WO2013091285A1

WO2013091285A1 - Urea compound, preparation method and use thereof

Info

Publication number: WO2013091285A1
Application number: PCT/CN2012/001719
Authority: WO
Inventors: 南发俊; 左建平; 李佳; 张梅; 布鲁姆·安娜; 唐炜; 杨筱莹
Original assignee: 中国科学院上海药物研究所
Priority date: 2011-12-21
Filing date: 2012-12-21
Publication date: 2013-06-27
Also published as: CN103172543A; CN103172543B

Abstract

Provided are a urea compound having a structure as represented by general formula I, preparation method thereof, pharmaceutical composition containing the compound, and uses thereof in the preparation of drugs for treating inflammatory response, immune hyperactivity and organ transplantation rejection, wherein R₁-R₇, X, Y and n in the general formula are as defined in the specification and the claims.

Description

Urea compound, preparation method and use thereof

The invention belongs to the field of medicinal chemistry, and relates to a urea compound, a preparation method thereof, a pharmaceutical composition comprising the same, and a use thereof, and the compound has complement inhibitory activity and can be applied to treat inflammatory reaction, hyperthyroidism and organ transplantation. Rejection and other aspects. BACKGROUND OF THE INVENTION The complement system is a group of immunologically-activated, enzymatically active proteins present on the surface of human and vertebrate serum, tissue fluid and cell membranes, including more than 20 serum proteins (as intrinsic components of complement) and complement regulatory proteins. And mediating complement activity fragments or regulatory protein biological effector receptors of the immune system.

Under physiological conditions, most of the complement components in serum are present as inactive enzyme precursors. The components of complement are activated in turn only under the action of certain activators or on specific solid surface. Whenever the former component is activated, it has the activity of cleavage of the next component, thereby forming a series of amplified chain reactions, ultimately leading to a cytolytic effect. At the same time, a variety of hydrolyzed fragments produced during the activation of complement have different biological effects and are widely involved in the immune regulation and inflammatory response of the body.

Activation of complement by the classical pathway and the alternative pathway results in the lysis of target cells. After activation, the system can lyse various target cells such as blood cells, virus-infected cells and pathogenic microorganisms. This complement-mediated lysis and cytolytic action is an important defense against the infection of pathogenic microorganisms. On the other hand, when the complement system is overactive, it can also cause some autoimmune diseases. Certain autoimmune diseases can cause the lysis of their own cells, leading to damage to their tissues, which are also involved in the involvement of complement. Therefore, complement inhibitors may be used to treat inflammatory reactions, hyperimmunity, and organ transplant rejection.

The hemolytic inhibition test (classical approach) is based on the principle that sheep red blood cells (SRBC) bind to the corresponding antibody (hemolysin) to activate complement in the serum to be tested, resulting in hemolysis of SRBC, the degree of hemolysis and the content and function of complement in serum. related. The complement inhibitory activity of the compound can be reflected by the degree of hemolysis (absorbance value). The more mature complement inhibitors currently studied are complement regulatory proteins, such as SCR1 and antibodies, which are less toxic, but more expensive and can only be administered intravenously. In recent years, several small molecule complement inhibitors have been reported in different stages. There are two main types: peptides and their analogues and various types of small molecule compounds. Currently there are two small molecules FUT-175 (Nafomostat ) and BCX-1470 are in clinical research.

Compared with traditional protein molecules, small molecule complement inhibitors have many advantages in terms of drug delivery, cost and pharmacokinetics, and have good application prospects. Therefore, it is necessary to develop novel small molecule complement inhibitors.

The inventors designed and synthesized a urea compound. The in vitro hemolysis inhibition test found that the compound has complement inhibitory activity, and the IC _5Q of the representative compound is about 20 nM. The mechanism of the further study suggests that the target of the compound is complement. Terminal Pathway C9 o of the Activation Pathway Accordingly, it is an object of the present invention to provide a novel urea compound having complement inhibitory activity;

Another object of the present invention is to provide a process for producing such a urea compound having complement inhibitory activity;

Still another object of the present invention is to provide a pharmaceutical composition having complement inhibitory activity, which comprises the urea compound of the present invention as an active ingredient.

A further object of the present invention is to provide a pharmaceutical composition of the present invention and a pharmaceutical composition thereof for use in the preparation of a medicament for the treatment of inflammatory response, hyperthyroidism and organ transplant rejection.

Wherein, and R ₂ are each independently H, a substituted or unsubstituted C1 to C8 alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 cycloalkyl group, or a N or 0 atom C3~C7 heterocyclic group, C2~C8 alkenyl group, C2~C8 alkynyl group; preferably and one of them is methyl group, the other is H, substituted or unsubstituted C1~C8 An alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 cycloalkyl group, or a heterocyclic group having a C or C atom of C or C, a C2 to C8 alkenyl group, An alkynyl group of C2 to C8; preferably a C4 to C6 alkyl group, a C4 to C6 alkenyl group, a C4 to C6 alkynyl group, and R ₂ is a C1 to C4 alkyl group; more preferably a C4 to C6 group; An alkyl group, an alkenyl group of C4 to C6, an alkynyl group of C4 to C6, and R ₂ is a methyl group;

R ₃ and R ₄ are each independently H, C1 to C4 alkyl, C1 to C4 alkyl optionally substituted by at least one hydroxy or amino group; preferably C1 to C3 substituted by H, methyl or hydroxy The alkyl group is H, C1~C4 alkyl; more preferably ₁₄ is 11, methyl, hydroxy substituted C2~C3 alkyl, R ₃ is H;

Is an alkyl group of 11, C1 to C4, preferably R ₅ is a methyl group;

Or R ₄ and R ₅ together with the carbon atom and the nitrogen atom to which they are bonded form a 5-7 membered ring; R ₆ to R ₇ are each independently selected from one of the following groups: H, halogen, hydroxy, amino, a carboxyl group, an alkoxycarbonyl group of C1 to C4, an alkoxy group of C1 to C4, a cyano group, a trifluoromethyl group or a fluorenyl group; preferably R ₆ is a halogen or a hydroxyl group, and R ₇ is H; more preferably R ₆ is F, a hydroxyl group , R ₇ is H;

n is 0, 1, 2, preferably n is 0;

X is CH or N, and preferably X is CH;

Y is 0 or S, and preferably Y is 0.

The present invention further provides a urea compound having the structure shown in Formula II.

II

Wherein, one of R and R ₂ is a methyl group, and the other is H, a substituted or unsubstituted C1 to C8 alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 naphthenic group. a heterocyclic group having a C or C atom of N or 0 atoms, an alkenyl group of C2 to C8, an alkynyl group of C2 to C8;

R ₃ and R ₄ are each independently H, a C1 to C4 alkyl group, optionally a C1 to C4 alkyl group substituted with at least one hydroxyl group or an amino group;

R ₅ is an alkyl group of C1 to C4;

Or R ₄ and R ₅ together with the carbon atom and the nitrogen atom to which they are bonded form a 5-7 membered ring; R ₆ to R ₇ are each independently selected from one of the following groups: H, halogen, hydroxy, amino, a carboxyl group, an alkoxycarbonyl group of C1 to C4, an alkoxy group of C1 to C4, a cyano group, a trifluoromethyl group;

X is CH or N;

Y is 0 or 8.

In the present invention, the alkyl group includes a linear or branched alkyl group, the alkenyl group includes a linear or branched alkenyl group, and the alkynyl group includes a straight chain or Branched alkynyl, said halogen includes? , Cl, Br and I.

The urea compound having complement inhibitory activity of the present invention is most preferably selected from the following compounds.

The aromatic oxypyrimidinecarboxamide or the aryloxypyridine carboxamide compound represented by the formula in the present invention can be produced by various steps and synthetic routes, and representative steps and synthesis methods are as follows, but are not limited to the following methods. :

For the preparation method of the above-mentioned compound of the present invention, the following method can be adopted

Step A1: The iso-vanillin 1 is protected with a benzyl group to give the intermediate 2, which is carried out by a conventional method in the art;

Step A3: Intermediate 3 is subjected to a modified Curtius rearrangement to obtain isocyanic acid. Step A4: Isocyanate 4 and substituted amine

(In addition to the examples, the preparation of the amine is given, the remaining amines are commercially available). After the condensation reaction, the key intermediate 5 is obtained, and the condensation reaction is carried out by a conventional method in the art;

Step A5: Intermediate 5 is deprotected by benzyl to give intermediate 6;

Ho step A6: Intermediate 6 and differently substituted bromide R _r Br (both shown in FIG. 7 to give the intermediate urea compound obtained by reaction of commercially available :) route;

Step A7: The intermediate 7 is reacted with R ₃ I under NaH under basic conditions to obtain the urea compound of the present invention as shown in Formula 8;

In the route A, ~1 ₇ is the same as defined in the formula I.

The respective reactions in the above experimental procedures are conventional experimental means by those skilled in the art, and the reaction conditions such as reaction temperature, time, atmosphere and the like can be determined by those skilled in the art based on the relevant reactions.

Route B:

^ Bl : The vanillin 9 is protected with a benzyl group to give the intermediate 10, which is carried out by a conventional method in the art;

Ho step B2: the intermediate 10 oxidation of _{_{_{2 PO 4/30% H 2}}} O 2 or PCC or Na _₂ Cr ₂ 0 ₇ acts as an oxidizing agent NaClO ₂ / NaH to give intermediate acid 11;

Step B3: Intermediate 11 is subjected to a modified Curtius rearrangement to obtain isocyanate 12;

B4: Isocyanate 12

(The preparation of the amine is given in the examples, and the remaining amines are commercially available.) After the condensation reaction, the key intermediate 13 is obtained, which is carried out by a conventional method in the art;

Step B5: Intermediate 13 is deprotected by benzyl to give intermediate 14;

Step B6: The intermediate 14 and the different substituted bromine R ₂ -Br (both obtained by commercially available route:) are reacted to obtain a urea compound represented by the intermediate 15; Step B7: The intermediate 15 is reacted with R ₃ I under NaH under basic conditions to obtain the urea compound of the present invention as shown in Formula 16; in Scheme B, ~ ₁₇ and Formula I The definition is the same. The respective reactions in the above experimental steps are conventional experimental means by those skilled in the art, wherein the reaction conditions such as reaction temperature, time, atmosphere and the like can be determined by those skilled in the art according to relevant reactions.

Route C:

twenty two

Step CI: Intermediate 17 (prepared by reference method: Molecular Simulation, Vol. 33, No. 14, December 2007, 1109-1117) is reacted with bromo: 3⁄4 to give intermediate 18;

Step C2: hydrolysis of intermediate 18 to give acid 19;

Step C3: The acid 19 is prepared as the isocyanate 20 in the same manner as in Scheme A;

Step C4: Isocyanate 20

(The preparation of the amine is given in the examples, and the remaining amines are commercially available.) After the condensation reaction, the intermediate 21 is obtained, and the condensation reaction is carried out by a conventional method in the art; Step C5: reacting intermediate 21 with R ₃ I under NaH under basic conditions to obtain a urea compound of the present invention as shown in Formula 22;

Where ~1 7 is the same as defined in Formula I.

The novel complement C9 inhibitor provided by the invention inhibits total complement hemolytic activity in vitro and finds that the compound has complement inhibitory activity and can be used for treating complement-associated inflammation, hyperthyroidism, transplant rejection, etc., including treating patients. An effective amount of one or more compounds selected from the group consisting of urea compounds as shown by the formula.

Another object of the present invention is to provide a method for preventing or treating inflammatory response, hyperthyroidism and organ transplant rejection comprising administering to a patient a therapeutically effective amount of one selected from the group consisting of urea compounds of the formula (I) Or several compounds.

The present invention provides a pharmaceutical composition for treating complement-associated inflammation, hyperthyroidism, transplant rejection, and the like, comprising a therapeutically effective amount of one or more of the above compounds of the present invention as an active ingredient, and further comprising Pharmaceutically acceptable adjuvants such as dispersing agents, excipients, disintegrating agents, antioxidants, sweeteners, coating agents and the like. The composition can be prepared according to a conventional preparation method in the pharmaceutical field, and can be prepared into various conventional dosage forms such as tablets, coated tablets, capsules, powders and the like.

Another object of the present invention is to provide a use of a urea compound of the formula 1 for the preparation of a medicament for preventing or treating inflammatory response, hyperthyroidism and organ transplant rejection. DRAWINGS

Figure 1 shows the OD value at 450 nm of Compound 11 of the classical route C4 component. Figure 2 is the OD value at 450 nm of Compound 11 of the classical route C3 component. Figure 3 is the OD value at 450 nm of Compound 11 of the classical route C9 component. Figure 4 is the OD value at 450 nm of Compound 11 of the classical pathway C5b-9 component. Figure 5 is the OD value at 450 nm of Compound 11 of the mannose pathway C4 component. Figure 6 is the OD value at 450 nm of Compound 11 of the mannose pathway C3 component. Figure 7 is the OD value at 450 nm of Compound 11 of the mannose pathway C9 component. Figure 8 is the OD value at 450 nm of Compound 11 of the mannose pathway C5b-9 component. Figure 9 is the OD value at 450 nm of Compound 11 of the alternative pathway C3 component. Figure 10 is the OD value at 450 nm of Compound 11 of the bypass route C9 component. Figure 11 is the OD value at 450 nm of Compound 11 of the alternative pathway C5b-9 component. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be further described with reference to specific embodiments, but the present invention is not limited to the embodiments. Compound preparation example

In the following preparation examples, NMR was measured with a Mercury-Vx 300M instrument manufactured by Varian, NMR calibration: 5 H 7.26 ppm (CDC1 ₃ ); mass spectrometer with Agilent 1200 Quadrupole LC/MS LC/MS; reagent mainly from Shanghai Provided by chemical reagent companies;

TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silicone Development Co., Ltd., model HSGF 254; normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao Marine Chemical Plant Branch, model zcx-l l, 200-300 Head. PREPARATION EXAMPLE 1 Synthesis of intermediate (S)-l-(3-hydroxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea

(1) 3-Benzyloxy-methoxy-benzaldehyde

Take iso-vanillin (3.04g, 20nmol) to a 100ml round bottom flask, add 50ml of acetone, add benzyl bromide (3.42g, 20nmol), anhydrous K ₂ C0 ₃ (11 g, 80nmol), heat reflux for 12 hours, TLC detection The reaction was completed, and the residue was evaporated to ethylamine crystals. 98%.

lH NMR (300 MHz, CDC1 ₃ ): δ 3.95 (s, 3H), 5.18 (s, 2H), 6.977-7.006 (d, J = 8.7 Hz, 1H), 7.312-7.40 (m, 2H), 7.45- 7.47 (m, 5H), 9.816(s, 1H).

(2) 3-Benzyloxy-4-methoxy-benzoic acid

3-Benzyloxy-4-methoxy-benzaldehyde (1.08 g, 4.46 mmol) and sodium dihydrogen phosphate (0.16 g, 0.134 mmol) were dissolved in 25 ml of acetonitrile / 5 ml of water, and 30% 3⁄4O ₂ (159 mg, 4.69 mmol), cooled in an ice water bath, and then slowly added sodium chlorite (0.562 g, 6.24 mmol) / 8 ml of water, and the dropwise addition temperature did not exceed 10 ° C. After the addition, the mixture was stirred at room temperature overnight. The reaction was completely detected by TLC, and the reaction was quenched with a 10% NaS ₂ O ₃ solution, extracted with ethyl acetate, and the organic phase was washed with water. The organic phase was washed with 10% NaHCO ₃ plus solution, adding water, acidified with 1N HC1, and extracted three times with ethyl acetate, the combined organic adding water, and saturated brine, dried and concentrated to give a white solid of 3-benzyloxy-4- Methoxy-benzoic acid 0.78 g, yield 72%.

lR NMR (300 MHz, CDC1 ₃ ): δ 3.98 (s, 3Η), 5.22 (s, 2H), 6.99-7.0021 (d, J=9Hz, 1H), 7.332-7.45 (m, 2H), 7.45-7.47 (m, 5H).

(3) 3-Benzyloxy-4-methoxy-phenyl isocyanate

3-Benzyloxy-4-methoxy-benzoic acid (0.78 g, 3 mmol) was suspended in 10 ml of benzene, and triethylamine (323 mg, 3.1 mmol) was added under argon, cooled in ice water, and added dropwise. DPPA (831 mg, 3 mmol) was stirred at 0 ° C for 2 hours, then stirred at room temperature for 2 hours, diluted with 10 ml of benzene, washed with water and brine, and dried over anhydrous magnesium sulfate.

After filtering off the desiccant, the benzene solution was heated to reflux for 2 hours, and the reaction was completed by TLC, and then concentrated to give 3-benzyloxy-4-methoxy-phenyl isocyanate. The intermediate was unstable and directly subjected to a hydrazine reaction.

- 1 -(3-benzyloxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea

The crude product 3-benzyloxy-4-methoxy-phenylisocyanate obtained in the upper hydrazine was dissolved in 5 ml of dichloromethane, and (s)-a-phenylethylamine lg was added thereto, and stirred at room temperature for 10 minutes, a white solid appeared. The reaction was completely detected by TLC, diluted with petroleum ether, and filtered to give (S)-lP-benzyloxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea 537 mg, The yield was 48%. NMR (300 MHz, CDC1 ₃ ): δ 1.416-1.44 (d, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.803-4.828 (d, J = 7.5 Hz, 1H ), 4.935-4.982 (m , 1H), 5.08 (s, 2H), 5.998 (s, 1H), 6.69-6.72 (m, 1H), 6.80-6.82 (d, J= 6Hz, 1H), 6.88-6.89 (d J= 2Hz, 1H ), 7.24-7.419 (m, 10H).

-l-(3-hydroxy-4-methoxyphenyl)-3-(l-phenyl-ethyl)-urea

To (S)-l-(3-Benzyloxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea (389 mg, 1.03 mmol), 5% Pd/C (40 mg Add 10 ml of DMF (Ν, Ν-dimethylformamide), stir at 3 ° of lamat at room temperature overnight, complete the reaction by TLC, filter off the catalyst, add water, extract with ethyl acetate 3 times, add organic phase water, The mixture was washed with saturated brine and dried and evaporated to dryness to give white crystals of (s)-(-(3-hydroxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea 0.25 g, yield 85 %.

¹ ι NMR (300 MHz, CDC1 ₃ ): δ 1.395-1.418 (d, J = 6.9 Hz, 3H), 3.824 (s, 3H), 4.911-4.959 (m, 1H), 5.265-5.290 (d, J= 7.5 Hz, 1H), 5.863 (s, 1H), 6.70-6.77 (m, 3H), 7.24-7.30 (m, 5H). Preparation Example 2 (S)-l-(3-Butoxy-4-methoxyphenyl)-3-(l-phenyl-ethyl)-urine

(S)-l-(3-Hydroxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea (20 mg, 0.07 mmol), n-butyl bromide 0.1 ml, Potassium carbonate, 80 mg, a catalytic amount of 18-crown-6, 2 ml of DMF was mixed and stirred at room temperature overnight. The reaction was complete by TLC. Add water and ethyl acetate to separate, and extract the aqueous phase with ethyl acetate for 3 times. Add the organic phase and add water and wash with saturated brine. The mixture was dried and concentrated to give a white solid (S)-l-(3-butoxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea 23 mg, yield 96%.

^NMR (300 MHz, CDC13): δ 0.904-0.95 (t, 3H), 1.388-1.406 (d, J = 5.4 Hz, 3H), 1.40-1.49 l (m, 2H), 1.709-1.805 (m, 2H) ), 3.79(s, 3H), 3.901-3.923(t,2H), 4.926-4.973 (m, IH), 5.397-5.423 (d, J=7.8Hz, IH), 6.578-6.612 (dd, IH), 6.709-6.737 (d, J = 8.4 Hz, IH), 6.81 (s, lH), 6.983-6.989 (d, J = 1.8 Hz, IH), 7.24-7.3 l (m, 5H). Preparation Example 3 (S)-l-(3-pentyloxy-4-methoxyphenyl)-3-(l-phenyl-ethyl)-urea

(S)-l-(3-pentyloxy-4-methoxyphenyl) was obtained in the same manner as in Preparation Example 2 except that n-butyl bromide was replaced by the corresponding number of n-butyl bromide. ) -3-(1-phenyl-ethyl:)-urea.

lU NMR (CDC13, 300 MHz): δΙ.38-1.41 (t, 3H), 1.388-1.406 (d, J=5.4 Hz, 3H), 1.40-1.49 l(m, 2H), 1.709-1.805 (m, 2H), 3.79(s, 3H), 3.901-3.923(t,2H), 4.926-4.973 (m, IH), 5.397-5.423 (d Hz, J=7.8, IH ), 6.578-6.612 (dd, IH) , 6.709-6.737 (d, J = 8.4 Hz, IH), 6.81 (s, lH), 6.983-6.989 (d, J = 1.8 Hz, IH), 7.24-7.3 l (m, 5H). Preparation Example 4 (S)-l-(3-hexyloxy-4-methoxyphenyl)-3-(l-phenyl-ethyl)-urea

(S)-l-(3-hexyloxy-4-methoxyphenyl) was obtained in the same manner as in Preparation Example 2 except that n-butyl bromide was replaced by the corresponding moles of n-hexane. -3-(1-phenyl-ethyl:)-urea. NMR NMR (CDC13, 300 MHz): δ 0.84-0.88 (t, 3H), 1.26-1.32 (m, 6H), 1.33-1.36 (d, J = 7.2 Hz, 3H), 1.72-1.77 (m, 2H) , 3.77(s,3H), 3.84-3.88(t,2H), 4.89-4.94(m,lH), 5.63-5.66 (d,lH),

6.55-6.58 (dd, Jl=2.1 Hz, J2=8.4 Hz, lH), 6.67-6.70 (d, J=8.4 Hz, lH), 7.02-7.03 (d, J=2.1 Hz, 1H), 7.11(s , lH), 7.21-7.28 (m, 5H). Preparation Example 5 (S)-l-(3-(pent-4-hinooxy)-4-methoxyphenyl)-3-(l-phenyl-

Compound 5

(S)-l-(3-(pent-4-enyloxy) was obtained in the same manner as in Preparation Example 2 except that n-butyl bromide was replaced by the corresponding number of moles of 5-bromopent-1-ene. yl) -4-methoxy-phenyl) - ₃ - ₍₁ - phenyl - ethyl) - urea.

^ NMR (CDC13, 300 MHz): δ 1.36-1.38 (d, J = 6.6 Hz, 3H), 1.83-1.88 (m, 2H), 2.15-2.17 (m, 2H), 3.78 (s, 3H), 3.87 -3.91(t,2H),

4.93-4.97(m,3H), 5.46(s,lH), 5.79-5.82 (m,lH),

6.60-6.63 (dd, Jl=2.1Hz, J2=8.4Hz, lH), 6.69-6.72 (d, J=8.4Hz, lH), 6.99-7.00 (d, J=2.1Hz, 1H), 7.19-7.26 (m, 5H). PREPARATIVE EXAMPLE 6 (S)-l-(3-(Butoxy-3-yloxy)-4-methoxyphenyl)-3-(l-phenyl-

Compound 6

(S)-l-(3-(but-3-enyloxy) was obtained in the same manner as in Preparation Example 2 except that the corresponding number of moles of 4-bromobut-1-ene was used instead of n-butyl bromide. Base: )-4-methoxyphenyl)- ₃ - ₍₁ -phenyl-ethyl)-urea.

^ NMR (CDC13, 300 MHz): δ 1.42-1.44 (d, J = 6.6 Hz, 3H), 1.70-1.72 (m, 2H), 3.81 (s, 3H), 3.92-4.00 (t, 2H), 4.94 -4.99(m,lH), 5.07-5.17(m,2H), 5.785-5.92 (m, lH), 6.43-6.46 (m,lH), 6.61-6.64(m,lH) 6.74-6.77 (d,J = 8.4 Hz, 1H), 6.93-6.95 (dd, Jl = 2.1 Hz, J2 = 8.4 Hz, lH), 7.19-7.33 (m, 5H). Preparation Example 7 (S)-l-(3-(pent-2-ynyloxy)-4-methoxyphenyl)-3-(1-phenyl-

(S)-l-(3-(pent-2-ynyloxy) was prepared in the same manner as in Preparation Example 2 except that n-bromopentane-2-alkyne was replaced by the corresponding number of moles. yl) -4-methoxy-phenyl) - ₃ - ₍₁ - phenyl - ethyl) - urea.

3⁄4 NMR (CDC13, 300 MHz): δ 1.06-1.11 (t, 3H), 1.43-1.45 (d, J = 6.6 Hz, 3H), 2.13-2.21 (m, 2H), 3.83 (s, 3H), 4.66 (s, 2H), 4.95-5.05 (m, 2H), 6.23 (s, lH), 6.78 (s, 2H), 6.97 (s, lH), 7.28-7.34 (m, 5H). PREPARATION EXAMPLE 8 Synthesis of (S)-l-(3-isopentyloxy-4-methoxyphenyl)-3-(l-phenyl-ethyl-urea)

(S)-l-(3-Isopentyloxy-4-methoxyl was obtained in the same manner as in Preparation Example 2 except that n-butyl bromide was replaced by the corresponding moles of isoamyl bromide. Phenyl)-3-(1-phenyl-ethyl)-urea.

^ NMR (CDC13, 300 MHz): δ 0.91 -0.93 (d, J = 6 Hz, 6H), 1.39-1.41 (d, J = 6.6 Hz, 3H), 1.65-1.80 (m, 3H), 3.80 (s, 3H), 3.91-3.96 (t, 2H), 4.93-4.98 (m, lH), 5.30-5.33 (d, lH), 6.58-6.62 (dd,

Jl=2.1 Hz, J2=8.4 Hz, lH), 6.66 (s, lH), 6.75-6.72 (d, J=8.4 Hz, 1H), 6.97-6.98 (d, J=2.1 Hz, lH), 7.22- 7.31 (m, 5H). PREPARATION EXAMPLE 9 Synthesis of (S)-l-(3-(cyclohexylmethoxy)-4-methoxyphenyl)-3-(l-phenyl-)urea

(S)-l-(3-(cyclohexylmethoxy:)-4 was obtained in the same manner as in Preparation Example 2 except that n-butyl bromide was replaced by the corresponding number of moles of bromomethylcyclohexane. - methoxyphenyl) - ₃ - ₍₁ - phenyl - ethyl) - urea.

3⁄4 NMR (CDC13, 300 MHz): δ 0.97- 1.01 (m, 2H), 1.22-1.30 (m, 5H) _: 1.43-1.45 ( d, J = 6.6 Hz, 3H ) , 1.71-1.76 (m, 2H) , 1.85-1.88 (m, 2H), 3.71-3.73 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H), 4.98-5.00 (m, 2H), 6.21 (s, lH), 6.63-6.65 (dd, Jl=8.7Hz, J2=2.1Hz, IH), 6.75-6.78 (d, J=8.7Hz, IH), 6.90-6.9 l(d, J=2.1Hz, IH), 7.28-7.32(m , 5H). Preparation Example 10 (S)-l-(3-(oxirano-2-ylmethoxy)-4-methoxyphenyl)-3 Synthesis

(S)-l-(3-(oxirane) was obtained in the same manner as in Preparation Example 2 except that the corresponding number of moles of 2-(bromomethyl)oxirane was used instead of n-butyl bromide. -2-ylmethoxy)-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea.

3⁄4 NMR (CDC13, 300 MHz): δ 1.38-1.41 (d, J = 6.6 Hz, 3H), 2.63-2.67 (m, lH), 2.80-2.83 (m, lH), 3.29-3.32 (m, lH) , 3.79(s, 3H), 3.83-3.90(m,lH), 4.14-4.21 (dt, IH), 4.91-4.96 (m,lH), 5.40-5.42(d,J=7.2Hz,lH), 6.64 -6.78 (m, 2H), 7.00-7.02 (m, lH), 7.20-7.3 l (m, 5H). PREPARATION EXAMPLE 11 Synthesis of (S)-l-(4-methoxy-3-(4-methylpentyloxy)-phenyl)-3-(1-phenyl-ethyl)-urea

(1) 3-(4-Methylpentyloxy)-4-methoxy-benzaldehyde

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Compound 11 The crude product obtained from the upper oxime 3-(4-methylpentyloxy)-4-methoxy-phenylisocyanate was dissolved in 50 ml of dichloromethane, and (S)-a-phenylethylamine 3 g was added at room temperature. The mixture was stirred for 10 minutes, and the reaction was completed by TLC. The solvent was evaporated to remove most solvent, and then petroleum ether/ethyl acetate=5/1 solvent 20 ml was added and stirred at room temperature for 1 hour to precipitate 3 g of white solid as (S)-l-( 3-(4-Methylpentyloxy)-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea. The yield of the two oximes was 67%.

3⁄4 NMR (300 MHz, CDC13): δ 0.898-0.929 (d, J = 6.6 Hz, 6H), 1.265-1.341 (m, 2H), 1.457-1.481 (d, J = 7.2 Hz, 3H), 1.539-1.617 (m, IH), 1.805-1.857 (m, 2H), 3.842 (s, 3H), 3.872-3.945 (t, 2H), 4.825-4.850 (d, J = 7.5 Hz, IH), 4.974-4.996 (m , IH ), 5.98 (s, IH), 6.635-6.672 (dd, J=8.7 Hz, 2.4 Hz, IH), 6.775-6.804 (d, J=8.7 Hz, IH), 6.877-6.885 (d, J= 2.4 Hz, IH), 7.267-7.365 (m, 5H). Preparation Example 12 (S)-l-(3-Hydroxypropyl)-3-[4-methoxy-3-(4-methylpentyloxy)-phenyl]-1-(1-phenyl -ethyl)-urea

-3- (1-phenyl-ethylamino)-propan-1-ol

Add 1 ml of water to (S)-a-phenylethylamine (2.5 g, 20.6 mmol) and 3-chloro-1-propanol (0.973 mg, 10.3 mmol), heat to 100 ° C for 6 hours, stop heating, add Dilute with benzene, add water, wash with saturated brine, dry and concentrate, silica gel column chromatography (dichloromethane / A The alcohol (S)-3-(1-phenyl-ethylamino)-propan-1-ol, 500 mg, yield 27%.

lR NMR (300 MHz, CDC13): δ 1.358-1.380 (d, J=6.6 Hz, 6H), 1.609-1.728(m, 2H), 2.611-2.676(m, 1H), 2.6190-2.782(m, 1H) , 3.701-3.713 (m, 2H), 3.715-3.783 (m, lH), 7.26-7.36 (m, 5H).

(2) (S)-l-(3-Hydroxypropyl)-3-[4-methoxy-3-(4-methylpentyloxy)-phenyl]-1-(1-phenyl- Ethyl)-urea

Compound 12 was prepared in the same manner as in the above Preparation Example 11 (3), using 3-(4-methylpentyloxy)-4-methoxy-benzoic acid (150 mg). Pentyloxy)-4-methoxy-phenylisocyanate, the isocyanate is dissolved in 10 ml of dichloromethane, and (S)-3-(l-phenyl-ethylamino)propan-1-ol is added, stirred at room temperature. After 10 minutes, the reaction was completed by TLC, and the reaction mixture was concentrated under reduced pressure. Silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 elution) to give a white solid (S)-l-(3-hydroxypropyl)-3-[4-methoxy-3-(4-methyl Pentyloxy)-phenyl]-1-(1-phenyl-ethyl)-urea, 150 mg, yield 59%.

^{! H NMR (300 MHz, CDC13} ): δ 0.88-0.902 (d, J = 6.6 Hz, 6H), 1.246-1.33 (m, 2H), 1.454-1.505 (m, 3H), 1.569-1.593 (d, J =7.2 Hz, 3H), 1.754-1.830(m,2H), 3.301-3.358(m,2H), 3.573-3.588(m,2H), 3.78(s, 3H), 3.922-3.968(t,2H), 5.542-5.567 (m, 1H), 6.68-6.695 (m, 2H), 7.26-7.35 (m, 6H). PREPARATIVE EXAMPLE 13 (S)-l-(3-Aminopropyl)-3-[4-methoxy-3-(4-methylpentyloxy)-urea

(S)-l was obtained in the same manner as in Preparation Example 12 except that the corresponding number of moles of 3-chloropropan-1-amine was used instead of 3-chloro-1-propanol in the preparation of Example 12 (1). -(3-Aminopropyl)-3-[4-methoxy-3-(4-methylpentyloxy)-phenyl]small (1-phenyl-ethyl)-urea.

3⁄4 NMR (CDC13, 300 MHz): δ 0.89-0.91 (d, J = 6.6 Hz, 6H), 1.25-1.35 (m, 2H), 1.57-1.59 (d, J = 7.2 Hz, 3H), 1.55-1.64 (m, lH), 1.78-1.88 (m, 2H), 2.22-2.24 (m, 2H), 3.25-3.32 (m, 2H), 3.80 (s, 3H), 3.96-4.0 l(t, 2H), 5.71-5.74 (m, lH), 6.72-6.80 (m, 2H), 7.23-7.25 (m, lH), 7.27-7.37 (m, 5H), 9.09 (s, lH). PREPARATIVE EXAMPLE 14 (S)-l-(2-Hydroxyethyl)-3-[4-methoxy-3-(4-methylpentyloxy)--1-(1-phenyl-ethyl ) - Urea

(S)-lP- was obtained in the same manner as in Preparation Example 12 except that the corresponding number of moles of 2-chloro-1-ethanol was used instead of 3-chloro-1-propanol in the preparation of Example 12 (1). Hydroxyethyl)-3-[4-methoxy-3-(4-methylpentyloxy)-phenyl]small (1-phenyl-ethyl)-urea.

lR NMR (CDC13, 300 MHz): δ 0.88-0.90 (d, J = 6.6 Hz, 6H), 1.25-1.34 (m, 2H), 1.54-1.56 (d, J = 7.2 Hz, 3H), 1.55-1.63 (m, lH), 1.77-1.86 (m, 2H), 3.26-3.38 (m, 4H), 3.79 (s, 3H), 3.93-3.98 (t, 2H), 5.63-5.65 (m, lH), 6.65 -6.71 (m, 2H), 7.15 (s, lH), 7.23-7.37 (m, 5H), 8.14-8.18 (d, lH). Preparation Example 15 (S)-l-(3-Butoxy-5-methoxyphenyl)-3-(l-phenyl-ethyl)-urea

In addition to the corresponding moles of 3-hydroxy-5-methoxybenzaldehyde instead of the isovanillin of Example 11, and replacing 1-methyl-1-bromopentane with 1-bromobutane, System In the same manner as in Example 11, (S)-l-(3-butoxy-5-methoxyphenyl: )-3-(1-phenyl-ethyl:)-urea was obtained.

^ NMR (CDC13, 300 MHz): δ 0.86-0.90 (t, 3H), 1.34-1.1.37 (m, 2H), 1.42-1.44 (d, J = 6.6 Hz, 3H), 1.63-1.73 (m, 2H), 3.70(s,lH), 3.82-3.86(t,2H), 4.92-4.94(m,lH), 5.35-5.37 (d,lH), 6.15-6.16(m, lH), 6.42-6.47( Dd, 2H), 6.64 (s, lH), 7.27-7.30 (m, 5H) _o Preparation Example 16 (S)-3-(3-butoxy-4-methoxy-phenyl)-1- Methyl-1-(1-phenyl-ethyl)-urea

Compound 16

3-butoxy-4-methoxy-phenylisocyanate was prepared by the same procedure as in the above Preparation Example 3 (3) using 3-butoxy-4-methoxy-benzoic acid (50 mg). The isocyanate was dissolved in 5 ml of dichloromethane, and (S)-N-methyl-1-phenylethylamine (50 mg) was added, and the mixture was stirred at room temperature for 10 minutes, and the reaction was completed by TLC. Silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) (1-Phenyl-ethyl)-urea, 41 mg, yield 55%.

3⁄4 NMR (300 MHz, CDC13): 50.94-0.99 (t, 3H), 1.44-1.52 (m, 2H), 1.54-1.56 (d, J = 6.6 Hz, 3H), 1.77-1.85 (m, 2H), 2.73(s,3H), 3.82(s,3H), 3.99-4.03(t,2H), 5.72-5.75 (m,lH), 6.27(s,lH), 6.68-6.7 l(dd, Jl=8.4Hz , J2 = 2.1 Hz, 1H), 6.75-6.78 (d, J = 8.4 Hz, 1H), 7.26-7.27 (d, J = 2.1 Hz, 1H), 7.26-7.30 (m, 5H) Preparation Example 17 l -(3-butoxy-4-methoxy-phenyl)-3-(l-phenyl-propyl)-urea

1 was prepared in the same manner as in Preparation Example 16 except that the corresponding number of moles of 1-phenylpropan-1-amine was used instead of (S)-N-methyl-1-phenylethylamine in Preparation Example 16. -(3-Butoxy-4-methoxy-phenyl)-3-(1-phenyl-propyl)-urea.

3⁄4 NMR (CDC13, 300 MHz): δ 0.86-0.91 (t, 3H), 0.94-0.99 (t, 3H), 1.43-1.53 (m, 2H), 1.72-1.83 (m, 4H), 3.84 (s, 3H), 3.92-3.96 (t,2H), 4.73-4.75(m, 1H), 4.84-4.86( d,lH), 5.98(s,lH), 6.65-6.66 (dd,Jl=8.7Hz, J2= 2.1 Hz, 1H), 6.757-6.80 (d, J=8.7 Hz, 1H), 6.88-6.89 (d, J=2.1 Hz, 1H), 7.26-7.33 (m, 5H). PREPARATIVE EXAMPLE 18 l-(3-Butoxy-4-methoxy-phenyl)-3-(l-(pyridin-4-yl)ethyl)-

The same procedure as in Preparation Example 16 was carried out except that the corresponding number of moles of 1-(pyridin-4-yl)ethylamine was substituted for (S)-N-methyl-1-phenylethylamine in Preparation Example 16. 1-(3-Butoxy-4-methoxy-phenyl)-3-(1-(pyridin-4-yl)ethyl)-urea is obtained.

3⁄4 NMR (CDC13, 300 MHz): δ 0.88-0.93 (t, 3H), 1.30-1.33 (d, J = 6.6 Hz, 3H), 1.45-1.53 (m, 2H), 1.77-1.84 (m, 2H) , 3.78(s,3H) _: 3.91-3.93(m,2H), 4.89-4.93(m,lH), 5.65-5.67(m,lH),

6.55-6.59 (d, J = 8.4 Hz, 1H), 6.70-6.74 (dd, J 1 = 2.1 Hz, J2 = 8.4 Hz, 1 H), 7.03-7.04 (d, J = 2.1 Hz, lH), 7.13 -7.15 (d, J = 4.2 Hz, 2H), 8.45-8.46 (d,

PREPARATIVE EXAMPLE 19 l-(3-Butoxy-4-methoxy-phenyl)-3-(l-(pyridin-3-yl)ethyl)-

The same procedure as in Preparation Example 16 was carried out except that the corresponding number of moles of 1-(pyridin-3-yl)ethylamine was used instead of (S)-N-methyl-1-phenylethylamine in Preparation Example 16. 1-(3-Butoxy-4-methoxy-phenyl)-3-(1-(pyridin-3-yl)ethyl)-urea is obtained. NMR NMR (CDC13, 300 MHz): δ 0.90-0.97 (t, 3H), 1.38-1.40 (d, J = 6.6 Hz, 3H), 1.45-1.50 (m, 2H), 1.72-1.82 (m, 2H) , 3.80(s,3H), 3.93-3.95(t,2H), 4.99-5.04(m,lH), 5.55-5.58 (m,lH),

6.60-6.64 (dd, Jl=8.4 Hz, J2=2.1 Hz, IH), 6.72-6.75 (d, J=8.4 Hz, IH), 7.05-7.06 (d, J=2.1 Hz, IH), 7.18-7.27 (m, 2H), 7.56-7.59 (d, J = 7.8 Hz, 2H), 8.44-8.46 (d, J = 6 Hz, IH), 8.53 (s, lH). Preparation Example 20 (S)-l-(3-Butoxy-4-methoxy-phenyl)-3-(l-p-tolyl-ethyl-urea

The same procedure as in Preparation Example 16 was carried out except that (S)-l-methyl-1-phenylethylamine in Preparation Example 16 was replaced by the corresponding number of moles of (S)-l-tolylethylamine. (S)-l-(3-Butoxy-4-methoxy-phenyl)-3-(1-p-tolyl-ethyl)-urea.

3⁄4 NMR (CDC13, 300 MHz): δ 0.93-0.98 (t, 3H), 1.42-1.44 (d, J = 6.6 Hz, 3H), 1.43-1.50 (m, 2H), 1.74-1.82 (m, 2H) , 2.31(s,3H) _: 3.82(s,3H), 3.93-3.95(t,2H), 4.93-4.96(m,lH), 5.00-5.03 (m, lH), 6.26(s,lH), 6.59 -6.63 (dd, Jl=8.4Hz, J2=2.1Hz, IH), 6.75-6.77 (d, J=8.4Hz, IH), 6.92-6.93(d, J=2.1Hz, IH), 7.10-7.13( d, J = 7.8 Hz, 2H), 7.17-7.20 (d, J = 7.8 Hz, 2H). Preparation Example 21 N-(3-Butoxy-4-methoxyphenyl)-2-phenylpyrrolidine-1-amide

N-(3) was obtained in the same manner as in Preparation Example 16 except that the corresponding moles of 2-phenylpyrrolidine was used instead of (S)-N-methyl-1-phenylethylamine in Preparation Example 16. - Butoxy-4-methoxyphenyl)-2-phenylpyrrolidine-1-amide. NMR NMR (CDC13, 300 MHz): δ 0.94-0.98 (t, 3H), 1.42-1.44 (m, 2H), 1.73-1.82 (m, 2H), 1.82-1.98 (m, 4H), 2.41 (m, lH), 3.23-3.28(m,lH), 3.77(s,3H), 3.94-3.96(t,2H), 4.85-4.95(m,lH), 5.91(s,lH), 6.29-6.33 (dd, Jl = 8.4 Hz, J2 = 2.1 Hz, IH), 6.67-6.70 (d, J = 8.4 Hz, IH), 7.12-7.13 (d, J = 2.1 Hz, IH), 7.27-7.41 (m, 5H). Preparation Example 22 (S)-l-(3-Butoxy-4-methoxy-phenyl)-1-methyl-3-(l-phenyl-urea-urea

Compound 22 was prepared from (S)-l-(3-butoxy-4-methoxyphenyl)-3-(1-phenyl-ethyl)-urea (100 mg), and 3 ml of anhydrous DMF was added. Cool to 0 ° C, add NaH (24 mg, 0.6 mmol), keep the temperature for 15 minutes, warm to room temperature for half an hour, add methyl iodide (85 mg, 0.6 mmol), stir at room temperature for half an hour, complete the disappearance of TLC detection, add 1M HC1 The reaction was quenched, EtOAc (EtOAc) (EtOAc (EtOAc). -l-(3-Butoxy-4-methoxy-phenyl)-1-methyl-3-(1-phenyl-ethyl)-urea, 15 mg, yield 14%.

3⁄4 NMR (CDC13, 300 MHz): δ 0.95-1.00 (t, 3H), 1.33-1.35 (d, J = 6.6 Hz, 3H), 1.42-1.53 (m, 2H), 1.77-1.84 (m, 2H) , 3.12(s,3H) _: 3.88(s,3H), 3.91-3.97(t,2H), 4.56-4.58(m,lH), 4.97-5.02(m,lH), 6.71-6.72(d, J= 2.1 Hz, IH), 6.76-6.80 (dd, Jl=8.4 Hz, J2=2.1 Hz, IH), 6.85-6.88 (d, J=8.4 Hz, IH), 7.19-7.30 (m, 5H) Preparation Example 23(S)-l-[l-(3-Hydroxy-phenyl)-ethyl]-3-[4-methoxy-3-(4-methyl-pentyloxy)-phenyl]-urea

3-(4-methylpentyloxy) was prepared by the same procedure as in the above Preparation Example 11 (3) using 3-(4-methylpentyloxy)-4-methoxy-benzoic acid (50 mg). Base -4-methoxy-phenyl isocyanate, the isocyanate is dissolved in 10 ml of dichloromethane, 3-hydroxy-(S)-a-phenylethylamine is added, stirred at room temperature for 10 minutes, and the reaction is complete by TLC. The reaction solution. Silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 elution) to give a white solid (S)-l-(3-hydroxyphenyl) _-3 -[4-methoxy-3-(4- Methylpentyloxy)-phenyl]-1-(1-phenyl-ethyl)-urea, 40 mg, yield 52%.

lR NMR (300 MHz, CDC13): δ 0.86-0.88 (d, J=6.6 Hz, 6H), 1.24-1.33 (m, 2H), 1.43-1.46 (d, J = 7.2 Hz, 3H), 1.56-1.61 (m, 1H), 1.75-1.78 (m, 2H), 3.78 (s, 3H), 3.84-3.89 (t, 2H), 4.82-4.871 (m, lH), 5.17-5.19 (m, 1H), 6.56 - 6.60 (m, 2H), 6.69-6.75 (m, 2H), 6.98-6 HN.99 (m, 1H), 7.12-7.24 (m, 2H). HN Preparation Example 24 l-(1-(2-Fluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy-phenyl)-urea

Compound 24

1 was obtained in the same manner as in Preparation Example 11 except that the corresponding number of moles of 1-(2-fluorophenyl)ethylamine was substituted for (S)-a-phenethylamine in Preparation Example 11 (4). -(1-(2-Fluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy)-phenyl]-urea.

^{! H NMR (CDC13, 300 MHz} ): δ 0.88-0.90 (d, J = 6.6Hz, 6H), 1.24-1.32 (m, 2H), 1.43-1.45 (d, J = 6.9Hz, 3H), 1.53- 1.60(m,lH), 1.76-1.86(m,2H), 3.83(s,3H), 3.89-3.94(t,2H), 5.14-5.19(m,lH), 5.38-5.41(d,lH), 6.51(s,lH), 6.63-6.67(dd,Jl=2.1Hz, J2=8.4Hz,lH) 6.76-6.79(d,J=8.4Hz,lH), 6.97- 6.97 (d, J = 2.1 Hz, lH), 6.99-7.08 (m, 2H) 7.17-7.28 (m, 2H). Preparation Example 25 (S)-l-(l-(4-Fluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyl)

The same procedure as in Preparation Example 11 except that (S)-l-(4-fluorophenyl:)ethylamine was used in the corresponding moles of (S)-a-phenethylamine in Preparation Example 11 (4) (S)-l-(l-(4-Fluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy)-phenyl] - Urea.

3⁄4 NMR (CDC13, 300 MHz): δ 0.89-0.92 (d, J = 6.6 Hz, 6H),

1.23- 1.34(m,2H), l.42-1.44(d,J=6.6Hz,3H), 1.53-1.60(m,lH), 1.77-1.87(m,2H), 3.84(s,3H), 3.89-3.94(t,2H), 4.85-4.88(d,2H), 4.96-5.00(m,lH), 6.10(s,lH), 6.63-6.67(dd,Jl=2.1Hz, J2=8.4Hz, lH), 6.77-6.80 (d, J=8.4 Hz, lH), 6.88-6.89 (d, J=2.1 Hz, lH), 6.96-7.02 (m, 2H),

7.24- 7.29 (m, 2H). Preparation Example 26 l-(l-(3,5-Difluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyl)

The same procedure as in Preparation Example 11 except that the corresponding number of moles of 1-(3,5-difluorophenyl:)ethylamine was substituted for (S)-a-phenethylamine in Preparation Example 11 (4). Process for the preparation of 1-(1-(3,5-difluorophenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy)-phenyl]-urea .

lR NMR (CDC13, 300 MHz): δ 0.90-0.88 (d, J = 8.1 Hz, 6H), 1.25-1.36 (m, 2H), 1.36-1.38 (d, J = 7.2 Hz, 3H), 1.56-1.63 (m, lH), 1.77-1.85 (m, 2H), 3.84 (s, 3H), 3.90-3.95 (t, 2H), 4.93-4.98 (m, lH), 5.11-5.13(d,lH), 6.49(s,lH)

6.64-6.67 (m, lH), 6.77-6.80 (m, 3H), 6.95-6.96 (d, lH). Preparation Example 27 (S)-l-(l-(4-Hydroxyphenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-phenyl]-urea

The same procedure as in Preparation Example 11 except that (S)-a-phenethylamine in Preparation Example 11 (4) was replaced by the corresponding number of moles of (S)-4-(1-aminoethyl)phenol. Preparation of (S)-l-(l-(4-hydroxyphenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy)-phenyl]-urea .

lR NMR (CDC13, 300 MHz): δ 0.84-0.88 (d, J=6.6 Hz, 6H), 1.21-1.26 (m, 2H), 1.33-1.35 (d, J=7.2 Hz, 3H), 1.56-1.63 (m, 1H), 1.79-1.85 (m, 2H), 3.76 (s, 3H), 3.82-3.87 (t, 2H), 4.81-4.83 (m, lH), 5.31-5.34 (m, 1H ), 6.56 -6.69 (m, 3H), 6.94-7.01 (m, 3H), 7.25-7.28 (m, lH). Example 28 Preparation of (S) -l- (l- (4- methoxycarbonyl-phenyl) - ethyl) -3- _[4-methoxy-3 _ _ ₍₄ Su

Except for the corresponding number of moles of (S)-l-(4-methoxycarbonylphenyl:)ethylamine in place of (S)-a-phenethylamine in Preparation Example 11 (4), In the same manner as in Example 11, (S)-l-(1-(4-methoxycarbonylphenyl)-ethyl)-3-[4-methoxy-3-(4-methyl-pentyloxy) was obtained. Base:) -Phenyl] - Urea.

^{! H NMR (CDC13, 300 MHz} ): δ 0.85-0.89 (d, J = 6.6 Hz, 6H), 1.23-1.27 (m, 2H), 1.36-1.38 (d, J = 7.2 Hz, 3H), 1.51- 1.58(m, 1H), 1.74-1.8 l(m,2H), 3.78(s, 3H), 3.88(s, 3H), 3.86-3.91(t,2H), 4.97-5.02(m, lH), 5.33-5.36(m, 1H), 6.56-6.60(m, lH), 6.72-6.75 (m, 2H) 6.98 (s, 1H), 7.25-7.32 (d, J= 7.8 Hz, 2H), 7.92-7.95 (d, J = 7.8 Hz, 2H). Preparation Example 29 (S)-l-[6-Methoxy-5-(4-methyl-pentyloxy)-3-pyridyl]-3-(1-phenyl-ethyl)-urea

(1) 6-Methyl-5-(4-methyl-pentyloxy)-methyl nicotinate

Reference text Molecular Simulation, Vol. 33, No. 14, December 2007, 1109-1117 synthetic method, to give the intermediate 6-methoxy-5 hydroxy-3-nicotinic acid methyl ester.

Take 6-methoxy-5-hydroxy-3-nicotinic acid methyl ester (45 mg, 0.24 mmol) to a 10 ml round bottom flask, add 2 ml of DMF, and add 4-methyl-1-bromopentane (31 mg, 0.269 mmol), aqueous _{_{K 2 C0 3 (138g, lmmol}} ), stirred at room temperature overnight, TLC the reaction was complete, ethyl acetate and water was added, extracted twice with ethyl acetate, the combined organic adding water, and saturated brine, dried and concentrated. Silica gel column chromatography (petroleum ether / ethyl acetate = 10/1 elution) afforded 6-methoxy- _5- (4-methyl-pentyloxy)-methyl nicotinate as a yield of 94%.

U NMR (300 MHz, CDC13): δ 0.880-0.902 (d, J = 6.6 Hz, 6H), 1.291-1.344 (m, 2H), 1.503-1.650 (m, 1H), 1.806-1.860 (m, 2H) , 3.876 (s, 3H), 3.966-4.026 (t, 2H), 4.031 (s, 3H), 7.538 (s, 1H), 8.37 (s, 1H).

-methoxy-5-(4-methyl-pentyloxy)-nicotinic acid

Dissolve 6-methoxy-5-(4-methyl-pentyloxy)-nicotinic acid methyl ester (60 mg, 0.22 mmol) in 4 ml of methanol / 1 ml of water, add 50 mg of lithium hydroxide, stir at room temperature overnight, TLC detection The reaction is complete, concentrated, and most of the methanol is removed by pressure. The mixture is neutralized to acid with 1N HCl, and extracted twice with ethyl acetate. The organic phase is combined with water and brine, and dried and concentrated to give 52 mg of 6-methoxy-5. -(4-Methyl-pentyloxy)-nicotinic acid, yield 93%. NMR NMR (300 MHz, CDC13): δ 0.837-0.859 (d, J = 6.6 Hz, 6H) 1.18-1.249 (m, 2H), 1.450-1.601 (m, 1H), 1.719-1.860 (m, 2H) 3.831 -3.921(t, 2H), 3.961(s, 3H), 7.432 (s, 1H), 8.333(s, 1H).

(3) 5-isoacid-2-methoxy-3-(4-methyl-pentyloxy)-pyridine

6-Methoxy-5-(4-methyl-pentyloxy)-nicotinic acid (50 mg, 0.2 mmol) was suspended in 5 ml of benzene, and triethylamine (0.1 ml) was added under ice argon. The mixture was cooled with a water bath, and then added dropwise with EtOAc (EtOAc) (EtOAc).

The desiccant was filtered off, and the benzene solution was heated to reflux for 3.5 hours. The reaction was completed by TLC and concentrated to give 5-isocyanate-2-methoxy-3-(4-methyl-pentyloxy)-pyridine. Stable, direct squat reaction.

The crude product 5-isocyanate-2-methoxy-3-(4-methyl-pentyloxy)-pyridine obtained from the upper hydrazine was dissolved in 5 ml of dichloromethane, and (S)-a-phenylethylamine was added. 50 mg, stirred at room temperature for 10 minutes, the reaction was completed by TLC, and concentrated to give a crude product. Silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 elution) afforded (S)-l-[6-methoxy-5-(4-methyl-pentyloxy)-3-pyridyl] -3-(1-phenyl-ethyl)-urea 36 mg, yield of 49%.

3⁄4 NMR (300 MHz, CDC13): δ 0.896-0.918 (d, J = 6.6 Hz, 6H), 1.237-1.336 (m, 2H), 1.476-1.498 (d, J = 6.6 Hz, 3H), 1.550-1.637 (m, 1H), 1.784-1.885 (m, 2H), 3.909-3.965 (t, 2H), 3.964 (s, 3H), 4.885-4.987 (m, 2H), 6.151 (s, lH), 7.267-7.399 (m, 6H). Experimental Example 1 Inhibition of total complement hemolytic activity by compounds

1. Detection purpose:

The inhibitory effect of the compound on the total complement hemolytic activity of the classical pathway was examined.

2. Experimental principle:

Complement is a group of plasma proteins that exist in the form of inactive zymogen under natural conditions. The binding of specific antibodies to red blood cells activates complement through the classical pathway, resulting in the formation of a membrane complex on the surface of red blood cells, with an inner diameter of l lnm, allowing water and electrolytes to pass but not allowing macromolecules to pass through. The formation of a large number of attacking membrane complexes causes moisture to enter the cells due to the large difference in osmotic pressure, causing hemolysis of red blood cells. Sheep red blood cells were purchased from Shanghai Jiayu Biotechnology Co., Ltd.; normal human serum, self-lifting; hemolysin (anti-sheep red blood cell antibody), sigma products

4. Experimental method:

The sheep red blood cell suspension was taken, washed and diluted with barbiturate buffer DGVB++, hemolysin was added at 1:3000, and incubated at 37 ° C for 100 minutes to sensitize sheep red blood cells. Wash and dilute the sensitized sheep red blood cells with DGVB++ buffer, add normal human serum and test samples of different concentrations, incubate at 37 °C for 240 hours, centrifuge for 1 hour, centrifuge, take the supernatant, and measure the OD value at 405 nm. The 50% hemolysis state is a control, and the degree of hemolysis of the sample well is detected.

5. Experimental results:

Table 1 Inhibition of total complement hemolytic activity of classical pathways by compounds

Compound 8 61.7 Compound 24 158

Compound 9 471 compound 25 309

Compound 10 277 Compound 26 502

Compound 11 26 compound 27 139

Compound 12 221 compound 28 535

Compound 14 321 compound 29 277

Compound 15 279 BCX1470 <152

19.6

The results of the positive control 2-thiophenecarboxylic acid 2-cyanobenzothiazepine-6-ester methanesulfonate (BCX1470) indicate that the test method and test results are reliable. According to the above test results of the inhibition of the classical pathway total complement hemolytic activity, the compound obtained by the present invention has a good inhibitory effect on the classical pathway complement hemolytic activity, and the best compound has an activity IC _5Q of 20 Å. Experimental Example 2 Complement component precipitation experiment

1. Purpose of testing

For compounds having a total inhibitory effect on complement hemolytic activity, the target of action is examined.

2, the principle of experiment

Three kinds of complement system activators were used to coat the ELISA plate, and after adding normal human serum to incubate at 37 ° C, the complement component in the serum was activated by the activator and cascaded, and then the antibody specific for the anti-complement component protein was added. The antibody conjugated to HRP (horseradish peroxidase) was then combined to form an antibody-antigen-enzyme-labeled antibody complex, which was thoroughly washed and then primed with TMB. Indole (3,3',5,5'-tetramethylbenzidine:) is converted to blue under the catalysis of HRP enzyme and converted to the final yellow, color shade and complement component protein under the action of acid The content is positively correlated. Rabbit anti-human C3d antibody, rabbit anti-human C4c antibody and HRP-conjugated goat anti-rabbit antibody were purchased from DAKO

Mouse anti-human C9 antibody and mouse anti-human C5b-9 antibody, purchased from abeam

HRP-conjugated goat anti-mouse antibody and IgM, purchased from Beijing Boaosen

Mannan and zymosan, Behook in sigma 4, the experimental method

The plate was coated with lOug/mL IgM (classical route), lOOug/mL mannan (mannose pathway) or 20ug/mL zymosan (bypass pathway) one day before the experiment, overnight at 4 °C. On the day of the experiment, the cells were blocked with PBS containing 10% serum, and then normal human serum and test samples of different concentrations were added, and incubated at 37 ° C for 1 hour. The anti-complement C3 component, the C4 component or the C9 component primary antibody and the HRP-conjugated secondary antibody were separately added, and TMB was developed for 30 minutes, and the OD value was measured at a wavelength of 450 nm.

5, the experimental results

The experimental results are shown in Fig. 1 to Fig. 11, wherein Fig. 1 is the OD value at 450 nm of the compound 11 of the classical route C4 component; Fig. 2 is the OD value at 450 nm of the compound 11 of the classical route C3 component; 3 is the OD value at 450 nm of the compound 11 of the classical route C9 component; FIG. 4 is the OD value at 450 nm of the compound 11 of the classical route C5b-9 component; FIG. 5 is the 450 of the compound 11 of the mannose pathway C4 component. OD value at nm; Figure 6 is the OD value at 450 nm of Compound 11 of the mannose pathway C3 component; Figure 7 is the OD value at 450 nm of Compound 11 of the mannose pathway C9 component; Figure 8 is the mannose pathway The OD value at 450 nm of compound 11 of the C5b-9 component; Figure 9 is the OD value at 450 nm of compound 11 of the C3 component of the alternative pathway; Figure 10 is the 450 nm of compound 11 of the C9 component of the alternative pathway. OD value; Figure 11 is the OD value at 450 nm of compound 11 of the alternative pathway C5b-9 component. It can be seen from the figure that the compounds have little inhibitory effect on the activation of C4/C3 by any means, but have inhibitory effects on the terminal pathways of the three activation pathways, indicating that the target of the compound is C9, which can be prepared. It has new targets for the treatment of inflammatory response, hyperthyroidism and organ transplant rejection.

Claims

Rights request

1, - I shown urea compounds:

I

Wherein, and R ₂ are each independently H, a substituted or unsubstituted C1 to C8 alkyl group, the substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 cycloalkyl group, or a a heterocyclic group of N or 0 atoms C3 to C7, an alkenyl group of C2 to C8, an alkynyl group of C2 to C8;

Is an alkyl group of 11, C1 to C4;

Or R ₄ , R ₅ and the carbon atom and nitrogen atom to which they are attached form a 5-7 membered ring;

R ₆ to R ₇ are each independently selected from one of the following groups: H, halogen, hydroxy, amino, carboxy, C1 to C4 alkoxycarbonyl, C1 to C4 alkoxy, cyano, trifluoromethyl Base, base;

n is 0, 1, 2;

X is CH or N;

Y is 0 or 8.

2. The urea compound according to claim 1,

R ₃ and R ₄ are each independently H, C1 ~ C4 alkyl, optionally at least one hydroxyl group or amino group substituted with an alkyl group of C1 ~ C4; Is an alkyl group of 11, C1 to C4;

Or R ₄ , R ₅ and the carbon atom and the nitrogen atom to which they are bonded form a 5-7 membered ring; R ₆ to R ₇ are each independently selected from one of the following groups: H, halogen,

Base, carboxyl group, C1-C4 alkoxycarbonyl group, C1~C4 alkoxy group, cyano group,

n is 0, 1, 2;

X is CH or N;

Y is 0 or 8. The urea compound according to claim 2, which has a structure of the formula II;

Wherein, wherein one of R and R ₂ is a methyl group, and the other is H, a substituted or unsubstituted C1 to C8 alkyl group, said substituent being a hydroxyl group, a halogen, a C1 to C4 alkoxy group, a C3 to C6 ring An alkyl group, or a heterocyclic group containing a C or C atom of C3 to C7, an alkenyl group of C2 to C8, an alkynyl group of C2 to C8;

R ₅ is an alkyl group of C1 to C4;

X is CH or N;

Y is 0 or 8.

4. The urea compound according to claim 2 or 3,

Wherein, the middle one is a methyl group, the other is a C4~C6 alkyl group, a C4~C6 alkenyl group, and a C4~C6 alkynyl group; R ₃ is H, 11, methyl, hydroxy-substituted C 1 ~ C3 alkyl group;

R ₅ is methyl; is 11, halogen or hydroxy, ₁₇ is 11;

n is 0; X is CH; Y is 0.

The urea compound according to claim 2 or 3,

Wherein, one of the is a methyl group, the other is a C4~C6 alkyl group, and a C4~C6 alkenyl group;

R ₃ is H, and R ₄ is H or methyl;

R ₅ is methyl; R ₆ and R ₇ are H;

n is 0; X is CH; Y is 0.

The urea compound according to claim 1, wherein the urea compound

One way to achieve: Route A:

Step Al: The iso-vanillin 1 is protected with a benzyl group to give the intermediate 2, which is carried out by a conventional method in the art; Step A3: Intermediate 3 is subjected to a modified Curtius rearrangement to give a different Cyanic acid

Step A4: Isocyanate 4

After the condensation reaction, key intermediate 5 is obtained, and the condensation reaction is carried out by a conventional method in the art;

Step A5: Intermediate 5 is deprotected by benzyl to give intermediate 6;

Step A6: reacting intermediate 6 with a differently substituted bromo-Br to obtain a urea compound represented by intermediate 7; Step A7: The intermediate 7 is reacted with R ₃ I under basic conditions to obtain a urea compound of the present invention as shown in Formula 8;

～ _{7 7 in} Route A is the same as defined in Formula I;

Route B:

16 Step B1: The vanillin 9 is protected with a benzyl group to give the intermediate 10 which is carried out by conventional methods in the art;

Step B3: Intermediate 11 is subjected to a modified Curtius rearrangement to obtain isocyanate 12; Ho step B4: isocyanate with a substituted amine 12 ^[chi] \ condensation reaction of the key intermediate 13 after the condensation reaction is carried out by conventional methods in the art;

Step Β5: Intermediate 13 is deprotected by benzyl to give intermediate 14;

Step 6: reacting intermediate 14 with a differently substituted bromine R ₂ -Br to give a urea compound of the intermediate 15;

Step B7: reacting intermediate 15 with R ₃ I under basic conditions to obtain a urea compound of the present invention as shown in Formula 16;

~1 _{7 in} Route B is the same as defined in Formula I;

Route C:

twenty two

Cl : intermediate 17 is reacted with bromo RiBr to give intermediate 18;

C2: hydrolysis of intermediate 18 to give acid 19;

'C3: The acid 19 is prepared as isocyanate 20 in the same manner as in Scheme A; Step C4: The isocyanate 20 is reacted with a substituted amine ^x R ₇ to obtain an intermediate 21, and the condensation reaction is carried out by a conventional method in the art; Step C5: Intermediate 21 is subjected to basic conditions with R urea compound represented by ₃ I of the present invention to obtain the reaction of the formula 22; ₁₇ Scheme C - the same as defined in formula I.

8. The preparation method according to claim 7, wherein

The oxidizing agent described in the steps A2 and B2 is NaClO ₂ /NaH ₂ PO ₄ /30%H ₂ O ₂ or PCC or Na ₂ Cr ₂ 0 _{7 ;}

The reagents for the Curtius rearrangement reaction described in steps A3 and B3 are DPPA and re-evaporated triethylamine;

The basic conditions described in the steps A7, B7 and C5 were obtained by adding NaH.

9. A pharmaceutical composition for treating an inflammatory response, hyperthyroidism or organ transplant rejection comprising a therapeutically effective amount of one or more urea compounds according to claim 1 and a pharmaceutically acceptable carrier, Additives or accessories.

The use of the urea compound according to claim 1 for the preparation of a medicament for preventing or treating inflammatory response, hyperthyroidism and organ transplant rejection.