapeutic doses of free acids is reduced or completely avoided when using the lactones. Furthermore, these lactones are surprisingly more useful than the free acids for the treatment of high pressure, since they have an unexpectedly longer duration of action.



   The PGF, -1, 15-lactones, 8 (3, 12a-PGF -1, 15-lactones, 11-deoxy-PGF? -1.15-lactones, 11-deoxy-8ss, 12? -PGF? -1 , 15-lactones, PGFss-1,15-lactones, 8ss, 12α-PGFss-1,15-lactones, 11-deoxy-PGFg-1, 15-lactones and 11-deoxy-8ss, 12a-PGFss-1 Therefore, 15-lactones are surprisingly more useful than the corresponding acids when used as nasal decongestants, oxytocin agents, mammalian reproductive cycle regulators and inhibitors of inflammatory proliferative dermatoses (such as psoriasis) by prolonged action.

  They are also more useful in surprising travel than the corresponding free acids when initiating a menstrual period ending pregnancy and for preventing excessive bleeding after delivery. Surprisingly, in addition to the prolonged duration of action at therapeutic doses, these compounds show a reduced incidence of gastrointestinal side effects associated with prostaglandin, in particular nausea, vomiting and diarrhea, and when used as oxytocin or other regulators of the reproductive cycle in mammals, a lower frequency of cardiovascular or pulmonary side effects.



   The PGF, 11-deoxy-PGF, PGE and 1 1-deoxy-PGE1,15-lactones and their 8tz, 12a isomers also produce hyperthermic or hypothermic reactions, and accordingly it is special when starting treatment with these lactones It is important to monitor body temperature, choosing the doses so that the absolute change in body temperature compared to normal values is less than or equal to 1.5 to 2 ° C. The administration of the lactone is thus interrupted or the administration amount is reduced if excessive changes in body temperature occur.



   The lactones described above can be administered orally, vaginally, topically, internasally, interamniotically or parenterally for the purposes described above and formulated as tablets, capsules, nasal drops, aerosols, creams, ointments, suppositories or solutions or suspensions on an oil or aqueous basis, such as this happens with the free acids and their alkyl esters.



   In the following examples, all infrared absorption spectra were recorded with a Perkin-Elmer Model 421 infrared spectrophotometer. Unless otherwise specified, undiluted samples were used. The ultraviolet spectra were recorded on a Cary Model 15 spectrophotometer. The nuclear magnetic resonance spectra were recorded on a Varian A-60, A-60D and T-60 spectrophotometer, using deutorochloroform solutions with tetramethylsilane as the internal standard (downfield). The mass spectra were recorded with a double-focusing high-resolution mass spectrometer CEC Model 21-110B or a gas chromatograph mass spectrometer LKB Model 9000. Unless otherwise stated, trimethylsilyl derivatives were used.



   The collection of the chromatographic eluate fractions begins as soon as the front of the eluent has reached the bottom of the column.



   The solvent system A-IX used in thin layer chromatography consists of ethyl acetate / acetic acid / cyclohexane / water in a ratio of 90: 20: 50: 100 according to M.



  Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966).



   Skellysolve B (SSB) is a mixture of isomeric hexanes.



   Silica gel chromatography is understood to mean elution, collecting the fractions and combining those fractions which, according to thin-layer chromatography, contain the pure product (that is to say free of starting material and impurities).



   The melting points were carried out with a Fisher-Johns or Thomas Hoover melting point apparatus.



   The specific rotations [a] were determined on solutions of a compound in the specified solvent at room temperature using an automatic polarimeter Perkin-Elmer model 141.



   Example I PGF2a-l, 9-lactone (Zl = cis-CH = CH4CH2) 3- R8 = hydroxy, Y1 = trans-CH = CH-, R3 and R4 from L and R5 from Ml = hydrogen, R7 n- Butyl).



   A solution of 35 mg PGF2a, 39 mg triphenylphosphine and 33 mg 2,2'-dipyridyl-disulfide in 0.5 ml dry oxygen-free benzene is stirred at 25 C for 18 hours. The resulting mixture is then diluted with 25 ml of benzene and refluxed for 24 hours. Thin-layer chromatography analysis in 15% acetone and methylene chloride shows a mixture of PGF2, -1, 9-lactone and -1.15-lactone in a ratio of about 8 to 1. The pure product is then isolated from the reaction mixture by silica gel chromatography separation.



   Example 2 8ss, 12a-PGE2-1,15-lactone (Zl, Yl, R5, L1 and R7 as in Example 1).

 

   The title compound is prepared by lactonizing 8ss, 12a-PGE2 according to the procedure of Example 1.



   The procedure of Example 2 is repeated, but using other 8, ss, 12a-PGF-like 1,1 5-lactones or the 8ss, 12α-PGE-like compounds described by formula I instead of 8ss, 12a-PGF2 " -1,15-lactone or 8ss, 12a-PGE2, the corresponding 8, ss, 12a- PGE-1, 15-lactones are obtained.



   Example 3 PGF2li-1,15-lactone (Formula LXXXV: Z1, R5, Y1, R5, L1 and R7 as in Example 1), see Scheme A.



   The PGE2-1,15-lactone (Zl, R8, Y1, Rs, L1 and R7 as in Example 1) is treated with sodium borohydride in methanol with stirring at 0 ° C. After stirring for a further 15 minutes at 0 C, the reaction mixture is carefully poured into a rapidly stirred mixture of ice, water, dilute sodium bisulfate solution and 50% ethyl acetate in hexane. After phase separation, the aqueous layer is extracted twice with ethyl acetate in hexane (1: 1). The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on 450 g of silica gel washed with acid.

  The column is packed with 10% ethyl acetate in hexane and is eluted with 20% ethyl acetate in hexane. This gives you the title link.



   If the procedure of Example 3 is repeated, but using other PGE-like 1,15-lactones instead of the PGE2-1,15-lactone, the corresponding PGFB-1,15-lactones are obtained.



   Example 4 8ss, 12α-PGF2ss-1,15-lactone (Formula LXXXVI: Z1, R8, Y1, R5, L1 and R7 as in Example 1), see Scheme A.



   According to the procedure of Example 3, 8ss, 12a-PGE2-1,15-lactone is reduced and chromatographed to give the title compound.



   If the procedure of Example 4 is repeated, but using other 8ss, 12a-PGE-like 1,15-lactones described in place of the 8ss, 12α-PGE2-1,15-lactone, the corresponding 8ss, 12α- is obtained. PGFss-1,15 lactones.



   Example 5 11-Deoxy-PGE2-1,15-lactone (formula CV: Z1, Yl, Ml, L1 and R7 as in Example 1), see Scheme B.



   According to the procedure of Example 1, 1 1-deoxy-PGE2 is lactonized, whereby the title compound is obtained.



   If the procedure of Example 5 is repeated, but using the various 11-deoxy-PGE-like compounds described by formula I instead of 1 1-deoxy-PGE2, the corresponding 11-deoxy-PGE-1,15- are obtained. lactone.



   Example 6 11-Deoxy-8ss, 12α-PGE2, see Scheme B.



   According to the procedure of Example 1, 1 1-deoxy-8ss, 12a-PGE2 is lactonized, whereby the title compound is obtained.



   Repeating the procedure of Example 6 but using the various 11-deoxy-8ss, 12-PGE-like compounds outlined by Formula I instead of the 11 deoxy-8ss, 12a-PGE2 gives the corresponding 8ss, 12α. -11-Deoxy-PGE-1,15-lactones.



   Example 7 11-Deoxy-PGF2α or 11-Deoxy-PGF2ss (Formula LXXXV: Z1, Yl, R5, L1 and R7 in Example 1, R8 = hydrogen) see Scheme A.



   According to the procedure of Example 3, 11-deoxy-PGE2-1,15-lactone is reduced and chromatographed to give the title compound.



   If the process of example 6 is repeated, but using the various 11-deoxy-PGE-like 1,15-lactones described in connection with example 5 instead of the 1 l-deoxy-PGE2-1,15-lactone, the result is thus obtained the corresponding 11-deoxy-PGE-1,15-lactones.



   Example 8 11-Deoxy-8ss, 12α-PGF2α or 11-deoxy-8ss, 12α-PGF213 (formula LXXXVI: Z1, Y1, R5, L1 and R7 as in Example 1, R8 = hydrogen), cf. Scheme A.



   According to the procedure of Example 3, 1 1-deoxy-8ss, 12a-PGE2 is reduced and chromatographed to give the title compounds.



   Repeating the procedure of Example 8, but using the various 8ss, 12α-PGE-like 1,15-lactones described in Example 6 instead of the 8ss, 12α-PGE2-1,15-lactone, is obtained the corresponding PGE-1,15-lactones.



   Example 9
PGA2-1,15-lactone (Zl, Yl, R5, L1 and R7 as in Example 1), see Scheme B.



   The title compound is prepared from PGA2 by direct lactonization using the procedure of Example 1.



   If the procedure of Example 9 is repeated, but using the various PGE-like 1,5-lactones described in Example 5 or PGA-like compounds, the corresponding PGA-1,15 lactones are obtained.



   Example 10 8ss, 12α-PGA2-1,15-lactone (Z1, Y1, R5, L1 and R7 as in Example 1), see Scheme B.



   Repeating the procedure of Example 9, 8 (3,12u-PGEr1,15-lactone or 8ss, 12α .PGA2 are converted into the title compound.



   The procedure of Example 10 is repeated, but using the various 8ss, 12α-PGE-like 1,15-lactones described in Example 6 or the PGA-like compounds described by Formula I instead of 8 (3.12ct -PGE2-1,15-lactone or 8 (3,12a-PGA2, the corresponding 8ss, 12α-PGA-1,15-lactones are obtained.



   Example 11
PGB2-1,15-lactone (formula CVI: Z1, Yl, R5, L1 and R7 as in Example 1), see Scheme B.



   0.334 g of PGB2, 5 ml of dry, oxygen-free xylene, 0.393 g of triphenylphosphine and 0.33 g of 2,2'-dipyridyl disulfide are stirred for 6 hours at room temperature in a nitrogen atmosphere. Then the resulting mixture is diluted with 250 ml of dry oxygen-free xylene and the solution is refluxed for 16 hours. The resulting mixture is concentrated under reduced pressure and a bath temperature of 40 C to remove the xylene. The residue is chromatographed on a dry packed column of 100 g silica gel and 20 ml diethyl ether.

  The column is eluted with 60% diethyl ether in hexane, giving 200 mg of PGB21,15-lactone, silica gel Rf = 0.37 in diethyl ether and hexane (1: 1). The mass spectrum shows a parent peak at 316.2021 and further peaks at 298.288.269 and 217; characteristic NMR absorptions at 5.97-6.80.5.07-5.70 and 2.83-3.126; UV absorption at 277 mF (E = 16800).

 

   If the procedure of Example 11 is repeated, but using the various PGB-like compounds described by formula I instead of PGB2, the corresponding PGB-1,15-lactones are obtained.



   Example 12 9-Deoxy-8ss, 12α-PGD2-1.15-lactone (formula CVI: Zl, Yl, R5, Ll, R7 as in Example 1), see Scheme B.



     9-Deoxy-9,10-didehydro-8ss, 12α-PGD2-1,15-lactone is converted to the title compound.



   If the procedure of Example 12 is repeated, but using the various other 9-deoxy-9,10-di dehydro-8B, 12a-PGD-like 1,15-lactones, the corresponding 9-deoxy-8ss, 12α is obtained ; -PGD2-1,15-lactones.



   Example 13 17-phenyl-18,19,20-trinor-PGE2-1,15-lactone (formula LXXXII: Z1, R8, Y1, R5 and L1 as in Example 1, R7 =
EMI13.1
 Cf. Scheme A.



   A solution of 735 mg of 17-phenyl-18,19,20-trinor-PGE2, 628 mg of 2,2'-dipyridyl disulfide and 748 mg of triphenylphosphine in 10 ml of anhydrous, oxygen-free xylene is stirred at 25 ° C. in a nitrogen atmosphere for 2 hours. The mixture is then diluted with 400 ml of anhydrous, oxygen-free xylene, refluxed for 2½ hours and concentrated to a residue in vacuo at 30.degree. This residue is chromatographed on 100 g of neutral silica, which is packed with 80% ether / hexane and eluted with this mixture (8 ml fractions).

  Those fractions which, according to the thin-layer chromatogram, contain homogeneous product are combined and give the purified 17-phenyl-18,19,20 trinor-PGE2,1,15-lactone. By recrystallizing twice from ether / hexane, the pure product of F. 81-83 C, IR peaks at 3440, 3000, 1725, 1605, 1500, 1330, 1240, 1160, 1145, 1085, 1045, 975, 745, 725 and 700 cm1; the mass spectrum shows fragments at m / e 368 (M-18), 350, 332, 297, 296, 277, 264, 259, 241 (no M + visible).



   If the processes of the above examples are repeated, all of the PG-like lactones listed in the following tables are obtained from the corresponding free acids.



   In the following tables, each formula denotes a prostaglandin-like lactone, the full name of which is obtained by combining the name given below the respective formula with the relevant prefix, which can be found in the Name column in the tabular part.



  Table A
EMI13.2
   PGF2 1,1 5-lactones
EMI13.3
   13.1 4-dihydro-PGF ,,, - 1,15-lactones
EMI13.4
   13,14-Didehydro-PGF2α-1,15-lactones
EMI13.5
   13,14-Didehydro-PGF1α-1,15-lactones
EMI13.6
   2,2-difluoro-PGF2u-l, 15-lactone Table A
EMI14.1
   2,2-difluoro-13,14-dihydro-PGF2α-1,15-lactones
EMI14.2
   2,2-difluoro-PGF1α-1,15-lactones
EMI14.3
   2,2-difluoro-13,14-dihydro-PGF1?

  ; -1,15-lactones
EMI14.4
   13,14-didehydro-2,2-difluoro-PGF2u-1,15-lactone
EMI14.5
   13,14-didehydro-2,2-difluoro-PGFla-1,15-lactone
EMI14.6
   cis-4,5-didehydro-PGF I ,, - 1,15-lactones
EMI14.7
   cis-4,5-didehydro-13,14-dihydro-PGF1α-1,15-lactones
EMI 14.8
   5-oxa-PGF1a-1, 15-lactones
EMI 14.9
   5-oxa-13,14-dihydro-PGF1α-1,15-lactones
EMI 14.10
   13,14-Didehydro-cis-4,5-didehydro-PGFIu-1,15-lactone Table A
EMI15.1
   13,14-Didehydro-5-oxa-PGF1α-1,15-lactones
EMI15.2
   4-Oxa-PGFia-1,15-lactone
EMI 15.3
   4-oxa-13,14-dihydro-PGF1?

  ; -1,15-lactones
EMI 15.4
   3-Oxa-PGF1α-1,15-lactones
EMI15.5
   3-oxa-13,14-dihydro-PGF1α-1,15-lactones
EMI15.6
   13,14-Didehydro-4-oxa-PGF1α-1,15-lactones
EMI15.7
   13,14-Didehydro-3-oxa-PGF1α-1,15-lactones
EMI 15.8
   3,7-inter-m-phenylene-4,5s6-trinor-PGFlu-l, 15-lactones
EMI 15.9
   3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-PGFIu-1,15-lactone
EMI 15.10
   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-PGFIt-1,15-lactone Table A
EMI16.1
 3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro PGF1a-1,154actone
EMI16.2
   13,14-didehydro-3,7-inter-m-phenylene-4,5,6-trinor-PGF1?

  ; - 1,15-lactones
EMI 16.3
 13,14-Didehydro-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor PGF1a 1,1 5-lactone
L1 Example gm R3 R4 R5 ¯0 Name A-1 1 3 methyl HH a 16-methyl A-2 1 3 methyl H methyl a 15,16-dimethyl A-3 1 3 methyl HH ss 15-epi-16-methyl A -4 1 3 methyl methyl H a 16,16-dimethyl A-5 1 3 methyl methyl methyl a 15,16,16-trimethyl A-6 1 3 methyl methyl H ss 15-epi-16,16-dimethyl A-7 1 3 fluor HH a 16-fluor A-8 1 3 fluor H methyl a 15-methyl-16-fluor A-9 1 3 fluor HH ss 15-epi-16-fluor A-10 1 3 fluor fluoro H o 16, 16-difluoro A-11 1 3 fluorofluoro methyl a 15-methyl-16,16-difluoro A-12 1 3 fluorofluoro H (3 15-epi-16,16-difluoro A-13 1 3 HHH a title compound A- 14 1 3 HHH ss 15-epi A-15 3 3 HHH?

  ; 2a, 2b-dihomo A-16 3 3 methyl methyl H a 2a, 2b-dihomo-16,16-dimethyl A-17 3 3 methyl methyl methyl a 2a, 2b-dihomo-15,16,16-trimethyl A-18 3 3 fluorofluor H a 2a, 2b-dihomo-16,16-difluoro A-19 3 3 fluorofluoro methyl a 2a, 2b-dihomo-15-methyl-16,16-difluoro Table B
EMI 16.4
   PGF2α -1,15 lactones
EMI 16.5
   13,14-dihydro-PGF2u, 15-lactone Table B
EMI17.1
   PGF1α -1,15 lactones
EMI17.2
   13,14-dihydro-PGF1α -1,15-lactones
EMI17.3
   13,14-Didehydro-PGF2α-1,15-lactones
EMI17.4
   13,14-Didehydro-PGF1α-1,15-lactones
EMI17.5
   2,2-difluoro-PGF2α-1,15-lactones
EMI17.6
   2,2-difluoro-13,14-dihydro-PGF2?

  ; -1,15-lactones
EMI17.7
   2,2-difluoro-PGF1α-1,15-lactones
EMI 17.8
   2,2-difluoro-13,14-dihydro-PGF1α -1,15-lactones
EMI17.9
   13,14-didehydro-2,2-difluoro-PGF2u-1,15-lactone
EMI 17.10
   1 3,14-didehydro-2,2-difluoro-PGF ,, - 1,15-lactones Table B
EMI18.1
   cis-4,5-didehydro-PGF1α -1,15 lactones
EMI18.2
   cis-4,5-didehydro-13,14-dihydro-PGF1α-1,15-lactones
EMI18.3
   5-Oxa-PGF1α-1,15-lactones
EMI18.4
   5-oxa-13,14-dihydro-PGF1α-1,15-lactones
EMI18.5
   1 3,14-Didehydro-cis-4,5-didehydro-PGFIa-1,15-lactone
EMI 18.6
   13,14-didehydro-5-oxa-PGF1?

  ; -1,15-lactones
EMI18.7
   4-Oxa-PGF1α -1,15 lactones
EMI 18.8
   4-0xa-13, 1Cdihydro-PGF1, -l, 15-lactone
EMI 18.9
   3-oxa-PGF1-1, 15-lactones
EMI18.10
   3-Oxa-13,14-dihydro-PGF1α -1,15-lactone Table B
EMI19.1
   13,14-Didehydro-4-oxa-PGF1α-1,15-lactones
EMI19.2
   13,14-Didehydro-3-oxa-PGF1α-1,15-lactones
EMI 19.3
   3,7-inter-m-phenylene-4,5,6-trinor-PGF1α-1,15-lactones
EMI 19.4
   3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-PGF1α-1,15-lactone
EMI19.5
   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-PGF1?

  ; -1,15-lactones
EMI19.6
 3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro PGF1-1,1 5-iactone
EMI19.7
   13,14-didehydro-3,7-inter-m-phenylene-4,5,6-trinor-PGF1? 1,15 lactones
EMI19.8
   13,1 4-didehydro-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-PGF1?

  ; -1,15-lactone Table BL, example gs T R3 R4 R5 0 Name B-1 1 0 HHH a 16-phenoxy-17,18,19,20-tetranor B-2 1 1 p-fluorine HHH a 16- (p-fluorophenoxy) -17,18,19,20 tetranor B-3 1 1 m-chloro HHH a 16- (m-chlorophenoxy) -17,18,19,20 tetranor B-4 1 1 m-trifluor - HHH a 16- (m-trifluoromethylphenoxy) methyl 17,18,19,20-tetranor B-5 10 HH methyl a 15-methyl-16-phenoxy-17,18,19,20 tetranor B-6 1 1 p -fluoro HH methyl a 15-methyl-16- (p-fluorophenoxy)
17,18,19,20-tetranor B-7 1 1 m-chloro H H methyl a 15-methyl-16- (m-chlorophenoxy)
17,18,19,20-tetranor B-8 1 1 m-trifluoro-HH methyl a 15-methyl-16- (m-trifluoromethyl-methyl phenoxy) -17,18,19,20-tetranor B-9 1 0 HHH ss 15-epi-16-phenoxy-17,18,19,20 tetranor B-10 1 1 <RTI

    ID = 20.7> fluor H H H p 15-epi-16- (p-fluorophenoxy) -
17,18,19,20-tetranor B-11 1 1 m-chloro H H H ss 15-epi-16- (m-chlorophenoxy)
17,18,19,20-tetranor B-12 1 1 m-trifluoro-HHH ss 15-epi-16- (m-trifluoromethylphen methyl oxy) -17,18,19,20-tetranor B-13 1 0 methyl methyl H a 16-methyl-16-phenoxy-18,19,20-trioron B-14 1 1 p-fluoromethyl methyl H a 16-methyl-16- (p-fluorophenoxy)
18,19,20-trinor B-15 1 1 m-chloro methyl methyl H a 16-methyl-16- (m-chlorophenoxy)
18,19,20-trinor B-16 1 1 m-trifluoromethyl methyl H cr a 16-methyl-16- (m-trifluoromethyl-methyl phenoxy) -18,19,20-trinor B-17 1 0 methyl methyl methyl a 15,16-dimethyl-16-phenoxy 1 8,19,20-trinor B-18 1 1 p-fluoro methyl methyl methyl a 15,16-dimethyl-16- (p-fluorophenoxy) -18.19 , 20-trinor B-19 1 1 m-chloro methyl methyl methyl a

   15,16-dimethyl-16- (m-chlorophenoxy) 18.1 9,20-trinor B-20 1 1 m-trifluoromethyl methyl methyl a 15,16-dimethyl-16- (m-trifluoromethyl methylphenoxy) - 18,19,20-trinor B-21 1 0 methyl methyl H ss 16-methyl-16-phenoxy 18,1 9,20-trinor B-22 1 1 p-fluoro methyl methyl H a 15-epi-16-methyl -16- (p-fluorophenoxy) -18,19,20-trinor B-23 1 1 m-chloro methyl methyl H ss 15-epi-16-methyl-16- (m-chlorophen oxy) -18,19 , 20-trinor B-24 1 1 m-trifluoromethyl methyl H ss 15-epi-16-methyl-16- (m-trifluoromethyl methylphenoxy) -18,19,20-trinor B-25 3 0 HHH a 2a , 2b-dihomo-16-phenoxy-17,18,19,20 tetranor B-26 3 1 p-fluoro HHH a 2a, 2b-dihomo-16- (p-fluorophenoxy)
17,18,19,20-tetranor B-27 3 1 m-chloro H H H 2a, 2b-dihomo-16- (m-chlorophenoxy) -
17,18,19,20-tetranor B-28 3 1 m-trifluoro-H H H <RTI

    ID = 20.16> 2a, 2b-dihomo-16- (m-trilfluoromethyl) methylphenoxy) -17,18,19,20-tetranor B-29 3 0 HH methyl a 2a, 2b-dihomo-15-methyl-16 -phenoxy-
17,18,19,20-tetranor B-30 3 1 p-fluoro HH methyl a 2a, 2b-dihomo-15-methyl-16- (p-fluorophenoxy) -17,18,19,20-tetranor B- 31 3 1 m-chloro HH methyl a 2a, 2b-dihomo-15-methyl-16- (m-chlorophenoxy) -17,18,19,20-tetranor B-32 3 1 m-trifluoro-HH methyl a 2a , 2b-dihomo-15-methyl-16- (m-trimethyl fluoromethylphenoxy) -17,18,19,20 tetranor table C.
EMI21.1
   18,19,20-trinor-PGF2α-1,15-lactones
EMI21.2
   18,19,20-trinor-13,14-dihydro-PGF2α -1,15-lactone
EMI21.3
   18,19,20-trinor-PGF1?

  ; -1,15-lactones
EMI21.4
   18,19,20-trinor-13,14-dihydro-PGF1α -1,15-lactone
EMI21.5
   13,14-Didehydro-18,19,20-trinor-PGF2α -1.15-lactone
EMI21.6
   13,14-Didehydro-18,19,20-trinor-PGF1α -1.15-lactone
EMI21.7
   18,19,20-trinor-2,2-difluoro-PGF2α -1.15-lactone
EMI21.8
   18,19,20-trinor-2,2-difluoro-13,14-dihydro-PGF2α -1,15-lactone
EMI21.9
   18,19,20-trinor-2,2-difluoro-PGF1α -1.15-lactone
EMI21.10
   18,19,20-trinor-2,2-difluoro-13,14-dihydro-PGF1α -1,15-lactone table
EMI22.1
   13,14-didehydro-18,19,20-trinor-2,2-difluoro-PGF2?

  ; -1.15-lac-tone
EMI22.2
   13,14-didehydro-18,19,20-trinor-2,2-difluoro-PGF1α -1.15-lac-tone
EMI22.3
   18,19,20-trinor-cis-4,5-didehydro-PGFla-1,15-lactone
EMI22.4
   18,19,20-trinor-cis-4,5-didehydro-13,14-dihydro-PGF1α-1,15-lactone
EMI22.5
   18,19,20-trinor-5-oxa-PGF1α -1.15-lactones
EMI22.6
   18,19,20-trinor-5-oxa-13,14-dihydro-PGFlu-1,15-lactone
EMI22.7
   13,14-Didehydro-18,19,20-tirnor-cis-4,5-didehydro-PGF1α-1,15-lactone
EMI22.8
   13,14-dideohydro-18,19,20-trinor-5-oxa-PGF1α -1,15-lactone
EMI22.9
   18,19,20-trinor-4-oxa-PGF1?

  ; -1,15-lactones
EMI22.10
   18,19,20-trinor-4-oxa-13,14-dihydro-PGFL-1,15-lactones
EMI23.1
   18,19,20-trinor-3-oxa-PGF1a-1,15-lactone
EMI23.2
   18,19,20-trinor-3-oxa-13,14-dihydro-PGF1α -1.15 lactones
EMI23.3
   13,14-didehydro-18,19,20-trinor-4-oxa-PGF1α -1.15-lactones
EMI23.4
   13,14-Didehydro-18,19,20-trinor-3-oxa-PGF1α -1.15-lactone
EMI23.5
   3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-PGF1α-1,15-lactones
EMI23.6
 3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-13,14-dihydro PGF1-1,15-lactone
EMI23.7
   3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-hexanor-PGF1?

  ; - 1,15-lactones
EMI23.8
 3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-hexanor-13,14-di hydro-PGF1 -1, 15-lactone
EMI23.9
 13,14-Didehydro-3,7-inter-m-phenylene-4,5,6,18,19,20-hexa nor-PGF1α-1,15-lactones
EMI23.10
 13,14-Didehydro-3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20 hexanor-PGF11,1 5-lactone Table C
L1 Example gs T R3 R4 R5 ¯0 Name C-1 1 0 HHH 17-phenyl C-2 1 1 p-fluoro HHH 17- (p-fluorophenyl) C-3 1 1 m-chloro HHH 17- (m-chlorophenyl ) C-4 1 1 m-trifluoro-HHH a 17- (m-trifluoromethylphenyl) methyl C-5 1 0 HH methyl a 15-methyl-17-phenyl C-6 1 1 fluoro HH methyl

   a 15-methyl-17- (p-fluorophenyl) C-7 1 1 m-chloro HH methyl 15-methyl-17- (m-chlorophenyl) C-8 1 1 m-trifluoro-HH methyl 15-methyl-17- (m-trifluoromethyl-methyl phenyl) C-9 1 0 HHH ss 15-epi-17-phenyl C-10 1 1 p-fluorine HHH ss 15-epi-17- (p-fluorophenyl) C-1 1 1 1 m -chlor HHH ss 15-epi-17- (m-chlorophenyl) C-12 1 1 m-trifluoro-HHH ss 15-epi-17- (m-trifluoromethyl methyl phenyl) C-13 10 methyl methyl H 16;

  ; 16-dimethyl-17-phenyl C-14 1 1 p-fluoro methyl methyl H a 16,16-dimethyl-17- (p-fluorophenyl) C-15 1 1 m-chloro methyl methyl H a 16,16-dimethyl -17- (m-chlorophenyl) C-16 1 1 m-trifluoromethyl methyl H a 16,16-dimethyl-17- (m-trifluoromethyl methylphenyl) C-17 1 0 methyl methyl methyl a 15,16, 16-trimethyl-17-phenyl C-18 1 1 p-fluoro methyl methyl methyl a 15,16,16-trimethyl-17- (p-fluorophenyl) C-19 1 1 m-chloro methyl methyl methyl a 15, 16,16-trimethyl-17- (m-chlorophenyl) C-20 1 1 m-trifluoromethyl methyl methyl a 15,16,16-trimethyl-17- (m-trifluoromethyl methylphenyl) C-21 10 methyl methyl H ss 15-epi-16,16-dimethyl-17-phenyl C-22 1 1 p-fluoro methyl methyl H ss 15-epi-16,16-dimethyl-17- (p-fluor

   phenyl) C-23 1 1 m-chloro methyl methyl H ss 15-epi-16,16-dimethyl-17- (m-chloro-phenyl) C-24 1 1 m-trifluoromethyl methyl H ss 15-epi- 16,16-dimethyl-17- (m-trimethyl fluoromethylphenyl) C-25 30 HHH a 2a, 2b-dihomo-17-phenyl C-26 3 1 p-fluoro HHH 2a, 2b-dihomo-17- ( p-fluorophenyl) C-27 3 1 m-chloro HHH 2a, 2b-dihomo-17- (m-chlorophenyl) C-28 3 1 m-trifluoro-HHH 2a, 2b-dihomo-17- (m-trifluoromethyl methyl phenyl ) C-29 3 0 HH methyl a 2a, 2b-dihomo-15-methyl-17-phenyl C-30 3 1 p-fluorine HH methyl a 2a, 2b-dihomo-15-methyl-17- (p-fluorophenyl) C-3 1 3 1 m-chloro HH methyl a 2a, 2b-dihomo-15-methyl-17- (m-chlorophenyl) C-32 3 1

   m-trifluoro-HH methyl a 2a, 2b-dihomo-15-methyl-17- (m-tri methyl fluoromethylphenyl) C-33 10 fluorofluor H 16.16-difluoro-17-phenyl C-34 1 1 p -fluorofluorofluor H a 16.16-difluoro-17- (p-fluorophenyl) C-35 1 1 m-chlorofluorofluor H 16.16-difluoro-17- (m-chlorophenyl) C-36 1 1 m -trifluor- fluorofluor H a 16,16-difluoro-17- (m-trifluoromethyl methylphenyl) C-37 1 0 fluorofluoromethyl a 15-methyl-16,16-difluoro-17-phenyl C-38 1 1 p-fluorofluorofluoromethyl a 15-methyl-16,16-difluoro-17- (p-fluorophenyl) C-39 1 1 m-chlorofluorofluoromethyl a 15-methyl-16,16-difluoro-17- (m chlorophenyl) C-40 1 1 m-trifluorofluorofluoromethyl a 15-methyl-16,16-difluoro-17- (m-methyl trifluoromethylphenyl) C-41 1 0 fluorofluor H a 16,16-difluoro-17- phenyl C-42 1 1 <RTI

    ID = 24.38> fluorine fluorine fluorine H a 16,16-difluoro-17- (p-fluorophenyl) C-43 1 1 m-chloro fluorine fluorine H ss 15-epi-16,16-difluoro-17- (m-chlorine - phenyl) C-44 1 1 m-trifluorofluorofluorine H ss 15-epi-16,16-difluoro-17- (m-trimethyl fluoromethylphenyl) Table D
EMI25.1
   PGF3U-I, 15-lactones
EMI25.2
   13,14-dihydro-PGF3α-1,15-lactones
EMI25.3
   5,6-dihydro-PGF3 -1, 15-lactones
EMI25.4
   5,6,13,14-tetrahydro-PGF3α-1,15-lactones
EMI25.5
   13,14-didehydro-PGF3?

  ; -1,15-lactones
EMI25.6
   13,14-didehydro-5,6-dihydro-PGF3a-1,15-lactone
EMI25.7
 2,2-difluoro-5,6-dihydro-PGF3a-1,15-lactone
EMI25.8
   2,2-difluoro-13,14-dihydro-PGF3a-1,15-lactones
EMI25.9
   2,2-difluoro-5,6-dihydro-PGF3α-1,15-lactones
EMI25.10
   2,2-difluoro-5,6,13,14-tetrahydro-PGF3α -1,15-lactone Table D
EMI26.1
 1 3,14-didehydro-2,2-difluoro-PGF3, -1.15-la
EMI26.2
   13,14-Didehydro-2,2-difluoro-5,6-dihydro-PGF3α-1,15-lactones
EMI26.3
   cis, cis-4,5,17,18-tetradehydro-13,14-diyhdro-PGF1α-1,15-lactones
EMI26.4
   cis, cis-4,5,17,18-tetradehydro-13,14-diyhdro-PGF1?

  ; -1,15-lactones
EMI26.5
   5-oxa-cis-17,18-didehydro-PGFI a¯l, 15-lactones
EMI26.6
   5-oxa-13,14-dihydro-cis- 17,18-didehydro-PGFlu-l, 15-lacto-
EMI26.7
   13,14-didehydro-cis, cis-4,5,17,18-tetrahydro-PGF1α -1,15-lactone
EMI 26.8
   13,14-Didehydro-5-oxa-cis-17,18-didehydro-PGF1α -1,15-lac-tone
EMI 26.9
   4-oxa-cis-17,18-didehydro-PGF1α -1,15-lactone
EMI26.10
   4-0xa-13,14-dihydro-17, 18-didehydro-PGF1a1, 15-lactone Table D.
EMI27.1
   3-oxa-cis-17,18-didehydro-PGF1?

  ; -1,15-lactones
EMI27.2
   3-oxa-13,14-dihydro-cis-17,18-didehydro-PGFIa-1,15-lactone
EMI27.3
 13,14-Didehydro-4-oxa-cis-17,18-didehydro-PGFla-1,15-lactone
EMI27.4
   13,14-Didehydro-3-oxa-cis-17,18-didehydro-PGF1α -1,15-lac-tone
EMI27.5
 3,7-inter-m-phenylene-4,5,6-trinor-cis-17,18-didehydro PGF1 -1,15-lactone
EMI 27.6
 3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-cis-17,18-di dehydro-PGFIa-1,15-lactone
EMI27.7
 3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis-17,18-didehydro PGFIa-1,15-lactone
EMI 27.8
 3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-cis 17,18-didehydro-PGF1?

  ; -1,15-lactones
EMI 27.9
 13,14-Didehydro-3,7-inter-m-phenylene-4,5,6-trinor-cis-17,18 didehydro-PGFla-1,15-lactone
EMI 27.10
 13,14-Didehydro-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis 17,18-didehydro-PGF1α -1,15-lactone Table D
L, Example g R3 R4 R5 0 Name D-1 1 methyl HH a 16-methyl D-2 1 methyl H methyl a 15,16-dimethyl D-3 1 methyl HH ss 15-epi-16-methyl D-4 1 methyl methyl H a 16,16-dimethyl D-5 1 methyl methyl methyl a 15,16,16-trimethyl D-6 1 methyl methyl H 16,16-dimethyl D-7 1 fluor HH ss 15-epi-16-fluor D-8 1 fluor H methyl 15-methyl-16-fluor D-9 1 fluor HH ss 15-epi-16-fluor D-10 1 fluor fluor H 16,16-difluoro D-11 1 fluor fluor methyl a 15- methyl-16,16-difluoro D-12 1 fluor fluor H ss

   15-epi-16,16-difluoro D-13 1 HHH a title compound D-14 1 HH methyl a 15-methyl D-15 3 HHH a 2a, 2b-dihomo D-16 3 HH methyl a 2a, 2b-dihomo 15-methyl D-17 3 methyl methyl H a 2a, 2b-dihomo-16,16-dimethyl D-18 3 methyl methyl methyl a 2a, 2b-dihomo-15,16,16-trimethyl D-19 3 fluorofluor H a 2a, 2b-dihomo-16,16-difluoro D-20 3 fluorofluoromethyl a 2a, 2b-dihomo-15-methyl-16,16-difluoro Table E
EMI28.1
   cis-13-PGF2, -1,15-lactones
EMI28.2
   cis-13-PGF1α -1,15 lactones
EMI28.3
   cis-13-PGF2α-1,15-lactones
EMI28.4
   cis- 1 3-PGF1-1,1 5-lactones
EMI28.5
   cis-4,5-didehydro-cis-13-PGF1α-1,15-lactones
EMI28.6
   5-oxa-cis-13-PGF1?

  ; -1,15-lactone Table E
EMI29.1
   4-oxa-cis-13-PGF1α -1,15-lactones
EMI29.2
   3-oxa-cis-13-PGF1α -1,15-lactones
EMI29.3
   3,7-inter-m-phenylene-4,5,6-trinor-cis-13-PGF1α-1,15-lactones
EMI29.4
 3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis-13-PGD1-1.15 lactones
L1 Example g m R3 R4 R5 ¯0 Name E-1 1 3 methyl H H a 15-epi-16-methyl E-2 1 3 methyl H methyl a 15-epi-15,

   16-dimethyl E-3 1 3 methyl HH ss 16-methyl E-4 1 3 methyl methyl H a 15-epi-16,16-dimethyl E-5 1 3 methyl methyl methyl a 15-epi-15,16,16 -trimethyl E-6 1 3 methyl methyl H ss 16,16-dimethyl E-7 1 3 fluor HH a 15-epi-16-fluor E-8 1 3 fluor H methyl 15-epi-15-methyl-16-fluor E-9 1 3 fluor HH a 15-epi-16-fluor E-10 1 3 fluor fluor H 15-epi-16,16-difluoro E-1 1 1 3 fluor fluor methyl a 15-epi-15-methyl- 16,16-difluoro E-12 1 3 fluorofluoromethyl ss 15-methyl-16,16-difluoro E-13 1 3 HHH a 15-epi E-14 3 3 HHH a 15-epi-21,2b-dihomo E -15 3 3 methyl methyl H a 15-epi-2a, 2b-dihomo-16,16-dimethyl E-16 3 3 methyl methyl methyl a 15-epi-2a, 2b-dihomo-15,16,16-trimethyl E -17 3 3 fluor fluor H a 15-epi-2a, 2b-dihomo-16,16-difluoro E-18

   3 3 fluorofluoromethyl a 15-epi-2a, 2b-dihomo-15-methyl-16,16-di-fluor Table
EMI29.5
   cis-13-PGF2α-1,15-lactones
EMI29.6
   cis-13-PGF1α -1,15-lactone Table F
EMI30.1
   2,2-difluoro-cis-13-PGF2α-1,15-lactones
EMI30.2
   2,2-difluoro-cis-13-PGF1α-1,15-lactones
EMI30.3
   cis-4,5-didehydro-cis-13-PGF1α-1,15-lactones
EMI30.4
   5-oxa-cis-13-PGF1α-1,15-lactones
EMI30.5
   4-oxa-cis-13-PGF1α -1,15-lactones
EMI30.6
   3-oxa-cis-13-PGF1α -1,15-lactones
EMI30.7
   3,7-inter-m-phenylene-4,5,6-trinor-cis-13-PGF1?

  ; -1,15-lactones
EMI30.8
   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis-13-PGF1α -1,15-lactone Table F
L1 Example gs T R3 R4 R5 ¯0 Name F-1 1 0 HHH a 15-epi-16-phenoxy-17,18,19,20 tetranor F-2 1 1 p-fluorine HHH a 15-epi-16- ( p-fluorophenoxy)
17,18,19,20-tetranor F-3 1 1 m-chloro H H H a 15-epi-16- (m-chlorophenoxy)
17,18,19,20-tetranor F-4 1 1 m-trifluoro-HHH a 15-epi-16- (m-trifluoromethylphen-methyl oxy) -17,18,19,20-tetranor F-5 1 0 HH methyl a 15-epi-15-methyl-16-phenoxy
17,18,19,20-tetranor F-6 1 1 p-fluoro HH methyl a 15-epi-15-methyl-16- (p-fluorophenoxy) -17,18,19,20-tetranor F-7 1 1 m-chloro HH methyl a 15-epi-15-methyl-16- (m-chlorophen oxy) -17,18,19,20-tetranor F-8 1 1 m-trifluoro-HH methyl a

   15-epi-15-methyl-16- (m-trifluoromethyl methylphenoxy) -17,18,19,20-tetranor F-9 10 HHH ss 16-phenoxy-17,18,19,20-tetranor F-10 1 1 p-fluor HHH ss 16- (p-fluorophenoxy) -17,18,19,20 tetranor F-11 1 1-chloro HHH ss 16- (m-chlorophenoxy) -17,18,19,20 tetranor F -12 1 1 m-trifluoro-HHH ss 16- (m-trifluoromethylphenoxy) methyl 17,18,19,20-tetranor F-13 1 0 methyl methyl H a 15-epi-16-methyl-16-phenoxy-
18,19,20-trinor F-14 1 1 p-fluoromethyl methyl H a 15-epi-16-methyl-16- (p-fluorophenoxy) -18,19,20-trinor F-15 1 1 m -chloromethyl methyl H a 15-epi-16-methyl-16- (m-chlorophen-oxy) - 18.1 9.20-trinor F-16 1 1 m-trifluoromethyl methyl H a 15-epi-16 -methyl-16- (m-trifluoromethyl methylphenoxy) -18,19,20-trinor F-17 10 methyl methyl methyl a <RTI

    ID = 31.10> 15-epi-15,16-dimethyl-16-phenoxy-
18,19,20-trinor F-18 1 1 fluoromethyl methyl methyl a 15-epi-15,16-dimethyl-16- (p-fluorophenoxy) -1 8,19,20-trinor F-19 1 1 m-chloro methyl methyl methyl a 15-epi-15,16-dimethyl-16- (m-chlorophenoxy) -18,19,20-trinor F-20 1 1 m-trifluoromethyl methyl methyl a 15-epi- 15,16-dimethyl-16- (m-trimethyl fluoromethylphenoxy) - 18,19,20- trinor F-21 10 methyl methyl H ss 16-methyl-16-phenoxy-18,19,20-trinor F- 22 1 1 p-fluoromethyl methyl H ss 16-methyl-16- (p-fluorophenoxy)
18,19,20-trinor F-23 1 1 m-chloro methyl methyl H ss 16-methyl-16- (m-chlorophenoxy)
18,19,20-trinor F-24 1 1 m-trifluoromethyl methyl H ss 16-methyl-16- (m-trifluoromethyl methyl phenoxy) -18,19,20-trinor F-25 3 0 H H H a <RTI

    ID = 31.16> 15-epi-2a, 2b-dihomo-16-phenoxy-
17,18,19,20-tetranor F-26 3 1 p-fluoro HHH a 15-epi-2a, 2b-dihomo-16- (p-fluorophenoxy) -17,18,19,20-tetranor F-27 3 1 m-chloro HHH a 15-epi-2a, 2b-dihomo-16- (m-chloro phenoxy) -17,18,19,20-tetranor F-28 3 1 m-trifluoro-HHH 15-epi-2a , 2b-dihomo-16- (m-trifluoromethyl methylphenoxy) -17,18,19,20-tetranor F-29 3 0 HH methyl a 15-epi-2a, 2b-dihomo-15-methyl-16 phenoxy-17 , 18,19,20-tetranor F-30 3 1 p-fluoro HH methyl a 15-epi-2a, 2b-dihomo-15-methyl-16 (p-fluorophenoxy) -18,19,20-tetranor F-31 3 1 m-chloro HH methyl a 15-epi-2a, 2b-dihomo-15-methyl-16 (m-chlorophenoxy) -17,18,19,20 tetranor F-32 3 1 m-trifluoro-HH methyl a 15 -epi-2a, 2b-dihomo-15-methyl-16 methyl (m-trifluoromethylphenoxy)
17,18,19,20-tetranor Table G
EMI32.1
  

     1 8,19,20-trinor-cis-13-PGF2a-1,15-lactone
EMI32.2
   18,19,20-trinor-cis-13-PGF1α -1.15-lactones
EMI32.3
   18,19,20-trinor-2,2-difluoro-cis-13-PGFza 1,15-lactone
EMI32.4
   18,19,20-trinor-2,2-difluoro-cis-13-PGF1α -1.15-lactone
EMI32.5
   18,19,20-trinor-cis-4,5-didehydro-cis-13-PGF1α -1.15-lactones
EMI32.6
   18,19,20-trinor-5-oxa-cis-13-PGF1α -1,15-lactone
EMI32.7
   18,19,20-trinor-4-oxa-cis-1 3-PGFIa-1,1 5-lactone
EMI32.8
   18,19,20-trinor-3-oxa-cis-13-PGF1α -1,15-lactone
EMI32.9
   3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-cis-13-PGF1?

  ; - 1,15-lactones
EMI32.10
 3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-hexanor-cis-13 PGF1a-1,15-lactone Table G
L1 Example g s T R3 R4 R5 ¯0 Name G-l 1 0 H H H a 15-epi-17-phenyl
G-2 1 1 p-fluoro HHH a 15-epi-17- (p-fluorophenyl) G-3 1 1 m-chloro HHH a 15-epi-17- (m-chlorophenyl) G-4 1 1 m-trifluor - HHH a 15-epi-17- (m-trifluoromethylphenyl) methyl G-5 10 HH methyl a 15-epi-15-methyl-17-phenyl G-6 1 1 p-fluoro HH methyl 15-epi-15- methyl-17- (p-fluorophenyl) G-7 1 1 m-chloro HH methyl a 15-epi-15-methyl-17- (m-chlorophenyl) G-8 1 1 m-trifluoro-HH methyl a 15-epi -15-methyl-17- (m-trifluoromethyl methylphenyl) G-9 10

   HHH ss 17-phenyl G-10 1 1 p-fluoro HHH ss 17- (p-fluorophenyl) G-1 1 1 1 m-chloro HHH ss 17- (m-chlorophenyl) G-12 1 1 m-trifluoro-HHH ss 17- (m-trifluoromethylphenyl) methyl G-13 1 0 methyl methyl H 15-epi-16,16-dimethyl-17-phenyl G-14 1 1 p-fluoromethyl methyl H a 15-epi-16,16- dimethyl-17- (p-fluorophenyl) G-15 1 1 m-chloro methyl methyl H a 15-epi-16,16-dimethyl-17- (m-chlorophenyl) G-16 1 1 m-trifluoromethyl methyl H a 15-epi-16,16-dimethyl-17- (m-tri methyl fluoromethylphenyl) G-17 1 0 methyl methyl methyl a 15-epi-15,16,16-trimethyl-17-phenyl G-18 1 1 p-fluoro methyl methyl methyl a 15-epi-15,16,16-trimethyl-17- (p fluorophenyl) G-19 1 1 m-chloro methyl methyl methyl a 15-epi-15,16,16-trimethyl- 17- (m-

   chlorophenyl) G-20 1 1 m-trifluoromethyl methyl methyl a 15-epi-15,16,16-trimethyl- (m-trimethyl fluoromethylphenyl) G-21 10 methyl methyl H (3 16,16-dimethyl -17-phenyl G-22 1 1 p-fluoromethyl methyl H ss (3 16,16-dimethyl-17- (p-fluorophenyl) G-23 1 1 m-chloro methyl methyl H ss 16,16-dimethyl-17 - (m-chlorophenyl) G-24 1 1 m-trifluoromethyl methyl H ss 16,16-dimethyl-17- (m-trifluoromethyl methylphenyl) G-25 3 0 HHH a 15-epi-2a, 2b-dihomo -17-phenyl G-26 3 1 p-fluor HHH 15-epi-2a, 2b-dihomo-17- (p-fluorophenyl) G-27 3 1 m-chloro HHH a 15-epi-2a, 2b- dihomo-17- (m-chlorophenyl) G-28 3 1 m-trifluoro-HHH a 15-epi -2a, 2b-dihomo-17- (m-tri methyl <RTI

    ID = 33.25> fluoromethylphenyl) G-29 3 0 HH methyl a 15-epi-2a, 2b-dihomo-15-methyl-17 phenyl G-30 3 1 p-fluorine HH methyl a 15-epi-2a, 2b-dihomo -15-methyl-17 (p-fluorophenyl) G-31 3 1 m-chloro HH methyl a 15-epi-2a, 2b-dihomo-15-methyl-17 (m-chlorophenyl) G-32 3 1 m-trifluor - HH methyl 15-epi-2a, 2b-dihomo-15-methyl-17 methyl (m-trifluoromethylphenyl) G-33 1 0 fluorofluor H a 15-epi-16,16-difluoro-17-phenyl G-34 1 1 p-fluorofluorofluor H a 15-epi-16,16-difluoro-17- (p-fluorophenyl) G-35 1 1-m-chlorofluorofluor H a 15-epi-16,16-difluoro-17 - (m-chlorophenyl) G-36 1 1 m-trifluorofluorofluorine H 15-epi-16,16-difluoro-17- (m-tri methyl fluoromethylphenyl) G-37 10 fluorofluoromethyl a 15-epi -15-methyl-16,16-difluoro-17-phenyl G-38 1 1 p-fluorofluorofluoromethyl a

   15-epi-15-methyl-16,16-difluoro-17 (p-fluorophenyl) G-39 1 1 m-chloro fluorofluoromethyl a 15-epi-15-methyl-16,16-difluoro-17 (m- chlorophenyl) G-40 1 1 m-trifluorofluorofluoromethyl a 15-epi-15-methyl-16,16-difluoro-17 methyl (m-trifluoromethylphenyl) Table G
L1 Example gs T R3 R4 R5 ¯0 Name G-41 1 0 fluorofluor H ss 16,16-difluoro-17-phenyl G-42 1 1 p-fluorofluorofluor H ss (3 16,16-difluoro-17- (p-fluorophenyl) G-43 1 1 m-chlorofluorofluor H ss 16,16-difluoro-17- (m-chlorophenyl) G-44 1 1 m-trifluorofluorofluor H ss 16,16-difluoro-17 - (m-fluoromethyl methyl phenyl) Table H
EMI34.1
   cis-13-PGF3α-1,15-lactones
EMI34.2
   cis-13-5,6-dihydro-PGF3α -1.15-lactones
EMI34.3
   2,2-difluoro-cis-13-PGF3?

  ; -1,15-lactones
EMI34.4
   2,2-difluoro-cis-13-5,6-dihydro-PGF1α-1,15-lactones
EMI34.5
   cis, cis-4,5,17,18-tetradehydro-cis-13-PGF1α -1,15-lactones
EMI34.6
   5-oxa-cis-13-cis-17,18-didehydro-PGF1α-1,15-lactones
EMI34.7
   4-oxa-cis-13-cis-17,18-didehydro-PGF1α-1,15-lactones
EMI34.8
   3-oxa-cis-13-cis-17,18-didehydro-PGF1α-1,15-lactones
EMI35.1
 3,7-inter-m-phenylene-4,5,6-trinor-cis-13-cis-17,18-didehydro PGF1α -1,15-lactone
EMI35.2
   3,7-inter-m-phenylene-3sxa-4,5,6-trinor-ci 3-cis-17,18-di-dehydro-PGF1?

  ; -1,15-lactones
L1 Example g R3 R4 R5 ¯0 Name H-1 1 methyl HH a 15-epi-16-methyl H-2 1 methyl H methyl ss 15,16-dimethyl H-3 1 methyl HH ss 16-methyl H-4 1 methyl methyl H a 15-spi-16,16-dimethyl H-5 1 methyl methyl methyl a 15-epi-15,16,16-trimethyl H-6 1 methyl methyl H ss 16,16-dimethyl H-7 1 fluor HH a 15-epi-16-fluor H-8 1 fluor H methyl a 15-epi-15-methyl-16-fluor H-9 1 fluor HH ss 16-fluor H-10 1 fluor fluor H a 15-epi- 16,16-difluoro H-11 1 fluorofluoromethyl?

  ; 15-epi-15-methyl-16,16-difluoro H-12 1 fluorofluor H ss 16,16-difluoro H-13 1 HHH a 15-epi H-14 1 HH methyl a 15-epi-15-methyl H -15 3 HHH a 15-epi-2a, 2b-dihomo H-16 3 HH methyl a 15-epi-2a, 2b-dihomo-15-methyl H-17 3 methyl methyl H a 15-epi-2a, 2b- dihomo-16,16-dimethyl H-18 3 methyl methyl methyl a 15-epi-2a, 2b-dihomo-15,16,16-trimethyl H-19 3 fluorofluor H a 15-epi-2a, 2b-dihomo 16,16-difluoro H-20 3 fluorofluoromethyl a 15-epi-2a, 2b-dihomo-15-methyl-16,16-di-fluorine


    

Claims (2)

 PATENT CLAIMS 1 . Process for the preparation of a new prostaglandin-like 1,1 5-lactone of the formula wherein EMI1.1 EMI1.2  or EMI1.3  R5 is hydrogen or methyl, R5 is hydrogen or the hydroxyl group, L1 EMI1.4  or a mixture of EMI1.5 EMI1.6  and EMI1.7  R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, R7 - (CH2) m -CH3, where my number is from 1 to 5, cis-CH-CH2-CH3 or a residue EMI 1.8  means in which T is chlorine, fluorine, the trifluoromethyl radical,  represents an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms, where the different radicals T can be the same or different, s is 0, 1, 2 or 3 and Z3 means the oxa or methylene group, with the proviso that not more than 2 radicals T are different from alkyl and with the further proviso that Z3 means the oxa group only when R3 and R4, which may be the same or different, are hydrogen or methyl, Y trans CH = CH-.  -CH2CH2-, cis-CH = CH- or -CC- and Zl 1) cis-CH = CH-CH2- (CH2) g-CH2-, 2) cis-CH = CH-CH2- (CH2) g-CF2 -, 3) cis-CH2-CH = CW (CH2) gCH2 4) - (CH2) 3- (CH2) g-CH2-, 5) - (CH2) 3- (CH2) g-CF2-, 6) - CH2-O-CH2- (CH2) g-CH2-, EMI1.9  where g is an integer from 1 to 3, characterized in that a prostaglandin-like compound of the formula EMI2.1  or EMI2.2 EMI2.3  wherein Z1, Y1, L1 and R7 have the meaning given above, and M1 or EMI2.4  is lactonized.  2. Process for the preparation of a new prostaglandinarti 1,15-lactone of the formula wherein EMI2.5 EMI2.6  or EMI2.7  R5 is hydrogen or methyl, R5 is hydrogen or the hydroxyl group, L1 EMI 2.8  or a mixture of EMI2.9  and EMI2.10  where R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only when the other is hydrogen or fluorine, R7 - (CH2) m-CH3 , wherein m is a number from 1 to 5, cis-CH = CH-CH2-CH3 or a radical EMI3.1  means in which T denotes chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms,  where the different radicals T can be the same or different, s is the number 0, 1, 2 or 3 and Z3 is the oxa or methylene group, provided that no more than 2 radicals T are different from alkyl and the other Provided that Z3 means the oxa group only if R3 and R4, which may be the same or different, are hydrogen or methyl, Y1 trans-CH = CH-, -CH2CH2-, cis-CH = CH- or C = C- and Zl 1) cis-CH = CH-CH24CH2) g-CH2-, 2) cis-CH = CH-CH2- (CH2) g-CF2-, 3) cis-CH2-CH = CH4CH2) g-CH2-, 4) - (CH2) 3- (CH2) g-CH25) QCH2) 3tCH2) g-CF2-, 6) -CH2-O-CH2- (CH2) g-CH2-. EMI3.2   wherein g is an integer from 1 to 3, characterized in that, according to the process of claim 1, a compound of formula I A with cyclopentane ring structures of the formula EMI3.3  and then reduced the 9-keto group in the cyclopentane ring structures to the corresponding 9a and 9P hydroxy groups.  The present invention relates to methods for producing new lactones of some known prostaglandins or prostaglandin analogs.  The new compounds which can be prepared according to the invention have the following formula: EMI3.4 EMI3.5  or EMI3.6   ** WARNING ** End of CLMS field could overlap beginning of DESC **.