JP2537378B2 - Cyclopentane compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cyclopentane compound.

2. Description of the Related Art At present, it has been suggested that in senile dementia represented by Alzheimer's disease, a significant change occurs in the cerebral cholinergic nervous system and its function is impaired (Perry.EKand.
Perry.RH “Biochemistry of Dimentia”, page 135 (198
0), John Wiley & Sons.,).

Therefore, compounds having nerve cell repairing ability (survival effect, neurite extension effect) are senile dementia representative of Alzheimer type dementia, Down's syndrome, Huntington's ataxia,
It can be effectively used as a therapeutic drug for amnesia, memory disorder, head injury, brain surgery, drug poisoning, circulatory disorder, cerebral metabolic disorder, sequelae due to a decrease in acetylcholinergic nervous system function due to encephalitis, mental disorder, etc. JWGeddes et al., Science, 23
0 , 1179-1181 (1985)).

Conventionally, NGF (nerve growth factor), GM ₁ (ganglioside), and the like, which are the only biological components of a polymer, are known as compounds having the above-mentioned ability to repair nerve cell degeneration. For NGF, for example, Euroscience (H
efti, F. et al., 14 , 55-68 (1985), Journal of Euroscience (Franz Hefli et al., 6 , 2155-2162 (198)
6), Proceedings of the Natural Academy of Science of the USA (Proc.Na
tl.Acad.Sci.USA, LRWilliams et al., 83, 9231-9235 (198
6), Science (LEKromer, 235 , 214-216 (1986), etc. Further, as for GM ₁ , for example, Science (Fred J. Roisen et al., 214 , 577-578 (1981), Brainless ( Brain Res., MVSofroniew et al., 398 , 393
−396 (1986), Brainless (M. Gradkowska et al., 37
5 , 417-422 (1986) and the like.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The inventors of the present invention have conventionally used natural products as part of a search for effective ingredients for gastrointestinal disorders, anxiety, neuropsychiatric disorders such as neurosis, and the like, as a part of Borneo moss (Mastigophora diclados). ,
Bird.Nees). In the course of the research, it was found that the compound represented by the following general formula (1) present in the moss has a neuronal degeneration repairing action. The present invention has been completed based on such knowledge.

An object of the present invention is to provide a novel compound which has not been published in the literature and is useful as a pharmaceutical.

Means for Solving the Problems According to the present invention, a compound represented by the following general formula (1) is provided.

Wherein R is a group (R ¹ represents a hydrogen atom or a lower alkanoyl group.), (R ¹ is the same as above.) Or group Indicates. ] The cyclopentane compound represented by these.

The compound represented by the general formula (1) has a function of significantly promoting survival of nerve cells and extension of neurites, and further increasing the enzymatic activity of chorioacetyltransferase (ChAT) of nerve cells. The above general formula (1)
The compound represented by the formula (3) has an action of promoting survival and growth of cholinergic neurons of the central nervous system.

As used herein, the term lower alkanoyl group refers to
It means a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups.

The compound of the general formula (1) of the present invention is produced, for example, by the method shown below.

That is, in the compounds of the present invention, R is a group And R ^{1 in} a group other than the above represented by R ¹
The compound in which is a hydrogen atom is extracted and isolated from the moss from Borneo. This extraction and isolation is carried out, for example, as follows. First, Borneo moss is extracted with a normal polar solvent such as diethyl ether, the extract is passed, and then the solution is concentrated under reduced pressure to obtain a primary extract. The target product is collected by various methods utilizing the physical properties. The target substance can be collected by a usual method,
For example, a method that utilizes the difference in solubility with impurities, activated carbon,
It can be carried out by a method of utilizing a difference in adsorption affinity with respect to an adsorbent such as amberlite, silica gel, an ion exchange resin, Sephadex, a method of utilizing a difference in distribution ratio between two liquid phases, a combination of these methods and the like. As a more preferable collection method, for example, the above-mentioned primary extract is subjected to silica gel column chromatography, extracted with a suitable solvent such as a mixed solvent of n-hexane and ethyl acetate, and the extract is concentrated under reduced pressure to obtain a concentrated solution. After purification by silica gel column chromatography, it is subjected to Sephadex and eluted with a suitable solvent such as methanol or chloroform.

Further, in the compound of the present invention represented by the general formula (1), a group Compounds in which R ¹ is a lower alkanoyl group in groups other than R are compounds of the general formula (R ² ) ₂ O (2) or general formula R ² X (3) In the above formulas, R ² represents a lower alkanoyl group and X represents a halogen atom. The compound of the present invention which is lower alkanoylated can be derived by reacting the compound represented by

This lower alkanoylation reaction is carried out in the presence or absence of a basic compound. Examples of the basic compound used include alkali metals such as sodium metal and potassium and hydroxides, carbonates, bicarbonates of these alkali metals, or N, N-dimethylaminopyridine, pyridine, piperidine, etc. An organic base etc. can be mentioned. The reaction proceeds either with or without a solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, water, pyridine and the like. General formula (2)
Alternatively, the compound (3) is used in an amount of at least about equimolar to the raw material compound, but it is generally preferable to use an equimolar amount to a large excess amount. The above reaction is 0-200
Although the reaction proceeds at 0 ° C, it is generally preferable to carry out the reaction at about 0 to 150 ° C. The reaction time of the reaction is generally about 0.5 to 5 days.

The compound of the general formula (1) obtained by the above method can be administered to humans or animals as it is or as an active ingredient together with a conventional pharmaceutical carrier. When using the compound of the present invention as a medicine, the form of the pharmaceutical preparation (dosage unit form), its preparation, its administration route and the like can be the same as those of ordinary pharmaceutical preparations. That is,
The compound of the present invention is a tablet, granule, or
The preparation can be orally or parenterally administered in the form of an oral preparation such as a capsule or an oral solution or a parenteral preparation such as an injection. The above-mentioned various forms of preparations may be prepared according to a conventional method, and the carrier used at that time may be any of the commonly used carriers.
For example, a tablet is formed by mixing the compound of the present invention as an active ingredient with an excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. Capsules are prepared by mixing the above-mentioned active ingredient with an inert formulation filler or diluent and filling the mixture into hard gelatin capsules, soft capsules or the like. Parenteral administration agents such as injections are produced by dissolving or suspending the compound of the present invention as an active ingredient in a sterilized liquid carrier. Examples of preferable carriers include water and physiological saline.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually about 1 to 70% by weight, preferably 1
It is recommended to be about 30% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, granules, capsules and oral preparations are orally administered. In the case of parenteral agents such as injections, alone or glucose,
It is administered intravenously as a normal replacement fluid of amino acids and the like, and further, if necessary, is independently administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of disease, etc., but the amount of the compound of the present invention which is an active ingredient is usually 10 per 1 kg of body weight per day. The dose is preferably up to 800 mg, and it is recommended to administer this once to several times daily. In addition, it is preferable to contain the active ingredient in an amount of about 1 to 200 mg in the unit dosage form.

Examples Examples of the compounds of the present invention (production examples), pharmacological test examples, and formulation examples are given below.

Example 1 Borneo moss Mastigophora diclados (Brid.) Nee
220 g of s was air-dried, then pulverized, and extracted with 800 ml of diethyl ether at room temperature for 2 months. After passing the reduced pressure, the liquid was concentrated under reduced pressure to obtain 6.0 g of an extract. This extract was added to silica gel (Merck, 70
-230 mesh, 160 g) chromatograph, eluting with n-hexane-ethyl acetate (4/1, v / v, 0.5), n-hexane-ethyl acetate (1/1, v / v, 0.6), Fraction I (1.5g), Fraction II (1.3g), Fraction
III (0.6g), Fraction IV (0.3g), Fraction V (0.07g), Fraction VI (0.45g), Fraction
Fractionation was carried out into 8 fractions of VII (0.4 g) and fraction VIII (0.5 g).

Fraction I (1.5 g) was applied to Sephadex LH-20 (Pharmacia, 200 ml) and eluted with methanol-dichloromethane (7/3, v / v, 500 ml) to give fraction 12
~ 18 were collected and the solvent was removed under reduced pressure to give 560 mg of an oil. 560 mg of this oily substance was further added to silica gel (Wako Gel C
(-300g, 60g) The purification was repeated by chromatography, and the fractions 43 to 52 eluted with n-hexane-dichloromethane (1/1, 500ml) were collected and the solvent was removed under reduced pressure to obtain 4,4'-di-
[1- (S) -1,2,2-trimethylcyclopentyl]-
36.2 mg of 6,6'-dimethyl-2,2 ', 3,3'-(S) -biphenyltetraol (Compound 2) was obtained as crystals. On the other hand, the fractions 60 to 68 were treated in the same manner, and 4,4′-di-
[1- (S) -1,2,2-trimethylcyclopentyl]-
61 mg of 6,6'-dimethyl-2,2 ', 3,3'-(R) -biphenyltetraol (Compound 3) was obtained.

Fractions II, III and IV were combined (2.2 g) and subjected to Sephadex LH-20 (300 ml) chromatography, eluting with methanol-chloroform (7/3, v / v) to obtain the obtained fractions 27-41. Collect and remove the solvent under reduced pressure to give 1.5 g of an oil. 1.5 g of this oily substance was purified by silica gel (Wakogel C-300, 200 g) chromatography. n-hexane-
Fraction 15 eluted with ethyl acetate (4/1, v / v, 100 ml), n-hexane-ethyl acetate (1/1, v / v, 100 ml)
~ 39 were collected and the solvent was removed under reduced pressure to give 1- [1- (S) -1,
20 mg of 2,2-trimethylcyclopentyl] -3,4-dihydroxy-5-methylbenzene (Compound 1) was obtained as crystals. Also, collect fractions 44-47 and perform the same processing,
1- {5- [1- (S) -1,2,2-trimethylcyclopentyl] -3,4-dihydroxyphenylmethyl} -4-
[1- (S) -1,2,2-trimethylcyclopentyl]-
2,3-Dihydroxy-6-methylbenzene (Compound 4) 3
0 mg was obtained as an oil.

Fractions VI, VII and VIII are combined (1.35 g),
For Sephadex LH-20 (500 ml) chromatography, elution was performed with methanol-chloroform (7/3, v / v, 1.5). The obtained fractions 19 to 25 were collected and the solvent was removed under reduced pressure to obtain 250 mg of oily matter. This oily substance was further purified by silica gel (Wakogel C-300, 20 g) chromatography repeatedly and eluted with n-hexane-ethyl acetate (4/1, v / v, 100 ml). The obtained fractions 11 to 20 were collected, the solvent was removed under reduced pressure, and 1,1'-di [1- (S) -1,2,2-trimethylcyclopentyl] -2,2 ', 3,3'-tetra 70 mg of hydroxy-5,5'-ethylenebibenzene (Compound 5) was obtained as crystals.

<Physical data> Compound 1 colorless needle crystal (reconstituted from n-hexane) mp150-151 ° C (decomposition) ▲ [α] ²⁰ _D ▼ ＝ -73.6 (C = 0.35, CHCl ₃ ) High resolution mass spectrum 234.1630 [M ] ⁺ ; Calculated value 234.1629 (as C ₁₅ H ₂₂ O ₂ ) MS m / z (rel.int.): 234 [M] ⁺ (76), 164 (100), 152 (87) 219 (ε19200) 285 (ε2300) 3550 (OH), 1605 (aromatic) ¹ H-NMR (400 MHz, CDCl ₃ ): shown in FIG. The main peaks are as follows.

δ: 0.56 (3H, s) 1.07 (3H, s) 1.20 (3H, s) 2.24 (3H, s) 2.90 (1H, m) 4.96 (1H, s, OH) 5.11 (1H, s, OH) 6.67 ( 1H, d, J = 2.2Hz) 6.74 (1H, d, J = 2,2Hz) ¹³ C-NMR (100.18Hz, CDCl ₃ ) δ: 15.89 (q) 19.61 (t), 24.26 (q), 24.56 ( q), 26.56 (q), 36.91 (t), 39.76 (t), 44.14 (s), 50.03 (s), 112.22 (d), 121.56 (d), 123.04 (s), 139.61 (s), 140.02 ( s), 142.24 (s) compound 2 acicular crystals (recrystallized from n- _{hexane) mp258~261 ℃ [α] D =} -65.3 (C = 0.4, CHCl 3) CD (EtOH): Δε 222nm +4.4, Δε _202nm −24.1 High resolution mass spectrum 466.3084 [M] ⁺ ; Calculated value 466.3083 (as C ₃₀ H ₄₂ O ₄ ) MS m / z (rel.int.): 466 [M] ⁺ (100), 423 (10) , 396 (15) 384 (33) 3550 (OH) 213 (ε31000) 287 (ε3700) ¹ H-NMR (400 MHz, CDCl ₃ ): shown in FIG. The main peaks are as follows.

δ: 0.80 (3H, s) 1.21 (3H, s) 1.46 (3H, s) 1.94 (3H, s) 2.68 (1H, m) 4.77 (1H, s, OH) 5.59 (1H, s, OH) 6.86 ( 1H, s) ¹³ C-NMR (50.3 MHz, CDCl ₃ ) δ: 19.21 (q) 20.48 (t), 22.87 (q), 25.55 (q), 27.23 (q), 38.93 (t), 41.22 (t). , 44.98 (s), 51.36 (s), 117.09 (s), 122.71 (d), 126.70 (s), 133.88 (s), 140.59 (s), 141.64 (s) Compound 3 White powder, mp210 ~ 211 ° C ▲ [Α] ¹⁹ _D ▼ = −39.1 (C = 0.35, CHCl ₃ ) CD (EtOH): Δε _215nm −15.5, Δε _202nm ＋24.6 High resolution mass spectrum 466.3084 [M] ⁺ ; Calculated value 466.3083 (C ₃₀ H ₄₂ As O ₄ ) MS m / z (rel.int.): 466 [M] ⁺ (100), 423 (10), 396 (15) 384 (50) 3550 (OH) 218 (ε34000) 287 (ε5000) ¹ H-NMR (400 MHz, CDCl ₃ ): shown in FIG. The main peaks are as follows.

δ: 0.79 (3H, s) 1.21 (3H, s) 1.47 (3H, s) 1.93 (3H, s) 2.64 (1H, m) 4.77 (1H, s, OH) 5.58 (1H, s, OH) 6.85 ( 1H, s) ¹³ C-NMR (50.3 MHz, CDCl ₃ ) δ: 19.22 (q) 20.48 (t), 22.60 (q), 25.82 (q), 27.15 (q), 39.18 (t), 41.25 (t) , 44.90 (s), 51.37 (s), 117.04 (s), 122.66 (d), 126.71 (s), 133.85 (s), 140.66 (s), 141.61 (s) Compound 4 Oily substance High resolution mass spectrum 466.3082 [ M] ⁺ ; Calculated value 466.3083 (as C ₃₀ H ₄₂ O ₄ ) MS m / z (rel.int.): 466 [M] ⁺ (100), 384 (22), 247 (61) 216 (ε16000) 280 (ε3000) 3530 (OH) ¹ H-NMR (400 MHz, CDCl ₃ ): shown in FIG. The main peaks are as follows.

δ: 0.72 (3H, s) 0.76 (3H, s) 1.09 (3H, s) 1.17 (3H, s) 1.38 (3H, s) 1.41 (3H, s) 2.49 (1H, m) 2.61 (1H, m) 2.32 (3H, s) 3.82 (2H, s) 4.88 (1H, OH) 5.14 (1H, OH) 5.46 (1H, OH) 5.48 (1H, OH) 6.51 (1H, d, J = 1.8Hz) 6.70 (1H , d, J = 1.8Hz) 6.76 (1H, s) ¹³ C-NMR (100.18MHz, CDCl ₃ ) δ: 19.78 (q) 20.25 (t), 20.31 (t), 22.86 (q), 22.95 (q) , 25.20 (q), 25.41 (q), 26.43 (q), 26.89 (q), 32.16 (t), 39.09 (t), 39.18 (t), 40.71 (t), 40.91 (t), 44.84 (s) 45.05 (s), 50.97 (s), 51.21 (s), 112.40 (d), 121.16 (d), 122.23 (d), 123.16 (s), 126.73 (s), 129.37 (s), 131.12 (s), 133.91 (s), 141.85 (s), 141.95 (s), 142.20 (s), 143.85 (s) Compound 5 Prism crystal, mp201-203 ° C [α] ²³ _D ▼ = -46.1 (C = 0.5, CHCl ₃ ) 3550 (OH), 1600 (aromatic) 217 (ε31000) 288 (ε8900) ¹ H-NMR (400MHz, CDCl ₃ ): δ: 0.73 (3H, s) 1.16 (3H, s) 1.39 (3H, s) 2.80 (2H, s) 4.95 (1H, s) , OH) 5.37 (1H, s, OH) 6.49 (1H, d, J = 2.0Hz) 6.62 (1H, d, J = 2.0Hz) Example 2 Compound 1 (5 mg) was dissolved in 2 ml of pyridine, and then acetic anhydride was added. 0.
5 ml was added and left overnight at room temperature. Ice water was added, and the mixture was extracted with diethyl ether. Ether layer is 1N HCl, 10% NaHCO
₃ , washed well with saturated brine and dried over MgSO ₄ . The solvent was removed under reduced pressure to obtain 5.1 mg of 1- [1- (S) -1,2,2-trimethylcyclopentyl] -3,4-diacetoxy-5-methylbenzene (Compound 1a) as crystals.

Compound 1a mp 65.5-66.5 ° C 1780, 1595, 1490 ¹ H-NMR (90MHz, CDCl ₃ ): δ: 0.59 (3H, s) 1.04 (3H, s) 1.24 (3H, s) 2.18 (3H, s) 2.27 (3H, s) 2.29 ( 3H, s) 6.97 (1H, d, J = 2.2Hz) 7.05 (1H, d, J = 2.2Hz) MS m / z (rel.int): 318 [M] ⁺ (11), 276 (71), 234 (100), 206 (27), 164 (100), 152 (66) Example 3 Compound 4 (15 mg) was added with pyridine (0.7 ml) and acetic anhydride (0.5 ml).
It was dissolved in and reacted at room temperature for 2 hours. Thereafter, the same treatment as in Example 2 was carried out to give 1- [5- [1- (S) -1,2,2-trimethylcyclopentyl] -3,4-diacetoxyphenylmethyl] -4- [1- (S). 14 mg of -1,2,2-trimethylcyclopentyl] -2,3-diacetoxy-6-methylbenzene (Compound 4a) was obtained as an oil.

Compound 4a 249 (ε22500) 268 (ε1100) MS m / z (rel.int): 634 [M] ⁺ (26), 592 (32), 574 (19), 550 (100), 532 (27), 508 (20 ) 490 (30), 466 (10), 247 (23) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.63 (3H, s) 0.75 (3H, s) 0.95 (3H, s) 1.13 (3H, s) 1.21 (3H, s) 1.27 (3H, s) 2.13 (3H, s) 2.17 (3H, s) 2.23 (3H, s) 2.25 (3H, s) 2.27 (3H, s) 3.80 (1H, d, J = 16Hz) 3.91 (1H, d, J = 16Hz) 6.83 (1H, d, J = 2.0Hz) 6.91 (1H, d, J = 2.0Hz) 7.15 (1H, bs) Example 4 Compound 5 (22mg) Was dissolved in 0.5 ml of acetic anhydride and 1 ml of pyridine and reacted at room temperature for 2 hours. Thereafter, the same treatment as in Example 2 was carried out to give 1,1'-di [1- (S) -1,2,2-trimethylcyclopentyl] 2,2 ', 3,3'-tetraacetoxy-
20 mg of 5,5'-ethylenebibenzene (compound 5a) was obtained.

Compound 5a MS m / z (rel.int): 634 [M] ⁺ (16), 592 (27), 574 (14), 550 (100), 233 (31) ¹ H-NMR (400MHz, CDCl ₃ ) : As shown in FIG. The main peaks are as follows.

δ: 0.72 (3H, s) 1.12 (3H, s) 1.26 (3H, s) 2.24 (3H, s) 2.28 (3H, s) 2.50 (1H, m) 2.90 (2H, s) 6.91 (1H, d, J = 2.0Hz) 7.09 (1H, d, J = 2.0Hz) Pharmacological test Neurons in the cerebral cortex of a rat fetus (17-day-old) were aseptically removed and the method of Asou et al. [Asou, H. Brainless, 332] was used. , p355-357 (1985)]. That is, after removing the taken out cerebral hemisphere, meninges, blood vessels, etc., pass through a stainless mesh (pore size 140 μm), and the isolated cells are suspended in a medium (15% calf serum, Eagle medium containing 1 g / glucose), 1.5 × 10 ⁶ cells were seeded on a 35 mm diameter dish coated with poly-L-lysine to start the culture (37 ° C., 3% CO ₂ ), and after 24 hours, the medium was replaced with a medium containing the test compound. The cells were further cultured for 9 days.

On the 4th, 7th, and 10th day after the start of culture, neurite outgrowth (NS) and network formation between nerve cells (N) were observed under a phase-contrast microscope.
N) and the extent of nerve fiber bundle elongation (NB) were compared and evaluated with the control group. The results are shown in Table 1 below.

On the 10th day after the start of the culture, the cells were scraped with 10 mM-phosphate buffer (pH 7.4) to measure the oxygen activity of choline acetyltransferase (ChAT) by the method of Fonum [Fonn].
um, F .; J. Neurochem., 34 , 407-409 (1975)], and the protein amount was determined by the Lowry method [Lowry, OH; J. Biol. chem., 19 ].
3 , 265-275 (1951)]. That is, the enzymatic activity of ChAT was determined by a certain amount of homogenate [ ¹⁴ C].
-Incubated with acetyl-CoA and choline for 30 minutes at 37 ° C, the produced [ ¹⁴ C] -acetylcholine was measured by a liquid scintillation counter, and the rate of acetylcholine synthesis (Pmol / min / dish or Pmol / min / mg protein) was measured. ). The results are shown in Table 2.

Formulation Example 1 Compound (2) 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were produced in a tablet by a conventional method.

Formulation Example 2 Compound (3) 200 mg Butto sugar 250 mg Distilled water for injection Appropriate amount 5 ml Dissolve compound (3) and butto sugar in distilled water for injection, then inject into a 5 ml ampoule, and replace with nitrogen at 121 ° C. After autoclaving for 15 minutes, an injection of the above composition was obtained.

[Brief description of drawings]

1 to 5 are ¹ H-NMR spectra of the compound of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 69/21 C07C 69/21

Claims (1)

(57) [Claims] 1. Wherein R is a group (R ¹ represents a hydrogen atom or a lower alkanoyl group.), (R ¹ is the same as above.) Or group Indicates. ] The cyclopentane compound represented by these.