JPH11228420A - Vascularization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine having excellent vascularization inhibitory action and easy to synthesize by including a new 9α-fluoro-6α- methylprogesterone derivative as an active ingredient. SOLUTION: This inhibitor includes a progesterone compound of formula I (R is H, acetyl or a 1-17C alkyl; R<2> is H or hydroxyl group) or a salt thereof. The compound of formula I is e.g. 6α-methyl-11β, 17α, 21-trihydroxy-4- pregnene-3,20-dione. The compound of formula I is obtained e.g. by treating a 9α-fluoroprogesterone compound of formula II, such as fluorometholone, with a metal catalyst, e.g. rhodium. It is preferable that the compound of formula I is used as a pharmaceutical composition in combination with usual pharmaceutical carrier(s) and that this compound is administered at a daily dose of 0.1-600 mg per adult in one to five portions. This compound is useful e.g. for the treatment of cancer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a progesterone compound and a pharmaceutically acceptable salt thereof which have an excellent angiogenesis inhibitory activity and are useful as a therapeutic agent for malignant tumors, diabetic retinopathy, rheumatism and the like. And an angiogenesis inhibitor.

[0002]

2. Description of the Related Art Malignant tumors, diabetic retinopathy, rheumatism and the like are known as diseases in which angiogenesis is significantly involved in the etiology or deterioration of the pathological condition. Among them, the relationship between malignant tumors and angiogenesis has been extensively studied, and it has been elucidated that angiogenesis is particularly important in metastasis and prognosis of malignant tumors. In recent years, several substances showing angiogenesis inhibitory activity have been reported, for example, sulfated polysaccharide, platelet factor-4 (PF-4), pentosan polysulfate, TNP-470
(Analogs of the fungus product fumagillin), tissue metalloproteinase inhibitor (TIMP), minocycline and the like are known. However, these angiogenesis inhibitory actions cannot be said to be sufficient, and the development of more excellent angiogenesis inhibitory actions has been desired.

[0003] In addition, since estrogen is closely involved in the occurrence of endometrial cancer and breast cancer, antiestrogens and progesterone in high doses are used for the treatment. From such a viewpoint, medroxyprogesterone acetate (MPA), which is one of progesterone,
Although used as a therapeutic agent for breast cancer and endometrial cancer, it has recently been reported that this MPA has a weak but angiogenesis inhibitory effect. We have found that 9α-fluoro-6α-
It has been found that a methylprogesterone derivative has a potent angiogenesis inhibitory activity at least 20 times that of MPA (WO95 / 26974). However, the progesterone derivative (1)
Had no clear angiogenesis inhibitory effect. Also, the preparation of these progesterone derivatives requires multi-step reactions from readily available compounds,
Synthesis of the compound on an industrial scale has been difficult.

[0004]

An object of the present invention is to provide a progesterone derivative which is easily synthesized and has an excellent angiogenesis inhibitory action, based on such facts.

[0005]

Means for Solving the Problems The present inventors synthesized several progesterone derivatives and screened for their angiogenesis inhibitory action.
The present inventors have found that a novel 9α-fluoro-6α-methylprogesterone derivative represented by the formula (1) has a strong angiogenesis inhibitory effect, and have completed the present invention.

[0006]

DETAILED DESCRIPTION OF THE INVENTION That is, the present invention provides the following general formula (1):

[0007]

Embedded image

Wherein R ¹ is hydrogen, an acetyl group or an alkyl group having 1 to 17 carbon atoms, and R ² is hydrogen or a hydroxyl group. It provides an inhibitor.

Examples of the compound (1) include R ¹ and R ²
A progesterone compound (2) wherein R ¹ is hydrogen and a progesterone compound (3) wherein R ¹ is hydrogen and R ² is a hydroxyl group
And the like. To synthesize the conventional (2), 10
Steps were required (WO95 / 26974). But,
Hydroprogesterone compound (2) can be synthesized in three steps of reduction, dehydration, and fluorination of progesterone compound (4). Also, in order to synthesize the conventional (3), four steps were required (FR222336).
Four). However, by treating the 9α-fluoroprogesterone compound (5) such as fluorometholone with a metal catalyst such as rhodium, it has become possible to synthesize the 1,2-dihydroprogesterone compound (3) in one step. As described above, the progesterone derivatives (2) and (3) can be synthesized from the available starting materials (4) and (5) by the present invention in a step significantly shorter than the conventional method (FIGS. 1 and 2). ). Furthermore, compounds (2) and (3) have a hydroxyl group, and when used as a medicine, derivatives for improving pharmacokinetics (absorption and distribution), sustaining drug action and improving solubility in water, etc. (Characteristics of New Pharmacology, 273-281, Nankodo). Examples of derivatization include glycosylation with sugars such as glucose and galactose (Japanese Patent Publication No. 1-43553, JP-A-9-95672), esterification (New Experimental Chemistry, 14 (II) 1002-1056), and phosphate ester. (Synthesis, 737-752 (1977))
Any of them can be synthesized by a known method.

When the compound (1) of the present invention is used for these purposes, it is preferably used as a pharmaceutical composition together with a commonly used pharmaceutical carrier. As such pharmaceutical compositions, oral compositions such as tablets, granules, capsules, etc., injection compositions, rectal compositions, transdermal compositions and the like are used. In preparing these compositions, pharmaceutical carriers such as excipients, binders, disintegrants, solubilizers, and flavoring agents are used.

When the compound (1) of the present invention is used as an angiogenesis inhibitor, the dose varies depending on the administration route, the patient's condition, age, body weight, etc., but is usually 0.1 to 1 day per adult.
Preferably, 600 mg is administered in 1 to 5 divided doses.

[0012]

The production examples of the compounds used in the present invention are shown below as examples, and the results of pharmacological tests of these compounds are shown below.

Example 1 6α-methyl-11β, 17α, 21-trihydroxy-4-pregnene-3,20-dione 6α-methyl-11β, 17α, 21-trihydroxy-1,4-pregnadiene-3,20 Chlorotris (triphenylphosphine) rhodium (I) (catalytic amount) was added to a dichloromethane-ethanol (1: 6) solution (3.5 ml) of -dione (74.8 mg, 0.200 mmol) in a hydrogen stream at room temperature (20-25 ° C). ) For 24 hours.
After the residue was filtered, the reaction solution was concentrated and subjected to silica gel column chromatography to obtain an enone compound (58.9 mg, 78%) from a 70% ethyl acetate / hexane stream.

¹ H NMR [500 MHz, CDCl ₃ ] δ: 0.96 (3H,
s), 1.06 (3H, d, J = 6.5Hz), 1.42 (3H, s), 3.03-3.07 (1
H, m), 4.30 (1H, dd, J = 4.5 and 19.8Hz), 4.46-4.52 (1
H, m), 4.65 (1H, dd, J = 1.5 and 19.8Hz), 5.73 (1H, d,
J = 1.5 Hz); MS m / z: 376 (M ⁺ ). Example 2 11β, 17α-dihydroxy-6α-methyl-4-
Pregnene-3,20-dione The enone compound obtained in Reference Example 1 (58.9 mg, 0.157 mmo
l) to a pyridine solution (3.0 ml) in methanesulfonyl chloride
(0.02 ml), and the mixture was stirred at an external temperature of 0-5 ° C. for 4.25 hours. After completion of the reaction, ice water and ethyl acetate were added to the reaction solution, and 10% HCl,
Wash with saturated NaHCO ₃ aqueous solution and saturated saline solution in that order, Na ₂ SO ₄
And dried. After evaporation of the solvent, the residue obtained is
(2.0 ml) and sodium iodide (47.1 mg, 0.314
mmol) and heated under reflux for 1.2 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was dissolved in acetic acid (3.0 ml). After stirring at room temperature for 1 hour, zinc powder (30.8 mg, 0.471 mmol)
And further stirred at room temperature for 23 hours. After filtration, the residue was diluted with ethyl acetate, neutralized with a saturated aqueous solution of NaHCO ₃ , extracted with ethyl acetate, washed with brine, and dried over Na ₂ SO ₄ . After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to obtain a methyl compound (38.4 mg, 68%) from a 50% ethyl acetate / hexane stream.

¹ H NMR [500 MHz, CDCl ₃ ] δ: 0.91 (3H,
s), 1.05 (3H, d, J = 6.0Hz), 1.47 (3H, s), 2.13 (3H,
s), 4.19-4.21 (1H, m), 5.57 (1H, d, J = 2.0 Hz); MS m / z: 360 (M ⁺ ). Example 3 9α-fluoro-17α-hydroxy-6α-methyl- 4-Pregnene-3,20-dione (2) Methyl form obtained in Example 2 (243 mg, 0.674 mmol)
Was dissolved in hydrogen pyridine (4.0 ml) at an external temperature of -15 ° C and stirred at an external temperature of -15 ° C for 89 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml, 30 ml). The organic layer was washed with 10% HCl, a saturated aqueous solution of NaHCO ₃ and a saturated saline solution in that order, and dried over Na ₂ SO ₄ . After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography.
(59.5 mg, 24%).

¹ H NMR [500 MHz, CDCl ₃ ] δ: 0.75 (3H,
s), 1.11 (3H, d, J = 6.5Hz), 1.30 (3H, s), 2.27 (3H,
s), 5.89 (1H, d, J = 1.5 Hz); MS m / z: 362 (M ⁺ ). Example 4 11β, 17α-dihydroxy-9α-fluoro-6
α-methyl-4-pregnene-3,20-dione (3) 11β, 17α-dihydroxy-9α-fluoro-6α-methyl-
1,4-pregnadiene-3,20-dione (fluorometholone) (S
igma) (188 mg, 0.500 mmol) in benzene-ethanol solution and chlorotris (triphenylphosphine) rhodium (I)
(Amount of catalyst) was added, and the mixture was stirred at room temperature (20 to 25 ° C) for 15 hours under a hydrogen stream. After the residue was filtered, the reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography.
The solvent was distilled off from the ethyl acetate elution part. The obtained residue was recrystallized from ethanol-benzene to give 1,2-dihydrofluorometholone (180 mg, 95%).

¹ H NMR [300 MHz, CDCl ₃ ] δ: 1.00 (3H,
s), 1.27 (3H, s), 2.66 (3H, s), 5.00-5.40 (1H, m),
5.85 (1H, s); IR: (CHCl ₃ ) νmax 3400, 1730, 1710, 1660. Test example Angiogenesis inhibitory effect Angiogenesis inhibitory effect was tested by the rabbit corneal method using the cornea of a Japanese white rabbit (male). did. That is, several drops of venoxil are dropped on the cornea of a Japanese white rabbit (male) under anesthesia, and then the eyeball is exposed and the cornea is half-incised. A rectangular pocket is formed in the cornea, and a tumor mass derived from DMBA (7,12-dimethylbenz [a] anthracene) -induced rat breast cancer and specimen-containing E
Place V (ethylene vinyl acetate copolymer) pellets at the bottom of the pocket and close the cut. The control group is treated similarly, and an EV pellet (control) containing no tumor mass and no specimen is placed.

On the 10th day after transplantation, the eyeball was exposed and the cornea was observed.-: No new blood vessels were observed. ±: New blood vessels were observed, but they did not reach the transplanted tumor. +: New blood vessels Has reached the transplanted tumor. The dose is 0 for all samples.
3 mg / pellet, and the number of transplanted corneas was 8 (9 for the control).

Table 1 shows the results.

[0020]

[Table 1]

As a result, in the control, neovascularization was observed in 8 out of 9 cases. On the other hand, when the compounds of Examples 3 and 4 were administered, neovascularization was not observed in 5 out of 8 cases, and it is clear that compound (1) has an excellent angiogenic action.

[0022]

The compound (1) has an excellent angiogenesis inhibitory effect and is effective as a therapeutic agent for malignant tumors such as cancer, diabetic retinopathy, rheumatism and the like.

[0023]

[Brief description of the drawings]

FIG. 1 is a diagram showing a synthesis example of a compound (2).

FIG. 2 is a view showing a synthesis example of a compound (3).

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hiroshi Tsuboi, 540 Narita, Odawara-shi, Kanagawa Meiji Dairies Co., Ltd. Inside the Health Science Laboratory Co., Ltd. (72) Inventor Natsuko Murata 540 Narita, Odawara-shi, Kanagawa Meiji Dairies Co., Ltd. In-house (72) Inventor Katsuyuki Uchida 540 Narita, Odawara-shi, Kanagawa Meiji Dairies Co., Ltd. Health Science Laboratory Co., Ltd. (72) Inventor Hideo Nemoto 2-9-1, Momijigaoka, Yamato-cho, Kurokawa-gun, Miyagi Prefecture (72) Inventor Hibino 2-7-15 Hisamatsudai, Fukuyama City, Hiroshima Prefecture

Claims (6)

[Claims] 1. The following general formula (1): [Wherein, R ¹ is hydrogen, an acetyl group or a carbon number of 1 to 17;
Wherein R ² represents hydrogen or a hydroxyl group], and an angiogenesis inhibitor comprising as an active ingredient a progesterone compound represented by the formula: 2. The angiogenesis inhibitor according to claim ¹ , wherein R ¹ is hydrogen and R ² is hydrogen, and the pharmaceutically acceptable salt thereof as an active ingredient. 3. The method according to claim 1, wherein R ¹ is a hydroxyl group and R ² is hydrogen.
An angiogenesis inhibitor comprising the progesterone compound described above and a pharmaceutically acceptable salt thereof as an active ingredient. 4. A therapeutic agent for malignant tumors comprising the progesterone compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A therapeutic agent for diabetic retinopathy comprising the progesterone compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A therapeutic agent for rheumatism comprising the progesterone compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.