JPS5916852A - Cis-bicyclo(3,3,0)octane compound - Google Patents

Abstract

NEW MATERIAL:The cis-bicyclo[3,3,0]octane compound of formula I (R1 is H or lower alkyl; R2 and R3 are H, lower alkyl or aryl or together form a saturated carbon ring; E is lower alkylene; A and B are H or protecting group which may be different from each other; the wavy line represents the alpha- or beta-steric configuration). EXAMPLE:3beta-( 4'-Carboxybutyl )-7alpha-hydroxy-8beta-( 3'beta-hydroxy-trans-1'-octenyl )-cis- bicyclo[3,3,0]octane. USE:Useful for the preventive and remedy of various circulatory diseases. PROCESS:The compound of formula I can be prepared by converting the compound of formula III to a thiocarbonyl compound of formula II (R4 is aryloxy), and reductively eliminating the hydroxyl group of the product with tributyltin hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostacyclin analogues.

More specifically, the general formula is 1] O [wherein, R1 is a hydrogen atom or a lower alkyl group, and R
2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, or an aryl group, or a group in which both are taken together to form a saturated carbon ring, E is a lower alkylene group, and A and B are the same or different and represent a hydrogen atom or a protective group which may be different, and the wavy bond in the formula is α
Represents either the configuration or the β configuration. ] This relates to a novel cis-bicyclo(3,3,0)octane compound represented by

In the compound represented by the above general formula, there are theoretically two stereoisomers derived from the asymmetric carbon bonded by the wavy line, but none of these isomers is currently known. It is a new compound.

Compounds similar to the compound represented by the general formula IjJ are described in JP-A-56-68640 and JP-A-56-13.
8130, but the former does not mention stereoisomers, and the compounds that can be produced by the disclosed method are called 6α-15α and 6α according to the prostaglanin nomenclature. It is only a mixture of compounds with -15β configuration. The compounds disclosed in the latter are also similar, and the compounds that can be produced by the disclosed method are a mixture of compounds having the 6α-15α and 6α-15β configurations. The novel compound represented by the general formula [2] provided by the present invention is a compound having a 6β-15α and/or 6β-15β configuration, and cannot be produced by conventionally known methods.

In the compound represented by the above general formula 0], examples of the lower alkyl group of R1 include C1 to C4 alkyl groups such as methyl, ethyl, D-propyl, isopropyl, and n-butyl; Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropylene, n-butyl, isobutyl, n-pentyl, indunthyl, n-hexyl, and other alkyl groups of 07 or less; examples of aryl groups include Examples include phenyl, substituted phenyl,
Examples include aryl groups such as naphthyl, substituted naphthyl, chenyl, and substituted chenyl. Examples of groups in which R1 and R2 together form a saturated carbon ring include tetramethylene,
Examples include alkylene groups such as pentamethylene and branched alkylene groups. Examples of the lower alkylene group of E include 01 to C4 alkylene chains such as methylene, ethylene, trimethylene, and tetramethylene.

Examples of the protecting groups represented by A and B include lower alkanoyl groups such as acetyl and propionyl, benozoyl,
Aroyl groups such as substituted benzoyl, further benzyl groups, tetrahydropyranyl, tetrahydrofuryl, (01-C4
) The usual hydroxyl protecting groups of ethers such as alfky/methyl and trimethylnoryl, t-butyldimethylnoryl, t-butylumphenylnoryl groups are opened.

In the compound represented by the general formula U'' in which R1 is a hydrogen atom, the carboxylic acid thereof can be converted into a pharmacologically acceptable salt form as required, and examples of the salt include, for example. , salts of metals such as sodium 5, potassium, madanenium, cal/ud, aluminum, and primary, secondary, 6th class, such as ammonium, methylammonium, ethylammonium, trimethylammonium, tetraethylammonium, etc. and quaternary ammonium salts.

Prostacyclin has a powerful anti-platelet aggregation action, an action to suppress gastric acid secretion, and a vascular smooth muscle relaxing action, making it useful for the prevention and treatment of various diseases such as thrombosis, arteriosclerosis, gastrointestinal ulcers, and other cardiovascular diseases. In recent years, it has also been reported to be effective in preventing cancer metastasis.

However, this compound is chemically unstable and has a wide variety of physiological activities, so it has not been put into practical use as a drug.

Therefore, it is hoped that analogues that are stable and have separate physiological effects will emerge. By the way, Vane, J.R.

etc., the 6β-P()-4 compound has antiulcer activity 1 despite its weak platelet aggregation inhibiting ability and antihypertensive effect.
Is it twice as strong as jPG Engineering 2? It has been reported that 1i=n, and that the 6β form has stronger activity than the δα form.A manufacturing method has been established to produce and supply this compound in large quantities as a pharmaceutical.

The present invention discloses a novel nsubicyclo (3,
3, C1) octane compound and its production method. As a result of pharmacological tests, the novel compound provided by the present invention was found to have physiological effects similar to those of prostacyclin, and to have the same selectivity of physiological activity as 6β-PG-1. It has been found that this product is useful for the prevention and treatment of diseases.

The compound represented by the above general formula is produced according to the route shown in the following reaction formula.

Reaction Formula [In the formula, R1, R2, R3, E, A, B, and the wavy bond represent the same meanings as above, and R4 represents an aryloquine group. ] The method shown in the reaction formula above reductively removes the secondary hydroxyl group of the compound represented by the general formula (5), which removes chemically unstable groups such as protecting groups and ester groups of A and B. This is the way to do it. It is generally quite difficult to reductively remove a secondary hydroxyl group when other unstable groups are present. That is, the present inventors have investigated the compound represented by the above general formula by Barton et al. (J, Che+), which is known as an effective method for removing secondary hydroxyl groups.
n, Soc, Perkin Trans, 1 1975
．． 1574,) and a method in which the hydroxyl group is replaced with a rogane atom and then reduced with tributyltin hydride, etc.7, but the reaction did not occur or side reactions occurred, etc. To remove the hydroxyl group, the hydroxyl group was converted into a carbonyl compound, and then the hydroxyl group was reductively removed using tributyltin hydride, resulting in the general formula 0.
] We succeeded in producing two stereoisomers represented by

The compound represented by the general formula (5) is produced according to the route shown in the reaction formula below.

Reaction formula (8) [In the formula, R1, R2, R3, E, A, B, and wavelength bond represent the same meanings as above. , J) After introducing a side chain into the compound represented by the general formula (V) by aldol condensation etc. to form an enone compound represented by the general formula, the compound represented by the general formula (5) is obtained by selecting the position and configuration by catalytic reduction. This 6α-ketone compound is then subjected to an isomerization reaction to lead to a thermodynamically more stable 6β-ketone compound represented by the general formula (a), and then the carbonyl By reducing the group, it can be converted to a compound represented by the general formula:

Examples of the present invention are shown below, but these are specific examples and the present invention is not limited thereto.

Example 1 3α-(4′-methoxycarbonylbutyl)-7α-t
-butyrunmethylsilyloxy-8β-(6'α-t-
Butyrunmethylsilyloxy-trans-1'-octenyl)cis-vinchlo[ro, 3.0] Production of octan-2-one 3-(4'-methoxycarbonylbutylidene)-7α
-t-butyrunmethylsilyluoquine-8β-(6'α-
t-Butyrunmethylsilyloxy-trans-1'-octenyl)cis-bicyclo[3,3,0)octane-2
-one was dissolved in anhydrous methanol, and the mixture was stirred for 7 hours using 10% Pd-0 as a catalyst and hydrogen gas at 1 atm while cooling at -30°C. Then, the catalyst was removed, methanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound in a yield of 92%.

IRνf11m: 1740.1460.1360.1
255.1080, aX 865.775 NMR δ (CDC13): 5.44 (2H, m) 3.
90-4.20 (2H, m) 5.65 (3H1θ) 2
．． 30 (2H, t) MASS (m/e): 608 (M+) 593.57
7.551 (M+-”Bu), 53 Example 2 2α-hydroxy-3β-(4′-methoxycarbonylbutyl)-7α-t-butyldimethylsilylokino8
β-(3'α-t-butyldimethylsilyloquinotrans-1'-octenyl)/Nobicyclo[s, 3. o
) Production of octane The ketone compound obtained in Example 1 is dissolved in anhydrous methanol, a methanol solution containing 0.1 equivalent of sodium methoxide is added, and the mixture is stirred at room temperature for 15 hours. Next, the mixture was cooled to -78°C, 10 times the mole of sodium polyhydride was added thereto, and after stirring for 24 hours, saturated brine was added at the same temperature to stop the reaction. Next, the heel extract layer was extracted with ether, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by 7 silica gel column chromatography, yielding 82% of the title compound.
was obtained in a yield of . (Yields are shown minus recovered raw materials) IRνmax, 3550(ah), 345011'74
0. l 460°1360.1250,835.775 NMRδ (CD073): 5.52 (2H, m) 4.
10 (IH, m) 3.60-3.90 (2H, m)
3.67 (3H, s) 2.35 (2H, t, J = near, Ω) MASS (m/e): 610 (M”),
553.535.478.461.421.329 Example 3 2α-phenoxythiocarbonyloxy-3β-(4'
-methoxycarbonylbutyl)-7α-t-butyldimethylsilyloxy7-8β=(3'α-1-butyldimethylsilyloxy-trans-1'-octenyl)cis-
Preparation of bicyclo[3,3,0,)octane 2α-hydroxy-3β-(4′-methoxycarbonylbutyl)-7α-7-butyldimethylsilyloxy-8
β-(3'α-t-butyldimethylnryluoquine-trans-11-octenyl)7Suhinocro[3,3,0
) Octano is dissolved in acetonitrile, 10 equivalents of phenylchlorothionocarbonate are added in the presence of 15 equivalents of 4-(dimethylamino)pyridine, and the mixture is stirred at room temperature for 4 days. The reaction solution was diluted with ether, washed with saturated brine, and then dried over anhydrous magnesium sulfate.

The ether was distilled off under reduced pressure, and the resulting residue was subjected to NM analysis using phosphorus column chromatography to obtain the title compound in a yield of 70%.

Engineering Rνf111'rl: 1740.1590.1495
．． 1460.1660aX NMR δ (c:oc65) Near, 0-7.5 (5H, m
) 5.58 (2H, m) 5.31 (IH, t, J
=8Hz) 4.0~4.2 (IH, m) 3.5~3
．． 7 (1H, m) 3.66 (RoH, s) 2.32 (
t, J=8Hz) 0.88'(18H,e,s
) MAEtS (no/e) Near 46 (M+), 731
．． 713.689 (M+-”Bu), 14 Example 4 3β-(4′-methoxycarbonylbutyl)-7α-t
-butyldimethylsilyloxy-8β-(3'α-t-
Butyrunmethylsilyloxy-trans-11-octenyl)cis-bicyclo(3,3,0,1 octane Production Example 3 The thiocarbonyl compound obtained in Example 3 was dissolved in toluene, and a catalytic amount of α, α′-ab In the presence of bisinbutyronitrile, add 10 equivalents of tributyltin hydride and heat at 75° to 80°C for 1 hour.Then, toluene is distilled off under reduced pressure, and the residue is purified by silica dull column chromatography. The title compound was then obtained in a yield of 65%.

Engineering RVflm: 1740.1460.1360.1
25o, 1120°aX 1005.965.935.900.835.810.
77ONMRδ (CDC15): 5.42 (2H, m
) 3.9[h-4,20(IH,m) 3.66(3
H.

s) 3-4 □-80 (I H+ m) 2-32
(2H+t+J=8) 0-86 (j 8H
9s r e) MAss (m/e): 595 (M++1
), 594 (M+), 579.563.537 (M
+-Bu) Example 5 6β-(4'-Methoquine) Vhonylbutyl-7α-hydroxy-8β-(3'α-hydroxy/-trans-1
'-Octenyl) nonobinoc o (3,5,0,1 octa/) The compound obtained in Example 4 was dissolved in anhydrous TetrahyI Lofurano, and 5 equivalents of tetra-n-butylammonium fluoride was added. Stir overnight at room temperature. After distilling off the common medium under reduced pressure, dissolve the residue in ether, wash with saturated brine, and dry over anhydrous magnesium sulfate/ram. Remove the solvent under reduced pressure. After evaporation, the residue was purified by silica gel column chromatography to obtain the title compound in quantitative yield.

Engineering RνCHCt25, 36o o, ro430.172
5.1435.1455, ax 1170.1060.970 NMR δ (CDC13): 5.62 (2H, m) 4
．． 0-4.6 (1H, m) 35-ro, 9 (IH, m)
6.66 (3H, e) 2.32 (2H, t,
J=8Hz) MASS(m/e): 366(M
++1), Ro65 (M+), 348 (M+-H2O
)-330 (M+-2H20), 304.305 Example 6 6β-(4′-carboquinbutyl)-7α-human0xy-8β-(6′α-hydroxy-trans-1′-octenyl)nonobicyclo[ g,,s,o) Production of octane The compound obtained in Example 5 was dissolved in methanol, 4 equivalents of 10% potassium hydroxide were added thereto, stirred at room temperature for 5 hours, and then dissolved in an aqueous oxalic acid solution. Acidify and extract with ether. This extract was washed with saturated brine, dried over anhydrous magnesium chloride, and the solvent was distilled off under reduced pressure to obtain the title compound in quantitative yield.

IRv"H013: 3600.3400.1705.
1460.141o, aX 1380.1090.1065.97ONMRδ(OD
C13)' 5-60 (2H+m) 4.0~
4.3 (IH2m) 3.5~6.8 (IH,m
) Example 7 2α-phenoxythiocarbonyloxy-6β-(4'
-methoxycarbonylbutyl)-7α-t-butyldimethylsilyloxy-8β-(3'β-1-bunarunmethyl/liluoquine-trans-1'-octenyl)cis-
Preparation of biaclo[6,ro,0]octane 2α-Hydroki/-3β-(4'-methoquinocarbonylbutyl)-7α-t-butyl 7methyl 7lyloquino 8
β-(6′β-t-butyldimethylsilyloquinotrans-1′-octenyl)nonbisocro[3,ro,0
] Octane was treated similarly to the method shown in Example No. to give the title compound in 70% yield.

film.

EngineeringRvmaX, 1740.1590.1490.146
0.1360°1280.1250.1190.830
．． 77ONMRδ (CDC13) Near, 0-7.6 (
5H,m) 5.54(2H,m) 5.25(H(
, dd, J-i, 9Hz) 3.90-4.3
0 (2H, m) 3.68 (3H, s) 2.34 (
t, J=8Hz) MASS (m/e): 747 (M”+1)
, 746(M+), 745.731.713.689
(M+-”Bu), 614.535.451 Example 8 β-(4′-Methoquinocarbonylbutyl)-7α-methyl/lyloxy-8β-(3′β-t-butyldimethyllyloxy-trans-1 Preparation of '-octenyl)nonvincro[ro,3.O]octane The thiocarbonyl compound obtained in Example 7 was treated in the same manner as shown in Example 4 to give the title compound in a yield of 80%. Ta.

IRvfllm: 1740.1460.1360.1
250.1110°aX 965.965.9[]5.830,77ON 1. A
Rδ (cDC13): 5.50 (2H, m) 3
．． 9-4.2 (IH, m) 6.5-3.8 (I
H2m) 3-66 (3H+8) 2-32
(t+J=8H”)MASS (m/e):
595 (M++1), 594 (M+), 579
．． 565.568.537'(M"-"Bu) Example 9 3β-(4'-methoxycarbonylbutyl)-7α-hydroxy-8β-(3'β-hydroxy/-trans-1
'-octenyl)cis-binculo['3,3,0)
Preparation of Octane The compound obtained in Example 8 was treated in a manner similar to that described in Example 5 to give the title compound in quantitative yield.

iRν0H013:3600.3400.1725.1
450.1435, maX 1360.1320.1260.123D, 1170.
1130.1065.1010,970.89O NMRδ (ODC15): 5.66 (2H, m) 3.9
-4.2 (IH, m) 3.5 to 3.90 (IH, m
) 3.70 (3H, e) 2.34 (t, J=8
Hz) MhSS (rn/e): 34B (M”-R2
0), Ro 30 (M” '2'H20) Example 10 Ro β-(4'-carboxybutyl)-7α-hydroxy 7
-8β-(RO'β-Hydroxy-trans-1'-octenyl)non-hicyclo(3,3,C1)octane When the compound obtained in Example 9 was treated in the same manner as in Example 6, The title compound was obtained in quantitative yield.

IR Shikonbuta'3: 3600, Ro400, 1705.14
60.1410.1090.1070.97O NMRδ(CDC(?3):5.58(2H,m) hand
Continuation of amendment (method)%
[Formula % ], Indication of the case Showa Tuff Year Patent Application No. 1 Koku Left θ2 No. 2 Name of the Invention Cis-bicycloC3,3,0]Octane Compound 3, Person making the amendment Relationship to the case Patent Applicant Address Kita, Tokyo No. λ, 2g, Kamijujo-no-chome, Ward Name: Ota Pharmaceutical Co., Ltd. 4, Agent Address: 3-a, Kojimachi, Chiyoda-ku, Tokyo Mutual First Pill Telephone (2oS) Waoto July 7th (Shipping date: July 2nd, 1960) 6. Specification subject to amendment (page 7, page 7, page 7, page 7) 7. Statement of contents of amendment (page 7, page 1.2) , 7, p. 9') Engraving (no changes in content) Above TSJi Book 1, Title of invention Cis-bicyclo(6,3,0)octane compound 2, Special #! Range of I-Kanjo General formula [In the formula, R1 is a water-based atom or a lower alkyl group, R
2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, or an aryl group, or both together form a saturated carbocyclic ring, E is a lower alkylev group, and A and B are The same or different hydrogen atoms or optionally different six groups are included, and the wavy bond in the formula represents either the α configuration or the β configuration. ] is the standard cis-bicyclo(3,6,0), t-cutane compound.

6. Detailed Description of the Invention The invention relates to a compound that is a prosthetic compound.

Furthermore, 64" (, < is the general formula 〇" O [wherein, R1 is a hydrogen atom or a lower alkyl group, and R
2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, an asol group, or a group in which piIJ members are taken together to form a saturated carbon ring, E is a lower alkylene group, A and B are the same or different and each represents two water atoms or a protective group which may be different, and the wavy bond in the formula represents either the α configuration or the β configuration. ) is expressed as
This relates to J-octane compounds.

Regarding the compound represented by the general formula RIJ, the compound represented by the general formula ljJ is produced according to the route shown in the following reaction formula.

Reaction Formula [In the formula, R1, R2, R3, E% A, B, and the wavy bond represent the same meanings as above, and R4 represents an aryloxy group. ] The method shown in the above reaction formula reductively removes the secondary hydroxyl group of a compound represented by general formula (5) that has chemically unstable groups such as A and B protecting groups and ester groups. It's a method. It is generally quite difficult to reductively remove a secondary hydroxyl group when other unstable groups are present. That is, the Ministry of Uninvention et al. regarding the compound represented by the above general formula: secondary hydroxyl φ [wherein R1, R2, R3, ffi, A, B, and wavelength bonds have the same meanings as above, t- represents . ]

Claims (1)

[Scope of Claims] General formula [wherein, R1 is a hydrogen atom or a lower alkyl group,
2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, or an aryl group, or both together form a saturated carbon ring, E is a lower alkylene group, and A and B are The same or different hydrogen atoms or optionally different protecting groups are used, and the wavy bond in the formula represents either the α configuration or the β configuration. ] A novel nosuvincro [ro, 3.0] octane compound.