JPH06145085A - Carbacyclin analogue - Google Patents

Abstract

PURPOSE: To provide the new compounds useful as an anti-thrombus agent, an anti-ulcer agent and an anti-tumor agent.

CONSTITUTION: The compounds of the formula I or their salts, e.g. 2- decarboxy-2-hydroxymethyl-9β-methyl-carbacyclin. The compounds are obtained by, for example, after removing protective group R₃₁ of the intermediate of the formula V obtained from the compound of the formula IV (R₃₁ is a protective group of hydroxy hydrogen; R₃₈ is H, OR₃₁ or the like), step-wisely oxidizing it, Wittig-oxyacylating and reducing it. In the formula I, L₁ is α-H: β-H; M₁ is α-OH: β-H, α-H: β-OH; R₇ is C_mH_2mCH₃ [(m) is 1 to 5]; R₈ is OH; R₁₅ is H, fluoro; R₁₆ is H, or CH₂ together with R₁₇; R₁₇ is H, 1-4C alkyl; X₁ is COOR₁ (R₁ is H, 1-12C alkyl or the like), CH₂O; Y₁ is trans or cis CH=CH; Z₁ is the formulae II, III [(f), (g) are each 0 to 3; Ph is 1,2-, 1,4-phenylene or the like]; provided that only when Z₁ is the formula III, all of the R₁₅ to R₁₇ are H, and that only when R₁₅ is H, Z₁ is the formula III.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

The present invention provides novel compounds.

The present invention is particularly directed to prostacyclin or PG
It relates to new analogues of I ₂ . Particularly, the present invention is C-5.
Or a carbacycline analog modified at the C-9 position, such as a C-5 interphenylene analog of carbacyclin, a 5-fluoro analog of carbacyclin,
It relates to 9β-alkyl analogs of carbacyclin, C-6a, 9 tricyclic (cyclopropyl) analogs of carbacyclin and combinations thereof, as well as novel benzindene analogs thereof.

Prostacyclin is a compound produced endogenously in mammalian species and is structurally and biosynthetically related to prostaglandins (PG's). Especially C
When the -5,6 position is unsaturated, the pstacycline exhibits the structure of Formula I and carbon atom numbering. For convenience, prostacyclin is often referred to simply as "PGI ₂ ". Carbacyclin, 6a-carba-PGI _2, is C-5,6
When the position is unsaturated, it represents the structure and carbon atom number shown in Formula II. Similarly, for convenience, carbacyclin is simply referred to as "CBA ₂ ".

A stable, partially saturated derivative of PGI ₂ is PGI ₁ . That is, when the C-5,6 position is saturated, it is 5,6-dihydro-PGI ₂ when the C-5,6 position depicted by the carbon atom number in formula II is saturated. The corresponding 5,6-dihydro-CBA ₂ is CBA ₁ depicted in Formula II. CBA ₂ is the CB drawn in Formula II
It is A ₁ .

As is evident from a review of formulas I and II, prostacyclin and carbacyclin are PGF-type compounds,
For example, it is commonly named as a derivative of PGF ₂ α of formula III. Therefore, prostacyclin is commonly named 9-deoxy-6,9α-epoxy- (5Z) -5,6-didehydro-PGF _1, and carbacyclin is 9-
It is named deosi-6,9α-methano- (5E) -5,6-didehydro-PGF ₁ . The article on Prostacyclin and its structural identification is reviewed by Johnson.
Volume 915 of Prostagrandins, etc.
See page (1976).

For convenience, this novel prostacyclin or carbacyclin analog is described by J. Med. Chem. 17: 911 (1974) NA Nelson for prostaglandins. According to the popular and technically accepted nomenclature system. Therefore, all novel prostacyclin derivatives herein are 9-deoxy-PGF ₁ -type compounds, P
Like GI ₂ derivatives, or preferably CBA ₁ or C
It will be named as BA ₂ derivatives.

In the formulas herein, the dashed bond to the ring represents the alpha (α) configuration, ie the substituent group below the face of the ring. The thick solid line bond to the ring indicates the beta (β) configuration, ie the substituent above the plane of the ring. The use of wavy lines (~) herein will indicate that the substituents are attached in the alpha or beta configuration, or in a mixture of the alpha and beta configurations. Alternatively, the dashed line should represent either the E or Z geometric isomeric configuration, or a mixture thereof.

The side chain hydroxy at C-15 in the formulas herein is the Cahn-Ingold-Prelog rank rule (Ca
hn-Ingold-Prelog sequence rules) (J. Chem. Ed.
Vol. 41, p. 16 (1964), as determined by S
And in the R configuration. See also Nature 212, page 38 (1966), for discussion of prostaglandin configurations. This discussion applies to the novel prostacyclin and carbacyclin analogs of the invention. The prostacyclin and halvacyclin molecules each have several asymmetric centers and therefore exist in either optically inactive form or in two enantiomeric forms (optically inactive), either dextrorotatory or levorotatory. sell. The formula for PGI ₂ as depicted corresponds to a particularly endogenously produced prostacyclin C-8 (α), C-9 (α) corresponding to PGI ₂ produced endogenously in mammalian species. , C
Note the stereochemical configuration at -11 (α) and C-12 (β). The mirror image of the above formula for prostacyclin represents the other enantiomer. The racemic form of prostacyclin contains the same number of both enantiomeric molecules.

For convenience, references to prostacyclin and carbacyclin will be directed to their optically active forms. As mentioned above, for prostacyclin, reference is made to its form having the same absolute configuration as that obtained from mammalian species.

The term "prostacyclin-type" product, as used herein, relates to any cyclopentane derivative of the present invention useful for at least one of the same pharmaceutical purposes for which prostacyclin is used. The formula depicted herein, which depicts a prostacyclin-type product or an intermediate useful in its preparation, is a prostacyclin-type product that has the same relative stereochemical configuration as prostacyclin obtained from mammalian tissue. A specific stereoisomer of an object,
Alternatively, it represents a particular stereoisomer of an intermediate useful in making the stereoisomer of the above-mentioned prostasaic type products.

The term "prostacyclin analog" or "carbacycline analog" refers to a stereoisomer or stereoisomer of a prostacyclin-type product that has the same relative stereochemical configuration as prostacyclin obtained from mammalian tissue. Represents a mixture of the body and its enantiomers. In particular, where the formula is used herein to describe a proscyclin-type product, the term "proscyclin analog" or "carbacycline analog" refers to a compound of the formula or a compound thereof and its enantiomers. Refers to the mixture.

Carbacyclin and related compounds are known in the art. Japanese Patent Publication 63,0
59 and 63,060 (also Derwent Farm Dock CPI Nos. 48154B / 26 and 4815, respectively)
5B / 26). See also British Published Specification No. 2,012,265 and German Published Publication No. 2,900,352 abstracted as Derwent Farm Dock CPI No. 54825B / 30. UK published applications 2,017,699,2
See also 014,143 and 2,013,661.

The synthesis of carbacyclin and related compounds has also been reported in the chemical literature as follows: Morton Day. R. (Morton DR) etc. Journal of Organic Chemistry (J. Organic Chem)
istry) 44, 2880 pages (1979); Shibasaki
M. (Shibasaki M.) et al., Tetrahedron Letters, pp. 433-436, (19).
1979); Kojima Kei. (Kojima K.) et al., Tetrahedron Letters, 3743-3746 (1978).
Year); Nicorou Kay. Journal of the Chemical Society, C, etc. (Nicolaou K. C)
Communications (J. Chem. Soc., Chemical Comm
unications) 1067-1068 (1978); Sugiay. (Sugie A.) et al., Tetrahedron Letters, 2607-2610 (1979); Shibasaki
M. Chemistry Letters 1
299-1300 (1979) and Hayashi M.
(Hayashi M.), Chem. Lett. Pp. 1437-40 (19).
1979), and Li (Tsung-te)
e) “A Facile Synthesis of 9 (0) -Methano-Pros
tacyclin) ”, Abstract No. 378 (organic chemistry) and P.
A. PA Aristoff “Synthesis of ba-Carbapr (6a-carbaprostacyclin I ₂
ostacyclin I ₂ ) ”, abstract number 236 (organic chemistry), both of which are the second congress of the North American continent (Second Congress of t) in San Francisco, California (Las Vegas, NV), 24-29 August 1980.
abstract of he North American Continent) (Part II)
It is published in.

7-oxo and 7-hydroxy-CBA ₂
The compounds are explicitly disclosed in US Pat. No. 4,192,891. The 19-hydroxy-CBA2 compounds, 1979 compounds, are disclosed in US Application No. 054,811 filed July 5. CBA ₂
Aromatic esters of U.S. Pat. No. 4,180,657.
Is disclosed in. 11-deoxy - △ ¹⁰ - or △ ¹¹ -
CBA ₂ compounds are disclosed in Japanese Patent Publication No. 77 / 24,865.
(Published February 24, 1979).

The present specification specifically provides carbacyclin analogs of formula X. In this formula, n is 1
Where L ₁ is α-H: β-H and M ₁ is α-OH:
beta-R ₅ or alpha-R _5: is and R ₅ is beta-OH is H, R ₇ is -CmH ₂ m-CH ₃ is (m is an integer of from 1 to 5), R ₈ is hydroxy There, R ₁₅ is hydrogen or fluoro, or R ₁₆ is hydrogen, or R ₁₆ is -CH ₂ together with R ₁₇ - represents either R ₁₇ are as defined above, or (1) Hydrogen or (2) (C ₁ -C ₄ ) alkyl, X ₁ is (1) —COOR ₁ (wherein R ₁ is (a) hydrogen (b) (C ₁ -C ₁₂ ) alkyl, or (c) drug is pharmacologically accepted is cationic) or (2) a -CH ₂ OH, Y ₁ is trans -CH = CH- or cis -CH
= A CH-, Z ₁ is _{(1) -CH 2 - (CH} 2) f -CH
₂ - (wherein f is 0, 1, 2 or 3), or (2) - (Ph) - (CH _{2) g} - (wherein (Ph) is 1,2-, 1,3-, Or 1,4-phenylene and g is 0, 1, 2 or 3), and as a whole, (1)
All of R ₁₅ , R ₁₆ and R ₁₇ can be hydrogen,
₁ - (Ph) - (CH ₂₎ and only when g- of, and (2) only when R ₁₅ is hydrogen, Z ₁ is - (Ph)
- (CH ₂₎ provided that the g- and is.

The above divalent substituent (symbol) (for example, L₁
And M₁), These divalent groups are α-Ri: β
-Defined as Rj. This Ri is C-8 to C-12
Divalent in alpha configuration with respect to the plane of the ropropane ring
Represents a partial substituent, and Rj is a base with respect to the plane of the ring.
Represents a substituent of the divalent moiety in the stereo configuration. Therefore M
1 is α-OH: β-R_FiveIs defined as M₁Part of
Droxy is in the alpha configuration, ie PGI above₂Nakato
R is R_FiveThe substituents are in the beta configuration.

The number of carbon atoms in a moiety containing various hydrocarbons is referred to by a prefix indicating the lowest and highest number of carbon atoms in the moiety. That is, prefix (Ci-Cj)
Refers to the portion of integer i to integer j carbon atoms. Thus, (C ₁ -C ₃ ) alkyl refers to alkyl of 1 to 3 carbon atoms, ie methyl, etime, propyl and isopropyl.

Certain of the novel prostacyclin analogs of the present invention, compounds of formula X, are all designated as CBA ₁ or CBA ₂ compounds, respectively, by substitution of methylene for oxa in the heterocycle of prostacyclin. To be done. C
The BA ₂ compounds represent an olefinic double bond at C-5,6, while the CBA ₁ compounds represent C-5,5.
6 is saturated.

The novel compounds in which Z ₁ is-(Ph)-(CH ₂ ) g-- are, depending on whether the bond between C-5 and-(CH ₂ ) g-- is ortho, meta or para, respectively. Interface
It is called o-, inter-m- or inter-p-phenylene.

For these compounds where g is 0, 1, 2 or 3, the carbacyclin analogs thus described have PGI ₂ with the side chain (not including phenylene) at the X ₁ terminus.
It is the case where each of them contains 2, 3 or 4 carbons instead of the 5 carbon atoms contained therein.
Characterized as trinor, 3,4-dinor or 4-nor. The missing carbon atoms are believed to be in the C-4 to C-2 positions, and therefore phenylene is C-5 and C-1.
~ C-3 position is linked. Therefore, when g is 0, 1, 2, or 3, these compounds are 1,5-, and
2,5-, 3,5- and 4,5-interphenylene-
It is named CBA compound.

Carbacyclin analogues for these compounds where f of Z ₁ is 0, 2 or 3 are substituted for the 5 carbon atoms contained in CBA ₂ in the X ₁ -terminal side chain. Since they contain 4, 6 or 7 carbon atoms respectively, they are further characterized as 2-nor, 2a-homo or 2a, 2b-homo. The lost carbon atom is C-
The C-1 carbon is attached to the C-3 position as it is believed to be in the 2-position. The additional carbon atoms are C-2 and C-3.
Suppose it is inserted between positions. Therefore, these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.

The novel compounds are further named as 9β-alkyl-CBA compounds when R ₁₇ is alkyl.
When R ₁₆ and R ₁₇ together are —CH ₂ — (methylene), the novel compounds are “6aβ, 9β-methano-CBA” compounds due to the methylene bridge between C-6a and C-9. is there.

When R ₁₅ is fluoro, "5-fluoro-CBA" compounds are described. Furthermore, Y ₁ is cis-
Compounds in which the M ₁ moiety contains a hydroxyl in the β-configuration, with the exception of compounds with CH═CH—, have a “15
-Epi-CBA "compounds.

Compounds in which Y ₁ is cis-CH═CH— and the M ₁ moiety contains hydroxy in the α-configuration are designated as “15-epi-CBA” compounds. A description of this convention of nomenclature for defining C-15 epimers is given in US Pat. No. 4,016,184, issued Apr. 5, 1977, and especially its 24-
See column 27.

The novel carbacyclin analogs of the present invention containing cis-CH = CH- as the Y ₁ moiety are therefore each referred to as "cis-13" compounds.

When R ₇ is a straight-chain --CmH ₂ m--CH ₃ where m is as defined above, the compounds described in that way are such that when m is 1, 2, 4 or 5, 19, 2
It is named like 0-dinor, "20-nor", "20-methyl" or "20 ethyl". R ₇ is branched-C
When mH ₂ m-CH _3, the compound so described is m
Is 4 or 5 and the unbranched portion of the chain is at least n-butyl, "17-, 18-, 19- or 20-alkyl" or "17,17-, 17,18-, 17,1"
9-, 17, 20-, 18, 18-, 18, 19-, 1
"8,20-, 19,19-, or 19,20-dialkyl" compound. For example, when m is 5 (1-methylpentyl), a 17,20-dimethyl compound is described.

When X ₁ is --CH ₂ OH, the compounds so depicted are termed "2-decarboxy-2-hydroxymethyl" compounds. Furthermore, X ₁ is -CO
When OR ₁ , the novel compounds herein are CBA-
Form esters or CBA-form salts are named.

Examples of alkyl of 1 to 12 carbon atoms are:
Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and their isomeric forms.

The novel CBA analogs disclosed herein produce certain prostacyclin-like pharmacological responses.
The novel CBA analogs of formula X are therefore of mammalian, especially human, valuable livestock, companion, zoological and laboratory animals (eg mouse, mouse, rabbit and monkey).
Use as a drug in the study, prevention, control and treatment of diseases and other undesired physiological conditions. In particular, these compounds have useful applications as antithrombotic agents, antiulcer agents and antiasthmatic agents, as shown below.

(A) Inhibition of Platelet Aggregation These novel CBA analogs disclosed herein can be used at any time to inhibit platelet aggregation, reduce platelet adhesion or prevent the removal or formation of thrombus in mammals, including humans. It is useful. For example, these compounds may be used for the treatment and prevention of myocardial infarction, the treatment and prevention of postoperative thrombosis, the promotion of patency of transplanted blood vessels after surgery, the treatment of peripheral vascular disease, and atherosclerosis. It is useful in the treatment of conditions such as infectious disease, arteriosclerosis, lack of blood coagulation due to lipemia, and other clinical conditions in which the underlying etiologies are combined with lipid imbalance or hyperlipidemia. Other in-vivo applications include the prevention of cerebral ischemic attacks and myocardial infarction and long-term treatment following attacks. For these purposes the compounds are administered systemically, eg intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for long-term action. Due to the rapid response, the intravenous route of administration is preferred, especially in the case of an emergency. Weight per day
Dosages in the range of about 0.01 to about 10 mg per kg are used, with the proper dose depending on the age, weight, condition of the patient or animal and the frequency and route of administration. Although the preferred administration of these compounds is oral, other non-parenteral routes (eg buccal, rectal, sublingual) are likewise used rather than the parenteral route. The oral dosage form is conveniently formulated in tablets, capsules and the like, and is administered 2 to 4 times per day. Dosages in the range of about 0.05 to 100 mg / kg body weight per day are effective.

Addition of these compounds to whole blood provides in vitro applications such as storage of whole blood used in cardiopulmonary devices. In addition, whole blood containing these compounds may circulate in organs that have been removed from the donor prior to transplant, such as the heart and kidneys. They are also useful in making platelet-rich concentrates for use in the treatment of thrombocytopenia, chemotherapy and radiation therapy. For in vitro applications, a dose of 0.001-1.0 μg / ml of whole blood is used. US Pat. No. 4,10 for the treatment of peripheral vascular disease
See 3,026.

(B) Reduction of gastric juice secretion The novel CBA analogs disclosed herein also reduce and control gastric juice secretion, thereby reducing or avoiding the formation of gastrointestinal ulcers, and already present in the gastrointestinal tract. It is useful for humans and certain useful animals, such as mammals including dogs and pigs, to promote healing of ulcers. For this purpose, these compounds may be administered in the dosage range of about 0.1 μg to about 20 μg / kg body weight per minute, or from about 0.01 to about 10 mg / kg body weight per day.
A total daily dose by injection or infusion of a range of intravenous,
Injected or infused subcutaneously or intramuscularly, the exact dose depends on the age, weight and condition of the patient or animal and the frequency and route of administration. However, preferably these novel compounds are administered orally or by other non-parenteral routes. When used orally, a dose range of about 1.0 to 100 mg / kg of body weight per day is used, with administration 1 to 6 times daily. Once healing of the ulcer is achieved, the maintenance dose required to prevent recurrence will be adjusted downward as long as the patient or animal is asymptomatic.

(C) Inhibition of NOSAC-induced Disorders These novel CBA analogs disclosed herein have undesired gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthase inhibitors. It is also useful for alleviation, and for this purpose by co-administration of a prostaglandin derivative and an anti-inflammatory prostaglandin synthase inhibitor. The ulcerative consequences of some non-steroidal anti-inflammatory drugs in mice
See Partridg for disclosure of the inhibition of certain prostaglandins by simultaneous oral administration.
See e.g. US Pat. No. 3,781,429. Thus, these novel CBA analogs herein are useful in reducing unwanted gastrointestinal effects resulting from systemic administration of, for example, indomethacin, phenylbutazone and aspirin. These are substances specifically mentioned as non-steroidal anti-inflammatory agents in the disclosure of Partridge et al. It is also known that they are also prostaglandin synthase regulators. The anti-inflammatory synthase inhibitors, such as indomethacin, aspirin or phenylbutazone, are administered by any method known in the art for alleviating inflammatory conditions, such as any ingestible dose and any known route of systemic administration. .

(B) Bronchodilation (anti-asthma) These novel analogs disclosed herein are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of bronchoconstriction induced by arbitrators such as SRS-A and histamine released from cells activated by an antigen-antibody complex.
Therefore, these compounds suppress seizures during conditions such as bronchitis, bronchiectasis, bronchial pneumonia and emphysema,
Facilitates breathing. For these purposes these compounds are orally in various dosage forms, for example tablets, capsules or solutions, in the case of which intravenous administration is preferred in most cases intravenously but rectally in the form of suppositories, parenterally. Subcutaneously or intramuscularly,
It is administered by inhalation in the form of an aerosol or solution for a nebulizer or by insufflation in the form of powder. Dosages in the range of about 0.01 to 5 mg / kg body weight are used 1 to 4 times daily, with the exact dose depending on the age, weight and condition of the patient and the frequency and route of administration. For these uses, these CBA analogs may be used as sympathomimetics (isoproterenol, phenylephrine, epheedrin, etc.), xanthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone), and others. Can be conveniently combined with other anti-asthma drugs.

These compounds are effectively administered to human asthmatics by oral inhalation or by aerosol inhalation. For administration by the oral inhalation route using a conventional nebulizer or by the oxygen aerosolization method, preferably about 100 to 2
It is convenient to supply the active ingredient in dilute solution at a concentration of about 1 part drug to form a total solution of 00 parts by weight. Quite common additives can be used to secure these solutions or to provide an isotonic medium. For example, sodium chloride, sodium citrate, citric acid,
Sodium bisulfite can be used. For administration as a self-propelling dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy, the composition is an inert propellant together with a co-solvent such as ethanol, a flavoring agent and a stabilizer. The active ingredient may be suspended in, for example, a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane. Suitable means for use in aerosol inhalation therapy technology are fully described in, for example, US Pat. No. 3,868,691.

When X ₁ is --COOR ₁ , the novel CBA analogs so described are used in the free acid, ester, or pharmaceutically acceptable salt form for the above purposes. . When the ester form is used, the ester is any of those within the above definition of R ₁ . However, it is preferred that the ester is an alkyl of 1 to 12 carbon atoms. Among the alkyl esters, methyl and ethyl are particularly suitable for optimal absorption of the compound by the body or experimental animal systems, and linear octyl, nonyl, decyl, undecyl and dodecyl are particularly suitable for long-term activity. Is.

For the above purposes, the pharmaceutically acceptable salts of the novel prostaglandin analogs of the present invention are pharmaceutically acceptable metal cations, ammonia, amine cations, or quaternary ammonium cations. And that. Particularly suitable metal cations are those derived from alkali metals such as lithium, sodium and potassium, and alkaline earth metals such as magnesium and calcium, but of other metals such as aluminum, zinc and iron. Cationic forms are also within the scope of the invention.

The pharmaceutically acceptable amine cations are those derived from primary, secondary and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzyl. Amines, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, adamantylamine and aliphatic, cycloaliphatic, araliphatic amines and heterocyclic amines containing up to about 18 carbon atoms, such as piperidine, morpholine. , Pyrrolidine, piperazine and lower alkyl derivatives thereof, for example, 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidone Gin, 1,4-dimethylpiperazine, 2-methylpiperidine, etc., as well as amines containing water-soluble or hydrophilic groups, such as mono-,
Di and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1
-Butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) aminomethane, N
-Phenylethanolamine, N- (p-tertiary amylphenyl) diethanolamine, galactamine, N-methylglycamine, N-methyl-glucosamine, efedrin, phenylephrine, epinephrine, procaine and the like. In addition, basic amino acid salts such as lysine and arginine are also useful amine salts.

Examples of suitable pharmaceutically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

Optimal combination of biological response specificities
In order to obtain sex, potency, and duration of activity, the
Certain compounds within the range are suitable. X₁Is the end
In the side chain, the inter-p-phenylene-CBA is formed.
For compound, g is 0 and inter-m-phenylene
For a CBA compound g is 0 or 1 (especially 0)
And to the inter-o-phenylene-CBA compound
Preferably, g is 0, 1 or 2 (particularly 1).
Good Inter-o- and inter-m-phenylene-CB
A compound, especially inter-m-phenylene-CBA compound
Is preferred. Furthermore, Z₁Is -CH₂-(CH₂)_f-C
H₂When negative, f is preferably 1. R₁₇But
(C₁~ C_Four) When it is alkyl, R 1₇Is preferably
It is methyl. Furthermore, the C-12 side chain is -CmH₂m-
CH₃When m is 3, 4, or 5,
Is preferred, and most preferred is 3. m is 5
Sometimes other linear isomeric forms, especially methyl-
Substituted butyl is preferred. Especially for biological efficacy
Most preferred is CBA₂C- same as itself
CBA of formula X showing the configuration of the five isomers₂Analogs of
is there.

Compounds satisfying two or more of the above selections are especially preferred. Further, the above selections seek to highlight suitable compounds within the general formula of the novel CBA analogs disclosed herein.

Protecting groups within the scope of R ₁₀ are substituted with hydroxy hydrogen and are not attacked or reactive like hydroxy by the reagents used in the conversions used herein, and are subsequently prostased. It is an arbitrary group capable of substituting hydrogen by oxidative water decomposition in the production of glandine type compounds. Several such protecting groups are known in the art, such as tetrahydropyranyl and substituted tetrahydropyranyl. For reference, EJ Corey's "Proceedings of
the Robert A. Welch Foundation Conferences on Chem
ical Research, XII Organic Synthesis ", 51-79
See page (1969). The protecting groups have been found to be useful include the following are included: (a) tetrahydropyranyl, (b) tetrahydrofuranyl, (c) formula _{-C (CR 11) (R 12} ) - CH (R ₁₃ )
The group of (R ₁₄ ), wherein R ₁₁ is alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, aralkyl having 7 to 12 carbon atoms, phenyl, or 1 carbon atom. 1 to 4 alkyl, 1 to 3 substituted phenyl, R ₁₂ and R ₁₃ are alkyl having 1 to 4 carbon atoms, phenyl, 1 to 4 carbon atoms, 1 Is phenyl substituted by 2 or 3 or R ₁₂ and R ₁₃ when taken together-
(CH ₂₎ a- or where R ₁₂ and R ₁₃ when taken together _{- (CH 2) b-O-} (CH 2) a c-, wherein a is 3, 4, or 5 and b is 1,
2 or 3, and c is 1, 2, or 3,
With the proviso that b + c is 2, 3 or 4, and further, R ₁₂ and R ₁₃ may be the same or different, and R ₁₄ is hydrogen or phenyl],
And (d) a silyl group according to R ₂₈ as defined below.

When the protecting group R ₁₀ is tetrahydropyranyl, the tetrahydropyranyl ether derivative of the hydroxy moiety of any of the CBA-type intermediates herein may be treated with an acid condensing agent, such as p, in an inert solvent such as dichloromethane. Obtainable by reaction of a hydroxy containing compound with 2,3-dihydropyran in the presence of toluenesulfonic acid or pyridine hydrochloride. Dihydropyran is used in a stoichiometric excess, preferably in an amount of 4 to 100 times the stoichiometric amount. The reaction is usually complete within 1 hour at 20-50 ° C.

When the protecting group is tetrahydrofuranyl, 2,3-dihydrofuran is used in place of 2,3-dihydropyran as described in the previous section. The protecting group has the formula —C (CR ₁₁ ) (R ₁₂ ) —CH (R ₁₃ ) (R
₁₄ ) when R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are as defined above, a vinyl ether or an unsaturated cyclic or heterocyclic compound such as 1 -Cyclohexen-1-yl methyl ether or 5,6-dihydro-4-methoxy-2H-pyran is used. J. Am such as CB Reese
erican Chemical Society 89, 3366 (196)
See 7). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for dihydropyran above. R ₂₈ is a silyl protecting group of formula —Si (G ₁ ) ₃ . In some cases, silylation methods are common in which all the hydroxyls of the molecule are silylated, while in other cases one or more hydroxyls are silylated and at least one other hydroxyl is It is selective as the hydroxyl remains unaffected. For any of these silylations, --Si
Silyl groups within the range of (G ₁ ) ₃ include trimethylsilyl, dimethylphenylsil, triphenylsilyl, tert-butyldimethylsilyl, or methylphenylbenzylsilyl. With respect to G ₁ , examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl and the like. Examples of aralkyl are benzyl, phenethyl, α-phenylethyl, 3-phenylpropyl, α-naphthylmethyl and 2- (α-naphthyl) ethyl. Examples of phenyl substituted with halogen or alkyl include p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl,
p-tert-butylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

These silyl groups are well known in the art.
For example, Pierce's “Silylation of Organic Compounds”, Pierce
Chemical Company, Rockford, Illinois,
See (1968). When attempting to chromatographically purify the silylated products in the figure below, the use of silyl groups known to be chromatographically unstable (eg, trimethylsilyl) should be avoided. Further, when selectively introducing a silyl group, a silylating agent which is easily available and known to be useful for selective silylation is used. For example, a tert-butyldimethylsilyl group is used when selective introduction is required. Further, when the silyl group is selectively hydrolyzed in the presence of a protecting group according to R ₁₀ or an acyl protecting group, it is known that it is easily available and can be easily hydrolyzed using tetra-n-butylammonium fluoride. The silyl groups used are used. A particularly well-known silyl group for this purpose is tert-butyldimethylsilyl, while other silyl groups (eg trimethylsilyl) are not used when selective introduction and / or hydrolysis is required.

The protecting groups defined by R ₁₀ are otherwise removed by mild acidic hydrolysis. For example, by reacting (1) hydrochloric acid in methanol, (2) a mixture of acetic acid, water and tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran at a temperature of 55 ° C. or lower, the protecting group is hydrolyzed. Decomposition is achieved.

As mentioned above, R ₃₁ is a hydroxy-hydrogen protecting group. Therein R ₃₁ is an acyl protecting group according to R ₉ , R
_It may be an acid-hydrolyzable protecting group according to ₁₀ , a silyl protecting group according to R ₂₈ , or a hydroxymethyl-substituted group according to R ₃₄ , arylmethyl.

Acyl protecting groups according to R ₉ include (a) benzoyl, (b) alkyl of 1 to 4 carbon atoms, or phenylalkyl of 7 to 12 carbon atoms, or 1 to 5 of nitro. Benzoyl substituted by, provided that the number of substituents other than alkyl optionally is less than 2, and the total number of carbon atoms in the substituents does not exceed 10, and further that the substituents are the same or different. Good
(C) Benzoyl having 2 to 5 carbon atoms substituted with alkoxycarbonyl, (d) naphthoyl, (e) alkyl having 1 to 4 carbon atoms, phenylalkyl having 7 to 10 carbon atoms, or nitro. 1 to 9 substituted naphthoyl, provided that less than two substituents other than alkyl on any fused aromatic ring, and in the substituents on any fused aromatic ring The total number of carbon atoms does not exceed 10, and further various substituents are the same or different, or (f) the number of carbon atoms is 2 to 12
Alkanoyl, included.

In preparing the acyl derivatives of these hydroxy-containing compounds, methods generally known in the art are used. Thus, for example, the formula R ₉ OH [wherein, R ₉
Is as defined above], a dehydrating agent such as p-toluenesulfonyl chloride or dicyclohexylcarbodiimide,
In the presence of a hydroxy-containing compound, or alternatively, an anhydride of an aromatic acid of formula (R ₉ ) OH,
For example, benzoic anhydride is used.

However, the method described in the preceding paragraph is preferably followed by the use of a suitable acyl halide such as R ₉ Hal, where Hal is chloro, bromo or iodo. For example, benzoyl chloride is reacted with a hydroxy containing compound in the presence of a hydrogen chloride scavenger, for example a tertiary amine such as pyridine, triethylamine and the like. The reaction is carried out under various conditions and using procedures generally known in the art. Generally mild conditions are used, ie contacting the reactants in a 0-60 ° C. liquid medium (eg excess pyridine or an inert solvent such as benzene, toluene or chloroform). The acylating agent is used in stoichiometric amount or substantially stoichiometric excess.

As an example of R ₉ , the following compounds are acid (R ₉ O
H), (R ₉ ) ₂ O, or acyl chloride (R ₉ Cl)
Available as: benzoyl; substituted benzoyl, such as (2-, 3- or 4-) methylbenzoyl,
(2-, 3-, or 4-) ethylbenzoyl, (2-,
3-, or 4-) isopropylbenzoyl, (2-, 3
-Or 4-) tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl (2-, 3- ,
Or 4-) toluyl, (2-, 3-, or 4-) phenethylbenzoyl, (2-, 3-, or 4-) nitrobenzoyl, (2,4-, 2,5-, or 2, 3-) Dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl, 3-nitro-2
-Phenethylbenzoyl; monoesterified, phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, such as (2
-, 3-, 4-, 5-, 6-, or 7-) methyl-1-
Naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1. -Naphthoyl,
(3-, 4-, 5-, or 8-) nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4
-, 6-, 7-, or 8-) methyl-1-naphthoyl,
4-Ethyl-2-naphthoyl, and (5- or 8-) nitro-2-naphthoyl and acetyl.

Thus, it is possible to use benzyl chloride, 4-nitro-benzoyl chloride, 3,5-dinitrobenzoyl chloride or the like, ie the R ₉ Cl compound corresponding to the R ₉ group above. If no acyl chloride is available, it is prepared from the corresponding acid and phosphorus pentachloride as is known in the art. R ₉ OH, (R ₉ ) ₂
It is preferred that the O, or R ₉ Cl reactant does not have bulky sterically hindering substituents on both ring carbon atoms adjacent to the carbonyl binding site, such as tert-butyl.

The acyl protecting group according to R ₉ is removed by deacylation. For this purpose, alkali metal carbonates or hydroxides are effectively used at room temperature. For example, about 25
Carbonic acid or potassium hydroxide in aqueous methanol at 0 ° C. is preferably used.

R ₃₄ can be replaced by an intermediate hydroxyhydrogen in the preparation of the various CBA analogs herein and then replaced by hydrogen in the process for preparation of their corresponding prostacyclin analogs, An aryl such that the R ₃₄ -containing compound is stable with respect to the various reactions undertaken and is subsequently introduced and subsequently removed by hydrogenolysis under conditions which result in a substantially quantitative yield of the desired product. Defined as a methyl group.

Examples of hydroxy-hydrogen substituting groups arylmethyl are: (a) benzyl, (b) alkyl of 1 to 4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, Benzyl substituted by 1-5 of phenylalkyl having 7-12 carbon atoms, provided that the various substituents are the same or different, provided that (c) benzhydryl, (d) carbon atoms are 1-4 alkyl, chloro, bromo, iodo, fluoro, nitro, 7 to 12 carbon atoms
1-10 benzhydryls of phenylalkyl, provided that the various substituents are the same or different on each aromatic ring, (e) trityl, (f) carbon atoms 1-4 alkyl, chloro, bromo, iodo, fluoro, nitro, 7 to 12 carbon atoms
1 to 15 substituted trityls of phenylalkyl, with the proviso that the various substituents are the same or different on each aromatic ring.

The introduction of such ether linkages, especially benzyl or substituted benzyl ethers, into the hydroxy-containing compounds herein may be accomplished by methods well known in the art, for example, the benzyl or benzyl corresponding to the hydroxy-containing compound and the desired ether. It is carried out by reaction with a substituted benzyl halide (chloride, bromide, or iodide). This reaction proceeds in the presence of a suitable condensing agent (eg silver oxide). The mixture is stirred and 50-80 ° C
Heat to. A reaction time of 4 to 20 hours is usually sufficient.

The figures herein show novel intermediates of the invention.
And the final products are produced by the novel process of the present invention.
Describe the method. For these figures, g, n, L
₁, M₁, R₇, R₈, R_Ten, R₁₅, R₁₆, R₁₇, R₂₈, R
₃₁, X₁, Y₁, And Z₁Is as defined above. M₆
 Is α-OR_Ten: Β-R_FiveOr α-R_Five: Β-OR_Ten(here
And R_FiveIs hydrogen or methyl. R₁₈Is hydrogen, hydroxy
Ci, hydroxymethyl, -OR_TenOr -CH₂OR
_Ten(Where R_TenIs a protecting group that can be hydrolyzed with an acid. R
₂₀, R_{twenty one}, R_{twenty two}, R_{twenty three}And R_{twenty four}Is one of the following
It (1) R₂₀, R_{twenty one}, R_{twenty two}, R_{twenty three}And R_{twenty four}Is all water
R, which is prime_{twenty two}Is either α-hydrogen or β-hydrogen
Is there (2) R₂₀Is hydrogen and R_{twenty one}And R_{twenty two}Together with C-
A second valence bond is formed between 9 and C-6a, and R_{twenty two}
And R_{twenty four}Together with the second valence bond between C-8 and C-9
Or both are hydrogen, or (3)
R_{twenty two}, R 2₃And R_{twenty four}Are all hydrogen, R_{twenty two}Is α-
Either hydrogen or β-hydrogen, and (a) R₂₀
And R_{twenty one}Are together oxo, or (b) R₂₀Is hydrogen
And R_{twenty one}Is α-hydroxy or β-hydroxy, hydr
It's Roxy. Z_FourIs -CH₂-Or- (CH₂)_f-CF
₂-(F is as defined above) but as a whole
To (1) R₁₅, R₁₆And R₁₇All of can be hydrogen
Of the Z₁Is-(Ph)-(CH₂) Only when g-
And again (2) R₁₅Z only when is hydrogen₁Is-(P
h)-(CH₂) It is a condition that it is g-. R₃₇Is
R₄₇Is the same as₂Other than OH. R₃₈Is
-OR₃₁, Hydrogen, or -CH₂OR₃₁And where R
₃₁Is as defined above. R₂₇Is-(CH₂)₂-C
H (OH) -CH₃Is-(CH₂)₂-CH (OR_Ten) −
CH₃R except that₇Is the same as. R₃₇Is R₁₇When
Same, but other than hydrogen. Ac is acetyl
Is. Z₂Is Z₁Same as, but-(Ph)-(C
H₂) Not g-. Z₃Is Z₁Is the same as
SU-CH₂Not -CH = CH-.

Referring to Figure A, a well-known bicyclic lactone of formula XXI is prepared, wherein R ₁₇ is alkyl or taken together with R ₁₆ and R ₁₇ between methano or C-6a and C-9. A method is provided for conversion to a carbacyclin intermediate of formula XXV for use in the preparation of the second valence bond, the formula XCBA compounds. Referring to Figure A, the compound of formula XXI is converted to the compound of formula XXII by treatment with the anion of dimethylmethylphosphonate. Methods for such reactions are known in the art. Dauben WG et al. JACS, 97: 4, describing this type of reaction.
973 (1975).

The lactol of formula XXII is converted to the diketone of formula XXIII by oxidation methods known in the art. For example, Collins reagent or Jones reagent is used in this oxidative conversion method. The diketone of formula XXIII is cyclized to the compound of formula XXII by an intramolecular Horner-Emmons reaction. Chemical methodologies for similar transformations are known in the art. Pierce E
s E.) Tetrahedron Letters (Tetrahedron Le
tters), 3279 (1979) and Clark RD (Synthetic Communications) 5: 1 (19)
See 75).

The compounds of formula XXI is by treatment with lithium dialkyl click plate is then R ₃₇ is R ₁ 6 is hydrogen are converted to the novel compounds of the formula XXV is alkyl. Lithium dialkylcuprates are prepared in a conventional manner, for example by reaction of anhydrous copper iodide in diethyl ether with alkyllithium in diethyl ether, and then reacted with a compound of formula XXV in, for example, diethyl ether.

The compounds of formula XXV are prepared by combining one of two methods in which R ₁₆ and R ₃₇ taken together are methylene (--CH).
_2- ) is a novel compound of formula XXV. According to the first method, the compound of formula XXV has the formula XXV with the anion of trimethyloxosulfonium iodide.
Produced by treatment of compound IV. See JACS 87: 1353 (1965), E. J. Coray et al. By this method, the anion is conveniently generated by treatment of silimethyloxosulhenium iodide in sodium hydride.

According to the second method, the compound of formula XXIV is prepared by photochemical addition of methanol (see eg GL Bundy, Tetr. Lett. 1957, 1975) to the corresponding hydroxymethyl of formula XXIV. Conversion to a compound first, followed by treatment of the hydroxymethyl compound formed with an excess (eg, 2 equivalents) of p-toluenesulfonyl chloride in a tertiary amine base to form the corresponding tosylate of formula XXI, and The final tosylate of formula XXVII formed is treated with a base (eg potassium tert-butoxide) to form the cyclopropyl compound of formula XXV such that R ₁₆ and R ₃₇ taken together are methylene. Convert to a compound of formula XXV.

Referring to FIG. B, a compound of formula XXXXI prepared according to the method of FIG. A is converted to a new CBA of formula XXXVI.
Methods are provided for conversion to the _two analogs.

The compound of formula XXXI is converted to compounds of formula XXXVI by methods known in the art for the preparation of carbacyclin. See, for example, the UK published application above. On the other hand, the compound of formula XXXXI is reacted with the compound of formula XXXII, and thereby the compound of formula XXXIII,
Sequential conversion to compounds of formula XXXIV and formula XXXV.

The reaction of the compound of formula XXXI with the compound of formula XXXII is carried out by methods known in the art.
J.Organ from Moersch GW
ic Chemistry 36: 1149 (1971) and Mulzer J. et al., Tetrahedron Letters,
See 2949 (1978). The reactants of formula XXXII are known in the art or can be prepared by methods known in the art. See Example 4 which describes one method of making such compounds of Formula XXXII.

The compound of formula XXXIII is then converted to the compound of formula XXXIV by decarboxylating dehydration. Procedures for this reaction are known in the art. Helvetica Chimka Acta 58: 1450 (197) such as Eschenmoser A.
5), Tetrahedron Letters by Hara S., etc.
s, 1545 (1975), and Mulzer J.A. (M
ulzer J.) et al., Tetrahedron Letters, 2953 (19)
78) and 1909 (1979).

Finally, the compound of formula XXXV has the formula XXXIV
Prepared by selective desilylation. Such procedures are known in the art and typically use tetra-n-butylammonium fluoride and tetrahydrofuran. Korei. E. Jay. See JACS 94: 6190 (1972) elsewhere.

The compounds of formula XXXV are converted into various acids, esters, amides and amines of formula XXXVI by methods known in the art. In this regard, the method described in the above mentioned British publication describing the preparation of the Albacyclin analogues is particularly useful.

The preparation of compounds of formula XXXVI from compounds of formula XXXV is carried out, for example, by oxidation to the corresponding carboxylic acid, followed by hydrolysis of any protecting group at the C-11 or C-15 position of the molecule. Such carboxylic acids are then esterified by conventional methods or amidated by conventional methods. Such amides are then reduced to the corresponding amines (X ₁ is —CH ₂ NL ₂ L ₃ ) by, for example, reduction with lithium aluminum hydride. See U.S. Pat. No. 4,073,808. In the preparation of a primary alcohol according to Formula XXXVI from a compound of Formula XXXV, C-11 or C-15
Hydrolysis of any of the protecting groups in. Directly produces the compound. Hydrolysis is achieved by the methods described above, for example under mildly acidic conditions at elevated temperature.

FIG. C provides a method for converting known Formula XLI compounds to the aldehyde of Formula XLIV used in FIG. D in the preparation of the inter-phenylene-CBA ₂ compounds herein. .

Referring to Figure C, compounds of formula XLII are prepared from compounds of formula XLI by reduction. Conventional methods known in the art are used to convert the carboxylic acids to the corresponding primary alcohols. For example, a particularly useful conventional method for reduction is to use lithium aluminum hydride as a reducing agent.

The compound of formula XLIII is then prepared from the compound of formula XLII by monosilylation. In particular, the formula XLIII in which R ₂₈ represents a relatively stable silyl group, most preferably tert-butyldimethylsilyl or phenyldimethylsilyl.
To produce the compound. Other silyl groups, especially trimethylsilyl (TMS), are not suitable for use with the method of Figure C.

The monosilyl derivatives of formula XLIII are prepared from the compounds of formula XLII by reacting the compounds of formula XLII with approximately equimolar amounts of the silylating agent. For example,
When R ₂₈ is tert-butyldimethylsilyl, one equivalent of tert-butyl-dimethylsilyl chloride is used for the conversion. Thus, both monosilyl derivatives of compounds of formula XLII as well as bis-silyl derivatives corresponding to formula XLII are prepared. From this mixture of products, the formula XLII
The compound of I is recovered by conventional means, eg column chromatography. Alternatively, the silylation proceeds under conditions conventional for silylation of hydroxyl groups. See discussion above.

The compound of formula XLIV is then prepared from the compounds of formula XLIII by oxidation of the alcohol of formula XLIII to the corresponding aldehyde. Common oxidants are used, eg manganese dioxide.

FIG. D provides a method for converting the known formula LI ketones to the disclosed formula LX interphenylene CBA ₂ analogs. According to Figure D, reduction of the ketone of formula LI to the corresponding secondary alcohol leads to formula L
Compounds of formula II are prepared from compounds of formula LI. This reduction is done by conventional means with readily available reducing agents. Therefore, in this reduction, sodium borohydride,
Potassium or lithium is conventionally used. afterwards,
The alcohol of formula LII is converted to the corresponding mesylate (methanesulfonate). The general method of conversion of alcohol to the corresponding mesylate is used. Therefore, the formula LIII
In the preparation of compounds of formula I, an alcohol of formula LII is reacted with methanesulfonyl chloride in the presence of a tertiary amine (eg triethylamine).

In the transformation of Figure D, the compound of formula LIII may be replaced by another sulfonyl derivative corresponding to the alcohol of formula LII. These other sulfonyl derivatives are preferably derived from readily available sulfonation reagents, ie the corresponding sulfonyl chlorides. One particularly important alternative to the compound of formula LIII is:
A tosylate (toluene sulfonate) corresponding to the compound of formula LII.

The compound of formula LIII, or the corresponding alternative sulfonate, is converted to the compound of formula XIV by treatment with sodium, lithium or potassium thiophenoxide. Thiophenoxide is generally conveniently prepared just prior to conversion by mixing approximately equimolar amounts of thiophenol with a base such as potassium tert-butoxide.

The compound of formula XLIV is then oxidized to the corresponding compound of formula LV by oxidation with a readily available oxidizing agent such as m-chloroperbenzoic acid. The compound of formula LV is then treated first with a compound of formula LV with a strong base such as n-butyllithium to generate an anion corresponding to the compound of formula LV, the anion being treated with an aldehyde of formula XLIV. By condensation with a compound of formula XLIV made according to Figure C, and finally the adduct formed is treated with acetic anhydride to form an acetyl compound of formula LVI. The compound of formula LVI is then converted to the compound of formula LVII by reaction with sodium amalgam. Formula LV
The method for producing the olefin of LVII from the compound of
"Field and Stereochemistry of Olefin Synthesis from β-Hydroxysulfones" by Kocienski PJ et al., JCS Parkin, I, 829-83.
4 (1978).

The compound of formula LVII is then converted to the compound of formula LVIII by selective hydrolysis of the silyl group according to R ₂₈ . Conventional means for this hydrolysis are eg tetra-n
-Butyl ammonium fluoride is used. See discussion above for a description of this hydrolysis.

C-of formula LVIII thus prepared
The diastereomer of 5 is well purified to the (5-E) and (5-Z) isomeric forms. This conversion is carried out by conventional means, for example column chromatography. afterwards,
Either the (5E) or (5Z) isomer of formula LVIII is
General oxidation and subsequent optional esterification gives formula L
Converted to carboxylic acid or ester of IX. A particularly conventional means of oxidation is the use of Jones reagent, but other oxidizing agents are also used. Next, esterification is performed by the following method. Finally, formula LX products are prepared from compounds of formula LIX by first hydrolyzing the protecting group under acidic conditions, eg with a mixture of water, tetrahydrofuran and acetic acid. The acetic acid and esters of formula LIX are then converted into various other C-1 derivatives by the following method.

The formula LX compound is converted into a free carboxylic acid (X ₁ is -C
One particularly conventional method for producing as OOH) is to purify the corresponding methyl ester and then saponify it under basic conditions (eg treatment with potassium carbonate or sodium or potassium hydroxide).

FIG. E shows a compound of formula LXI known as CB
Provided are methods for converting intermediates of formula LXIII useful in the preparation of A ₂ analogs. The procedure for converting a compound of formula LXI to a compound of formula LXIII is similar to that describing the conversion of a compound of formula XXI to a compound of formula XXXVI and LX in Figures A, B and D (ie Formula L of the compound of LXI
The conversion of the compound of formula XII to the compound of formula XXV in Figure A corresponds to the conversion of the compound of formula XXV in FIG.
Of the compound of formula LXIII to the compound of formula LX corresponds to the conversion of the compound of formula LI to the compound of formula LX in Figure D). For convenience the protecting groups R ₃₁ and R ₃₈ may be the same or different, but preferably such protecting groups are different. Hydrolysis of the protecting group by R _{31 is} thereby achieved in the presence of the protecting group by R ₃₈ .

FIG. F then shows formula L prepared according to FIG.
Provided is a method of converting a compound of XXI into a carbacyclin analog of formula LXXII according to the present invention.
Referring to Figure F, the compound of formula LXXI is converted to the compound of formula LXXII by selective hydrolysis of the protecting groups according to R ₃₁ . Thereafter, the compound of formula LXXII is oxidized to the corresponding aldehyde by methods known in the art, for example, oxidation of the primary alcohol of formula LXXII, acylation of the aldehyde with Witetsuoxyl, and reduction of the ketone formed to M Conversion to a compound of formula LXXIII by conversion to a secondary or tertiary alcohol corresponding to ₁ . See Figure A (Part VI) of U.S. Pat. No. 4,107,427 issued Aug. 15, 1978 for examples of various transformations used in accordance with Figure F.

FIG. G shows a novel C-6a- and / or C-containing intermediate of the novel formula LXXXI prepared according to FIG.
-9-Substituted CBA ₂ analogs of formulas LXXXVIII and LX
Methods for converting XXIX isomers are provided. With respect to Diagram G, a compound of formula LXXXIII is prepared from a ketone of formula LXXXI by Wittig ω-carboxyalkylation using a triphenylphosphonium compound of formula LXXXII. The Wittig reaction is carried out under general reaction conditions for producing a prostaglandin type substance. The compound of formula LXXXIII is then optionally hydrolyzed to give the carboxylic acid product of formula X or used in ester form in the subsequent transformation of Figure G.

Formula LXXXIII thus prepared
A compound of formula LXXXVIII and LXX
Directly separated into C-5 isomers of XIX (eg chromatographic methods and subsequent C-11 or C-1 of the molecule)
Conversion to the ester of formula LXXXIV by hydrolysis of the protecting group at the 5 position) or by conventional esterification techniques such as ethereal diazomethane treatment or treatment with methyl iodide. The ester of formula LXXXIV is then reacted by reduction with a suitable reducing agent such as lithium aluminum hydride by methods well known in the art for preparing prostaglandin-type primary alcohols from the corresponding prostaglandin esters. Reduce to primary alcohol.

The compound of formula LXXXV is a particularly convenient intermediate for the easy separation of the C-5 diastereomers. Thus, the compound of formula LXXXV can be separated by conventional means of separating diastereomeric mixtures, such as column chromatography, whereby formula LXXXVI and formula LXX
The compound of XVII is prepared in isomerically pure form. These primary alcohols are then conveniently converted to formulas LXXXVIII and LXXXIX by the method described above. See Conversion of Formula XXXV Compound to Compound of Formula XXXVI in Figure B.

FIG. H shows 5-fluoro-CB of formula XCVII
Provided is a method of preparing an A ₂ compound from a CBA ₂ intermediate of formula XCIII which is well known in the art. See, for example, British Published Application 2,014,143, particularly the discussion relating to step (b) of Figure A of that specification. The anion of the compound of formula XCII is first generated by treatment with, for example, n-butyllithium in hexane, and the anion thus formed is treated with a fluorine source.
The CI sulfoximine is converted to a fluorinated sulfoximine of formula XCII. Particularly suitable as a fluorine source is fluorine chlorate (FClO ₃ ).

The compound of formula XCII thus prepared and the known compound of formula XCIII above are then used in the preparation of compound of formula XCIV by known methods. See, again, British Published Application 2,014,143, Step (b) of Figure A.

The thus-prepared compound of formula XCIV is hydrolyzed under mildly acidic conditions (eg a mixture of acetic acid, water and tetrahydrofuran) as is well known in the art to give a primary compound of formula XCV. Converted to alcohol. The primary alcohol of formula XCV is then oxidized to the corresponding carboxylic acid of formula XCVI using conventional methods.
For example, treatment with oxygen and an aqueous suspension of platinum oxide under hydrogen at ambient temperature and pressure produces a carboxylic acid of formula LXXVI. The compound of formula XCVI is then converted to various products of formula XCVII by derivatization or conversion of the carboxyl group of the compound of formula XCVI.

The C-5 isomers of formula XCIX to formula XCVII are conveniently separated at any stage in the process of Figure H, although most conveniently and preferably formula XCIV
From the diastereomeric mixture of. Conventional means such as column chromatography are used for the separation.

Figure I provides any method of converting the well-known compounds of formula CI to the formula CIII products of the present invention.
With respect to Figure I, Formula XCII is prepared from a compound of Formula XCI by the method described in Figure H for the preparation of a compound of Formula XCVII from a compound of Formula XCIII. This CBA ₂ intermediate of formula CII is then converted to a compound of formula CIII by the method described in Figure F for the conversion of a formula LXXI compound to a formula LXXIII compound.

In Fig. J, Z ₁ is trans-CH ₂ -CH = C.
A preferred method is provided for preparing CBA analogs of formula X that are H-. For Figure J herein, R ₁ is other than hydrogen or a cation, and is preferably lower alkyl. Formula CXIV is derived from the formula CXI compound
It is prepared by first preparing its α-phenylselenyl derivative and dehydrophenylselenizing it, thereby preparing the α, β-unsaturated ester of formula CXIII. The ester is then converted by saponification to the free acid of formula CXIV (X ₁ is --COOH), and the free acid is converted to various other compounds of formula CXIV as shown in FIG. (See Conversion of Formula XCVI Compound to Formula XCVII Compound).

In the diagram K, Z ₁ is trans-CH ₂ -CH = C.
A preferred method of making a CBA intermediate product of formula VI that is H-is provided. For Diagram K, a compound of Formula CXXI was prepared by a method similar to that described in Diagram J for the preparation of a compound of Formula CXIV from a compound of Formula CXI.
Convert to compound XIII.

For a detailed description of the methodology used in Figures JK, see the discussion in British Patent 2,014,143 and the references cited therein. Figure LO
Provides methods for using CBA ₂ intermediates and analogs in the synthesis of corresponding CBA ₁ intermediates and analogs. FIG. L provides a suitable method for preparing CBA ₁ intermediates of formula VII where Z ₁ is trans-CH ₂ —CH═CH—. Referring to Figure L, a compound of Formula CXXXI prepared like a compound of Formula CXXXII in Figure K is reduced to a compound of Formula CXXXII by general methods. For a discussion of such methods, and general methodology for converting CBA ₂ intermediates and analogs to the corresponding CBA ₁ intermediates and analogs, see UK Published Application 2,
See 017, 699. For example, catalytic hydrogenation using conventional catalysts at atmospheric pressure is used.

This compound of formula CXXXII was then converted to Figure J.
-K by the method described in K (i.e. conversion of a compound of formula CXII to the corresponding compound of formula CXIV and conversion of a compound of formula CXXII to a compound of formula CXXIII).
Α, β-unsaturated ester of XXXIII and the formula CXXXIV
_One after another to the CBA ₁ intermediate product.

Alternatively, the CBA ₁ intermediates of formula VII are prepared according to the method of Figure M, wherein the compound of Formula CXLI prepared above is shown in Figure L and in the references cited therein. According to the technology described, the formula CXLII
Is reduced to the intermediates.

FIG. N shows the formula CLI produced in FIGS.
The preparation of various CBA ₁ analogues from the compounds of US Pat. The method used in Figure N is that described in Figure F above.

Finally, Figure O provides an alternative method for preparing CBA ₁ analogs of formula CLXII directly from CBA ₂ analogs of formula CLXI. This conversion of Figure O is carried out by direct reduction of the compound of formula CLXI by the method described in Figure M and the references cited therein. FIG. O is a particularly common method for the preparation of CBA ₁ analogs where Y ₁ is —CH ₂ CH ₂ —.

CBA analogs of formula XI are prepared according to the method described in Figures P-U. Regarding Figure P,
Compounds of formula CLXXI are well known in the art or are prepared by methods well known in the art. US Patent 4,18
See 1,789. This compound corresponds to the corresponding methylene of formula CLXXII and formula CL by methods well known in the art.
Conveniently converted to the hydroxymethyl compounds of XXIII. Such a method is especially described in US Pat.
7 and 4,060,534. The compound of formula CLXXIII thus prepared is then treated by methods well known in the art, for example by reaction with methanesulfonyl chloride in a tertiary amine base,
Convert to LXXIV mesylate. Instead, the formula C
Other sulfonated derivatives corresponding to compounds of LXXIV are prepared as those described for Formula LIII in Figure D.

The mesylate (or other sulfonate) of formula CLXXIV is then selectively hydrolyzed to give formula CLX
This produces the phenol derivative of XV. Selective hydrolysis of the R ₂₈ silyl ether group in the presence of a protected R ₁₈ or M ₆ hydryloxyl group is described by the method described above, well known in the art and by the method described above, tetra-n-butylammonium fluoride. Is achieved by the use of. Next, the phenol derivative of formula CLXXV is cyclized to give formula CL
This produces compounds of XXVI. Cyclization is best accomplished by treatment of the compound of formula XVI with a base at elevated temperature. For example n-butyllithium, sodium hydride or potassium hydride are conveniently used at reflux temperature in an organic solvent such as tetrahydrofuran or glyme.

Then the cyclized compound of formula CLXXVI is
-Converted to a compound of formula CLXXVII by carboxyalkylation. Methods well known in the art, eg 3,7
-Inter-phenylene-PGFα compounds and methods for preparing the corresponding phenolic intermediates are used. For example, the preparation of a compound of formula CLXXVII is described by formula C
Reaction of LXXVI compound with sodium hydride and -Z
_It is carried out by adding into the molecule an alkylbromoalkanoate corresponding to the _4- COOR ₁ group. Then the formula CL
Compounds of XXVIII are prepared by deprotection, ie the protection group, is hydrolyzed under mildly acidic conditions, followed by conversion to various other C-1 derivatives by the methods described below.

FIG. Q provides a method of making another CBA analog of formula XI according to the present invention. In particular, R ₂₀ , R ₂₁ ,
Formula wherein at least one of R ₂₃ or R ₂₄ is not hydrogen
The compound of XI is produced. According to FIG. Q, the compound of formula CLXXXI referred to previously in the discussion of FIG. P is oxidized to the corresponding formula CL by methods well known in the art.
Use the aldehyde of XXXII. For example, Collins reagent is used in this oxidation. See the methods in Figure R when the conversion of the C-9 stereoisomer of formula CLXXXIII to another is noted.

Thereafter, the aldehyde of formula CLXXXII was
Hydrolysis to the corresponding phenol derivatives of formula CLXXXIII by the methods described above to prepare compounds of formula CLXXV from compounds of formula CLXXIV in Figure P.

Cyclization of the compound of formula CLXXXIII to the corresponding compound of formula CLXXXIV is then accomplished by heating to reflux the phenoxide anion of the compound of formula CLXXXIII in an organic solvent. Casira G
ghi G.) et al JCS Parkin I, 2027 (1979)
checking ... The C-9 isomers of the compound of formula CLXXXIV are conveniently separated by conventional techniques such as column chromatography. The compound of formula CLXXXIV is then converted to the compound of formula C by the method described in Figure P for the preparation of the compound of formula CLXXVII from the compound of formula CLXXVI.
It is converted to the compound of LXXXV. The alcohol is then oxidized to the corresponding ketone of formula CLXXXVI (eg, by the methods described above for the preparation of compounds of formula CLXXXII from compounds of formula CLXXXI) or dehydrated to produce compounds of formula CLXXXVIII. Such dehydration is carried out by methods well known in the art, which involve first preparing the mesylate corresponding to the compound of formula CLXXXV and then treating with a base. Then, a compound of formula CLXXXVI or CLXXXVIII is prepared according to the following method, respectively as formula CLXXXVII or CLXXXIX.
To the compound.

Finally, the formula CL produced in this way
Common procedures for compounds of XXXIX, such as catalytic dehydrogenation (palladium on carbon catalyst) or DDQ (2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone)
Is dehydrogenated to produce a compound of formula CXC.

Figure R provides a method of making the C-9 epimeric form of the compound prepared according to Figure P. Referring to Figure R, a formula CXCI aldehyde prepared as a compound of formula CLXXXII of Figure Q is treated with an organic base under basic conditions (ie, an organic base in an organic solvent such as methylene chloride),
For example, 1,8-diazobicyclo [5.4.0] undec-
7-ene is used) to perform isomerization. The 9β-aldehyde is then reduced to the corresponding alcohol of formula CXCIII by treatment with a suitable reducing agent such as a borohydride reducing agent (eg sodium borohydride, lithium or potassium). The alcohol of formula CXCIII thus produced is then converted to the corresponding 9β-CBA analogs by the method described in Figure P, for example by conversion to the compound of formula CLXXIII.

Optionally, various CBA analogs of formula XI prepared according to Figures P, Q, and R are prepared by the method of Figure S. The method of FIG. S uses the formula CCI described in FIG.
Starting material of formula CLXXI
Preparation of Formula CLXXVIII Compound from Compound, Formula CL of Figure Q
From the XXXI compound to the formula CLXXXVII, formula CLXXXIX,
Preparation of formula CXC compounds and conversion to formula CCII, prepared according to the method described for the preparation of formula CXCIV compound from formula CXCI compound of Figure R. The compound of formula CCII thus prepared is then converted to compounds of formula CCIII by the method described above, eg, by converting the compound of formula LXXI of FIG. F to the compound of formula LXXIII.

Figure T shows 9-deoxo- of the formula CCXIII
2 ', 9-metheno-3-oxa-4,5,6-trinor-3,7- (1,3-inter-phenylene) -PGE ₁
A suitable method for producing compounds is provided. According to Figure T,
A compound of formula CCXI prepared like the compound of formula CLXXXIII in Figure Q is treated with the methyl Grignard reagent methylmagnesium bromide and heated to reflux in an organic solvent (eg glyme).

The formula CCXII thus produced is
Then from the phenol intermediate of formula CLXXVI to formula CLXXVI
The formula CCXIII product is converted by the method described in Figure P for the preparation of the product of II.

Figure U is a convenient representation for converting the compounds of Formula XI of Formula U, wherein the compound of Formula CCXXI, Y ₁ is trans-CH = CH-, to the corresponding aldehyde intermediates of Formula CCXXII. Provide a way. This conversion is accomplished by ozonolysis by methods otherwise known in the art.

The intermediates of formula CCXXII are then prepared by the methods described above, ie, the reaction of a compound of formula CCXXII with a suitable Wittig reagent followed by reduction and hydrolysis, to give various products of formula XI (of formula CCXXIII of FIG. U). Compound). Thus, by the method depicted in Figure U, the C-12 side chains of various Formula CCXXI compounds are conveniently modified with aldehyde intermediates of Formula CCXXII. As noted above, the methods described herein can be varied for various carboxylic acids (X ₁ is —COOR ₁ and R ₁ is hydrogen) or esters or primary alcohols (X ₁ is —CH ₂ OH). There is).

When the alkyl ester is obtained and the acid is desired, a saponification procedure as known in the art for PGF type compounds is used. When the acid is prepared and an alkyl, cycloalkyl or aralkyl ester is desired, esterification by reaction between the acid and the appropriate diazo hydrocarbon is advantageously carried out. For example, methyl esters are produced when diazomethane is used. For example, diazoethane, diazobutane and 1-diazo-2-ethylhexane, and diazodecane are similarly used to give ethyl, butyl and 2-ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexane and phenyldiazomethane produce cyclohexyl and benzyl esters, respectively.

Esterification with a diazo hydrocarbon comprises mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, preferably with the acid reactant in the same or different inert diluent. It is done by
After completion of the esterification reaction the solvent is removed by evaporation and the ester is purified if desired by conventional methods, preferably chromatography. The contact of the acid reactant with the diazo hydrocarbon is preferably no longer than necessary to achieve the desired esterification to avoid undesired molecular changes, and is preferably from about 1 to about 10 minutes.
Diazo hydrocarbons are well known in the art or can be prepared by methods well known in the art. For example, "Organic Reactions" by Joan Willie and Sons Incorporated, New York, N.
See Y. 8, 389-394 (1954).

Another method for the alkyl, cycloalkyl or aralkyl esterification of the carboxy portion of the acid compound is to convert the free acid to the corresponding substituted ammonium salt, which is then reacted with the alkyl iodide. Has become. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide,
Examples include tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, and phenethyl iodide.

For the preparation of phenyl or substituted phenyl esters within the scope of the present invention from the corresponding aromatic alcohols and free acids, different methods are used with different yields and product purities. it can.

Phenyl, especially p as disclosed in this invention.
- substituted phenyl ester (i.e. X ₁ is -COOR ₁ and R ₁ is p- substituted phenyl), with respect to the manufacture, such compounds U.S. Patent 3,890,3
Manufactured by the method described in 72. Thus, by the preferred method described therein, p-substituted phenyl esters are prepared by first forming a mixed anhydride, which formation of the mixed anhydride as a first step in the preparation of amide and cycloamide derivatives. According to the following method for producing the anhydride.

Next, this anhydride was converted into p-
React with a solution of the phenol corresponding to the substituted phenyl ester. This reaction preferably proceeds in the presence of a tertiary amine such as pyridine. When the conversion is complete,
The p-substituted phenyl ester is recovered by conventional techniques.

A preferred method for substituted phenyl esters is that disclosed in US Pat. No. 3,890,372, in which the mixed anhydride is reacted with the appropriate phenol or naphthol. The anhydride is formed from the acid and isobutyl chloroformate in the presence of a tertiary amine.

The phenacyl-type ester is prepared from the acid using phenacyl bromide, for example P-phenylphenacyl bromide, in the presence of a tertiary amine. For example, U.S. Pat. No. 3,984,454, German Laid-Open Publication 2,535,693 and Derwent Farmdoc 16
See 828X.

Carboxamides (X ₁ is —COL ₄ ) are one of several amidation methods well known in the prior art.
Manufactured by seed. For example, U.S. Pat. No. 3,981,868 issued Sep. 21, 1976, which describes the preparation of amide and cycloamide derivatives of the present invention of the prostaglandin type free acid, and the carbonyl of the prostaglandin type free acid. See US Pat. No. 3,954,741 which describes the preparation of amide and sulfonylamide derivatives.

The preferred method for preparing the amide and cycloamide derivatives of the acids of the present invention is by first converting the free acid to the corresponding mixed anhydride. According to this method, the free acid of prostaglandin type is first neutralized with 1 equivalent of amine base, and then the stoichiometric excess of chloroformate corresponding to the mixed anhydride to be prepared is reacted. Let

The preferred amine base for neutralization is triethylamine, but other amines (eg pyridine, methyldiethylamine) are used as well. Further, a readily available chloroformate for use in the preparation of mixed anhydrides is isobutyl chloroformate.

The mixed anhydride formation is carried out by conventional methods, so the free acid is mixed with both the tertiary amine base and the chloroformate in a suitable solvent (eg aqueous tetrahydrofuran) and the reaction is conducted at -10 ° C. Proceed at ~ 20 ° C. The mixed anhydride is then converted to the corresponding amide or cycloamide derivative by reaction with the amine corresponding to the amide to be prepared. When manufacturing simple amide (-NH _2), the transformation proceeds by the addition of ammonia. Therefore, the corresponding amine (ie, ammonia) is mixed with the mixed anhydride at about -10 to + 10 ° C until the reaction is shown to be complete. The new amide or cycloamide derivative is then recovered from the reaction mixture by conventional techniques.

The carbonylamide and sulfonylamide derivatives of the PG-type compounds disclosed herein are similarly prepared by well known methods. See, for example, U.S. Pat. By this known method, the acid is reacted with the carboxyacyl or sulfonyl isocyanate corresponding to the carbonylamide or sulfenylamide derivative to be prepared.

The sulphonyl amide derivatives of the present compounds are prepared by another more suitable method, first producing a PG-type mixed anhydride and using the methods described above for the preparation of amide and cycloamide derivatives. The corresponding sulfonamide natrium salt is then reacted with the mixed anhydride and hexamethylphosphoramide. The reaction mixture formed then yields the pure PG-type sulfonylamide derivative by conventional techniques.

The sodium salt of sulfonamide corresponding to the sulfonylamide derivative to be prepared is formed by reacting sulfonamide with alcoholic sodium methoxide. Therefore, the methanolic natriam methoxide is reacted with an equimolar amount of the sulfonamide by a suitable method. The sulfonamide salt is then reacted with the mixed anhydride as described above using about 4 equivalents of sodium salt per equivalent of anhydride. A reaction temperature of about 0 ° C. is used.

The free acid form of a compound of the invention prepared by a method of the invention is converted to a pharmaceutically acceptable salt by neutralization with a suitable amount of the corresponding inorganic or organic base, examples of which are: Corresponds to the above cations and amines. These turns are carried out by various methods well known in the art to be generally useful for the production of inorganic or metal or ammonium salts. The choice of method depends in part on the solubility characteristics of the particular salt to be produced. In the case of inorganic salts, usually the acid of the invention is dissolved in water containing a stoichiometric amount of the hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. Is suitable. For example, sodium hydroxide, sodium carbonate,
Alternatively, sodium bicarbonate is used to provide dissolution of the sodium salt. Evaporation of water or addition of a water-miscible solvent of moderate polarity, such as a lower alkanol or a lower alkanone, gives the solid inorganic salt in its form if desired.

To prepare the amine salt, the acid of the present invention is dissolved in a suitable solvent of medium or low polarity. Examples of the former are ethanol, acetone and ethyl acetate. Examples of the latter are diethyl ether and benzel. Then at least a stoichiometric amount of the amine corresponding to the desired cation is added to this solution. If the salt formed does not precipitate, it is usually obtained in solid form by evaporation.
If the amine is relatively volatile, the excess can be easily removed by evaporation. It is preferred to use stoichiometric amounts of relatively less volatile amines.

Salts in which the cation is a quaternary ammonium are prepared by mixing the acid of the present invention in aqueous solution with the stoichiometric amount of the corresponding quaternary ammonium hydroxide and then evaporating the water. To be done. The invention will be more fully understood by the operation of the following examples.

1) Reference Example 1 3-oxo-7α-tetrahydropyran-2-yloxy
Ci-6β [(3'S) -3'-tetrahydropyran-2-
Iloxy-trans-1′-octenyl] -bicyclo
[3.3.0] -Oct-1-ene (Formula XXIV: R ₁₈ is tetrahydropyranyloxy, Y ₁ is trans-CH═CH
-, M ₆ is α-tetrahydropyranyloxy: β-H, L ₁
Α-H: β-H, R ₂₇ is n-butyl, and n is the integer 1) See Figure A.

A. To a stirred solution of 19 ml (170 mmol) of dilymethylmethylphosphonate and 600 ml of dry tetrahydrofuran at -78 ° C. under an argon atmosphere for 5 minutes in 1.5 of hexane.
110 ml (172 mmol) of 6Mn-butyllithium was added dropwise. The resulting solution was stirred at -78 ° C for 30 minutes,
25.4 g of 3 in 100 ml of dry tetrahydrofuran
α, 5α-dihydroxy-2β- (3α-hydroxy-
Trans-1-octenyl) -1α-cyclopentaneacetic acid, lactone, bis (tetrahydrofuranyl) ether were added dropwise over 1 hour, and the mixture was stirred at −78 ° C. for 1 hour and at room temperature for 4 hours. The reaction was then quenched by the addition of 10 ml glacial acetic acid, diluted with 700 ml brine and extracted with diethyl ether (3 x 700 ml). The combined ether layers were washed with 200 ml bicarbonate and 500 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 37 g of compound of formula XXII as an oily white solid: 3-dimethylphosphoric acid. Nomethyl-3-hydroxy-2
-Oxa-7α-tetrahydropyran-2-yloxy-6β [(3'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl] -bicyclo [3.3.0] octane was produced. . The crude product was recrystallized from hexane and ether to give 22.1 g of the purified product of formula XXII. Rf of silica gel TLC was 0.22 in ethyl acetate. Melting point range is 8
It was 9-93 degreeC. NMR absorptions are 3.72 (doublet, J = 11 Hz) and 3.83 (doublet, J = 11H).
z) observed in δ. The characteristic infrared absorption is 3
340, 1250, 1185, 1130, 1075 and 1030 cm.

B. To a solution of 10.0 g of the product of Part A in 75 ml of acetone at -10 ° C under a nitrogen atmosphere at 3 ° C.
9.0 ml of Jones reagent was added over 0 minutes.
The resulting suspension is stirred for 30 minutes at -10 ° C, then 4 ml
Stopped with 2-propanol. The solvent was decanted from the green residue and most of the acetone was removed under reduced pressure. The acetone concentrate was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, then brine.
Then dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give 8.2 g of the product of formula XXIII: 2-decarboxy-6-desbutyl-6-dimethylphosphonomethyl-6.
- keto -PGE _1, to produce a 11,15- bis (tetrahydropyranyl ether). The product of formula XXIII is
Elute with 20% acetone in methylene chloride 60
Chromatography on 0 g silica gel
This gave 4.95 g of pure product of formula XXIII. Rf of silica gel TLC (in 20% acetone in methylene chloride) was 0.22. Characteristic NMR absorption is 3.1
4 (double wire, J = 23Hz) and 3.80 (double wire, J
= 11 Hz), observed at 5.4-5.8 (m) delta. The characteristic infrared absorption is 1745, 1715, 12
60, 1200, 1185, 1130, 1030, 97
It was observed at 0,870 cm ^-1 .

C. A suspension of 5.37 g of Reference Example 1, the product of Part B, 1.33 g of anhydrous potassium carbonate, and 5.37 g of 18-crown-6-ether in 200 ml of toluene was added. Heat to 75 ° C under nitrogen atmosphere for 6 hours, cool to 0 ° C, and 200 ml brine, 200 ml.
Washed with 3: 1 water: brine, and 200 ml brine and dried over anhydrous sodium sulfate. Most of the solvent was removed under reduced pressure and the residue was filtered through 50 g of silica gel, eluting with 250 ml of ethyl acetate,
3.9 g of the product of formula XXIV: 3-oxo-7-α-tetrahydropyranyl-2-yloxy-6β [(3 ′
S) -3'-Tetrahydropyran-2-yl-trans-1'-octenyl] bicyclo [3.3.0] oct-1
-Given En. The crude product was chromatographed on 300 g of silica gel, eluting with 60:40 hexane: ethyl acetate to give 2.39 g of pure title product. Rf of silica gel TCL is 6
It was 0.22 in 0:40 hexane: ethyl acetate. NMR absorption is 5.18-5.86 (m) and 5.94
Observed at (wide singlet) δ. Infrared absorption is 1
Observed at 710 and 1632 cm- ₁ .

According to the procedure of Reference Example 1, but with different formula XXI:
3α, 5α-hydroxy-2-substituted-1α-cyclope
With n-acetic acid δ-lactone
Each of the corresponding products of formula XXIV were prepared. It
In addition, according to the procedure of Reference Example 1, 3 of various formulas XXI
α, 5α-Dihydroxy-2-substituted-1α-cyclopen
Using each of the tanpropionic acid delta-lactones,
Each of the various compounds of formula XXIV in which n is 2 was prepared
It was Further, according to the procedure of Reference Example 1, various formulas XXI
5α-hydroxy-2-substituted-1α-cyclopentane
With each of the alkanoic acid lactones, R₁₈Is hydrogen
Each of a variety of compounds of Formula XXIV were prepared.
Finally, according to the procedure of Reference Example 1, various formulas XXI-3
α-hydroxymethyl-5α-hydroxy-2-substituted-
Each of the 1α-cyclopentanealkanoic acid lactones is used.
When used, R 1₈Is -CH₂OR_TenVarious formulas XXI
Each of the V compounds was prepared.

2) Reference Example 2 3-oxo-8α-tetrahydropyran-2-yloxy
Ci-7β ° (3 ′S) -3′-tetrahydropyran-2-
Iloxy-trans-1′-octenyl] bicyclo
[4.3.0] Non-1-ene (Formula XXIV: R ₁₈ , Y ₁ ,
M ₆ and R ₇ are defined in Reference Example 1 and n is the integer 2) See Figure A.

A. A solution of 2.05 ml (18.9 mmol) of dimethyl methylphosphonate and 100 ml of dry tetrahydrofuran was stirred under a nitrogen atmosphere at -78 ° C and 1.6 mol of n-butyllithium 1 in hexane.
It was treated dropwise with 1.8 ml (18.9 mmol). -78 ° C
After stirring for 30 minutes in
Over the course of a minute, 4.25 g of 3α, 5α-dihydroxy-2β- (3α in 30 ml of dry tetrahydrofuran were added.
-Hydroxy-trans-1-octenyl) 1α-cyclopentanepropionic acid, δ-lactone, 11,15-
Dropwise treatment with bis (tetrahydropyranyl ether). The resulting mixture was then stirred at 78 ° C. for 1 hour. The solution was then stirred at room temperature for 2 hours and stopped by the addition of 1.2 ml acetic acid. The mixture was then added to 250 ml brine and 200 ml diethyl ether. Then the aqueous and organic layers were separated and the aqueous layer was extracted twice with diethyl ether. The ether extract is then washed with brine, dried over anhydrous sodium sulfate and concentrated to 5.6g.
Crude compound of formula XXII: 3- (dimethylphosphonomethyl) -3-hydroxy-2-oxa-8α-tetrahydropyran-2-yl-oxy-7β [(3 ′S) -3 ′.
-Tetrahydropyran-2-yloxy-trans-
1'-octenyl] -bicyclo [4.3.0] nonane was produced as an oil. Chromatography on silica gel, eluting with 4: 1 ethyl acetate: acetone,
This yielded 4.1 g of the purified product of formula XXII. A characteristic NMR absorption was observed at 5.15-5.65 (multiline) δ. Silica gel TLC Rf was 0.34 in 4: 1 ethyl acetate: acetone. Characteristic infrared absorption is 3350, 1235 and 1030 cm ^-1
Was observed in.

B. 3.42 g of chromium trioxide and 80 ml
A suspension of methylene chloride was treated with 5.8 ml of pyridine, stirred at room temperature under a nitrogen atmosphere for 30 minutes and combined with 3 glasses of dry diatomaceous earth. The resulting mixture is then treated with 3.25 g of the reaction product of Part A and 8 ml of dry dichloromethane and stirred at room temperature under nitrogen for 30 minutes,
It was filtered through g silica gel (eluted with 200 ml ethyl acetate and acetone (2: 1)) and concentrated under reduced pressure. The residue (3.73g) was chromatographed on 120g of silica gel, eluting with ethyl acetate and acetone (4: 1) to give 2.07g of the product of formula XXIII: 2-decarboxy-5-despropyl-6-. Dimethylphosphonomethyl-5-keto-PGE ₁ , 11, 15
-Produces bis (tetrahydropyranyl ether).
Characteristic infrared absorptions were observed at 1740 and 1715 cm ^-1 . Characteristic NMR absorption is 3.1 (doublet, J
= 23 Hz) and 3.8 (doublet, J = 11 Hz) δ.

C. 50% Sodium Hydride in Mineral Oil 1
2 mg of suspension and 3 ml of diglyme were stirred at 0 ° C. under argon atmosphere. The suspension was then treated with 150 mg of Part B product in 3 ml diglyme. One hour later,
The cooling bath was removed and the resulting solution was stirred at room temperature under argon. 20 hours after the addition of the reactants of formula XXIII, the resulting solution is added to 30 ml of water and 90
It was extracted with ml of diethyl ether. The ether extract was washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg), and on 10 g of silica gel with hexane and ethyl acetate (1: 1). Elute and chromatograph. Thus, 15 mg of the compound of formula XXIV: 3-oxo8
α-tetrahydropyran-2-yloxy-7β-
[(3's) -3'-Tetrahydropyran-2-yloxy-trans-1'-octenyl] bicyclo [4.3.
..] Non-1-ene was produced. NMR absorption is 4.7
(Wide singlet) and 5.3-6.0 (multiplet) δ observed. IR absorption was observed at 1670 cm ^-1 .

On the other hand, the compound of formula XXIV above was prepared as follows: 150 mg of the product of Part B and 5 ml of a solution of dry tetrahydralofuran at 0 ° C. in tetrahydrofuran under an atmosphere of argon. 0.5 ml of 0.52 M potassium hydride and 18-crown-6 ether (Aldrich Chemical Company, Aldrich Chemical C
o.) Catalog Handbook of Fine Chemicals, 1979-1980, Milwaukee, Wisconsin, p. 133; Pedersen, C. (Pedersen
JC), JACS 92: 386 (1970)), which was prepared dropwise from 800 mg potassium hydroxide and 1.0 g 18-crown-6 ether in 8.7 ml dry tetrahydrofuran. After stirring for 1 hour under argon at 0 ° C., the mixture was added to 30 ml of water, extracted with 90 mg of diethyl ether, and the ether extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. And on 9 g of silica gel,
Chromatograph, eluting with ethyl acetate and hexane. This gave the product of formula XXIV (40 mg). Rf of silica gel TLC was 0.30 in ethyl acetate and hexane (1: 1).

[0140]3) Reference example 3 1β-methyl-3-oxo-7α-tetrahydropyran
-2-yl-oxy-6β-[(3'S) -3'-tetra
Hydropyran-2-yloxy-trans-1′-oct
Tenyl] -bicyclo- [3.3.0] octane (Formula XX
Y: R₁₈, Y₁, M 6, n, L₁, R₇Is defined in Reference Example 1
As it is, R₁₆Is hydrogen, and R₃₇Is meth
See Figure A.

A suspension of 2.70 g of anhydrous copper iodide in 100 ml of anhydrous diethyl ether at −20 ° C. under an argon atmosphere was treated dropwise with 20.0 ml of 1.4M ethereal methyllithium. The resulting solution is then-
Stirred at 20 ° C. for 15 minutes and treated at −20 ° C. for 2.5 hours with 2.00 g of a solution of the title product of Reference Example 1 in 100 ml of anhydrous diethyl ether. -20 ° C
Stirring was continued for a further 1.5 hours and the resulting mixture was added to 200 ml 1M aqueous ammonium chloride. The aqueous and organic layers were then separated and the aqueous layer was extracted with diethyl ether (400ml). The combined organic extracts were then washed with 200 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 2.4 g of the title product as a pale green oil. Chromatography on 25 g of silica gel, eluting with hexane (1: 3) in ethyl acetate, gave 2.0 g of the title product as a colorless oil. Characteristic NMR absorption (CDCl ₃ ) is 1.1
8, 3.20-4.43, 4.70 and 5.2-5.9δ. The characteristic infrared absorption is 1745, 166
5, 1200, 1130, 1110, 1075, 103
It was observed at 5, 1020, 980, and 870 cm- ₁ . Silica gel R _f is ethyl acetate and hexane (1:
It was 0.26 in 3).

Various novel methods are known by methods well known in the art.
Each of the intermediates of formula XXV is exemplified below:
Or British Bulletin No. 2,013,661, 2,014,
143 and 2,017,699
From 9β-methyl-CBA 2 or CBA₁Convert to compound
did.

4) Reference Example 4 5-Carboxypentanol, tert-butyldimethylsilyl
Rue - methano of ether 100 ml - le and water (4: 1) 4g solution of sodium hydroxide was treated with caprolactone 10ml in, and stirred at room temperature under a nitrogen atmosphere. After 20 hours, the solvent was evaporated after the addition of toluene to yield 15 g of solid crude 5-carboxypentanol.

The above solid was suspended under nitrogen in 300 ml of dimethylformamide, cooled to 0 ° C. and 35 g.
Of imidazole, suspended at 0 ° C. for 15 minutes and at room temperature for 15 minutes, cooled to 0 ° C. and treated with 39 g of tert-butyldimethylsilyl chloride. The resulting solution was then allowed to warm to room temperature under nitrogen atmosphere. Two
After 6 hours the resulting solution was treated under nitrogen with continuous stirring with 40 ml of water and 8 g of sodium hydroxide in 40 ml of methanol. 500 hours after 13 hours
Acidified to pH 4 with ml of 1N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate.
The ethyl acetate extract was then washed with 1N aqueous sodium hydroxide. The basic extract was then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine and extracted with ethyl acetate. The ethyl acetate extract was then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to 22.6 g of a yellow liquid, 5-carboxy-pentane, tert-butyldimethylsilyl ether. -Generated a tell. On 800 g of silica gel, ethyl acetate and hexane (1: 9 to 1: 1).
Elute with 1) and chromatograph to 1
4.8 g of 5-carboxypentanol, tert-butyldimethylsilyl ether was produced. NMR absorption is 0.0
Observed at 5 (single line) and 0.90 (single line) δ. Infrared absorption was observed at 3000 (broad) and 1700 cm ^-1 .

According to the procedure of Reference Example 4, ω of the formula XXXII
Different products of formula XXXII were prepared from each of the different lactones corresponding to the -carboxyalkanol compounds.

5) Reference Example 5 2-Decarboxy-2- (tert-butyldimethylsilyloxy)
Ci) Methyl-5-carboxy-6-hydroxy-9β-
Methyl -CBA _1, 11,15- bis (Tetorahidoropi
Oran) ether (formula XXXIII: R ₂₈ is tert-butyldimethylsilyl, Z ₂ is — (CH ₂ ) ₃ —, n is 1, and R ₁₆ , R ₁₈ , R ₃₇ , M ₆ , L ₁ , and R ₄ is as defined in Reference Example 3) See Figure B.

A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry tetrahydrofuran was treated with 2.6 ml of 1.56 Mn-butyllithium in hexane at 0 ° C. under an argon atmosphere and treated as in Reference Example 4 in 5 ml of tetrahydrofuran. Treat with 0.50 g of the title product, 15 at 0 ° C.
Stir for 1 minute and at room temperature for 1 hour, cool to 0 ° C., treat with 0.91 g of the title product of Reference Example 3 in 5 ml of tetrahydrofuran, and allow it to slowly warm to room temperature under an argon atmosphere. Then 130 ml of water and 2
0 ml of brine was added and the mixture was extracted with diethyl ether. The ether extract is then washed with 4 ml 1N aqueous hydrochloric acid and 150 ml brine, dried over sodium sulphate and concentrated under reduced pressure to give the title product.

Using the procedure of Reference Example 5, but using each of the various compounds of Formula XXXI described after Reference Example 1, R ₂₈ is tert-butyldimethylsilyl and Z ₂ is-. Each of a variety of compounds of Formula XXXXXIII that is (CH ₂ ) ₃ — was prepared.

6) Reference Example 6 2-Decarboxy-2- (tert-butyldimethylsilyloxy)
) Methyl -9β- methyl CBA _2, 11,15- bis
-(Tetrahydropyranyl ether) (Formula XXXIV: R
₂₈ , Z ₂ , n, R ₁₈ , Y ₁ , M ₆ , L ₁ and R ₇ refer to Reference Example 1
And as defined in 5) The reaction product of Reference Example 5 (1.37 g) and 16 ml of methylene chloride are treated with 2.9 ml of dimethylformamide dinopenpentyl acetal and at room temperature under nitrogen. Stirred for 3 hours, added to 160 ml of ice water and 40 ml of brine and extracted with diethyl ether. The ethereal extract was then washed with 150 ml sodium bicarbonate and 150 ml brine, dried over sodium sulphate and concentrated under reduced pressure to yield the crude title compound. Elution on 100 g of silica gel with 10% ethyl acetate in hexane gave the pure title product.

By following the procedure of Reference Example 6 but using various compounds of Formula XXXIII described after Reference Example 5, R ₂₈ is tert-butyldimethylsilyl and Z
₂ is - (CH _{2) 3} - each of the various corresponding product such formula XXXIV is prepared is.

7) Example 1 2-Decarboxy-2-hydroxymethyl-9β-methyi
Le -CBA _2, 11,15- bis (tetrahydropyranyl
Le) et - ether (Formula _{XXXV: Z 2, n, R} 16, R 37, R
₁₈ , Y ₁ , M ₆ , L ₁ and R ₇ are as defined in Reference Examples 1 and 5) See Figure B. 0.71 g of the title product of Reference Example 6 and 1
A solution of 6 ml dry tetrahydrofuran was treated with 0.75 molar tetra-n-butylammonium fluoride and 3.2 ml tetrahydrofuran. After slowly warming the reaction mixture to room temperature with stirring overnight, 15
0 ml brine was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract is then combined with 0.5N aqueous potassium hydrogen sulfate, 100 ml sodium hydrogen carbonate, and 1
Wash with 00 ml brine, dry over sodium sulfate and concentrate under reduced pressure to give the crude title product. Two
Filtration through 5 g of silica gel with 200 ml of ethyl acetate and hexane yielded 0.61 g of further purified product. 3 in hexane on silica gel
Chromatography, eluting with 5% ethyl acetate, gave the pure title product.

Following the method of Example 1, but using each of the various compounds of Formula XXXIV described after Reference Example 6, various Formula XXXV in which Z ₂ is-(CH ₂ ) _3-.
Each of the above compounds was prepared.

By the procedures of Reference Examples 5 and 6 and Example 1, but with the various starting materials described subsequent to these Examples and the various compounds of formula XXXII described in and after Reference Example 4. And each of the various formulas XXX
Each of the compounds of V were made.

[0154]8) Example 2 2-decarboxy-2-hydroxymethyl-9β-methyl
Ru-CBA ₂  (Formula XXXVI: X₁Is -CH₂OH, Z₂Is-
(CH₂)₃-, R₈Is hydroxy, Y₁Is trans-CH
= CH-, M₁Is α-OH: β-H, L₁Is α-H: β-
H and R 7 is n-butyl) See Figure B. 9 m of the title product of Example 1 (0.25 g)
l of acetic acid, water and tetrahydrofuran (6: 3: 1)
Combined and heated to 37-40 ° C for 2 hours. That
The resulting mixture was cooled and with diethyl ether.
Extracted. The ethereal extract is then washed with brine and
Dry over sodium acidate and concentrate to give the crude title compound.
Produced a product. Chromatography is pure on silica gel
This gave the title product.

By following the procedure of Example 1 but using each of the various primary alcohols of Formula XXXV described in and after Example 1, various corresponding X ₁ is --CH ₂ OH. Each of the products of formula XXXVI was prepared.

9) Reference Example 7 o- (t-butyldimethylsilyloxyethyl) benzua
Ludehide (Formula XLIV: R ₂₈ is tert-butyldimethylsilyloxy and g is 1) See Figure C. A. To a mixture of 7.6 g of lithium aluminum hydride and 400 ml of dry tetrahydrofuran was added dropwise 18 g of homophthalic acid (Aldrich Chemical Company) in 250 ml of dry tetrahydrofuran with stirring under a nitrogen atmosphere. The rate of drop wise addition was adjusted to maintain a gentle reflux during the exothermic reaction process. The resulting mixture is then heated at reflux for 5 hours, cooled to 0 ° C. and 7.6 in 50 ml of tetrahydrofuran.
g of water was added dropwise with stirring. Then 27 ml of 1
0% aqueous sodium hydroxide was added and the resulting mixture was stirred at room temperature for 20 minutes, filtered and the filtered solid washed with 150 ml of tetrahydrofuran. Then, the filtrate and the tetrahydrofuran washings are concentrated under reduced pressure to obtain 1
4.0 g of crude formula XXXII diol, 2- (o-hydroxymethylphenyl) ethanol, was produced. 240
Chromatography on 1.2 kg of silica gel deactivated by addition of ml of ethyl acetate, eluting with ethyl acetate, yielded 13.5 g of product of formula XLII. The melting point range was 41.5-43 ° C.

B. 13.5 g of Part A reaction product 50
To 0.5 ml of dry tetrahydrofuran solution was added 9.05 g of imidazole with stirring under nitrogen atmosphere. The resulting solution was then cooled to -5 ° C and 13.9g tert-butyldimethylsilyl chloride was added. The resulting mixture was then held for 20 minutes and then allowed to warm to room temperature. After 1 hour, the resulting mixture was shaken with 500 ml hexane and diethyl ether (2: 1) and 250 ml water and brine (1: 1). The organic layer was then washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to yield a crude mixture of mono- and bis-silyl ethers corresponding to the starting material of Part A. This mixture of products was then chromatographed on 2 kg of silica gel deactivated with 400 ml of ethyl acetate, eluting with 25% ethyl acetate and Skelisolve B to give 6.82 g of formula XLIII. A substance, o- (tert-butyl-dimethylsilyloxyethyl) phenylmethano-
I gave Le. NMR absorption is 7.20 to 7.52, 4.5
7, 3.91 (t, JG.1), 2.93 (t, J6.
1), 0.82 and -0.08δ. The Rf of silica gel TCL was 0.54 in 25% ethyl acetate and hexane.

C. 5.0 g of the reaction product of Part B, 100
A mixture of ml of trichloromethane and 25 g of activated manganese dioxide (MnO ₂ ) was stirred at room temperature for 4 hours. Chloroform (100 ml) was then added and the resulting mixture was filtered through diatomaceous earth. After washing the filtered solid with trichloromethane in 200 ml, the resulting filtrate and washings were then concentrated under reduced pressure to give a residue containing the title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and eluted with 25% ethyl acetate and hexane, yielded 2.93 g of pure title product. The Rf of silica gel TCL was 0.74 in 25% ethyl acetate and hexane. NMR absorption is 10.34, 7.2
5 to 8.00, 3.89 (t, J6.0), 3.27 (t,
J6.0), 0.83 and -0.09δ. Mass spectrum shows a peak at 265 (M + 1) and m / e 75,207,73,133,223,20.
Other peaks of decreasing strength were shown at 8, 77, 177, 76 and 105.

Following the procedure set forth in Figure C, but using each of the various acids of formula XXXI, various corresponding formulas XXXIV where R ₂₈ is t-butyl-dimethylsilyl.
Each of the aldehydes was prepared.

10) Reference Example 8 m- (t-butyldimethylsilyloxymethyl) benzua
Ludehydride (Formula XLIV: g is 0 and R ₂₈ is t-butyldimethylsilyl) See Figure C. A. To a solution of 10.0 g of m- (hydroxymethyl) phenyl methanol in 40 ml of dry tetrahydrofuran was added 7.35 g of imidazole with stirring under a nitrogen atmosphere. The resulting solution was then cooled to 0 ° C and 11.3g tert-butyldimethylsilyl was added. The resulting mixture was then stirred with cooling for 15 minutes and then allowed to warm to room temperature. The mixture formed after 90 minutes is then mixed with 400 ml of hexane and diethyl ether.
Tell (2: 1) and 200 ml water and brine (1: 1)
Shook inside. The organic layer is then washed with water and brine (1: 1, 300
ml) and brine (150 ml), dried over magnesium sulfate and concentrated under reduced pressure to give formula XX
A mixture of mono- and bis-tert-butyldimethylsilyloxy ethers corresponding to the compound of XII was produced. The product mixture was then deactivated by the addition of 280 ml ethyl acetate and chromatographed on 1.4 kg silica gel eluting with 25-40% ethyl acetate in hexane to give 7.65 g of pure. The product of formula XLIII is m- (tert-butyldimethylsilyloxymethyl)
Phenyl methanol was produced. R of silica gel TLC
f was 0.46 in 25% ethyl acetate and hexane. NMR absorption is 7.25, 4.72, 4.60, 2.
Observed at 23, 0.92 and 0.09δ. The mass spectrum shows the peak at 251 (M ⁺ -1) and m
/ e235, 121, 195, 237, 105, 133,
At 75, 89, 236 and 119, other peaks with reduced strength were shown.

B. 5.0 g of the reaction product of Part A and 10
A mixture of 0 ml trichloromethane and 25 g activated manganese dioxide (MnO ₂ ) was stirred at room temperature for 4 hours.
Then chloroform (100 ml) was added and the resulting mixture was filtered through diatomaceous earth. 20 filtered solids
Wash with 0 ml trichloromethane, then concentrate the filtrate and trichloromethane washes under reduced pressure to give 5.2 g of the crude title product. Chromatography on 400 g of silica gel deactivated with 80 ml of ethyl acetate and eluted with ethyl acetate and hexane (1: 3) yielded 3.65 g of pure title product. Rf of silica gel TLC was 0.46 in 10% ethyl acetate and hexane. NMR absorption is 10:00, 7.26
Observed at ˜7.86, 4.81, 0.95 and 0.11 δ.

11) Reference Example 9 3-Phenylsulfonyl-7α-tetrahydropyran-
2-yloxy-6β-[(3 ′S) -3′-tetrahydr
Ropran-2-yloxy-trans-1'-octeni
L] -bicyclo [3.3.0] octane (formula LV: n is an integer 1, R ₁₈ is tetrahydropyranyloxy, Y ₁ is trans-CH═CH—, M ₆ is α-tetrahydropyranyloxy: β-hydrogen. , L ₁ is α-hydrogen: β-hydrogen, R ₁₆ and R
₁₇ is both hydrogen, and R ₂₇ is n-butyl) See Figure D. A. 2.90 g of 3-oxo-7α-tetrahydropyran-2-yloxy-6β-[(3 ′S) -3′-tetrahydropyran-2-yloxy while stirring sodium borohydride (0.38 g) 25 ml of trans-1 -'- octenyl] -bicyclo [3.3.0] octane 95
% Aqueous ethanol solution. The resulting mixture was then stirred at room temperature for 20 minutes. The resulting mixture was then shaken in 100 ml brine and 200 ml ethyl acetate. Immediately the organic layer is washed with brine, dried over magnesium sulphate and concentrated under reduced pressure and 2.94 g of the formula LII alco-:( 3RS) -3-hydroxy-7.
α-tetrahydropyran-2-yloxy-6β-
[(3'S) -3'-Tetrahydropyran-2-yloxy-trans-1'-octenyl] -bicyclo [3.3.
0] octane was produced. Infrared absorption is 3600 and 3
Observed at 450 cm ^-1 , and no carbonyl absorption was observed. Rf of silica gel TLC was 0.63 and 0.67 in ethyl acetate and hexane (1: 1).

B. 25 ml of dry dichloromethane and 1.
4 ml (1.02 g) of triethylamine, 2.9 g of A
To a portion of the reaction product solution was added 0.57 ml (0.848 g) of methanesulfonyl chloride over 5 minutes with stirring at 0 ° C. The resulting mixture was then stirred for a further 20 minutes and shaken with 160 ml diethyl ether and 80 ml cold (0 ° C) dilute aqueous hydrochloric acid solution. The organic layer is then washed successively with brine, dilute aqueous potassium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure to give 3.5 g of crude compound of formula LIII: (3RS). -3-Hydroxy-7α-tetrahydropyran-2-yloxy-6β-[(3'S) -3'-
Tetrahydropyran-2-yloxy-trans-1 '
-Octenyl] -bicyclo [3.3.0] octane, 3-
Methyl sulphonate was produced.

C. Cytophenol 0.13 ml (1.21)
g) was added under a nitrogen atmosphere to a mixture of 1.12 g potassium tert-butoxide in 15 ml dry dimethylsulfoxide (DMSO). To the solution of potassium thiophenoxide prepared in this way was added 3.5 g of the reaction product of Part B in 8 ml of dimethylsulfoxide. The resulting mixture was then stirred at room temperature for 16 hours, more potassium tert-butoxide was added and the solution turned a clear yellow color. The resulting mixture was then stirred at room temperature for a further 4 hours, diluted with 100 ml diethyl ether and 100 ml hexane and 5% aqueous potassium oxide (200 ml).
And washed with brine (200 ml), dried over magnesium sulphate and concentrated under reduced pressure to give 5 g of crude product of formula LIV: 3-phenylthio-7α-tetrahydropyran-
This gave 2-yloxy-6β-[(3 ′S) -3′-tetrahydropyran-2-yloxy-trans-1′-octenyl] -bicyclo [3.3.0] octane. 40 ml
Chromatography on 300 g of silica gel deactivated with 40 ml of diethyl ether and 40 ml of trichloromethane and eluted with 5% diethyl ether in trichloromethane yielded 3.1 g of pure product. . Rf of silica gel TLC is 1 in dichloromethane
It was 0.75 in 0% ethyl acetate.

D. 3.1 g of Part C reaction product and 50
To a solution of ml dichloromethane was added 2.43 g of 85% m-chloroperbenzoic acid over 10 minutes with stirring at 0 ° C. The resulting mixture is then stirred for 30 minutes at 0 ° C., diluted with 150 ml of dry ethyl ether, washed with ice-cold dilute aqueous potassium hydroxide solution and brine, dried over magnesium sulphate and concentrated under reduced pressure. Then 3.
This gave 4 g of crude title product. Deactivated with 70 ml of ethyl acetate and 30 in 500 ml of hexane
Chromatography on 350 g of silica gel, eluting with .about.50% ethyl acetate gave 2.90 g of pure title product as a mixture of C-6 isomers.
The Rf of silica gel TLC was 0.41, 0.45 and 0.48 in 30% ethyl acetate in hexane (stereoisomers). NMR absorption is 7.52 to 8.02, 5.30 to 5.
67, 4.70 and 3.30-4.13 δ.

By following the procedure in Reference Example 9, each of the compounds of formula LI was converted to each of the corresponding 3-phenylsulfonyl compounds of formula LV.

12) Example 3 (5E) -2,5-Inter-O-phenylene-3,4-
Dinor-CBA ₂ (Formula LX: X ₁ is —COOH, g is 1,
n is 1, R ₁₆ and R ₁₇ are hydrogen, R ₈ is hydroxy, Y ₁ is trans-CH═CH—, M ₁ is α-OH: β-H, L ₁
Is α-H: b-H, and R ₇ is n-butyl),
Its Methyl Esters and Their Corresponding (5Z) Isomers See Figure C A. To a solution of 1.26 g of the title product of Reference Example 9 in 15 ml of dry tetrahydrofuran at -78 ° C under nitrogen atmosphere. With stirring, 1.48 ml of 1.6M n-butyllithium in hexane was added over 1 minute. 10
After minutes 0.66 g in 5 ml dry tetrahydrofuran
The title product of Reference Example 4 of 1. was added. After 45 minutes, 0.
26 ml of distilled acetic anhydride was added. Next, stir -7
Continued for 3 hours at 8 ° C. and another 2 hours at room temperature. The resulting mixture is then mixed with 120 ml diethyl ether and 80 ml.
It was shaken with a saturated aqueous solution of ammonium chloride. The organic layer is then washed with 15 ml brine, dried over magnesium sulfate,
Then concentrated under reduced pressure and 2.21 g of the product of formula LVI: 3- [α-acetoxy-O- (tert-butyldimethylsilyloxyethyl) -α-tolyl] -3-phenylsulfonyl-7α- ( Tetrahydropyran-2-yl) oxy-6β-[(3 ′S) -3 ′-(tetrahydropyran-
2-yl) oxy-trans-1'-octenyl] bicyclo [3.3.0] -octane was produced as a mixture of isomers. R ₂₈ , g, R ₁₇ , n, R ₁₈ , Y ₁ , M ₆ , L ₁
And R ₂₇ are as defined in Reference Examples 7 and 11. The Rf range of silica gel TLC was 0.30-0.53 (8 spots) in 25% ethyl acetate and hexane (stereo).

B. A mixture of Part A isomeric product (2.21 g) and 40 ml of methanol and 20 ml of ethyl acetate was stirred with 5.6% sodium amalgam flakes for 60 minutes at -20 ° C. After decanting the liquid, excess amalgam and solids were rinsed by decanting with 200 ml diethyl ether. The organic solutions are then combined, washed with brine, dried and concentrated under reduced pressure to give 1.8 g of crude 2-decarboxy-2- (tert-butyldimethylsilyloxymethyl) -2.5. -Inter-O-phenylene-
3,4 dinor -CBA _2, 11,15- bis - were generated (tetrahydropyranyl Rue ether). Deactivated with 50 ml diethyl ether and 30% in hexane
Chromatography on 250 g of silica gel, eluting with diethyl ether, gave 1.06 g of pure product. The Rf of silica gel TLC was 0.49, 0.56 and 0.62 (stereoisomers) in 30% diethyl ether and hexane. NMR absorption is 7.2
0, 6.54, 5.22 ~ 5.80, 4.72, 3.38 ~
Observed at 4.16 and 2.74-3.00.

C. 1.06 g of the reaction product of Part B, 1
A solution of 0 ml dry tetrahydrofuran in 0.75 N tetrahydrofuran in 40 minutes at room temperature
3.2 ml of tetra-n-butylammonium fluoride
Processed in. The resulting mixture was then diluted with 125 ml diethyl ether. The resulting solution is then washed with brine, dried over magnesium sulphate and concentrated under reduced pressure to give the isomers of formula LVII product: (5E)-and (5
Z) -2-Decarboxy-2-hydroxymethyl-2.
5-inter-O-phenylene-3,4-dinor-CBA
_2, 11,15- bis - to produce a residue (tetrahydropyranyl Rue ether). Chromatography on 100 g of silica gel deactivated with 20 ml of ethyl acetate and eluted with 25-50% ethyl acetate in hexane gave 0.40 g of (5Z) isomer and 0.51 g.
The (5E) isomer of was produced. For the (5Z) isomer, the Rf of silica gel TLC was 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorption is 7.20, 6.51, 5.10-5.7
2, 4.69, 3.32 to 4.16 and 2.76 to 300δ
Was observed in. For the (5E) isomer, the Rf of silica gel TLC was 0.20 and 0.24 (stereoisomers) in 25% ethyl acetate and hexane. NM
R absorption is 7.19, 6.50, 5.10-5.64, 4.
70, 3.32 to 4.10, and 2.88 to 3.01 δ.

D. To a solution of 400 mg of Part C (5Z) reaction product in 20 ml of dry acetone was added 1.0 ml of Jones reagent (prepared as follows: 26.72 g chromium trioxide in 23 ml concentrated sulfuric acid, diluted with water to 100 ml solution) was added. The resulting mixture was allowed to warm to -20 ° C over 20 minutes and stirred at -20 ° C for 30 minutes.
The Jones reagent was then decomposed by the addition of 0.5 ml of isopropanol. After 5 minutes, the reaction mixture is 80 ml containing 100 ml ethyl acetate and 0.5 ml concentrated hydrochloric acid.
Shaken in salt water. Then the organic layer, trace amount (10 drops)
Was washed twice in 50 ml water, containing twice concentrated hydrochloric acid, twice in 50 ml water and in brine. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure,
360 mg of crude (5Z) -2, a compound of formula LIX.
5-inter-O-phenylene-3,4-dinor-CBA
_2, 11,15- bis - were generated (tetrahydropyranyl Rue ether). The crude formula LIX compound was then taken up in 30 ml of diethyl ether and a trace amount (10 drops) was taken.
Was extracted into a mixture of 15 ml water containing 45% aqueous potassium hydroxide and 5 ml methanol. The extraction was repeated 6 times until the acid was completely extracted from the ethereal solution. The aqueous extract was then acidified to pH 2 and extracted with ethyl acetate. The organic extract is then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure,
This produced a pure title product residue. Silica gel TL
C was a streak of about Rf 0.50 in ethyl acetate and hexane (1: 1). The purified acid was then converted to the corresponding ethyl ester by treatment with excess ethereal diazomethane for 10 minutes. After esterification, the resulting reaction mixture was treated with ethyl acetate and washed with dilute aqueous potassium hydroxide solution and brine. After drying, it was concentrated to a residue, deactivated with 4 ml ethyl acetate and chromatographed on 20 g silica gel eluting with 10% ethyl acetate in trichloromethane to give 210 mg (5Z) -2.5-intern. -O- phenylene-3,4-dinor -CBA _2, 11,15- bis - generating a (tetrahydropyranyl Rue ether). The Rf of silica gel TLC was 0.52, 0.56, and 0.60 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorption is 7.20, 6.45, 5.34 ~
Observed at 5.78, 4.70, 3.68 and 3.30-4.28δ.

E. 200 mg of Part D methyl ester,
A mixture of 5 ml acetic acid, 2.5 ml water, and 1 ml tetrahydrofuran was heated to 40 ° C. and stirred for 4 hours. The resulting mixture is then diluted with 100 ml ethyl acetate and 6 g 85% in 20 ml water and 30 g ice.
Wash with a mixture of aqueous potassium hydroxide and brine (40 ml), dry over magnesium sulfate and concentrate under reduced pressure to give 180 mg of crude (5Z) -2.5-inter-O.
- phenylene-3,4-dinor-CBA _2, yielded methyl ester. Chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and eluted with 100 ml of 50% ethyl acetate in trichloromethane and 100 ml of 50% acetone in trichloromethane gave 105 mg of pure product. I gave you something. Silica gel TLC Rf was 0.57 in 40% acetone and trichloromethane and 0.52 in ethyl acetate. NMR absorption is 7.20, 6.43, 5.45-5.
59, 3.65, 3.40-4.20 and 3.18δ. The mass spectrum of the bis TMS derivative is
m / e 73, 75, 74, 147, 43, 129, 41,
45, 167 and 59, peaks of decreasing strength,
And M ⁺ -C ₅ H ₁₁ peak at 485.2513 - showed click.

F. 5 ml of 105 mg of the reaction product of Part E
To a solution of methanol and 2.5 ml of water in an atmosphere of nitrogen was added 0.33 g of potassium carbonate. The resulting mixture was stirred at room temperature for 20 hours whereupon a small amount (5 drops) of 45
% Potassium hydroxide aqueous solution was added. The resulting mixture was stirred at room temperature for another 4 hours. The mixture was then shaken with 100 ml ethyl acetate and excess cold dilute aqueous hydrochloric acid.
The organic layer is then washed with brine, dried and concentrated under reduced pressure to give 100 mg of pure (5Z) -2,5 inter-O.
- generating the phenylene-3,4-dinor-CBA _2.
Rf of silica gel TLC is A-IX solvent system (ethyl acetate, acetic acid, cyclohexane and water, 9: 2: 9: 10.
Was 0.56 in the organic phase of the equilibrated mixture of. The mass spectrum of the tris TMS derivative is m / e 73, 75,
Peaks of decreasing intensity at 129, 167, 74, 55, 69, 57, 147 and 45, and 59.
M ⁺ -CH ₃ peak at 9.3418 - showed click.

G. 510 mg of C according to the procedure of Part D
(5E) -2,5 of 310 mg of (5E) reaction product
-Inter-O-phenylene-3,4-dinor-CB
A _2, 11,15- bis (tetrahydropyranyl Rue - ether) (Rf silica gel TLC is 0.41 in 25% ethyl acetate and hexane containing 1% acetic acid) and of 220 mg (5E) - 2,5 inter -O- phenylene-3,4-dinor -CBA _2, 11,15- bis (tetrahydropyranyl Rue - ether) is Rf of the methyl ester (silica gel TLC, 0 in 25% ethyl acetate and hexane. Are 48, 0.51 and 0.56 (stereoisomers)). NMR absorption is 7.20, 6.43,
5.26-5.64, 4.70, 3.65 and 3.30-4.
Observed at 10 δ.

According to the procedure of Part E, but with the reaction product of part G (210 mg), 110 mg of (5E) -2,5-inter-O-phenylene-3,4-dinor-CBA ₂ , methyl ester Converted to. Rf of silica gel TLC
Is 0.5% in 40% acetone and trichloromethane.
7 and 0.46 in ethyl acetate. N
MR absorption is 7.22, 6.44, 5.32 to 5.47,
Observed at 3.68, 3.50-4.08, and 3.10δ. The mass spectrum of the bis TMS derivative is m / e
73, 75, 129, 227, 167, 55, 57, 1
Peak of decreasing intensity at 73,74,466 - showed click - click, and M ⁺ -CH ₃ peak at 541.3198.

Following the procedure of Part IF, the reaction product of Part H (110 mg) was converted to 102 mg of (5E) -2,5-inter-O-phenylene-3,4-dinor-CBA ₂ . The Rf of silica gel TLC was 0.50 in the A-IX solvent system. The mass spectrum of the tris TMS derivative is m / e 73, 75, 167, 129, 524, 45.
Peaks of decreasing intensity at 3, 285, 147, 434, 213, and M ⁺ -CH at 599.3424.
_It showed ₃ peaks.

13) Example 4 (5E) -1,5-inter-m-phenylene-2,3
4-trinor-CBA 2, its methyl ester, and
See the corresponding (5Z) isomer diagram D. A. By the procedure of Part A of Example 3, 1.26 g of the title product of Reference Example 6 and 0.62 g of the title product of Reference Example 5 were converted to 2.3 g of the formula LVI compound. . Silica gel TLC Rf range is 0.37 to 0.56 (7 spots) in 25% ethyl acetate in hexane (stereoisomers).
Met.

B. By following the procedure in Part B of Example 3, 1.0 g of the reaction product of Part A (2.3 g) is added to 1.0 g of the isomeric compound of formula LVII: (5E)-and (5Z) -2-de Carboxy-
2- (tert-butyldimethylsilyloxymethyl) -1,5
-Inter-m-phenylene-2,3,4-trinor-C
BA _2, 11, 15, bis (tetrahydropyranyl Rue -
Tell). Rf of silica gel TLC is 30
% In diethyl ether and hexane 0.47, 0.5
4 and 0.58 (stereoisomers).

C. According to the procedure of Part C of Example 3, 1.0
0.55 g (5 parts) of the isomer mixed reaction product of Part B.
Z) -2-decarboxy-2-hydroxymethyl-1,
5-inter-m-phenylene-2,3,4-trinor-C
BA _2, 11,15- bis (tetrahydropyranyl Rue -
Tell) and 0.40 g of (5E) -2-decarboxy-
2-hydroxymethyl-1,5-inter -m- phenylene-2,3,4-trinor -CBA _2, 11,15- bis - was converted to (tetrahydropyranyl Rue ether).
For the (5Z) -isomer, Rf of silica gel TLC
Is 0.31 and 0.3 in 25% ethyl acetate and hexane.
35 (stereoisomer). NMR absorption is 7.1
8, 6.36, 5.19-5.65, 4.63, 4.58,
Observed at 3.31 to 4.08 and 2.92δ.
For the (5E) -isomer, Rf of silica gel TLC
Is 0.23 and 0.2 in 25% ethyl acetate and hexane.
It was 27 (stereoisomer). NMR absorption is 7.1
9, 6.37, 5.29-5.72, 4.67, 4.60,
Observed at 3.30-4.17 and 2.78δ.

D. According to the procedure of Part D of Example 3, 510 m
g of Part C (5Z) reaction product, 310 mg of (5Z)
1,5 inter -m- phenylene-2,3,4-trinor -CBA _2, 11,15- bis (tetrahydropyranyl Rue - ether) and of 240 mg (5Z)-1,5 inter -m- phenylene -2,3,4-trinor-CB
It was converted to - (Tel tetrahydropyranyl Rue) A _2, methyl ester, 11,15- bis. For the acid, silica gel TLC was a trace of Rf ˜0.54 in 50% ethyl acetate and hexane. For the methyl ester, the Rf of silica gel TLC was 0.58, 0.63 and 0.68 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorption is 7.28 to 8.00,
6.40, 5.13-5.73, 4.71, 3.89 and 3.
Observed from 28 to 4.08 delta.

E. By the procedure of Part E of Example 3, 24
0 mg of Part D methyl ester product was added to 140 mg (5
Z) -1.5-inter-m-phenylene-2,3,4-
Trinor-CBA _2, was converted to the methyl ester. The Rf of silica gel TLC was 0.49 in ethyl acetate. NMR absorption is 7.28-7.93, 6.40, 5.
Observed at 34-5.48, 3.88 and 3.32δ.
The mass spectrum of the bis TMS derivative is m / e83,8
5, 73, 47, 213, 75, 129-, 48, 8
Peaks and 527.2 of reduced strength at 7, 77
M ⁺ -CH ₃ peak at 996 - showed click.

F. 6 ml of 140 mg of Part E reaction product
Was added to a solution of methanol in 0.25 g of a solution of 0.20 g of 85% potassium hydroxide in 2 ml of water under a nitrogen atmosphere. The resulting mixture was then stirred at room temperature for 7 hours and shaken with 200 ml ethyl acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried over magnesium sulfate,
Concentrate under reduced pressure to give 110 g of pure (5Z) -1.5.
-Inter-m-phenylene-2,3,4-trinor-C
BA ₂ was produced. Rf of silica gel TLC is A-IX
It was 0.60 in the solvent system. The mass spectrum of the tris TMS derivative is m / e 73, 271, 394, 129,
Peaks of decreasing intensity at 420, 510, 75, 147, 32, 74 and M ⁺ − at 585.3234.
CH ₃ peak is shown.

G. According to the procedure of Part D of Example 3, 40
0 mg of Part C (5E) reaction product was added to 260 mg of (5E)
-1,5-inter-m-phenylene-2,3,4-tri
Nor-CBA₂, 11,15-bis (tetrahydropyra
Nyl ether) and 190 mg of (5E) -1,5-yne
Term-phenylene-2,3,4-trinor-CBA
2, methyl ester, 11,15-bis (tetrahydro
Pyranyl ether). For acids, silica
Gel TLC streak in 50% ethyl acetate and hexane
Rf was about 0.36. Regarding methyl ester
For silica gel TLC, the Rf was 25% ethyl acetate and
In hexane and 0.50, 0.53 and 0.57 (stereo).
Isomer). NMR absorption is 7.38-7.95,
6.42, 5.13-5.75, 4.68, 3.89 and 3.
Observed at 30-4.09 delta.

H. By the procedure of Part E of Example 3, 19
0 mg of the reaction product of Part G was added to 81 mg of (5E) -1,5-
Inter-m-phenylene-2,3,4-trinor-CB
A ₂ , converted to methyl ester. Silica gel TLC
Rf of was 0.51 in ethyl acetate. NMR absorption is 7.30 to 7.93, 6.43, 5.45 to 5.5
9, 3.89, 3.50-4.14, and 3.09δ. The mass spectrum of the bis TMS derivative is
m / e 73, 213, 129, 75, 83, 452, 17
Intensity peak decreasing at 3, 85, 262, 362
Click, and M ⁺ -CH ₃ peak at 527.2996 - showed click.

I. According to the procedure in Part F of Example 4, 81 m
65 g of the reaction product of the H part was converted to 65 mg of (5E) -1.5-inter-m-phenylene-2,3,4-trinor-CBA _2.
Converted to. The Rf of silica gel TLC was 0.60 in the A-IX solvent system. The mass spectrum of the tris TMS derivative is m / e 73, 271, 394, 75, 51.
Peaks of decreasing intensity at 0, 129, 420, 147, 173, 395 and M ^{+ at} 585.3227.
Showed click - -CH ₃ peak.

According to the procedure of Examples 3-4, the various Formulas LV described in Reference Example 9 and thereafter, respectively, and the various Formula XL described in Reference Examples 7 and 10 and thereafter.
Using each of IV, each of the various compounds of Formula L were prepared in the free acid or methyl ester form.

14) Example 5 9β-Methyl-CBA ₂ , methyl ester, 11, 15
-Bis (tetrahydro-pyranyl ether) (formula LXX
XIV: R ₁₆ is hydrogen, R ₃₇ is methyl, Z ₂ is — (CH ₂ ) ₃
-And R ₁₈ , Y ₁ , M ₆ , L ₁ and R ₇ are as defined in Example 3) and the corresponding (5E)
And (5Z) free acid (formula LXXXIII). See Figure G. A. 57% sodium hydride suspension in mineral oil (1.90
g) was washed with hexane and treated with 130 ml of dry dimethylsulfoxide (DMSO). The resulting suspension was heated to 65 ° C. under a nitrogen atmosphere for 1 hour,
Then, it was treated dropwise with 10.0 g of 4-carboxybutyltriphenylphosphonium bromide over 15 minutes. Stir the resulting orange solution at 10 ° C. for 15 minutes,
It was then treated dropwise with a solution of 2.12 g of the title product of Example 3 in 20 ml of dry DMSO over 15 minutes. The resulting solution was then stirred under a nitrogen atmosphere at room temperature for 60 hours, treated with 15 ml water, stirred at room temperature for 30 minutes, added to 200 ml ice water and 100 ml brine,
Acidified with aqueous N hydrochloric acid and extracted with 900 ml of diethyl ether. The ether extract is then washed with 1 L of water and 200 ml of brine, dried over sodium sulfate,
And concentrated under reduced pressure to give 4.8 g of a yellow oil of formula L
This produced the carboxylic acid of XXXIII.

B. Formula L in 120 ml of acetonitrile
The product of XXXIII and 42 ml of diisopropylethylamine were treated with 15 ml of methyl iodide under a nitrogen atmosphere at 10 ° C and slowly warmed to room temperature. The resulting suspension was then stirred for 16 hours, treated with 3.0 ml of methyl iodide, stirred for a further 2 hours, added to 500 ml of brine and extracted with 1 L of ethyl acetate. Then add the organic extract to 250 ml of 0.5N potassium bisulfate, 250 ml.
Washed with 250 ml of saturated aqueous sodium hydrogen carbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a solid residue. The residue was then chromatographed on 500 g silica gel eluting with 8% acetone in hexanes and 2.25 g of the title formula LXX.
This resulted in the product of XIV. NMR absorption (CDCl ₃ ) is
0.9, 1.05, 1.08, 3.66, 3.02 to 4.3
Observed at 5, 4.70 and 4.95δ. Infrared absorption is 1730, 1670, 1645, 1200, 11
65, 1135, 1080, 1035, 1020, 98
Observed at 0 and 870 cm ^-1 . Silica gel TL
The Rf of C was 0.46 in ethyl acetate and hexane (1: 3) and 0.26 in ethyl acetate and hexane (1: 6).

C. On the other hand, the reaction product of the Formula LXXXIII isomer of Part A was treated with 10 to 3 parts of hexane on acid-washed silica gel.
By chromatography eluting with 0% ethyl acetate,
It was separated into the title free acid products of (5E) and (5Z).

By following the procedure of Reference Example 7 but substituting each of the various ketones of formula LXXXI for the product of Example 3, various formulas LXXXIV where Z ₂ is-(CH ₂ ) _3-.
Each of the methyl esters of was prepared. Further according to the procedure of Example 5, but with formula LX wherein Z ₂ is other than-(CH ₂ ) _3-.
Using the ω-carboxytriphenylphosphonium compound of XXII, each of the various ketones of formula LXXXI is converted to each of the corresponding formula LXXXIV esters where Z ₂ is other than — (CH ₂ ) ₃ —.

[0190]15) Example 6 (5Z) -2-decarboxy-2-hydroxymethyl-
9β-methyl-CBA 2,11,15-bis (tetrahi
Doropyranyl ether) (Formula LXXXVI: R₁₆, R₃₇,
Z₂, R₁₈, M₆, L₁And R₇Is defined in Example 5
And the (5E) isomer thereof (formula L)
XXXVII). See Figure G. 0.16g lithium aluminum hide
45 ml of a suspension of Ride in dry tetrahydrofuran,
15 ml of dry tetrahydro under a nitrogen atmosphere at 0 ° C
Dropwise with 1.98 g of the title product of Example 5 in furan.
Processed. The resulting suspension is allowed to stand at 0 ° C for 1 hour and then at room temperature.
It was stirred for 1 hour. Then cool the resulting mixture to 0 ° C
Then 0.16 ml water, 0.16 ml 15% aqueous sodium hydroxide
It was stopped by the addition of helium. Stirred at room temperature for 1 hour
Later, it was treated with magnesium sulfate and filtered with diatomaceous earth.
And rinse with diethyl ether to give a mixture, which is
Concentrated under reduced pressure. 180 of 0.25 g of the resulting product
Chromatography on g silica gel, hexane
1.03 g of formula LX, eluting with 30% ethyl acetate in
The product of XXVII and 1.06 g of the product of formula LXXXVI
Occurred. For the product of formula LXXXVI, NMR absorption
Yield (CDCl₃) Is 0.90, 1.09, 3.2 to 4.
It was observed at 4, 4.72, 5.0-5.9 delta. Red
External line absorption is 3470, 1760, 1200, 113.
5, 1120, 1075, 1035, 1020, and 9
80 cm -¹Was observed in. Rf of silica gel TLC
Is 0.2 in ethyl acetate and hexane (35:65).
It was 9. For products of formula LXXXVII, see NM
R absorption (CDCl₃) Is 0.90, 1.05, 3.2.
In 4.4, 4.6 ~ 4.95, 5.05 ~ 5.97δ
Was observed. Infrared absorption is 3470, 1670, 120
0, 1125, 1110, 1080, 1035, 102
0 and 985 cm^-1Was observed in. Silica gel TL
Rf of C is in ethyl acetate and hexane (35:65)
It was 0.36. According to the procedure of Example 6,
Various esters of formula LXXXIV described after 5
Using each of the formula LXXXVI and the formula L
A primary alcohol of each of XXXVII was prepared.

[0191]16) Example 7 (5Z) -9β-methyl-CBA ₂ , methyl ester
 (Formula LXXXVIII: X₁Is -COOCH₃, R₈Is hydro
Kisshi, M₁Is α-OH: β-H, and R₁₆, R₁₇,
L₁, R₇, Y₁And Z₂Is defined in Example 6
See Figure G. A. of formula LXXXVI of Example 6 in 38 ml of acetone
A solution of the title product at -20 ° C under nitrogen atmosphere.
1.9 ml Jones reagent (133.
6 g of chromium trioxide was dissolved in 115 ml of concentrated sulfuric acid,
Then dilute with water to a volume of 500 ml.
Manufactured by the method described above) and stirred at −20 ° C. for 2 hours,
It was stopped by the addition of 2.3 ml isopropanol,
Stir for 40 minutes at 20 ° C and dilute with 200 ml brine.
And extract with 400 ml of ethyl acetate and 600 ml of brine.
Wash, dry over sodium sulfate, and concentrate under reduced pressure.
When contracted, 1.01 g of a primary alcohol of formula LXXXVI-
The carboxylic acid corresponding to the oil was produced as a pale green oil.

B. A solution of the product of Part A in 11 ml of acetonitrile at 15 ° C. under a nitrogen atmosphere was 4.1 ml.
Of diisopropylethylamine and 1.5 ml of methyl iodide. The resulting suspension was then stirred at room temperature for 17 hours, treated with 0.3 ml of methyl iodide, stirred at room temperature for 2 hours, diluted with 50 ml of brine and extracted with 100 ml of ethyl acetate, 50 ml of ethyl acetate. 0.5M potassium bisulfate, 50ml
Wash with sodium hydrogen carbonate aqueous solution and 50 ml of brine,
Drying over anhydrous sodium sulfate and concentration under reduced pressure yielded 1.02 g of the methyl ester corresponding to the carboxylic acid product of Part A.

C. A solution of the product of Part B in 56 ml of a mixture of 56 ml of tetrahydrofuran, water and acetic acid (1: 2: 4) was heated to 45 ° C. under a nitrogen atmosphere for 3 hours, cooled and 200 ml of brine. Dilute with and extract with 400 ml of ethyl acetate. The organic extract is then washed with 600 ml of saturated aqueous sodium hydrogen carbonate solution and 400 ml of brine,
Drying over anhydrous sodium sulfate and concentration under reduced pressure yielded 0.9 g of crude title product as a yellow oil. Chromatography on 100 g of silica gel, eluting with hexane and ethyl acetate (3: 7), gave 0.39 g of pure title product as a colorless oil. NMR absorption (CDCl ₃ ) 0.89, 1.0
8, 3.5 to 4.35, 3.66, 5.0 to 5.7. Infrared absorption is 3360, 1740, 16
70, 1455, 1435, 1370, 1240, 12
25, 1195, 1170, 1075, 1020 and 9
Observed at 70 cm ^-1 . Rf of silica gel TLC
Was 0.22 in ethyl acetate and hexane (7: 3).

By the procedure of Example 7, but using the various compounds of formula LXXXVI described after Example 6,
9β- of various formulas LXXXVIII in which X ₁ is —COOR ₁
Each methyl-CBA ₂ compounds were prepared.

[0195]17) Example 8 (5E) -9β-methyl-CBA ₂ , methyl ester
 (Formula LXXXIX: R₁₆, R₁₇, X₁, Z₂, R₈, R₁, M
₁, L₁And R₇Is as defined in Example 7
See Figure G. A. According to the procedure of Part A of Example 7, 0.60 g of Example
The product of formula LXXXVII of formula 6 is converted to a primary compound of formula LXXXVII
When converted to the carboxylic acid corresponding to the alcohol,
66 g of a green oil was produced.

B. The product of Part A above (0.66 g) was converted to the methyl ester corresponding to the carboxylic acid product of Part A by the procedure of Part B of Example 7 at 0.58.
g yellow oil was produced.

C. The product of Part B above (0.58 g) was converted to the title product as a colorless oil, 0.25 g, following the procedure of Example 7, Part C. NMR absorption (CDCl ₃ )
Is 0.90, 1.05, 3.30, 3.66, 3.75 ~
It was observed at 4.25, 5.0-5.7 delta. Infrared absorption is 3360, 1470, 1670, 1455, 1
435, 1250, 1225, 1195, 1170, 1
It was observed at 075, 1020 and 970 ^cm-1 .
The Rf of silica gel TLC was 0.22 in ethyl acetate and hexane (3: 7).

By following the procedure of Example 8 but using each of the various compounds of Formula LXXXVII described after Example 6, various Formula LXXs wherein X ₁ is --COOCH _3.
Each of the XIX products was produced.

[0199] 18) Example 9 (5Z) -9β- methano methyl-CBA ₂ 8 ml - in Le, title product of Example 7 0.28
g solution was stirred at room temperature under a nitrogen atmosphere and treated with 1 ml of 8M aqueous sodium hydroxide solution. The resulting yellow solution was then stirred at room temperature under nitrogen for 5 hours, diluted with 90 ml of ice and brine, acidified to pH 2 with 1N hydrochloric acid and extracted with 360 ml of ethyl acetate, 120 ml.
Washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.25 g of crude title product. Chromatography on 30 g of silica gel, eluting with the A-IX solvent system (organic phase of a 9: 2: 5: 10 equilibrated mixture of ethyl acetate, acetic acid, cyclohexane and water) gave 0. 235 g of pure title product are produced as a colorless oil. NMR absorption (CDC
l ₃ ) is 0.89, 1.08, 3.5 to 4.35, 5.0
It was observed at 5.7 and 6.05δ. Infrared absorption
3340, 2660, 1710, 1240, 1205,
Observed at 1175, 1130, 1075, 1055, 1020 and 970 ^cm-1 . Rf of silica gel TLC was 0.25 in A-IX solvent system.

Following the procedure of Example 9, each of the methyl esters prepared according to Example 7 was converted to the corresponding carboxylic acid.

19) Example 10 (5E) -9β-Methyl-CBA _{2 Following} the procedure of Example 9, convert 0.25 g of the title product of Example 8 to 0.21 g of the title product as a colorless oil. Let NMR absorption (CDCl ₃ ) was 0.90, 1.06,
Observed at 3.5-4.3, 5.0-5.7 and 5.93δ. Infrared absorption is 3340, 2660, 171
0, 1300, 1240, 1175, 1130, 107
5, 1055, 1020, and 970 ^cm-1 . The Rf of silica gel TLC was 0.27 in the A-IX solvent system.

Each of the various carboxylic acids corresponding to LXXXVIII and LXXXIX in which X ₁ is --COOH is derived from the corresponding reaction product of formula LXXXIII as C-11 and C--.
It could be prepared by acid hydrolysis of 15 tetrahydropyranyl ether protecting groups. [From Part C of Example 5 (5Z)
The LXXXIII reaction product becomes the product of formula LXXXVIII and (5E) LXXXIII from Part C of Example 5
The reaction product of is a product of formula LXXXIX. ]

By following the procedure of Example 10, but using each of the various methyl esters of Formula LXXXIX described after Example 8, each of the various corresponding carboxylic acids was prepared.

20) Reference Example 10 2β- (tert-butyldimethylsilyloxymethyl) -5β
-Methyl-7-oxo-3α-tetrahydropyran-2
-Yl-oxy-bicyclo [3.3.0] octane (formula L
XII: n is the integer 1, R ₃₁ is t-butyl-dimethylsilyl, and R ₃₈ is tetrahydropyranyloxy) See Figure E. A. 40.6 g of a solution of 3α-benzoyloxy-5α-hydroxy-2β-hydroxy-methyl-1α-cyclopentaneacetic acid, ω-lactone in 250 ml of dimethylformamide at 0 ° C. under a nitrogen atmosphere was added to 28 g of Treated with 25 g of imidazole in tributyldimethylsilyl chloride. The resulting solution is then stirred at room temperature for 67 hours, added to 500 ml of water and extracted three times with 500 ml of diethyl ether three times, 500 ml of 10% potassium bisulfate aqueous solution, 500 ml of sodium hydrogen carbonate aqueous solution and 500 ml of brine. Washed with, dried over sodium sulfate,
Then concentrated under reduced pressure to give 59.9 g of 3α-benzoyloxy-5α-hydroxy-2β- (tert-butyldimethylsilyloxymethyl) -1α-cyclopentaneacetic acid,
The ω-lactone occurred as a white solid. NMR absorption (CDCl ₃₎ is 0.06,0.91,2.1～3.1
2, 3.74, 4.94 to 5.54, 7.24 to 7.67,
And 7.9-8.2δ. Infrared absorption is 1780, 1720, 1600, 1585, 149
0, 1270, 1255, 1180, 1115, 110
0, 1070, 1050, 830, 790, and 710
Observed at cm- ¹ . Rf of silica gel TLC is
It was 0.20 in ethyl acetate and hexane (1: 4).

B. 59.1 g of the reaction product of Part A and 5
A solution of 00 ml of anhydrous methanol was treated with 35 ml of a 25% solution of sodium methoxide and methanol under stirring at room temperature under a nitrogen atmosphere. The resulting reaction mixture was then stirred at room temperature for 90 minutes and quenched by the addition of 9.5 ml glacial acetic acid. Remove the methanol under reduced pressure,
The resulting residue was diluted with 500 ml of saturated aqueous sodium hydrogen carbonate solution. The resulting mixture is then extracted twice with 500 ml of ethyl acetate each time, 30 times in 200 ml of brine.
Wash with 0 ml of saturated aqueous sodium hydrogen carbonate solution, dry over sodium sulfate and concentrate under reduced pressure to give 58 g of an oily solid, crude 3α, 5α-dihydroxy-2.
β- (tert-butyldimethylsilyloxymethyl) -1α
-Cyclopentaneacetic acid, omega-lactone was produced. The crude product was then chromatographed in 800 g of silica gel, eluting with 20-75% ethyl acetate in hexanes to give the title product as a white crystalline solid. The melting range was 60.5 ° C to 62 ° C. NMR
Absorption (CDCl ₃₎ is, 0.06,0.90,1.7～3.
0, 3.67, 3.9-4.4, and 4.7-5.13δ. The Rf of silica gel TLC was 0.3 in 50% ethyl acetate in hexane. C. A solution of 37.3 g of the reaction product of Part B in 400 ml of methylene chloride was treated with 18 ml of dihydropyran and 0.14 g of pyridine hydrochloride with stirring at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 13 hours, treated with a further 3 ml of dihydropyran and 30 ml of pyridine hydrochloride and stirred for a further 4 hours, twice with 400 ml of saturated aqueous sodium hydrogen carbonate solution and 400 times.
Wash with ml of brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give 49 g of a pale yellow oil, crude 5α-hydroxy-3α-tetrahydropyran-2-.
Iloxy-2β- (tert-butyldimethylsilyloxymethyl) -1α-cyclopentaneacetic acid, ω-lactone was produced. Chromatography on 800 g of silica gel, eluting with 0-75% ethyl acetate in hexane, gave 37 g of pure product as a colorless oil.
NMR absorption (CDCl ₃ ) was 0.05, 0.90, 1.6
2, 2.0-3.0, 3.6, 3.2-4.4, 4.67, and 4.8-5.2δ. Infrared absorption
1780, 1255, 1175, 1160, 1116,
1080, 1035, 1020, 1005, 975, 8
Observed at 35 and 775 cm ^-1 . Silica gel T
The Rf of the LC was 0.25 in hexane and ethyl acetate (2: 1).

D. A solution of 28 ml of dimethylmethylphosphonate in 800 ml of dry tetrahydrofuran was added to -7
Treatment with 160 ml of 1.56 M n-butyllithium in hexane under a nitrogen atmosphere at 0 ° C and 30 at -70 ° C.
Stir for minutes. The resulting mixture, which was kept at -70 ° C, was then added to 41.7 g in 200 ml of tetrahydrofuran.
Was treated dropwise with the reaction product of Part C for 30 minutes.
The resulting solution was then stirred at -70 ° C for 1 hour, allowed to warm and stirred at room temperature for a further 2.5 hours, quenched by the addition of 14 ml glacial acetic acid, added to 1 L brine and 700 ml.
Extract three times with each diethyl ether, wash with 500 ml brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give 63 g of a yellow oil, crude 6β-.
(Tert-butyldimethylsilyloxymethyl) -3-dimethyl-phosphonomethyl-3-hydroxy-2-oxa-7
α-Tetrahydropyranyloxy-bicyclo [3.3.0]
Generated Octane. Chromatography on 800 g of silica gel, eluting with 50-75% ethyl acetate in hexanes, gave 44.2 g of pure title product as a colorless oil. NMR absorption (CDCl ₃ ) is 0.0
5, 0.89, 1.23 to 3.02, 2.2 to 4.37, 4.
Observed at 70 and 4.99δ. Infrared absorption is 3380, 1255, 2235, 1120, 105
It was observed at ⁰ , 1035, 835, and 775 cm ^-1 . Rf of silica gel TLC is 0.1 in ethyl acetate.
It was 25.

E. 29.2 in 700 ml methylene chloride
A suspension of G in chromium trioxide was rapidly treated with 50 ml of pyridine at room temperature under nitrogen atmosphere with stirring, treated with dry diatomaceous earth and stirred for 5 minutes, and then in 60 ml of methylene chloride. 23.8 g of Part D title product. The resulting suspension was then stirred at room temperature under a nitrogen atmosphere for 45 minutes and filtered through 300 g of silica gel eluting with 2 L of ethyl acetate (1: 2) in acetone. Concentrate under reduced pressure to 24
g of a tan oil, crude 3β- (tert-butyldimethylsilyloxymethyl) -2α- (2′-dimethylphosphonomethyl-2′-oxoethyl) -4α-tetrahydropyranyloxy-pentanone was produced. 20 in methylene chloride
High pressure liquid chromatography of 12 g of the crude product on silica gel eluting with% acetone gave 4.54 g of pure product as a colorless oil. NM
R absorption (CDCl ₃ ) is 0.05, 0.88, 2.8-
Observed at 4.5, 3.77 and 4.86δ. Infrared absorption is 1745, 1715, 1255, 113
It was observed at ⁰ , 1115, 1060, 1025, 835, 810 and 775 cm ^-1 . Rf of silica gel TLC is 0.27 in 20% acetone in methylene chloride.
And was 0.3 in ethyl acetate.

F. 0.52 g of the reaction product of Part E, 0.5
A degassed suspension of 15 g anhydrous potassium carbonate and 0.59 g 18-crown-6 ether in 20 ml toluene was stirred at 75 ° C. for 6 hours under a nitrogen atmosphere,
And it cooled to 0 degreeC after that. The resulting solution is then 20
ml of brine, a solution of 15 ml of water and 5 ml of brine, and 2
Wash successively with 0 ml brine, dry over anhydrous sodium sulfate and concentrate to a brown residue, crude 6β-tert-butyldimethylsilyloxymethyl-7α-tetrahydropyran-2-yl-oxybicyclo [. 3.3.0] Oct-1-en-2-one was produced, filtered through 7 g of silica gel, and hexane and ethyl acetate (70 m
Elution with 1: 1) gave 0.31 g of product oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml / min flow rate) on silica gel eluting with hexane and ethyl acetate (3: 1) gave 0.20.
g of pure product was produced as a colorless oil. The NMR absorption (CDCl ₃ ) of the trimethylsilyl derivative was 0.06, 0.0.
90, 120-3.20, 3.20-4.85, and 5.8.
Observed at 5-6.0 delta. Infrared absorption is 17
10, 1630, 1250, 1130, 1115, 10
75, 1030, 965, 870, 835, 810, 7
Observed at 75 ^cm-1 . Rf of silica gel TLC
Was 0.34 in hexane and ethyl acetate (2: 1).

G. A suspension of 0.35 g of anhydrous copper iodide in 12 ml of anhydrous diethyl ether was treated dropwise with 2.0 ml of 1.4 M methyllithium under an atmosphere of argon at -20 ° C. The resulting solution was then stirred at -20 ° C for 15 minutes and treated dropwise with a solution of 0.22 g of Part F reaction product in 12 ml of anhydrous diethyl ether at -20 ° C for 1.5 hours. The resulting suspension was then stirred at -20 ° C for 2 hours, added to 50 ml of 1M aqueous ammonium chloride solution, extracted with 150 ml of diethyl ether, washed with 50 ml of brine and dried over anhydrous sodium sulfate, It was then concentrated under reduced pressure to yield 0.23 g of the crude title product, a pale yellow oil. Ethyl acetate and hexane (1:
Chromatography on 30 g of silica gel, eluting with 4), gave 0.22 g of pure title product as a colorless oil. NMR absorption (CDCl ₃ ) is
0.05, 0.90, 1.16, 1.3-2.9, 3.3-
Observed at 4.4 and 4.63δ. Infrared absorption is 1745, 1255, 1135, 1110, 109
5, 1075, 1035, 1020, 835 and 775
Observed at cm- ¹ . Rf of silica gel TLC is
It was 0.32 in ethyl acetate and hexane (1: 4).

21) Reference Example 11 N-methyl- (1-fluoro-5-tetrahydropyrani
Roxypentyl) -phenyl sulfoximine (formula XCI
I: Z ₂ is - (CH _{2) 2} - and is, and R ₁₀ is tetrahydropyranyl) Referring to FIG H. Diisopropylamine (0.59g) 2
It was dissolved in 1 ml of tetrahydrofuran and the resulting mixture was cooled to -78 ° C with stirring under an atmosphere of argon. Triphenylmethane was then added for use as an indicator and a solution of n-butylium and hexane was added dropwise until the resulting mixture became pink. After stirring for a further 75 minutes, the resulting mixture was dissolved in 6 ml of dry tetrahydrofuran 1.
Treated with 50 g of N-methyl- (5-tetrahydropyranyloxypentyl) -phenyl sulfoximine. The resulting mixture was then stirred at -78 ° C for an additional 30 minutes.
After that, an excess amount of fluorine chlorate (FC1O ₃ ) is added to the solvent in an amount of 4 to 4
Bubble for 5 minutes, during which time argon was also bubbled through the mixture for safety reasons. The resulting mixture was then stirred at -78 ° C for a further 90 minutes and then the reaction was quenched by the addition of 5% aqueous sodium hydrogen carbonate solution. After equilibrating the reaction mixture to room temperature, the mixture was further diluted with 5% aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic extract was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 1.64g of a yellow oil. Ethyl acetate and hexane (1: 1)
Chromatography on a series of silica gel columns eluting with 0.18 g yielded 0.18 g of the title product of formula XCII as a mixture of diastereomers. The Rf of silica gel TLC in ethyl acetate and hexane (1: 1) is:
It was 0.54 (relatively low polarity isomer) and 0.45 (relatively high polarity isomer). For relatively low polarity isomer of, NMR absorption (CDCl ₃₎ is 1.2 to 2.
15, 3.65, 3.68, 3.1-4.1, 4.4-4.
It was 8, 5.5, and 7.4-8.1 (delta). The NMR absorption (CDCl ₃ ) for the higher polar isomer is
1.15 ~ 2.20, 3.63, 3.1 ~ 4.1, 4.45 ~
It was 4.65, 5.27 and 7.4-8.1δ.

According to the procedure of Reference Example 11, various formulas XC
Using each of the phenylsulfoxamines of I, various corresponding fluorinated phenylsulfoxamines of formula XCII were prepared.

[0212]22) Example 11 5-fluoro-2-decarboxy-2-hydroxymethyl
Le -CBA _2, 1,11,15- tris (tetrahydro
(Pyranyl ether) (Formula XCIV: R₁₆And R 1₇Is both
Both hydrogen and R_TenIs tetrahydropyranyl, Z₂Is-(C
H₂)₃-, N is an integer 1, R₁₈Is tetrahydropyranyloxy
Shi, Y₁Is trans-CH = CH-, M₆Is α-tetrahi
Doropyraniloxy: β-hydrogen, L₁Part of R₃And R_FourIs
Both hydrogen, and R₇Is n-butyl) See Figure H. Diisopropylamine (164 mg) and g
Liphenylmethane (1.5 mg) in 4 ml of dry tetrahydride
It was dissolved in lofran and the resulting solution was placed in a nitrogen atmosphere.
Cooled to -78 ° C under air. n-butyllithium and F
A solution of xane was added until a pale pink color was obtained.
The solution was then stirred for a further 80 minutes. Then 4 ml
0.488 g of Reference Example 1 in dry tetrahydrofuran of
The title product of 1 was added dropwise. Then 4 ml of Tet
608 mg of 7-oxo-3α-teto in lahydrofuran
Lahydropyran-2-yloxy-2β-[(3'S)
-3'-tetrahydropyran-2-yloxy-tolan
Su-1'-octenyl] bicyclo [3.3.0] octane
(Formula XCIII: R₁₆, R₁₇, N, R₁₈, Y₁, M₆, L₁Over
And R₇Is as defined for the title product
Yes) was added to the reaction mixture. After 4 minutes, the resulting mixture
The compound was stopped by adding saturated aqueous ammonium chloride solution.
And then keep the ethyl acetate at -78 ° C.
Added to the reaction mixture. Solids then separate the resulting mixture
I kept it warm until. Then add more ethyl acetate.
The reaction was extracted with brine. Next, the ethyl acetate layer is treated with sulfuric acid.
Dry over sodium and concentrate under reduced pressure.

Aluminum amalgam was then prepared by reacting 0.31 g of 20 mesh aluminum with 2.5 ml of an aqueous mercury chloride solution followed by washing with ethyl acetate and diethyl ether. The residue from the ethyl acetate layer (described in the previous section) was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to 0 ° C. The cooled solution is then treated with aluminum amalgam, 2 ml water and 1 ml.
Treated with glacial acetic acid. The resulting mixture was then stirred at 0 ° C. for 2 hours and 20 ° C. for 16 hours. The reaction product was then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer is then washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate,
Then it was concentrated under reduced pressure to yield 0.96 g of an oily residue. Chromatography on 100 g of silica gel and 500 m of 15% ethyl acetate in mixed hexanes.
Elution with 500 ml of 25% ethyl acetate in mixed hexane, 300 ml of 50% ethyl acetate in mixed hexane, and 800 ml of 50% acetone in methylene chloride to collect 20 ml fractions showed low polarities in fractions 22-26. Isomers (80 mg) and fractions 30-3
The higher polar isomer (74 mg) was produced in 6. These isomers represented the C-5 diastereomer of the formula XCIV product. For the isomer of low polarity, NMR absorption (CDCl ₃₎ is 0.65～2.65,3.15～4.1
5, 4.35 to 4.75, and 5.25 to 5.57 ?. For the high polarity isomer of, NMR absorption (CDCl ₃₎ is 0.6～2.65,3.10～4.1
5, 4.40-4.7 and 5.2-5.7δ. The Rf of silica gel TLC in ethyl acetate and mixed hexanes (3: 7) is 0 for the less polar isomer.
66, and 0.5 for the more polar isomer
It was 7.

According to the procedure of Example 11, the various formulas XC
With each of the ketones of III, each of the various intermediates of formula XCIV in which Z ₂ is — (CH ₂ ) ₃ — was obtained.

Further, according to the procedure of Example 11, but in Reference Example 1
Using various fluorinated phenyl sulfoximine listed after 1, ketone of the various formula XCIII, Z ₂ is - (CH _{2) 3} - except in a different formula XCIV
Of each of the products were produced.

23) Example 12 5-Fluoro-2-decarboxy-2-hydroxymethyi
Le-CBA ₂ (highly polar isomer) (formula XCV: R ₁₆ ,
R ₁₇ , Z ₂ , n, R ₈ , M ₁ , L ₁ and R ₇ are as defined in Example 8) See Figure H. 2 ml of the title product of Example 11 (74 mg)
Of tetrahydrofuran, water and glacial acetic acid (2: 2: 1)
It was dissolved in the mixture and the resulting mixture was stirred under a nitrogen atmosphere. The reaction mixture was kept at room temperature for 17 hours, then at 40 ° C. for 7 hours and finally at 23 ° C. for another 24 hours. The resulting mixture is then diluted with ethyl acetate, 5
% Aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give:
This gave 52 mg of crude title product. Chromatography on silica gel eluting with acetone and methylene chloride (60:40) yielded 19 mg of pure title product. NMR absorption (CDCl ₃₎ is 0.6 to 2.6
0, 2.60-3.30, 3.30-4.15, 5.1-5.
Observed at 9δ. ¹³ C-NMR absorption (CDCl
₃ ) is 135.8, 133.0, 117.5 (d, J = 1)
8 Hz), 77.4, 7.3, 62.6, 57.6, 46.
4, 41.1, 38.0, 37.2, 36.2 ((d, J =
5Hz), 31.9, 31.8, 31.2, 29.5 (d,
J = 29 Hz), 25.2, 22.5, 14.0 δ. Rf of silica gel TLC was 0.280 in acetone and methylene chloride (1: 1).

24) Example 13 5-Fluoro-2-decarboxy-2-hydroxymethyi
Le-CBA ₂ (Lower Polar Isomer) Following the procedure of Example 12, 85 mg of the less polar title product of Example 11 was converted to 25 mg of the pure title product. NMR absorption (CDCl ₃₎ is 0.5～2.5,3.1
˜4.75, and 5.05-5.8 δ. ¹³ C-NMR absorption (CDCl ₃ ) is 137.0, 1
32.6, 77.0, 73.6, 62.3, 57.4, 45.
5, 41.6, 36.9, 36.5, 34.4 (d, J =
3.1 Hz), 32.5 (d, J = 5.4 Hz), 31.
8, 31.7, 29.2 (d, J = 28.9 Hz), 25.
It was observed at 4, 22.6, 22.4 and 14.0 δ. The Rf of silica gel TLC was 0.33 in acetone and methylene chloride.

By following the procedures of Examples 12 and 13, but using the various diastereomeric products described after Example 11, each of the various diastereomers corresponding to Formula XCV was prepared.

25) Example 14 5-Fluoro-CBA ₂ (highly polar isomer) (Formula LX
XVI: Z ₂ , n, R ₈ , Y ₁ , M ₁ , L ₁ and R ₇ are those of Example 1
(As defined in 2.) See Figure H. A platinum oxide catalyst was prepared by suspending 46 mg of 85% platinum oxide in 9 ml of water and hydrogenating the resulting mixture at room temperature and pressure for 34 minutes.
To this suspension, 58 dissolved in 2 ml of acetone
mg sodium bicarbonate and 18 mg title product of Example 12 were added. Then warm the resulting mixture to 60 ° C.,
Then oxygen was bubbled through it for 80 minutes. Then filter the reaction mixture through diatomaceous earth and filter.
Ki was washed in water. The filtrate was then acidified to pH 4 with 5% aqueous sodium hydrogensulfate solution and extracted with ethyl acetate. The organic extract is then dried over magnesium sulfate,
Then concentrated under reduced pressure to yield 21 mg of pure title product. NMR absorption (CDCl ₃₎ is 0.6 to 2.
8, 3.3-4.2, and 4.65-5.8 [delta]. ¹³ C-NMR absorption (CDCl ₃ ) 176.
9, 135.5, 133.2, 118.5 (d, J = 17.
5Hz), 77.7, 73.5, 57.3, 46.5, 4
1.0, 38.2, 37.0, 36.2 (d, J = 4.8H
z), 32.3, 31.7, 31.1 (d, J = 13.5H)
z), 28.5 (d, J = 28.3 Hz), 25.2, 2
Observed at 2.6, 21.0, and 14.0. The Rf of silica gel TLC was 0.39 in the A-IX solvent system.

26) Example 15 5-Fluoro-CBA ₂ (Lower polar isomer) The procedure of Example 14 provided 24 mg of the title product of Example 13 to give 23 mg of the pure title product. NMR absorption (CDCl ₃₎ is 0.6～2.9,3.3～4.2,5.0
Observed at ˜6.0 δ. ¹³ C-NMR absorption (C
DCl ₃ ) is 176.8, 135.4, 132.9, 11
8.3 (d, J = 18.2Hz), 77.6, 73.4, 5
7.2, 46.3, 41.2, 37.8, 36.8, 34.6
(D, J = 2.7 Hz), 32.8, 32.4, 31.7,
28.7 (d, J = 28.4 Hz), 25.2, 22.6,
Observed at 21.1 and 14.0 δ. TLC R
f was 0.50 in the A-IX solvent system.

The reaction products of Examples 14 to 15 are (5
Obtained as a diastereomeric mixture of geometric isomers of E) and (5Z). These geometric isomers are referred to here as T
It is characterized as "low polarity" and "high polarity" based on LC mobility. The isomers of these 5-fluoro-CBA ₂ compounds correspond to the (5E) and (5Z) geometric isomers of CBA ₂ itself. On the basis of the relative biological activity, the highly polar 5-fluoro-CBA ₂ isomers gave a more effective pharmacological effect, and on this basis, based on pharmaceutical considerations alone, the (5Z) structure Can be selected. However, ¹³ C-NMR data suggests that the highly polar isomer corresponds to the (5E) structure of the 5-fluoro-CBA ₂ compound.

Following the procedures of Examples 14-15, each of the various 5-fluoro-CBA ₂ diastereomers of Formula XCVI were prepared from the starting materials described after Example 13.

Further according to methods well known in the art, various 5-fluoro-CBs described in Examples 13-14 were used.
Each of the A ₂ compounds was converted to the corresponding 5-fluoro-CBA ₂ analogs of formula XCVII.

27) Example 16 (5Z) -9β-Methyl-CBA ₂ adamantylamine
Diethyl salt 6 ml - title product of Example 9 in ether,
(5Z) -9β-methyl-CBA ₂ (54 mg) was added to 23 m
with g adamantylamine. Precipitation occurred after 10 minutes, which was then stirred for 12 hours, decanted and concentrated under reduced pressure to yield 68 mg of solid title product pure. The melting point was 110-114 ° C.

28) Example 17 (5Z) -9β-methyl-CBA ₂ , calcium salt hydration
Title product of goods Example 9, 9β- methyl - (5Z) -CB
A ₂ (0.95 g), calcium oxide (0.064 g),
Freshly boiled water (9.2 ml) and distilled tetrahydrofuran (6 ml) were combined by heating to 50 ° C. with stirring under a nitrogen atmosphere for 20 minutes.
The resulting mixture was then filtered, washed with tetrahydrofuran and concentrated under reduced pressure to yield a residue. Then the residue is dissolved in tetrahydrofuran (10 ml),
It was then concentrated eight times to produce a cream colored foam. The foam was then dissolved in 6 ml of tetrahydrofuran and this was added dropwise to anhydrous diethyl ether (95 ml). The resulting suspension was then stirred under a nitrogen atmosphere at room temperature for 15 minutes and filtered. The filter cake was then washed with anhydrous diethyl ether.
Wash with tel and dry under reduced pressure at room temperature for 20 hours to yield 0.686 g of the title product. The melting point range was 101-108 ° C. The melting point range after equilibration in air was 80 to 117 ° C. Infrared absorption is 333
0, 1670, 1555, 1455, 1345, 131
It was observed at ⁰ , 1270, 1075, 1020, 970 cm ^-1 .

29) Reference Example 12 8α-hydroxy-7β- (3α-hydroxy-tran
Su-1-octenyl) -tricyclo [4.3.1] nonane
-4-one, 8.3'-bis (tetrahydropyranylene-
Tell) (Formula XXV: R ₁₈ , Y ₁ , M ₆ , L ₁ , R ₂₇ and n
Is as defined in Example 1 and R ₁₆ and R ₁₇
See in which) Figure A - -CH ₂ together. A. 4.0 g of the title product of formula XXIV of Example 1 and benzophenone (2 g) in 1 L of methanol were photolyzed (3500 A °) for 3 hours while bubbling argon through the solution. . The methanol was then removed by concentration under reduced pressure and the residue was chromatographed on 600 g silica gel eluting with a mixture of ethyl acetate (3: 1) in hexane to 100% ethyl acetate. Mixture XXVI, 1β-hydroxymethyl-7α
-Hydroxy-6β- (6'α-hydroxy-trans-1'-octenyl) bicyclo [3.3.0] octane-
3-one, 7,3'-bis (tetrahydropyranyl-
Tell) was obtained as a white solid (3.45 g. Crystallization from ethyl acetate in hexane gave a white solid with a melting range of 65-70 ° C. NMR absorption (C
DCl ₃ ) is 0.89, 1.17 to 2.90, 2.92 to
Observed at 4.40, 4.69, and 5.24-5.77δ. Infrared absorption is 3420, 1730, 120
0, 1125, 1110, 1070, 1040, 102
Observed at 0 and 970 cm ^-1 . Silica gel TL
The Rf of C was 0.29 in hexane and ethyl acetate (1: 4).

B. 0.6 g of the reaction product of Part A and
A solution of 49 g of p-toluenesulfonyl chloride in 30 ml of pyridine was cooled to 0 ° C. under argon for 70 hours, added to 100 ml of ice, diluted with 300 ml of water and extracted with diethyl ether (800 ml). . Next
The telluric extract is washed with brine, dried over magnesium sulphate, concentrated under reduced pressure and 50% to 50% in ethyl acetate.
Chromatography eluting with 80% hexane gave 0.49 g of the compound of formula XXVII, 3-oxo-.
7α-Tetrahydropyran-2-yloxy-6β-
[(3'S) -3'-Tetrahydropyran-2-yloxy-trans-1'-octenyl] -1β- (p-toluenesulfonyl) -oxymethyl-bicyclo [3.3.
0] octane was given as a colorless oil. NMR absorption (C
DCl ₃₎ is, 0.88,1.06～2.9,2.45,3.
17-4.35, 4.52-4.83, 5.2-5.8, 7.
Observed at 37 and 7.81 δ. Infrared absorption is 1740, 1600, 1360, 1200, 119
0, 1175, 1130, 1110, 1075, 103
It was observed at 5, 1020, 970, and 820 cm ^-1 . The Rf of silica gel TLC was 0.45 or 0.26 in ethyl acetate and hexane (1: 1 or 1: 2).

C. A degassed solution of 0.49 g of the reaction product of Part B and 1 ml of tert-butanol in 50 ml of dry tetrahydrofuran was stirred at 0 ° C. under an atmosphere of argon at 1.7 ° C. Tributoxide 0.8
treated with ml. After 5 minutes the reaction was allowed to warm and the resulting brown solution was stirred at room temperature for 3 hours. Then 90 ml of brine were added and the mixture was extracted with 270 ml of ethyl acetate. The ethyl acetate extract is then washed with 100 ml of saturated aqueous sodium hydrogen carbonate solution, 100 ml of brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 0.37 g of a brown oil, which is Chromatography on 40 g of silica gel eluting with hexane and ethyl acetate (2: 1) yielded 0.32 g of pure title product of formula XXV as a colorless oil.

D. Alternatively, a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 g of trimethyloxosulfonium iodide were treated dropwise with 6 ml of dimethylsulfoxide under a nitrogen atmosphere. The resulting gray slurry was then stirred at room temperature for 20 minutes, treated with 2.03 g of the title product of Example 1 in 4 ml of dry dimethylsulfoxide and stirred at room temperature for 2 hours. After that, stirring is continued at 50 ° C. for 1 hour to cool the reaction mixture,
Then, it was diluted with 200 ml of water and then extracted with 100 ml of diethyl ether three times. The combined ethereal extracts were washed with 200 ml water, 100 ml brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a brown oil, and ethyl acetate and hexane (1 Chromatography on 250 g of silica gel, eluting with: 2) gave 453 mg of pure title product.

E. For the title product prepared according to Part C or Part D above, NMR absorption (CDCl ₃ )
Were observed at 0.25 to 2.75, 3.15 to 4.39, 4.68 and 5.2 to 5.8δ. Infrared absorption is 1
725, 1665, 1135, 1080, 1040, 1
Observed at 020,980 cm ^-1 .

The mass spectrum shows a molecular ion at 446, and the Rf of silica gel TLC was 0.30 in ethyl acetate and hexane.

30) Example 18 (5Z) and (5E) -6aβ, 9β-methanol-C
BA ₂ (wherein X: X ₁ is -COOH, Z ₁ is - (CH _2)
3- , R ₁₅ are hydrogen, R ₁₆ and R ₁₇ taken together are methano, n is 1, R ₈ is hydroxy, Y ₁ is trans-CH =
CH-, M ₁ is α-OH: β-H, L ₁ is α-H: β-
(H, R ₇ are n-butyl, and the C-5 and C-6 positions are unsaturated) See Figure G. A. 425 mg of 57% sodium hydride suspension in mineral oil
And 30 ml of dimethylsulfoxide were heated to 65 ° C. under nitrogen atmosphere for 1 hour, cooled to 17 ° C. and then treated with 2.39 g of 4-carboxybutyltriphenylphosphonium bromide for 15 minutes. The resulting red solution was then stirred at 17-20 ° C. for 15 minutes, treated with 716 ml of the title product of Reference Example 12, 6 ml of a solution of dry dimethylsulfoxide, stirred at 40 ° C. for 43 hours and cooled to 0 ° C. Then treat with 3.5 ml of water and stir at 0 ° C. for 30 minutes,
It was added to 75 ml water and brine (2: 1), acidified with 1N aqueous hydrochloric acid solution and extracted with 225 ml diethyl ether. The ether extract was then washed with 375 ml water and 75 ml brine, dried over magnesium sulphate, concentrated under reduced pressure and eluted with 150 g of acid, eluting with 10-25% ethyl acetate in hexane. Chromatography on washed silica gel, 290 mg of (5Z) -6aβ, 9
β- methanol - Le -CBA _2, 11,15- bis (tetrahydropyranyl Rue - ether), of 70 mg (5E) -6A
β, 9β- methanol - Le -CBA _2, 11,15- bis (tetrahydropyranyl Rue - ether) and 400 mg (5
A mixture of E) and (5Z) formula LXXXIII isomers was produced. The isomer mixture was rechromatographed on 150 g of acid-washed silica gel to give a further 50 mg of (5
This gave the E) isomer and 180 mg of the (5Z) isomer.

For the (5Z) isomer, the NMR absorption (CDCl ₃ ) is 0.5-2.85, 3.22-4.4,
Observed at 4.70, 4.9-5.75, and 10.1 delta. Infrared absorption is 3600 to 3000 (wide band), 1740, 1710, 1240, 1210, 11
35, 1080, 1035, 1020, 980, and 8
Observed at 70 cm ^-1 . Rf of silica gel TLC
Is hexane, ethyl acetate and acetic acid (65: 34: 1)
It was 0.27. For the 5 (E) isomer, N
MR absorption is 0.40 to 2.70, 3.2 to 4.4, 4.7.
Observed at 0, 5.0-5.8 and 8.82δ. Infrared absorption is 3600-3000, 1740, 1710, 1
460, 1445, 1200, 1135, 1075, 1
It was observed at 035, 1020, and 980 cm ^-1 . Silica gel TLC Rf was 0.32 in hexane, ethyl acetate and acetic acid (65: 34: 1).

B. A solution of 446 mg of Part A (5Z) reaction product in 44 ml of acetic acid, water, and tetrahydrofuran (6: 3: 2) was heated to 45 ° C. under nitrogen for 3 hours and cooled. , 200 ml brine, extracted with 160 ml ethyl acetate (2: 3) in hexane, washed with 500 ml brine, extracted with 120 ml ethyl acetate and hexane (3: 2), dried over sodium sulfate And concentrated under reduced pressure to yield 0.38 g of a yellow oil and chromatographed on 60 g of acid washed silica gel eluting with 70% ethyl acetate in hexane to give 170 mg of pure (5Z ) Title product as a colorless oil. NMR absorption is 0.5-2.90, 0.9.
89, 4.05, 4.85-5.8 and 6.13δ. Infrared absorption is 3360, 2260, 17
10, 1245, 1240, 1075, 1025 and 9
Observed at 70 cm ^-1 . The mass spectrum for the tris-trimethyl-silyl derivative is 578.365.
3 shows a high resolution peak. The Rf of silica gel TLC was 0.30 in the A-IX solvent system (ethyl acetate, acetic acid, cyclohexane, and organic phase of a 9: 2: 5: 10 equilibrated mixture of water).

C. 90 mg according to the method of Part B above
The (5E) reaction product of Part A of
E) Converted to 46 mg of the title product. NMR absorption is
4.40 to 2.8, 0.89, 4.06 and 5.0 to 5.85
Observed at δ. Infrared absorption is 3340, 26
Observed at 30, 1710, 1070, 970 cm ^-1 . The mass spectrum showed a high resolution peak at 578.3664. Rf of silica gel TLC is A-
It was 0.32 in the IX solvent system.

Following the procedures of Examples 16-17 and Reference Example 12, each of the various Formula X products in which R ₁₆ and R ₁₇ are methano were prepared from the corresponding Formula LXXXI reactants of Figure G. It was

The above examples thus provide a method of making each of the various Formula X CBA analogs of the present invention.

The following compounds were prepared according to the method described above.
: (5E) -9β-methyl-CBA₂Compound, (5Z)-
9β-methyl-CBA₂Compound, (5E) -5-fluor
Ro-9β-methyl-CBA₂Compound, (5Z) -5-fu
Luoro-9β-methyl-CBA₂Compound, (5E) -5
-Fluoro-CBA₂Compound, (5Z) -5-fluoro
-CBA₂Compound, (5E) -9β-methyl-2,5-
Inter-o-phenylene-3,4-dinor-CBA₂Conversion
Compound, (5Z) -9β-methyl-2,5-inter-o-
Phenylene-3,4-dinor-CBA₂Compound, (5
E) -9β-Methyl-1,5-inter-o-phenylene
-2,3,4-trinor-CBA₂Compound, (5E)-
9β-methyl-1,5-inter-o-phenylene-3,
4,5-trinor-CBA₂Compound, (5E) -2,5
-Inter-o-phenylene-3,4-dinor-CBA₂
Compound, (5Z) -2,5-inter-o-phenylene-
3,4-dinor-CBA₂Compound, (5E) -1,5-
Inter-m-phenylene-2,3,4-trinor-CB
A 2 compounds, (5Z) -1,5-inter-m-phenyle
-2,3,4-trinor-CBA 2 compounds, compounds
For example, with a side chain substituent of 17,20-dimethyl-
It is the acid free form or the methyl ester form. Structural formula

[Chemical 2]

[Chemical 3]

[Chemical 4]

[Chemical 5]

[Chemical 6]

[Chemical 7]

[Chemical 8]

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12]

[Chemical 13]

[Chemical 14]

[Chemical 15]

[Chemical 16]

[Chemical 17]

[Chemical 18]

[Chemical 19]

[Chemical 20]

[Chemical 21]

[Chemical formula 22]

[Chemical formula 23]

[Chemical formula 24]

[Chemical 25]

[Chemical formula 26]

[Chemical 27]

[Chemical 28]

[Chemical 29]

[Chemical 30]

[Chemical 31]

[Chemical 32]

[Chemical 33]

[Chemical 34]

[Chemical 35]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 309/12 7252-4C // C07C 69/708 B 9279-4H (31) Priority claim number 142 , 953 (32) Priority date April 23, 1980 (33) Priority claiming country United States (US) (72) Inventor Norman Alan Nelson United States Gailsberg, Michigan, Sixtyth Street South 1643

Claims (2)

[Claims] 1. A carbacyclin analog of formula X: [Wherein n is 1, L ₁ is α-H: β-H, M ₁ is α-OH: β-H or α-H: β-OH, and R ₇ is -CmH ₂ m-CH ₃ (m is an integer from 1 to 5), R ₈ is hydroxy, R ₁₅ is hydrogen or fluoro, R ₁₆ is hydrogen, or R ₁₆ together with R ₁₇ is-. CH ₂
Represents —, R ₁₇ is as defined above or is (1) hydrogen or (2) (C ₁ -C ₄ ) alkyl and X ₁ is (1) —COOR ₁ (wherein R ₁ is (a) hydrogen, (b) (C ₁ -C ₁₂ ) alkyl, or (c) a pharmaceutically acceptable cation) or (2) —CH ₂ OH, and Y ₁ is , Trans-CH = CH- or cis-CH = CH
And Z ₁ is (1) —CH ₂ — (CH ₂ ) _f —CH ₂ — (where f is
Is 0, 1, 2 or 3), or (3)-(Ph)
- (CH _{2) g} - (wherein, Ph) is 1,2-, 1,3
-Or 1,4-phenylene, or g is 0, 1,
2 or 3), and (1) all of R ₁₅ , R ₁₆ and R ₁₇ can be hydrogen only when Z ₁ is-(Ph)-(CH ₂ ) g-. And (2) only when R ₁₅ is hydrogen, Z ₁ is-(P
_{h) - (CH 2) g} - and with the proviso that it becomes. ] Or a pharmacologically acceptable salt thereof, Wherein (5E)-5-fluoro -CBA _2, (5Z) -5- fluoro -CBA _2, (5E) -5- fluoro-CBA ₂ methyl ester, (5Z) -5- fluoro-CBA ₂ Methyl ester, (5E) -3,4-dinor-2,5-inter-o-phenylene-CBA ₂ (5Z) -3,4-dinor-2,5-inter-o-phenylene-CBA ₂ (5E) -2,3,4-trinor-1,5-inter-m
- phenylene -CBA _2, (5Z) -2,3,4- trinor -1,5 inter -m
- phenylene -CBA _2, (5E) -9β- methyl -CBA _2, (5Z) -9β- methyl -CBA _2, (5E) -9β- methyl-CBA ₂ methyl ester, (5Z) -9β- methyl-CBA ₂ methyl ester, (5E) -6aβ, 9β-methano-CBA ₂ , (5Z) -6aβ, 9β-methano-CBA ₂ , (5E) -6aβ, 9β-methano-CBA ₂ methyl ester, or (5Z)- A carbacyclin analog of formula X according to claim 1 selected from the group consisting of 6aβ, 9β-methano-CBA ₂ methyl ester.