TWI410246B - 8-phenylisoquinolines and pharmaceutical composition used in treatment for sepsis - Google Patents

Abstract

The present invention provides a series of 8-phenylisoquinoline derivatives. The derivatives are used for the treatment of sepsis. These derivatives which are 5-HT2A receptor antagonist could inhibit 5-HT induced aorta contraction and 5-HT induced platelet aggregation. The derivatives include the following formula.

Description

Octaphenylisoquinoline derivative for treating sepsis and pharmaceutical composition thereof

The present invention relates to a derivative compound based on 8-phenylisoquinoline for the treatment of sepsis.

Sepsis syndrome is caused by bacteria releasing toxins into the blood. It is a serious systemic inflammatory reaction that often causes blood clots, multiple organ failure, and shock death. According to statistics, in every 100,000 inpatients in the United States, 50 to 300 patients are diagnosed with severe sepsis, while those with severe septicemia have a mortality rate of between 18% and 55%. In addition, the medical expenses for each patient are as high as $26,450 to $39,100.

In Taiwan, the proportion of patients with severe sepsis is about 359/100000, and the mortality rate is about 30%; and the cost of treatment for each person is between $866-6505. Clinically, the treatment of severe sepsis is mainly based on symptomatic treatment, such as the use of anti-inflammatory drugs, antibiotics, vasoconstrictor drugs, and a large number of infusions.

The only clinically proven clinically effective to reduce mortality in patients with severe sepsis, and the only drug approved by the US Food and Drug Administration is Drotrecogin alfa ( ). Xigris It is a recombinant human activated protein C produced by genetic engineering technology. Recombinant human activating protein C inhibits the production of thrombin (thrombin) by inhibiting the activity of factor Va and factor VIIIa, and inhibits plasminogen activator inhibitor-1 (PAI). -1) Synthesis to regulate the clotting reaction and has anti-thrombotic and fibrinolytic properties. However in clinical practice It is still controversial whether there is any help in the mortality rate of patients with severe sepsis. Therefore, in clinical applications and in the pharmaceutical market, new therapeutic drugs for severe sepsis still have clinical needs and development value.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that triggers platelet aggregation and coronary artery contraction. The serotonin _2A receptor is one of the serotonin receptors (5-HT receptors) and is a G protein coupled receptor.

The serotonin 2A receptor antagonists currently available on the market include sarpogrelate and ketanserin. The use of serotonin 2A receptor antagonists for sepsis is a treatment that is still under investigation. For this reason, the applicant invented the "octaphenylisoquinoline derivative for treating sepsis and its pharmaceutical composition" in view of the lack of the prior art to improve the lack of the prior art.

One aspect of the present invention provides an octaphenylisoquinoline compound having the following structural formula:

Another aspect of the present invention provides an octaphenylisoquinoline compound or a pharmaceutically acceptable salt thereof having the following structural formula:

R ₁ is selected from the group consisting of hydrogen, a C _1-12 straight or branched alkyl group, a heterocyclic ring having n carbon chains [(CH ₂ ) _n (Hete)R ₁₀ R ₁₁ R ₁₂ ], and an aromatic [(CH _{2 ) n} ArR ₁₀ R ₁₁ R ₁₂ ], and n is 1-6, and R ₁₀ , R ₁₁ and R ₁₂ are each a substituent on the hetero ring (Hete) or the aromatic ring (Ar). They are respectively selected from the group consisting of hydrogen, a halogen, a nitro group, an amine group, a cyano group, an ethyl sulfonyl group, a C _1-6 linear saturated alkyl group, a C _1-6 linear saturated alkoxy group, and a C _1-6 straight One of the saturated haloalkyl groups of the chain; R ₂ is selected from one of hydrogen and a saturated alkyl group of a C _1-6 straight chain; and R ₃ is selected from a saturated alkoxy group having a hydroxyl group and a C _1-6 straight chain. One of R ₄ is one selected from the group consisting of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain; and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are independently selected from hydrogen, a halogen, and a nitrate. Alkyl, amino, cyano, ethyl hydrazino, C _1-6 straight or branched saturated alkyl, C _1-6 straight or branched saturated alkoxy, C _1-6 straight or branched One of a saturated alkylthio group and a C _1-6 linear or branched saturated haloalkyl group.

A further aspect of the invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and an active ingredient in an amount effective as follows:

R ₁ is selected from the group consisting of hydrogen, a C _1-12 straight or branched alkyl group, a heterocyclic ring having n carbon chains [(CH ₂ ) _n (Hete)R ₁₀ R ₁₁ R ₁₂ ], and an aromatic [(CH _{2 ) n} ArR ₁₀ R ₁₁ R ₁₂ ], and n is 1-6, and R ₁₀ , R ₁₁ and R ₁₂ are each a substituent on the hetero ring (Hete) or the aromatic ring (Ar). They are respectively selected from the group consisting of hydrogen, a halogen, a nitro group, an amine group, a cyano group, an ethyl sulfonyl group, a C _1-6 linear saturated alkyl group, a C _1-6 linear saturated alkoxy group, and a C _1-6 straight One of the saturated haloalkyl groups of the chain; R ₂ is selected from one of hydrogen and a saturated alkyl group of a C _1-6 straight chain; and R ₃ is selected from a saturated alkoxy group having a hydroxyl group and a C _1-6 straight chain. One of R ₄ is one selected from the group consisting of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain; and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are independently selected from hydrogen, a halogen, and a nitrate. Alkyl, amino, cyano, ethyl hydrazino, C _1-6 straight or branched saturated alkyl, C _1-6 straight or branched saturated alkoxy, C _1-6 straight or branched One of a saturated alkylthio group and a C _1-6 linear or branched saturated haloalkyl group.

The above excipients, or "pharmaceutically acceptable carriers or excipients", "bioavailable carriers or excipients", include vehicles, dispersing agents, coatings, antibacterial or antifungal agents, or Any suitable compound suitable for the preparation of a dosage form such as an absorbent is delayed. Usually such carriers or excipients do not themselves have the activity of treating diseases, and the derivatives disclosed in the present invention, together with pharmaceutically acceptable carriers or excipients, are prepared for administration to animals or humans. Causes adverse reactions, allergies or other inappropriate reactions. Thus, the derivatives disclosed herein, in combination with pharmaceutically acceptable carriers or excipients, are suitable for use in clinical and human applications. The therapeutic effect can be achieved by administering the dosage form of the compound of the present invention intravenously, orally, by inhalation or by local or sublingual administration such as nasal, rectal, vaginal or the like. For patients with different conditions, about 0.1 mg to 100 mg of active ingredient is administered daily.

The carrier will vary with each dosage form, and the sterile injectable compositions may be solution or suspended in a non-toxic intravenous diluent or solvent such as 1,3-butanediol. A carrier acceptable therebetween may be Mannitol or water. In addition, fixed oils or synthetic single or diglyceride suspension media are common solvents. Fatty acids, such as oleic acid, olive oil or castor oil, and their glyceride derivatives, especially in the form of polyoxyethylation, are useful as injections and are natural pharmaceutically acceptable oils. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tween, Spans or other similar emulsifiers or generally used in the pharmaceutical industry are commercially available solid, liquid or other bioavailable enhancers which are useful in the development of dosage forms.

The composition for oral administration is in any orally acceptable dosage form, and the form thereof includes a capsule, a tablet, a tablet, an emulsifier, a liquid suspension, a dispersing agent, and a solvent. Oral dosage forms are generally used as carriers, and in the case of tablets, lactose, corn starch, and a lubricant such as magnesium stearate are basic additives. The diluent used in the capsules includes lactose and dried corn starch. The liquid suspension or emulsifier dosage form is prepared by suspending or dissolving the active substance in an oily interface combined with an emulsifier or a suspending agent, and adding a moderate sweetener, flavor or pigment as needed.

Nasal gasifying sprays or inhalant compositions can be prepared according to known formulation techniques. For example, the composition is dissolved in physiological saline, benzyl alcohol or other suitable preservative, or an absorbent is added to enhance bioavailability. The compositions of the compounds of the invention may also be formulated as a suppository for rectal or vaginal administration.

The compound of the present invention can also be administered by "injection method", which includes subcutaneous, intraperitoneal, intravenous, intramuscular, or intra-articular, intracranial, intra-articular, intraspinal injection, aortic injection, intrathoracic injection, and diseased parts. Injection, or other suitable medication technique.

Therefore, the present invention is an innovative invention that is difficult and capable of industrial value, and is required to apply in accordance with the law.

The present invention is fully understood by the following examples and illustrations, and can be made by those skilled in the art, but the embodiments of the present invention are not limited to the following embodiments. .

The present invention provides a series of novel compounds having 8-phenylisoquinoline as the core backbone. The synthesis process has the following six types:

Scheme 1 (first panel): a hydroxyl group in vanillin and a benzyl bromide produce an aldehyde (code 1 compound). A nitrostyrene (code 2 compound) is produced between the code 1 compound and nitromethane by a Henry reaction. The code 2 compound was dissolved in tetrahydrofuran (THF) and reduced to an amine (code 3 compound) with lithium aluminum hydride. The compound of code 3 reacts with an excess of methyl formate to produce formamide (code 4 compound). The code 5 compound was obtained by cyclizing the code 4 compound with phosphorus oxychloride (POCl ₃ ) and via a Bischler-Napieralski reaction. After the alkylation of the code 5 compound and iodopropane, the compound of the code 6 can be produced in high yield by reduction with sodium borohydride (NaBH ₄ ). A palladium on carbon catalyst (Pd-C) is added to saturate with hydrogen to remove the protecting group of the compound of claim 6 to produce the compound of the code number 7. The compound of the code 7 is treated with Pb(OAc) ₄ dissolved in acetic acid, by an acid-catalyzed aromatic substitution reaction, using 1,3-dimethoxybenzene and using three Trifluoroacetic acid (TFA) gave the code 8 compound.

Scheme 2 (second panel): The code 3 compound was treated with an excess of methyl acetate to synthesize acetamide (code 9 compound), and the code 9 compound was converted to the code 10 compound using POCl ₃ . After the alkylation of the code 10 compound with an alkyl halide ( N- Alkylation), the compound of No. 11 and the compound of No. 12 were obtained by reduction with sodium borohydride (NaBH ₄ ). The benzyl protecting group of the compound No. 11 and the compound of the code 12 was removed by catalytic hydrogenation to give the compound No. 13 and the compound of the code 14 respectively. The compound of code 13 and the compound of code 14 are treated with Pb(OAc) ₄ dissolved in acetic acid, and acid-catalyzed aromatic substitution reaction with 1,3-dimethoxybenzene And using the trifluoroacetic acid (TFA) to obtain the code 15 compound and the code 16 compound, respectively.

Scheme 3 (third diagram): The compound of the code 20 (commercially available) is alkylated with phenylethyl bromide by N, and then reduced by sodium borohydride to obtain an amine (code No. 21). After the compound of the code 21 was treated with Pb(OAc) ₄ , the compound of the code 22 was synthesized by aromatic substitution with hydrobromic acid (HBr). The compound number 29-45 can be measured by using a different substituted-arylboranes and by a Suzuki coupling reaction.

Scheme 4 (fourth panel): The compound of code 20 was treated with a different halide and then reduced by sodium borohydride to give the compound 61-76. The compound 61-76 was oxidized with Pb(OAc) ₄ dissolved in acetic acid, and the aromatic substitution catalyzed by trifluoroacetic acid using 1,3-dimethoxybenzene gave the compound 101-125, respectively.

Scheme 5 (fifth panel): The compound of the code 20 was treated with different phenylpropyl bromides, and the compound of the code 77-78 was obtained by reduction with sodium borohydride, respectively. After the compound of the formula 77-78 was treated with Pb(OAc) ₄ , the compound of the formula 97-98 was separately synthesized by hydrohalic acid (HBr) by aromatic substitution. The compound number 141-142 can be separately measured by a different substituted-arylborane and by Suzuki reaction.

Scheme 6 ( Sixth Diagram ): The compound of the formula 150-154 was synthesized by methylating the methyl iodide (O-Methylation) code 60-96 in the presence of sodium hydride. The compound No. 151-173 was synthesized by a different substituted-arylborane and an Aryl coupling reaction of the code 150-154 compound by Suzuki reaction.

The specific synthesis steps of the compounds from the above Schemes 1 to 6 are as follows:

Code 7 Compound : First dry the bottle, add the starting material C ₁₇ H ₁₇ NO ₂ (5,500 mg, 1.87 mmol) in a 50 mL two-necked flask at room temperature under N ₂ , add IPA (17 mL), add C ₃ H ₇ Br (0.51 mL, 5.63 mmol), placed in a frying pan and kept at 110-120 ° C. The solution was completely dissolved at a temperature of 60 ° C. The solution became transparent yellow, reacted for 16 hours, concentrated at room temperature; MeOH was added. (25 mL) and stirring for 10 minutes, the solution was cloudy orange, ice-cooled and slowly added NaBH ₄ (s) (167 mg, 4.41 mmol) under N ₂ and stirred for 10 minutes. The solution was cloudy and light orange and concentrated. Extracted with chloroform (35 mL), dried over anhydrous magnesium sulfate (MgSO ₄ ), stirred for 5 min, filtered over a sifting glass funnel to a 250 mL single-neck round bottom flask, concentrated to dryness purified by chromatography (silica gel, EA / n -hexane = 1: 2), to give a beige solid product (442 mg, 1.42 mmol, 76 %). C ₂₀ H ₂₅ NO ₂ (16, 431.0 mg, 1.38 mmol) was added to a 50 mL round bottom flask at room temperature, and EA (8.5 mL) was added. After complete dissolution, the solution was transparent orange, followed by 10% Pd/C (160). Mg), connected with a hydrogen balloon, stirred for 2 hours, filtered with Celite on a glazed glass funnel, concentrated and drained, and purified by flash column chromatography (silica gel, MeOH/CH ₂ Cl ₂ = 1:100) to obtain rice. White solid product (266 mg, 1.20 mmol, 87%)

Code 21 compound : first dry bottle, add the starting material C ₁₀ H ₁₁ NO ₂ (20,100 mg, 0.56 mmol) in a 25 mL double-necked flask at room temperature under N ₂ , add IPA (3.5 mL), add phenethyl bromide ( 311 mg, 1.68 mmol), placed in a frying pan and heated to reflux. The temperature of the oil bath was maintained at 110-120 ° C. The starting material was completely dissolved at a temperature of 65 ° C. The solution became transparent yellow, reacted for 15 hours, and concentrated to room temperature. Add MeOH (5 mL) and stir for 10 minutes. After dissolving, the solution was cloudy and yellow, and then slowly added NaBH ₄ (s) (49 mg, 1.29 mmol) under N ₂ and stirred for 20 minutes. The solution was opaque powder orange After concentration, water (20 mL) and chloroform (20 mL) were added and extracted. The organic layer was dried over anhydrous magnesium sulfate and stirred for 5 minutes, filtered over a glass fritted glass funnel to a 100 mL one-neck round bottom flask, concentrated. dryness to give a pale orange solid The crude product was purified by flash column chromatography to _{(silica gel, MeOH / CH 2} Cl 2 = 1/100), to give the product as a white solid (146 mg, 0.52 mmol, 92 %).

Ref. _No. 30 compound: Add the starting material C ₁₈ H ₂₀ BrNO ₂ (50 mg, 0.14 mmol) in a microwave reaction flask at room temperature, add 4-methoxyphenylboronic acid (26 mg, 0.19 mmol), add IPA (2.0 mL) ), after stirring for 30 minutes, it was cloudy with a white liquid, then Pd(OAc) ₂ (1.3 mg, 0.006 mmol), triphenylphosphine (4.7 mg, 0.02 mmol), 2 M Na ₂ CO ₃ (aq) (0.09 mL) , 0.17 mmol), water (0.1 mL), EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was washed with 5% NaHCO ₃ (aq), then washed with brine, dried over anhydrous magnesium sulfate, stirred for 30 minutes, and filtered on a molten glass funnel with a thickness of about one centimeter of Celite and a thin layer of Florisil. drained concentrated, purified by flash column chromatography to (silica gel, EA / n -hexane = 2/1), to give the product as an orange oil (40 mg, 0.10 mmol, 73 %).

Code 29 and 31-40 compounds: Table of synthesis parameters can be found in Table 1. Add ( parameter 1 ) to the microwave reaction flask at room temperature under air, dissolve in ( parameter 2 )mL IPA, the solution is ( parameter 3 ), add the starting material ( parameter 4 ), stir ( parameter 5 ) minutes, the solution is ( parameter 6 ), then add Pd(OAc) ₂ ( parameter 7 ), add PPh ₃ ( parameter 8 ), add 2 M Na ₂ CO ₃ (aq) ( parameter 9 ), add ( parameter 10 ) mL H2O, microwave ( parameter 11), before the cooled solution was added (parameter 12) mLH2O, stirred in air to room temperature, then diluted with (parameter 13) mL EtOAc and extracted with ₂ O (parameter 14) mL H. The organic layer was washed first with 5% NaHCO ₃ (aq), then washed with brine and then added ( parameter 15 ) mg Darco G-60, stirred ( parameter 16 ), dried over anhydrous magnesium sulfate and stirred ( parameter 17 ) Filtration of about one centimeter of Celite and a thin layer of Florisil on a fused glass funnel, concentrated and drained, and purified by flash column chromatography ( parameter 18 ) to obtain ( parameter 19 ).

Substituting Compound No. 44: addition of starter air at room temperature C _{18 H 20 BrNO 2 (100 mg} , 0.28 mmol) in a microwave reaction vial, was added 3,5-dimethoxybenzeneboronic acid (62 mg, 0.34 mmol), was added IPA (1.5 mL), after stirring for 20 minutes, a cloudy yellow liquid, followed by Pd(OAc) ₂ (2.2 mg, 0.01 mmol), triphenylphosphine (8.0 mg, 0.03 mmol), and 2 M Na ₂ CO ₃ (aq) ( 0.17 mL, 0.34 mmol), was added H ₂ O (0.2 mL), microwave 100 ℃ 20 minutes before cooling the solution was added H ₂ O (0.7 mL), was stirred in air to room temperature, then diluted with EtOAc (10 mL) and The organic layer was washed with 5% NaHCO3 (aq) (10 mL), then washed with brine, dried over anhydrous magnesium sulfate, stirred for 30 minutes, and spread on a molten glass funnel with a thickness of about one centimeter of Celite and a thin layer. Filtration of a thin Florisil, concentrating and concentrating to give 137 mg of crude product (yield: silica gel, EA/ n- hexane = 1/1) to give the product as an orange oil (76 mg, 0.18 mmol, 65%).

Ref. 45 Compound: Add the starting material C ₁₈ H ₂₀ BrNO ₂ (100 mg, 0.28 mmol) in a microwave reaction vial, add 2,3-dimethoxyphenylboronic acid (62 mg, 0.34 mmol), add IPA 2.0 mL), after stirring for 30 minutes, it was a cloudy yellow liquid, then Pd(OAc) ₂ (2.0 mg, 0.009 mmol), plus triphenylphosphine (3.7 mg, 0.014 mmol), plus 2 M Na ₂ CO ₃ (aq) (0.18 mL, 0.36 mmol), was added H ₂ O (0.2 mL), microwave 120 ℃ 10 minutes before cooling the solution was added H ₂ O (0.7 mL), was stirred in air to room temperature, then diluted and extracted with EtOAc (5 mL) . The organic layer was washed with 5% NaHCO ₃ (aq), then washed with brine and then added with Darco G-60 (100 mg), stirred for 30 minutes, dried over anhydrous magnesium sulfate and stirred for 30 minutes on a glazed glass funnel. Filtration of Celite and a thin layer of Florisil, about 1 cm thick, concentrated and drained, and purified by flash column chromatography (silica gel, EA/n-hexane = 1/1) to give an orange oily product (82 mg) , 0.20 mmol, 71%).

Compounds 60, 85 and 95-98: See Table 2 for the synthetic parameter table. Was added at room temperature under N ₂ in a starting parameter 50 mL two-necked flask, (parameter 2) mL HOAc was dissolved, was added after complete dissolution of Pb (OAc) ₄ (3 parameters), the solution was dissolved (parameter 4 After stirring for 15 minutes, pour into a conical flask, stir with stirring stone and slowly add ( parameter 5 ) mL Na ₂ CO ₃ (sat) until the bubble is no longer present, the pH of the water layer is alkaline (pH= parameter 6), and the solid produced when the sand to melt to a glass filter funnel and the filter cake was washed CH ₂ Cl _2, the filtrate to the parameter 7 mL CH ₂ Cl _2. the organic layer was washed brine anhydrous magnesium sulfate, It was stirred for 5 minutes, filtered through a glazed glass funnel and concentrated to dryness (yield 8 ). This crude product was used directly in the next step without purification.

Add HBr ( parameter 9 ) at room temperature, stir vigorously with stirring stone, and the solution is ( parameter 10 ). After stirring ( parameter 11 ), the solution is slowly added under ice bath ( parameter 12 ) mL Na ₂ CO ₃ (sat And ( parameter 13 ) mL CH ₂ Cl _{2 in} a mixed solution, the pH of the aqueous layer is alkaline ( parameter 14 ), then add ( parameter 15 ) mL CH ₂ Cl ₂ and ( parameter 16 ) mL H ₂ O After extraction, the organic layer was washed with brine and dried over anhydrous magnesium sulfate and stirred for 5 min, filtered over a fritted glass funnel, and concentrated to dryness to give crude product ( parameter 17 ) mg, which was purified by flash column chromatography (silica gel, ( Parameter 18 )), obtained ( parameter 19 ).

Codes 63-67, 69-70 and 74-78 compounds: Table of synthesis parameters can be found in Table 3. First dry the bottle, add the starting material ( parameter 1 ) in a double neck bottle at room temperature N ₂ , add ( parameter 2 ) mL IPA, add ( parameter 3 ), and put it into the oil pan to heat and keep at 110~120 ℃, the temperature (parameter 4) ℃ starting material completely dissolved, the solution to (5 parameters), approximately (parameter 6) minutes, the solution was (7 parameters), the reaction (8 parameters) hours, back to room temperature and concentrated; plus (parameter 9 ) mL MeOH and stir ( parameter 10 ) for a minute. After dissolving, the solution was ( parameter 11 ), ice-cooled and slowly added NaBH ₄ (s) under N ₂ ( parameter 12 ) and stirred ( parameter 13 ) for a minute. Parameter 14 ), concentration, add ( parameter 15 ) mL H ₂ O, extract with ( parameter 16 ) mL CHCl ₃ , take the organic layer and dry with anhydrous magnesium sulfate, stir ( parameter 17 ), and filter the single neck with a fritted glass funnel. The round bottom flask was concentrated to dryness (yield 18 ) and purified by flash column chromatography (yield 19 ) to afford ( para. 20 ).

For the 68 compound: first dry the bottle, add the starting material C ₁₀ H ₁₁ NO ₂ (20,300 mg, 1.69 mmol) in a 50 mL double-necked flask at room temperature under N ₂ , add IPA (10 mL), add C ₈ H ₈ Br ₂ (1.00 g, 3.79 mmol), placed in a frying pan and kept at 110-120 ° C. The solution was completely dissolved at a temperature of 80 ° C. The solution became transparent yellow. The solution was cloudy yellow for about 1 hour. Hour, concentrate back to room temperature; add MeOH (15 mL) and stir for 10 min. After dissolving, the solution was obtained as a transparent yellow, and then, and then, NaBH ₄ (s) (420 mg, 11.09 mmol) was slowly added under N ₂ and stirred for 20 minutes. The solution was opaque orange, concentrated, added with H ₂ O (30 mL), and then extracted with CHCl ₃ (30 mL). The organic layer was dried over anhydrous magnesium sulfate and stirred for 5 min. The round bottom bottle was concentrated and drained to obtain a crude orange solid. Purification by precipitation, the crude product was dissolved by adding 5 mL of ethyl acetate, and then 10 mL of n- hexane was added to give the product as a white solid ( 620 mg, 1.71 mmol, 101%).

Code 121 Compound: The starting material C ₁₉ H ₂₃ NO ₂ (250 mg, 0.84 mmol) was added to a 50 mL two-necked flask at room temperature under N ₂ and dissolved in HOAc (4.2 mL). Liquid, Pb(OAc) ₄ (579 mg, 1.31 mmol) was added. After dissolution, the solution was transparent and light brown. After 4 hours, the starting material was not reacted, and Pb(OAc) ₄ (192 mg, 0.43 mmol) was added to dissolve. After the solution was transparent dark red brown, stir for 15 minutes, pour into a 125 mL Erlenmeyer flask, stir with stirring stone and slowly add Na ₂ CO ₃ (sat) (20 mL) until no more bubbles, pH of the water layer Alkaline (pH=8-9), the solid produced during neutralization was filtered off with a fritted glass funnel, and the filter cake was washed with CH ₂ Cl ₂ , and the filtrate was extracted with CH ₂ Cl ₂ (40 mL). After washing with brine, it was dried over anhydrous magnesium sulfate and stirred for 5 min, then filtered and evaporated to a 250 ml single-necked round bottom flask, and concentrated to dryness to give a red brown oily product (480 mg, 1.35 mmol). It was used directly in the next reaction without purification. Add CH ₂ Cl ₂ (17 mL) at room temperature to completely dissolve the crude product. The solution was red brown, 1,3-dimethoxybenzene (0.17 mL, 1.3 mmol), trifluoroacetic acid (0.84 mL), red brown Change to brown and turn into red brown. After 30 minutes, stir and slowly add Na ₂ CO ₃ (sat) (20 mL) until no more bubbles are present, so that the pH of the water layer is alkaline (pH=8- 9), followed by extraction with CH ₂ Cl ₂ (18 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and stirred for 5 minutes, filtered over a fritted glass funnel, concentrated and dried to give a crude product 1.23 g. in purified by flash column chromatography _{(silica gel, MeOH / CH 2} Cl 2 = 1/100), to obtain a reddish brown oily product (214 mg, 0.49 mmol, 59 %).

Codes 105-110, 114-116, 120, 122, 123 and 125 compounds: Table of synthesis parameters can be found in Table 4. The starting material ( parameter 1 ) was added to a 50 mL double-necked flask at room temperature under N ₂ , dissolved in ( parameter 2 ) mL HOAc, and completely dissolved ( parameter 3 ) liquid, plus Pb(OAc) ₄ ( parameter 4 After dissolving, the solution is ( parameter 5 ), stirred ( parameter 6 ), poured into a 125 mL Erlenmeyer flask, stirred with stirring stone and slowly added ( parameter 7 ) mL Na ₂ CO ₃ (sat) until no longer Until the bubble, the pH of the water layer is alkaline (pH=8-9), the solid produced during neutralization is filtered off with a fused glass funnel, and the filter cake is washed with CH ₂ Cl ₂ , and the filtrate is ( parameter 8 ). Extracted with mL CH ₂ Cl ₂ , the organic layer was washed with brine and dried over anhydrous magnesium sulfate, stirred for 5 min, filtered over a glass fritted glass funnel to a 250 mL single-neck round bottom flask, concentrated and drained ( parameter 9 ), this coarse The product was used directly in the next reaction without purification.

At room temperature under N ₂ was added (parameter 10) mL CH ₂ Cl ₂ The crude product was completely dissolved, the solution was (parameter 11), was added 1,3-dimethoxybenzene (parameter 12), was added trifluoroacetic acid (13 parameters), a solution of ( After parameter 14 ), ( parameter 15 ), stir and slowly add ( parameter 16 ) mL Na ₂ CO ₃ (sat) until the bubble is no longer present, so that the pH of the water layer is alkaline (pH=8-9 ) was added followed by (parameter 17) mL CH ₂ Cl ₂ was extracted, the organic layer was washed brine dried over anhydrous magnesium sulfate was added, stirred for 5 minutes to melt the sand glass filter funnel, drained and concentrated to give the crude product (18 parameter The mg was purified by flash column chromatography (silica gel, ( parameter 19 )) to give ( parameter 20 ).

Codes 141 and 142 compounds: Table of synthesis parameters can be found in Table 5. 2-methoxyphenylboronic acid (46 mg, 0.30 mmol) was added to a microwave reaction flask at room temperature under air, dissolved in 2 mL of IPA. The solution was transparent and colorless, and the starting material C ₁₉ H ₂₁ BrN ₂ O ₄ ( parameter 1 ) After stirring for 30 minutes, the solution was cloudy white, then Pd(OAc) ₂ ( parameter 2 ) was added, triphenylphosphine ( parameter 3 ) was added, 2 M Na ₂ CO ₃ (aq) (0.14 mL, 0.28 mmol) was added, and H _{2 was} added. O (0.2 mL), microwave 120 ℃ 20 min, the solution before cooling H ₂ O (0.7 mL), was stirred in air to room temperature, then diluted with 10 mL EtOAc and extracted with 10 mL H ₂ O. The organic layer was washed first with 5% NaHCO ₃ (aq), then washed with brine and then added ( parameter 4 ) mg Darco G-60, stirred for 10 minutes, dried over anhydrous magnesium sulfate and stirred for 10 minutes in a fused glass funnel. The above was coated with Celite and a thin layer of Florisil, which were about 1 cm thick, and concentrated and drained, and purified by flash column chromatography (silica gel, EA/n-hexane = parameter 5 ) to give a pale yellow oily product ( parameter 6 ). After the product C ₂₆ H ₂₈ N ₂ O ₅ ( parameter 7 ) was dissolved in a little CH ₂ Cl ₂ , HCl was added until pH 1 and concentrated to dryness ( parameter 8 ).

Ref. _No. 150 Compound: First dry bottle, add the starting material C ₁₈ H ₂₀ BrNO ₂ (100 mg, 0.28 mmol) in a 25 mL double flask at room temperature under N ₂ and add DMF (2 mL). Dissolve, the solution is transparent and pale yellow, add trimethylphenylammonium chloride ((CH ₃ ) ₃ PhNCl, 102 mg, 0.59 mmol), add t-BuOK (67 mg, 0.60 mmol), and put in a pan to heat to 60 ° C, reaction 3.5 (H3) ₃ PhNCl (52 mg, 0.30 mmol) was added, and the reaction was carried out for 4.5 hr, then (CH3) ₃ PhNCl (50 mg, 0.29 mmol), and the starting material was not reacted and returned to room temperature. After diluting with 5% aqueous NaOH (20 mL) in CHCl ₃ (10 mL), the organic layer was taken prior to H ₂ O wash. After washing with brine, it was dried over anhydrous magnesium sulfate, stirred for 10 minutes, filtered over a fritted glass funnel, concentrated and dried, and purified by flash column chromatography (silica gel, EA/n-hexane = 1/4). Yellow solid product (83 mg, 0.22 mmol, 79%).

Code Compound 152: first dry flask, was added to the starting _{C 18 H 19 BrN 2 O 4} (406 mg, 1.00 mmol) in 25 mL two-neck flask, was added DMF (9 mL) under N ₂ at room temperature, starting The solution was completely dissolved, the solution was dried to orange, cooled to 0 ° C, and then degassed; NaH (40 mg, 1.67 mmol) was added, and CH ₃ I (0.06 mL, 0.98 mmol) in DMF (1 mL) was added for 10 min. NH ₄ Cl (111 mg, 2.08 mmol) was added. After diluting with diethyl ether (100 mL) and extracting with H ₂ O (100 mL), the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and stirred for 10 min. Purification by column chromatography (silica gel, EtOAc/EtOAc-EtOAc)

Ref. _No. 153 Compound: First dry bottle, add the starting material C ₁₈ H ₁₉ BrClNO ₂ (300 mg, 0.75 mmol) in a 25 mL double flask at room temperature under N ₂ and add DMF (6 mL). Dissolve, the solution is transparent orange, add trimethylphenylammonium chloride ((CH ₃ ) ₃ PhNCl, 542 mg, 3.16 mmol), add t-BuOK (333 mg, 2.97 mmol), and put in a pan to heat to 60 ° C, reaction 16 After an hour, the temperature was raised to 70 ° C for 1 hour, and the starting material was not reacted and returned to room temperature. After diluting with diethyl ether (100 mL) and H ₂ O (100 mL), the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and stirred for 10 min, filtered over a fritted glass funnel and concentrated to dryness Analysis of purified (silica gel, EA / n -hexane = 1/4), to give the product as a white solid (189 mg, 0.46 mmol, 61 %).

Code Compound 154: first dry flask under N ₂ was added the starting C ₁₈ H ₁₉ BrFNO ₂ at room temperature (400 mg, 1.05 mmol) in 25 mL two-neck flask, add DMF (8 mL), the starting material completely Dissolved, the solution became transparent pale yellow, add (CH ₃ ) ₃ PhNCl (727 mg, 4.23 mmol), add t -BuOK (468 mg, 4.17 mmol), and put in a frying pan and heat to 70 ° C for 16 hours. The starting material did not react and returned to room temperature. After diluting with diethyl ether (100 mL) and H ₂ O (100 mL), the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and stirred for 10 min, filtered over a fritted glass funnel and concentrated to dryness Purification (silica gel, EA/n-hexane = 1/4) gave product as a white solid (247 mg, 0.63 mmol, 60%).

Compounds 157-159, 165-168 and 171-173: See Table 6 for the synthetic parameter table. Add parameter 1 to the microwave reaction flask at room temperature under air, dissolve in ( parameter 2 ) mL IPA, the solution is transparent and colorless, add the starting material parameter 3 , stir for 30 minutes, add Pd(OAc) ₂ ( parameter 4 ) Add triphenylphosphine ( parameter 5 ), add 2 M Na ₂ CO ₃ (aq) ( parameter 6 ), add ( parameter 7 ) mL water, microwave 120 ° C for 20 minutes, add ( parameter 8 ) mL water before the solution is cooled, in the air It was stirred to room temperature, then diluted with 10 mL EtOAc and extracted with 10 mL water. The organic layer was washed first with 5% NaHCO ₃ (aq), then washed with brine and then added ( parameter 9 ) mg of Darco G-60, stirred for 10 minutes, dried over anhydrous magnesium sulfate, stirred for 10 minutes, in molten glass. The funnel was topped with Celite and a thin layer of Florisil, which were about 1 cm thick, and concentrated and drained, and purified by flash column chromatography (silica gel, EA/n-hexane = parameter 10 ) to obtain the parameter 11 . After the product parameter 12 was dissolved in a little CH ₂ Cl ₂ , hydrochloric acid was added until pH = 1 and concentrated to dryness to give a parameter 13 .

The data on the physical properties of the compounds prepared above are shown in Table 7.

Code 167 and 116,157 compounds for the serotonin receptor 2A (5-HT _2A receptor) affinity: the affinity expressed as K _i. As shown in Table 8, the compounds of the codes 116 , 157 , and 167 have higher affinity for the serotonin 2A receptor than the serotonin 2A receptor antagonist sarpogrelate or ketanserin which is currently available on the market.

The protective effect of the code of the 116 compound on the survival rate of endotoxin-induced sepsis in mice : In the ICR mouse 72-hour survival test, lipopolysaccharide (LPS) 100 mg/kg was injected intraperitoneally into the mouse. From the 12th hour after the LPS injection, to the 48th hour, the mice received an intraperitoneal injection of the compound 116 every 6 hours, and the therapeutic components were 100 μg/kg and 300 μg/kg of each injection code 116 compound. Two groups. The vehicle control group was the control group for the injection of the vehicle, and the pseudo group (Sham) was not injected with any drug or vehicle after the LPS injection. See the seventh picture for the experimental results. The survival curves of the two groups treated with the code of the 116 compound showed a right shift relative to the vector control group and reached statistical differences. The survival curve was analyzed using a log rank test, and the survival rate after three days was analyzed using a chi square test.

The protective effect of the code 167 compound on the survival rate of endotoxin-induced sepsis in mice : the experimental method is the same as above, and the experimental results are shown in the eighth figure .

The code 116 compound inhibits serotonin-induced platelet aggregation enhancement: the blood collected from male adult SD rats (Sprague Dawley rat) is centrifuged to separate "platelet rich plasma" (PRP) and "oligo-containing" Platelet poor plasma (PPP) was used for platelet aggregation experiments. The amount of platelets contained in the platelet-rich plasma is between 5 x 10 ⁸ /ml and 10 ¹⁰ /ml. The agglutination reaction is determined by measuring the transmittance of platelet-rich plasma in a Lumi-aggregometer by turbidity measurement, and the transmittance of the platelet-rich plasma is 100%, and the platelet-rich plasma is transparent. The luminosity is corrected to 0%. In the ninth panel (a) of the control group, the platelet-rich plasma was equilibrated for two minutes after being placed in a cold-light platelet aggregometer, and Dimethyl sulfoxide (DMSO) was added as a vehicle control for the subsequent administration group, and equilibrated for 30 seconds. Thereafter, deionized water was added as a vehicle control to which serotonin was administered, and after balancing for 30 seconds, collagen (collagen) 3 μg/ml was added as a platelet aggregation inducer. Visible transmittance platelet-rich plasma was significantly increased after addition of collagen; in the ninth (b) of FIG was added after 10 μM serotonin can significantly enhance the collagen-induced agglutination; FIG ninth (c) and section Figure 9 (d) shows that the effect of serotonin-enhanced collagen-induced agglutination can be inhibited by ketanserin 10 μM and code 116 compound 3 μg/ml.

The code 116 compound inhibits serotonin-induced contraction of the denervated descending thoracic aorta in adult rats: adult male Sprague Dawley rats weigh approximately 250-350 g, intraperitoneally injected with pentobarbital (25 mg/kg) and heparin (heparin) (16 mg/kg) was anesthetized. After it is asleep, the cervical vertebrae are separated, the thoracic cavity is cut, and the aorta of the thoracic cavity is located (between the arterial arch and the diaphragm). The removed aorta was placed in a Krebs-Henseleit (KHS) solution (pH 7.4) with a mixture (95% O ₂ and 5% CO ₂ ) containing 118.2 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO ₄ , 1.2 mM KH ₂ PO ₄ , 25.0 mM NaHCO ₃ , 11.7 mM Glucose and 1.9 mM CaCl ₂ ‧2H ₂ O were added simultaneously with 10 μM of indomethacin and equilibrated on ice for 30 minutes. After the balance, the fat and connective tissue around the aorta were removed and cut into a vascular ring of about 3 mm in length. To remove the endothelium, gently remove the endothelium with a silver hook. The treated vascular ring was placed in an organ bath containing 10 mL of KHS-mixed gas at a temperature of 37 ° C. One end was fixed with a sigmoid silver hook to the glass hook at the lower end of the tissue bath; the other end was sigmoid The silver hook was attached to a tension transducer (Force transducer, Type BG25, Gould Inc. Cleveland, Ohio, USA) to record the change in tension with a recorder (Gould Recorder, RS 3400). Balance for two hours to achieve a suitable resting tension of between 1.5 ± 0.2 grams. After the balance was completed, 0.1 M phenylephrine and 1 M acetylcholine were used to determine the degree of vascular endothelial integrity: when the endothelium was removed, 0.1 M phenylephrine was administered and then 1 M was administered. When acetylcholine was used, there was no relaxation reaction. After determining the vascular status, the drug was washed away with 10 mL of KHS, once every 10 minutes for a total of 8 times; after completion, it was equilibrated for another 30 minutes, and the resting tension after the balance was still about 1.5 ± 0.2 g. For the experiment, the compound of code 116 (0.03 μM or 0.1 μM) was first equilibrated for 20 minutes, or dimethyl sulfoxide (DMSO) was administered as a control group. After equilibration, serotonin is added to the vasoconstriction in a cumulative manner, and the next dose of drug or dose is added when the contractile response needs to reach a plateau response. The contraction response is expressed as a percentage of the maximum amount of contractile force increase. As shown in the tenth figure , the compound of the code 116 can inhibit the vasopressin-induced vasoconstriction reaction, and this inhibition is enhanced by the increase in the dose of the compound of the code 116 .

First: Synthesis of octaphenylisoquinoline.

Figure 2: Synthesis of octaphenylisoquinoline.

Figure 3: Synthesis of octaphenylisoquinoline III.

Figure 4: Synthesis of octaphenylisoquinoline IV.

Figure 5: Synthesis process of octaphenylisoquinoline.

Figure 6: Synthesis of octaphenylisoquinoline.

Figure 7: The protective effect of the compound of code 116 on the survival rate of sepsis induced by endotoxin injection in mice.

Figure 8: The protective effect of the code 167 compound on the survival rate of sepsis induced by endotoxin injection in mice.

Figure 9 (a) to ninth (d): The code 116 compound inhibits serotonin-induced platelet aggregation enhancement.

Figure 10: The code 116 compound inhibits the serotonin-induced contraction response of the denervated descending thoracic aorta in rats.

Claims (10)

An octaphenylisoquinoline compound having the following structural formula: An octaphenylisoquinoline compound or a pharmaceutically acceptable salt thereof having the following structural formula: R ₁ is selected from a C _3-12 straight or branched alkyl group, a heterocyclic ring having n carbon chains [(CH ₂ ) _n (Hete)R ₁₀ R ₁₁ R ₁₂ ], and an aromatic [(CH ₂ ) _n ArR ₁₀ R ₁₁ R ₁₂ ], and n is 2-6, and R ₁₀ , R ₁₁ and R ₁₂ are each a substituent on the hetero ring (Hete) or the aromatic ring (Ar), respectively. Selected from hydrogen, halo, nitro, amine, cyano, ethyl hydrazino, C _1-6 linear saturated alkyl, C _1-6 linear saturated alkoxy, and C _1-6 straight One of a saturated haloalkyl group; R ₂ is one selected from the group consisting of hydrogen and a saturated alkyl group of a C _1-6 straight chain; and R ₃ is selected from one of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain. And R ₄ is one selected from the group consisting of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain; and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are independently selected from the group consisting of hydrogen, a halogen group, and a nitro group. Amino, cyano, ethoxylated, C _1-6 straight or branched saturated alkyl, C _1-6 straight or branched saturated alkoxy, C _1-6 straight or branched saturated One of an alkylthio group and a C _1-6 linear or branched saturated haloalkyl group. The compound of claim 2, wherein the halogen group is one selected from the group consisting of fluorine, chlorine, bromine, and iodine. The compound of claim 2, wherein the heterocyclic ring is selected from the group consisting of naphthyl, indolyl, isoindolyl, indazolyl, and benzofuran. Benzofuranyl, isobenzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl one. Use of an octaphenylisoquinoline compound for the preparation of a medicament having antagonism of the serotonin 2A receptor (5-HT _2A receptor). The use according to claim 5, for the preparation of a medicament for inhibiting serotonin-induced arterial contraction. The use of claim 6, wherein the arterial contraction is induced by serotonin. The use according to the fifth aspect of the patent application is for the preparation of a medicament for inhibiting serotonin-induced platelet aggregation. The use of the platelet agglutination as claimed in claim 8 It is induced by serotonin. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and a principal component of the following structural formula: R ₁ is selected from a C _3-12 straight or branched alkyl group, a heterocyclic ring having n carbon chains [(CH ₂ ) _n (Hete)R ₁₀ R ₁₁ R ₁₂ ], and an aromatic [(CH ₂ ) _n ArR ₁₀ R ₁₁ R ₁₂ ], and n is 2-6, and R ₁₀ , R ₁₁ and R ₁₂ are each a substituent on the hetero ring (Hete) or the aromatic ring (Ar), respectively. Selected from hydrogen, halo, nitro, amine, cyano, ethyl hydrazino, C _1-6 linear saturated alkyl, C _1-6 linear saturated alkoxy, and C _1-6 straight One of a saturated haloalkyl group; R ₂ is one selected from the group consisting of hydrogen and a saturated alkyl group of a C _1-6 straight chain; and R ₃ is selected from one of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain. And R ₄ is one selected from the group consisting of a hydroxyl group and a saturated alkoxy group of a C _1-6 straight chain; and X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are independently selected from the group consisting of hydrogen, a halogen group, and a nitro group. Amino, cyano, ethoxylated, C _1-6 straight or branched saturated alkyl, C _1-6 straight or branched saturated alkoxy, C _1-6 straight or branched saturated One of an alkylthio group and a C _1-6 linear or branched saturated haloalkyl group.