Pyrimidine diamine compounds and uses thereof
By providing pyrimidine diamine compounds and their preparation methods, the problem of significant side effects in existing hair loss treatments has been solved, achieving the effects of promoting hair growth and inhibiting hair loss, especially showing superior effects compared to minoxidil in chemotherapy and androgenic alopecia.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANJING CHEMPION BIOTECHNOLOGY CO LTD
- Filing Date
- 2026-04-07
- Publication Date
- 2026-05-29
AI Technical Summary
Existing hair loss treatments such as minoxidil and finasteride have side effects, and hair transplantation treatments vary from person to person. There is a need to find substances that promote hair growth with fewer side effects and significant effects.
A pyrimidine diamine compound and its preparation method are provided, which can be applied to a pharmaceutical composition by topical skin application or oral administration to promote hair growth and prevent hair loss.
Pyrimidine diamine compounds can promote the entry of telogen effluvium hairs into the anagen phase, stimulate hair growth, inhibit chemotherapy-induced androgenetic alopecia, and are more effective than minoxidil. They also reduce the growth rate and weight of hair after hair loss.
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Figure CN122103234A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medicinal chemistry, specifically to a pyrimidine diamine compound and its applications. Background Technology
[0002] In clinical practice, androgenetic alopecia is the most common type, accounting for 80% to 90% of hair loss cases. Secondly, telogen effluvium is also relatively common in women and young people.
[0003] Currently, the FDA has only approved topical minoxidil and oral finasteride as treatments for hair loss. However, both drugs have significant side effects. Minoxidil requires long-term consistent use, and hair loss symptoms will reappear after discontinuation; while long-term use of finasteride can lead to side effects such as gynecomastia, erectile dysfunction, and decreased libido. Furthermore, there is still a risk of hair loss in the transplanted areas after hair transplantation. In addition, the results of hair transplantation vary due to factors such as technical conditions, the surgeon's skill level, and individual patient differences.
[0004] Therefore, there is an urgent need to find an active substance that can effectively promote hair growth and reduce hair loss, and to develop and apply it in the fields of medicine and cosmetics. Summary of the Invention
[0005] In view of the above-mentioned problems existing in the prior art, this application provides a pyrimidine diamine compound and its application.
[0006] To address the above problems, the present invention provides the following technical solution: In a first aspect, this application provides a pyrimidine diamine compound, as shown in Formula I: .
[0007] Secondly, this application provides a method for preparing a pyrimidine diamine compound, comprising the following steps: ; Compound III and compound II undergo a condensation reaction to give the compound shown in formula I.
[0008] In one embodiment of this application, the equivalent ratio of compound III to compound II is 1:1.
[0009] In one embodiment of this application, the condensation reaction is carried out in an organic solvent.
[0010] In one embodiment of this application, the organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, and acetonitrile.
[0011] In one embodiment of this application, the condensation reaction is carried out under the action of a condensing agent.
[0012] In one embodiment of this application, the condensing agent is selected from at least one of HATU, DCC, EDCI, and CDI.
[0013] In one embodiment of this application, the equivalent ratio of compound III, compound II and condensing agent is 1:1:1.
[0014] In one embodiment of this application, a condensation aid, including but not limited to HOBt, DMAP, and NHS, may be added to the condensation reaction.
[0015] In one embodiment of this application, the temperature of the condensation reaction is 20-40°C.
[0016] In one embodiment of this application, the temperature of the condensation reaction is 20-30°C.
[0017] In one embodiment of this application, the condensation reaction takes 1-12 hours.
[0018] Thirdly, this application provides a pharmaceutical composition comprising a pyrimidine diamine compound as an active ingredient and a pharmaceutically acceptable carrier.
[0019] In one embodiment of this application, a pharmaceutically acceptable carrier may optionally include surfactants, excipients, humectants, emulsifiers, suspending agents, salts or buffers for adjusting osmotic pressure, colorants, fragrances, stabilizers, bactericides, preservatives, or other conventional supplements.
[0020] Fourthly, this application provides the use of pyrimidine diamine compounds or pharmaceutical compositions in the preparation of products for hair growth and / or prevention of hair loss.
[0021] In one embodiment of this application, the pyrimidine diamine compound accounts for 0.05-5 wt.% of the total weight of the product.
[0022] In one embodiment of this application, hair loss includes androgenetic alopecia, anagen baldness, telogen effluvium, drug-induced alopecia, alopecia areata, partial hair loss caused by tinea capitis or hypotrichosis, total hair loss, or generalized hair loss.
[0023] In one embodiment of this application, the product includes pharmaceuticals and daily chemical products.
[0024] In one embodiment of this application, the daily chemical products include shampoo, conditioner, hair serum, hair oil, hair lotion, scalp cream, hair gel, hair spray, hair mask, eyebrow serum, and eyelash serum.
[0025] In one embodiment of this application, the dosage form of the product includes powders, granules, capsules, tablets, pills, sprays, lotions, ointments, patches, liniments, pastes, mud dressings, injections, emulsions, aerosols, drops, gels, microneedles, controlled-release agents, and sustained-release agents.
[0026] When treating hair loss-related diseases, pyrimidine diamine is used as the active ingredient. It can be applied topically through the skin, such as in creams, patches, ointments, lotions, gels, and sprays, or orally, such as in tablets, granules, capsules, oral liquid preparations, pills, suspensions, and drops.
[0027] There are no particular limitations on the types of solvents that can be further added to the daily chemical products of this application. Solvents may include water, brine, DMSO, or combinations thereof. Additionally, carriers, excipients, or diluents include, but are not limited to, purified water, oils, waxes, fatty acids, fatty acid alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, and lower alcohols. Furthermore, if desired, the daily chemical products may also contain humectants, fragrances, dyes, antibiotics, and antibacterial agents. For example, antibacterial agents may be copper pyridine sulfate, selenium sulfide, micronized sulfur, and combinations thereof.
[0028] Compared with the prior art, the present invention has the following beneficial effects: The pyrimidine diamine compound of this application can promote the entry of telogen hair into the anagen phase and stimulate hair growth; it can inhibit chemotherapy-induced hair loss, resist chemotherapy toxicity and prevent hair loss in chemotherapy-induced hair loss; it can also inhibit androgens, thereby preventing androgenic alopecia.
[0029] The pyrimidine diamine compound of this application can accelerate the natural growth rate of hair and effectively increase the growth weight and length of newly grown hair or hair remaining after hair loss, with better effects than minoxidil approved by the FDA. Detailed Implementation
[0030] The technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments.
[0031] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of the particular range. The range defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range.
[0032] Unless otherwise stated, when this invention relates to percentages between liquids, it is volume / volume percentage; when this invention relates to percentages between liquids and solids, it is volume / weight percentage; when this invention relates to percentages between solids and liquids, it is weight / volume percentage; the rest are weight / weight percentage.
[0033] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.
[0034] Example 1 Synthesis of pyrimidine diamine compounds The synthesis route is as follows:
[0035] 250.0 mL of dichloromethane, 31.9 g (1.00 eq) of compound III, 12.6 g of 4-dimethylaminopyridine, and 21.1 g of compound II were added to a three-necked flask. After addition, the mixture was stirred at 20-30 °C for 1 h. 20.6 g of dicyclohexylcarbodiimide was added. TLC monitoring showed no remaining starting material. The mixture was filtered, and the filtrate was directly passed through silica gel. Eluent was extracted with ethyl acetate / n-heptane: 4 / 1. The product was collected and dissolved under reduced pressure at 40-50 °C until no obvious fraction was observed. 200 mL of methanol was added, and the mixture was heated to 40-50 °C and stirred for 4 h. The mixture was then cooled to 0-5 °C and stirred for 1 h. The mixture was filtered, washed with a small amount of methanol, and dried under blast at 40-50 °C to obtain 41.2 g of an off-white solid. Yield: 80.6%. ESI-MS: m / z 513.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6): δ 7.92 (s, 1H), 7.81 (s, 1H), 6.20 (s,4H), 3.73 (m, 4H), 3.43 (m, 4H), 3.34 (m, 1H), 2.25 (m, 1H), 2.16 (m, 2H),1.77 (m, 2H), 1.67 (m, 2H), 1.61 (m, 2H), 1.50 (m, 4H), 1.44 (m, 2H), 1.43(m, 2H), 1.14 (m, 1H), 1.12 (s, 3H), 1.04 (m, 2H), 0.89 (s, 3H). Example 2 Synthesis of pyrimidine diamine compounds The synthesis route is as follows: ; 250.0 mL of acetonitrile, 31.9 g (1.00 eq) of compound III, 13.5 g of 1-hydroxybenzotriazole, and 21.1 g of compound II were added to a three-necked reaction flask. After addition, the mixture was stirred at 20-30 °C for 1 h. 19.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added. TLC monitoring showed no remaining starting material. 200 mL of water was added, and the organic phase was dissolved under reduced pressure at 40-50 °C until no obvious fraction was observed. 200 mL of methanol was added, and the mixture was heated to 40-50 °C and stirred for 4 h. The mixture was then cooled to 0-5 °C and stirred for 1 h. The mixture was filtered, washed with a small amount of methanol, and dried by blast drying at 40-50 °C to obtain 43.3 g of an off-white solid. Yield: 84.7%. ESI-MS: m / z 513.5 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6): δ 7.92 (s, 1H), 7.81 (s, 1H), 6.20 (s, 4H), 3.73 (m,4H), 3.43 (m, 4H), 3.34 (m, 1H), 2.25 (m, 1H), 2.16 (m, 2H), 1.77 (m, 2H),1.67 (m, 2H), 1.61 (m, 2H), 1.50 (m, 4H), 1.44 (m, 2H), 1.43 (m, 2H), 1.14(m, 1H), 1.12 (s, 3H), 1.04 (m, 2H), 0.89 (s, 3H). Example 3: Evaluation of the therapeutic effect of pyrimidine diamine compounds on shaved mouse model mice. 1. Laboratory animals The experimental animals were male C57BL / 6J mice, 6-7 weeks old, weighing 18-22 g, purchased from Nanjing University Medical Center. The C57BL / 6J mice were housed under normal conditions: temperature 25±2℃, humidity 40%-60%, with alternating 12-hour light and dark cycles. They had free access to food and water, and their corn cob bedding was changed every two days. Experiments began after they had acclimatized to their environment for 7 days.
[0036] 2. Drug preparation 4% Chloral hydrate: Weigh 0.8 g of chloral hydrate and pour it into a 20 mL centrifuge tube. Add 19.2 mL of physiological saline and dissolve thoroughly to prepare a 4% chloral hydrate solution. Prepare and use immediately.
[0037] The topical cream containing pyrimidine diamine (concentration: 0.5%) is made from the following ingredients listed in Table 1: Table 1 Raw material composition and content ; The topical cream of this invention is prepared according to the above-mentioned raw material components: (1) Weigh the aqueous phase and oil phase into beakers according to the above formula, and place them in a water bath at 80°C for 20-30 minutes. (2) Under stirring conditions, the aqueous phase is slowly added to the oil phase, and stirring is continued for 10 min to emulsify; (3) When the oil-water mixture is stirred and cooled to about 40°C, add the weighed pyrimidine diamine raw material while stirring until it is evenly mixed with the cream to obtain a 0.5% topical cream.
[0038] Pyrimidine diamine oral formulation: The dosage is 50 mg / kg. Before use, dissolve in 0.5% CMC-Na, titrate and centrifuge, and after complete resuscitation, administer orally to mice by gavage.
[0039] 3. Establishment of the shaving model (1) Experimental principle: C57BL / 6 mice aged 6-7 weeks are in a quiescent phase with arrested hair growth, making them a suitable model for hair removal. All telogen hairs are removed using a hair remover to create the hair removal model.
[0040] (2) Specific operations: After weighing, the mice were intraperitoneally injected with 4% chloral hydrate at a dose of 10 μL / g body weight (BW). After the mice were anesthetized, the hair on their backs was removed using a shaver.
[0041] Thirty-two male C57BL / 6 mice were randomly divided into a control group, an oral pyrimidine diamine group, a 0.5% pyrimidine diamine ointment group, and a 0.5% minoxidil group, with eight mice in each group.
[0042] 4. Evaluation experiment on the efficacy of pyrimidine diamine on hair growth in shaved mouse model mice. Drug administration began on day 1 after shaving and modeling. Commercially available minoxidil tincture, at a concentration of 5%, was diluted to 0.5% with 9 times its volume of anhydrous ethanol, and the dosage was 200 μL per mouse. The control group received a blank cream without the drug; the pyrimidine diamine ointment group received a 0.5% concentration, at a dosage of 0.2 g per mouse, applied with a cotton swab to the shaved area each time. Scoring began when melanin appeared on the back of the first mouse. The scoring criteria were: X = percentage of area with hair growth + percentage of area with melanin deposition / 2. A score of 50 was given if 50% of the area had hair growth or if 25% of the area had hair growth and an additional 50% had melanin deposition. Administration was twice weekly. On day 28, mice were intraperitoneally injected with 10 μL / g BW 4% chloral hydrate. After the mice were stable under anesthesia, the hair grown in the shaved area was removed with a shaver, collected on weighing paper, and weighed using a 1 / 100,000 electronic balance.
[0043] 5. Experimental Results As shown in Table 2, compared with the control group, each group showed a dose-dependent increase in hair weight and promoted hair growth. The pyrimidine diamine ointment group showed a significant effect, and its effect was superior to that of the positive control drug minoxidil. The oral pyrimidine diamine group also showed an increase in hair weight.
[0044] Table 2 ; In summary, it can be seen that pyrimidine diamine can promote hair in the resting phase to enter the growth phase and promote growth.
[0045] Example 4: Evaluation of the therapeutic effect of pyrimidine diamine compounds on mice with a natural hair regrowth model. 1. Laboratory animals The experimental animals were the same as in Example 3.
[0046] 2. Drug preparation The preparation of 4% chloral hydrate, pyrimidine diamine ointment, and pyrimidine diamine oral preparation is the same as in Example 1.
[0047] 3. Natural hair growth model creation (1) Experimental principle: Hair growth arrest in 6-7 week old C57BL / 6 mice is in the quiescent phase, which can be used to construct a natural hair growth model. All telogen hairs are removed with wax paper to induce hair follicles to enter the anagen phase synchronously. These hair follicles are morphologically indistinguishable from spontaneously formed anagen phase hair follicles.
[0048] (2) Specific operations: After weighing the mice, inject them intraperitoneally with 4% chloral hydrate at a dose of 10 μL / g BW (body weight). After the mice are anesthetized, shave the hair off their backs with a shaver. Warm a 5.20 cm × 2.60 cm strip of waxing paper by hand and apply it from behind the ear to the tail in the direction of the mouse's hair growth. Hold the mouse with your hand for at least 2 minutes. Hold the legs with your left hand, place the hind legs face up in the web of your hand, press down on the tail with your thumb, and quickly tear off the waxing paper from the tail against the direction of the hair growth with your right hand. Wipe the back with a clean, damp paper.
[0049] Thirty-two male C57BL / 6 mice were randomly divided into a control group, an oral pyrimidine diamine group, a 0.5% pyrimidine diamine ointment group, and a 0.5% minoxidil group, with eight mice in each group.
[0050] 4. Evaluation experiment on the efficacy of pyrimidine diamine on hair growth in mice with a natural hair growth model. The medication was administered once daily for 13 consecutive days, starting on day 1 after hair removal. Commercially available minoxidil solution was 5% diluted to 0.5% with 9 times its volume of anhydrous ethanol, with a dosage of 200 μL per animal. The control group received a blank cream containing the drug; the pyrimidine diamine ointment group received a 0.5% concentration, with a dosage of 0.2 g per animal. Approximately 0.2 g of the ointment was applied to the hair removal area using a cotton swab each time.
[0051] On the 14th day after administration, the experimental mice were injected intraperitoneally with 10 μL / g BW 4% chloral hydrate. After the mice were under stable anesthesia, the mice were carefully tweezed at 6 fixed sites on their backs, about 10 hairs at a time. The hairs were placed on clean white paper, and the lengths were measured with calipers. The longest hair was recorded. The entire measurement process was repeated twice.
[0052] After the hair length is measured, use a shaver to remove the hair that has grown out of the hair removal area, collect it with weighing paper, and weigh the gross weight with a 1 / 100,000 electronic balance.
[0053] 5. Experimental Results As shown in Table 3, compared with the control group, all groups showed a dose-dependent increase in hair weight. The pyrimidine diamine ointment group showed a significant effect, and its effect was superior to that of the positive control drug minoxidil. The oral pyrimidine diamine group also showed an increase in hair weight.
[0054] In conclusion, it can be seen that pyrimidine diamine has a significant effect on promoting hair growth in mice.
[0055] Table 3 ; Example 5: Evaluation of the efficacy of pyrimidine diamine compounds on androgenetic alopecia model mice. 1. Laboratory animals The experimental animals were the same as in Example 1.
[0056] 2. Drug preparation The preparation of the 4% chloral hydrate and pyrimidine diamine oral formulation is the same as in Example 1.
[0057] 0.25% testosterone solution: Accurately weigh 0.25 g of testosterone powder, add 70 mL of anhydrous ethanol solution and 30 mL of glycerol solution, dissolve evenly, and store at 4°C for later use.
[0058] Blank solvent: Mix 35 mL of anhydrous ethanol solution and 15 mL of propylene glycol solution evenly to form 50 mL of blank solvent, and store it in a refrigerator at 4°C for later use.
[0059] 3. Establishment of an androgenetic alopecia model (1) Experimental principle: The establishment of the C57BL / 6 mouse androgenic alopecia model was initially similar to the natural hair growth and hair removal mouse model. Starting from the day after the hair on the back of 6-7 week old male C57 mice was removed, 0.25% testosterone solution was used daily to induce the model and inhibit hair growth.
[0060] (2) Specific operations: The hair removal method is the same as in Example 2.
[0061] Thirty-two male C57BL / 6 mice were randomly divided into a control group, an oral pyrimidine diamine group, a 0.5% pyrimidine diamine ointment group, and a 0.5% minoxidil group, with eight mice in each group.
[0062] Starting on day 1 after hair removal, 200 μL of the modeling agent was applied to the back of the hair-removed area of the mice once a day for 14 days. The blank control group was treated with a blank solvent, while the other groups were treated with 0.25% testosterone solution.
[0063] 4. Efficacy evaluation experiment of pyrimidine diamine in androgenetic alopecia model After daily modeling and once the modeling agent has been absorbed, the mice were given the drug applied to their backs once daily for 14 consecutive days. Commercially available minoxidil was 5% diluted to 0.5% with 9 times its volume of anhydrous ethanol, with a dosage of 200 μL per mouse. The control and model groups received a blank cream without the drug; the pyrimidine diamine ointment group received a 0.5% concentration, at a dosage of 0.2 g per mouse, applied with a cotton swab to the hair-removing area each time.
[0064] On the 15th day after administration, the experimental mice were injected intraperitoneally with 10 μL / g 4% chloral hydrate. After the mice were under stable anesthesia, the mice were carefully tweezed at 6 fixed sites on their backs, about 10 hairs at a time. The hairs were placed on clean white paper, and the lengths were measured with calipers. The longest hair was recorded. The entire measurement process was repeated twice.
[0065] After the hair length is measured, use a shaver to remove the hair that has grown out of the hair removal area, collect it with weighing paper, and weigh the gross weight with a 1 / 100,000 electronic balance.
[0066] 5. Experimental Results As shown in Table 4, compared with the blank control group, the hair length and weight of the model group were slightly lower, proving the model's success. Compared with the model group, each treatment group showed a dose-dependent increase in hair length and weight. The pyrimidine diamine ointment group showed significant effects, and its effect was superior to the positive control drug minoxidil. The pyrimidine diamine oral group also showed an increase in hair length and weight compared with the model group, and the pyrimidine diamine oral group significantly increased hair length. The above experimental results indicate that pyrimidine diamine can alleviate androgen-induced hair loss.
[0067] Table 4 ; The present application has been described in detail above with reference to specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present application. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and implementation methods of the present application without departing from the spirit and scope of the present application, and all such modifications and improvements fall within the scope of the present application.
Claims
1. A pyrimidine diamine compound, as shown in Formula I: 。 2. A pharmaceutical composition comprising the pyrimidine diamine compound of claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.
3. The use of the pyrimidine diamine compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of products for hair growth and / or prevention and treatment of hair loss.
4. The application according to claim 3, characterized in that, The pyrimidine diamine compound accounts for 0.05-5 wt.% of the total weight of the product.
5. The application according to claim 3, characterized in that, The hair loss includes androgenetic alopecia, anagen baldness, telogen effluvium, drug-induced alopecia, alopecia areata, partial hair loss caused by tinea capitis or hypotrichosis, total hair loss, or generalized hair loss.
6. The application according to claim 3, characterized in that, The products include pharmaceuticals and daily chemical products; The daily chemical products include shampoos, conditioners, hair serums, hair oils, hair lotions, scalp creams, hair gels, hair sprays, hair masks, eyebrow serums, and eyelash serums. The dosage forms of the products include powders, granules, capsules, tablets, pills, sprays, lotions, ointments, patches, liniments, pastes, mud dressings, injections, emulsions, aerosols, drops, gels, microneedles, controlled-release agents, and sustained-release agents.