JP2007161677A - Anti-platelet agent containing cyclic diamine derivative as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having a blood platelet coagulation-inhibiting action. <P>SOLUTION: This agent for preventing/treating diseases caused by blood platelet coagulation contains a cyclic diamine derivative represented by the general formula (1), its salt or their solvates as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a cyclic diamine derivative having excellent platelet aggregation inhibitory action, a salt thereof, or a solvate thereof.

  Platelets, also called plug globules, are important constituent particles of blood, and normally accumulate in damaged blood vessels during a trauma and exert a hemostatic function. However, in arteriosclerotic disease sites, blood vessel walls are often damaged by blood flow, lipid deposition, etc., causing vascular breakdown, and platelets that are activated and accumulated in these sites are often found in arteriovenous blood vessels. Induces thrombus formation. On the other hand, an antiplatelet agent (platelet aggregation inhibitor) has a function of suppressing the enhancement of platelet aggregation that triggers the formation of thrombus. Therefore, antiplatelet agents lead to fatal symptoms from diseases caused by thrombus formation in arteriovenous blood vessels, such as decreased oxygen and nutrient supply in peripheral tissues including brain, heart and other organs caused by ischemia It is thought to be effective in the prevention and treatment of diseases, and is considered to be particularly important for the prevention and treatment of arteriosclerosis, myocardial infarction, cerebral thrombosis, peripheral arterial occlusion that develops with diabetes and hypertension. Literatures 1-4).

From this point of view, anti-platelet agents such as aspirin, ticlopidine, clopidogrel, and cilostazol reduce the blood coagulation progression field by suppressing platelet aggregation, and suppress the ability of thrombus and clot formation at pathological vascular injury sites. It is used for the purpose of However, it is known that aspirin induces damage to the vasculature by inhibiting the production of gastrointestinal mucosal protective substances and causing severe gastrointestinal disorders as well as the production of vasodilatory substances ( Non-Patent Documents 5 and 6). Furthermore, ticlopidine and clopidogrel are known to induce granulocytopenia (Non-Patent Documents 7 to 9), and cilostazol is known to cause severe headache (Non-Patent Document 10). In addition, since the existence of patients with low sensitivity to these drugs is known (Non-patent Document 11), development of new antiplatelet agents is desired.
Matsuda Tamotsu & Nobuyoshi Masayoshi, Antithrombotic Therapy, Nanedo Co., Ltd. (1991) Matsuda Yasu, Hemostasis and Thrombus Therapy, Shinsei Medical Publishing Co., Ltd. (1996) Yasuo Ikeda et al., Thrombus and Circulation 6: 9 (1998) AD Michelson, Platelets, Academic Press, (2002) B. Cryer, N. Engl. J. Med. (2003) 352: 3 GJ Hankey et al., BMJ (2004) 328: 477 S. Matetzky et al., Circulation (2004) 109: 3171 M. Cattaneo, Arterioscler. Thromb. Vasc. Biol. (2004) 24: 1980 Fumio Goto et al., Highlights of the 17th Ticlopidine Symposium (2003) K. Yamashita et al., Arzneim.-Forsch./Drug Res. (1990) 40 (I) 587 RR Gollapudi et al., JAMA (2004) 292: 3017

  Therefore, an object of the present invention is to provide a new platelet aggregation inhibitor.

As a result of intensive studies in view of such circumstances, the present inventors have found a compound group having a piperazine structure or a homopiperazine structure included in WO99 / 02520, which is known to be useful as an antiallergic agent. The present invention was completed by finding that it has an excellent inhibitory effect on platelet aggregation.
That is, the present invention relates to the general formula (1),

[Wherein R ¹ represents a hydrogen atom, a hydroxy group, an aralkyloxy group or a halogen atom;
R ² represents a hydrogen atom or a C _1-6 alkyl group;
A represents —C (R ³ ) ═CH— (wherein R ³ represents a hydrogen atom or a hydroxy group),
—CH═N—, or —N (R ⁴ ) — (wherein R ⁴ represents a hydrogen atom, a C _1-6 alkyl group or an alkoxyalkyl group), —O—, or —S—;
B is a single bond, —C (R ⁵ ) (R ⁶ ) — (CH ₂ ) _k — (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group; 0 to 2)
_{-S (O) q CH (R} 7) - ( where q is a number of 0 to 2, R ⁷ represents a hydrogen atom or a hydroxy group), or indicates -CH = CH-;
E represents a single bond or — (CH ₂ ) ₃ —;
W and Y are the same or different and each represents —CH ₂ — or —CO—;
Z represents an oxygen atom or a sulfur atom;
l is 0 or 1, m is 2 or 3, and n is a number from 0 to 5. However, when B is a single bond, E is — (CH ₂ ) ₃ —, and when B is a group other than a single bond, E is a single bond. ]
The present invention provides a preventive / therapeutic agent for diseases caused by platelet aggregation, comprising as an active ingredient a cyclic diamine derivative represented by the formula: salt thereof or a solvate thereof.

  Furthermore, the present invention provides use of the cyclic diamine derivative represented by the general formula (1), a salt thereof, or a solvate thereof for the production of a prophylactic / therapeutic agent for diseases caused by platelet aggregation. is there.

  Furthermore, the present invention provides a method for treating a disease caused by platelet aggregation, which comprises administering an effective amount of the cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof. Is.

  The cyclic diamine derivative of the present invention, a salt thereof, or a solvate thereof is excellent in platelet aggregation inhibitory action, and diseases caused by platelet aggregation, such as myocardial infarction, cerebral thrombosis, peripheral artery occlusion, obstructive thromboangiitis, etc. It can be used for prevention and treatment of ischemic diseases.

In the general formula (1), examples of the halogen atom in R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the aralkyloxy group include a phenyl C _1-6 alkyloxy group. R ¹ is preferably a hydrogen atom.

In the general formula (1), the C _1-6 alkyl group in R ² , R ⁴ , R ⁵ and R ⁶ is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group. , Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group, etc., with a methyl group being particularly preferred.

In the general formula (1), the alkoxyalkyl group in R ⁴ is an alkyl group having 1 to 6 carbon atoms substituted by an alkoxy group having 1 to 6 carbon atoms, such as a methoxymethyl group, a methoxyethyl group, or a methoxypropyl group. Group, methoxybutyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, ethoxybutyl group, propoxymethyl group, propoxyethyl group, propoxypropyl group, propoxybutyl group and the like.

In the general formula (1), R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are particularly preferably a hydrogen atom or a methyl group.

In the general formula (1), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z, l, k and q are as defined above,

Preferably, the following groups are mentioned.

  Among these groups, the following groups are particularly preferable, and the case where 1 = 0 in the following groups is more preferable.

W and Y are each preferably —CH ₂ —. n is preferably 1 to 4.
In the general formula (1), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z, l, k and q are as defined above,

Preferably, the following groups are mentioned.

Of these groups, the following groups are particularly preferred. Further, in these groups, when k = 1, both R ⁵ and R ⁶ are preferably hydrogen atoms, and Z is preferably an oxygen atom.

As a more preferred structure, the general formula (2)

[Wherein, G represents —CH═CH— or —N (R ⁸ ) — (wherein R ⁸ represents a hydrogen atom or a C _1-6 alkyl group);
The dashed portion in the quinoline ring indicates that there may be a double bond;
J represents a C _1-6 alkylene group;
R ⁹ represents a hydrogen atom or a C _1-6 alkyl group;
m represents an integer of 2 or 3. ]
Can be mentioned.

In the general formula (2), J is particularly preferably a C _2-5 alkylene group. JO- is preferably substituted at the 5-position, 6-position, or 7-position of the quinoline ring.
R ⁸ and R ⁹ have the same definitions as R ⁴ and R ^2, and R ⁸ and R ⁹ are particularly preferably a hydrogen atom or a methyl group. Further, R ⁹ is preferably substituted at the 8-position of the quinoline ring.

  The salt of the cyclic diamine derivative represented by the general formula (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, hydrobromide, hydroiodide, and the like. Acid addition salts of mineral acids such as sulfates, nitrates, phosphates, carbonates, or benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, sulphate And acid addition salts of organic acids such as acid salts, maleates, fumarate, tartrate, citrate. Of these, oxalate or fumarate is particularly preferable.

  In addition, the cyclic diamine derivative represented by the general formula (1) of the present invention may exist in the form of a solvate represented by a hydrate or a tautomer of a keto-enol. Solvates and isomers are also encompassed by the present invention.

The cyclic diamine derivative represented by the general formula (1) of the present invention can be produced, for example, by the method described in WO99 / 02520 pamphlet.
The cyclic diamine derivative represented by the general formula (1) of the present invention can be further purified by a usual purification means such as recrystallization or column chromatography, if necessary. If necessary, the above-mentioned desired salt can be obtained according to a conventional method.

  The antiplatelet agent of the present invention comprising the thus obtained cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof as an active ingredient is obtained from rat platelet-rich plasma, as shown in Examples below. Used to strongly suppress the aggregation ability induced by the collagen used. Therefore, the antiplatelet agent of the present invention is a disease caused by platelet aggregation, for example, ischemic disease, particularly myocardial infarction, which develops based on vascular disorders associated with hypertension, vasospasm, arteriosclerosis, diabetes alone or in combination. It is effective for the prevention and treatment of cerebral thrombosis, peripheral artery occlusion or obstructive thromboangiitis.

  The medicament of the present invention contains a cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof, and may be used alone, but is usually pharmaceutically acceptable. Used in combination with carriers, additives and the like. The administration form of the medicine is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceuticals suitable for these administration forms can be produced by known preparation methods.

  When preparing an oral solid preparation, the cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof, an excipient, and further a binder, a disintegrant, and a lubricant as necessary. After adding a coloring agent, a flavoring agent, a flavoring agent, etc., tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, and tartaric acid.

  When preparing an oral liquid preparation, a conventional method by adding a flavoring agent, a buffering agent, a stabilizer, a flavoring agent and the like to the cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof. Can be used to produce liquid preparations, syrups, elixirs and the like. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. And a subcutaneous, intramuscular and intravenous injection can be produced by a conventional method. Examples of the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a cyclic diamine derivative represented by the general formula (1), a salt thereof or a solvate thereof, a known suppository carrier, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc. After adding a surfactant such as Tween (registered trademark) as necessary, it can be produced by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the cyclic diamine derivatives represented by the general formula (1), salts thereof or solvates thereof are necessary. According to the conventional method, they are mixed and formulated. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.

  In addition to the above, inhalants, eye drops, and nasal drops can be prepared by conventional methods.

  The dose of the antiplatelet agent of the present invention is appropriately selected depending on the symptoms, but is preferably 1 to 2000 mg, preferably 1 to 500 mg, more preferably 1 to 200 mg per day. Moreover, administration may be performed once a day, but may be divided into two or more.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

<Test example>
For the compounds 1 to 12 and Cylostazol (comparative compound) shown in Table 1 and Table 2 below, the inhibitory effect on rat platelet aggregation induced by collagen was measured according to the following method.

(1) Test animals and breeding environment Wistar male rats (Japan SLC) 8-10 weeks old were tested. Throughout the experimental period, the light and dark cycle (bright period with room light: 7 am to 7 pm), raised in a breeding room maintained at a temperature of 23 ± 3 ° C. and a humidity of 55 ± 15%, solid feed (CE2; Oriental yeast) Industrial) and tap water ad libitum.
(2) Drug preparation Each compound and cilostazol were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM. During the period until use, it was stored in a freezer (−30 ° C.) protected from light.

(3) Test Method The rat used in Test Example 1 was anesthetized with sodium pentobarbital (Tokyo Kasei Co., Ltd., 50 mg / kg intraperitoneal administration), and 1/10 amount of sodium citrate (Wako Pure Chemical Industries) aqueous solution from the abdominal vena cava. Blood was collected to contain. Subsequently, a centrifugation operation (domestic centrifuge, H500R) was performed at 25 ° C. at 1,600 rpm for 7 minutes, and a platelet-rich plasma fraction (PRP) corresponding to about 30% of the whole blood was collected. The remaining blood was further centrifuged at 3,000 rpm for 5 minutes to obtain plasma (PPP).
Platelet aggregation measurement was performed using MCM Hematracer 313M (MC Medical). That is, 0.1 mL of PRP was added to a dedicated cuvette, 0.2 mL of PPP was added as a control, and 0.011 mL of dedicated collagen suspension (MC Medical, MCM Collagen) was added to PRP at a time, and platelet aggregation was measured for 10 minutes. .
The platelet aggregation inhibitory action of each compound was determined as the maximum aggregation (%) generated when a collagen suspension was added so that the final concentration was 0.02 mg / mL. The compound was added so as to have a final concentration of 0.1 mM, and a compound that suppressed aggregation of 50% or more was added so as to have a final concentration of 0.03 mM.

(4) Data processing method The inhibitory effect on platelet aggregation is the maximum at the time of addition of the compound DMSO solution of the same dose (sample) to the maximum coagulation (%) at the time of addition of 0.001 mL of DMSO (1/100 amount) (control). It was shown by comparison of aggregation (%) (aggregation inhibition rate (%) obtained by the following formula).
Aggregation inhibition rate (%) = (1− (maximum sample aggregation / maximum control aggregation)) × 100
For compounds that showed an aggregation inhibitory action of 50% or more at 0.1 mM, the aggregation inhibitory action at 0.03 mM was measured, and each inhibitory rate was applied to the following formula to determine the compound concentration required for 50% inhibition (IC ₅₀ ).
IC ₅₀ (M) = ((0.0001 × (50−I _0.03 ) − (0.00003 × (50−I _0.1 ))) / (I _0.1 −I _0.03 ))
However,
I _0.03 (%) = Inhibition rate when compound _0.03 mM is added I _0.1 (%) = Inhibition rate when compound 0.1 mM is added

(5) Test results Tables 1 and 2 show the test results of the collagen-induced rat platelet aggregation inhibitory effects of compounds 1 to 13 and Cilostazol. Each compound 1-13 exhibited an inhibitory action on platelet aggregation at 0.1 mM. In particular, Example 11 showed an IC ₅₀ value of 59 μM, which was confirmed to be a potent antiplatelet agent.

Claims (8)

General formula (1)

[Wherein R ¹ represents a hydrogen atom, a hydroxy group, an aralkyloxy group or a halogen atom;
R ² represents a hydrogen atom or a C _1-6 alkyl group;
A represents —C (R ³ ) ═CH— (wherein R ³ represents a hydrogen atom or a hydroxy group),
-CH = N -, - N ( R 4) - ( wherein R ⁴ represents a hydrogen atom, an alkyl group or an alkoxyalkyl group of C _1-6), - O-, or -S- shown;
B is a single bond, —C (R ⁵ ) (R ⁶ ) — (CH ₂ ) _k — (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group; 0 to 2)
_{-S (O) q CH (R} 7) - ( where q is a number of 0 to 2, R ⁷ represents a hydrogen atom or a hydroxy group), or indicates -CH = CH-;
E represents a single bond or — (CH ₂ ) ₃ —;
W and Y are the same or different and each represents —CH ₂ — or —CO—;
Z represents an oxygen atom or a sulfur atom;
l is 0 or 1, m is 2 or 3, and n is a number from 0 to 5. However, when B is a single bond, E is — (CH ₂ ) ₃ —, and when B is a group other than a single bond, E is a single bond. ]
A prophylactic / therapeutic agent for diseases caused by platelet aggregation, comprising as an active ingredient a cyclic diamine derivative represented by the formula: salts thereof or solvates thereof. The active ingredient is general formula (2)

[Wherein, G represents —CH═CH— or —N (R ⁸ ) — (wherein R ⁸ represents a hydrogen atom or a C _1-6 alkyl group);
The dashed portion in the quinoline ring indicates that there may be a double bond;
J represents a C _1-6 alkylene group;
R ⁹ represents a hydrogen atom or a C _1-6 alkyl group;
m represents an integer of 2 or 3. ]
The prophylactic / therapeutic agent according to claim 1, which is a cyclic diamine derivative represented by the formula: The preventive / therapeutic agent according to claim 1 or 2, wherein the disease is an ischemic disease. The prophylactic / therapeutic agent according to claim 3, wherein the ischemic disease is myocardial infarction, cerebral thrombosis, peripheral artery occlusion or obstructive thromboangiitis. General formula (1)

[Wherein R ¹ represents a hydrogen atom, a hydroxy group, an aralkyloxy group or a halogen atom;
R ² represents a hydrogen atom or a C _1-6 alkyl group;
A represents —C (R ³ ) ═CH— (wherein R ³ represents a hydrogen atom or a hydroxy group),
-CH = N -, - N ( R 4) - ( wherein R ⁴ represents a hydrogen atom, an alkyl group or an alkoxyalkyl group of C _1-6), - O-, or -S- shown;
B is a single bond, —C (R ⁵ ) (R ⁶ ) — (CH ₂ ) _k — (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group; 0 to 2)
_{-S (O) q CH (R} 7) - ( where q is a number of 0 to 2, R ⁷ represents a hydrogen atom or a hydroxy group), or indicates -CH = CH-;
E represents a single bond or — (CH ₂ ) ₃ —;
W and Y are the same or different and each represents —CH ₂ — or —CO—;
Z represents an oxygen atom or a sulfur atom;
l is 0 or 1, m is 2 or 3, and n is a number from 0 to 5. However, when B is a single bond, E is — (CH ₂ ) ₃ —, and when B is a group other than a single bond, E is a single bond. ]
The cyclic diamine derivative represented by these, its salt, or those solvates are used for manufacture of the preventive / therapeutic agent of the disease resulting from platelet aggregation. The compound represented by the general formula (1) is represented by the general formula (2).

[Wherein, G represents —CH═CH— or —N (R ⁸ ) — (wherein R ⁸ represents a hydrogen atom or a C _1-6 alkyl group);
The dashed portion in the quinoline ring indicates that there may be a double bond;
J represents a C _1-6 alkylene group;
R ⁹ represents a hydrogen atom or a C _1-6 alkyl group;
m represents an integer of 2 or 3. ]
The use according to claim 5, which is a cyclic diamine derivative represented by the formula: General formula (1)

[Wherein R ¹ represents a hydrogen atom, a hydroxy group, an aralkyloxy group or a halogen atom;
R ² represents a hydrogen atom or a C _1-6 alkyl group;
A represents —C (R ³ ) ═CH— (wherein R ³ represents a hydrogen atom or a hydroxy group),
-CH = N -, - N ( R 4) - ( wherein R ⁴ represents a hydrogen atom, an alkyl group or an alkoxyalkyl group of C _1-6), - O-, or -S- shown;
B is a single bond, —C (R ⁵ ) (R ⁶ ) — (CH ₂ ) _k — (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group; 0 to 2)
_{-S (O) q CH (R} 7) - ( where q is a number of 0 to 2, R ⁷ represents a hydrogen atom or a hydroxy group), or indicates -CH = CH-;
E represents a single bond or — (CH ₂ ) ₃ —;
W and Y are the same or different and each represents —CH ₂ — or —CO—;
Z represents an oxygen atom or a sulfur atom;
l is 0 or 1, m is 2 or 3, and n is a number from 0 to 5. However, when B is a single bond, E is — (CH ₂ ) ₃ —, and when B is a group other than a single bond, E is a single bond. ]
A method for treating a disease caused by platelet aggregation, which comprises administering an effective amount of the cyclic diamine derivative represented by the formula: salt thereof or solvate thereof. The compound represented by the general formula (1) is represented by the general formula (2).

[Wherein, G represents —CH═CH— or —N (R ⁸ ) — (wherein R ⁸ represents a hydrogen atom or a C _1-6 alkyl group);
The dashed portion in the quinoline ring indicates that there may be a double bond;
J represents a C _1-6 alkylene group;
R ⁹ represents a hydrogen atom or a C _1-6 alkyl group;
m represents an integer of 2 or 3. ]
The treatment method of Claim 7 which is a cyclic diamine derivative represented by these.