WO2001062724A1 - Prostaglandin e derivatives - Google Patents

Abstract

Novel prostaglandin E derivatives of the general formula (I), pharmaceutically acceptable salts of the same, or hydrates thereof, or pharmaceutical compositions containing such compounds exhibit an inhibitory effect on the proliferation of vascular smooth muscle and are useful as preventive or therapeutic drugs for post-PTCA restenosis and other diseases wherein Y is ethylene or the like; Z is S(O)p or the like; R1 is C¿3-10? cycloalkyl or the like; R?2¿ is hydrogen or the like; m is an integer of 1 to 4; n is an integer of 0 to 3; p is an integer of 0 to 2; and q is an integer of 1 to 4.

Description

 Specification

 Prostaglandin E derivatives

 The present invention relates to a novel prostadarandin E derivative, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition containing the same and having an excellent smooth muscle growth inhibitory action and the like. Background art

 Prostaglandins (hereinafter referred to as “PG”) are known to exert various important physiological actions in trace amounts. To date, a large number of derivatives, including natural PG, have been synthesized with the intention of applying PG to medicines, and their biological activities have been studied and reported in numerous documents. Such documents include, for example, Japanese Patent Application Laid-Open No. 52-104446 and US Patent Nos. 4,131,738.

 Physiological actions of PG and its derivatives include vasodilatory action, inflammation action, platelet aggregation inhibitory action, uterine muscle contraction action, intestinal contraction action, intraocular pressure lowering action, etc., cardiomyocardial infarction, angina, It is useful for treatment or prevention of arteriosclerosis, hypertension, induction of labor, etc.

 On the other hand, percutaneous coronary angioplasty (hereinafter referred to as “PTCA”) is rapidly progressing in recent years as a treatment for ischemic heart disease because of its low invasiveness to patients and excellent initial treatment effect. This is the technique I have been using.

However, PTCA has the problem that within a few months after surgery, coronary artery restenosis appears at a frequency of 30 to 40%. Vascular smooth muscle cells are thought to be deeply involved in the occurrence of such restenosis (see Ross, R. (1993) Nature 362, 801-809). The migration of vascular smooth muscle cells from the intima to the media and proliferation in the media are deeply involved in the mechanism of restenosis, and compounds that suppress this are effective drugs for preventing restenosis. Although highly promising, no clinically useful drug has yet been found. Disclosure of the invention

 An object of the present invention is to provide a compound having a vascular smooth muscle growth inhibitory activity, which is highly expected as an agent for preventing or treating diseases such as restenosis after PTCA, and a pharmaceutical composition containing such a compound. I do.

 The present inventors have conducted intensive studies and found that the novel PGE derivative represented by the following formula (I) has a vascular smooth muscle growth inhibitory effect and is useful as a pharmaceutical composition. The present invention has been completed.

 That is, the present invention provides a compound represented by the formula (I):

(Wherein, m represents an integer of 1 to 4, n represents an integer of 0 to 3, p represents an integer of 0 to 2, q represents an integer of 1 to 4, Y represents an ethylene group, A vinylene group or an ethynylene group, Z represents S (O) _p , 0, an ethylene group, a vinylene group or an ethynylene group, R ¹ represents a cycloalkyl group having 3 to 10 carbon atoms, and a hydrogen atom having 1 carbon atom. Alkyl group having 3 to 10 carbon atoms, alkyl group having 4 to 13 carbon atoms, alkyl group having 1 to 10 carbon atoms, alkyl group having 1 to 10 carbon atoms, substituted with alkyl group A alkynyl group having 2 to 10 carbon atoms or a bridged cyclic hydrocarbon group; R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl having 3 to 10 carbon atoms; Or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter referred to as “PGE derivative or the like”).

Further, the present invention provides a method for producing a PGE derivative represented by the formula (I) in a pharmaceutically acceptable carrier. Provided is a pharmaceutical composition containing a body or the like. In particular, the present invention provides a vascular smooth muscle growth inhibitor containing a PGE derivative represented by the formula (I) or the like as an active ingredient, an agent for preventing a disease or condition caused by vascular smooth muscle proliferation, and a vascular smooth muscle proliferation. A therapeutic agent for a disease or condition caused by

 Further, the present invention provides a method for preventing a disease or medical condition caused by vascular smooth muscle proliferation, which comprises administering the above pharmaceutical composition to human, and a vascular smoothing method comprising administering the above pharmaceutical composition to a patient. Provided is a method for treating a disease or medical condition caused by muscle growth. In addition, the present invention 0, the use of the above-mentioned PGE derivative or the like for the prevention or treatment of a disease or medical condition caused by vascular smooth muscle proliferation, and the use of a vascular smooth muscle proliferating agent or a disease or medical condition caused by vascular smooth muscle proliferation. It is intended to provide use of the above PG II derivative or the like for producing a prophylactic or therapeutic agent. BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, in formula (I), the configuration of the substituent bonded to the vinylene group may be any of Ε and Ζ. The alkyl group having 1 to 10 carbon atoms may be linear or branched, and examples thereof include a methyl group, an ethyl group, an η-propyl group, an isopropyl group, an η-butyl group, an isobutyl group, and a tert-butyl group. Petit / le, n-pentyl, isopentyl, 2-ethizolepropyl, n-hexyl, isohexyl, 1-ethylbutyl, n-heptyl, isoheptyl, n-octyl , N-Noel group, n-decyl group, 2,4-dimethynolepentinole group, 2-ethylpentyl group, 2-ethylhexyl group, 2-propylpentyl group, 2-propylhexyl group, 2, 6-dimethylheptyl group and the like.

The alkenyl group having 2 to 10 carbon atoms may be linear or branched, for example, a butyl group, an aryl group, a butenyl group, a 3-pentenyl group, a 4-hexenyl group, and a 5-heptenyl group A 4-methyl-13-pentenyl group, a 2,4-dimethyl-3-pentenyl group, a 6-methyl-5-heptenyl group, and a 2,6-dimethyl-5-heptenyl group. The alkynyl group having 2 to 10 carbon atoms may be either straight-chain or branched, and includes, for example, an ethur group, a 2-propyl group, a 3-butyl group, a 3-pentynyl group, and a 3-pentynyl group. —Hexinole group, 4 1-hexinole group, 1-methinolepenta-1 3 —Ininole group, 2-methylinolepenter 3-ininole group, 1-methinolehexa 3-ininole group, 2-methylhexa 3-inyl group and the like.

 Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclobutynol group, a cyclopentynol group, a cyclohexynole group, a cycloheptynol group, a cyclooctyl group, a cyclonol group, and a cyclodecyl group. No. Examples of the cycloalkyl group having 3 to 10 carbon atoms in which a hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms include, for example, methylcyclopropyl group, methylcyclohexyl group, ethylcyclohexyl group, and propylcyclononyl. And the like. Examples of the cycloalkylalkyl group having 4 to 13 carbon atoms include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentynoletyl group, a cyclohexynolemethynol group, a cyclohexynoletinol group, and a cycloalkyl group. Examples include a heptinolemethyl group and a cyclononylbutyl group.

 Examples of the crosslinked cyclic hydrocarbon group include a bornyl group, a norbornyl group, an adamantyl group, a pininole group, a thiol group, a caryl group, a camphanyl group, and the like.

Pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with ammonium chloride; methylamine, dimethizoleamine; Salts with amines such as pliers / reamine, benzinoleamine, piperidine, monoethanolamine, diethanolamine, monomethinole monoethanolamine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane, etc. It is the _c hydrate which may be mentioned, as long as it is pharmaceutically acceptable, and there is no particular limitation on the number of water binding to PGE derivatives of 1 molecule.

In the present invention, m in the formula (I) is preferably an integer of 1 to 3. n is preferably an integer of 0 to 2. p may be any integer from 0 to 2, and is preferably 0. q is preferably 2 or 3. Y may be any of an ethylene group, an (E) vinylene group, a (Z) vinylene group, and an ethynylene group, and is preferably an (E) vinylene group, a (Z) vinylene group, or an ethylene group. Z is preferably an ethylene group, 〇, S, S (O). R ¹ is a hydrogen atom substituted with a substituent Unsubstituted cycloalkyl group having 4 to 7 carbon atoms, linear or branched alkyl group having 4 to 8 carbon atoms, branched alkenyl group having 6 to 1 ◦ carbon atoms, 6 to 1 carbon atoms A branched alkynyl group of 0 is preferred. The configuration may be either R or S. Alternatively, it may be racemic. Of these, cyclopentyl, cyclohexynole, n-pentyl, (S) -2_methylhexyl, (R) -2-methylhexyl, (R) -2,6-dimethyl-5 Heptenyl, (S) -2,6-dimethyl-5-heptenyl and (R) _1-methyl-3-hexyl are more preferred. R ² is preferably a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, and an isobutyl group. In formula (I), the bond between the carbon atom at position 7 and the carbon atom at position 8 (denoted as position 8 in Tables 1 and 2), the bond between the carbon atom at position 11 and the sulfur atom (see Tables 1 and 2) The configuration of the bond between the carbon atom at position 15 and the hydroxyl group (described as position 15 in Tables 1 and 2) and j3 may be either j or j3. The PGE derivative and the like of the present invention are those wherein m, n, p and q in the formula (I) are any of the above-mentioned preferred integers, and Y, Z and RR ² are any of the above-mentioned preferred groups. Preferably, RR ² is any of the more preferred groups described above.

Among the prostaglandin E derivatives of the present invention, particularly preferred ones are shown in Tables 1 and 2 as Compounds 1 to 48.

Compound Y z m n P q R R

1 CHaCH ₂ CH2CH2 100 ₂ Cyclohexyl t-Bu aa at

2 CHaCH _S CH2CH2 200 2 Cyclohex i-Pr aaa

3 CH ₂ CH ₂ 0 2 1 0 2 n-Hentium hydrogen aa

4 CHaCH ₂ s 2 102 (S) 2-Methylhexyl Hydrogen a β a

5 CHJCHZ S (0) 2 1 1 2 (S) 2 Tylhexyl Hydrogen a a β

6 CHiCHa 0 3 2 0 2

7 (E) CH = CH CH ₂ CH ₂ 2 0 2 Sita hexyl if aa

8 (E) CH = CH CH 2 CH 2 2 0 0 2 hexyl consequent a. Beta

 ゝ

 9 (E) CH = CH CHaCHi 2 0 0 2

1H (E) CH = CH 0 2 1 0 2 (R) — 1H

11 (E) CH = CH 0 2 1 0 2 (R) — 2— S aaa 2 (E) CH = CH S 2 102 (S) — 2-Methylhexyl Water β Hi 3 (E) CH = CH S 2 I 0 2 (S) -2, 6-Dmhep Hydrogen a β a 4 (E) CH = CH 0 3 2 0 2 Methyl aa HI 5 (Z) CH = CH 0 2 1 0 2 Hydrogen aaa & C≡C CHzCf 1 0 2 Cyclohexylethyl a 7 C≡C CHaCHi 1 0 0 2 Cyclohexyl hydrogen aa HI 8 C≡C 1 0 0 2 Cyclohexyl ff aaa 9 C≡C CHzCHs 2 0 0 2 Cyclohexyl methyl aa 0 C≡C CH2CH2 2 0 0 2 Cyclohexyl hydrogen aa 1 Cmi C CH2CH2 20 22 Hydrogen aa 2 C≡C CH2CH2 2 0 3 (10-2 tylhexyl methyl aa 3 C 3C CHaCHs 2 0 3 (R) — 2 —Methylhexyl hydrogen aaa 4 C≡C CH2CH2 202 (R) — 2 Methylhexyl a H a 5 c C CH2CH2 200 (R) — 2-Methylhexyl a β a 6 c ≡c CHiCHi 2 0 2 (R) —2 methylhexy hydrogen a oc 7 c≡c CH ₂ CH ₂ 2 0 2 (R)-2, 6-Dmhep hydrogen aa Table 2

Y zmn P q R ¹ R ² 8 {t 1 15 {v:

28 C≡C 0 2 1 0 2 Cyclohexyl methyl a a

 29 C≡C 0 1 1 0 2 (R) 1 2—! Tylhexyl methyl a a a

30 c≡c 0 2 1 0 2 (R) -1-Methylhexyl methyl a a a

31 c≡c 0 2 1 0 2 (R) — 2— ;! tylhexyl methyl a a

32 c≡c 0 2 1 0 3 (R) — 2-methylhexyl methyl a a a

33 c≡c 0 2 1 0 3 (R) -2-methylhexyl hydrogen a a

 34 c≡c 0 2 1 0 3 (S) — 2-Methylhexyl methyl a a a

35 c≡c 0 2 1 0 3 (S) — 2—; 1-tylhexyl water a a a

36 c≡c 0 2 1 0 2 (S) — 2-Methylhexyl Methyl a a a

37 c≡c 0 2 1 0 2 (S) — 2-Methylhexyl methyl a 0

 38 c c 0 2 1 0 2 (S) — 2-Methylhexyl Water 3 # a a a

39 c≡c s 2 1 0 2 Cyclohexyl methyl a a a

40 c≡c s 2 102 (S)-2 tylhexyl hydrogen a β a

41 c≡c s 2 103 (R)-2-methylhexyl methyl a a a

42 c≡c s 2 103 (R) -2-methylhexyl methyl β a

 43 c≡c s 2 1 0 2 (R) -2, 6-Dmhep Water ^ a a 'a

44 c≡c s 2 1 0 2 (R) — 2—! Tylhexyl methyl a a a

 (K) 一 —Me T hehekinru a β a

46 c≡c s 2 1 u 2 (R) — 2-methylhexyl a a a

47 c≡c s 2 1 0 3 (S) '_ 2—! Tylhexyl hydrogen a a a

48 c≡cs 3 102 (R) — 2-methylhexyl hydrogen aaat-Bu: tert-butynole, i'-Pr: iso- ■ TP hill, (R) —11-!! 3_Hxyn: ( R) -1--Methyl-3 ':

2, 6 - Drahep: 2, 6- sheet 'methyl-5 to off' thenyl, 8th: 7 of bonded carbon atoms and 8-position carbon atoms, 11: consequent port binding penta down ring and R ^3, 15th position: Bond between 15th carbon atom and hydroxyl group The compound of the above formula (I) can be produced, for example, by the method summarized in the following reaction formula,

H

H

Power solution (In the reaction formula, Y ′ represents an ethylene group or a vinylene group, pi represents 1 or 2,

Z ¹ represents ethylene group, vinylene group, ethynylene group, o S, S ² represents ethylene group, vinylene group, ethynylene group, 0 SS (O) _pl , Et represents ethyl group, TB S represents a tert- butyldimethylsilyl group, R ³ is an alkyl group or carbon number 3 to 0 1 1 carbon atoms; a cycloalkyl group of L 0, YR, is nq are as defined above. )

 The above reaction formula will be described.

(1) First of all, according to the method of Sato et al. [Journal of Organic Chemistry (J. Org. Chem.), Vol. 53, Vol. 55, page 90 (1988)]. To a compound of the known formula (II), about 0.82.0 equivalents of the compound of the formula (III) or the formula (III ') is added in an inert solvent (for example, benzene) at about 17830C. , Toluene, tetrahydrofuran, jeti / leate methylene chloride, _n- hexane, etc.) to give the compound of formula (IV) stereospecifically. Here, in order to obtain a compound in which Y is an ethylene group or a vinylene group (that is, a compound in which Y is Y,), a compound of the formula (III ') is used. The compound of formula (III) is used to obtain a compound of the ren group, and is reacted at about 030 ° C.

 (2) About 0.54 equivalents of the compound of the formula (V) is added to the compound of the formula (IV) and, if necessary, a base (for example, triethylamine, diisopropylamine, pyridin, dimethylaminopyridine, etc.). Base resins such as organic amines, polyvinylpyrrolidone, diisopropylaminomethyl-polystyrene, (piperidinomethyl) polystyrene) or, if necessary, radical generators (eg, azobisisobutyl nitrile, azobiscyclohexanecarbo-tolyl, peroxide peroxide) About 0.0012 equivalents in an inert solvent (for example, benzene, toluene, xylene, n-xane, n-pentane, acetone, chlorophonolem, etc.). By reacting at 00 ° C, a compound of the formula (VI) is obtained.

(3) The compound of formula (VI) is treated with methanol, ethanol, acetonitrile or methanol using hydrofluoric acid, pyridinum poly (hydrogen fluoride), hydrochloric acid, etc. In a mixed solvent thereof or a mixed solvent thereof and water, tert-butyldimethylsilyl group, which is a protecting group for a hydroxyl group, is removed under a condition usually used to obtain a compound of the formula (VII).

 (4) An organic acid (eg, formic acid, acetic acid, etc.) or an inorganic acid (eg, formic acid, acetic acid, etc.) in an organic solvent (eg, methanol, ethanol, ethyl acetate, dioxane, etc.), water or a mixture thereof, (For example, sulfuric acid, hydrochloric acid, etc.) at about 0 to 60 ° C. to obtain a compound of the formula (VIII).

(5) A compound of the formula (VIII) is compounded with about 1 to 5 equivalents of the compound of the formula (IX) and, if necessary, an amine (eg, triethylamine, diisobutylamine, etc.) or an Radical generator (e.g., azobisisobutyl mouth-tolyl, azobiscyclohexanecarbonitrile, benzoyl peroxide, triethylporan, etc.) About 0.05 to 2 equivalents of an inert solvent (e.g., benzene, toluene, xylene, n —Hexane, n-pentane, acetone, black honolem, etc.) and react at about 1780 to 100 ° C. In the formula (I), R ² is a group other than a hydrogen atom (ie, R ³ ) p is 0, and the formulas according to the present invention, each having a different configuration at the 1-position

PGE derivatives of (la) and (la ') are obtained. These compounds of formulas (la) and (la ′) can be purified by a commonly used separation method such as column chromatography.

 (6) The compound of the formula (Ia) or (Ia ') is added to a buffer solution such as a phosphate buffer or a tris-hydrochloride buffer, if necessary, with an organic solvent (acetone, methanol, ethanol or other water). Reaction with an enzyme using a (miscible solvent)

R ² is a hydrogen atom in (I), P GE derivative of a compound formula of the present invention p is 0 (lb) or (lb ') is obtained.

Enzymes include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas) and enzymes prepared from animal organs (for example, prepared from pig liver and pig knee). Enzymes). Specific examples of commercially available enzymes include Lipase VII (manufactured by Sigma and derived from Candida microorganism), Lipase AY (manufactured by Amano Pharmaceutical and derived from Candida microorganism), and Lipase PS ( Amano Pharmaceutical, derived from a microorganism of the genus Pseudomonas), Lipase MF (Amano Pharmaceutical, PLE (prepared from pig liver, manufactured by Sigma), Lipase II OOSMM (prepared from pig kidney), lipoprotein lipase (prepared from staple knee, manufactured by Tokyo Chemical Industry Co., Ltd.) ) And so on.

The amount of the enzyme to be used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound of the formula (Ia) or (Ia ')], but is usually about 0.1 to 20% by weight of the substrate. _c the reaction temperature is double is from about 2 5~ 5 0 ° C, preferably about 30 to 40 ° C.

(7) The compound of the formula (Ia) or (Ia ') is converted to an oxidizing agent such as sodium metaperiodate, aqueous hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and tert-butyl hydroperoxide. When R ² is a hydrogen atom other than a hydrogen atom in the formula (I), it is oxidized by reacting it in getyl ether, methanol, ethanol, methylene chloride, water or a mixed solvent thereof at about 120 to 50 ° C. in the group (i.e., R ^3), PGE derivatives of p is 1 or 2 (i.e., p 1) compound formula of the present invention (I c) or (I c ') are obtained.

Note that S (Ο) _ρ in α is

〇

 II

 — Represents S, and when ρ = 2,

Represents

(8) The compound of the formula (Ib) or (Ib ′) is oxidized in the same manner as in the above (7), and in the formula (I), R ² is a hydrogen atom and p is 1 or 2 (that is, p 1 ) A PGE derivative of the formula (Id) or (Id ') of the present invention is obtained. Equation (I c) or

The PGE derivative of the formula (Id) or (Id ') can be obtained by hydrolyzing the compound of (Ic') in the same manner as in (6) above. Next, the pharmaceutical composition of the present invention will be described. The pharmaceutical composition of the present invention contains a PGE derivative represented by the above formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

 In particular, the pharmaceutical composition of the present invention can be used as a vascular smooth muscle cell growth inhibitor, and can be used for diseases and conditions caused by vascular smooth muscle cell proliferation, in particular, for thickening or obstruction of blood vessels due to vascular smooth muscle cell proliferation. It is useful as a prophylactic or therapeutic agent.

 It is known that the thickening of blood vessels caused by the proliferation of vascular smooth muscle cells is responsible for restenosis after PTCA as described above.

 In other words, the mechanism of restenosis after PTCA has been confirmed by R. Ross as "a vascular injury-one reaction hypothesis". It is thought that coagulation is induced, and the release of PDGF, site force, etc. causes secondary subintimal proliferation of vascular smooth muscle cells and intercellular substances, resulting in thickening of blood vessels and arteriosclerosis. Have been. The migration mechanism of vascular smooth muscle cells from the intima to the media and the proliferation in the media are deeply involved in the mechanism of the occurrence of restenosis. The pharmaceutical composition of the present invention has a high vascular smooth muscle growth inhibitory effect, and is therefore useful as a preventive or therapeutic agent for restenosis after PTCA.

 Further, the pharmaceutical composition of the present invention may be used as a vascular smooth muscle growth inhibitor as a preventive or therapeutic agent for diseases and conditions caused by proliferation of vascular smooth muscle cells such as arteriosclerosis, in addition to restenosis after PTCA. Can be used as

 The pharmaceutical composition of the present invention can be systemically or locally administered orally or parenterally, such as rectally, subcutaneously, muscle, intravenously, transdermally, and the like. Of these, oral administration and intravenous administration are preferred. The pharmaceutical composition of the present invention can be produced by mixing a pharmaceutically acceptable carrier, which is usually used, with a PGE derivative or the like. Specifically, a pharmaceutical composition for oral administration is obtained by adding an excipient, a binder, a disintegrant, a bulking agent, a coating agent, a sugar coating, or an aqueous or non-aqueous solvent to a PGE derivative or the like, It can be manufactured in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, and the like according to a conventional method.

Pharmaceutical compositions for intravenous administration include aqueous or non-aqueous solutions, emulsions, suspensions, or solid preparations to be dissolved in an injection solvent immediately before use, according to a conventional method. Can be manufactured. Further, the PGE derivative of the present invention can also be formulated by forming an inclusion compound with «or γ-cyclodextrin or methylated cyclodextrin. Further, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like.

 The dosage of the PGE derivative etc. of the present invention varies depending on the disease, symptom, body weight, age, sex, administration route, etc., but it is preferably 0.1 ng to 10 mg / day for an adult, and is preferably once a day. Or, it is administered in several divided doses. When used as a vascular smooth muscle growth inhibitor, the dose is preferably 1 ng to 1 mgZ days for an adult, which is administered once or several times a day. In particular, when administering a pharmaceutical composition containing the PGE derivative of the present invention for the purpose of preventing the occurrence of restenosis after PTCA, for example, the above-described period of about 1 to 3 months from the date of performing PTCA, Preferably, the amounts are administered sequentially. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by these descriptions. In the compound naming, "nor" means that there is no carbon chain at that position. For example, "17,18,19,20-tetranor" means that there is no carbon chain at the 17-20 position. Example 1

 (11R, 17R)-6-thia-11-deoxy 11- (2-hydroxylthiothio) -17,20-dimethyl-13,14-didehydro PGE methyl ester (Compound 24) And (11S, 17R) -6-thia-11-doxy-11- (2-hydroxyshethylthio) -11,20-dimethyl-13,14-dehydro_PGE Production of methyl ester (compound 25)

(1) Dissolve (3S, 5R) -3- (tert-butyldimethylcyclohexyl) -1-5-methylnona-1-yne (13.96 g) in 160 ml of toluene. At C, n-butyllithium (3.02M, hexane solution, 16.Oml) was added, and the mixture was stirred at the same temperature for 30 minutes. The solution 0 ° C in Jeffrey chill aluminum chloride Li de (0. 9 6 M solution in hexane,, 5 8. 3m l) was added, _t the temperature was raised to room temperature and stirred for 30 minutes At room temperature, add (4R) -2- (N, N-getylamino) methyl_41- (tert-butyldimethinoresi oxy) cyclopento-2-ene-1one (0.25M, toluene solution, 1 60 ml) and stirred for 15 minutes. The reaction mixture was poured into a mixture of hexane (300 ml)-saturated ammonium chloride aqueous solution (450 ml)-hydrochloric acid aqueous solution (3 M, 112 ml) with stirring, and the organic layer was separated and saturated. Washed with an aqueous solution of sodium bicarbonate (50 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was purified by silica column chromatography (developing solvent; hexane: ether = 10: 1) to give (3R, 4 R) 1-2-methylene-1 3 _ [(3S, 5R) -3- (tert-butyldimethyloxy) 1-5-methylnon-1--1-inole] _4— (tert-butynoledimethyloxy) 10.9 g of cyclopentan-1-one was obtained.

¹ H-NMR (CD C 13, 20 OMHz) 6 ppm: 0.10 (s, 6H), 0.11 (s, 3H), 0.14 (s, 3H), 0.80—0.96 (m, 24 H), 1.05-1.85 (m, 9H), 2.32 (dd, J = 18.0, 7.

3 Hz, 1 H), 2.72 (dd, J = 18.0, 6.4 Hz, 1 H), 3.4

8—3.57 (m, 1H), 4.20—4.32 (m, 1H), 4.39—4.50 (m, 1H), 5.55 (dd, J = 2.8, 0.7 Hz, 1 H), 6.1

4 (d, J = 2.8 Hz, 1 H)

 IR (neat): 2 9 56, 2 930, 28 5 8, 2 2 34, 1 7 3 7, 1 64 5, 147 1, 1 388, 1 3 62, 1 283, 1 2 54, 1 2 2 2, 1 1 86, 1 1 23, 1 0 8 8, 1 00 6, 94 2, 9 0 2, 8 3 7, 7 78, 6 6

9, 5 74 cm ^_1 .

(2) To a solution of the compound (1.97 g) obtained in (1) above in toluene (4 ml) was added 5-mercaptopentanoic acid methyl ester (1.19 g) at room temperature, and the mixture was added at the same temperature overnight. Stirred. Then, diisopropylamine (41) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 20: 1 to L0: 1), and (17R) -6-thia-17,20-dimethyl-13, 14—Jidehi Draw PGE i (tert-butyldimethylsilyl ether) (1.54 g) was obtained.

 'H-NMR (CD C 13, 20 OMHz) δ ppm; 0.09 (s, 6H), 0.11 (s, 3H), 0.13 (s, 3H), 0.76—1.03 (m, 6H), 0.89 (2 s, 18H), 1.08—2.06 (m, 13H), 2.12−3.30 (m, 10H), 3.67 (s, 3H), 4.25—4.58 (m, 2H) IR (neat): 2956, 2929, 2858, 1 746, 1 47 2, 1

46 3, 143 6,1 3 6,2 1 2 5 2,1 20 7,1 1 1,7,10 84,100,9,39,8 6,9,8,7,8 1,0,7 7 7, 6 70 cm ^_1 .

(3) To a solution of the compound (475 mg) obtained in (2) above in acetonitrile (25 ml) was added a 46% aqueous solution of hydrofluoric acid (5.6 ml) at 0 ° C, and the mixture was heated at the same temperature for 2 hours. Stirred. The reaction solution was poured into ethyl acetate (50 ml) -saturated aqueous sodium bicarbonate (170 ml) with stirring, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1) to give (17R) —6-thia-17, 20-Dimethyl-13,14-dide mouth_PGE i methinoleester (228 mg) was obtained.

 'H-NMR (CDC 13, 300 MHz) δ pp m; 0.83—0.96 (m,

3 H), 0.93 (d, J = 6.5 Hz, 3 H), 1.09-2.07 (m, 1

5H), 2.28 (dd, J = 18.6, 8.2Hz, 1H), 2.35 (t, J = 7.OHz, 2H), 2.49- 2.59 (m, 1H), 2.55 (t, J = 7.1 Hz, 2H), 2.73-2.88 (m, 1H), 2.82 ( dd, J = 13.6, 4.4 Hz, 1H), 2.95 (dd, J = 13.6, 6.OHz, 1H), 3.08-3.17 (m, 1H), 3.68 (s, 3H), 4.34-

4.5 5 (m, 2 H)

IR (neat): 3400, 2953, 2930, 2871, 2236, 1740, 143 9, 1380, 1277, 1218, 1158, 1 0 56, 7 5 7 cm ¹

(4) Dissolve the compound (178 mg) obtained in (3) above in ethyl acetate (14.4 ml). A solution of hydrochloric acid in ethyl acetate (4N, 0.65 ml) was added to the solution at room temperature, and the mixture was stirred for 4 hours. After the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, the organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 3) to give (17 R) — 6-thia-17,2 0-Dimethyl13,14-didehydro-PGAi methyl ester (56 mg) was obtained.

¹ H-NMR (CD C 13, 200 MHz) 6 ppm; 0.82—1.0 1 (m,

3 H), 0.92 (d, J = 6.6 Hz, 3 H), 1.08—1.90 (m, 1

4H), 2.34 (t, J = 7.1 Hz, 2H), 2.49-2.81 (m, 2H), 2.57 (t, J = 6. 9 Hz, 2 H), 2.93—3.1 1 (m, 1 H), 3.68 (s, 3 H), 3.76-3.84 (m, 1 H) , 4. 3 8—4.5 5 4

(m, 1H), 6.21 (dd, J = 5.7, 2.4Hz, 1H), 7.54 (dd, J = 5.7, 2.6Hz, 1 H)

IR (neat): 3 4 3 6, 2 9 5 3, 2 9 2 9, 2 2 3 0, 1 7 4 0, 1 7 1 8, 1 5 9 0, 1 4 6 0, 1 4 3 8, 1 4 1 8, 1 3 7 9, 1 3 4 7, 1 2 9 3, 1 2 6 0, 1 2 0 2, 1 1 7 4, 1 0 5 4, 9 0 8, 8 3 3, 7 5 ¹ cm ~ 1 ₀

(5) In a solution of the compound (50 mg) obtained in (4) above in chloroform-form (1.27 m 1) solution, 2-mercaptoethanol (17.7 μ1) and disopropylamine ( 3 ·

5 μl) was added, and the mixture was stirred at room temperature overnight. The reaction solution was subjected to short silica gel column chromatography (developing solvent; ethyl acetate), and the obtained crude product was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1). (11R, 17R) — 6—Thia-11—Doxy1-111 (2-Hydroxyshetylthio) 117,20—Dimethyl-13,14,14_Didehydro PG Ε methyl ester (6 mg) and (11S, 17R)-6-thia 1-11-doxy

11_ (2-Hydroxyshetylthio) -117,20-dimethyl-13,14-didehydro PGE methyl ester (16 mg) was obtained.

(1 1R, 17 R)-6 1 1 1-Deoxy 1 1 1 (2-Hydroxy 1,7,20—Dimethyl-1,3,14—Didehydro-1 PGE Methyl Esthenol

 ^ -NMR (CDC 1 a, 200 MHz) 5 ppm; 0.8 1—0.99 (m, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1 . 08—2.42 (m, 1

5H), 2.15 (dd, J = 18.8, 11.5Hz, 1H), 2.34 (t, J = 7.0Hz, 2H), 2.46 — 3.40 (m, 5 H), 2.55 (t, J = 6.7 Hz, 2 H), 2.79 (dd, J = 1 3.7, 4.6 Hz, 1H), 2.98 (dd, J = 13.7, 4.6Hz, 1H), 3.29 (ddd, J

11.5, 10.3, 7.7 Hz, 1 H), 3.68 (s, 3H), 3.87 (t, J = 6.3 Hz, 2H), 4 . 3 6 -4. 54 (m, 1 H)

 I R (neat): 3400, 2953, 2929, 2871, 2236,

1 7 5 0, 1 746, 1 4 56, 1 436, 14 1 8, 1 3 80, 1 3 5 3, 1

28 2, 1 208, 1 1 5, 8, 1 046, 9 58, 876 cm—

 (1 1 S, 17 R)-6—Thia 1 1—Doxy 1 1— (2—Hydroxysche thiol) 1 1 7, 20—Dimethinole 1 3, 14 1 Jideh draw PGE Methinole Esthenore

¹ H-NMR (CDC 1 a, 200 MHz) δ ppm; 0.8 0—1.00 (m,

3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.06—2.1 2 (m, 1

6 H), 2.34 (t, J = 7.1 Hz, 2 H), 2.45 5-320 (m, 9 H), 3.47-3.92 (m, 3 H ), 3.68 (s, 3 H) 4.39-45 5 (m, 1 H)

 I R (neat): 34 36, 2 9 5 3, 29 2 9, 2 8 7 1 223 6,

746, 1 740, 1 4 5 6, 1 4 36, 380, 1 2 7 8, 1 208,

 70, 1 05 0, 849 cm—Example 2

(1 1 R, 1 7 R) — 3 — Oxa 6 — Thia 1: Doxy 1 1 — (2 — Hydroxicetyl thio) 1 1 7, 20 — Dimethinole: 3, 1 4 — Jidehi draw P GEi methyl ester (compound 30) and (11S, 17R) 13-oxer 6 1-Dia- 1-doxy-1 1 1 (2-hydroxydoxythiol) — 1,7,20-Dimethinole 13, 14-didehydro-1 PGE i-methyl ester (Compound 31)

(1) Substantially the same as in Example 1 (2) except that methyl 5-mercaptopentanoate was used in place of methyl 5-mercaptopentanoate in Example 1 (2). , (17 R) — 3-oxa 6-thia 17, 20 dimethynole 13, 14 -didehydro 1 PGE methylenoleestenol 11, 15 -bis (tert-butyldimethylsilyl ether) Obtained.

¹ H-NMR (CDC 13-200MHζ) δ ppm; 0.09 (s, 6H), 0.11 (s, 3H), 0.13 (s, 3H), 0. 80—0.99 (m, 6H), 0.89 (s, 18H), 1.09-1.81 (m, 9H), 2.22 (dd, J = 18.1, 6.0 Hz, 1 H), 2.41—2.55 (m, 1 H), 2.64—2.82 (m, 1 H), 2.77 (t, J = 6.7Hz, 2H), 2.88-2.97 (m, 2H), 3.08-3.20 (m, 1H), 3.71 ( t, J = 6.7Hz, 2H), 3.76 (s, 3H), 4.13 (s, 2H), 4.29-4.47 (m, 2H)

IR (neat); 2956, 2930, 2235, 1762, 1472, 1464, 1439, 1380, 1366, 1257, 1208, 1 1 38, 1 0 84, 1 00 6, 940, 90 3, 86 8, 8 3 7, 7 78, 66 9, 5 7 8 cm ~ ¹ _D

(2) Using the compound obtained in (1) above, in substantially the same manner as in Example 1 (3),

(17R) — 3-oxa-6-thia-17,20-dimethyl-13,14-didehydro-1 PGE i methyl ester was obtained.

¹ H-NMR (CDC 13, 200 MHz) δ ppm; 0.8 3-2.20 (m, 12 H), 0.93 (d, J = 6.6 Hz, 3 H), 2.29 (dd, J = 18.5, 7.9Hz, 1H), 2.48-2.64 (m, 1H), 2.69-3.08 (m, 3 H), 2.77 (t, J = 6.5 Hz, 2 H), 3.16 (ddd, J = 1 0.1, 7.5, 1.8 Hz, 1 H), 3.73 (t, J = 6.5 Hz, 2 H), 3.77 (s, 3 H) , 4.14 (s, 2 H), 4.32-4.54 (m,

2 H)

 IR (neat); 3400, 2956, 2992, 2887, 2236, 1746, 14444, 138, 12889, 1 2 1 8, 1 1 3 7, 1 0 5 6, 7 6

2 cm per ¹ o

(3) In Example 1 (4), instead of (17R) —6_thia_17,20—dimethyl-13,14_didehydro_PGEi methyl ester, the above (2) (17R) _3-oxer 6-thia-17,20-dimethyl-13,14-didedrawing was carried out in substantially the same manner as in Example 1 (4) using the compound obtained in (1). PG methinoleester was obtained.

 'H-NMR (CDC 13, 200 MHz) δ ppm; 0.83-1.90 (m, 13H), 0.92 (d, J = 6.6 Hz, 3 H), 2.64-3.18 (m, 5H), 3.68-3.86 (m, 1H), 3.74 (t, J = 6.4Hz, 2H), 3.76 (s, 3H), 4.14 (s, 2H), 4.39—4.53 (m, 1H), 6.21 (dd, J = 5.7, 2.2 Hz, 1H), 7.54 (dd, J = '5.7, 2.4Hz, 1H)

 IR (neat); 3 4 3 6, 2 9 5 5, 2 9 2 9, 2 8 7 2, 1 7 5 2, 1 7 1 2, 1 5 9 0, 1 4 3 9, 1 3 4 7, 1 290, 1 2 1 3, 1 1 3 0, 1 0 5 5, 9 0 6, 8 4 4, 5 8 0 cm-

(4) Using the compound obtained in the above (3), the title compound was obtained in substantially the same manner as in Example 1 (5).

 (1 1 R, 17 R) 13 -oxa _ 6 -thia 1 11 -doxy 1 1 1-(2 -hydroxyxethylthio) 1 17, 20-dimethyl-13, 14- Jidehi Draw PGE Mechinore Estenolle

¹ H-NMR (CDC 13, 200 MHz) 6 ppm; 0.83-3.55 (m, 24H), 0.93 (d, J = 6.6 Hz, 3 H), 2.16 (dd, J = 18. 9, 11.4 Hz, 1 H), 3.72 (J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.86 (t, J = 6 3 Hz, 2 H), 4.14 (s, 2 H), 4.

3 6-4.54 (m, 1 H)

 I R (neat); 3400, 2953, 2929, 1746, 1461, 1

440, 140 2, 1 3 84, 1 3 5, 2, 1288, 1 2 1 4, 1 1 37, 1 0 4, 9, 952, 848, 504 cm—

 (1 1 S, 17 R)-3-oxa 1 6-thia 1 1-dexoxy 1 1-(2-hydroxyxethylthio) 1 17, 20-dimethinole 1 3, 1 4 PGE Methinolester

¹ H-NMR (CDC 13, 200 MHzζ) δ ppm; 0.84—1.87 (m, 14 H), 0.93 (d, J = 6.6 Hz, 3 H), 2 . 5 5—3.1 1 1 (m,

6H), 2.78 (t, J = 6.6Hz, 2H), 3.72 (t, J = 6.6Hz, 2H), 3.46-3.89 (m , 5H), 3.76 (s, 3H), 4.13 (s, 2H), 4.40—4.54 (m, 1H)

 I R (neat); 3400, 2955, 2929, 2871, 2236, 1

746, 14 56, 1 440, 1402, 1 380, 13 52, 1 288, 1 218, 1 13 7, 1046, 9 52, 84 9, 70 8, 580 cm— Example 3

 (11R, 17R) — 3,6-dithia-11-doxy-1 11— (2-hydroxyxethylthio) 1-1,20-dimethinole-1,3,14-didehydro PGE methyl ester ( Compound 44) and (11S, 17R) — 3,6-dithia-11-doxy-1 11— (2-hydroxyxethylthio) 1-17,20-dimethyl-13,14_didehi Production of methyl PGEi methyl ester (compound 45)

(1) In the same manner as in Example 1 (2), except that in Example 1 (2), methyl 5-mercapto-13-thia-monopentanoate was used instead of methyl 5-mercaptopentanoate. , (17 R) — 3,6-dithia-17,20—dimethyl-13,14_didehydro PGE i methylester-11,15-bis (tert-butyldimethinoresilyl ether) and (17R) — 3,6-dithia — 17,20-dimethinole 13, 1 4-didehydro 8] 3—PGE1 5-bis (tert-butyldimethylsilyl ether) was obtained.

 (17R) -3,6-dithia-17,20-dimethyl13,14diethyl mouth PGE methyl ester-11,15-bis (tert-butyldimethylsilyl ether)

'H-NMR (CD C 1 3, 20 OMH z) δ ppm; 0. 1 0 (s, 6 H), 0. 1 1 (s, 3 H), 0. 1 3 (s, 3H), 0 . 8 1— 0.97 (m, 6H), 0.89 (s, 18H), 1.06-1.82 (m, 9H), 2.22 (dd, J = 18.4, 6.2Hz, 1H), 2.41—2.54 (m, 1H), 2.64—2.94 (m, 7H), 3.06 -3.18 (m, 1H), 3.27 (s, 2H), 3.75 (s, 3H), 4.29-4.48 (m, 2H)

IR (neat); 2956, 2930, 2885, 2 23, 6, 1751, 1 746, 147 2, 1 4 36, 1 407, 1 37 7, 1 36, 1 2 5, 7, 1 1 2, 2, 1 084, 1 006, 940, 90 3, 8 3 7, 7 78, 670 c ml _c

(17R) -3,6-dithia-17,20-dimethyl-13,14-dide mouth _8-PGEi methinoleestenole 11 1,15-bis (tert-petit / resime Tylsilyl ether)

 -NMR (CDC 1 a, 20 OMHz) δ ppm; 0.07 (s, 3H), 0.09 (s, 6H), 0.11 (s, 3H), 0.79 — 0.98 (m, 6H) 0.88 (s, 18H), 1.04—1.79 (m, 9H), 2.16—2.3

2 (m, 1 H), 2.5 3-2.95 (m, 7 H), 3.01-3.14 (m, 1H), 3.2 1—3.36 ( m, 1H), 3.26 (s, 2H), 3.75 (s _;

3 H), 4.3 1—4.4.43 (m, 1 H), 4.47-4.5.5 (m, 1 H)

I R (neat); 2929, 2855, 2236, 1750, 1746, 1

4 7 2, 1464, 1 4 3 6, 1 3 90, 1 36 2, 1 2 5 8, 1 1 6, 8, 1 0 90, 1 06 7, 1 006, 9 61, 8 9 9, 8 3 7, 8 1 0, 7 78, 6 70 cm- ¹ . · (2) Using the compound obtained in the above (1) and in substantially the same manner as in Example 1 (3), (17R) -3,6-dithia-17,20-dimethinole-13, 1 4 One Sided Memo-P GE! Methyl ester and (17R) -3,6-dithia-17,20-dimethyl-13,14-didehydro8 (3-PGE methyl ester) were obtained.

 (17R) 1,3,6-dithia-17,20-dimethyl13,14dihydro PGEi

_{'H-NMR (CDC 1 3} , 200MH z) δ ppm; 0. 8 2- 1. 0 1 (m, 3 H), 0. 9 3 (d, J = 6. 6 H z, 3 H), 1.07-2.42 (m, 1 1H), 2.28 (dd, J = 18.6, 8.2Hz, 1H), 2.48—2.63 ( m, 1H), 2.70—3.19 (m, 8H), 3.28 (s, 2H), 3.76 (s, 3H), 4.33-4.5 3 (m, 2 H)

 IR (neat); 34 22, 2955, 292.9, 2871, 2236, 1746, 1740, 1437, 1289, 1202, 1149, 1 0 8 2, 1 0 08, 7 14, 5 90 cm—

 (17R) _3,6-dithia-17,20-dimethyl13,14-didehide 8 / 3—PGEi methinoleestenole

^X H-NMR (CDC 13, 200 MHz) 6 ppm; 0.8 3-2.18 (m,

1 3 H), 0.91 (d, J = 6.6Hz, 3H), 2.25—2.44 (m,

1H), 2.60-3.18 (m, 9H), 3.28 (s, 2H), 3.40—

3.50 (m, 1H), 3.76 (s, 3H), 4.34—4.52 (m, 1H),

4. 60-4. 70 (m, 1 H)

IR (neat); 3400, 2 95 3, 29 29, 1 740, 144, 13 8 5, 5, 12 9 9, 1 19 6, 1 1 48, 1 034, 76 2 ^cm_1 .

(3) Using (17R) —3,6-dithia-17,20-dimethyl-13,14_didehydro-1-PGE methyl ester obtained in (2) above, In substantially the same way, (17R) —3,6-dithia-17,20—dimethyl-13,

14 4-didehydro PGAi methyl ester was obtained.

¹ H-NMR (CDC 1 200 MHz) δ ppm; 0.83-2.02 (m, 13 H), 0.92 (d, J = 6.6 Hz, 3 H), 2.65—3.14 (m, 7H), 3.28 (s, 2H), 3. 7 3—3.85 (m, 1H), 3.75 (s,

3H), 4.38-4.54 (m, 1H), 6.22 (dd, J = 5.7, 2.

4 H z, 1 H), 7.55 (dd, J = 5.7, 2.4 H z, 1 H)

 IR (neat); 3442, 2 954, 29 29, 2871, 2 236, 1 7 30, 1 7 18, 8, 5 90, 1 436, 1 346, 1 289, 1 1 48, 1 0 0 9, 905, 8 28, 5 8 5 cm—

(4) Using the compound obtained in (3) above, the title compound was obtained in substantially the same manner as in Example 1 (5).

 (1 1 R, 17 R) 1 3,6-Dithia 1 1-Doxy 1 1 1 (2-Hydroxicetylthio) 1 1,7,20-Dimethinolate 13, 1 4 -Didehydro 1 PGE Methinoleste Nore

¹ H-NMR (CD C 13, 200 MHz) δ ppm; 0.82-1.86 (m, 12H), 0.93 (d, J = 6.6 Hz, 3 H ), 2.16 (dd, J = 19.0, 11.5 Hz, 1 H), 2.40-3.42 (m, 14 H), 3.28 (s,

2 H), 3.76 (s, 3 H), 3.87 (t, J = 6.3 Hz, 2 H), 4.

3 7-4.5 3 (m, 1 H)

IR (neat); 3400, 2953, 2929, 2871, 1746, 1740, 1461, 1436, 1407, 1381, 1352, 1284, 1 2 0 2, 1 1 5 3, 1 0 50, 100 9, 7 14, 5 9 3 cm_l ₀

 (1 1 S, 17 R) 1 3, 6—Dithia 1 1—Doxy 1 1— (2—Hydroxyxechinorecio) 1 17, 20—Dimethygray 1 3, 1 4 1 Jidehi draw PGE Esthenore

'H-NMR (CDC 13 ₎ 20 OMH z) δ ppm; 0.84-1.87 (m,

1 2 H), 0.93 (d, J = 6.6 Hz, 3 H), 2.10-3.19 (m,

13 H), 3.27 (s, 2H), 3.48—3.93 (m, 4H), 3.76 (s, 3H), 4.40-4.55 ( m, 1 H)

IR (neat); 3400, 2953, 2929, 2871, 223, 1 740, 173 0, 146 1, 1 436, 1 396, 1 284, 1202, 1 154, 1 050, 10 11, 7 14 cm—Test example

 [Measurement of DNA Synthesis Inhibitory Activity of PGEi Derivatives on Human Vascular Smooth Muscle Cells] Compound 24, 25, or 44 produced in the above Example was used as a test compound for human vascular smooth muscle cells by the following method. The DNA synthesis inhibitory activity was measured, and the growth inhibitory activity was evaluated.

Fifth culture of normal human aorta-derived vascular cells (human normal vascular smooth muscle cells, manufactured by Kurabo Industries) on 24-well plates (manufactured by Koeng) (medium Hv Media-SG2, 37 ° C, 5% C0) what) cells cultured in ₂ were seeded at 1 X 1 0 ⁴ cell Uweru, growth for culture locations (SG 2; at Ltd. Kurabo Industries), and cultured for 2 days at 3 7 ° C, 5% C0 2. Thereafter, the medium was changed from the growth medium to 500 ml of a basal medium (SB2; manufactured by Kurabo Industries), and cultured at 37 ° C for 24 hours. Thereto, the embodiments of the compound prepared in Example 24, 2 5, or 44, respectively 1 X 1 0- ³ M increasing殖用medium supplemented with ethanol solution 5 mu 1 at a concentration of (SG 2) 4 9 0 μ1 was added. At this time, ³ Eta - added thymidine (Daiichi Pure Chemicals) at 0. O lmc i / Ueru, after 24 hours of cultivation, the culture supernatant to suction removal removed by and washed with phosphate buffer (PBS).

Add 5% trichloroacetic acid (TCA) 750/1 and leave it at 4 ° C for 20 minutes. Washed once with eight. After washing with PBS, it was dissolved in 0.5 M potassium hydroxide aqueous solution 1. Oml. A 20 / X 1 aqueous solution of oxidative lysate containing cells into which nuclei had incorporated ³ H-thymidine was taken, and the amount of ³ H-thymidine incorporated was measured using a liquid scintillation counter (manufactured by Hewlett Packard).

On the other hand, as a control, the uptake of ³ H-thymidine was similarly measured for the group treated with ethanol to which no test compound was added, and the growth inhibition rate of each test compound was calculated according to the following formula. The results are shown in Table 3. Uptake of test compound-treated cells:

Growth inhibition rate (%) = X100 uptake of control-treated cells

Table 3

この結果より、 化合物 2 4、 2 5、 及び 4 4は、 ヒ ト血管平滑筋細胞に対する 高い増殖阻害活性を有することがわかつた。

From these results, it was found that Compounds 24, 25, and 44 had high growth inhibitory activity on human vascular smooth muscle cells.

Industrial applicability

 The PGE derivative and the like of the present invention exhibit an excellent inhibitory action on proliferation of vascular smooth muscle cells, and a pharmaceutical composition containing the same can be used as a prophylactic or therapeutic agent for diseases or conditions caused by proliferation of vascular smooth muscle cells. It is useful as a therapeutic agent, particularly as an agent for suppressing the thickening or obstruction of blood vessels, and particularly as a preventive or therapeutic agent for restenosis after PTCA caused by thickening of blood vessels due to proliferation of vascular smooth muscle cells.

Claims

 Claim formula (I)

(In the formula, m represents an integer of 1 to 4, n represents an integer of 0 to 3, p represents an integer of 0 to 2, q represents an integer of 1 to 4, Y represents an ethylene group, vinylene. represents a group or Echiniren group, Z is S (O) _p, 0, ethylene group, shows a vinylene group or Echiniren group, R ¹ is a cycloalkyl group 0 1 3 carbon, hydrogen atoms are 1 carbon atoms A cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyl group having 4 to 13 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms, R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms, which represents an alkenyl group, an alkynyl group having 2 to 10 carbon atoms or a bridged cyclic hydrocarbon group. A prostaglandin E derivative represented by the following formula: or a pharmaceutically acceptable salt or hydrate thereof. 2. The prostaglandin E derivative, the pharmaceutically acceptable salt or the hydrate thereof according to claim 1, wherein in formula (I), p = 0. 3. In the formula (I), the prostaglandin derivative according to claim 1 or 2 wherein Y is a vinylene group, a pharmaceutically acceptable salt thereof or a hydrate _c thereof. 4. The prostaglandin II derivative according to claim 1 or 2, wherein Y is an ethynylene group in the formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof. 5. A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, the prostaglandin Ε derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a hydrate thereof. 6. A vascular smooth muscle growth inhibitor comprising the prostaglandin II derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 7. A disease or medical condition caused by vascular smooth muscle proliferation, comprising the prostaglandin II derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Prophylactic drugs. 8. A disease or medical condition caused by vascular smooth muscle proliferation, comprising the prostaglandin II derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Remedy. 9. A method for preventing a disease or medical condition caused by vascular smooth muscle proliferation, which comprises administering the pharmaceutical composition according to claim 5 to a human. 10. A method for treating a disease or medical condition caused by vascular smooth muscle proliferation, which comprises administering the pharmaceutical composition according to claim 5 to a patient. 11. The prostaglandin Ε derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a hydrate thereof for preventing a disease or medical condition caused by vascular smooth muscle proliferation. Use of. 12. The prostaglandin E derivative, pharmaceutically acceptable salt or water thereof according to item 1 or 2 of the claims, for the treatment of a disease or medical condition caused by vascular smooth muscle proliferation. Use of Japanese products. 13. Use of the prostaglandin E derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 1 or 2 for producing a vascular smooth muscle growth inhibitor. 14. The prostaglandin E derivative according to claim 1 or 2 for producing a prophylactic or therapeutic agent for a disease or medical condition caused by vascular smooth muscle proliferation, and a pharmaceutically acceptable product thereof. Use of a salt or a hydrate thereof.