JP2934035B2 - Hydroxybicyclo [2,2,1] heptane sulfonamide derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

_2. Description of the Related Art It has been reported that a sulfonylaminobicyclo ring carboxylic acid derivative (hereinafter, simply referred to as a carboxylic acid derivative) has a strong receptor antagonistic effect on thromboxane A ₂ (TXA ₂ ) (Japanese Unexamined Patent Publication (KOKAI) No. 2000-163). No. 63-139161, USP 4,654,357, EP-
A-312906 and DE 3720760). T
XA ₂ is known to have a platelet aggregation action, a smooth muscle contraction action, and the like. Therefore, the carboxylic acid derivative is considered effective in the treatment and prevention of diseases associated with action of such TXA _2. As such diseases,
Myocardial infarction, cerebral infarction, pulmonary embolism, thrombosis, pregnancy toxemia, renal failure, asthma based on bronchoconstriction, and the like. In addition, this carboxylic acid derivative prevents vasospasm after subarachnoid hemorrhage, and reduces T after circulatory or digestive artery reperfusion.
Prevention of shock XA _2, blood loss, sepsis, trauma, cardiac dysfunction, endotoxin, have been suggested to be also effective for thrombocytopenia prevention in acute pancreatitis or the like shock prevention or during extracorporeal circulation by burns.

[0002]

As described above, since clinical effectiveness is expected in the prevention and treatment of various diseases, the development of many new and useful carboxylic acid derivatives has been strongly demanded. I have.

[0003]

Means for Solving the Problems The present inventors have solved the above-mentioned problems by providing 2,3-substituted bicyclo [2,
[2,1] By introducing a hydroxyl group at the 5- or 6-position of the heptane skeleton, a novel compound having TXA ₂ receptor antagonist activity was successfully synthesized. Since this compound has a hydroxyl group, it is possible to further improve various biological or physicochemical properties by performing various chemical modifications. Therefore, the compounds of the present invention, by not only is itself valid TXA ₂ antagonists, as more derivatives intermediates for the production of, or are very useful as a raw material for producing prodrugs.

That is, the present invention provides a compound of the formula I:

Embedded image Wherein R ¹ and R ² are hydrogen or hydroxy (at least one of which is hydroxy); R ³ is hydrogen or an ester residue; R ⁴ is hydrogen, lower alkyl, or halogen.
Or a pharmaceutically acceptable salt thereof. The outline of the method for producing the carboxylic acid derivative of the present invention will be described below. 1) Production of intermediate (6) (reaction formula 1)

Embedded image Wherein R ⁴ is as defined above, R ⁵ is a hydroxy protecting group,
Ph represents phenyl.

[0005] 5-norbornene-2,3 having a double bond
-Dicarboxylic anhydride (1) is replaced with benzohydryl R-
After asymmetric cleavage with (-)-mandelate, deprotection and recrystallization from ethyl acetate give diacid (2).
This was treated with sodium methoxide in methanol to give (+)-half ester (3) (JP-A-2-25665).
After that, benzenesulfonamide as an ω-side chain is constructed according to a conventional method to obtain (5). The ester is reduced to an alcohol and protected under basic conditions with a stable hydroxy protecting group to give intermediate (6).

2) Production of hydroxide (reaction formula 2)

Embedded image Wherein R ⁵ is as defined above.

Step a (6) is reacted with 9-BBN (9-borabicyclo [3.3.1] nonane) and then treated with hydrogen peroxide in dilute caustic soda to give two types of hydroxides: 18 are obtained. When this is subjected to column chromatography and then recrystallization, it is separated into a crystalline main product and an amorphous by-product. Their structure ¹
When confirmed by the decoupling method using H-NMR, the 5-exo-OH form (7) and the 6-exo-OH form (8) were obtained, respectively.
Occurred in a ratio of about 82:18. Step b : Epoxidation of (6) to give epoxide (10), which is reduced with LiAlH ₄ to give 6-exo-OH
A mixture is obtained in which the body (8) is for the most part (about 98%).

3) Preparation of the compound of the present invention (Scheme 3)

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and ph are as defined above, and R ¹ ′, R ² ′ are hydrogen or protected hydroxy (where one is protected hydroxy) Represents The hydroxyl groups of the hydroxylated intermediates (7) and (8) obtained in the above 2) are protected, and then the α-side chain is deprotected and oxidized to convert to aldehydes (11a) and (11b). These are led to the carboxylic acid derivative (I) of the present invention according to a conventional method.

In the present specification, the term "ester residue" means a phenyl which may be substituted by phenyl or a hydrocarbon group which may be substituted, for example, lower alkyl, lower alkoxyalkyl, halogenated alkyl and the like. Examples thereof include alkyl which may have a group, and aralkyl which may have a substituent on an aromatic ring.

[0010] Lower alkyl is a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Examples thereof include butyl, pentyl, isopentyl, neopentyl, 1,2-dimethylbutyl, hexyl, heptyl, and octyl. Lower alkoxy refers to alkoxy having 1 to 8 carbon atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy and the like.

The lower alkoxyalkyl is a group formed by replacing a hydrogen atom of the above-defined alkoxy group with the above-defined alkyl group, and includes methoxymethyl, ethoxymethyl and the like. The alkyl halide is an alkyl group as defined above substituted with 1 to 4 halogen atoms, and includes 2,2,2-trichloroethyl, 2-iodoethyl and the like. Halogen refers to boiling, bromine, chlorine, iodine and the like.

Aralkyl optionally having a substituent on the aromatic ring includes benzyl, p-methoxybenzyl, p-nitrobenzyl and the like. Examples of phenacyl in which phenyl may be substituted include phenacyl, p-bromophenacyl, p-nitrophenacyl and the like.

[0013] Pharmaceutically acceptable salts include salts of organic or inorganic bases prepared by methods known to those skilled in the art,
For example, acceptable salts of the compounds of the present invention include alkali metals such as lithium, sodium or potassium;
Alkaline earth metals such as calcium or magnesium; triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, dicyclohexylamine, N-isopropylcyclohexylamine, Furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,
N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylmethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene,
-Aminoanthracene, dehydroapiethylamine, N
Organic bases such as methylmorpholine or pyridine;
Or salts with amino acids such as lysine, arginine or histidine; and the like, with salts with sodium, calcium or lysine being particularly preferred.

The compounds of the present invention can be formulated into oral preparations, injections, inhalants and suppositories. In the case of oral administration, the compound of the present invention can be prepared by a conventional preparation, for example, a solid preparation such as tablets, powders, capsules or granules or a liquid preparation such as an aqueous or oily suspension, syrup or elixir. It can also be used as a mold. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection. In the preparation thereof, any of conventional excipients, binders, lubricants, aqueous solvents, oily solutions, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives, It may contain a stabilizer or the like. The dose of the compound of the present invention varies depending on the target therapeutic effect, administration method, age, body weight, and the like, and thus cannot be unconditionally specified. However, the daily adult dose is usually about 1 kg per body weight, orally. 0.01 mg to about 5
0 mg, preferably about 0.05 to about 10 mg, and parenterally about 0.001 to about 5 mg, preferably about 0.005.
mg to about 1 mg, which may be administered in 1 to 5 divided doses. Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples, but the present invention is not limited thereto. All of the compounds of the present invention in Examples and Test Examples are optically active compounds having the absolute configuration shown in the formula. In order to more clearly prove the pharmacological effect of the compound of the present invention, an optically active substance was used, and its enantiomer was not excluded.

The main abbreviations used in this embodiment have the following meanings. THF: tetrahydrofuran nBuli: n-butyllithium TFA: trifluoroacetic acid EtOAc: ethyl acetate NaOMe: sodium methylate Et ₃ N: triethylamine ClCOOEt: ethyl chloroformate NaN ₃ ... sodium azide 9-BBN.. 9-borabicyclo [3.3.1] nonane CH ₂ Cl _2.. of methylene chloride p-TsOH · p-toluenesulfonic acid DMF ... dimethylformamide nBu ₄ NF: Tetra n-butylammonium fluoride

Production Example 1 Production of Intermediate (6) [R ⁵ = tetrahydropyranyl; R ⁶ = phenyl]

Embedded image 1) (1) → (2) [R-(-)-diphenylmethyl mandelicate 28.4
To a solution of 7 g (89.42 mmol) in 200 ml of dry THF,
1.6N-nBuLi (55.
9 ml) in 8 minutes and stir for a further 5 minutes. Then 14.68 g (89.42 mmol) of cis-5-norbornene-endo-2,3-dicarboxylic anhydride in dry THF 8
0 ml solution is added in 15 minutes. After stirring at the same temperature for 1.5 hours, the reaction solution is poured into a mixture of water, 2N HCl and ethyl acetate, and separated. The solvent part was washed with saturated NaCl,
After drying over gSO _4, it is concentrated in vacuo to give an oily residue. The residue obtained above was treated with CH ₂ Cl ₂ (60 ml), anisole (1
8 ml) and TFA (50 ml), and stirred under ice-cooling for 1 hour. After the reaction solution is concentrated under reduced pressure, toluene is added and the mixture is again concentrated under reduced pressure. 5% by adding EtOAc to the residue
Extract with NaHCO ₃ . The water part is 2N in the presence of EtOAc.
Acidify with HCl. The solvent was washed with saturated NaCl, dried over MgSO ₄ and concentrated under reduced pressure. Recrystallization from ethyl acetate gave 13.37 g of the diacid (compound 2) having a mp of 169-171 ° C. Yield 47%.

2) (2) → (3) MeO was added to a solution of 15 g of the diacid in dry THF (100 ml).
H (50 ml) and 2N-NaOMe (71 ml) were added, and the mixture was heated under reflux for 2 hours. The reaction solution was treated with water, ethyl acetate, and 2N-
Add to HCl and separate. The solvent was washed with saturated NaCl, dried over MgSO ₄ and concentrated under reduced pressure. CH residue
Dissolved in ₂ Cl ₂ and containing 100 ml of water containing 2N HCl (2 ml).
Wash three times with ml. After washing with saturated NaCl, MgS
After drying with O _4, it is concentrated under reduced pressure. The column eluted with SiO ₂ (2: 1) was collected by SiO ₂ column chromatography and recrystallized from n-hexane to obtain m.
7.96 g of half ester (compound 3) at p72-73 ° C
Get. 93.2%.

3) (3) → (4) [R ⁷ = benzyloxycarbonyl] 7.7 g (42.73 mmol) of half ester, acetone 1
Et ₃ N (7.74 m 2) was added to a 20 ml solution in a nitrogen stream under ice cooling.
l) (1.3 x 42.73 mmol) followed by ClCOOEt
(4.08 ml) (42.73 mmol) was added and stirred at the same temperature for 30 minutes. Then NaN ₃ (8.33 g) (3 × 42.73)
The H ₂ O (46ml) solution of mmol) was added and stirred for an additional 1 hour. The reaction solution is poured into water, ethyl acetate and 2N-HCl, and separated. The solvent part was washed with 5% -NaHCO ₃ ,
After drying over SO ₄ and concentration under reduced pressure, an oily acid azide is obtained.

A solution of the above acid azide in 90 ml of dry benzene is heated at 80 ° C. for 1 hour. After the generation of nitrogen ends,
8.7 ml of benzyl alcohol (2 × 42.73 mmol), E
Add t ₃ N (7.7 ml) (1.3 × 42.73 mmol) and heat at the same temperature for 1 hour. The reaction solution was 2N-HCl, 5% NaHC
After washing with O ₃ and water, it is dried over MgSO ₄ and concentrated under reduced pressure. The column eluted with SiO ₂ column chromatography was collected with n-toluene-ethyl acetate (10: 1).
Recrystallization from hexane gives 9 g of the desired product (compound 4) having a mp of 81-82 ° C. 70.7% yield.

4) (4) → (5) [(5): R ⁶ = phenyl] 8.0 g (26.54 mmol) of raw material 25 ml of anisole, T
A 100 ml solution of FA is heated at 45 ° C. for 6 hours. After concentration under reduced pressure, the residue is rinsed with n-hexane. Residual CH ₂ C
To a solution of l ₂ (50 ml) was added Et ₃ N (14.8 ml) (4 × 26.
54 mmol), 4 ml of benzenesulfonyl chloride (1.2
× 26.54 mmol) under ice-cooling and stirred at the same temperature for 30 minutes. The reaction solution is washed with 2N-HCl, 5% -NaHCO ₃ and water, dried with MgSO ₄ and concentrated under reduced pressure. After performing SiO ₂ column chromatography, n-hexane-EtOAc (2: 1) was used.
The eluted portion is collected and recrystallized from CH ₂ Cl ₂ / n-hexane to obtain the desired product (compound 5) having an mp of 128 to 129 ° C.
6.75 g are obtained. 82.7% yield.

5) (5) → (6) [(6): R ⁵ = tetrahydropyranyl; R ⁶ = phenyl] LiAlH ₄ (3.88 g) (4.8 × 21.29 mmol) suspended in 120 ml of ether 6.54 g (21.29 mmol) of ester (5) in dry THF under ice-cooling in a stream of nitrogen in the liquid
ml and a solution in 90 ml of dry ether are added in 40 minutes. Further 30 minutes after stirring EtOAc, added 2N-HCl to decompose the LiAlH _4. 5% Na after extraction with ethyl acetate
After washing with HCO ₃ and then with water, drying over MgSO ₄ and concentration in vacuo. The column eluted with n-hexane-EtOAc (1: 1) was collected by SiO ₂ column chromatography to obtain 5.0 g of alcohol. Yield 84%.

The alcohol 5.0 g of CH ₂ Cl ₂ (50
ml) solution, 3.3 ml of dihydropyran and p-TsO under ice-cooling.
H.H ₂ O (100 mg) is added. At room temperature for 1 hour and 20 minutes after 5% NaHCO _3, water washed, MgSO ₄ dried, concentrated in vacuo. A portion eluted with n-hexane-EtOAc (4: 1) was collected by SiO ₂ column chromatography to obtain 5.7 g of the desired product (compound 6). Yield 88%.

Production Example 2 Production of Intermediate 7 or 8

Embedded image 1) (6) → (7) [R ⁵ = tetrahydropyranyl; R ⁶
= Phenyl] 4.6 g (12.7 mmol) of olefin compound (6) T
0.5N-9BBN (in THF) in 23 ml of HF 50.
6 ml (25.3 mmole) is added and the mixture is stirred at room temperature for 80 minutes. Then, 6.3 ml (38 mmole) of 6N-NaOH under ice-cooling,
5 ml (44.3 mmol) of 30% H ₂ O ₂ was added, and
Heat for hours. The reaction solution is poured into water and extracted with EtOAc. After washing the solvent part with 2N HCl, 5% NaHCO ₃ and water,
After drying over magnesium sulfate and concentration under reduced pressure, 4.83 g of a gummy residue was obtained. HPLC (nucleosil 100, ^n- hexane-THF = 4: 1, 7 ml / min, 225 nm)
OH / 6-OH = 82: 18. After performing SiO ₂ column chromatography, n-hexane-EtOAc
The part eluted with (2: 1) -EtOAc is collected. CH
_When recrystallized from ₂ Cl ₂ -ether, mp 155-160 ° C
3.0 g of the first crystals of Furthermore, mp155-1 from mother liquor
0.39 g of a second crystal at 60 ° C. is obtained (compound 7). Yield 7
0.2%. NMR δ ppm (CDCl ₃ ); 1.17 to 1.90 (m, 11
H), 1.94 to 2.10 (m, 1H), 2.35 to 2.4
9 (m, 1H), 2.83 to 3.19 (m, 2H), 3.2
9 to 3.62 (m, 2.5H), 3.79 to 3.95 (m,
0.5H), 4.27-4.48 (m, 2H), 4.83-
4.92 (m, 0.5H), 5.37 to 5.46 (m, 0.5
H), 7.47-7.67 (m, 3H), 7.85-7.9
7 (m, 2H)

2) (6) → (8) [R ⁵ = tetrahydropyranyl; R ⁶ = phenyl] To a solution of 3.75 g (10.3 mmol) of the olefin compound (6) in CH ₂ Cl ₂ (80 ml) was added 80%. 3.33 g (15.5 mmole) of% m-chloroperbenzoic acid are stirred and added under ice-cooling. After stirring at room temperature for 2.5 hours, the mixture is cooled on ice and the precipitated crystals are filtered off. The solvent part is washed with a diluted hypo solution. Then 5%
After washing with -NaHCO ₃ and water, drying over magnesium sulfate and concentration under reduced pressure. The fraction eluted with n-hexane-EtOAc (1: 1) was collected by SiO ₂ column chromatography to obtain 3.55 g of epoxide (compound 9). 86% yield.

Then, 3.5 g of epoxide (9) (9.2
mmole) in 1.4 ml of LiAlH ₄
(36.8 mmol) in a suspension of 40 ml of ether and 20 ml of THF are added with stirring. After 0.5 hour at room temperature, Et under ice cooling
OAc, 2N-HCl, to decompose the LiAlH ₄ with water. Et
After OAc extraction, the solvent part is washed with 5% -NaHCO ₃ and water, dried over MgSO ₄ and concentrated under reduced pressure. After performing SiO ₂ column chromatography, n-hexane-EtOAc
The portion eluted with (1: 1) -EtOAc is collected to obtain 3.0 g of the desired product (compound 8). 85.5% HPLC (Nucleosyl 100, n-hexane-THF4: 1, 5 ml
/ Min, 225 nm) was 6 / 2-OH / 5-OH = 98/2. NMR δ ppm (CDCl ₃ ); 1.02 to 2.46 (m, 14
H), 2.82 to 2.95 (m, 0.5H), 3.00 to 3.
20 (m, 1.5H), 3.34 to 3.69 (m, 2.5
H), 3.75-3.93 (m, 1.5H), 4.33-4.
46 (m, 1H), 4.83 (d, J = 5.0 Hz, 0.5
H), 5.25 (d, J = 4.8 Hz, 0.5 H), 7.25
-7.66 (m, 3H), 7.84-7.95 (m, 2H)

Production Example 3 Production of Intermediate 13

Embedded image 1) (7) → (10a) [R ¹ ′ = OSiPh ₂ Bu-t;
R ² ′ = H; R ⁶ = phenyl] 1.35 g (3.54 mmol) of DMF1 as the starting compound (7)
865 mg of dimethylaminopyridine (2 × 3.
54 mmol), 1.4 ml of t-butylchlorodiphenylsilane
(1.5 × 3.54 mmol), and the mixture is heated and stirred at 50 ° C. overnight. After the reaction solution was poured into water and extracted with EtOAc, the solvent portion was reduced to 5%.
After washing with -NaHCO ₃ and water, drying over MgSO ₄ and concentration under reduced pressure.
The fraction eluted with n-hexane-EtOAc (9: 1 to 8: 2) was collected by SiO ₂ column chromatography to obtain 2.15 g of a compound protected with 6-OH. Yield 98%.

The obtained compound (2.1 g) was added to THF 5m
1, with a mixture of 15 ml of AcOH and 5 ml of H ₂ O at 50 ° C. overnight. After the reaction solution was poured into water and extracted with CH ₂ Cl ₂ , the solvent was washed with 5% -NaHCO ₃ and water, dried over MgSO ₄ and concentrated under reduced pressure. After performing SiO ₂ column chromatography, n-
The fraction eluted with hexane-EtOAc (2: 1) is collected to obtain 1.18 g of the target compound 10a. Yield 65%.
Recrystallization of ether-petroleum ether gave mp.
It becomes a prism crystal at 3 ° C. [Α] _D : -6.9 ± 0.5 (24 ° C., c = 1.011, CHCl ₃ ) Elemental analysis Calculated value (%); C: 67.25, H: 6.96, N: 2. 61 actual value (%); C: 67.22, H: 6.98, N: 2.75

2) (8) → (10b) [R ¹ ′ = H; R ² ′
_{= OSiPh 2 Bu-t; R} 6 = phenyl] material (Compound 8) DMF35ml of 3.5 g (9.2 mmol)
2.25 g (2 × 9.2 mm) of dimethylaminopyridine was added to the solution.
ol), 3.6 ml of t-butylchlorodiphenylsilane (1.
5 × 9.2 mmol), and the mixture is heated and stirred at 50 ° C. overnight.
After the reaction solution was poured into water and extracted with EtOAc, the solvent was added to 5% -Na.
After washing with HCO ₃ and water, it is dried over MgSO ₄ and concentrated under reduced pressure. SiO
Perform ₂ column chromatography, n-hexane-Et
The fraction eluted with OAc (4: 1) was collected to give 5-OH
To give 5.29 g of the protected compound. Yield 93%.

5.29 g of this THP-ether was added to THF
50 ml with a mixture of 10 ml, 30 ml of AcOH and 10 ml of H ₂ O.
Heat at ° C overnight. After the reaction solution was poured into water and extracted with CH ₂ Cl ₂ , the solvent was washed with 5% -NaHCO ₃ and water, dried over MgSO ₄ and concentrated under reduced pressure. The fraction eluted with n-hexane-EtOAc (2: 1) was collected by SiO ₂ column chromatography to obtain 3.85 g of the desired product (10b). 84.2% yield.

3) (10a → 11a) [R ¹ ′ = OSiPh
^{_{2 Bu-t; R 2 '}} = H; R 6 = phenyl] alcohol (Compound 10a) 600mg (1.12mmole)
Chlorochrome pyridine 7 in CH ₂ Cl ₂ (45 ml) solution of
24 mg (3 × 1.12 mmol) and 1 g of Molecular Sieves 4A (powder) are added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is subjected to SiO ₂ column chromatography to obtain 564 mg of the desired product (Compound 11a). 94% yield.

4) (10b → 11b) [R ¹ ′ = H; R ² ′
_{= OSiPh 2 Bu-t; R} 6 = CH 2 Cl 2 phenyl] material 4.97g (9.27mmole) (360m
l) Add 6 g of chlorochrome pyridine (3 x 9.27 mmo) to the solution.
l), 13 g of molecular sieves 4A (powder) are added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is subjected to SiO ₂ column chromatography to obtain 4.9 g of the desired product (compound 11b). Yield 99%.

5) (11a → 12a) [R ¹ ′ = OSiPh
^{_{2 Bu-t; R 2 '}} = H; R 6 = phenyl] methoxymethyl triphenyl phosphonyl chloride 19.
In a suspension of 27 g (3 × 18.74 mmol) of 190 ml of dry THF, under ice-cooling, t-BuOK (6 g) (2.9 × 18.
74 mmol) are added. After stirring at the same temperature for 1 hour, 10 g (18.74 mmol) of the starting aldehyde was dried at -20 ° C in dry TH.
Add F60 ml solution. After stirring for 20 minutes under ice cooling, water,
Open in toluene. After the solvent portion is washed with water, it is dried over MgSO ₄ and concentrated under reduced pressure to obtain a crude product.

The above compound was converted to 90% HCOOH (20 m
l), stir with 2 ml of THF at room temperature for 1.5 hours. The reaction is poured into 5% NaHCO ₃ , CH ₂ Cl ₂ . The solvent is washed with water, dried with MgSO ₄ and concentrated under reduced pressure. Residue is S
Performed iO ₂ column chromatography, n-hexane-
The fraction eluted from EtOAc (2: 1) is collected. Recrystallized from ether-n-hexane, mp 137-139 ° C
8.43 g of the desired product are obtained. 82% yield from compound (11a).

6) (11b) → (12b) [R ¹ ′ = H;
_{^{R 2 '= OSiPh 2 Bu-}} t; R 6 = phenyl] methoxymethyl triphenyl phosphonyl chloride 9.5
In a suspension of 3 g (3 × 9.27 mmol) of 90 ml of dry THF, under ice-cooling, 3 g (2.9 × 9.27 mmol) of t-BuOK
Add. After stirring at the same temperature for 1 hour, 4.9 g (9.27 mmol) of the starting aldehyde is stirred at -20 ° C, and then a solution of 30 ml of THF is added. After stirring for 20 minutes under ice cooling, the mixture is poured into water and toluene. The solvent was washed with water, dried with MgSO ₄ and concentrated under reduced pressure to obtain 4.7 g of a crude target compound. Yield 83%.

The above compound was treated with 90% HCOOH (10 m
l), stir with 4 ml of THF at room temperature for 1.5 hours. The reaction is poured into 5% NaHCO ₃ , CH ₂ Cl ₂ . The solvent is washed with water, dried with MgSO ₄ and concentrated under reduced pressure. Residue is S
Performed iO ₂ column chromatography, n-hexane-
The fraction eluted from EtOAc (4: 1) was collected to obtain 4.22 g of the desired product. Yield 83%.

7) (12a) → (13a) [R ¹ ′ = OS
^{_{iPh 2 Bu-t; R 2}} '= H; R 3 = methyl; R ⁶ = phenyl] 4-carboxybutyl - Drying of bromide 1.43g (3 × 1.08mmol) THF60ml
T-BuOK under ice-cooling, in a nitrogen stream, and with stirring
(654 mg) (5.4 x 1.08 mmol) are added. After stirring at room temperature for 1 hour, cool to -15 ° C. Raw material 590mg
(1.08 mmol) in 5 ml of dry THF are added. 30
After cooling to 0 ° C. for 2 minutes, water, 2N HCl, EtOAc
Open in c. The solvent is washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to SiO ₂ column chromatography to obtain n-hexane-EtOAc (1: 1) to EtOAc.
The fraction eluted with c is collected and methylated with CH ₂ N ₂ . The fraction eluted with n-hexane-EtOAc (9: 1 to 2: 1) was collected again by SiO ₂ column chromatography to obtain 647 mg of the target compound (13a) as a gum. Yield 93
%.

IRνmax cm ^-1 (film); 3275, 17
25,1740 NMR δ ppm (CDCl ₃ ); 0.74 to 0.88 (m, 1
H), 1.04 (s, 9H), 1.22-1.37 (m, 1
H), 1.48-1.98 (m, 10H), 2.19-2.
32 (m, 1H), 2.25 (t, J = 6 Hz, 2H),
2.75 (q, J = 4 Hz, 1 H), 3.66 (s, 3
H), 4.10 (d, J = 5 Hz, 1H), 4.15-4.
25 (m, 1H), 4.97 to 5.28 (m, 2H), 7.
33-7.80 (m, 15H)

8) (12b → 13b) [R ¹ ′ = H; R ² ′
_{= OSiPh 2 Bu-t; R} 3 = methyl; R ⁶ = phenyl] 4-carboxybutyl - Drying of bromide 2.11g (3 × 1.59mmol) THF80ml
The suspension was added to t-BuOK9 under ice cooling and in a nitrogen stream under stirring.
60 mg (5.4 × 1.59 mmol) are added. After stirring at room temperature for 1 hour, cool to -15 ° C. 590mg of raw material (1.08m
mol) in 5 ml of dry THF. 0 ° C for 30 minutes
After cooling to room temperature, it is poured into water, 2N HCl, and EtOAc. The solvent is washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to SiO ₂ column chromatography.
- hexane -EtOAc (1: 1) collect fractions eluted with to EtOAc, methylation with CH ₂ N _2. The column was again subjected to SiO ₂ column chromatography to obtain n-hexane-EtOAc.
The portion eluted at (9: 1 to 2: 1) is collected to obtain 876 mg of the target product as a gum. Yield 85%.

IRνmax cm ⁻¹ (CHCl ₃ ): 3390,
1727, 1160, 1110, 1070 NMR δ ppm (CDCl ₃ ): 0.39 to 0.54 (m, 1
H), 1.02 (s, 9H), 1.20-2.37 (m, 1
4H), 2.28 to 2.38 (m, 1H), 3.55 to 3.
64 (m, 1H), 3.67 (s, 3H), 4.63 (d,
J = 6 Hz, 1 H), 4.81 to 5.41 (m, 2 H),
7.28 to 7.68 (m, 13H), 7.75 to 7.88
(M, 2H)

Example 1 (13a → 14a) [R ¹ ＯO
H; R ² = H; R ⁶ = phenyl] The above residue was added to 5 ml of THF and 1 M nBu ₄ NF in 3 ml of THF.
(3 eq) and heat and stir at 60 ° C. overnight. Saturated NH ₄ Cl is added to the reaction solution to perform EtOAc extraction. The solvent is washed with water, dried with MgSO ₄ and concentrated under reduced pressure. The residue is Si
O ₂ column chromatography, n-hexane-Et
The fraction eluted with OAc (9: 1 to 1: 1) is collected to obtain 360 mg of the methyl ester of compound (14a) as a gum. Yield 88%.

IRνmax cm ^-1 (film); 3500,3
272, 1733, 1443, 1320, 1160, NMR δ ppm (CDCl ₃ ); 0.84 to 0.99 (m, 1
H), 1.24 to 1.48 (m, 2H), 1.50 to 2.0
0 (m, 10H), 2.27 (t, J = 7.2 Hz, 2
H), 2.30 (brs, 1H), 2.88 (q, J = 4H
z, 1H), 3.70 (s, 3H), 4.25 (dd, J =
7.0, 2.0 Hz, 1H), 4.96 (d, J = 4 Hz, 1
H), 5.03-5.30 (m, 2H), 7.48-7.6.
8 (m, 3H), 7.85 to 7.98 (m, 2H)

350 mg of this methyl ester in MeOH
(3 ml), 1N-KOH (2.6 ml) was added to the solution, and 40
Stir for 1 hour and 20 minutes at ° C. The reaction solution is poured into water and washed with ethyl ether. The aqueous layer was washed with 2N-
Acidify with HCl. The solvent was washed with water, dried with MgSO ₄ and concentrated under reduced pressure to give 281 mg of free carboxylic acid (14%).
Obtain a). Yield 83%.

Example 2 Sodium salt of compound (14a) A solution of 281 mg of carboxylic acid in 0.1 ml of MeOH (4 ml) was added with 0.17
7N-NaOMe (3.63 ml) (0.9 eq) is added. 5
After minutes, the mixture was concentrated under reduced pressure, and the residue was freeze-dried with 5 ml of water to obtain 281 mg of a colorless powder. 95% yield.

EA; C ₂₀ H ₂₆ NO ₅ SNa: 1.7H ₂ O Calculated; C: 53.84, H: 6.64, N: 3.14, S: 7.19 Actual; C: 53 .58, H: 6.51, N: 3.22, S: 7.72 IRvmax cm ^-1 (KBr); 3400br, 1620br,
1555 NMR δ ppm (CD ₃ OD); 0.88 to 1.05 (m, 1
H), 1.25-1.96 (m, 11H), 2.09 (t,
J = 7.8 Hz, 2H), 2.26 (brs, 1H), 2.8
3 (t, J = 4 Hz, 1 H), 4.18 to 4.28 (m, 1
H), 4.94-5.25 (m, 2H), 7.49-7.7.
0 (m, 3H), 7.83 to 7.94 (m, 2H)

Example 3 (13b) → (14b) [R ¹
= H; R ² = OH; R ⁶ = phenyl] The above residue was treated with 5 ml of THF and 1 M-nBu ₄ NF in ₄ ml of THF.
(3 eq) and heat and stir at 60 ° C. overnight. Saturated NH ₄ Cl is added to the reaction solution to perform EtOAc extraction. The solvent is washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to SiO ₂ column chromatography to obtain n-hexane-
The portion eluted with EtOAc (9: 1 to 1: 1) was collected to give 455 mg of the methyl ester of compound (14b) as a gum. 82% yield.

EA: Calculated; C: 61.89, H: 7.17, N: 3.44, S: 7.87 Found: C: 61.45, H: 7.15, N: 3. 56, S: 7.66 IRνmax cm ⁻¹ (CHCl ₃ ); 3605, 3385, ₃
280, 1729, 1601, 1448, 1438, 1
159, 1094, 1062 NMR δ ppm (CDCl ₃ ); 0.74 to 0.84 (m, 1
H), 1.08-2.13 (m, 12H), 2.20-2.
34 (m, 1H), 2.28 (t, J = 7.2 Hz, 2
H), 2.85 to 2.95 (m, 1H), 3.70 (s, 3
H), 3.65 to 3.75 (m, 1H), 5.02 (d, J
= 5Hz, 1H), 5.10-5.36 (m, 2H), 7.
42 to 7.66 (m, 3H), 7.80 to 7.93 (m, 2
H)

350 mg of this methyl ester in MeOH
(3 ml) 1N-KOH (1.7 ml) (2 eq) was added to the solution and stirred at room temperature for 4 hours. The reaction solution is poured into water and washed with ethyl ether. The aqueous layer was washed with 2N-H in the presence of EtOAc.
Acidify with Cl. The solvent was washed with water, dried over MgSO ₄ and concentrated under reduced pressure to obtain 323 mg of free carboxylic acid (14%).
Obtain b). This was purified by HPLC (Develosil
ODS-15 / 30, acetonitrile-methanol-
(Water = 200-200-450, 80 ml / min, 225 nm)
When recrystallized from methanol-ether, mp.
It becomes a crystal of １２８128 ° C. )

EA: Calculated; C: 61.02, H: 6.92, N: 3.56, S: 8.15 Found: C: 60.92, H: 6.97, N: 3. 42, S: 7.88 IRνmax cm ⁻¹ (CHCl ₃ ); 3605, 3385,
3265, 1709, 1602, 1448, 1322
1157,1092,1062

Example 4 Sodium salt of compound (14b) To a solution of 268 mg of carboxylic acid in 5 ml of MeOH was added 0.1N-N
aOH (6.13 ml) (0.9 eq) is added. After 5 minutes, the mixture was concentrated under reduced pressure, and the residue was freeze-dried in the presence of 5 ml of water to obtain 243 mg of a colorless powder. 86% yield.

[0049] _{EA; C 20 H 26 NO 5} SNa: 0.7H 2 O Calculated; C: 56.11, H: 6.45 , N: 3.27, S: 7.49 Na: 5.37 Found Value: C: 56.29, H: 6.44, N: 3.56, S: 7.43 Na: 5.31 IRνmax cm ^-1 (KBr); 3400br, 1645, 1
560, 1447, 1405, 1157, NMR δ ppm (CD ₃ OD); 0.80 to 0.96 (m, 1
H), 1.00 to 1.15 (m, 1H), 1.24 to 1.3
8 (m, 1H), 1.45 to 2.20 (m, 12H), 2.
80 to 2.90 (m, 1H), 3.63 (d, J = 6 Hz,
1H), 5.02-5.32 (m, 2H), 7.45-7.
68 (m, 3H), 7.77 to 7.92 (m, 2H)

[0050]

The compound of the present invention acts as a potent antagonist for the thromboxane A ₂ receptor,
Significantly inhibits platelet aggregation or defect contraction associated with or caused by thromboxane A ₂ . Therefore, the compound of the present invention is a compound that can be a useful antithrombotic agent / antivasoconstrictor. The representative compounds were tested for their platelet aggregation inhibitory activity in vitro by the method described in the following Test Examples.

[0051]Test example 1  Antagonist activity (rat platelet aggregation inhibitory action) [Test materials and test methods] Male rats (JCL-SD
ACD (85 mM citric acid) from abdominal artery
Sodium, 70 mM citric acid, 110 mM glucose)
1.5 ml and prostaglandin E₁(20 μg)
10 ml of blood using a plastic syringe
Was. Blood is mixed by inverting gently in a plastic test tube.
After centrifugation at 160 g for 10 minutes,
Plate plasma [PRP (platelet rich plasma)]
Was. Apyrase (25 μg / ml) was added to the obtained PRP.
After that, layered on 40% bovine serum albumin,
Centrifuged at 0 × g for 25 minutes. Small amount of platelet pellet
Buffer (137 mM NaCl, 2.7 mM KCl, 1.0 mM)
M MgCl_Two3.8 mM NaH_TwoPO_Four3.8 mM Hepe
s, 5.6 mM glucose, 0.035% bovine serum albumin
Min, pH 7.35) and floated on Sepharose 2B (S
epharose 2B) and buffer (10 ml).
And washed platelets were obtained.

The platelet aggregation reaction was measured using an aggregometer (N
KK HEMA TRANSCER 1 MODEL PAT
-6A · 6M, Nikko Bioscience). That is, 245 μl of washed platelets adjusted to a platelet count of 5 × 10 ⁸ / μl was put in a measurement cuvette, set in an aggregometer, and stirred at 37 ° C. (100 rp).
m) and 0.1 M CaCl ₂ (3.8 μl) were added, and after 1 minute, 0.5 μl of the test compound solution (dimethyl sulfoxide solution)
2 minutes later, collagen [Col] was used as an aggregation-inducing substance.
lagen reagent Horm ^R , hormone-chemie, Munich (HORMAN-CHEMIE Munchen GMBH)]
Was added (final concentration: 4 μg / ml), and the change in light transmittance caused by aggregation was recorded over time.

The 50% platelet aggregation inhibitory concentration is calculated from the aggregation rate. (The platelet aggregation rate was measured as the light transmittance 3 minutes after the addition of the aggregation-inducing substance, with the transmittance of the washed platelets and the buffer solution being 0% and 100%, respectively.)

Table 1 shows the test results.

[Table 1] 1) Test compounds were used as sodium salts. The control compound has the formula:

Embedded image Indicated by The above test results show that the compound of the present invention has a platelet aggregation inhibitory action.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07M 7:00 9:00

Claims (3)

(57) [Claims] 1. Formula I: ## STR1 ## Wherein R ¹ and R ² are hydrogen or hydroxy (at least one of which is hydroxy); R ³ is hydrogen, unsubstituted phenacyl, phenacyl substituted with halogen or nitro, lower alkyl, lower alkoxyalkyl, Alkyl halide, unsubstituted aralkyl, or aralkyl substituted with lower alkoxy or nitro; R ⁴ represents hydrogen, lower alkyl, or halogen) or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which is an exo-OH form. 3. The compound according to claim 1, which is in a (+)-form.